how to do a research trail

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• Clinical Trials: What Patients Need to Know

Basics About Clinical Trials

What are clinical trials.

Clinical trials are research studies in which people volunteer to help find answers to specific health questions. When carefully conducted, they are the safest and fastest way to find new treatments and ways to improve health.

Clinical trials are conducted according to a plan, called a protocol, which describes:

• the types of patients who may enter the study
• the schedules of tests and procedures
• the drugs involved
• the dosages, or amount of the drug
• the length of the study
• what the researchers hope to learn from the study.

Volunteers who participate in the study must agree to the rules and terms outlined in the protocol. Similarly, researchers, doctors, and other health professionals who manage the clinical trials must follow strict rules set by the FDA. These rules make sure that those who agree to participate are treated as safely as possible.

Learn more about the basics of clinical trial participation, read first hand experiences from actual clinical trial volunteers, and see explanations from researchers at the NIH Clinical Research Trials and You Web site.

Why are clinical trials done?

Clinical trials are conducted for many reasons:

• to determine whether a new drug or device is safe and effective for people to use.
• to study different ways to use standard treatments or current, approved treatments so that they will be more effective, easier to use, or decrease certain side effects.
• to learn how to safely use a treatment in a population for which the treatment was not previously tested, such as children.

Who should consider clinical trials and why?

Some people participate in clinical trials because none of the standard (approved) treatment options have worked, or they are unable to tolerate certain side effects. Clinical trials provide another option when standard therapy has failed. Others participate in trials because they want to contribute to the advancement of medical knowledge.

Ensuring people from diverse backgrounds join clinical trials is key to advancing health equity. Participants in clinical trials should represent the patients that will use the medical products. This is often not the case—people from racial and ethnic minority and other diverse groups are underrepresented in clinical research. This is a concern because people of different ages, races, and ethnicities may react differently to certain medical products. Learn more about the clinical trial diversity initiative from the Office of Minority Health and Health Equity.

All clinical trials have guidelines, called eligibility criteria, about who can participate. The criteria are based on such factors as age, sex, type and stage of disease, previous treatment history, and other medical conditions. This helps to reduce the variation within the study and to ensure that the researchers will be able to answer the questions they plan to study. Therefore, not everyone who applies for a clinical trial will be accepted.

It is important to test drugs and medical products in the people they are meant to help. It is also important to conduct research in a variety of people, because different people may respond differently to treatments.  FDA seeks to ensure that people of different ages, races, ethnic groups, and genders are included in clinical trials. Learn more about FDA’s efforts to increase diversity in clinical trials .

Where are clinical trials conducted?

Clinical trials can be sponsored by organizations (such as a pharmaceutical company), Federal offices and agencies (such as the National Institutes of Health or the U.S. Department of Veterans Affairs), or individuals (such as doctors or health care providers). The sponsor determines the location(s) of the trials, which are usually conducted at universities, medical centers, clinics, hospitals, and other Federally or industry-funded research sites.

Are clinical trials safe?

FDA works to protect participants in clinical trials and to ensure that people have reliable information before deciding whether to join a clinical trial. The Federal government has regulations and guidelines for clinical research to protect participants from unreasonable risks. Although efforts are made to control the risks to participants, some may be unavoidable because we are still learning more about the medical treatments in the study.

The government requires researchers to give prospective participants complete and accurate information about what will happen during the trial. Before joining a particular study, you will be given an informed consent document that describes your rights as a participant, as well as details about the study, including potential risks. Signing it indicates that you understand that the trial is research and that you may leave at any time. The informed consent is part of the process that makes sure you understand the known risks associated with the study.

What should I think about before joining a clinical trial?

Before joining a clinical trial, it is important to learn as much as possible. Discuss your questions and concerns with members of the health care team conducting the trial. Also, discuss the trial with your health care provider to determine whether or not the trial is a good option based on your current treatment. Be sure you understand:

• what happens during the trial
• the type of health care you will receive
• any related costs once you are enrolled in the trial
• the benefits and risks associated with participating. 

What is FDA’s role in approving new drugs and medical treatments?

FDA makes sure medical treatments are safe and effective for people to use. We do not develop new therapies or conduct clinical trials. Rather, we oversee the people who do. FDA staff meet with researchers and perform inspections of clinical trial study sites to protect the rights of patients and to verify the quality and integrity of the data.

Learn more about the Drug Development Process .

Where can I find clinical trials?

One good way to find out if there are any clinical trials that might help you is to ask your doctor. Other sources of information include:

• FDA Clinical Trials Search. Search a database of Federally and privately supported studies available through clinicaltrials.gov. Learn about each trial’s purpose, who can participate, locations, and who to contact for more information.
• Clinicaltrials.gov. Conduct more advanced searches
• National Cancer Institute or call 1–800–4–CANCER (1–800–422–6237). Learn about clinical trials for people with cancer.
• AIDS Clinical Trials and Information Services (ACTIS) or call 1–800–TRIALS–A (1–800–874–2572). Locate clinical trials for people with HIV.
• AIDSinfo. Search a database of HIV/AIDS trials, sponsored by the National Institutes of Health’s National Library of Medicine.

What is a placebo and how is it related to clinical trials?

A placebo is a pill, liquid, or powder that has no treatment value. It is often called a sugar pill. In clinical trials, experimental drugs are often compared with placebos to evaluate the treatment’s effectiveness.

Is there a chance I might get a placebo?

In clinical trials that include placebos, quite often neither patients nor their doctors know who is receiving the placebo and how is being treated with the experimental drug. Many cancer clinical trials, as well as trials for other serious and life-threatening conditions, do not include placebo control groups. In these cases, all participants receive the experimental drug. Ask the trial coordinator whether there is a chance you may get a placebo rather than the experimental drug. Then, talk with your doctor about what is best for you.

How do I find out what Phase a drug is in as part of the clinical trial?

Talk to the clinical trial coordinator to find out which phase the clinical trial is in. Learn more about the different clinical trial phases and whether they are right for you.

What happens to drugs that don't make it out of clinical trials?

Most drugs that undergo preclinical (animal) research never even make it to human testing and review by the FDA. The drug developers go back to begin the development process using what they learned during with their preclinical research. Learn more about drug development .

How to conduct a clinical trial

Chris nickson.

• Nov 3, 2020

Reviewed and revised 26 August 2015

• This page provides a broad overview of the complicated process of conducting a clinical trial
• Conducting a clinical trial can be conceptualised as having 14 key steps

(1) Research question

• is it worth while?
• could it help improve patient outcome?

(2) Define hypothesis

• take an opinion on what the answer to the question is.

(3) Literature review

• make sure no one has already conclusively answered the question
• make sure it’ll benefit patients

(4) Involve statistician, and discuss:

• type of study
• calculate sample size (alpha and beta values, power, effect size , variance of population)
• -> blinding (single, double or triple)
• -> crossover
• -> randomization
• -> controls

(5) Develop inclusion & exclusion criteria

• stick to them when carrying out study!

(6) Calculate sample size needed

• beta value and power (small sample size is the commonest cause of a false negative result)
• alpha value (e.g. p < 0.05; limits false positive results)
• variance of population
• effect size
• statistical test

(7) Develop methodology

• side effects
• how to collect information

(8) Gain ethical approval

• consider professional virtue of medical loyalty
• autonomy, non-maleficence, beneficence & distributive justice.

Some issues include

• use of placebos when efficacious therapy available
• whether every research participant needs to sign a written consent
• whether informed consent is necessary (ICU patients)
• accepting drug company gifts
• misleading information from the drug reps.

(9) Perform pilot study

• modify protocol based on pilot study

(10) Carry out study

• patient information & informed consent important
• collect data
• measure outcomes
• monitor safety

(11) Analysis

• using appropriate statistical methods

(12) Compare to null hypothesis

• proven or disproven
• statistically significant difference or not

(13) Consider errors

• sources of bias
• patients lost to follow up
• adverse effects
• surprising benefits

(14) Submit for publication

• survive the peer review process and hope that the article is accepted!
• educate others of the findings so it can be implemented into clinical practice (knowledge translation)

References and Links

• CCC —  How to conduct a clinical trial
• CCC —  Early stopping of clinical trial
• CCC —  How to analyse a clinical trial

Critical Care

Chris is an Intensivist and ECMO specialist at the  Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University . He is a co-founder of the  Australia and New Zealand Clinician Educator Network  (ANZCEN) and is the Lead for the  ANZCEN Clinician Educator Incubator  programme. He is on the Board of Directors for the  Intensive Care Foundation  and is a First Part Examiner for the  College of Intensive Care Medicine . He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website,  INTENSIVE .  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the  FOAM  movement (Free Open-Access Medical education) and is co-creator of  litfl.com , the  RAGE podcast , the  Resuscitology  course, and the  SMACC  conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is  @precordialthump .

| INTENSIVE | RAGE | Resuscitology | SMACC

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• Knowledge Base
• Starting the research process

A Beginner's Guide to Starting the Research Process

When you have to write a thesis or dissertation , it can be hard to know where to begin, but there are some clear steps you can follow.

The research process often begins with a very broad idea for a topic you’d like to know more about. You do some preliminary research to identify a  problem . After refining your research questions , you can lay out the foundations of your research design , leading to a proposal that outlines your ideas and plans.

This article takes you through the first steps of the research process, helping you narrow down your ideas and build up a strong foundation for your research project.

Table of contents

Step 1: choose your topic, step 2: identify a problem, step 3: formulate research questions, step 4: create a research design, step 5: write a research proposal, other interesting articles.

First you have to come up with some ideas. Your thesis or dissertation topic can start out very broad. Think about the general area or field you’re interested in—maybe you already have specific research interests based on classes you’ve taken, or maybe you had to consider your topic when applying to graduate school and writing a statement of purpose .

Even if you already have a good sense of your topic, you’ll need to read widely to build background knowledge and begin narrowing down your ideas. Conduct an initial literature review to begin gathering relevant sources. As you read, take notes and try to identify problems, questions, debates, contradictions and gaps. Your aim is to narrow down from a broad area of interest to a specific niche.

Make sure to consider the practicalities: the requirements of your programme, the amount of time you have to complete the research, and how difficult it will be to access sources and data on the topic. Before moving onto the next stage, it’s a good idea to discuss the topic with your thesis supervisor.

>>Read more about narrowing down a research topic

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So you’ve settled on a topic and found a niche—but what exactly will your research investigate, and why does it matter? To give your project focus and purpose, you have to define a research problem .

The problem might be a practical issue—for example, a process or practice that isn’t working well, an area of concern in an organization’s performance, or a difficulty faced by a specific group of people in society.

Alternatively, you might choose to investigate a theoretical problem—for example, an underexplored phenomenon or relationship, a contradiction between different models or theories, or an unresolved debate among scholars.

To put the problem in context and set your objectives, you can write a problem statement . This describes who the problem affects, why research is needed, and how your research project will contribute to solving it.

>>Read more about defining a research problem

Next, based on the problem statement, you need to write one or more research questions . These target exactly what you want to find out. They might focus on describing, comparing, evaluating, or explaining the research problem.

A strong research question should be specific enough that you can answer it thoroughly using appropriate qualitative or quantitative research methods. It should also be complex enough to require in-depth investigation, analysis, and argument. Questions that can be answered with “yes/no” or with easily available facts are not complex enough for a thesis or dissertation.

In some types of research, at this stage you might also have to develop a conceptual framework and testable hypotheses .

>>See research question examples

The research design is a practical framework for answering your research questions. It involves making decisions about the type of data you need, the methods you’ll use to collect and analyze it, and the location and timescale of your research.

There are often many possible paths you can take to answering your questions. The decisions you make will partly be based on your priorities. For example, do you want to determine causes and effects, draw generalizable conclusions, or understand the details of a specific context?

You need to decide whether you will use primary or secondary data and qualitative or quantitative methods . You also need to determine the specific tools, procedures, and materials you’ll use to collect and analyze your data, as well as your criteria for selecting participants or sources.

>>Read more about creating a research design

Finally, after completing these steps, you are ready to complete a research proposal . The proposal outlines the context, relevance, purpose, and plan of your research.

As well as outlining the background, problem statement, and research questions, the proposal should also include a literature review that shows how your project will fit into existing work on the topic. The research design section describes your approach and explains exactly what you will do.

You might have to get the proposal approved by your supervisor before you get started, and it will guide the process of writing your thesis or dissertation.

>>Read more about writing a research proposal

If you want to know more about the research process , methodology , research bias , or statistics , make sure to check out some of our other articles with explanations and examples.

Methodology

• Sampling methods
• Simple random sampling
• Stratified sampling
• Cluster sampling
• Likert scales
• Reproducibility

 Statistics

• Null hypothesis
• Statistical power
• Probability distribution
• Effect size
• Poisson distribution

Research bias

• Optimism bias
• Cognitive bias
• Implicit bias
• Hawthorne effect
• Anchoring bias
• Explicit bias

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• Clinical Trials

Clinical Research Trials and You: Questions and Answers

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What is a clinical trial?

A clinical trial is a research study that involves people like you. Researchers conduct clinical trials to find new or better ways to prevent, detect, or treat health conditions. Often, researchers want to find out if a new test, treatment, or preventive measure is safe and effective. Tests can include ways to screen for, diagnose, or prevent a disease or condition. Treatments and preventive measures can include medications, surgeries, medical devices, and behavioral therapies.

Clinical trials are important because they serve as the foundation for most medical advances. Without clinical trials, many of the medical treatments and cures we have today wouldn’t exist.

Why should I volunteer for a clinical trial?

People volunteer for clinical trials for many reasons. Some want to advance science or help doctors and researchers learn more about disease and improve health care. Others, such as those with an illness, may join to try new or advanced treatments that aren’t widely available.

Whatever your reason for joining a clinical trial, researchers generally need two types of volunteers: those without specific illnesses or conditions and those with them.  

A healthy volunteer is someone in a clinical trial with no known related health problems. Researchers need healthy volunteers to establish a healthy or optimal reference point. They use data from healthy volunteers to test new treatments or interventions, not to provide direct benefit to participants.

A patient volunteer is someone in a clinical trial who has the condition being studied. Researchers need patient volunteers to learn if new tests, treatments, or preventive measures are safe and effective. Not all trial participants will receive experimental medications or treatments; sometimes, participants may receive a placebo. Researchers need to vary medications and treatments so they can compare results and learn from their differences.

While a study’s treatment or findings may help patients directly, sometimes participants will receive no direct benefit. However, in many cases, study results can still serve as building blocks that are used to help people later.

What would I experience during a clinical trial?

During a clinical trial, the study team will track your health. Participating in a clinical trial may take more time than standard treatment, and you may have more tests and treatments than you would if you weren’t in a clinical trial. The study team also may ask you to keep a log of symptoms or other health measures, fill out forms about how you feel, or complete other tasks. You may need to travel or reside away from home to take part in a study.

What are the risks and benefits of my participation in a clinical trial?

Clinical trials can provide many benefits to participants and society. However, before volunteering for a clinical trial, you should talk with your health care provider and the study team about the risks and benefits.

Potential Risks

When weighing the risks of volunteering, you should consider:

• The likelihood of any harm occurring
• How much harm could result from your participation in the study

Researchers try to limit patient discomfort during clinical trials. However, in some cases, volunteers have complications that require medical attention. In rare cases, volunteers have died when participating in clinical trials.

Potential Benefits

The benefits of volunteering can include:

• Treatment with study medications that may not be available elsewhere
• Care from health care professionals who are familiar with the most advanced treatments available
• The opportunity to learn more about an illness and how to manage it
• Playing an active role in your health care
• Helping others by contributing to medical research

Where can I find a mental health clinical trial?

The National Institute of Mental Health (NIMH) is the lead federal agency for research on mental disorders. While NIMH supports research around the world, it also conducts many clinical trials at the National Institutes of Health (NIH) campus in Bethesda, Maryland.

To learn more about NIMH studies conducted on the NIH campus, visit  NIMH's Join a Study webpage . These studies enroll volunteers from the local area and across the nation. In some cases, participants receive free study-related evaluations, treatment, and transportation to NIH.

To learn more about NIMH-funded clinical trials at universities, medical centers, and other institutions, visit  NIMH's clinical trials webpage .

What is the next step after I find a clinical trial?

To learn more about a specific clinical trial, contact the study coordinator. You can usually find this contact information in the trial’s description.

If you decide to join a clinical trial, let your health care provider know. They may want to talk to the study team to coordinate your care and ensure the trial is safe for you. Find tips to help prepare for and get the most out of your visit .

How do I know if I can join a clinical trial?

People of all ages, ethnicities, and racial backgrounds can volunteer for clinical trials. If you want to join a clinical trial, you must be eligible to participate in that specific trial. Your eligibility can usually be determined by phone or online screening.

All clinical trials have eligibility guidelines called inclusion and exclusion criteria. These criteria may include:

• The type and stage of an illness
• Treatment history
• Other medical conditions

Researchers use these guidelines to find suitable study participants, maximize participant safety, and ensure trial data are accurate.

What kinds of questions should I ask the study team before deciding if I want to take part in a clinical trial?

It can be helpful to write down any questions or concerns you have. When you speak with the study team, you may want to take notes or ask to record the conversation. Bringing a supportive friend or family member may also be helpful.

The following topics may give you some ideas for questions to ask:

• The study’s purpose and duration
• The possible risks and benefits
• Your participation and care
• Personal and cost concerns

For a list of specific questions, check out Questions to Ask About Volunteering for a Research Study  from the U.S. Department of Health and Human Services’ Office for Human Research Protections.

How is my safety protected if I choose to take part in a clinical trial?

Strict rules and laws help protect participants in research studies, and the study team must follow these rules to conduct research. Below are some measures that can help ensure your safety.  

Ethical Guidelines

Ethical guidelines protect volunteers and ensure a study’s scientific integrity. Regulators created these guidelines primarily in response to past research errors and misconduct. Federal policies and regulations require that researchers conducting clinical trials obey these ethical guidelines.

Informed Consent

Before joining a trial, you should understand what your participation will involve. The study team will provide an informed consent document with detailed information about the study. The document will include details about the length of the trial, required visits, medications, and medical procedures. It will also explain the expected outcomes, potential benefits, possible risks, and other trial details. The study team will review the informed consent document with you and answer any questions you have. You can decide then or later if you want to take part in the trial.

If you choose to join the trial, you will be asked to sign the informed consent document. This document is not a contract; it verifies you understand the study and describes what your participation will include and how your data will be used. Your consent in a clinical trial is ongoing and your participation is voluntary. You may stop participating at any time.

Institutional Review Board Review

Institutional review boards (IRBs) review and monitor most clinical trials in the United States. An IRB works to protect the rights, welfare, and privacy of human subjects. An IRB usually includes a team of independent doctors, scientists, and community members. The IRB’s job is to review potential studies, weigh the risks and benefits of studies, and ensure that studies are safe and ethical.

If you’re thinking about volunteering for a clinical trial, ask if an IRB reviewed the trial.

What happens when a clinical trial ends?

When a clinical trial ends, researchers will analyze the data to help them determine the results. After reviewing the findings, researchers often submit them to scientific journals for others to review and build on.

Before your participation ends, the study team should tell you if and how you’ll receive the results. If this process is unclear, be sure to ask about it.

Where can I find more information?

This fact sheet covers the basics of clinical trials. To find more details and resources, visit  NIMH's clinical trials webpage .

For More Information

MedlinePlus  (National Library of Medicine) ( en español  )

ClinicalTrials.gov  ( en español  )

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health NIH Publication No. 23-MH-4379 Revised 2023

The information in this publication is in the public domain and may be reused or copied without permission. However, you may not reuse or copy images. Please cite the National Institute of Mental Health as the source. Read our copyright policy to learn more about our guidelines for reusing NIMH content.

Legal Research Strategy

Preliminary analysis, organization, secondary sources, primary sources, updating research, identifying an end point, getting help, about this guide.

This guide will walk a beginning researcher though the legal research process step-by-step. These materials are created with the 1L Legal Research & Writing course in mind. However, these resources will also assist upper-level students engaged in any legal research project.

How to Strategize

Legal research must be comprehensive and precise.  One contrary source that you miss may invalidate other sources you plan to rely on.  Sticking to a strategy will save you time, ensure completeness, and improve your work product. 

Follow These Steps

Running Time: 3 minutes, 13 seconds.

Make sure that you don't miss any steps by using our:

• Legal Research Strategy Checklist

If you get stuck at any time during the process, check this out:

• Ten Tips for Moving Beyond the Brick Wall in the Legal Research Process, by Marsha L. Baum

Understanding the Legal Questions

A legal question often originates as a problem or story about a series of events. In law school, these stories are called fact patterns. In practice, facts may arise from a manager or an interview with a potential client. Start by doing the following:

• Read anything you have been given
• Analyze the facts and frame the legal issues
• Assess what you know and need to learn
• Note the jurisdiction and any primary law you have been given
• Generate potential search terms

Jurisdiction

Legal rules will vary depending on where geographically your legal question will be answered. You must determine the jurisdiction in which your claim will be heard. These resources can help you learn more about jurisdiction and how it is determined:

• Legal Treatises on Jurisdiction
• LII Wex Entry on Jurisdiction

This map indicates which states are in each federal appellate circuit:

Getting Started

Once you have begun your research, you will need to keep track of your work. Logging your research will help you to avoid missing sources and explain your research strategy. You will likely be asked to explain your research process when in practice. Researchers can keep paper logs, folders on Westlaw or Lexis, or online citation management platforms.

Organizational Methods

Tracking with paper or excel.

Many researchers create their own tracking charts.  Be sure to include:

• Search Date
• Topics/Keywords/Search Strategy
• Citation to Relevant Source Found
• Save Locations
• Follow Up Needed

Consider using the following research log as a starting place: 

• Sample Research Log

Tracking with Folders

Westlaw and Lexis offer options to create folders, then save and organize your materials there.

• Lexis Advance Folders
• Westlaw Edge Folders

Tracking with Citation Management Software

For long term projects, platforms such as Zotero, EndNote, Mendeley, or Refworks might be useful. These are good tools to keep your research well organized. Note, however, that none of these platforms substitute for doing your own proper Bluebook citations. Learn more about citation management software on our other research guides:

• Guide to Zotero for Harvard Law Students by Harvard Law School Library Research Services Last Updated Sep 12, 2023 211 views this year

Types of Sources

There are three different types of sources: Primary, Secondary, and Tertiary.  When doing legal research you will be using mostly primary and secondary sources.  We will explore these different types of sources in the sections below.

Secondary sources often explain legal principles more thoroughly than a single case or statute. Starting with them can help you save time.

Secondary sources are particularly useful for:

• Learning the basics of a particular area of law
• Understanding key terms of art in an area
• Identifying essential cases and statutes

Consider the following when deciding which type of secondary source is right for you:

• Scope/Breadth
• Depth of Treatment
• Currentness/Reliability

For a deep dive into secondary sources visit:

• Secondary Sources: ALRs, Encyclopedias, Law Reviews, Restatements, & Treatises by Catherine Biondo Last Updated Sep 12, 2023 3687 views this year

Legal Dictionaries & Encyclopedias

Legal dictionaries.

Legal dictionaries are similar to other dictionaries that you have likely used before.

• Black's Law Dictionary
• Ballentine's Law Dictionary

Legal Encyclopedias

Legal encyclopedias contain brief, broad summaries of legal topics, providing introductions and explaining terms of art. They also provide citations to primary law and relevant major law review articles.  

Here are the two major national encyclopedias:

• American Jurisprudence (AmJur) This resource is also available in Westlaw & Lexis .
• Corpus Juris Secundum (CJS)

Treatises are books on legal topics.  These books are a good place to begin your research.  They provide explanation, analysis, and citations to the most relevant primary sources. Treatises range from single subject overviews to deep treatments of broad subject areas.

It is important to check the date when the treatise was published. Many are either not updated, or are updated through the release of newer editions.

To find a relevant treatise explore:

• Legal Treatises by Subject by Catherine Biondo Last Updated Sep 12, 2023 2593 views this year

American Law Reports (ALR)

American Law Reports (ALR) contains in-depth articles on narrow topics of the law. ALR articles, are often called annotations. They provide background, analysis, and citations to relevant cases, statutes, articles, and other annotations. ALR annotations are invaluable tools to quickly find primary law on narrow legal questions.

This resource is available in both Westlaw and Lexis:

• American Law Reports on Westlaw (includes index)
• American Law Reports on Lexis

Law Reviews & Journals

Law reviews are scholarly publications, usually edited by law students in conjunction with faculty members. They contain both lengthy articles and shorter essays by professors and lawyers. They also contain comments, notes, or developments in the law written by law students. Articles often focus on new or emerging areas of law and may offer critical commentary. Some law reviews are dedicated to a particular topic while others are general. Occasionally, law reviews will include issues devoted to proceedings of panels and symposia.

Law review and journal articles are extremely narrow and deep with extensive references. 

To find law review articles visit:

• Law Journal Library on HeinOnline
• Law Reviews & Journals on LexisNexis
• Law Reviews & Journals on Westlaw

Restatements

Restatements are highly regarded distillations of common law, prepared by the American Law Institute (ALI). ALI is a prestigious organization comprised of judges, professors, and lawyers. They distill the "black letter law" from cases to indicate trends in common law. Resulting in a “restatement” of existing common law into a series of principles or rules. Occasionally, they make recommendations on what a rule of law should be.

Restatements are not primary law. However, they are considered persuasive authority by many courts.

Restatements are organized into chapters, titles, and sections.  Sections contain the following:

• a concisely stated rule of law,
• comments to clarify the rule,
• hypothetical examples,
• explanation of purpose, and
• exceptions to the rule  

To access restatements visit:

• American Law Institute Library on HeinOnline
• Restatements & Principles of the Law on LexisNexis
• Restatements & Principles of Law on Westlaw

Primary Authority

Primary authority is "authority that issues directly from a law-making body."   Authority , Black's Law Dictionary (11th ed. 2019).   Sources of primary authority include:

• Constitutions
• Statutes 

Regulations

Access to primary legal sources is available through:

• Bloomberg Law
• Free & Low Cost Alternatives

Statutes (also called legislation) are "laws enacted by legislative bodies", such as Congress and state legislatures.  Statute , Black's Law Dictionary (11th ed. 2019).

We typically start primary law research here. If there is a controlling statute, cases you look for later will interpret that law. There are two types of statutes, annotated and unannotated.

Annotated codes are a great place to start your research. They combine statutory language with citations to cases, regulations, secondary sources, and other relevant statutes. This can quickly connect you to the most relevant cases related to a particular law. Unannotated Codes provide only the text of the statute without editorial additions. Unannotated codes, however, are more often considered official and used for citation purposes.

For a deep dive on federal and state statutes, visit:

• Statutes: US and State Codes by Mindy Kent Last Updated Mar 26, 2024 2094 views this year
• 50 State Surveys

Want to learn more about the history or legislative intent of a law?  Learn how to get started here:

• Legislative History Get an introduction to legislative histories in less than 5 minutes.
• Federal Legislative History Research Guide

Regulations are rules made by executive departments and agencies. Not every legal question will require you to search regulations. However, many areas of law are affected by regulations. So make sure not to skip this step if they are relevant to your question.

To learn more about working with regulations, visit:

• Administrative Law Research by AJ Blechner Last Updated Sep 12, 2023 431 views this year

Case Basics

In many areas, finding relevant caselaw will comprise a significant part of your research. This Is particularly true in legal areas that rely heavily on common law principles.

Running Time: 3 minutes, 10 seconds.

Unpublished Cases

Up to  86% of federal case opinions are unpublished. You must determine whether your jurisdiction will consider these unpublished cases as persuasive authority. The Federal Rules of Appellate Procedure have an overarching rule, Rule 32.1  Each circuit also has local rules regarding citations to unpublished opinions. You must understand both the Federal Rule and the rule in your jurisdiction.

• Federal and Local Rules of Appellate Procedure 32.1 (Dec. 2021).
• Type of Opinion or Order Filed in Cases Terminated on the Merits, by Circuit (Sept. 2021).

Each state also has its own local rules which can often be accessed through:

• State Bar Associations
• State Courts Websites

First Circuit

• First Circuit Court Rule 32.1.0

Second Circuit

• Second Circuit Court Rule 32.1.1

Third Circuit

• Third Circuit Court Rule 5.7

Fourth Circuit

• Fourth Circuit Court Rule 32.1

Fifth Circuit

• Fifth Circuit Court Rule 47.5

Sixth Circuit

• Sixth Circuit Court Rule 32.1

Seventh Circuit

• Seventh Circuit Court Rule 32.1

Eighth Circuit

• Eighth Circuit Court Rule 32.1A

Ninth Circuit

• Ninth Circuit Court Rule 36-3

Tenth Circuit

• Tenth Circuit Court Rule 32.1

Eleventh Circuit

• Eleventh Circuit Court Rule 32.1

D.C. Circuit

• D.C. Circuit Court Rule 32.1

Federal Circuit

• Federal Circuit Court Rule 32.1

Finding Cases

Headnotes show the key legal points in a case. Legal databases use these headnotes to guide researchers to other cases on the same topic. They also use them to organize concepts explored in cases by subject. Publishers, like Westlaw and Lexis, create headnotes, so they are not consistent across databases.

Headnotes are organized by subject into an outline that allows you to search by subject. This outline is known as a "digest of cases." By browsing or searching the digest you can retrieve all headnotes covering a particular topic. This can help you identify particularly important cases on the relevant subject.

Running Time: 4 minutes, 43 seconds.

Each major legal database has its own digest:

• Topic Navigator (Lexis)
• Key Digest System (Westlaw)

Start by identifying a relevant topic in a digest.  Then you can limit those results to your jurisdiction for more relevant results.  Sometimes, you can keyword search within only the results on your topic in your jurisdiction.  This is a particularly powerful research method.

One Good Case Method

After following the steps above, you will have identified some relevant cases on your topic. You can use good cases you find to locate other cases addressing the same topic. These other cases often apply similar rules to a range of diverse fact patterns.

• in Lexis click "More Like This Headnote"
• in Westlaw click "Cases that Cite This Headnote"

to focus on the terms of art or key words in a particular headnote. You can use this feature to find more cases with similar language and concepts.  ​

Ways to Use Citators

A citator is "a catalogued list of cases, statutes, and other legal sources showing the subsequent history and current precedential value of those sources.  Citators allow researchers to verify the authority of a precedent and to find additional sources relating to a given subject." Citator , Black's Law Dictionary (11th ed. 2019).

Each major legal database has its own citator.  The two most popular are Keycite on Westlaw and Shepard's on Lexis.

• Keycite Information Page
• Shepard's Information Page

Making Sure Your Case is Still Good Law

This video answers common questions about citators:

For step-by-step instructions on how to use Keycite and Shepard's see the following:

• Shepard's Video Tutorial
• Shepard's Handout
• Shepard's Editorial Phrase Dictionary
• KeyCite Video Tutorial
• KeyCite Handout
• KeyCite Editorial Phrase Dictionary

Using Citators For

Citators serve three purposes: (1) case validation, (2) better understanding, and (3) additional research.

Case Validation

Is my case or statute good law?

• Parallel citations
• Prior and subsequent history
• Negative treatment suggesting you should no longer cite to holding.

Better Understanding

Has the law in this area changed?

• Later cases on the same point of law
• Positive treatment, explaining or expanding the law.
• Negative Treatment, narrowing or distinguishing the law.

Track Research

Who is citing and writing about my case or statute?

• Secondary sources that discuss your case or statute.
• Cases in other jurisdictions that discuss your case or statute.

Knowing When to Start Writing

For more guidance on when to stop your research see:

• Terminating Research, by Christina L. Kunz

Automated Services

Automated services can check your work and ensure that you are not missing important resources. You can learn more about several automated brief check services.  However, these services are not a replacement for conducting your own diligent research .

• Automated Brief Check Instructional Video

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How Do Clinical Trials Work?

Clinical trials are designed to work in phases that follow strict guidelines, including who can participate. Learning how clinical trials work can help you decide if you want to join. 

Who Is Eligible for Cancer Clinical Trials?

"I want to participate in the clinical trial to advance our research and technology. I want to contribute in saving our women in the coming generations."   —Madhu Sood, NCI clinical trial participant

Every clinical trial has requirements that must be met for you to join. These requirements are called eligibility criteria.

Common eligibility criteria address things such as your:

• medical history
• family medical history
• risk factors
• treatment history
• tumor’s genetic changes 

These criteria help reduce the medical differences among people in the trial, reduce the risk that people will be harmed, and limit people in the trial to those most likely to benefit.

When people taking part in a trial are alike in specific ways, researchers can be more certain that the results are due to the intervention or drug being tested and not to other factors.

What Are the Phases of Clinical Trials?

Clinical trials to test new cancer treatments involve a series of steps, called phases. Depending on the results of each phase, a treatment may move to testing in the next phase. 

What Are Clinical Trial Phases?

This video explains the main phases of clinical trials.

The Four Phases of Clinical Trials   Early clinical trial phases (phases 1 and 2) test for safety, such as what the side effects are and what a safe dose is. Later phases (phase 3 and 4) compare the treatment to current standard treatments.

In a phase 1 clinical trial, researchers figure out whether a new treatment is safe, what its side effects are, whether people can tolerate it, and the highest dose that people can tolerate. These trials are done in a small group of people (around 15 to 30). They also make sure a treatment affects the cancer.

A phase 2 clinical trial includes more people (50 to 100) to see if the new treatment seems to work against the cancer, such as by shrinking tumors or slowing their growth. Researchers want to see how the new treatment affects the body and fights cancer. In this phase, teams continue to study safety, including short-term side effects.

In a phase 3 clinical trial, researchers compare the treatment to the current standard therapy to see which works better. They also compare the side effects of the treatments. Participants are randomly assigned to one of the treatments to ensure that any differences are real and not the result of differences in the people in each group. Phase 3 trials include large numbers of people (from 100 to several thousand) to make sure that the result is valid. 

Results from phase 1–3 trials are used to make decisions about approving new treatments or existing treatments for new conditions by agencies like the US Food and Drug Administration (FDA). 

A phase 4 clinical trial looks at long-term safety and effectiveness that take place after a new treatment has been approved by the FDA and is available to the public. Treatment effectiveness and safety are monitored in large, diverse populations. More information is gathered as more people use the drug or device over a longer period of time.

Randomization and Bias in Cancer Clinical Trials

Randomization in Clinical Trials

Learn how researchers randomly assign clinical trial participants to different treatment groups in order to prevent bias in the results.

Clinical trial randomization is the process of assigning people by chance to groups that receive different interventions or drugs in later phase trials. A computer is most often used to assign people to groups.

In the simplest trial design, the investigational group receives the study intervention or drug and the control group receives standard treatment.  

At several points during and at the end of the clinical trial, researchers compare the groups to see which intervention or drug is more effective or has fewer side effects. 

Randomization, in which people are assigned to groups by chance alone, helps prevent bias. Bias occurs when a trial's results are affected by human choices or other factors not related to the treatment being tested.

For example, if doctors could choose which patients to assign to which groups, some might assign healthier patients to the treatment group and sicker patients to the control group even without meaning to. This might make the treatment group appear better than the control group even if it isn’t. Randomization helps avoid biases of this type.

If you are thinking about joining a clinical trial that includes randomization, it is important to understand that neither you nor your doctor can choose which group you will be assigned to.

Use of Placebos in Clinical Trials

Placebos are another way to help prevent bias in research. The placebo is designed to look like the medicine being tested, but it is not active. Using a placebo in this way can help prevent you and your doctors from figuring out which group you are assigned to. If doctors know which group you are in, it may affect how they assess your response without meaning to. 

Placebos are rarely used in cancer treatment clinical trials. If placebos are used it is likely because no standard treatment exists. Or they may be used in a trial that compares standard treatment plus a placebo, with standard treatment plus the study treatment. You always will be told ahead of time if a study uses a placebo.

Placebos may be used in other types of trials, such as prevention trials.

Research Team Members

Designing and running a clinical trial requires the skills of many experts. Different sites of the same trial may set up their teams differently. Typical team members and their duties include:

Where Do Cancer Clinical Trials Take Place?

Cancer clinical trials take place in cities and towns across the United States and throughout the world.

They take place in doctors’ offices, cancer centers, medical centers, community hospitals and clinics, and veterans’ and military hospitals. A single trial may take place in one or two places, or at hundreds of different sites.

Trials that are funded in full or in part by NCI, include trials that take place at NCI-Designated Cancer Centers and at the NIH Clinical Center in Bethesda, Maryland .

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Clinical Trials How Clinical Trials Work

Language switcher, what are clinical trials.

Clinical trials are medical studies that involve people like you. They help find new ways to prevent, detect, or treat diseases that are safe and effective. The National Heart, Lung, and Blood Institute (NHLBI) leads and supports many studies aimed at preventing, diagnosing, and treating heart, lung, blood, and sleep disorders.

Clinical trials are an important part of the research spectrum. The idea for a clinical trial often starts in the lab. After researchers test new treatments or procedures in the lab and in animals, the most promising treatments are moved into clinical trials. As studies about new treatments move through a series of steps called phases, researchers learn more information about the treatment, its risks, and its effectiveness.

Each clinical trial has criteria describing who can join. Children as well as adults, patients and healthy volunteers, and people of a diverse range of ethnic and racial backgrounds can and are encouraged to participate in clinical trials.

Clinical trials follow a protocol, a carefully designed plan to safeguard your health and answer specific research questions. The protocol describes what you will be doing and what you can expect from the research team. It is important to understand the risks and benefits of participation before joining. You also have rights and protections as a participant in clinical trials.

National Institutes of Health (NIH) Institutes and Centers, including the NHLBI, support many types of clinical trials that contribute to medical knowledge and practice. Clinical trials can be described in a number of different ways, including by their purpose or by phase.

Purpose of clinical trials

Clinical trials have different purposes. What that purpose is helps define the type of trial it is.

• Behavioral trials evaluate or compare ways to promote behavioral changes designed to improve health.
• Diagnostic trials study or compare tests or procedures for diagnosing a particular disease or condition.
• Prevention trials look for better ways to prevent a disease in people who have never had the disease or to prevent the disease from returning. Approaches may include medicines, vaccines, or lifestyle changes.
• Quality-of-life trials, or supportive care trials, explore and measure ways to improve the comfort and quality of life for people with conditions or illnesses.
• Screening trials test new ways for detecting diseases or health conditions.
• Treatment trials test new treatments, new combinations of medicines, or new approaches to surgery or radiation therapy.

Clinical trial phases

Researchers conduct clinical trials in a series of steps called phases. Each phase has a different purpose and helps researchers answer different questions.

• Phase I trials: Researchers test a medicine or other treatment in a small group of people for the first time. The purpose is to learn about the best dosage for a medicine or other treatment and to learn about the safety and side effects.
• Phase II trials: Researchers study the new medicine or treatment in a larger group of people to determine its effectiveness and to further study its safety.
• Phase III trials: Researchers give the new medicine or treatment to an even larger group of participants to confirm its effectiveness, monitor side effects, compare it with standard or similar treatments or a placebo , and collect information that will allow the new medicine or treatment to be used safely.
• Phase IV trials: After the U.S. Food and Drug Administration (FDA) approves a medicine or treatment and it is made available to the public, researchers track its safety in the general population, seeking more information about the medicine or treatment’s benefits and optimal use.

Clinical trial experience

As a participant in a clinical trial, you may work with a healthcare team, and you may need to go to a hospital or other location. Everything that happens throughout your experience follows a plan called a clinical trial protocol.

Governing bodies called Institutional Review Boards (IRBs) approve protocols and are responsible for ensuring your safety. The research team will also operate by other national and international standards that protect you and help produce reliable study results. The NHLBI is one of many types of organizations that support clinical trials.

Before you join a clinical trial, you will be told all about the study, what procedures you will be undergoing, how much time you will be spending on aspects of the study, and any other information you need to know. Once your questions have been answered and you are comfortable, you will be asked to give your consent to participate.

During a clinical trial, you may see doctors, nurses, social workers, and other healthcare providers who will monitor your health closely. You may have more tests and medical exams than you would if you were not taking part in a clinical trial. You may also be asked to do other tasks, such as keeping a log about your health or filling out forms about how you feel.

You may need to travel or stay in a hospital to take part in clinical trials. For example, the NIH Clinical Center in Bethesda, Maryland, runs clinical trials. It is the largest research hospital in the world. Many other clinical trials take place in medical centers and doctors’ offices around the country. If you decide that a trial is not for you, it is important to remember that you can withdraw at any time. Whether you participate will not affect your regular medical care.

Clinical trial protocols

Clinical trials follow a plan known as a protocol. The protocol is carefully designed to balance the potential benefits of a trial with the risks to participants. It also answers specific research questions. A protocol describes the following:

• Details about tests, procedures, and treatments
• Eligibility requirements
• Expected duration, or how long the study will last
• Goals of the study
• Information to be gathered
• Protections against risks to participants

A clinical trial team is led by a principal investigator (PI). Members of the research team regularly monitor the participants’ health to determine the study’s safety and effectiveness.

Clinical trial designs

There are different types of clinical trials and different trial designs. However, many clinical trials include standard design elements.

• In single-blind (single-masked) studies, you are not told what you are being given, but the research team knows.
• In double-blind studies, neither you nor the research team are told what you are given; only the pharmacist knows. Members of the research team are not told which participants are receiving which treatment, in order to reduce bias. If medically necessary, however, it is always possible to find out which treatment you are receiving.
• Randomization is the process by which participants are randomly assigned a treatment instead of being selected for one or the other. This is done to avoid bias when making assignments. The effects of each treatment are compared at specific points during a trial. If one treatment is found superior, the study is stopped so that all the volunteers receive the more beneficial treatment.

When the study is finished

After a clinical trial is completed, the researchers carefully examine information collected during the study before making decisions about the meaning of the findings and about the need for further testing. After a Phase I or II trial, the researchers decide whether to move on to the next phase or to stop testing the treatment or procedure because it was unsafe or not effective. When a Phase III trial is completed, the researchers examine the information and decide whether the results have medical importance.

Results from clinical trials are often published in scientific journals in articles that have gone through peer review . Results that are particularly important may be featured in the news and discussed at scientific meetings and by patient advocacy groups. Once a new approach has been proven safe and effective in a clinical trial, it may become a new standard of medical practice. In many cases, if you participated in a blinded or masked study, you will get information about the treatment you received

Ask the research team members if the study results have been or will be published. Published study results are also available by searching for the study’s official name or Protocol ID number in the National Library of Medicine’s PubMed® database .

Participate in an NHLBI clinical trial

Search our list of research studies by topic, location, and age to see whether you or someone you know is eligible to join.

• Clinical Trials

About Clinical Studies

Research: it's all about patients.

Mayo's mission is about the patient, the patient comes first. So the mission and research here, is to advance how we can best help the patient, how to make sure the patient comes first in care. So in many ways, it's a cycle. It can start with as simple as an idea, worked on in a laboratory, brought to the patient bedside, and if everything goes right, and let's say it's helpful or beneficial, then brought on as a standard approach. And I think that is one of the unique characteristics of Mayo's approach to research, that patient-centeredness. That really helps to put it in its own spotlight.

At Mayo Clinic, the needs of the patient come first. Part of this commitment involves conducting medical research with the goal of helping patients live longer, healthier lives.

Through clinical studies, which involve people who volunteer to participate in them, researchers can better understand how to diagnose, treat and prevent diseases or conditions.

Types of clinical studies

• Observational study. A type of study in which people are observed or certain outcomes are measured. No attempt is made by the researcher to affect the outcome — for example, no treatment is given by the researcher.
• Clinical trial (interventional study). During clinical trials, researchers learn if a new test or treatment works and is safe. Treatments studied in clinical trials might be new drugs or new combinations of drugs, new surgical procedures or devices, or new ways to use existing treatments. Find out more about the five phases of non-cancer clinical trials on ClinicalTrials.gov or the National Cancer Institute phases of cancer trials .
• Medical records research. Medical records research involves the use of information collected from medical records. By studying the medical records of large groups of people over long periods of time, researchers can see how diseases progress and which treatments and surgeries work best. Find out more about Minnesota research authorization .

Clinical studies may differ from standard medical care

A health care provider diagnoses and treats existing illnesses or conditions based on current clinical practice guidelines and available, approved treatments.

But researchers are constantly looking for new and better ways to prevent and treat disease. In their laboratories, they explore ideas and test hypotheses through discovery science. Some of these ideas move into formal clinical trials.

During clinical studies, researchers formally and scientifically gather new knowledge and possibly translate these findings into improved patient care.

Before clinical trials begin

This video demonstrates how discovery science works, what happens in the research lab before clinical studies begin, and how a discovery is transformed into a potential therapy ready to be tested in trials with human participants:

How clinical trials work

Trace the clinical trial journey from a discovery research idea to a viable translatable treatment for patients:

See a glossary of terms related to clinical studies, clinical trials and medical research on ClinicalTrials.gov.

Watch a video about clinical studies to help you prepare to participate.

Let's Talk About Clinical Research

Narrator: This presentation is a brief introduction to the terms, purposes, benefits and risks of clinical research.

If you have questions about the content of this program, talk with your health care provider.

What is clinical research?

Clinical research is a process to find new and better ways to understand, detect, control and treat health conditions. The scientific method is used to find answers to difficult health-related questions.

Ways to participate

There are many ways to participate in clinical research at Mayo Clinic. Three common ways are by volunteering to be in a study, by giving permission to have your medical record reviewed for research purposes, and by allowing your blood or tissue samples to be studied.

Types of clinical research

There are many types of clinical research:

• Prevention studies look at ways to stop diseases from occurring or from recurring after successful treatment.
• Screening studies compare detection methods for common conditions.
• Diagnostic studies test methods for early identification of disease in those with symptoms.
• Treatment studies test new combinations of drugs and new approaches to surgery, radiation therapy and complementary medicine.
• The role of inheritance or genetic studies may be independent or part of other research.
• Quality of life studies explore ways to manage symptoms of chronic illness or side effects of treatment.
• Medical records studies review information from large groups of people.

Clinical research volunteers

Participants in clinical research volunteer to take part. Participants may be healthy, at high risk for developing a disease, or already diagnosed with a disease or illness. When a study is offered, individuals may choose whether or not to participate. If they choose to participate, they may leave the study at any time.

Research terms

You will hear many terms describing clinical research. These include research study, experiment, medical research and clinical trial.

Clinical trial

A clinical trial is research to answer specific questions about new therapies or new ways of using known treatments. Clinical trials take place in phases. For a treatment to become standard, it usually goes through two or three clinical trial phases. The early phases look at treatment safety. Later phases continue to look at safety and also determine the effectiveness of the treatment.

Phase I clinical trial

A small number of people participate in a phase I clinical trial. The goals are to determine safe dosages and methods of treatment delivery. This may be the first time the drug or intervention is used with people.

Phase II clinical trial

Phase II clinical trials have more participants. The goals are to evaluate the effectiveness of the treatment and to monitor side effects. Side effects are monitored in all the phases, but this is a special focus of phase II.

Phase III clinical trial

Phase III clinical trials have the largest number of participants and may take place in multiple health care centers. The goal of a phase III clinical trial is to compare the new treatment to the standard treatment. Sometimes the standard treatment is no treatment.

Phase IV clinical trial

A phase IV clinical trial may be conducted after U.S. Food and Drug Administration approval. The goal is to further assess the long-term safety and effectiveness of a therapy. Smaller numbers of participants may be enrolled if the disease is rare. Larger numbers will be enrolled for common diseases, such as diabetes or heart disease.

Clinical research sponsors

Mayo Clinic funds clinical research at facilities in Rochester, Minnesota; Jacksonville, Florida; and Arizona, and in the Mayo Clinic Health System. Clinical research is conducted in partnership with other medical centers throughout the world. Other sponsors of research at Mayo Clinic include the National Institutes of Health, device or pharmaceutical companies, foundations and organizations.

Clinical research at Mayo Clinic

Dr. Hugh Smith, former chair of Mayo Clinic Board of Governors, stated, "Our commitment to research is based on our knowledge that medicine must be constantly moving forward, that we need to continue our efforts to better understand disease and bring the latest medical knowledge to our practice and to our patients."

This fits with the term "translational research," meaning what is learned in the laboratory goes quickly to the patient's bedside and what is learned at the bedside is taken back to the laboratory.

Ethics and safety of clinical research

All clinical research conducted at Mayo Clinic is reviewed and approved by Mayo's Institutional Review Board. Multiple specialized committees and colleagues may also provide review of the research. Federal rules help ensure that clinical research is conducted in a safe and ethical manner.

Institutional review board

An institutional review board (IRB) reviews all clinical research proposals. The goal is to protect the welfare and safety of human subjects. The IRB continues its review as research is conducted.

Consent process

Participants sign a consent form to ensure that they understand key facts about a study. Such facts include that participation is voluntary and they may withdraw at any time. The consent form is an informational document, not a contract.

Study activities

Staff from the study team describe the research activities during the consent process. The research may include X-rays, blood tests, counseling or medications.

Study design

During the consent process, you may hear different phrases related to study design. Randomized means you will be assigned to a group by chance, much like a flip of a coin. In a single-blinded study, participants do not know which treatment they are receiving. In a double-blinded study, neither the participant nor the research team knows which treatment is being administered.

Some studies use an inactive substance called a placebo.

Multisite studies allow individuals from many different locations or health care centers to participate.

Remuneration

If the consent form states remuneration is provided, you will be paid for your time and participation in the study.

Some studies may involve additional cost. To address costs in a study, carefully review the consent form and discuss questions with the research team and your insurance company. Medicare may cover routine care costs that are part of clinical trials. Medicaid programs in some states may also provide routine care cost coverage, as well.

When considering participation in a research study, carefully look at the benefits and risks. Benefits may include earlier access to new clinical approaches and regular attention from a research team. Research participation often helps others in the future.

Risks/inconveniences

Risks may include side effects. The research treatment may be no better than the standard treatment. More visits, if required in the study, may be inconvenient.

Weigh your risks and benefits

Consider your situation as you weigh the risks and benefits of participation prior to enrolling and during the study. You may stop participation in the study at any time.

Ask questions

Stay informed while participating in research:

• Write down questions you want answered.
• If you do not understand, say so.
• If you have concerns, speak up.

Website resources are available. The first website lists clinical research at Mayo Clinic. The second website, provided by the National Institutes of Health, lists studies occurring in the United States and throughout the world.

Additional information about clinical research may be found at the Mayo Clinic Barbara Woodward Lips Patient Education Center and the Stephen and Barbara Slaggie Family Cancer Education Center.

Clinical studies questions

• Phone: 800-664-4542 (toll-free)
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Cancer-related clinical studies questions

• Phone: 855-776-0015 (toll-free)

International patient clinical studies questions

• Phone: 507-284-8884
• Email: [email protected]

Clinical Studies in Depth

Learning all you can about clinical studies helps you prepare to participate.

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• J Thorac Dis
• v.9(8); 2017 Aug

How to design a randomized clinical trial: tips and tricks for conduct a successful study in thoracic disease domain

Francesco guerrera.

1 Department of Thoracic Surgery, University of Torino, Torino, Italy;

Stéphane Renaud

2 Department of Thoracic Surgery, Nancy University Hospital, Nancy, France;

Fabrizio Tabbò

3 Department of Oncology, University of Torino, Torino, Italy

Pier Luigi Filosso

Randomized controlled trials (RCTs) are considered one of the highest level of evidence in clinical practice, due to their strong confidence and robustness in producing data. The “randomization” (e.g., allocating patients randomly in each group of the study) allows eliminating many pre-analytical differences that might bias the entire study. Nevertheless, RCTs aren’t free of internal pitfalls that might make them not easy to be developed or utilized. Our objective is to explain RCT management difficulties and suggest certain tips useful for the design of a RCT in thoracic disease domain. In particular have a realistic timeline, define a clear objective and precise endpoints, balance the study with a correct randomization and focus on the right equilibrium between strict selection criteria and more heterogeneous parameters are key elements that help researchers assuring a strong scientific validity.

Introduction

Nowadays, medical decisions such as which type of surgical approach, whether to treat or not a patient and with which pharmacological intervention are evaluated considering the evidence-based medicine ( 1 ). In medicine, levels of evidence, as described by the National Cancer Institute, are arranged in “a ranking system used to describe the strength of the results measured in a clinical trial or research study. The design of the study and the endpoints measured affect the strength of the evidence” ( 2 ). So far different classifications have been proposed to classify levels of evidence. Among them, the United States Preventive Service Task Force (USPSTF) classified levels of evidence from level I (evidence obtained from at least one properly designed randomized trial) to level III (opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees) ( 3 ). Another example is the Oxford CEBM levels of evidence, which ranges from level 1a (systematic reviews of randomized controlled trials) to level 5 (expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”) ( 4 ).

Regardless the chosen classification, randomized clinical trials (RCTs) are considered as one of the highest level of evidence in clinical practice, due to their strong confidence and robustness in producing data. Allocating patients randomly in each considered groups of the study, the “randomization” allows eliminating many pre-analytical differences that might bias the entire study. This is one of the major aspect that contribute to the robustness of this type of clinical trial and one of the reasons why RCTs have been extensively adopted by clinician-trialists.

Therefore, the ability, not only to properly interpret, but also to design correctly a RCT is mandatory if we aim to obtain a high-level clinical trial, which may impact on the scientific community.

Definition, strengths and limitations

RCTs are usually utilized to assess treatments’ efficacy or effectiveness, in term of “superiority” (to determine if a novel treatment is better than a placebo or a standard intervention), “non-inferiority” (the novel treatment is no worse than a placebo or a standard intervention) or “equivalence” (analogous to non-inferiority, but permit of the novel intervention is no better than a placebo or a standard intervention) ( 5 ). These studies may analyze a comparison between treatment and not treatment or placebo, different treatment strategies or different dosage/intensity of the same treatment. The term “randomized” defines the random assignment to each study group. This implies a balance in baseline characteristics (known and unknown) amongst patients’ groups, reducing confounding factors and improving internal validity of the results ( 6 ).

On the other hand, the “ideal condition” to correctly perform RCTs determines its proper limitations: the population analyzed in RCT is for definition “selected” and obviously differs from the usual care population ( 7 , 8 ). Finally, RCTs are performed in a clinical trial setting, which is obviously dissimilar from the actual clinical practice; thus, specialization, rate of control and visit results are more intense and often not generalizable or comparable with a general practice setting.

Road map and documents

Tips: prepare in advance a detailed study protocol, a realistic timeline and proper data collection forms. A procedure manual must be necessary according to the complexity of the RCT and of the demanded tasks.

A detailed study protocol and manual of operations have central roles in RCT design and progress. The study protocol should contain in details the background, the objective, the rationale and the importance, as well as the design, the methodology, the Institutional Review Board approval, the informed consent and the statistical considerations of the RCT. In addition, the selection criteria for patient eligibility (i.e., inclusion and exclusion) and the concrete organization of the RCT (e.g., recruitment, baseline data collection, randomization, treatment administration, control visits and follow-up) should be described in the document ( 9 ).

Even if small or simple clinical trial require only a study protocol document, a procedures manual should be needed in more complex or large RCT. The procedures manual should contain study definitions, descriptions and instructions of each procedure and each task/item of data collection process. The manual should be written in details and could contain figure or diagrams to elucidate and forecast possible problems in procedures finalization ( 10 ).

Data collection forms should include all crucial items for evaluate baseline characteristics and outcomes. In order to easily collect, to avoid interferences and to limit related cost in data collection, these forms should be consistent and organized in logical order, according to the timing of procedures amongst RCTs. Data collection forms should be easy to be completed properly and unnecessary secondary variables should be avoided, as well as possible non-response and write-in responses. Baseline data collection should include items needed to confirm eligibility, to permit randomization and to collect predictors for possible stratification. Follow-up data collection encompasses information on primary and secondary outcomes, as well as treatment toxicity and morbidity.

Finally, another crucial and sometimes underestimated element to be prepared in advance is a realistic timeline document. Timeline document should report all the crucial steps of the starting RCT, with realistic and achievable time-objective.

A comprehensive study protocol with a detailed procedures manual, a realistic timeline and proper data collection forms define the Road Map needed to perform a correct RCT.

Hypothesis and outcome

Tips: formulate a single, simple and clear main hypothesis, accompanied by limited number of secondary ones. Select an intervention or a treatment that is clinically relevant and could be correctly assessed. Choose a significant endpoint that could be simply and practically verified.

RCTs typically assess a single intervention or a treatment in a limited and controlled setting. This because of strengths and restrictions associated to the nature of this kind of study. For these reasons, they have certain limitations to explore composite interventions in complex populations (e.g., elder patients, multiple pharmacological interactions, numerous comorbidity), which is the common scenario in actual clinical practice ( 11 , 12 ). Mostly, RCTs demonstrate to be an excellent setting for phase II (evaluation of treatment efficacy and safety) and phase III (evaluation of treatment efficacy and effectiveness in comparison with ‘gold standard’ or placebo) studies. Nevertheless, they have limitations in investigate rare outcomes or delayed effects.

Thus, results imperative to choose a clear hypothesis, verifiable by a limited number of strong and clinically significant endpoints. The general objective of RCTs is to obtain results of easy and concrete applicability for clinicians and that can be easy implemented in ordinary clinical settings. Is about transfer scientific knowledge in medical decision-making strategies.

For example, Wolfe et al. recently reported how the surgical intervention of thymectomy improves clinical outcomes in non-thymomatous myasthenic patients in a period over 3 years when compared with only prednisone treatment. The robust underlying hypothesis, the clear endpoints, and the relevance of the intervention, such as thymectomy, highlight how this RCT has a strong validity and helps changing clinical practice ( 13 ).

On the other hand, Kleinberg et al. demonstrated the value of choosing an appropriate endpoint; using as parameter the pathological complete response at the primary site, which may not predict correctly the overall survival outcome, might jeopardize study’s results. Indeed, the proposed alternative neoadjuvant treatments, with considerable toxic effects, didn’t impact on long-term survival when compared to standard therapeutic protocols ( 14 ).

Selection criteria and sample size

Tips: find an equilibrium between very strict and selective criteria (standardized patient group) and more heterogeneous conditions (external validity of the results). Always taking account of possible under recruitment and loss to follow up.

A precise statistical preparation of the RCT must taking account of the selection criteria and the power needed to obtain valuable results. The patient selection criteria (inclusion and exclusion, both) must be chosen to avoid possible confounding factors, to exclude patients in whom the intervention is useless or dangerous. Moreover, the selection criteria should be not too severe; the risk is to conduct the RCT in an overly selected population and to obtain results not generalizable at the actual clinical practice.

A sufficient sample size is fundamental to detect a reliable statistical difference among the study groups. The sample size needed to reach an adequate power in a study is inversely proportional to the intervention effect squared ( 15 ). Consequently, considering that frequently the effect of the studied intervention is relatively small, the number of patients needed is relatively large. Nevertheless, an insufficient sample size is a frequent problematic issue in several published RCTs.

For example, Portier et al. compared adjuvant fluorouracil and folinic acid administration with surgery alone after colorectal liver metastases resection ( 16 ). The results indicated an effect of adjuvant chemotherapy with an improved progression-free survival but not a statistically significant effect on overall survival. However, a trend towards an improvement on overall survival was observed and, probably, significance was not reached because a lacking statistical power due to a small sample size. Indeed, diverse RCTs on adjuvant chemotherapy regimens after liver metastasectomy are usually underpowered to find significant conclusion ( 17 ).

Contrariwise, Pompili et al. performed a power analysis to determinate a correct sample size to detect a difference in duration of chest tube placement after segmentectomy or lobectomy of at least 1 day ( 18 ). The proper number of recruited patients permit them to demonstrate a significant improvement from digital chest drain utilization.

Another recurrent problem in most of RCTs is a low recruitment rate. This is due to recruitment difficulties, inadequate selection criteria or patient willing. Moreover, some patients leave the intervention group due to patient or physician choices or treatment complications. Finally, other patients will be lost at the follow-up, and define the outcome for this patient will be not possible. Therefore, is mandatory to forecast that the RCT will be completed only in a relatively small percentage of all potentially eligible population.

For example, the ENG trial on adjuvant systemic treatment after liver resection for colorectal metastasis, closed prematurely due to poor recruitment. The final analysis was carried out on 107 patients and no effect on overall survival was observed. However, a successive pooled analysis that merged this trial with FFCD ACHBTH AURC 9002 Trial, showed a significant effect of chemotherapy on overall survival and progression-free survival, both ( 19 ).

Randomization, stratification, blind and intention to treat analysis

Tips: choose and report the methods of Randomization correctly. Balance the study group using stratification technique. At least, outcomes evaluation should be blinded. Always apply intention to treat analysis.

A key aspect of RCTs is the method of randomization. Random allocation of patients in the study or in the control group assures that all participants’ known and unknown characteristics are similar and balanced between groups at the beginning of RCTs ( 6 , 11 ). Therefore, the study group will differ for treatments type assigned only, avoiding the selection bias ( 20 ). One of the most important aspects of randomization is the impossibility to determine a priori the allocation of each patient. Consequently, is mandatory to report all the aspects of the randomization process: the randomization method (e.g., a coin toss, a table of random numbers, computer based schedule), personnel involved (physician, nurse, technician), randomization timing, existence of a randomizations register.

For example, Pompili et al. performed a trial on advantage of digital chest drain and accurately describe randomization method (a randomization list, generated by a computer software, blinded in consecutively numbered sealed envelopes) and timing (end of each surgical procedure) ( 18 ).

Despite randomization, especially in small RCTs, the risk of unbalance in important prognostic factors amongst groups could remain relevant. The stratification method allows to balance groups over the predictors of interest and to increase analysis power.

Blind methodology is used to prevent the possible bias derivate from the knowledge of group allocation of a patient (e.g., subjective evaluation of results). A “double blinded” approach is when both physician and patients don’t know which is the treatment received. Indeed, even if exist numerous methods to maintain a “double blinding” of a RCT (e.g., placebo treatment in drug therapies, sham procedure in surgical studies), sometimes is not possible to disguise treatment allocation. In these cases, at least the personnel dedicated to the evaluation of the response to the treatment should do not have information regarding group allocation. This assures to avoid subjectivity in outcome assessing and to permit the reliability and the objectivity of the results ( 21 , 22 ).

For example, in the recent trial, evaluating effect of surgical thymectomy for improve clinical outcomes in non-thymomatous myasthenia patients, double blinding is fairly difficult. Thus, to preserve rater blinding almost in outcome, patients were evaluated 4 months after surgical procedure by a neurologist who was not aware of the trial-group assignments.

The intention to treat analysis (ITT) analysis is a solid method to avoid analytical bias ( 23 ). The ITT considers each patient belonging to the group to which he/she was initially allocated, regardless if he/she finally will or will not be submitted to assigned treatment. The patients that did not performed the planned intervention will be not excluded from RCTs, and this prevent the possible bias of patient withdraw or crossover.

For example, Corris et al. used ITT analysis to evaluate the efficacy of azithromycin treatment vs. placebo in bronchiolitis obliterans post-transplantation. In this way, the authors avoid the bias effect due to patients’ withdrawal that did not complete the 12-weeks of study drug ( 24 ).

Conclusions

RCTs are incredible and irreplaceable tools for clinical researchers; nevertheless, aren’t free of internal pitfalls that might render them not easy to be developed or utilized. Our aim in this article is to suggest certain tips useful for the design of a RCT; have a realistic timeline, define a clear objective and precise endpoints, balance the study with a correct randomization are key elements that help us assuring a strong study’s validity.

RCTs conducted in perfect and ideal conditions often are not easy to be applied in routine clinical contest. A major point is to focus on the right equilibrium between strict selection criteria and more heterogeneous parameters that can help in a “real life” contest.

Based on these indications, is clear that each point from the design to the realization of a RCT is important for the study’s results. If we aim to obtain RCT strengthening evidence for clinical practice, we have to build them on strong hinges that allow us to influence the scientific literature and change the clinical decision-making activity of physicians involved in thoracic disease management.

Acknowledgements

Conflicts of Interest: The authors have no conflicts of interest to declare.

Assessment 1: Legal Research

An Introductory Look at the Core Modules

Mooting – A Ten Step Guide

• Surviving the LPC
• Uncategorized

The first practical assessment you are likely to encounter is the Legal Research assignment. On the face of it a simple task, but a surprisingly large amount of just-graduated students fall down at the first hurdle. The research task is not assessed in the same way as your undergraduate coursework assignments. You are asked to demonstrate your research skills as in any degree coursework. However, for the LPC your ability to compile the results into a useful format and apply the law to the scenario is also assessed. Your competence will be judged as ‘satisfactory’ or ‘unsatisfactory’ over several criteria. You need to produce an overall satisfactory piece of research to pass the assessment.

The research is often formulated around a client problem, possibly in an area of law that you are unlikely to have dealt with in your degree. The question will require you to research the current law that relates to the problem and to apply this to suggest a solution. You may be asked to submit your results in a particular format: for example, a memo to your supervisor or a paragraph in a letter to the client.

Now, you may be thinking that you know how to do research. After all, you have done huge amounts of it to get where you are; many of you will have done dissertations in your third year, some of you will have masters projects under your belt. Unfortunately, the better your dissertations were, the more likely you are to go wrong here. Let me stress – this is not academic research. If you treat it the same as your coursework to date, you are not approaching it in the right way.

Where students often go wrong is they forget they are no longer studying for a degree and attack the assignment with their undergraduate hat on. A discussion of the history of intellectual property rights and the effectiveness of European versus national protection is not what you are being asked for if the client has a design rights query. Neither the client nor your lecturers are interested in how many articles you can quote if you haven’t really answered the question fully.

Having spent a year now training, I can completely see the relevance of this; clients aren’t interested in knowing the law – that’s what they pay you for. All they want is some answers, with enough information to understand them. They certainly won’t want to pay you for doing research that is irrelevant or unusable. Your supervisor (or lecturer) wants enough information to understand the issue and to be confident you have done the research fully.

When I am given a piece of research now, I follow a set of steps to obtain the answer. I think my steps will equally be applicable to the Legal Research assessment and have shared them with you below. I have based these on solving a problem for a client – if you are set a query that doesn’t fit this scenario, the steps should still be useful.

They are as follows:

•  Identify the question. What are you actually being asked? Find the problems that you are being asked to research and write these down so you don’t forget them. Be aware, sometimes the questions are implied in the scenario, not explicitly asked. Put yourself in the client’s shoes: what would you want?
• Identify and research the relevant current law provisions. Apply the law to the problem and decide what the legal position is. Check you have all the solutions; there might be more than one. Are there any imminent changes in law that the client should be aware of?
• Look at it from a commercial point of view. For example: a client may be able to sue for a debt owed through the civil courts but in practice would not do this unless the amount of debt justified it – the time, cost and uncertainty implications of litigation are unattractive to a client.
• Identify any other information you need to be able to advise the client fully. If there is any, making it clear that this information is required is a good idea. If there are only a couple of options, for example, the company either is or is not based in the UK, explain what the answer would be in each case.
• Compile your findings in a way that is easy to read and understand using headings and bullet points if necessary. For example, break down the information into sections headed: background of the situation, applicable law, legal solution, next steps.
• If advising the client, get a non-lawyer to read it through to see if they understand it (in practice, you will have to be aware of client confidentiality!).
• Consider suggesting next steps to progress the matter.
• Provide your sources in a way that your research can be quickly checked. If the assessor has to do the research again because he can’t follow your trail, you will lose marks.
• Finally, double check you have actually answered the question.

For extra brownie points, you could look into possible reforms in the future that might affect your answer and include these.

[two_third_last].

One point to remember is that if you have hit a brick wall and can’t find the answer, you have misunderstood the question or need more information to answer that particular problem. ‘No answer’ is not the answer, believe me!

Really, as long as you have the focus right from the start, the research project is as simple as it seems and shouldn’t pose much of an issue. Get it out of the way and forget about it. There will be more challenges coming your way soon!

[/two_third_last]

In the next post I will look at the first part of Property, Law and Practice.

Matt Carter

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This section of the website is to support unit 2: cold start research and mooting., below is a very quick overview of the research process.  more detail including short videos can be found using the right hand menu., overview of the legal research process.

The following overview is adapted from notes prepared by Ruth Bird, former Bodleian Law Librarian

The research path you follow will vary depending on the nature of your topic and legal issue. There is no single “right” path to take in conducting legal research. While there will be times when you will follow the research steps suggested herein in a linear fashion, that will not always be the case.

You will find that as you move through the research process, you will identify sources that will require you to revisit sources consulted earlier in the process. For instance, a secondary source may direct you to a statute, which leads you to an annotated section of Halsbury’s Statutes. In your review of Halsbury’s Statutes, you will locate relevant cases. Upon your review of one of the cases, you may find a reference to another statute that provides an exception to the statutory rule identified by your original secondary source. Your research would not end there, of course. You would return to Halsbury’s Statutes to review the section for the new statute to see if the exception applies to your factual scenario and to locate relevant cases.

Regardless of the path you follow using the steps below, if you are thorough and flexible in your research you will succeed!

Identify the scope of the legal question.

Ask specific questions to identify: (1) the relevant jurisdiction, (2) key sources and search terms, and (3) the applicable time period. Put all of this down in a research plan (see more detail from the links on the right hand side)

Begin your research by consulting a secondary source.

Core texts, Halsbury’s Laws, key articles, can give perspective on how your specific issue fits into a broader legal context and will assist you in finding on-point primary authority. Note references to pertinent statutes and case citations.  See right hand side on using the databases effectively.

Identify relevant statutes.

If you located an applicable statute in your review of secondary sources, review the annotations for the applicable provision in Halsbury’s Statutes. Browse the contents of the statute to identify any other pertinent sections. Browse the contents page of the Halsbury's Statutes volume to find other relevant statutes..

Identify the cases that are on-point for your specific facts.

When reading secondary sources, note cases that relate to your set of facts. Follow up the cases, checking headnotes and reading judgments that seem applicable. One good case can be a great starting point for research on narrow topics.

Use digests to find more cases. Digests provide another excellent resource to identify relevant case law. The Digest is a good source for finding English and Commonwealth cases by topic. It has the same subject structure as Halsbury’s Laws.

Confirm that your authority is still good law.

Use Westlaw Case Analysis, Lexis Overview, VLex Justis or a print citator to check that your cases are still good law and provide the most current, direct authority available for your set of facts.

Search online to fill any gaps in your research.

Thorough research depends on the use of multiple research methods. Supplement the research uncovered in your review of secondary sources, digests, and other sources with keyword and/or natural language searches of relevant legal databases in Westlaw, Lexis+ UK, VLex Justis and Practical Law. Use Boolean operators and connectors when possible to increase the accuracy of your results. Check the Journals Index in Westlaw for recent articles. Blogs, policy websites and so on are also useful, depending on the topic.

Keep a record of your research trail.

Document all sources reviewed, including all sections and page numbers, regardless of whether you located relevant materials in them. This will help you later when you write up your research and need to check points.

 Some keys to legal research success:

• Get to know your librarians
• Take the courses on topics/searching/endnote etc on offer
• Get out of the Google-search mindset – ask us the tricks of each database
• Look beyond Lexis and Westlaw
• Use secondary sources
• Know when to stop!

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How to Write a Report of a Research Study

• First Online: 15 December 2017

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Preparing a report of a research trial is a special type of medical writing. The experienced author of research reports follows the IMRAD model: introduction, methods, results, and discussion, although this scheme is often expanded to include subheadings such as participants, randomization and intervention, data collection, outcomes, and statistical analysis. This chapter discusses clinical trial registration, statistics, reference citations, reproducibility, and generalizability.

In questions of science, the authority of a thousand is not worth the humble reasoning of a single individual. Italian physicist and philosopher Galileo Galilei (1564–1642).

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How to do legal research in 3 steps

Knowing where to start a difficult legal research project can be a challenge. But if you already understand the basics of legal research, the process can be significantly easier — not to mention quicker.

Solid research skills are crucial to crafting a winning argument. So, whether you are a law school student or a seasoned attorney with years of experience, knowing how to perform legal research is important — including where to start and the steps to follow.

What is legal research, and where do I start? 

Black's Law Dictionary defines legal research as “[t]he finding and assembling of authorities that bear on a question of law." But what does that actually mean? It means that legal research is the process you use to identify and find the laws — including statutes, regulations, and court opinions — that apply to the facts of your case.

In most instances, the purpose of legal research is to find support for a specific legal issue or decision. For example, attorneys must conduct legal research if they need court opinions — that is, case law — to back up a legal argument they are making in a motion or brief filed with the court.

Alternatively, lawyers may need legal research to provide clients with accurate legal guidance . In the case of law students, they often use legal research to complete memos and briefs for class. But these are just a few situations in which legal research is necessary.

Why is legal research hard?

Each step — from defining research questions to synthesizing findings — demands critical thinking and rigorous analysis.

1. Identifying the legal issue is not so straightforward. Legal research involves interpreting many legal precedents and theories to justify your questions. Finding the right issue takes time and patience.

2. There's too much to research. Attorneys now face a great deal of case law and statutory material. The sheer volume forces the researcher to be efficient by following a methodology based on a solid foundation of legal knowledge and principles.

3. The law is a fluid doctrine. It changes with time, and staying updated with the latest legal codes, precedents, and statutes means the most resourceful lawyer needs to assess the relevance and importance of new decisions.

Legal research can pose quite a challenge, but professionals can improve it at every stage of the process . 

Step 1: Key questions to ask yourself when starting legal research

Before you begin looking for laws and court opinions, you first need to define the scope of your legal research project. There are several key questions you can use to help do this.

What are the facts?

Always gather the essential facts so you know the “who, what, why, when, where, and how” of your case. Take the time to write everything down, especially since you will likely need to include a statement of facts in an eventual filing or brief anyway. Even if you don't think a fact may be relevant now, write it down because it may be relevant later. These facts will also be helpful when identifying your legal issue.

What is the actual legal issue?

You will never know what to research if you don't know what your legal issue is. Does your client need help collecting money from an insurance company following a car accident involving a negligent driver? How about a criminal case involving excluding evidence found during an alleged illegal stop?

No matter the legal research project, you must identify the relevant legal problem and the outcome or relief sought. This information will guide your research so you can stay focused and on topic.

What is the relevant jurisdiction?

Don't cast your net too wide regarding legal research; you should focus on the relevant jurisdiction. For example, does your case deal with federal or state law? If it is state law, which state? You may find a case in California state court that is precisely on point, but it won't be beneficial if your legal project involves New York law.

Where to start legal research: The library, online, or even AI?

In years past, future attorneys were trained in law school to perform research in the library. But now, you can find almost everything from the library — and more — online. While you can certainly still use the library if you want, you will probably be costing yourself valuable time if you do.

When it comes to online research, some people start with free legal research options , including search engines like Google or Bing. But to ensure your legal research is comprehensive, you will want to use an online research service designed specifically for the law, such as Westlaw . Not only do online solutions like Westlaw have all the legal sources you need, but they also include artificial intelligence research features that help make quick work of your research

Step 2: How to find relevant case law and other primary sources of law

Now that you have gathered the facts and know your legal issue, the next step is knowing what to look for. After all, you will need the law to support your legal argument, whether providing guidance to a client or writing an internal memo, brief, or some other legal document.

But what type of law do you need? The answer: primary sources of law. Some of the more important types of primary law include:

• Case law, which are court opinions or decisions issued by federal or state courts
• Statutes, including legislation passed by both the U.S. Congress and state lawmakers
• Regulations, including those issued by either federal or state agencies
• Constitutions, both federal and state

Searching for primary sources of law

So, if it's primary law you want, it makes sense to begin searching there first, right? Not so fast. While you will need primary sources of law to support your case, in many instances, it is much easier — and a more efficient use of your time — to begin your search with secondary sources such as practice guides, treatises, and legal articles.

Why? Because secondary sources provide a thorough overview of legal topics, meaning you don't have to start your research from scratch. After secondary sources, you can move on to primary sources of law.

For example, while no two legal research projects are the same, the order in which you will want to search different types of sources may look something like this:

• Secondary sources . If you are researching a new legal principle or an unfamiliar area of the law, the best place to start is secondary sources, including law journals, practice guides , legal encyclopedias, and treatises. They are a good jumping-off point for legal research since they've already done the work for you. As an added bonus, they can save you additional time since they often identify and cite important statutes and seminal cases.
• Case law . If you have already found some case law in secondary sources, great, you have something to work with. But if not, don't fret. You can still search for relevant case law in a variety of ways, including running a search in a case law research tool.

Once you find a helpful case, you can use it to find others. For example, in Westlaw, most cases contain headnotes that summarize each of the case's important legal issues. These headnotes are also assigned a Key Number based on the topic associated with that legal issue. So, once you find a good case, you can use the headnotes and Key Numbers within it to quickly find more relevant case law.

• Statutes and regulations . In many instances, secondary sources and case law list the statutes and regulations relevant to your legal issue. But if you haven't found anything yet, you can still search for statutes and regs online like you do with cases.

Once you know which statute or reg is pertinent to your case, pull up the annotated version on Westlaw. Why the annotated version? Because the annotations will include vital information, such as a list of important cases that cite your statute or reg. Sometimes, these cases are even organized by topic — just one more way to find the case law you need to support your legal argument.

Keep in mind, though, that legal research isn't always a linear process. You may start out going from source to source as outlined above and then find yourself needing to go back to secondary sources once you have a better grasp of the legal issue. In other instances, you may even find the answer you are looking for in a source not listed above, like a sample brief filed with the court by another attorney. Ultimately, you need to go where the information takes you.

Step 3: Make sure you are using ‘good’ law

One of the most important steps with every legal research project is to verify that you are using “good" law — meaning a court hasn't invalidated it or struck it down in some way. After all, it probably won't look good to a judge if you cite a case that has been overruled or use a statute deemed unconstitutional. It doesn't necessarily mean you can never cite these sources; you just need to take a closer look before you do.

The simplest way to find out if something is still good law is to use a legal tool known as a citator, which will show you subsequent cases that have cited your source as well as any negative history, including if it has been overruled, reversed, questioned, or merely differentiated.

For instance, if a case, statute, or regulation has any negative history — and therefore may no longer be good law — KeyCite, the citator on Westlaw, will warn you. Specifically, KeyCite will show a flag or icon at the top of the document, along with a little blurb about the negative history. This alert system allows you to quickly know if there may be anything you need to worry about.

Some examples of these flags and icons include:

• A red flag on a case warns you it is no longer good for at least one point of law, meaning it may have been overruled or reversed on appeal.
• A yellow flag on a case warns that it has some negative history but is not expressly overruled or reversed, meaning another court may have criticized it or pointed out the holding was limited to a specific fact pattern.
• A blue-striped flag on a case warns you that it has been appealed to the U.S. Supreme Court or the U.S. Court of Appeals.
• The KeyCite Overruling Risk icon on a case warns you that the case may be implicitly undermined because it relies on another case that has been overruled.

Another bonus of using a citator like KeyCite is that it also provides a list of other cases that merely cite your source — it can lead to additional sources you previously didn't know about.

Perseverance is vital when it comes to legal research

Given that legal research is a complex process, it will likely come as no surprise that this guide cannot provide everything you need to know.

There is a reason why there are entire law school courses and countless books focused solely on legal research methodology. In fact, many attorneys will spend their entire careers honing their research skills — and even then, they may not have perfected the process.

So, if you are just beginning, don't get discouraged if you find legal research difficult — almost everyone does at first. With enough time, patience, and dedication, you can master the art of legal research.

Thomson Reuters originally published this article on November 10, 2020.

Related insights

Westlaw tip of the week: Checking cases with KeyCite

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Request a trial and experience the fastest way to find what you need

Clinical Trials Information System: training and support

For information on CTIS, the Clinical Trials Regulation, and EMA's online training modules for CTIS users, see: 

• Clinical Trials Regulation
• Clinical Trials Information System (CTIS): online training modules

Also on this topic

Handbook for clinical trial sponsors.

The CTIS sponsor handbook covers priority topics identified with the help of clinical trial sponsors, with references and links to further supporting materials.

It is aimed at pharmaceutical companies, contract research organisations (CROs), small and medium-sized enterprises (SMEs), academic sponsors and other organisations working on clinical trials.

EMA regularly updates the handbook. 

Clinical Trial Information System (CTIS) - Sponsor handbook

Evaluation timelines

This document is for CTIS sponsor and authority users and includes:

• an overview of timelines and deadlines for tasks and actions across the Clinical Trial Application process
• an explanation of the dynamic character of the workflow - earlier completion of a task (before its deadline) might cause recalculation of the deadline of subsequent or relevant tasks, changing effectively their initially projected deadlines

Clinical Trial Information System (CTIS) evaluation timelines

Additional reference materials for CTIS users

Reference materials are available below to help users work with CTIS. 

European Union Member State Public Holidays Recorded in CTIS (year: 2024)

European Union Member State Public Holidays Recorded in CTIS (year: 2023)

Getting started with CTIS: Sponsor quick guide

Principles for Sponsor organisation modelling for CTIS

Clinical Trial Information System (CTIS) - Sponsor user personas

Clinical Trial Information System (CTIS) structured data form - Initial application, additional Member State Concerned, substantial modification, non-substantial modification

Clinical Trial Information System (CTIS) structured data form - Multi trial substantial modification

Clinical Trial Information System (CTIS) structured data form - Notifications

Clinical Trial Information System (CTIS) structured data form - Request for information (RFI)

Clinical Trial Information System (CTIS) structured data form - Annual Safety Report (ASR)

Clinical Trial Information System (CTIS) list values

Clinical Trials Information System (CTIS) - Technical requirements for optimal use

Training and information events

EMA offers  live   training sessions  to provide additional learning opportunities, including bitesize talks, walk-in clinics and webinars.  

Recordings and supporting materials become available after each event. 

You can look up both past and upcoming events below: 

Walk-in clinics

• Clinical Trials Information System (CTIS): Walk-in clinic - March 2024 (12/03/2024)
• Clinical Trials Information System (CTIS): Walk-in clinic - January 2024 (24/01/2024)
• Clinical Trials Information System (CTIS): Walk-in clinic - December 2023  (13/12/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - November 2023  (15/11/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - October 2023 (10/10/2023) - Cancelled
• Clinical Trials Information System (CTIS): Walk-in clinic - September 2023  (20/09/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - August 2023 (23/08/2023) - Cancelled
• Clinical Trials Information System (CTIS): Walk-in clinic - July 2023  (19/07/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - June 2023  (14/06/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - May 2023  (17/05/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - April 2023  (19/04/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - March 2023  (16/03/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - January 2023  (18/01/2023)
• Clinical Trials Information System (CTIS): Walk-in clinic - November 2022  (15/11/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic - October 2022  (05/10/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic - September 2022  (20/09/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic - August 2022  (31/08/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic - June 2022  (15/06/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic  (02/06/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic - May 2022  (19/05/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic - 5 May 2022  (05/05/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic - April 2022  (22/04/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic  (04/04/2022)
• Clinical Trials Information System (CTIS): Walk-in clinic - March 2022  (28/03/2022)

Bitesize talks

• CTIS Bitesize Talk: Alternate IMPD-Q and New guidance AxMP (24/04/2024)
• Clinical Trials Information System (CTIS) bitesize talk: How to submit a transitional trial in CTIS (29/02/2024)
• Clinical Trials Information System (CTIS) bitesize talk: Training materials, CTIS pre-requisites, and updates on transparency rules  (29/11/2023)
• Clinical Trials Information System (CTIS) bitesize talk: Part I-only applications and Part II requirements in CTIS  (30/08/2023)
• Clinical Trials Information System (CTIS) bitesize talk: How to submit a transitional trial in CTIS  (21/06/2023)
• Clinical Trials Information System (CTIS) bitesize talk: IMPD-Q only submission  (10/05/2023)
• Clinical Trials Information System (CTIS) bitesize talk: Document and personal data in CTIS  (23/02/2023)
• Clinical Trials Information System (CTIS) bitesize talk: Annual safety report (ASR)  (15/12/2022)
• Clinical Trials Information System (CTIS) bitesize talk: Notifications - Part 2  (23/11/2022)
• Clinical Trials Information System (CTIS) bitesize talk: Notifications - Part 1  (28/09/2022)
• Clinical Trials Information System (CTIS) bitesize talk: Deferral rules and Public website  (20/07/2022)
• Clinical Trials Information System (CTIS) bitesize talk: Transitional trials and additional Member State concerned (MSC) application  (23/06/2022)
• Clinical Trials Information System (CTIS) bitesize talk: Modifications  (31/05/2022)
• Clinical Trials Information System (CTIS) bitesize talk: Requests for information  (28/04/2022)
• Clinical Trials Information System (CTIS) bitesize talk: Initial clinical trial application  (23/03/2022)
• Clinical Trials Information System (CTIS) bitesize talk: User access and role management  (24/02/2022)

Sponsor end user training

• Clinical Trials Information System (CTIS) sponsor end user training programme - June 2024 (10-13/06/2024)
• Clinical Trials Information System (CTIS) sponsor end user training programme - April 2024 (8-11/04/2024)
• Clinical Trials Information System (CTIS) sponsor end user training programme - February 2024 (12-15/02/2024)
• Clinical Trials Information System (CTIS) sponsor end user training programme - December 2023  (11-14/12/2023)
• Clinical Trials Information System (CTIS) sponsor end user training programme - November 2023  (10-13/10/2023)
• Clinical Trials Information System (CTIS) sponsor end user training programme - September 2023  (19-22/09/2023)
• Clinical Trials Information System (CTIS) sponsor end user training programme - June 2023  (27-30/06/2023)
• Clinical Trials Information System (CTIS) sponsor end user training programme - May 2023  (02-05/05/2023)
• Clinical Trials Information System (CTIS) sponsor end user training programme - February 2023  (07-10/02/2023)
• Clinical Trials Information System (CTIS) sponsor end user training programme - November 2022  (07-10/11/2022)
• Clinical Trials Information System (CTIS) sponsor end user training programme - September 2022  (20-23/09/2022)
• Clinical Trials Information System (CTIS) sponsor end user training programme - June 2022  (20-23/06/2022)
• Clinical Trials Information System (CTIS) sponsor end user training programme - May 2022  (10-13/05/2022)
• Clinical Trials Information System (CTIS) sponsor end user training programme - April 2022  (05-08/04/2022)
• Clinical Trials Information System (CTIS) sponsor end user training programme - March 2022  (01-04/03/2022)
• Clinical Trials Information System (CTIS) sponsor end user training programme - February 2022  (15-18/02/2022)
• Clinical Trials Information System (CTIS) sponsor end user training programme - January 2022  (24-27/01/2022)

Troubleshooting series

• Organisation Management System (OMS) Trouble Shooting Session for CTIS users - November 2022  (24/11/2022)
• Organisation Management System (OMS) Trouble Shooting Session for CTIS users - October 2022  (19/10/2022)
• Organisation Management System (OMS) Trouble Shooting Session for CTIS users - September 2022  (22/09/2022)
• Organisation Management System (OMS) Trouble Shooting Session for CTIS users - July 2022  (21/07/2022)
• Organisation Management System (OMS) Trouble Shooting Session for CTIS users - June 2022  (30/06/2022)

Events for academia and small and medium-sized enterprises (SMEs)

• SME and academia Clinical Trials Information System (CTIS) two-part training webinar - Day 2  (04/03/2021)
• SME and academia Clinical Trials Information System (CTIS) two-part training webinar - Day 1  (22/02/2021)
• Webinar for small and medium-sized enterprises (SMEs) and academia on the Clinical Trials Regulation and the Clinical Trials Information System (CTIS)  (29/11/2021)

Webinars, information days, demonstrations and other events

• Clinical Trials Information System Webinar: Last Year of Transition (25/03/2024)
• Clinical Trials Information System (CTIS): Information day  (17/10/2023)
• Clinical Trials Information System Webinar: Second Year of Transition  (04/07/2023)
• Clinical Trials Information System (CTIS): Readiness for mandatory use of the Clinical Trials Regulation from 31 January 2023  (20/01/2023)
• Clinical Trials Information System (CTIS) Webinar - 9 months on and going forward - November 2022  (16/11/2022)
• Clinical Trials Information System (CTIS) webinar: How sponsor organisations can prepare for CTIS  (29/07/2021)
• Clinical Trials Information System (CTIS) webinar: Six months of CTIS and looking forward  (01/07/2021)
• Clinical Trials Information System (CTIS): Virtual information day  (26/01/2021)
• Clinical Trials Information System (CTIS) demonstration for stakeholders  (20/01/2022)
• EMA Clinical Trial Information System (CTIS) webinar: dynamic demo of sponsor workspace  (21/09/2020)

Master trainers

EMA is working closely with master trainers , a core group of users who will train and support other users in their organisations in preparing to work with CTIS.

Master trainers from the national competent authorities and ethics committees of each EU Member State have been working with EMA since October 2020.

A programme for Master trainers for sponsors in pharmaceutical companies , including contract research organisations (CROs) took place in 2021. 

Guidance is available on training techniques and materials to support master trainers, or anyone responsible for rolling out the CTIS training programme.

Dissemination guidelines for training materials: CTIS training programme

This guide is intended to support instructors in disseminating the training materials prepared for the CTIS training programme. We suggest the trainers to follow a blended learning approach combining asynchronous with synchronous activities for an optimal learning experience of end-users while making efficient use of their time.

Protection of personal data and commercially confidential information

Guidance is available for CTIS users on the protection of personal data and commercially confidential information while using CTIS.   

This aims to assist sponsors and authorities in fulfilling the transparency obligations set out in the Clinical Trials Regulation.

The guidance is based on the outcome of a public consultation concluded in 2022. It will apply until the revised CTIS transparency rules are implemented, which is expected in the second quarter of 2024.

The European Commission, EMA and the Heads of Medicines Agency (HMA) have also prepared a questions and answers document on data protection.

Both documents can be found on the Accelerating Clinical Trials in the EU website, at the link listed below.

For more information, see:

• Clinical Trials Information System: Processing of personal data
• Development of the Clinical Trials Information System: Transparency requirements
• Accelerating Clinical Trials in the EU (ACT EU): Implementation of the Clinical Trials Regulation

Documents on ACT EU website:

• Guidance on transparency rules in CTIS
• Annex I - Guidance document on how to approach the protection of personal data and commercially confidential information while using the Clinical Trials Information System (CTIS)
• Annex II   Annex II to the guidance document of protection of personal data and commercially confidential information while using CTIS
• Q&A on the protection of commercially confidential information and personal data while using CTIS
• User guide: Revised CTIS transparency rules, Interim period & Historical trials

Related EU legislation

• Clinical Trials Regulation EU No. 536/2014
• Regulation (EU) 2016/679 (GDPR)
• Regulation (EU) 2018/1725 (EUDPR)

Related content

• Clinical trials in human medicines
• Accelerating Clinical Trials in the EU (ACT EU)
• Supporting SMEs

Contact point

• Send a question to the European Medicines Agency

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• Open access
• Published: 10 April 2024

“So at least now I know how to deal with things myself, what I can do if it gets really bad again”—experiences with a long-term cross-sectoral advocacy care and case management for severe multiple sclerosis: a qualitative study

• Anne Müller   ORCID: orcid.org/0000-0002-2456-2492 1 ,
• Fabian Hebben   ORCID: orcid.org/0009-0003-6401-3433 1 ,
• Kim Dillen 1 ,
• Veronika Dunkl 1 ,
• Yasemin Goereci 2 ,
• Raymond Voltz 1 , 3 , 4 ,
• Peter Löcherbach 5 ,
• Clemens Warnke   ORCID: orcid.org/0000-0002-3510-9255 2 &
• Heidrun Golla   ORCID: orcid.org/0000-0002-4403-630X 1

on behalf of the COCOS-MS trial group represented by Martin Hellmich

BMC Health Services Research volume  24 , Article number:  453 ( 2024 ) Cite this article

Metrics details

Persons with severe Multiple Sclerosis (PwsMS) face complex needs and daily limitations that make it challenging to receive optimal care. The implementation and coordination of health care, social services, and support in financial affairs can be particularly time consuming and burdensome for both PwsMS and caregivers. Care and case management (CCM) helps ensure optimal individual care as well as care at a higher-level. The goal of the current qualitative study was to determine the experiences of PwsMS, caregivers and health care specialists (HCSs) with the CCM.

In the current qualitative sub study, as part of a larger trial, in-depth semi-structured interviews with PwsMS, caregivers and HCSs who had been in contact with the CCM were conducted between 02/2022 and 01/2023. Data was transcribed, pseudonymized, tested for saturation and analyzed using structuring content analysis according to Kuckartz. Sociodemographic and interview characteristics were analyzed descriptively.

Thirteen PwsMS, 12 caregivers and 10 HCSs completed interviews. Main categories of CCM functions were derived deductively: (1) gatekeeper function, (2) broker function, (3) advocacy function, (4) outlook on CCM in standard care. Subcategories were then derived inductively from the interview material. 852 segments were coded. Participants appreciated the CCM as a continuous and objective contact person, a person of trust (92 codes), a competent source of information and advice (on MS) (68 codes) and comprehensive cross-insurance support (128 codes), relieving and supporting PwsMS, their caregivers and HCSs (67 codes).

Conclusions

Through the cross-sectoral continuous support in health-related, social, financial and everyday bureaucratic matters, the CCM provides comprehensive and overriding support and relief for PwsMS, caregivers and HCSs. This intervention bears the potential to be fine-tuned and applied to similar complex patient groups.

Trial registration

The study was approved by the Ethics Committee of the University of Cologne (#20–1436), registered at the German Register for Clinical Studies (DRKS00022771) and in accordance with the Declaration of Helsinki.

Peer Review reports

Introduction

Multiple sclerosis (MS) is the most frequent and incurable chronic inflammatory and degenerative disease of the central nervous system (CNS). Illness awareness and the number of specialized MS clinics have increased since the 1990s, paralleled by the increased availability of disease-modifying therapies [ 1 ]. There are attempts in the literature for the definition of severe MS [ 2 , 3 ]. These include a high EDSS (Expanded disability Status Scale [ 4 ]) of ≥ 6, which we took into account in our study. There are also other factors to consider, such as a highly active disease course with complex therapies that are associated with side effects. These persons are (still) less disabled, but may feel overwhelmed with regard to therapy, side effects and risk monitoring of therapies [ 5 , 6 ].

Persons with severe MS (PwsMS) develop individual disease trajectories marked by a spectrum of heterogeneous symptoms, functional limitations, and uncertainties [ 7 , 8 ] manifesting individually and unpredictably [ 9 ]. This variability can lead to irreversible physical and mental impairment culminating in complex needs and daily challenges, particularly for those with progressive and severe MS [ 5 , 10 , 11 ]. Such challenges span the spectrum from reorganizing biographical continuity and organizing care and everyday live, to monitoring disease-specific therapies and integrating palliative and hospice care [ 5 , 10 ]. Moreover, severe MS exerts a profound of social and economic impact [ 9 , 12 , 13 , 14 ]. PwsMS and their caregivers (defined in this manuscript as relatives or closely related individuals directly involved in patients’ care) often find themselves grappling with overwhelming challenges. The process of organizing and coordinating optimal care becomes demanding, as they contend with the perceived unmanageability of searching for, implementing and coordinating health care and social services [ 5 , 15 , 16 , 17 ].

Case management (CM) proved to have a positive effect on patients with neurological disorders and/or patients with palliative care needs [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. However, a focus on severe MS has been missed so far Case managers primarily function as: (1) gatekeeper involving the allocation of necessary and available resources to a case, ensuring the equitable distribution of resources; as (2) broker assisting clients in pursuing their interests, requiring negotiation to provide individualized assistance that aligns as closely as possible with individual needs and (3) advocate working to enhance clients’ individual autonomy, to advocate for essential care offers, and to identify gaps in care [ 25 , 26 , 27 , 28 , 29 ].

Difficulties in understanding, acting, and making decisions regarding health care-related aspects (health literacy) poses a significant challenge for 54% of the German population [ 30 ]. Additionally acting on a superordinate level as an overarching link, a care and case management (CCM) tries to reduce disintegration in the social and health care system [ 31 , 32 ]. Our hypothesis is that a CCM allows PwsMS and their caregivers to regain time and resources outside of disease management and to facilitate the recovery and establishment of biographical continuity that might be disrupted due to severe MS [ 33 , 34 ].

Health care specialists (HCSs) often perceive their work with numerous time and economic constraints, especially when treating complex and severely ill individuals like PwsMS and often have concerns about being blamed by patients when expectations could not be met [ 35 , 36 ]. Our hypothesis is that the CCM will help to reduce time constraints and free up resources for specialized tasks.

To the best of our knowledge there is no long-term cross-sectoral and outreaching authority or service dedicated to assisting in the organization and coordination of the complex care concerns of PwsMS within the framework of standard care addressing needs in health, social, financial, every day and bureaucratic aspects. While some studies have attempted to design and test care programs for persons with MS (PwMS), severely affected individuals were often not included [ 37 , 38 , 39 ]. They often remain overlooked by existing health and social care structures [ 5 , 9 , 15 ].

The COCOS-MS trial developed and applied a long-term cross-sectoral CCM intervention consisting of weekly telephone contacts and monthly re-assessments with PwsMS and caregivers, aiming to provide optimal care. Their problems, resources and (unmet) needs were assessed holistically including physical health, mental health, self-sufficiency and social situation and participation. Based on assessed (unmet) needs, individual care plans with individual actions and goals were developed and constantly adapted during the CCM intervention. Contacts with HCSs were established to ensure optimal care. The CCM intervention was structured through and documented in a CCM manual designed for the trial [ 40 , 41 ].

Our aim was to find out how PwsMS, caregivers and HCSs experienced the cross-sectoral long-term, outreaching patient advocacy CCM.

This study is part of a larger phase II, randomized, controlled clinical trial “Communication, Coordination and Security for people with severe Multiple Sclerosis (COCOS-MS)” [ 41 ]. This explorative clinical trial, employing a mixed-method design, incorporates a qualitative study component with PwsMS, caregivers and HCSs to enrich the findings of the quantitative data. This manuscript focuses on the qualitative data collected between February 2022 and January 2023, following the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines [ 42 ].

Research team

Three trained authors AM, KD and FH (AM, female, research associate, M.A. degree in Rehabilitation Sciences; KD, female, researcher, Dr. rer. medic.; FH, male, research assistant, B.Sc. degree in Health Care Management), who had no prior relationship with patients, caregivers or HCSs conducted qualitative interviews. A research team, consisting of clinical experts and health services researchers, discussed the development of the interview guides and the finalized category system.

Theoretical framework

Interview data was analyzed with the structuring content analysis according to Kuckartz. This method enables a deductive structuring of interview material, as well as the integration of new aspects found in the interview material through the inductive addition of categories in an iterative analysis process [ 43 ].

Sociodemographic and interview characteristics were analyzed descriptively (mean, median, range, SD). PwsMS, caregivers and HCSs were contacted by the authors AM, KD or FH via telephone or e-mail after providing full written informed consent. Participants had the option to choose between online interviews conducted via the GoToMeeting 10.19.0® Software or face-to-face. Peasgood et al. (2023) found no significant differences in understanding questions, engagement or concentration between face-to-face and online interviews [ 44 , 45 ]. Digital assessments were familiar to participants due to pandemic-related adjustments within the trial.

Out of 14 PwsMS and 14 caregivers who were approached to participate in interviews, three declined to complete interviews, resulting in 13 PwsMS (5 male, 8 female) and 12 caregiver (7 male, 5 female) interviews, respectively (see Fig.  1 ). Thirty-one HCSs were contacted of whom ten (2 male, 8 female) agreed to be interviewed (see Fig.  2 ).

Flowchart of PwsMS and caregiver participation in the intervention group of the COCOS-MS trial. Patients could participate with and without a respective caregiver taking part in the trial. Therefore, number of caregivers does not correspond to patients. For detailed inclusion criteria see also Table  1 in Golla et al. [ 41 ]

Flowchart of HCSs interview participation

Setting and data collection

Interviews were carried out where participants preferred, e.g. at home, workplace, online, and no third person being present. In total, we conducted 35 interviews whereof 7 interviews face-to-face (3 PwsMS, 3 caregivers, 1 HCS).

The research team developed a topic guide which was meticulously discussed with research and clinical staff to enhance credibility. It included relevant aspects for the evaluation of the CCM (see Tables  1 and 2 , for detailed topic guides see Supplementary Material ). Patient and caregiver characteristics (covering age, sex, marital status, living situation, EDSS (patients only), subgroup) were collected during the first assessment of the COCOS-MS trial and HCSs characteristics (age, sex, profession) as well as interview information (length and setting) were collected during the interviews. The interview guides developed for this study addressed consistent aspects both for PwsMS and caregivers (see Supplementary Material ):

For HCSs it contained the following guides:

Probing questions were asked to get more specific and in-depth information. Interviews were carried out once and recorded using a recording device or the recording function of the GoToMeeting 10.19.0® Software. Data were pseudonymized (including sensitive information, such as personal names, dates of birth, or addresses), audio files were safely stored in a data protection folder. The interview duration ranged from 11 to 56 min (mean: 23.9 min, SD: 11.1 min). Interviews were continued until we found that data saturation was reached. Audio recordings were transcribed verbatim by an external source and not returned to participants.

Data analysis

Two coders (AM, FH) coded the interviews. Initially, the first author (AM) thoroughly reviewed the transcripts to gain a sense of the interview material. Using the topic guide and literature, she deductively developed a category system based on the primary functions of CM [ 25 , 26 , 27 , 28 , 29 ]. Three interviews were coded repeatedly for piloting, and inductive subcategories were added when new themes emerged in the interview material. This category system proved suitable for the interview material. The second coder (FH) familiarized himself with the interview material and category system. Both coders (AM, FH) independently coded all interviews, engaging in discussions and adjusting codes iteratively. The finalized category system was discussed and consolidated in a research workshop and within the COCOS-MS trial group and finally we reached an intercoder agreement of 90% between the two coders AM and FH, computed by the MAXQDA Standard 2022® software.

We analyzed sociodemographic and interview characteristics using IBM SPSS Statistics 27® and Excel 2016®. Transcripts were managed and analyzed using MAXQDA Standard 2022®.

Participants were provided with oral and written information about the trial and gave written informed consent. Ethical approvals were obtained from the Ethics Committee of the University of Cologne (#20–1436). The trial is registered in the German Register for Clinical Studies (DRKS) (DRKS00022771) and is conducted under the Declaration of Helsinki.

Characteristics of participants and interviews

PwsMS participating in an interview were mainly German (84.6%), had a mean EDSS of 6.8 (range: 6–8) and MS for 13.5 years (median: 14; SD: 8.1). For detailed characteristics see Table  3 .

Most of the interviewed caregivers (9 caregivers) were the partners of the PwsMS with whom they lived in the same household. For further details see Table  3 .

HCSs involved in the study comprised various professions, including MS-nurse (3), neurologist (2), general physician with further training in palliative care (1), physician with further training in palliative care and pain therapist (1), housing counselling service (1), outpatient nursing service manager (1), participation counselling service (1).

Structuring qualitative content analysis

The experiences of PwsMS, caregivers and HCSs were a priori deductively assigned to four main categories: (1) gatekeeper function, (2) broker function, (3) advocacy function [ 25 , 26 , 27 , 28 , 29 ] and (4) Outlook on CCM in standard care, whereas the subcategories were developed inductively (see Fig.  3 ).

Category system including main and subcategories of the qualitative thematic content analysis

The most extensive category, housing the highest number of codes and subcodes, was the “ Outlook on CCM in standard care ” (281 codes). Following this, the category “ Advocacy Function ” contained 261 codes. The “ Broker Function ” (150 codes) and the “ Gatekeeper Function ” (160 codes) constituted two smaller categories. The majority of codes was identified in the caregivers’ interviews, followed by those of PwsMS (see Table  4 ). Illustrative quotes for each category and subcategory can be found in Table  5 .

Persons with severe multiple sclerosis

In the gatekeeper function (59 codes), PwsMS particularly valued the CCM as a continuous contact person . They appreciated the CCM as a person of trust who was reliably accessible throughout the intervention period. This aspect, with 41 codes, held significant importance for PwsMS.

Within the broker function (44 codes), establishing contact was most important for PwsMS (22 codes). This involved the CCM as successfully connecting PwsMS and caregivers with physicians and therapists, as well as coordinating and arranging medical appointments, which were highly valued. Assistance in authority and health and social insurance matters (10 codes) was another subcategory, where the CCM encompassed support in communication with health insurance companies, such as improving the level of care, assisting with retirement pension applications, and facilitating rehabilitation program applications. Optimized care (12 codes) resulted in improved living conditions and the provision of assistive devices through the CCM intervention.

The advocacy function (103 codes) emerged as the most critical aspect for PwsMS, representing the core of the category system. PwsMS experienced multidimensional, comprehensive, cross-insurance system support from the CCM. This category, with 43 statements, was the largest within all subcategories. PwsMS described the CCM as addressing their concerns, providing help, and assisting with the challenges posed by the illness in everyday life. The second-largest subcategory, regaining, maintaining and supporting autonomy (25 codes), highlighted the CCM’s role in supporting self-sufficiency and independence. Reviving personal wellbeing (17 codes) involved PwsMSs’ needs of regaining positive feelings, improved quality of life, and a sense of support and acceptance, which could be improved by the CCM. Temporal relief (18 codes) was reported, with the CCM intervention taking over or reducing tasks.

Within the outlook on CCM in standard care (84 codes), eight subcategories were identified. Communications was described as friendly and open (9 codes), with the setting of communication (29 codes) including the frequency of contacts deemed appropriate by the interviewed PwsMS, who preferred face-to-face contact over virtual or telephone interactions. Improvement suggestions for CCM (10 codes) predominantly revolved around the desire for the continuation of the CCM beyond the trial, expressing intense satisfaction with the CCM contact person and program. PwsMS rarely wished for better cooperation with the CCM. With respect to limitations (7 codes), PwsMS distinguished between individual limitations (e.g. when not feeling ready for using a wheelchair) and overriding structural limitations (e.g. unsuccessful search for an accessible apartment despite CCM support). Some PwsMS mentioned needing the CCM earlier in the course of the disease and believed it would beneficial for anyone with a chronic illness (6 codes).

In the gatekeeper function (75 codes), caregivers highly valued the CCM as a continuous contact partner (33 codes). More frequently than among the PwsMS interviewed, caregivers valued the CCM as a source of consultation/ information on essential individual subjects (42 codes). The need for basic information about the illness, its potential course, treatment and therapy options, possible supportive equipment, and basic medical advice/ information could be met by the CCM.

Within the broker function (63 codes), caregivers primarily experienced the subcategory establish contacts (24 codes). They found the CCM as helpful in establishing and managing contact with physicians, therapists and especially with health insurance companies. In the subcategory assistance in authority and health and social insurance matters (22 codes), caregivers highlighted similar aspects as the PwsMS interviewed. However, there was a particular emphasis on assistance with patients' retirement matters. Caregivers also valued the optimization of patients’ care and living environment (17 codes) in various life areas during the CCM intervention, including improved access to assistive devices, home modification, and involvement of a household support and/ or nursing services.

The advocacy function, with 115 codes, was by far the broadest category . The subcategory multidimensional, comprehensive, cross-insurance system support represented the largest subcategory of caregivers, with 70 statements. In summary, caregivers felt supported by the CCM in all domains of life. Regaining, maintaining and supporting autonomy (11 codes) and reviving personal wellbeing (8 codes) in the form of an improved quality of life played a role not only for patients but also for caregivers, albeit to a lower extend. Caregivers experienced temporal relief (26 codes) as the CCM undertook a wide range of organizational tasks, freeing up more needed resources for their own interests.

For the Outlook on CCM in standard care , caregivers provided various suggestions (81 codes). Similar to PwsMS, caregivers felt that setting (home based face-to-face, telephone, virtual) and frequency of contact were appropriate (10 codes, communication setting ) and communications (7 codes) were recognized as open and friendly. However, to avoid conflicts between caregiver and PwsMS, caregivers preferred meeting the CCM separately from the PwsMS in the future. Some caregivers wished the CCM to specify all services it might offer at the beginning, while others emphasized not wanting this. Like PwsMS, caregivers criticized the CCM intervention being (trial-related) limited to one year, regardless of whether further support was needed or processes being incomplete (13 codes, improvement suggestions ). After the CCM intervention time had expired, the continuous contact person and assistance were missed and new problems had arisen and had to be managed with their own resources again (9 codes, effects of CCM discontinuation ), which was perceived as an exhausting or unsolvable endeavor. Caregivers identified analogous limitations (8 codes), both individual and structural. However, the largest subcategory, was the experienced potential of CCM (27 codes), reflected in extremely high satisfaction with the CCM intervention. Like PwsMS, caregivers regarded severe chronically ill persons in general as target groups for a CCM (7 codes) and would implement it even earlier, starting from the time of diagnosis. They considered a CCM to be particularly helpful for patients without caregivers or for caregivers with limited (time) resources, as it was true for most caregivers.

Health care specialists

In the gatekeeper function (26 codes) HCSs particularly valued the CCM as a continuous contact partner (18 codes). They primarily described their valuable collaboration with the CCM, emphasizing professional exchange between the CCM and HCSs.

Within the broker function (43 codes), the CCM was seen as a connecting link between patients and HCSs, frequently establishing contacts (18 codes). This not only improved optimal care on an individual patient level (case management) but also at a higher, superordinate care level (care management). HCSs appreciated the optimized care and living environment (18 codes) for PwsMS, including improved medical and therapeutic access and the introduction of new assistive devices. The CCM was also recognized as providing assistance in authority and health and social matters (7 codes) for PwsMS and their caregivers.

In the advocacy function (43 codes), HCSs primarily reported temporal relief through CCM intervention (23 codes). They experienced this relief, especially as the CCM provided multidimensional, comprehensive, and cross-insurance system support (15 codes) for PwsMS and their caregivers. Through this support, HCSs felt relieved from time intensive responsibilities that may not fall within their area of expertise, freeing up more time resources for their actual professional tasks.

The largest category within the HCSs interviews was the outlook on CCM in standard care (116 codes). In the largest subcategory, HCSs made suggestions for further patient groups who could benefit (38 codes) from a CCM. Chronic neurological diseases like neurodegenerative diseases (e.g. amyotrophic lateral sclerosis), typical and atypical Parkinson syndromes were mentioned. HCSs considered the enrollment of the CCM directly after the diagnosis of these complex chronic diseases. Additionally, chronic progressive diseases in general or oncological diseases, which may also run chronically, were regarded worthwhile for this approach. HCSs also provided suggestions regarding improvement (21 codes). They wished e.g. for information or contact when patients were enrolled to the CCM, regular updates, exchange and collaborative effort. On the other hand, HCSs reported, that their suggestions for improvement would hardly be feasible due to their limited time resources. Similar to patients and caregivers, HCSs experienced structural limits (13 codes), which a CCM could not exceed due to overriding structural limitations (e.g. insufficient supply of (household) aids, lack of outreach services like psychotherapists, and long processing times on health and pension insurers' side). HCSs were also asked about their opinions on financial resources (14 codes) of a CCM in standard care. All interviewed HCSs agreed that CCM would initially cause more costs for health and social insurers, but they were convinced of cost savings in the long run. HCSs particularly perceived the potential of the CCM (20 codes) through the feedback of PwsMS, highlighting the trustful relationship enabling individualized help for PwsMS and their caregivers.

Persons with severe multiple sclerosis and their caregivers

The long-term cross-sectoral CCM intervention implemented in the COCOS-MS trial addressed significant unmet needs of PwsMS and their caregivers which previous research revealed as burdensome and hardly or even not possible to improve without assistance [ 5 , 6 , 9 , 10 , 33 , 35 , 46 ]. Notably, the CCM service met the need for a reliable, continuous contact partner, guiding patients through the complexities of regulations, authorities and the insurance system. Both, PwsMS and their caregivers highly valued the professional, objective perspective provided by the CCM, recognizing it as a source of relief, support and improved care in line with previous studies [ 37 , 47 ]. Caregivers emphasized the CCM’s competence in offering concrete assistance and information on caregiving and the fundamentals of MS, including bureaucratic, authority and insurances matters. On the other hand, PwsMS particularly appreciated the CCMs external reflective and advisory function, along with empathic social support tailored to their individual concerns. Above all, the continuous partnership of trust, available irrespective of the care sector, was a key aspect that both PwsMS and their caregivers highlighted. This consistent support was identified as one of the main components in the care of PwsMS in previous studies [ 5 , 33 , 35 ].

As the health literacy is inadequate or problematic for 54% of the German population and disintegration in the health and social care system is high [ 30 , 31 , 32 ], the CCM approach serves to enhance health literacy and reduce disintegration of PwsMS and their caregivers by providing cross-insurance navigational guidance in the German health and social insurance sector on a superordinate level. Simultaneously PwsMS and caregivers experienced relief and gained more (time) resources for all areas of life outside of the disease and its management, including own interests and establishing biographical continuity. This empowerment enables patients to find a sense of purpose beyond their illness, regain autonomy, and enhance social participation, reducing the feeling of being a burden to those closest to them. Such feelings are often experienced as burdensome and shameful by PwsMS [ 6 , 48 , 49 , 50 ]. Finding a sense of purpose beyond the illness also contributes to caregivers perceiving their loved ones not primarily as patient but as individuals outside of the disease, reinforcing valuable relationships such as partners, siblings, or children, strengthening emotional bonds. These factors are also highly relevant and well-documented in a suicide-preventive context, as the suicide rate is higher in persons diagnosed with neurological disorders [ 19 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ] and the feeling of being a burden to others, loss of autonomy, and perceived loss of dignity are significant factors in patients with severe chronic neurological diseases for suicide [ 50 , 57 ].

The temporal relief experienced by the CCM was particularly significant for HCSs and did not only improve the satisfaction of HCSs but also removed unfulfilled expectations and concerns about being blamed by patients when expectations could not be met, which previous studied elaborated [ 35 , 36 ]. Moreover, the CCM alleviated the burden on HCSs by addressing patients’ concerns, allowing them to focus on their own medical responsibilities. This aspect probably reduced the dissatisfaction that arises when HCSs are expected to address issues beyond their medical expertise, such as assistive devices, health and social insurance, and the organization and coordination of supplementary therapies, appointments, and contacts [ 35 , 36 , 61 ]. Consequently, the CCM reduced difficulties of HCSs treating persons with neurological or chronical illnesses, which previous research identified as problematic.

HCSs perceive their work as increasingly condensed with numerous time and economic constraints, especially when treating complex and severely ill individuals like PwsMS [ 36 ]. This constraint was mentioned by HCSs in the interviews and was one of the main reasons why they were hesitant to participate in interviews and may also be an explanation for a shorter interview duration than initially planned in the interview guides. The CCM’s overarching navigational competence in the health and social insurance system was particularly valued by HCSs. The complex and often small-scale specialties in the health and social care system are not easily manageable or well-known even for HCSs, and dealing with them can exceed their skills and time capacities [ 61 ]. The CCM played a crucial role in keeping (temporal) resources available for what HCSs are professionally trained and qualified to work on. However, there remains a challenge in finding solutions to the dilemma faced by HCSs regarding their wish to be informed about CCM procedures and linked with each other, while also managing the strain of additional requests and contact with the CCM due to limited (time) resources [ 62 ]. Hudon et al. (2023) suggest that optimizing time resources and improving exchange could involve meetings, information sharing via fax, e-mail, secure online platforms, or, prospectively, within the electronic patient record (EPR). The implementation of an EPR has shown promise in improving the quality of health care and time resources, when properly implemented [ 63 , 64 ]. The challenge lies ineffective information exchange between HCSs and CCM for optimal patient care. The prospect of time saving in the long run and at best for a financial incentive, e.g., when anchoring in the Social Security Code, will help best to win over the HCSs.If this crucial factor can be resolved, there is a chance that HCSs will thoroughly accept the CCM as an important pillar, benefiting not only PwsMS but also other complex patient groups, especially those with long-term neurological or complex oncological conditions that might run chronically.

Care and case management and implications for the health care system

The results of our study suggest that the cross-sectoral long-term advocacy CCM in the COCOS-MS trial, with continuous personal contacts at short intervals and constant reevaluation of needs, problems, resources and goals, is highly valued by PwsMS, caregivers, and HCSs. The trial addresses several key aspects that may have been overlooked in previous studies which have shown great potential for the integration of case management [ 17 , 47 , 62 , 65 , 66 ]. However, they often excluded the overriding care management, missed those patient groups with special severity and complexity who might struggle to reach social and health care structures independently or the interventions were not intended for long-term [ 22 , 37 ]. Our results indicate that the CCM intervention had a positive impact on PwsMS and caregivers as HCSs experienced them with benefits such as increased invigoration, reduced demands, and enhanced self-confidence. However, there was a notable loss experienced by PwsMS and caregivers after the completion of the CCM intervention, even if they had stabilized during the intervention period. The experiences of optimized social and health care for the addressed population, both at an individual and superordinate care level, support the integration of this service into standard care. Beyond the quantitatively measurable outcomes and economic considerations reported elsewhere [ 16 , 20 , 21 ], our results emphasize the importance of regaining control, self-efficacy, self-worth, dignity, autonomy, and social participation. These aspects are highlighted as preventive measures in suicidal contexts, which is particularly relevant for individuals with severe and complex illnesses [ 19 , 50 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. Our findings further emphasize the societal responsibilities to offer individuals with severe and complex illnesses the opportunity to regain control and meaningful aspects of life, irrespective of purely economic considerations. This underscores the need for a comprehensive evaluation that not only takes into account quantitative measures but also the qualitative aspects of well-being and quality of life when making recommendations of a CCM in standard care.

The study by J. Y. Joo and Huber (2019) highlighted that CM interventions aligned with the standards of the Case Management Society of America varied in duration, ranging from 1 month to 15.9 years, and implemented in community- or hospital-based settings. However, they noted a limitation in understanding how CM processes unfold [ 67 ]. In contrast, our trial addressed this criticism by providing transparent explanations of the CCM process, which also extends to a superordinate care management [ 40 , 41 ]. Our CCM manual [ 40 ] outlines a standardized and structured procedure for measuring and reevaluating individual resources, problems, and unmet needs on predefined dimensions. It also identifies goals and actions at reducing unmet needs and improving the individual resources of PwsMS and caregivers. Importantly, the CCM manual demonstrates that the CCM process can be structured and standardized, while accounting for the unique aspects of each individual’s serious illness, disease courses, complex needs, available resources, and environmental conditions. Furthermore, the adaptability of the CCM manual to other complex chronically ill patient groups suggests the potential for a standardized approach in various health care settings. This standardized procedure allows for consistency in assessing and addressing the individual needs of patients, ensuring that the CCM process remains flexible while maintaining a structured and goal-oriented framework.

The discussion about the disintegration in the social and health care system and the increasing specialization dates back to 2009 [ 31 , 32 ]. Three strategies were identified to address this issue: (a) “driver-minimizing” [Treiberminimierende], (b) “effect-modifying” [Effektmodifizierende] and (c) “disintegration-impact-minimizing” [Desintegrationsfolgenminimierende] strategies. “Driver-minimizing strategies” involve comprehensive and radical changes within the existing health and social care system, requiring political and social pursuit. “Disintegration-impact-minimizing strategies” are strategies like quality management or tele-monitoring, which are limited in scope and effectiveness. “Effect-modifying strategies”, to which CCM belongs, acknowledges the segmentation within the system but aims to overcome it through cooperative, communicative, and integrative measures. CCM, being an “effect-modifying strategy”, operates the “integrated segmentation model” [Integrierte Segmentierung] rather than the “general contractor model” [Generalunternehmer-Modell] or “total service provider model” [Gesamtdienstleister-Modell] [ 31 , 32 ]. In this model, the advantage lies in providing an overarching and coordinating service to link different HCSs and services cross-sectorally. The superordinate care management aspect of the CCM plays a crucial role in identifying gaps in care, which is essential for future development strategies within the health and social care system. It aims to find or develop (regional) alternatives to ensure optimal care [ 17 , 23 , 24 , 68 , 69 ], using regional services of existing health and social care structures. Therefore, superordinate care management within the CCM process is decisive for reducing disintegration in the system.

Strengths and limitations

The qualitative study results of the explorative COCOS-MS clinical trial, which employed an integrated mixed-method design, provide valuable insights into the individual experiences of three leading stakeholders: PwsMS, caregivers and HCSs with a long-term cross-sectoral CCM. In addition to in-depth interviews, patient and caregiver reported outcome measurements were utilized and will be reported elsewhere. The qualitative study’s strengths include the inclusion of patients who, due to the severity of their condition (e.g. EDSS mean: 6.8, range: 6–8, highly active MS), age (mean: 53.9 years, range: 36–73 years) family constellations, are often underrepresented in research studies and often get lost in existing social and health care structures. The study population is specific to the wider district region of Cologne, but the broad inclusion criteria make it representative of severe MS in Germany. The methodological approach of a deductive and inductive structuring content analysis made it possible to include new findings into an existing theoretical framework.

However, the study acknowledges some limitations. While efforts were made to include more HCSs, time constraints on their side limited the number of interviews conducted and might have biased the results. Some professions are underrepresented in the interviews. Complex symptoms (e.g. fatigue, ability to concentrate), medical or therapeutic appointments and organization of the everyday live may have been reasons for the patients’ and caregivers’ interviews lasting shorter than initially planned.

The provision of functions of a CCM, might have pre-structured the answers of the participants.

At current, there is no support system for PwsMS, their caregivers and HCSs that addresses their complex and unmet needs comprehensively and continuously. There are rare qualitative insights of the three important stakeholders: PwsMS, caregivers and HCSs in one analysis about a supporting service like a CCM. In response to this gap, we developed and implemented a long-term cross-sectoral advocacy CCM and analyzed it qualitatively. PwsMS, their caregivers and HCSs expressed positive experiences, perceiving the CCM as a source of relief and support that improved care across various aspects of life. For patients, the CCM intervention resulted in enhanced autonomy, reviving of personal wellbeing and new established contacts with HCSs. Caregivers reported a reduced organizational burden and felt better informed, and HCSs experienced primarily temporal relief, allowing them to concentrate on their core professional responsibilities. At a higher level of care, the study suggests that the CCM contributed to a reduction in disintegration within the social and health care system.

The feedback from participants is seen as valuable for adapting the CCM intervention and the CCM manual for follow-up studies, involving further complex patient groups such as neurological long-term diseases apart from MS and tailoring the duration of the intervention depending on the complexity of evolving demands.

Availability of data and materials

Generated and/or analyzed datasets of participants are available from the corresponding author on reasonable request to protect participants. Preliminary partial results have been presented as a poster during the EAPC World Congress in June 2023 and the abstract has been published in the corresponding abstract booklet [ 70 ].

Abbreviations

Amyotrophic lateral sclerosis

• Care and case management

Case management

Central nervous system

Communication, Coordination and security for people with multiple sclerosis

Consolidated criteria for reporting qualitative research

German register for clinical studies

Extended disability status scale

Electronic patient record

Quality of life

Multiple sclerosis

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Acknowledgements

We would like to thank all the patients, caregivers and health care specialists who volunteered their time to participate in an interview and the trial, Carola Janßen for transcribing the interviews, Fiona Brown for translating the illustrative quotes and Beatrix Münzberg, Kerstin Weiß and Monika Höveler for data collection in the quantitative study part.

COCOS-MS Trial Group

Anne Müller 1 , Fabian Hebben 1 , Kim Dillen 1 , Veronika Dunkl 1 , Yasemin Goereci 2 , Raymond Voltz 1,3,4 , Peter Löcherbach 5 , Clemens Warnke 2 , Heidrun Golla 1 , Dirk Müller 6 , Dorthe Hobus 1 , Eckhard Bonmann 7 , Franziska Schwartzkopff 8 , Gereon Nelles 9 , Gundula Palmbach 8 , Herbert Temmes 10 , Isabel Franke 1 , Judith Haas 10 , Julia Strupp 1 , Kathrin Gerbershagen 7 , Laura Becker-Peters 8 , Lothar Burghaus 11 , Martin Hellmich 12 , Martin Paus 8 , Solveig Ungeheuer 1 , Sophia Kochs 1 , Stephanie Stock 6 , Thomas Joist 13 , Volker Limmroth 14

1 Department of Palliative Medicine, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

2 Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

3 Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), University of Cologne, Cologne, Germany

4 Center for Health Services Research (ZVFK), University of Cologne, Cologne, Germany

5 German Society of Care and Case Management e.V. (DGCC), Münster, Germany

6 Institute for Health Economics and Clinical Epidemiology (IGKE), Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

7 Department of Neurology, Klinikum Köln, Cologne, Germany

8 Clinical Trials Centre Cologne (CTCC), Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

9 NeuroMed Campus, MedCampus Hohenlind, Cologne, Germany

10 German Multiple Sclerosis Society Federal Association (DMSG), Hannover, Germany

11 Department of Neurology, Heilig Geist-Krankenhaus Köln, Cologne, Germany

12 Institute of Medical Statistics and Computational Biology (IMSB), Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

13 Academic Teaching Practice, University of Cologne, Cologne, Germany

14 Department of Neurology, Klinikum Köln-Merheim, Cologne, Germany

Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Innovation Funds of the Federal Joint Committee (G-BA), grant number: 01VSF19029.

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Anne Müller, Fabian Hebben, Kim Dillen, Veronika Dunkl, Raymond Voltz & Heidrun Golla

Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany

Yasemin Goereci & Clemens Warnke

Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), University of Cologne, Cologne, Germany

Raymond Voltz

Center for Health Services Research, University of Cologne, Cologne, Germany

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• Anne Müller
• , Fabian Hebben
• , Kim Dillen
• , Veronika Dunkl
• , Yasemin Goereci
• , Raymond Voltz
• , Peter Löcherbach
• , Clemens Warnke
• , Heidrun Golla
• , Dirk Müller
• , Dorthe Hobus
• , Eckhard Bonmann
• , Franziska Schwartzkopff
• , Gereon Nelles
• , Gundula Palmbach
• , Herbert Temmes
• , Isabel Franke
• , Judith Haas
• , Julia Strupp
• , Kathrin Gerbershagen
• , Laura Becker-Peters
• , Lothar Burghaus
• , Martin Hellmich
• , Martin Paus
• , Solveig Ungeheuer
• , Sophia Kochs
• , Stephanie Stock
• , Thomas Joist
•  & Volker Limmroth

Contributions

HG, KD, CW designed the trial. HG, KD obtained ethical approvals. HG, KD developed the interview guidelines with help of the CCM (SU). AM was responsible for collecting qualitative data, developing the code system, coding, analysis of the data and writing the first draft of the manuscript, thoroughly revised and partly rewritten by HG. FH supported in collecting qualitative data, coding and analysis of the interviews. KD supported in collecting qualitative data. AM, FH, KD, VD, YG, RV, PL, CW, HG discussed and con-solidated the finalized category system. AM, FH, KD, VD, YG, RV, PL, CW, HG read and commented on the manuscript and agreed to the final version.

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Ethics approval and consent to participate.

Participants were provided with oral and written information about the trial and provided written informed consent. Ethical approval was obtained from the Ethics Committee of the University of Cologne (#20–1436). The trial is registered in the German Register for Clinical Studies (DRKS) (DRKS00022771) and is conducted under the Declaration of Helsinki.

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Competing interests.

Clemens Warnke has received institutional support from Novartis, Alexion, Sanofi Genzyme, Janssen, Biogen, Merck and Roche. The other authors declare that they have no competing interests.

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Müller, A., Hebben, F., Dillen, K. et al. “So at least now I know how to deal with things myself, what I can do if it gets really bad again”—experiences with a long-term cross-sectoral advocacy care and case management for severe multiple sclerosis: a qualitative study. BMC Health Serv Res 24 , 453 (2024). https://doi.org/10.1186/s12913-024-10851-1

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DOI : https://doi.org/10.1186/s12913-024-10851-1

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A Randomized, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of VIR-2482 in Healthy Adults for Prevention of Influenza A Illness (PENINSULA)

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Background Influenza A results in significant morbidity and mortality. VIR-2482, an engineered human monoclonal antibody with extended half-life, targets a highly conserved epitope on the stem region of influenza A hemagglutinin, and may protect against seasonal and pandemic influenza.

Methods This double-blind, randomized, placebo-controlled, phase 2 study examined the safety and efficacy of VIR-2482 for seasonal influenza A illness prevention in unvaccinated healthy adults. Participants (N = 2977) were randomized 1:1:1 to receive VIR-2482 450 mg, VIR-2482 1200 mg, or placebo via intramuscular (IM) injection. Primary and secondary efficacy endpoints were the proportions of participants with reverse transcriptase-polymerase chain reaction (RT-PCR)–confirmed influenza A infection and either protocol-defined influenza-like illness (ILI) and Centers for Disease Control and Prevention (CDC)–defined ILI or World Health Organization (WHO)–defined ILI, respectively.

Results VIR-2482 450 mg and 1200 mg prophylaxis did not reduce the risk of protocol-defined ILI with RT-PCR–confirmed influenza A versus placebo (relative risk reduction [RRR], 3.8% [95% CI: −67.3, 44.6] and 15.9% [95% CI: −49.3, 52.3], respectively). At the 1200 mg dose, the RRRs in influenza A illness were 57.2% [95% CI: −2.5, 82.2] using CDC-ILI and 44.1% [95% CI: −50.5, 79.3] using WHO-ILI definitions, respectively. Serum VIR-2482 levels were similar regardless of influenza status; variants with reduced VIR-2482 susceptibility were not detected. Local injection-site reactions were mild and similar across groups.

Conclusion VIR-2482 1200 mg IM was well tolerated but did not significantly prevent protocol-defined ILI. Secondary endpoint analyses suggest this dose may have reduced influenza A illness.

Trial registration ClinicalTrials.gov identifier, NCT05567783

Key points Prophylactic administration of 1200 mg of VIR-2482, an engineered human monoclonal antibody targeting a highly conserved epitope on the stem region of influenza A hemagglutinin, did not significantly reduce risk of influenza-like illness from influenza A virus in healthy adults.

Competing Interest Statement

Susanna K. Tan, Deborah Cebrik, David Plotnik, Maria L. Agostini, Keith Boundy, Wendy W. Yeh, and Philip S. Pang are employees of Vir Biotechnology, Inc and report stock ownership in Vir Biotechnology, Inc. Christy M. Hebner is a former employee and shareholder of Vir Biotechnology, Inc. and is a co-author on select Vir Biotechnology, Inc. patents. Jaynier Moya and Manuchehr Darani have nothing to disclose. Charles Fogarty reports receiving grant support from Vir Biotechnology, Inc. for conduct of the clinical trial. Frederick G. Hayden has served as a nonpaid consultant to Vir Biotechnology, Inc. and other companies involved in developing influenza therapeutics or vaccines, including Appili, Arcturus, Gilead, GSK, Janssen/JNJ, MedImmune, Medivector/Fujifilm, Merck, Ridgeback, Roche/Genentech, and Visterra. Cidara, Enanta, Shionogi, and Versatope have made charitable donations for Dr. Hayden's consulting time, and both Shionogi and Roche have provided meeting travel support.

Clinical Trial

ClinicalTrials.gov identifier, NCT05567783

Funding Statement

This study was supported by Vir Biotechnology, Inc. and with federal funds from the Department of Health and Human Services (HHS); Administration for Strategic Preparedness and Response (ASPR); and Biomedical Advanced Research and Development Authority (BARDA) under contract number 75A50122C00081. The findings and conclusions herein are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of WCG Institutional Review Board, Puyallup, Washington, USA gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Relevant data can be found within the manuscript and supplemental data.

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Published on 12.4.2024 in Vol 26 (2024)

The Effectiveness of a Digital App for Reduction of Clinical Symptoms in Individuals With Panic Disorder: Randomized Controlled Trial

Authors of this article:

Original Paper

• KunJung Kim, MD   ; 
• Hyunchan Hwang, MD, PhD   ; 
• Sujin Bae, PhD   ; 
• Sun Mi Kim, MD, PhD   ; 
• Doug Hyun Han, MD, PhD  

Chung Ang University Hospital, Seoul, Republic of Korea

Corresponding Author:

Doug Hyun Han, MD, PhD

Chung Ang University Hospital

102 Heucsock ro

Seoul, 06973

Republic of Korea

Phone: 82 2 6299 3132

Fax:82 2 6299 3100

Email: [email protected]

Background: Panic disorder is a common and important disease in clinical practice that decreases individual productivity and increases health care use. Treatments comprise medication and cognitive behavioral therapy. However, adverse medication effects and poor treatment compliance mean new therapeutic models are needed.

Objective: We hypothesized that digital therapy for panic disorder may improve panic disorder symptoms and that treatment response would be associated with brain activity changes assessed with functional near-infrared spectroscopy (fNIRS).

Methods: Individuals (n=50) with a history of panic attacks were recruited. Symptoms were assessed before and after the use of an app for panic disorder, which in this study was a smartphone-based app for treating the clinical symptoms of panic disorder, panic symptoms, depressive symptoms, and anxiety. The hemodynamics in the frontal cortex during the resting state were measured via fNIRS. The app had 4 parts: diary, education, quest, and serious games. The study trial was approved by the institutional review board of Chung-Ang University Hospital (1041078-202112-HR-349-01) and written informed consent was obtained from all participants.

Results: The number of participants with improved panic symptoms in the app use group (20/25, 80%) was greater than that in the control group (6/21, 29%; χ 2 1 =12.3; P =.005). During treatment, the improvement in the Panic Disorder Severity Scale (PDSS) score in the app use group was greater than that in the control group ( F 1,44 =7.03; P =.01). In the app use group, the total PDSS score declined by 42.5% (mean score 14.3, SD 6.5 at baseline and mean score 7.2, SD 3.6 after the intervention), whereas the PDSS score declined by 14.6% in the control group (mean score 12.4, SD 5.2 at baseline and mean score 9.8, SD 7.9 after the intervention). There were no significant differences in accumulated oxygenated hemoglobin (accHbO 2 ) at baseline between the app use and control groups. During treatment, the reduction in accHbO 2 in the right ventrolateral prefrontal cortex (VLPFC; F 1,44 =8.22; P =.006) and the right orbitofrontal cortex (OFC; F 1,44 =8.88; P =.005) was greater in the app use than the control group.

Conclusions: Apps for panic disorder should effectively reduce symptoms and VLPFC and OFC brain activity in patients with panic disorder. The improvement of panic disorder symptoms was positively correlated with decreased VLPFC and OFC brain activity in the resting state.

Trial Registration: Clinical Research Information Service KCT0007280; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=21448

Introduction

Panic disorder is a common and important disease in clinical practice that leads to a reduction of individual productivity and increased use of health care [ 1 ]. The lifetime prevalence of panic disorder in the general population is 4.8%, and 22.7% of people experience panic attacks [ 2 ]. The most common symptoms of panic disorder include palpitations, shortness of breath, chest pain, numbness of the hands and feet, and cardiorespiratory-type symptoms, in addition to fear of dying, sweating, tremors, dizziness, nausea, and chills [ 3 ]. The US Food and Drug Administration has currently only approved selective serotonin reuptake inhibitors (SSRIs) for the treatment of panic disorder [ 4 ]. However, it is clinically difficult to expect an improvement in symptoms using SSRIs alone in the acute phase; thus we treat patients with benzodiazepine, which can lead to dependence and withdrawal symptoms [ 5 , 6 ]. The most common side effects of SSRIs reported by patients are reduced sexual function, drowsiness, and weight gain [ 7 ], and clinicians may hesitate to use benzodiazepines due to dependence and withdrawal symptoms [ 8 ]. Cognitive behavioral therapy (CBT) is the most widely used nonpharmaceutical treatment for anxiety disorders [ 9 ]. Additional nonpharmaceutical treatments, such as group therapy and supportive psychotherapy, are also available for patients with panic disorder [ 10 , 11 ]. However, these treatments have the disadvantage of requiring face-to-face contact; therefore, other therapeutic alternatives should be offered to patients during pandemics such as COVID-19.

The definition of a digital therapeutic (DTx) is a therapeutic that delivers evidence-based interventions to prevent, manage, or treat a medical disorder or disease; DTxs are currently used in many areas [ 12 ]. This kind of medical and public health use of smartphones and digital technologies is also known as mobile health (mHealth). DTxs related to mental health medicine are actively used in various psychiatric disorders, such as insomnia, substance abuse, attention-deficit/hyperactivity disorder, and anxiety and depression, among others [ 13 ]. In particular, the use of Freespira, a panic disorder DTx, reduced panic symptoms, avoidance behaviors, and treatment costs in patients with panic disorder [ 14 ].

As brain imaging technology advances, a great deal of functional mapping information on the human brain has been accumulated from positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and functional near-infrared spectroscopy (fNIRS). Among these technologies, fNIRS can measure brain activity in a noninvasive and safe manner through measuring changes in the hemoglobin oxygenation state of the human brain [ 15 ]. Various studies have been conducted using fNIRS and fMRI to reveal correlations between panic disorder and brain regions. For example, patients with panic disorder show increased activity in the inferior frontal cortex, hippocampus, cingulate (both anterior and posterior), and orbitofrontal cortex (OFC) [ 16 ]. Previously, we confirmed that patients with panic disorder during rest periods showed increased activity in the OFC [ 17 ].

In this study, we determined whether an app for panic disorder would improve panic disorder symptoms. In addition, we used fNIRS to confirm the association between changes in panic disorder symptoms and changes in activity in specific brain regions.

Participants

Patients who had experiences of panic attacks were recruited between March 1 and July 30, 2022, through billboard advertisements at our hospital. The inclusion criteria for the study were as follows: (1) age between 20 and 65 years, (2) diagnosis of panic disorder based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and (3) ability to use apps without problems. The exclusion criteria were as follows: (1) a history of other psychiatric disorders, except for anxiety disorder, or substance dependence, except for habitual alcohol and tobacco use; and (2) a history of head trauma and chronic medical conditions. The research clinician assessed whether patients fulfilled the inclusion or exclusion criteria. Written informed consent was acquired from all participants at the first visit. This study has been registered with the Clinical Research Information Service (KCT0007280).

Assessment Scales for Anxiety Symptoms

The severity of panic symptoms was assessed using the Panic Disorder Severity Scale (PDSS). The PDSS was developed by Shear et al [ 18 ] in 1997. It is a 7-item instrument used to rate the overall severity of panic disorder and was validated in Korea by Lim et al [ 19 ] in 2001.

The anxiety symptoms of all participants were assessed using the clinician-based Hamilton Anxiety Scale (HAM-A) questionnaire and the participant-based Generalized Anxiety Disorder-7 (GAD-7) questionnaire. The HAM-A was developed by Hamilton in 1969 [ 20 ]. The 14-item version remains the most used outcome measure in clinical trials of treatments for anxiety disorders and was validated in Korea by Kim [ 21 ] in 2001.

The GAD-7 questionnaire, developed by Spitzer et al [ 22 ], is a 7-item self-report anxiety questionnaire designed to assess the patient’s health status during the previous 2 weeks. The GAD-7 was translated into the Korean language and is freely downloadable on the Patient Health Questionnaire website [ 23 ].

Hemodynamic Response of the Prefrontal Cortex

The hemodynamics in the frontal cortex during the resting state were measured using the fNIRS device (NIRSIT; OBELAB Inc). The NIRSIT has 24 laser diodes (sources) emitting light at 2 wavelengths (780 nm and 850 nm) and 32 photodetectors with a sampling rate of 8.138 Hz [ 24 ]. The distance between the source and photodetector is 15 mm. Based on the suggested suitable sensor-detector separation distance for measuring cortical hemodynamic changes, only 30-mm channels were analyzed in this study [ 25 ].

For our study, we used the 48-channel configuration ( Figure 1 ). The detected light signals in each wavelength were filtered with a band-pass filter (0.00 Hz-0.1 Hz) to reduce the effect of environmental noise–related light and body movements. In addition, channels with low-quality information (signal-to-noise ratio <30 dB) were removed from the hemodynamic analysis. The accumulated oxygenated hemoglobin (accHbO 2 ) values in the resting state represent the activation of the prefrontal cortex. In accordance with the theory that oxygenated hemoglobin has superior sensitivity and signal-to-noise ratio compared to deoxygenated hemoglobin data, only oxygenated hemoglobin were used for this analysis [ 26 - 28 ].

The means and SDs for accHbO 2 were calculated from regions of interest (ROIs) in the right and left dorsolateral prefrontal cortices (DLPFCs), right and left ventrolateral prefrontal cortices (VLPFCs), right and left frontopolar cortices (FPCs), and right and left orbitofrontal cortices (OFCs), based on Brodmann area 46. The right and left DLPFCs comprise channels 1, 2, 3, 5, 6, 11, 17, and 18 and channels 19, 20, 33, 34, 35, 38, 39, and 43, respectively. The right and left VLPFCs comprise channels 4, 9, and 10 and channels 40, 44, and 45, respectively. The right and left FPCs comprise channels 7, 8, 12, 13, 21, 22, 25, and 26 and channels 23, 24, 27, 28, 36, 37, 41, and 42, respectively. The right and left OFCs comprise channels 14, 15, 16, 29, and 30 and channels 31, 32, 46, 47, and 48, respectively ( Figure 1 ).

Digital App for Panic Disorder

The app for panic disorder is a smartphone-based app for treatment of clinical symptoms of panic disorder. The mobile app has 4 categories: diary, education, quest, and serious games. The diary category has three items: (1) assessment of daily psychological status, including mood and anxiety; (2) assessment of panic symptoms, including frequency and severity; and (3) consumption of medication, including regular medication and pro re nata medications. The education category has three items: (1) knowledge about panic disorders, (2) knowledge about medications for panic disorder, and (3) knowledge about panic disorder treatment, including CBT, breathing therapy, and positive thinking therapy. The quests include two treatments: (1) eye movement desensitization and reprocessing therapy and (2) positive thinking therapy. The serious games include two games: (1) a breathing game and (2) an exposure therapy game.

The diary, education, and serious games (ie, the breathing game and exposure therapy game) are important parts of CBT for panic disorder [ 29 - 32 ]. The efficacy of CBT for panic disorder has been examined in various randomized controlled trials [ 33 , 34 ]. Eye movement desensitization and reprocessing therapy are also known to help reduce panic symptoms [ 35 , 36 ]. We confirmed that the replacement of worry with different forms of positive ideation shows beneficial effects [ 37 ], so a similar type of positive thinking therapy can also be expected to show benefits. Multimedia Appendix 1 provides additional information on the app.

Ethical Considerations

The study trial was approved by the institutional review board of Chung-Ang University Hospital (1041078-202112-HR-349-01) and written informed consent was obtained from all participants. Participants received an explanation from the researchers that included an overview of the study and a description of the methodology and purpose before deciding to participate. Additionally, they were informed that participation was voluntary, informed about our confidentiality measures, given the option to withdraw, and informed about potential side effects and compensation. Participants in this study received ₩100,000 (US $75.50) as transportation reimbursement. Additionally, the various scales and fNIRS assessments were offered at no cost to the participants. The participants received the results of the tests in the form of a report via postal mail or email after the conclusion of the study. They also receive an explanatory document and consent form from the researchers that included contact information for any inquiries. If the participant agreed to take part in the study after understanding the consent form, the research proceeded. The participants’ personal information was not collected. Instead, a unique identifier was assigned to the collected data for the sole purpose of research management.

Study Procedure

A randomized and treatment-as-usual–controlled design was applied in this study. After screening, all participants with panic disorder were randomly assigned to the app use group or the control group. The randomization sequence in our design was generated using SPSS (version 24.0; IBM Corp), with a 1:1 allocation between groups. At baseline and after intervention, all patients with panic disorder were assessed with the PDSS for panic symptoms, the HAM-A for objective anxiety symptoms, and the GAD-7 for subjective anxiety symptoms. At baseline and after intervention, the hemodynamic response in all patients with panic disorder was assessed using NIRSIT. The app use group was asked to use the app for panic disorder 20 minutes per day, 5 times per week, for 4 weeks. The control group was asked to read short educational letters that were delivered via a social network service 5 times per week for 4 weeks. The short letters contained information about panic disorder and its treatment.

Demographic and Clinical Characteristics

After recruitment, 56 patients underwent eligibility assessments. A total of 6 individuals were excluded because they did not meet the inclusion criteria. The remaining patients were divided into 2 groups: 25 were assigned to the app use group and 21 to the control group, as 4 patients were excluded; contact was suddenly lost with 1 patient contact and 1 dropped out for personal reasons. In addition, 2 patients in the control group quit the study after reporting poor benefits from the short educational letters. Therefore, 25 people in the app use group and 21 people in the control group were analyzed. Figure 2 shows the Consolidated Standards of Reporting Trials (CONSORT) flowchart for participant flow through the trial.

There were no significant differences in age, sex ratio, years of education, marital status, employment status, or substance habits, including smoking and alcohol use, between the app use group and the control group ( Table 1 ).

b Chi-square.

There were no significant differences in HAM-A score, GAD-7 score, or PDSS score at baseline between the app use group and control group ( Table 1 ).

Comparison of Changes in Clinical Scales Between App Use Group and Control Group

The number of participants with improved panic symptoms in the app use group (20/25, 80%) was greater than in the control group (6/21, 29%; χ 2 1 =12.3; P =.005).

During the treatment period, the app use group showed greater improvement in PDSS score than the control group ( F 1,44 =7.03; P =.01). In the app use group, the PDSS score decreased by 42.5% (mean score 14.3, SD 6.5 at baseline and mean score 7.2, SD 3.6 after the intervention), while the score decreased by 14.6% in the control group (mean score 12.4, SD 5.2 at baseline and mean score 9.8, SD 7.9 after intervention) ( Figure 3 ).

During the treatment period, there were no significant differences in the change in HAM-A scores ( F 1,44 =2.83; P =.09) and GAD-7 scores ( F 1,44 =0.22; P =.64) between the app use group and control group ( Figure 3 ).

Comparison of Changes in accHbO 2 Values Between App Use Group and Control Group

There were no significant differences in accHbO 2 in the right (t 45 =0.84; P =.40) or left (t 45 =0.73; P =.46) DLPFCs, right (t 45 =1.04; P =.31) or left (t 45 =0.88; P =.39) VLPFCs, right (t 45 =-0.18; P =.86) or left (t 45 =1.85; P =.07) FPCs, or right (t 45 =0.33; P =.74) or left (t 45 =1.89; P =.07) OFCs in the app use and control groups at baseline.

During the treatment period, the app use group showed a greater reduction in accHbO 2 in the right VLPFC ( F 1,44 =8.22; P =.006) and right OFC ( F 1,44 =8.88; P =.005) compared to the control group ( Figure 1 ). During the treatment period, there were no significant differences in the change in accHbO 2 in the other ROIs between the app use and control groups.

Correlations Between the Changes in PDSS Scores and the Changes in accHbO 2

In all participants (ie, the app use group plus the control group), there was a positive correlation between the change in PDSS score and the change in accHbO 2 in the right VLPFC ( r =0.44; P =.002). In the app use group, there was a positive correlation between the change in PDSS score and the changes in accHbO 2 in the right VLPFC ( r =0.42; P =.04). However, in the control group, there was no significant correlation between the change in PDSS score and the change in accHbO 2 in the right VLPFC ( r =0.22; P =.16).

In all participants, there was a positive correlation between the change in PDSS score and the change in accHbO 2 in the right OFC ( r =0.44; P =.002). In both the app use group ( r =0.34; P =.09) and control group ( r =0.33; P =.13), there was no significant correlation between the change in PDSS score and the change in accHbO 2 in the right OFC ( Figure 4 ).

Principal Findings

This study showed that a digital app was effective for symptom reduction, as well as decreasing brain activity in the VLPFCs and OFCs, in patients with panic disorder. In addition, the panic disorder symptom improvement was positively correlated with decreased brain activity in the VLPFCs and OFCs in the resting state.

The digital app used in this trial proved to be effective in reducing panic symptoms when compared to the control group, as demonstrated by the reduction in the PDSS score. We believe that this is due to the combined effect of the 4 parts of the program, namely the diary, education, quest, and serious games. The diary component helps identify and correct faulty perceptions and enables cognitive reconstruction. The education component provides information about the nature and physiology of panic disorder. The breathing game helps the participant return to a relaxed condition, while the exposure therapy game allows the participant to experience agoraphobic situations in a safe environment, which helps cognitive restructuring. These are the important parts of CBT for panic disorder and have shown efficacy, as reported earlier [ 29 - 32 ]. The control group also received educational data, including the importance of keeping a diary of one’s panic symptoms and how to do it, as well as self-guided direction on breathing exercises, but failed to show a significant reduction of symptoms compared to the app use group. We think this is due to lack of proper feedback in the control group. The app shows real-time feedback on breathing exercises using breathing sounds, and a message was sent if the user of the program failed to use the program for more than 2 days. We know that the therapeutic effect is better when immediate feedback is provided to patients undergoing CBT treatment [ 38 ]. Therefore, we think that the decrease in PDSS score was smaller because the control group did not receive feedback from the app.

The control group also received educational data on diary recording, panic disorder information, and how to execute breathing therapy and exposure therapy. We measured their reduction in the PDSS score, but we found it was less than in the app use group due to a lack of proper daily management.

However, the app failed to lead to a difference in the reduction in anxiety, as defined by the HAM-A and GAD-7 scales, between the 2 groups. This is most likely due to a lack of power, as the trial was conducted as a pilot study. Other studies using CBT techniques or serious games have demonstrated reductions in anxiety symptoms in patients with panic disorder [ 14 ]. Likewise, this study showed a trend toward a reduction in anxiety symptoms, although this was not statistically significant, and future research with more participants may show that these kinds of programs are also effective in controlling anxiety.

Two major changes in brain activity were noted in the app use group, namely reductions in VLPFC and OFC activation. The functions of the OFC are varied and include control of inappropriate behavior and emotional responses, decision-making, and solving problems [ 39 , 40 ]. Abnormalities in the function of the OFC can cause problems in dealing with anxiety and show that it is deeply involved in the increasing the sense of fear in the fear response [ 17 ]. The results of this study confirm that OFC activity decreases as treatment progresses. This reinforces the results of a previous study, which showed that patients with panic disorder had increased OFC activity and that when the panic disorder was treated, the activity of the OFC was reduced, as indicated by decreased cerebral glucose metabolic rates [ 17 , 41 ].

The VLPFC is known to be associated with the amygdala and to maintain flexible attention and responses to environmental threats [ 42 , 43 ]. The amygdala is the backbone of the fear network, and the VLPFC is also known to be deeply involved in the processing of fear [ 43 - 45 ]. Several studies have shown increased activity in patients with panic disorder in the inferior frontal gyrus, which envelops the VLPFC, and other related regions, including the prefrontal cortex, hippocampus, and OFC [ 16 , 46 , 47 ]. After panic disorder treatment, such as with CBT, decreased amygdala and inferior frontal gyrus activation in fear situations was confirmed [ 48 , 49 ]. Through panic disorder treatment, inferior frontal gyrus activation decreased to a normal level; this happened because the treatment reduced fear cognition related to harm expectancy or attention to threats [ 49 - 51 ]. We consider that VLPFC activation increases to modulate the amygdala and decreases with treatment for panic disorder.

We believe that these reductions of brain activity in the VLPFC and OFC reflect how the app affected the patients. We know that overprediction of fear or panic is an important feature of anxiety disorders [ 52 ]. The app for panic disorder, including diary, education, quest, and serious game components, allowed users to correct their faulty perceptions about fear. As mentioned earlier, the VLPFC and OFC are related to fear management, so we can expect that activity of the VLPFC and OFC will be reduced through repeated app use as users learn how to deal with fear.

Limitations

This study has the following limitations: Most of the patients were effectively treated with alprazolam or other anxiolytics, such as SSRIs. Thus, treatment with antianxiety drugs may have influenced our results. Moreover, this study assessed changes immediately after app use. A long-term follow-up to evaluate the sustainability of the observed improvements would provide valuable insights into the effectiveness of the intervention over time. App use time could be easily tracked for the app use group; however, it was challenging to independently monitor the time the control group spent reading educational materials. Due to the limitations of available research tools, no investigation has been conducted on deep brain structures such as the amygdala, which is most closely related to panic disorders.

Conclusions

We believe that this app for panic disorder effectively reduces symptoms and noticeably impacts brain activity in specific areas. We observed a positive link between improvement in panic symptoms and decreased brain activity in the VLPFCs and OFCs in a resting state. These findings support the use of targeted interventions to determine the brain’s contribution to symptom relief. Further research should explore the duration of these positive effects and make digital therapy accessible to more individuals, thus unlocking its full potential in mental health care.

Data Availability

The data sets generated and analyzed during this study are not publicly available as they contain information that could compromise the privacy and consent of the research participants. However, the transformed data are available upon reasonable request from the authors.

Conflicts of Interest

None declared.

Digital app for panic disorder.

CONSORT-eHEALTH checklist (V 1.6.1).

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Abbreviations

Edited by A Mavragani; submitted 03.08.23; peer-reviewed by M Aksoy; comments to author 01.09.23; revised version received 11.09.23; accepted 08.03.24; published 12.04.24.

©KunJung Kim, Hyunchan Hwang, Sujin Bae, Sun Mi Kim, Doug Hyun Han. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 12.04.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.

• What's My Car Worth?
• Buyer's Guide

2025 Toyota 4Runner Is Finally Here and Appears Worth the Wait

The fifth-generation off-road SUV had a successful 15-year run, but the sixth-gen's new powertrains and upgraded frame make it easy to move on.

• Most models will be powered by an i-Force 2.4-liter turbo four that makes 278 horsepower, while others get an i-Force Max hybrid with an added electric motor that ups total output to 326 horses.
• Appearing more like a Tacoma SUV than it has in decades, the new 4Runner shares many exterior styling cues and interior features with the recently released pickup, while also nodding to its past.

After an impressive 15-year run, the fifth-generation Toyota 4Runner finally hands the baton to the 2025 Toyota 4Runner to kick off the model's sixth generation. The previous model's popularity hardly waned, but its time had finally come thanks to the arrival of the new crop of engines, eight-speed automatic transmission, and the TNGA-F frame and suspension architecture that recently came online with the newest Toyota Tacoma and the reintroduced Land Cruiser.

More Like a Tacoma SUV Than Ever Before

The 4Runner's new front-end styling is not a direct Tacoma carryover, but it does bear a striking resemblance. Its stance is similar too, with a wider track and three extra inches of overall body width. Like the Tacoma, much of the extra width comes from prominent fender flares that protrude farther to cover the suspension’s wider track. Many specific dimensions have not yet been released, but the Toyo Open Country AT III tires fitted to the TRD Pro and Trailhunter are sized at 265/70R-18, a sizing that translates to 33 inches tall.

Larger tires of this sort are now possible because, like the Tacoma, the 4Runner's wheelbase has been lengthened at the front to gain more body-mount clearance. Fitting larger tires to past versions of both trucks was problematic because of the relative lack of daylight in that area. For the 4Runner, this amounts to a 2.4-inch wheelbase increase (from 109.8 to 112.2 inches), which matches the new Land Cruiser , Lexus GX550 , and even the Lexus LX600 . Further back, the 4Runner's new styling jogs up past the rear doors in a way that makes its rear haunches appear even more muscular, while the rear side window's upper edge rolls into the roof in a way that pays homage to its first- and second-generation forebears.

Inside, the instrument cluster, center stack, and all the various buttons, switches and knobs look identical to those found in the new Tacoma, right down to the controls for the part-time four-wheel-drive transfer case (full-time on the Platinum and some versions of the Limited). The same 14.0-inch infotainment touchscreen is available on some trims, standard on others, and includes wireless Apple CarPlay and Android Auto. The overall interior styling is a dead ringer too, apart from different material and color choices for the TRD Pro and Trailhunter examples we sampled. This is outstanding news, because our recent test of the Tacoma TRD Off-Road proved that this interior is thoughtfully laid out, has handy storage features, and is easy to get familiar with.

Two Familiar New Engines

Under the hood, the 2025 4Runner's base engine is the 2.4-liter i-Force, a turbocharged inline-four that makes the same 278 horsepower and 317 pound-feet of torque it does in the Tacoma. Backed solely by an eight-speed automatic, this engine will be the lone offering in the SR5 and TRD Sport and will be the base fitment in the TRD Off-Road and Limited. We were highly impressed by this setup in a recent comparison between a Tacoma TRD Off-Road and a Chevy Colorado ZR2 , where the i-FORCE punched well above its weight by matching the significantly more powerful Chevy step for step and recording an identical 6.8-second 60-mph time. Meanwhile, the outgoing 4Runner's 4.0-liter V-6 produced just 270 hp and 278 pound-feet and feels lazier than that deficit suggests because of the dated five-speed automatic transmission it's hooked to. Fuel economy for the new model hasn't been revealed, but it's bound to be a leap forward from the thirsty V-6/five-speed combo.

Even more power is available with the 2.4-liter i-Force Max 4Runner Hybrid , which sandwiches an electric motor between the 278-hp engine and eight-speed transmission to up total output to 326 hp and 465 pound-feet of torque. It'll be optional in the TRD Off-Road and Limited; it will be the standard fitment in the TRD Pro, Trailhunter, and full-luxe Platinum. This engine has not yet surfaced in the Tacoma, so we have not tested it. But the extra power and torque are significant and can only make an already strong combination that much more compelling. Increasing fuel economy over the standard setup isn't necessarily the prime objective here, but fuel economy is bound to nudge up anyway because the system can recapture deceleration energy and redeploy it strategically later on.

An optional third-row seat returns to the 4Runner lineup. Toyota isn't saying, but based on what we've seen we think it'll be restricted to the standard i-Force engine. The hybrid's battery pack resides under the rear cargo floor, and its presence would seemingly make it impossible for that powertrain to coexist with the third-row seat. Expect the third row to be available on the SR5 and on Limiteds that lack the hybrid powertrain option. Access to that third row has been carved out by a change in the rear seat, which does away with the current two-step flip/fold design and switches to a one-step tumble that's faster and creates a third-row entry point.

New Suspension Thinking

Because the new 4Runner shares the TNGA-F architecture with the Tacoma and Land Cruiser, its suspension layout utilizes the same sort control-arm suspension up front and multilink live axle arrangement in the back. It's the same basic concept as before, but the geometry has been thoroughly rethought. Details about the full range of offerings across the entire model range are scarce, but we do know that the TRD Pro will be fitted with Fox QS3 dampers with manually adjustable compression “clicker” adjustments, while the Trailhunter will ride on ARB/Old Man Emu dampers. Both will have external reservoirs at the rear.

As with the Tacoma, the TRD Pro's suspension tuning will be geared more toward high-speed desert running, while the Trailhunter's is optimized for overland-style off-road exploration and rockier trail work. As such, the Trailhunter has additional skid plates and more robust rock sliders that are bolted directly to the frame. The one we saw had a built-in air compressor that looked stock, with a Trailhunter-branded roof basket and snorkel air intake that may or may not have been standard equipment. Time will tell.

Toyota has said that the electronic rear differential locker is standard fare for the TRD Off-Road, TRD Pro, and Trailhunter, which matches the Tacoma's strategy. We also spied a disconnecting front anti-roll bar on the TRD Pro and Trailhunter and were told this feature will be optional on the TRD Off-Road. Whether that'll be a stand-alone option as it is on the Tacoma or a part of some yet-to-be-announced option package remains to be seen. What all this means, though, is the current-generation 4Runner's optional KDSS system of hydraulically defeatable front and rear anti-roll bars is a goner.

Coming This Fall

We know enough about the new 2025 Toyota 4Runner to be excited about it, and the announced fall 2024 release means we won't have to wait long to drive one and learn how much the various trim levels will cost and what sort of fuel economy the two powertrains can deliver. It has clearly been a long time coming, but the new sixth-generation 2025 4Runner seems well worth the painfully long wait.

Dan Edmunds was born into the world of automobiles, but not how you might think. His father was a retired racing driver who opened Autoresearch, a race-car-building shop, where Dan cut his teeth as a metal fabricator. Engineering school followed, then SCCA Showroom Stock racing, and that combination landed him suspension development jobs at two different automakers. His writing career began when he was picked up by Edmunds.com (no relation) to build a testing department.

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