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Understanding Clinical Trials

Clinical research: what is it.

Your doctor may have said that you are eligible for a clinical trial, or you may have seen an ad for a clinical research study. What is clinical research, and is it right for you?

Clinical research is the comprehensive study of the safety and effectiveness of the most promising advances in patient care. Clinical research is different than laboratory research. It involves people who volunteer to help us better understand medicine and health. Lab research generally does not involve people — although it helps us learn which new ideas may help people.

Every drug, device, tool, diagnostic test, technique and technology used in medicine today was once tested in volunteers who took part in clinical research studies.

At Johns Hopkins Medicine, we believe that clinical research is key to improve care for people in our community and around the world. Once you understand more about clinical research, you may appreciate why it’s important to participate — for yourself and the community.

What Are the Types of Clinical Research?

There are two main kinds of clinical research:

Observational Studies

Observational studies are studies that aim to identify and analyze patterns in medical data or in biological samples, such as tissue or blood provided by study participants.

Clinical Trials

Clinical trials, which are also called interventional studies, test the safety and effectiveness of medical interventions — such as medications, procedures and tools — in living people.

Clinical research studies need people of every age, health status, race, gender, ethnicity and cultural background to participate. This will increase the chances that scientists and clinicians will develop treatments and procedures that are likely to be safe and work well in all people. Potential volunteers are carefully screened to ensure that they meet all of the requirements for any study before they begin. Most of the reasons people are not included in studies is because of concerns about safety.

Both healthy people and those with diagnosed medical conditions can take part in clinical research. Participation is always completely voluntary, and participants can leave a study at any time for any reason.

“The only way medical advancements can be made is if people volunteer to participate in clinical research. The research participant is just as necessary as the researcher in this partnership to advance health care.” Liz Martinez, Johns Hopkins Medicine Research Participant Advocate

Types of Research Studies

Within the two main kinds of clinical research, there are many types of studies. They vary based on the study goals, participants and other factors.

Biospecimen studies

Healthy volunteer studies.

 Goals of Clinical Trials

Because every clinical trial is designed to answer one or more medical questions, different trials have different goals. Those goals include:

Treatment trials

Prevention trials, screening trials, phases of a clinical trial.

In general, a new drug needs to go through a series of four types of clinical trials. This helps researchers show that the medication is safe and effective. As a study moves through each phase, researchers learn more about a medication, including its risks and benefits.

Is the medication safe and what is the right dose?   Phase one trials involve small numbers of participants, often normal volunteers.

Does the new medication work and what are the side effects?   Phase two trials test the treatment or procedure on a larger number of participants. These participants usually have the condition or disease that the treatment is intended to remedy.

Is the new medication more effective than existing treatments?  Phase three trials have even more people enrolled. Some may get a placebo (a substance that has no medical effect) or an already approved treatment, so that the new medication can be compared to that treatment.

Is the new medication effective and safe over the long term?   Phase four happens after the treatment or procedure has been approved. Information about patients who are receiving the treatment is gathered and studied to see if any new information is seen when given to a large number of patients.

“Johns Hopkins has a comprehensive system overseeing research that is audited by the FDA and the Association for Accreditation of Human Research Protection Programs to make certain all research participants voluntarily agreed to join a study and their safety was maximized.” Gail Daumit, M.D., M.H.S., Vice Dean for Clinical Investigation, Johns Hopkins University School of Medicine

Is It Safe to Participate in Clinical Research?

There are several steps in place to protect volunteers who take part in clinical research studies. Clinical Research is regulated by the federal government. In addition, the institutional review board (IRB) and Human Subjects Research Protection Program at each study location have many safeguards built in to each study to protect the safety and privacy of participants.

Clinical researchers are required by law to follow the safety rules outlined by each study's protocol. A protocol is a detailed plan of what researchers will do in during the study.

In the U.S., every study site's IRB — which is made up of both medical experts and members of the general public — must approve all clinical research. IRB members also review plans for all clinical studies. And, they make sure that research participants are protected from as much risk as possible.

Earning Your Trust

This was not always the case. Many people of color are wary of joining clinical research because of previous poor treatment of underrepresented minorities throughout the U.S. This includes medical research performed on enslaved people without their consent, or not giving treatment to Black men who participated in the Tuskegee Study of Untreated Syphilis in the Negro Male. Since the 1970s, numerous regulations have been in place to protect the rights of study participants.

Many clinical research studies are also supervised by a data and safety monitoring committee. This is a group made up of experts in the area being studied. These biomedical professionals regularly monitor clinical studies as they progress. If they discover or suspect any problems with a study, they immediately stop the trial. In addition, Johns Hopkins Medicine’s Research Participant Advocacy Group focuses on improving the experience of people who participate in clinical research.

Clinical research participants with concerns about anything related to the study they are taking part in should contact Johns Hopkins Medicine’s IRB or our Research Participant Advocacy Group .

Learn More About Clinical Research at Johns Hopkins Medicine

For information about clinical trial opportunities at Johns Hopkins Medicine, visit our trials site.

Video Clinical Research for a Healthier Tomorrow: A Family Shares Their Story

Clinical Research for a Healthier Tomorrow: A Family Shares Their Story

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About Clinical Research

Research participants are partners in discovery at the NIH Clinical Center, the largest research hospital in America. Clinical research is medical research involving people The Clinical Center provides hope through pioneering clinical research to improve human health. We rapidly translate scientific observations and laboratory discoveries into new ways to diagnose, treat and prevent disease. More than 500,000 people from around the world have participated in clinical research since the hospital opened in 1953. We do not charge patients for participation and treatment in clinical studies at NIH. In certain emergency circumstances, you may qualify for help with travel and other expenses Read more , to see if clinical studies are for you.

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Email sent to the National Institutes of Health Clinical Center may be forwarded to appropriate NIH or outside experts for response. We do not collect your name and e-mail address for any purpose other than to respond to your query. Nevertheless, email is not necessarily secure against interception. This statement applies to NIH Clinical Center Studies website. For additional inquiries regarding studies at the National Institutes of Health, please call the Office of Patient Recruitment at 1-800-411-1222

Find NIH Clinical Center Trials

The National Institutes of Health (NIH) Clinical Center Search the Studies site is a registry of publicly supported clinical studies conducted mostly in Bethesda, MD.

About Clinical Trials

What is a clinical trial.

Clinical trials look at new ways to prevent, detect, or treat disease. The goal of clinical trials is to determine if a new test or treatment works and is safe. 

The idea for a clinical trial —also known as a clinical research study —often originates in the laboratory. After researchers test new therapies or procedures in the laboratory and in animal studies, the most promising experimental treatments are moved into clinical trials, which are conducted in phases. During a trial, more information is gained about an experimental treatment, its risks, and its effectiveness.

Types of Clinical Trials

• Natural history studies provide valuable information about how disease and health progress.
• 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. Better approaches may include medicines, vaccines, or lifestyle changes, among other things.
• Screening trials test the best way to detect certain diseases or health conditions.
• Diagnostic trials determine better tests or procedures for diagnosing a particular disease or condition.
• Treatment trials test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
• Quality of life trials (or supportive care trials) explore and measure ways to improve the comfort and quality of life of people with a chronic illness.

Clinical Trial Phases

Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.

• Phase I trials: Researchers test an experimental drug or treatment in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
• Phase II trials: The experimental drug or treatment is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
• Phase III trials: The experimental drug or treatment is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the experimental drug or treatment to be used safely.
• Phase IV trials: After a drug is approved by the FDA and made available to the public, researchers track its safety, seeking more information about a drug or treatment’s risks, benefits, and optimal use.

For more information about clinical trials, see the webpage at National Institute of Health.

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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.

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Published Clinical Research Conducted at the Clinical Center

The NIH Clinical Center is the world's largest hospital entirely devoted to clinical research. It is a national resource that makes it possible to rapidly translate scientific observations and laboratory discoveries into new approaches for diagnosing, treating, and preventing disease.

Clinical research is at the heart of the Clinical Center's mission.

Over 1,600 clinical research studies are conducted at the NIH Clinical Center, including those focused on cancer, infectious diseases, blood disorders, heart disease, lung disease, alcoholism and drug abuse. Most of these studies are sponsored by the Institutes and Centers at NIH.

Here is a sample of abstracts from the clinical research conducted at the NIH Clinical Center and published in a peer-reviewed medical journal in 2018. Links to the full text and video formats are provided if available.

The National Institutes of Health Measure of Healing Experience of All Life Stressors (NIH-HEALS): Factor Analysis and Validation

Published in: PLOS ONE (December 2018)

The NIH-HEALS was developed and validated to better understand and measure psychosocial spiritual healing. Sometimes in the midst of significant life stressors including severe or life-threatening disease, psychosocial healing can be experienced.

Read the article .

MRI Robot for Prostate Focal Laser Ablation: An Ex Vito Study in Human Prostate

Published in: Journal of Imaging (November 2018)

Researchers have designed and integrated the hardware and software of a prototype robot that successfully demonstrated - in an ex vivo prostate tissue from a human cadaver - the potential to improve the clinical workflow, accuracy, and effectiveness of MRI-guided focal laser ablation of prostate cancer.

Performance of RGM Medium for the Isolation of Nontuberculous Mycobacteria from Respiratory Specimens from Non-Cystic Fibrosis Patients

Published in: Journal of Clinical Microbiology (November 2018)

RGM medium - an agar-based culture medium - provided a simple and rapid method to identify fast-growing nontuberculous mycobacteria in non-cystic fibrosis patients with chronic lung cancer.

On the Threshold of a New Analgesic: Shaping a Novel Treatment for Osteoarthritis Pain

Published in: ISAP Pain Research Forum (September 2018)

Alternatives to obtain a non-opioid analgesic for severe pain and chronic pain conditions are discussed. A promising development is resiniferatoxin, which can target peripheral nerve terminals through a local interventional approach versus systematic dosing to target the central nervous system.

Challenges in Pulmonary Hypertension: Controversies in Treating the Tip of the Iceberg. A Joint National Institutes of Health Clinical Center and Pulmonary Hypertension Association Symposium Report

Published in: American Journal of Respiratory and Critical Care Medicine (July 2018)

The unmet need for innovative therapeutic approaches to pulmonary hypertension is apparent across World Health Organization patient subtypes. Improvements in the clinical phenotyping of pulmonary hypertension are a necessary first step to better utilize existing therapies and develop new ones.

A Proposal for a Rational Transfusion Strategy in Patients of European and North African Descent with Weak D Type 4.0 and 4.1 Phenotype

Published in: Blood Transfusion (March 2018)

Patients with weak D blood types 4.0 and 4.1 are so rarely associated with alloanti-D production that treatment guidelines should be changed to recommend D positive blood transfusions and no anti-D immunoglobulin prophylaxis.

A Role for Hydrocortisone Therapy in Septic Shock?

Published in: The New England Journal of Medicine (March 2018)

Eagerly awaited to provide definitive guidelines for or against the use and effects of corticosteroids in treating septic shock were the results of two landmark studies: the Adjunctive Corticosteroid Treatment in Critical Ill Patients with Septic Shock trial and the Activated Protein C and Corticosteroid for Human Septic Shock trial.

Transcriptional Changes in Dorsal Spinal Cord Persist After Surgical Incision Despite Preemptive Analgesia with Peripheral Resiniferatoxin

Published in: Anesthesiology (March 2018)

A new approach is presented for post-operative pain control using a naturally occurring plant molecule called resiniferatoxin (RTX) to block post-operative incisional pain. RTX is not an opioid and does not act in the brain but rather on the nerve endings in the skin.

Ethics and Practice of Trials within Cohorts: An Emerging Pragmatic Trial Design

Published in: Clinical Trials (February 2018)

Trials within Cohorts is a promising new pragmatic randomized control trial design that is increasingly used in various countries. Although the asymmetric procedures for the experimental versus control arm subjects can initially raise ethical concerns, it is ethically superior to previous post-randomization consent designs.

Spironolactone-Induced Degradation of the TFIIH Core Complex XPB Subunit Suppresses NF-KB and AP-1 Signalling

Published in: Cardiovascular Research (January 2018)

Spironolactone-induced breakdown of the protein XPB reduces the expression of pro-inflammatory genes. This previously unrecognized anti-inflammatory mechanism may be beneficial in diseases with vascular inflammation, including pulmonary arterial hypertension, the focus of an ongoing clinical trial at the NIH Clinical Center.

Read the article

Read more articles about research in the NIH Clinical Center in 2018.

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Step 3: Clinical Research

While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. “Clinical research” refers to studies, or trials, that are done in people. As the developers design the clinical study, they will consider what they want to accomplish for each of the different Clinical Research Phases and begin the Investigational New Drug Process (IND), a process they must go through before clinical research begins.

On this page you will find information on:

Designing Clinical Trials

Clinical Research Phase Studies

The Investigational New Drug Process

Asking for FDA Assistance

FDA IND Review Team

Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called a protocol , that is developed by the researcher or manufacturer. Before a clinical trial begins, researchers review prior information about the drug to develop research questions and objectives. Then, they decide:

Who qualifies to participate (selection criteria)

How many people will be part of the study

How long the study will last

Whether there will be a control group and other ways to limit research bias

How the drug will be given to patients and at what dosage

What assessments will be conducted, when, and what data will be collected

How the data will be reviewed and analyzed

Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies.

What are the Clinical Trial Phases?

Watch this video to learn about the three phases of clinical trials.

Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.

Length of Study: Several months

Purpose: Safety and dosage

During Phase 1 studies, researchers test a new drug in normal volunteers (healthy people). In most cases, 20 to 80 healthy volunteers or people with the disease/condition participate in Phase 1. However, if a new drug is intended for use in cancer patients, researchers conduct Phase 1 studies in patients with that type of cancer.

Phase 1 studies are closely monitored and gather information about how a drug interacts with the human body. Researchers adjust dosing schemes based on animal data to find out how much of a drug the body can tolerate and what its acute side effects are.

As a Phase 1 trial continues, researchers answer research questions related to how it works in the body, the side effects associated with increased dosage, and early information about how effective it is to determine how best to administer the drug to limit risks and maximize possible benefits. This is important to the design of Phase 2 studies.

Approximately 70% of drugs move to the next phase

Study Participants: Up to several hundred people with the disease/condition.

Length of Study: Several months to 2 years

Purpose: Efficacy and side effects

In Phase 2 studies, researchers administer the drug to a group of patients with the disease or condition for which the drug is being developed. Typically involving a few hundred patients, these studies aren't large enough to show whether the drug will be beneficial.

Instead, Phase 2 studies provide researchers with additional safety data. Researchers use these data to refine research questions, develop research methods, and design new Phase 3 research protocols.

Approximately 33% of drugs move to the next phase

Study Participants: 300 to 3,000 volunteers who have the disease or condition

Length of Study: 1 to 4 years

Purpose: Efficacy and monitoring of adverse reactions

Researchers design Phase 3 studies to demonstrate whether or not a product offers a treatment benefit to a specific population. Sometimes known as pivotal studies, these studies involve 300 to 3,000 participants.

Phase 3 studies provide most of the safety data. In previous studies, it is possible that less common side effects might have gone undetected. Because these studies are larger and longer in duration, the results are more likely to show long-term or rare side effects

Approximately 25-30% of drugs move to the next phase

Study Participants: Several thousand volunteers who have the disease/condition

Purpose: Safety and efficacy

Phase 4 trials are carried out once the drug or device has been approved by FDA during the Post-Market Safety Monitoring

Learn more about Clinical Trials .

Drug developers, or sponsors , must submit an Investigational New Drug (IND) application to FDA before beginning clinical research.

In the IND application, developers must include:

Animal study data and toxicity (side effects that cause great harm) data

Manufacturing information

Clinical protocols (study plans) for studies to be conducted

Data from any prior human research

Information about the investigator

Drug developers are free to ask for help from FDA at any point in the drug development process, including:

Pre-IND application, to review FDA guidance documents and get answers to questions that may help enhance their research

After Phase 2, to obtain guidance on the design of large Phase 3 studies

Any time during the process, to obtain an assessment of the IND application

Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s suggestions. As long as clinical trials are thoughtfully designed, reflect what developers know about a product, safeguard participants, and otherwise meet Federal standards, FDA allows wide latitude in clinical trial design.

The review team consists of a group of specialists in different scientific fields. Each member has different responsibilities.

Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor.

Medical Officer: Reviews all clinical study information and data before, during, and after the trial is complete.

Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data.

Pharmacologist: Reviews preclinical studies.

Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and excretion processes.Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules.

Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, the presence of impurities, etc.

Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes.

The FDA review team has 30 days to review the original IND submission. The process protects volunteers who participate in clinical trials from unreasonable and significant risk in clinical trials. FDA responds to IND applications in one of two ways:

Approval to begin clinical trials.

Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons, including:

Participants are exposed to unreasonable or significant risk.

Investigators are not qualified.

Materials for the volunteer participants are misleading.

The IND application does not include enough information about the trial’s risks.

A clinical hold is rare; instead, FDA often provides comments intended to improve the quality of a clinical trial. In most cases, if FDA is satisfied that the trial meets Federal standards, the applicant is allowed to proceed with the proposed study.

The developer is responsible for informing the review team about new protocols, as well as serious side effects seen during the trial. This information ensures that the team can monitor the trials carefully for signs of any problems. After the trial ends, researchers must submit study reports.

This process continues until the developer decides to end clinical trials or files a marketing application. Before filing a marketing application, a developer must have adequate data from two large, controlled clinical trials.

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FAQs About Clinical Studies

If you are in the process of learning about clinical trials or are considering participating in one, you may be interested in reviewing our Are Clinical Studies for You? page. In addition, we encourage anyone with questions to call the Patient Recruitment Office at 1-800-411-1222 . You may also want to try the " Topics A-Z " tool, an alphabetical index to all visitor- and patient-related subject areas.

What are clinical studies? +

Clinical studies are research studies in which real people participate as volunteers. Clinical research studies are a means of improving our understanding of disease, such as in observational studies, or developing new treatments and medications for diseases and conditions, such as clinical trials, which are evaluating the effects of a biomedical or behavioral intervention on health outcomes. There are strict rules for clinical trials, which are monitored by the National Institutes of Health for the trials it funds, and the U.S. Food and Drug Administration more broadly. Some of the research studies at the Clinical Center involve promising new treatments that may directly benefit patients. Understanding Clinical Studies .

Why should I participate? +

The health of millions has been improved because of advances in science and technology, and the willingness of thousands of individuals like you to take part in clinical research. The role of volunteer subjects as partners in clinical research is crucial in the quest for knowledge that will improve the health of future generations. Without your help, the research studies at the Clinical Center cannot be accomplished.

Will I be compensated? +

The NIH may compensate study participants for their time and, in some instances, for the inconvenience of a procedure. There are standard compensation rates for the participant's time; the study's principal investigator determines inconvenience rates.

NIH reports compensation of $600 or more to the Internal Revenue Service and sends a "Form 1099-Other Income" to the participant at the end of the year.

Please be aware that, under U.S. law, some or all of that compensation may be garnished by the U.S. Treasury if the participant has outstanding debts to the federal or state government. The NIH does not have any way of knowing if a volunteer has an outstanding debt to the government and is not told when the U.S. Treasury garnishes compensation. The U.S. Treasury will notify the payee directly in this circumstance.

What is a "healthy volunteer"? +

A volunteer subject with no known significant health problems who participates in research to test a new drug, device, or intervention is known as a "healthy volunteer" or "Clinical Research Volunteer." The clinical research volunteer may be a member of the community, an NIH investigator or other employee, or family members of a patient volunteer. Research procedures with these volunteers are designed to develop new knowledge, not to provide direct benefit to study participants. Clinical research volunteers have always played a vital role in medical research. We need to study healthy volunteers for several reasons: When developing a new technique such as a blood test or imaging device, we need clinical research volunteers to help us define the limits of "normal." These volunteers are recruited to serve as controls for patient groups. They are often matched to patients on such characteristics as age, gender, or family relationship. They are then given the same test, procedure, or drug the patient group receives. Investigators learn about the disease process by comparing the patient group to the clinical research volunteers.

What are Phase I, Phase II and Phase III studies? +

The phase 1 study is used to learn the "maximum tolerated dose" of a drug that does not produce unacceptable side effects. Patient volunteers are followed primarily for side effects, and not for how the drug affects their disease. The first few volunteer subjects receive low doses of the trial drug to see how the drug is tolerated and to learn how it acts in the body. The next group of volunteer subjects receives larger amounts. Phase 1 studies typically offer little or no benefit to the volunteer subjects.

The phase 2 study involves a drug whose dose and side effects are well known. Many more volunteer subjects are tested, to define side effects, learn how it is used in the body, and learn how it helps the condition under study. Some volunteer subjects may benefit from a phase 2 study.

The phase 3 study compares the new drug against a commonly used drug. Some volunteer subjects will be given the new drug and some the commonly used drug. The trial is designed to find where the new drug fits in managing a particular condition. Determining the true benefit of a drug in a clinical trial is difficult.

What is a placebo? +

Placebos are harmless, inactive substances made to look like the real medicine used in the clinical trial. Placebos allow the investigators to learn whether the medicine being given works better or no better than ordinary treatment. In many studies, there are successive time periods, with either the placebo or the real medicine. In order not to introduce bias, the patient, and sometimes the staff, are not told when or what the changes are. If a placebo is part of a study, you will always be informed in the consent form given to you before you agree to take part in the study. When you read the consent form, be sure that you understand what research approach is being used in the study you are entering.

What is the placebo effect? +

Medical research is dogged by the placebo effect - the real or apparent improvement in a patient's condition due to wishful thinking by the investigator or the patient. Medical techniques use three ways to rid clinical trials of this problem. These methods have helped discredit some previously accepted treatments and validate new ones. Methods used are the following: randomization, single-blind or double-blind studies, and the use of a placebo.

What is randomization? +

Randomization is when two or more alternative treatments are selected by chance, not by choice. The treatment chosen is given with the highest level of professional care and expertise, and the results of each treatment are compared. Analyses are done at intervals during a trial, which may last years. As soon as one treatment is found to be definitely superior, the trial is stopped. In this way, the fewest number of patients receive the less beneficial treatment.

What are single-blind and double-blind studies? +

In single- or double-blind studies, the participants don't know which medicine is being used, and they can describe what happens without bias. Blind studies are designed to prevent anyone (doctors, nurses, or patients) from influencing the results. This allows scientifically accurate conclusions. In single-blind ("single-masked") studies, only the patient is not told what is being given. In a double-blind study, only the pharmacist knows; the doctors, nurses, patients, and other health care staff are not informed. If medically necessary, however, it is always possible to find out what the patient is taking.

Are there risks involved in participating in clinical research? +

Risks are involved in clinical research, as in routine medical care and activities of daily living. In thinking about the risks of research, it is helpful to focus on two things: the degree of harm that could result from taking part in the study, and the chance of any harm occurring. Most clinical studies pose risks of minor discomfort, lasting only a short time. Some volunteer subjects, however, experience complications that require medical attention. The specific risks associated with any research protocol are described in detail in the consent document, which you are asked to sign before taking part in research. In addition, the major risks of participating in a study will be explained to you by a member of the research team, who will answer your questions about the study. Before deciding to participate, you should carefully weigh these risks. Although you may not receive any direct benefit as a result of participating in research, the knowledge developed may help others.

What safeguards are there to protect participants in clinical research? +

The following section describes safeguards that protect the safety and rights of volunteer subjects. These safeguards include:

• The Protocol Review Process
• Informed Consent Procedures
• The Patient Representative
• The Patient Bill of Rights

Protocol review. As in any medical research facility, all new protocols produced at NIH must be approved by an institutional review board (IRB) before they can begin. The IRB, which consists of medical specialists, statisticians, nurses, social workers, and medical ethicists, is the advocate of the volunteer subject. The IRB will only approve protocols that address medically important questions in a scientific and responsible manner.

Informed consent. Your participation in any Clinical Center research protocol is voluntary. For every study in which you intend to participate, you will receive a document called "Consent to Participate in a Clinical Research Study" that explains the study in straightforward language. A member of the research team will discuss the protocol with you, explain its details, and answer your questions. Reading and understanding the protocol is your responsibility. You may discuss the protocol with family and friends. You will not be hurried into making a decision, and you will be asked to sign the document only after you understand the nature of the protocol and agree to the commitment. At any time after signing the protocol, you are free to change your mind and decide not to participate further. This means that you are free to withdraw from the study completely, or to refuse particular treatments or tests. Sometimes, however, this will make you ineligible to continue the study. If you are no longer eligible or no longer wish to continue the study, you will return to the care of the doctor who referred you to NIH.

Patient representative.  The Patient Representative acts as a link between the patient and the hospital. The Patient Representative makes every effort to assure that patients are informed of their rights and responsibilities, and that they understand what the Clinical Center is, what it can offer, and how it operates. We realize that this setting is unique and may generate questions about the patient's role in the research process. As in any large and complex system, communication can be a problem and misunderstandings c

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Yale, our community partners, and the FDA Office of Minority Health and Health Equity are catalyzing racial equity in clinical trials through community empowerment. For more than a decade under the CTSA, the Yale Center for Clinical Investigation and our Cultural Ambassadors have focused on addressing diverse participation in clinical trials and bridging health gaps. In partnership with the FDA Office of Minority Health and Health Equity, we are connecting investigators to our community and patients—the heroes of clinical research—as one of the hallmarks of YCCI. Learn more about Yale's program, the FDA and minority health, and the importance of participating in clinical trials for all populations. Help Us Discover.

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Health Equity

Medicaid Could Become a Powerful Tool to Improve Racial and Ethnic Representation in Cancer Clinical Trials

One key may be medicaid’s recent coverage of the routine costs for enrolling in clinical trials, paula chatterjee, md, mph.

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Diversifying clinical trial participation is a national priority. Federal research institutions , regulators, and Congress have called for efforts to include historically underrepresented populations in clinical studies. Yet ensuring diversity in clinical trials remains challenging for several reasons including limited trust in the health care system, barriers to access, and the financial burden of participating in clinical trials. One potential fix may actually lie where few have looked: Medicaid.

In a recent study , we found an increase in oncology clinical trial participation among Black and Hispanic patients in Medicaid expansion states that mandated Medicaid coverage for the routine costs of trial participation. 

Clinical Trial Diversity in Medicaid Expansion Versus Non-Expansion States

Our team, which included William Schpero , Assistant Professor at the Joan and Sanford I Weill Medical College at Cornell University, and LDI Senior Fellow Samuel Takvorian , used a national database of 47,870 nonelderly adult oncology clinical trial participants who were enrolled in a U.S.-based trial from January 1, 2012 to December 31, 2019. The sample included 1,353 clinical trials and 344 clinical trial sites across the country. 

We compared states that did not mandate the coverage of routine costs for trial participation to those that did and found that in the years before states expanded Medicaid coverage, the proportion of Black and Hispanic participants enrolled in clinical trials were similar in non-expansion and expansion states. However, in states that had existing coverage mandates, non-expansion states had higher rates of trial participation than states that later expanded Medicaid. 

Further analyses showed that over time, the proportion of trial participants who were Black or Hispanic rose in both non-expansion and expansion states. However, Medicaid expansion was associated with a 5.3 percentage point increase in the enrollment of Black or Hispanic participants, specifically in states where Medicaid was required to cover the routine costs of trial participation, but not in states without such mandates. In expansion states without coverage mandates, the increase was only 1.1 percentage point. Medicaid coverage for the routine costs of participating in clinical trials made a difference.

Remove Cost-Related Barriers to Participation

While strategies to improve racial and ethnic representation in clinical trials are needed at every level, this study points to several actions that could reduce financial barriers to participation.

• The findings are relevant to the CLINICAL TREATMENT Act , which mandated that state Medicaid programs cover routine costs of trial enrollees beginning January 1, 2022. Monitoring the implementation of this is important given the decentralized nature of state Medicaid programs. The Centers for Medicare & Medicaid Services could offer guidance based on the experiences of states that offered coverage of trial costs before the 2022 mandate. 
• Clinicians serving Medicaid-enrolled patients are a key source of information, referral, and advocacy for patients for whom the enrollment cost is a barrier. Informing clinicians of these policies can reduce implicit and explicit biases that influence enrollment of minoritized and low-income populations in clinical trials. 
• The findings of this study also support education and outreach efforts among low-income populations who may find that cost is a barrier to clinical trial participation.

The study, “ Association Between State Medicaid Policies and Accrual of Black or Hispanic Patients to Cancer Clinical Trials ,” was published on July 25, 2024 in the Journal of Clinical Oncology. Authors include William L. Schpero, Samuel U. Takvorian , Daniel Blickstein, Afrah Shafquat, Jingshu Liu, Arnaub K. Chatterjee, Elizabeth B. Lamont, and Paula Chatterjee .

Director, Health Equity Research, Leonard Davis Institute of Health Economics; Assistant Professor, Medicine, Perelman School of Medicine

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October 18, 2016

Understanding Clinical Studies

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Part of the challenge of explaining clinical research to the public is describing the important points of a study without going into a detailed account of the study’s design. There are many different kinds of clinical studies, each with their own strengths and weaknesses, and no real shorthand way to explain them. Researchers sometimes don’t explicitly state the kind of study they’re talking about. To them, it’s obvious; they’ve been living and breathing this research for years, sometimes decades. But study design can often be difficult even for seasoned health and science communicators to understand.

The gold standard for proving that a treatment or medical approach works is a well-designed randomized controlled trial. This type of study allows researchers to test medical interventions by randomly assigning participants to treatment or control groups. The results can help determine if there’s a cause-and-effect relationship between the treatment and outcomes. But clinical researchers can’t always use this approach. For example, scientists can’t ethically study risky behaviors by asking people to start smoking or eating an unhealthy diet. And they can’t study the health effects of the environment by assigning people to live in different places.

Thus, researchers must often turn to some type of observational study, in which a population’s health or behaviors are observed and analyzed. These studies can’t prove cause and effect, but they can be useful for finding associations. Observational studies can also help researchers understand a situation and come up with hypotheses that can then be put to the test in clinical trials. These types of studies have been essential to understanding the genetic, infectious, environmental, and behavioral causes of disease.

We’ve developed a one-page guide to clarify the different kinds of clinical studies researchers use, to explain why researchers might use them, and to touch a little on each type’s strengths and weaknesses. We hope it can serve as a useful resource to explain clinical research, whether you’re describing the results of a study to the public or the design of a trial to a potential participant. Please take a look and share your thoughts with us by sending an email to [email protected] .

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Tap into the A4 Study for unprecedented Alzheimer’s clinical trial data September 18, 2024

NIA has a long-standing commitment to the principles of open science to accelerate dementia research. As part of that pledge, we are pleased to announce that trial data and biosamples from the pivotal Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study, are now available for download and exploration by the scientific community. Although the results of the A4 trial demonstrated that the drug did not meet its primary endpoints , its early and sustained data and biosample sharing set a new precedent and will be discussed at the 2024 NIH Alzheimer’s Research Summit coming up Sept. 23-25.

Generating a wealth of dementia research data

Part of the Accelerating Medicines Partnership® Program for Alzheimer’s Disease , the A4 study was a multisite trial that tested whether the investigational anti-amyloid drug solanezumab would slow cognitive decline in the earliest stages of Alzheimer’s. The study was the first of its kind in individuals with preclinical Alzheimer’s (high levels of amyloid on brain scans but without cognitive impairment). A4 pioneered the sharing of screening data and biosamples from its nearly 1,200 participants within 12 months of enrollment, and the study team has continued to share them regularly with the scientific community for nearly five years.

So far, more than 1,500 requests for clinical data from the study have been approved, and the data have generated approximately 60 peer-reviewed research articles. Analyses of A4 screening data and biosamples have already provided new insights on disease biology, Alzheimer’s biomarkers in ancestrally diverse individuals, and gender differences in cognitive performance and neuroimaging biomarkers. The release of the full trial data are expected to lead to further insights into this devastating disease and possible avenues for prevention and treatment.

Check out the A4 data and register to attend the summit

If you want to tap into these exciting data for your research, visit www.a4studydata.org . Once you’re registered, keep an eye out for future waves of data, biosamples, and exploration tools, including neuroimaging and algorithms for characterizing novel biomarkers.

To learn more about the A4 study and its data, check out the 2024 NIH Alzheimer's Research Summit , Sept. 23-25; email Laurie Ryan ; or leave a comment below.

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Types of Study in Medical Research

Bernd röhrig.

1 MDK Rheinland-Pfalz, Referat Rehabilitation/Biometrie, Alzey

Jean-Baptist du Prel

2 Zentrum für Präventive Pädiatrie, Zentrum für Kinder- und Jugendmedizin, Mainz

Daniel Wachtlin

3 Interdisziplinäres Zentrum Klinische Studien (IZKS), Fachbereich Medizin der Universität Mainz

Maria Blettner

4 Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Johannes Gutenberg Universität Mainz

The choice of study type is an important aspect of the design of medical studies. The study design and consequent study type are major determinants of a study’s scientific quality and clinical value.

This article describes the structured classification of studies into two types, primary and secondary, as well as a further subclassification of studies of primary type. This is done on the basis of a selective literature search concerning study types in medical research, in addition to the authors’ own experience.

Three main areas of medical research can be distinguished by study type: basic (experimental), clinical, and epidemiological research. Furthermore, clinical and epidemiological studies can be further subclassified as either interventional or noninterventional.

Conclusions

The study type that can best answer the particular research question at hand must be determined not only on a purely scientific basis, but also in view of the available financial resources, staffing, and practical feasibility (organization, medical prerequisites, number of patients, etc.).

The quality, reliability and possibility of publishing a study are decisively influenced by the selection of a proper study design. The study type is a component of the study design (see the article "Study Design in Medical Research") and must be specified before the study starts. The study type is determined by the question to be answered and decides how useful a scientific study is and how well it can be interpreted. If the wrong study type has been selected, this cannot be rectified once the study has started.

After an earlier publication dealing with aspects of study design, the present article deals with study types in primary and secondary research. The article focuses on study types in primary research. A special article will be devoted to study types in secondary research, such as meta-analyses and reviews. This article covers the classification of individual study types. The conception, implementation, advantages, disadvantages and possibilities of using the different study types are illustrated by examples. The article is based on a selective literature research on study types in medical research, as well as the authors’ own experience.

Classification of study types

In principle, medical research is classified into primary and secondary research. While secondary research summarizes available studies in the form of reviews and meta-analyses, the actual studies are performed in primary research. Three main areas are distinguished: basic medical research, clinical research, and epidemiological research. In individual cases, it may be difficult to classify individual studies to one of these three main categories or to the subcategories. In the interests of clarity and to avoid excessive length, the authors will dispense with discussing special areas of research, such as health services research, quality assurance, or clinical epidemiology. Figure 1 gives an overview of the different study types in medical research.

Classification of different study types

*1 , sometimes known as experimental research; *2 , analogous term: interventional; *3 , analogous term: noninterventional or nonexperimental

This scheme is intended to classify the study types as clearly as possible. In the interests of clarity, we have excluded clinical epidemiology — a subject which borders on both clinical and epidemiological research ( 3 ). The study types in this area can be found under clinical research and epidemiology.

Basic research

Basic medical research (otherwise known as experimental research) includes animal experiments, cell studies, biochemical, genetic and physiological investigations, and studies on the properties of drugs and materials. In almost all experiments, at least one independent variable is varied and the effects on the dependent variable are investigated. The procedure and the experimental design can be precisely specified and implemented ( 1 ). For example, the population, number of groups, case numbers, treatments and dosages can be exactly specified. It is also important that confounding factors should be specifically controlled or reduced. In experiments, specific hypotheses are investigated and causal statements are made. High internal validity (= unambiguity) is achieved by setting up standardized experimental conditions, with low variability in the units of observation (for example, cells, animals or materials). External validity is a more difficult issue. Laboratory conditions cannot always be directly transferred to normal clinical practice and processes in isolated cells or in animals are not equivalent to those in man (= generalizability) ( 2 ).

Basic research also includes the development and improvement of analytical procedures—such as analytical determination of enzymes, markers or genes—, imaging procedures—such as computed tomography or magnetic resonance imaging—, and gene sequencing—such as the link between eye color and specific gene sequences. The development of biometric procedures—such as statistical test procedures, modeling and statistical evaluation strategies—also belongs here.

Clinical studies

Clinical studies include both interventional (or experimental) studies and noninterventional (or observational) studies. A clinical drug study is an interventional clinical study, defined according to §4 Paragraph 23 of the Medicines Act [Arzneimittelgesetz; AMG] as "any study performed on man with the purpose of studying or demonstrating the clinical or pharmacological effects of drugs, to establish side effects, or to investigate absorption, distribution, metabolism or elimination, with the aim of providing clear evidence of the efficacy or safety of the drug."

Interventional studies also include studies on medical devices and studies in which surgical, physical or psychotherapeutic procedures are examined. In contrast to clinical studies, §4 Paragraph 23 of the AMG describes noninterventional studies as follows: "A noninterventional study is a study in the context of which knowledge from the treatment of persons with drugs in accordance with the instructions for use specified in their registration is analyzed using epidemiological methods. The diagnosis, treatment and monitoring are not performed according to a previously specified study protocol, but exclusively according to medical practice."

The aim of an interventional clinical study is to compare treatment procedures within a patient population, which should exhibit as few as possible internal differences, apart from the treatment ( 4 , e1 ). This is to be achieved by appropriate measures, particularly by random allocation of the patients to the groups, thus avoiding bias in the result. Possible therapies include a drug, an operation, the therapeutic use of a medical device such as a stent, or physiotherapy, acupuncture, psychosocial intervention, rehabilitation measures, training or diet. Vaccine studies also count as interventional studies in Germany and are performed as clinical studies according to the AMG.

Interventional clinical studies are subject to a variety of legal and ethical requirements, including the Medicines Act and the Law on Medical Devices. Studies with medical devices must be registered by the responsible authorities, who must also approve studies with drugs. Drug studies also require a favorable ruling from the responsible ethics committee. A study must be performed in accordance with the binding rules of Good Clinical Practice (GCP) ( 5 , e2 – e4 ). For clinical studies on persons capable of giving consent, it is absolutely essential that the patient should sign a declaration of consent (informed consent) ( e2 ). A control group is included in most clinical studies. This group receives another treatment regimen and/or placebo—a therapy without substantial efficacy. The selection of the control group must not only be ethically defensible, but also be suitable for answering the most important questions in the study ( e5 ).

Clinical studies should ideally include randomization, in which the patients are allocated by chance to the therapy arms. This procedure is performed with random numbers or computer algorithms ( 6 – 8 ). Randomization ensures that the patients will be allocated to the different groups in a balanced manner and that possible confounding factors—such as risk factors, comorbidities and genetic variabilities—will be distributed by chance between the groups (structural equivalence) ( 9 , 10 ). Randomization is intended to maximize homogeneity between the groups and prevent, for example, a specific therapy being reserved for patients with a particularly favorable prognosis (such as young patients in good physical condition) ( 11 ).

Blinding is another suitable method to avoid bias. A distinction is made between single and double blinding. With single blinding, the patient is unaware which treatment he is receiving, while, with double blinding, neither the patient nor the investigator knows which treatment is planned. Blinding the patient and investigator excludes possible subjective (even subconscious) influences on the evaluation of a specific therapy (e.g. drug administration versus placebo). Thus, double blinding ensures that the patient or therapy groups are both handled and observed in the same manner. The highest possible degree of blinding should always be selected. The study statistician should also remain blinded until the details of the evaluation have finally been specified.

A well designed clinical study must also include case number planning. This ensures that the assumed therapeutic effect can be recognized as such, with a previously specified statistical probability (statistical power) ( 4 , 6 , 12 ).

It is important for the performance of a clinical trial that it should be carefully planned and that the exact clinical details and methods should be specified in the study protocol ( 13 ). It is, however, also important that the implementation of the study according to the protocol, as well as data collection, must be monitored. For a first class study, data quality must be ensured by double data entry, programming plausibility tests, and evaluation by a biometrician. International recommendations for the reporting of randomized clinical studies can be found in the CONSORT statement (Consolidated Standards of Reporting Trials, www.consort-statement.org ) ( 14 ). Many journals make this an essential condition for publication.

For all the methodological reasons mentioned above and for ethical reasons, the randomized controlled and blinded clinical trial with case number planning is accepted as the gold standard for testing the efficacy and safety of therapies or drugs ( 4 , e1 , 15 ).

In contrast, noninterventional clinical studies (NIS) are patient-related observational studies, in which patients are given an individually specified therapy. The responsible physician specifies the therapy on the basis of the medical diagnosis and the patient’s wishes. NIS include noninterventional therapeutic studies, prognostic studies, observational drug studies, secondary data analyses, case series and single case analyses ( 13 , 16 ). Similarly to clinical studies, noninterventional therapy studies include comparison between therapies; however, the treatment is exclusively according to the physician’s discretion. The evaluation is often retrospective. Prognostic studies examine the influence of prognostic factors (such as tumor stage, functional state, or body mass index) on the further course of a disease. Diagnostic studies are another class of observational studies, in which either the quality of a diagnostic method is compared to an established method (ideally a gold standard), or an investigator is compared with one or several other investigators (inter-rater comparison) or with himself at different time points (intra-rater comparison) ( e1 ). If an event is very rare (such as a rare disease or an individual course of treatment), a single-case study, or a case series, are possibilities. A case series is a study on a larger patient group with a specific disease. For example, after the discovery of the AIDS virus, the Center for Disease Control (CDC) in the USA collected a case series of 1000 patients, in order to study frequent complications of this infection. The lack of a control group is a disadvantage of case series. For this reason, case series are primarily used for descriptive purposes ( 3 ).

Epidemiological studies

The main point of interest in epidemiological studies is to investigate the distribution and historical changes in the frequency of diseases and the causes for these. Analogously to clinical studies, a distinction is made between experimental and observational epidemiological studies ( 16 , 17 ).

Interventional studies are experimental in character and are further subdivided into field studies (sample from an area, such as a large region or a country) and group studies (sample from a specific group, such as a specific social or ethnic group). One example was the investigation of the iodine supplementation of cooking salt to prevent cretinism in a region with iodine deficiency. On the other hand, many interventions are unsuitable for randomized intervention studies, for ethical, social or political reasons, as the exposure may be harmful to the subjects ( 17 ).

Observational epidemiological studies can be further subdivided into cohort studies (follow-up studies), case control studies, cross-sectional studies (prevalence studies), and ecological studies (correlation studies or studies with aggregated data).

In contrast, studies with only descriptive evaluation are restricted to a simple depiction of the frequency (incidence and prevalence) and distribution of a disease within a population. The objective of the description may also be the regular recording of information (monitoring, surveillance). Registry data are also suited for the description of prevalence and incidence; for example, they are used for national health reports in Germany.

In the simplest case, cohort studies involve the observation of two healthy groups of subjects over time. One group is exposed to a specific substance (for example, workers in a chemical factory) and the other is not exposed. It is recorded prospectively (into the future) how often a specific disease (such as lung cancer) occurs in the two groups ( figure 2a ). The incidence for the occurrence of the disease can be determined for both groups. Moreover, the relative risk (quotient of the incidence rates) is a very important statistical parameter which can be calculated in cohort studies. For rare types of exposure, the general population can be used as controls ( e6 ). All evaluations naturally consider the age and gender distributions in the corresponding cohorts. The objective of cohort studies is to record detailed information on the exposure and on confounding factors, such as the duration of employment, the maximum and the cumulated exposure. One well known cohort study is the British Doctors Study, which prospectively examined the effect of smoking on mortality among British doctors over a period of decades ( e7 ). Cohort studies are well suited for detecting causal connections between exposure and the development of disease. On the other hand, cohort studies often demand a great deal of time, organization, and money. So-called historical cohort studies represent a special case. In this case, all data on exposure and effect (illness) are already available at the start of the study and are analyzed retrospectively. For example, studies of this sort are used to investigate occupational forms of cancer. They are usually cheaper ( 16 ).

Graphical depiction of a prospective cohort study (simplest case [2a]) and a retrospective case control study (2b)

In case control studies, cases are compared with controls. Cases are persons who fall ill from the disease in question. Controls are persons who are not ill, but are otherwise comparable to the cases. A retrospective analysis is performed to establish to what extent persons in the case and control groups were exposed ( figure 2b ). Possible exposure factors include smoking, nutrition and pollutant load. Care should be taken that the intensity and duration of the exposure is analyzed as carefully and in as detailed a manner as possible. If it is observed that ill people are more often exposed than healthy people, it may be concluded that there is a link between the illness and the risk factor. In case control studies, the most important statistical parameter is the odds ratio. Case control studies usually require less time and fewer resources than cohort studies ( 16 ). The disadvantage of case control studies is that the incidence rate (rate of new cases) cannot be calculated. There is also a great risk of bias from the selection of the study population ("selection bias") and from faulty recall ("recall bias") (see too the article "Avoiding Bias in Observational Studies"). Table 1 presents an overview of possible types of epidemiological study ( e8 ). Table 2 summarizes the advantages and disadvantages of observational studies ( 16 ).

1 = slight; 2 = moderate; 3 = high; N/A, not applicable.

*Individual cases may deviate from this pattern.

Selecting the correct study type is an important aspect of study design (see "Study Design in Medical Research" in volume 11/2009). However, the scientific questions can only be correctly answered if the study is planned and performed at a qualitatively high level ( e9 ). It is very important to consider or even eliminate possible interfering factors (or confounders), as otherwise the result cannot be adequately interpreted. Confounders are characteristics which influence the target parameters. Although this influence is not of primary interest, it can interfere with the connection between the target parameter and the factors that are of interest. The influence of confounders can be minimized or eliminated by standardizing the procedure, stratification ( 18 ), or adjustment ( 19 ).

The decision as to which study type is suitable to answer a specific primary research question must be based not only on scientific considerations, but also on issues related to resources (personnel and finances), hospital capacity, and practicability. Many epidemiological studies can only be implemented if there is access to registry data. The demands for planning, implementation, and statistical evaluation for observational studies should be just as high for observational studies as for experimental studies. There are particularly strict requirements, with legally based regulations (such as the Medicines Act and Good Clinical Practice), for the planning, implementation, and evaluation of clinical studies. A study protocol must be prepared for both interventional and noninterventional studies ( 6 , 13 ). The study protocol must contain information on the conditions, question to be answered (objective), the methods of measurement, the implementation, organization, study population, data management, case number planning, the biometric evaluation, and the clinical relevance of the question to be answered ( 13 ).

Important and justified ethical considerations may restrict studies with optimal scientific and statistical features. A randomized intervention study under strictly controlled conditions of the effect of exposure to harmful factors (such as smoking, radiation, or a fatty diet) is not possible and not permissible for ethical reasons. Observational studies are a possible alternative to interventional studies, even though observational studies are less reliable and less easy to control ( 17 ).

A medical study should always be published in a peer reviewed journal. Depending on the study type, there are recommendations and checklists for presenting the results. For example, these may include a description of the population, the procedure for missing values and confounders, and information on statistical parameters. Recommendations and guidelines are available for clinical studies ( 14 , 20 , e10 , e11 ), for diagnostic studies ( 21 , 22 , e12 ), and for epidemiological studies ( 23 , e13 ). Since 2004, the WHO has demanded that studies should be registered in a public registry, such as www.controlled-trials.com or www.clinicaltrials.gov . This demand is supported by the International Committee of Medical Journal Editors (ICMJE) ( 24 ), which specifies that the registration of the study before inclusion of the first subject is an essential condition for the publication of the study results ( e14 ).

When specifying the study type and study design for medical studies, it is essential to collaborate with an experienced biometrician. The quality and reliability of the study can be decisively improved if all important details are planned together ( 12 , 25 ).

Acknowledgments

Translated from the original German by Rodney A. Yeates, M.A., Ph.D.

Conflict of interest statement

The authors declare that there is no conflict of interest in the sense of the International Committee of Medical Journal Editors.

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Deep learning model based on primary tumor to predict lymph node status in clinical stage IA lung adenocarcinoma: a multicenter study

Affiliations.

• 1 Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
• 2 Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, Beijing, China.
• 3 CAS Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
• 4 Department of Radiology, PLA General Hospital, Beijing, China.
• 5 Department of Radiology, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
• 6 School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China.
• PMID: 39281718
• PMCID: PMC11401490
• DOI: 10.1016/j.jncc.2024.01.005

Objective: To develop a deep learning model to predict lymph node (LN) status in clinical stage IA lung adenocarcinoma patients.

Methods: This diagnostic study included 1,009 patients with pathologically confirmed clinical stage T1N0M0 lung adenocarcinoma from two independent datasets (699 from Cancer Hospital of Chinese Academy of Medical Sciences and 310 from PLA General Hospital) between January 2005 and December 2019. The Cancer Hospital dataset was randomly split into a training cohort (559 patients) and a validation cohort (140 patients) to train and tune a deep learning model based on a deep residual network (ResNet). The PLA Hospital dataset was used as a testing cohort to evaluate the generalization ability of the model. Thoracic radiologists manually segmented tumors and interpreted high-resolution computed tomography (HRCT) features for the model. The predictive performance was assessed by area under the curves (AUCs), accuracy, precision, recall, and F1 score. Subgroup analysis was performed to evaluate the potential bias of the study population.

Results: A total of 1,009 patients were included in this study; 409 (40.5%) were male and 600 (59.5%) were female. The median age was 57.0 years (inter-quartile range, IQR: 50.0-64.0). The deep learning model achieved AUCs of 0.906 (95% CI: 0.873-0.938) and 0.893 (95% CI: 0.857-0.930) for predicting pN0 disease in the testing cohort and a non-pure ground glass nodule (non-pGGN) testing cohort, respectively. No significant difference was detected between the testing cohort and the non-pGGN testing cohort ( P = 0.622). The precisions of this model for predicting pN0 disease were 0.979 (95% CI: 0.963-0.995) and 0.983 (95% CI: 0.967-0.998) in the testing cohort and the non-pGGN testing cohort, respectively. The deep learning model achieved AUCs of 0.848 (95% CI: 0.798-0.898) and 0.831 (95% CI: 0.776-0.887) for predicting pN2 disease in the testing cohort and the non-pGGN testing cohort, respectively. No significant difference was detected between the testing cohort and the non-pGGN testing cohort ( P = 0.657). The recalls of this model for predicting pN2 disease were 0.903 (95% CI: 0.870-0.936) and 0.931 (95% CI: 0.901-0.961) in the testing cohort and the non-pGGN testing cohort, respectively.

Conclusions: The superior performance of the deep learning model will help to target the extension of lymph node dissection and reduce the ineffective lymph node dissection in early-stage lung adenocarcinoma patients.

Keywords: Adenocarcinoma; Clinical stage IA; Deep learning; Lung neoplasm; Lymph node status.

© 2024 Chinese National Cancer Center. Published by Elsevier B.V.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The architecture of the deep-learning…

The architecture of the deep-learning model. CT, computed tomography; HRCT, high-resolution computed tomography.

The contributions of clinic-radiological features…

The contributions of clinic-radiological features to the deep learning model. CT, computed tomography.

ROC analysis to evaluate the…

ROC analysis to evaluate the model for N0 disease and N2 disease in…

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