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INTRODUCTION

Based on this definition, guidelines have two parts:

● The foundation is a systematic review of the research evidence bearing on a clinical question, focused on the strength of the evidence on which clinical decision-making for that condition is based.

● A set of recommendations, involving both the evidence and value judgments regarding benefits and harms of alternative care options, addressing how patients with that condition should be managed, everything else being equal.

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Nih clinical research trials and you.

The NIH Clinical Trials and You website is a resource for people who want to learn more about clinical trials. By expanding the below questions, you can read answers to common questions about taking part in a clinical trial. 

What are clinical trials and why do people participate?

Clinical research is medical research that involves people like you. When you volunteer to take part in clinical research, you help doctors and researchers learn more about disease and improve health care for people in the future. Clinical research includes all research that involves people.  Types of clinical research include:

• Epidemiology, which improves the understanding of a disease by studying patterns, causes, and effects of health and disease in specific groups.
• Behavioral, which improves the understanding of human behavior and how it relates to health and disease.
• Health services, which looks at how people access health care providers and health care services, how much care costs, and what happens to patients as a result of this care.
• Clinical trials, which evaluate the effects of an intervention on health outcomes.

What are clinical trials and why would I want to take part?

Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease. Clinical trials can study:

• New drugs or new combinations of drugs
• New ways of doing surgery
• New medical devices
• New ways to use existing treatments
• New ways to change behaviors to improve health
• New ways to improve the quality of life for people with acute or chronic illnesses.

The goal of clinical trials is to determine if these treatment, prevention, and behavior approaches are safe and effective. People take part in clinical trials for many reasons. Healthy volunteers say they take part to help others and to contribute to moving science forward. People with an illness or disease also take part to help others, but also to possibly receive the newest treatment and to have added (or extra) care and attention from the clinical trial staff. Clinical trials offer hope for many people and a chance to help researchers find better treatments for others in the future

Why is diversity and inclusion important in clinical trials?

People may experience the same disease differently. It’s essential that clinical trials include people with a variety of lived experiences and living conditions, as well as characteristics like race and ethnicity, age, sex, and sexual orientation, so that all communities benefit from scientific advances.

See Diversity & Inclusion in Clinical Trials for more information.

How does the research process work?

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 new treatments move through a series of steps called phases, more information is gained about the treatment, its risks, and its effectiveness.

What are clinical trial protocols?

Clinical trials follow a plan known as a protocol. The protocol is carefully designed to balance the potential benefits and risks to participants, and answer specific research questions. A protocol describes the following:

• The goal of the study
• Who is eligible to take part in the trial
• Protections against risks to participants
• Details about tests, procedures, and treatments
• How long the trial is expected to last
• What information will be gathered

A clinical trial 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.

What is an Institutional Review Board?

Most, but not all, clinical trials in the United States are approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are reduced and are outweighed by potential benefits. IRBs are committees that are responsible for reviewing research in order to protect the rights and safety of people who take part in research, both before the research starts and as it proceeds. You should ask the sponsor or research coordinator whether the research you are thinking about joining was reviewed by an IRB.

What is a clinical trial sponsor?

Clinical trial sponsors may be people, institutions, companies, government agencies, or other organizations that are responsible for initiating, managing or financing the clinical trial, but do not conduct the research.

What is informed consent?

Informed consent is the process of providing you with key information about a research study before you decide whether to accept the offer to take part. The process of informed consent continues throughout the study. To help you decide whether to take part, members of the research team explain the details of the study. If you do not understand English, a translator or interpreter may be provided. The research team provides an informed consent document that includes details about the study, such as its purpose, how long it’s expected to last, tests or procedures that will be done as part of the research, and who to contact for further information. The informed consent document also explains risks and potential benefits. You can then decide whether to sign the document. Taking part in a clinical trial is voluntary and you can leave the study at any time.

What are the types of clinical trials?

There are different types of clinical trials.

• 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.
• Screening trials test new ways for detecting diseases or health conditions.
• Diagnostic trials study or compare 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.
• Behavioral trials evaluate or compare ways to promote behavioral changes designed to improve health.
• Quality of life trials (or supportive care trials) explore and measure ways to improve the comfort and quality of life of people with conditions or illnesses.

What are the phases of clinical trials?

Clinical trials are conducted 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 drug or treatment in a small group of people (20–80) for the first time. The purpose is to study the drug or treatment to learn about safety and identify side effects.
• Phase II trials : The new drug or treatment is given to a larger group of people (100–300) to determine its effectiveness and to further study its safety.
• Phase III trials : The new drug or treatment is given to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or similar treatments, and collect information that will allow the new 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 in the general population, seeking more information about a drug or treatment’s benefits, and optimal use.

What do the terms placebo, randomization, and blinded mean in clinical trials?

In clinical trials that compare a new product or therapy with another that already exists, researchers try to determine if the new one is as good, or better than, the existing one. In some studies, you may be assigned to receive a placebo (an inactive product that resembles the test product, but without its treatment value).

Comparing a new product with a placebo can be the fastest and most reliable way to show the new product’s effectiveness. However, placebos are not used if you would be put at risk — particularly in the study of treatments for serious illnesses — by not having effective therapy. You will be told if placebos are used in the study before entering a trial.

Randomization is the process by which treatments are assigned to participants by chance rather than by choice. This is done to avoid any bias in assigning volunteers to get one treatment or another. The effects of each treatment are compared at specific points during a trial. If one treatment is found superior, the trial is stopped so that the most volunteers receive the more beneficial treatment.  This video helps explain randomization for all clinical trials .

" Blinded " (or " masked ") studies are designed to prevent members of the research team and study participants from influencing the results. Blinding allows the collection of scientifically accurate data. In single-blind (" single-masked ") studies, you are not told what is being given, but the research team knows. In a double-blind study, 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.

Who takes part in clinical trials?

Many different types of people take part in clinical trials. Some are healthy, while others may have illnesses. Research procedures with healthy volunteers are designed to develop new knowledge, not to provide direct benefit to those taking part. Healthy volunteers have always played an important role in research.

Healthy volunteers are needed for several reasons. When developing a new technique, such as a blood test or imaging device, healthy volunteers help define the limits of "normal." These volunteers are the baseline against which patient groups are compared and are often matched to patients on factors such as age, gender, or family relationship. They receive the same tests, procedures, or drugs the patient group receives. Researchers learn about the disease process by comparing the patient group to the healthy volunteers.

Factors like how much of your time is needed, discomfort you may feel, or risk involved depends on the trial. While some require minimal amounts of time and effort, other studies may require a major commitment of your time and effort, and may involve some discomfort. The research procedure(s) may also carry some risk. The informed consent process for healthy volunteers includes a detailed discussion of the study's procedures and tests and their risks.

A patient volunteer has a known health problem and takes part in research to better understand, diagnose, or treat that disease or condition. Research with a patient volunteer helps develop new knowledge. Depending on the stage of knowledge about the disease or condition, these procedures may or may not benefit the study participants.

Patients may volunteer for studies similar to those in which healthy volunteers take part. These studies involve drugs, devices, or treatments designed to prevent,or treat disease. Although these studies may provide direct benefit to patient volunteers, the main aim is to prove, by scientific means, the effects and limitations of the experimental treatment. Therefore, some patient groups may serve as a baseline for comparison by not taking the test drug, or by receiving test doses of the drug large enough only to show that it is present, but not at a level that can treat the condition.

Researchers follow clinical trials guidelines when deciding who can participate, in a study. These guidelines are called Inclusion/Exclusion Criteria . Factors that allow you to take part in a clinical trial are called "inclusion criteria." Those that exclude or prevent participation are "exclusion criteria." These criteria are based on factors such as age, gender, the type and stage of a disease, treatment history, and other medical conditions. Before joining a clinical trial, you must provide information that allows the research team to determine whether or not you can take part in the study safely. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy volunteers. Inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe, and to help ensure that researchers can find new information they need.

What do I need to know if I am thinking about taking part in a clinical trial?

Risks and potential benefits

Clinical trials may involve risk, as can routine medical care and the activities of daily living. When weighing the risks of research, you can think about these important factors:

• The possible harms that could result from taking part in the study
• The level of harm
• The chance of any harm occurring

Most clinical trials pose the risk of minor discomfort, which lasts only a short time. However, some study participants experience complications that require medical attention. In rare cases, participants have been seriously injured or have died of complications resulting from their participation in trials of experimental treatments. The specific risks associated with a research protocol are described in detail in the informed consent document, which participants are asked to consider and sign before participating in research. Also, a member of the research team will explain the study and answer any questions about the study. Before deciding to participate, carefully consider risks and possible benefits.

Potential benefits

Well-designed and well-executed clinical trials provide the best approach for you to:

• Help others by contributing to knowledge about new treatments or procedures.
• Gain access to new research treatments before they are widely available.
• Receive regular and careful medical attention from a research team that includes doctors and other health professionals.

Risks to taking part in clinical trials include the following:

• There may be unpleasant, serious, or even life-threatening effects of experimental treatment.
• The study may require more time and attention than standard treatment would, including visits to the study site, more blood tests, more procedures, hospital stays, or complex dosage schedules.

What questions should I ask if offered a clinical trial?

If you are thinking about taking part in a clinical trial, you should feel free to ask any questions or bring up any issues concerning the trial at any time. The following suggestions may give you some ideas as you think about your own questions.

• What is the purpose of the study?
• Why do researchers think the approach may be effective?
• Who will fund the study?
• Who has reviewed and approved the study?
• How are study results and safety of participants being monitored?
• How long will the study last?
• What will my responsibilities be if I take part?
• Who will tell me about the results of the study and how will I be informed?

Risks and possible benefits

• What are my possible short-term benefits?
• What are my possible long-term benefits?
• What are my short-term risks, and side effects?
• What are my long-term risks?
• What other options are available?
• How do the risks and possible benefits of this trial compare with those options?

Participation and care

• What kinds of therapies, procedures and/or tests will I have during the trial?
• Will they hurt, and if so, for how long?
• How do the tests in the study compare with those I would have outside of the trial?
• Will I be able to take my regular medications while taking part in the clinical trial?
• Where will I have my medical care?
• Who will be in charge of my care?

Personal issues

• How could being in this study affect my daily life?
• Can I talk to other people in the study?

Cost issues

• Will I have to pay for any part of the trial such as tests or the study drug?
• If so, what will the charges likely be?
• What is my health insurance likely to cover?
• Who can help answer any questions from my insurance company or health plan?
• Will there be any travel or child care costs that I need to consider while I am in the trial?

Tips for asking your doctor about trials

• Consider taking a family member or friend along for support and for help in asking questions or recording answers.
• Plan what to ask — but don't hesitate to ask any new questions.
• Write down questions in advance to remember them all.
• Write down the answers so that they’re available when needed.
• Ask about bringing a tape recorder to make a taped record of what's said (even if you write down answers).

This information courtesy of Cancer.gov.

How is my safety protected?

Ethical guidelines

The goal of clinical research is to develop knowledge that improves human health or increases understanding of human biology. People who take part in clinical research make it possible for this to occur. The path to finding out if a new drug is safe or effective is to test it on patients in clinical trials. The purpose of ethical guidelines is both to protect patients and healthy volunteers, and to preserve the integrity of the science.

Informed consent

Informed consent is the process of learning the key facts about a clinical trial before deciding whether to participate. The process of providing information to participants continues throughout the study. To help you decide whether to take part, members of the research team explain the study. The research team provides an informed consent document, which includes such details about the study as its purpose, duration, required procedures, and who to contact for various purposes. The informed consent document also explains risks and potential benefits.

If you decide to enroll in the trial, you will need to sign the informed consent document. You are free to withdraw from the study at any time.

Most, but not all, clinical trials in the United States are approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are minimal when compared with potential benefits. An IRB is an independent committee that consists of physicians, statisticians, and members of the community who ensure that clinical trials are ethical and that the rights of participants are protected. You should ask the sponsor or research coordinator whether the research you are considering participating in was reviewed by an IRB.

Further reading

For more information about research protections, see:

• Office of Human Research Protection
• Children's Assent to Clinical Trial Participation

For more information on participants’ privacy and confidentiality, see:

• HIPAA Privacy Rule
• The Food and Drug Administration, FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective

For more information about research protections, see: About Research Participation

What happens after a clinical trial is completed?

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 peer-reviewed scientific journals. Peer review is a process by which experts review the report before it is published to ensure that the analysis and conclusions are sound. If the results are particularly important, they may be featured in the news, and discussed at scientific meetings and by patient advocacy groups before or after they are published in a scientific journal. Once a new approach has been proven safe and effective in a clinical trial, it may become a new standard of medical practice.

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 .

How does clinical research make a difference to me and my family?

Only through clinical research can we gain insights and answers about the safety and effectiveness of treatments and procedures. Groundbreaking scientific advances in the present and the past were possible only because of participation of volunteers, both healthy and those with an illness, in clinical research. Clinical research requires complex and rigorous testing in collaboration with communities that are affected by the disease. As research opens new doors to finding ways to diagnose, prevent, treat, or cure disease and disability, clinical trial participation is essential to help us find the answers.

This page last reviewed on October 3, 2022

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How to Interpret and Use a Clinical Practice Guideline or Recommendation : Users’ Guides to the Medical Literature

• 1 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
• 2 Department of Evidence Synthesis and Translation Research, American Dental Association, Chicago, Illinois
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Importance   Clinicians may rely on recommendations from clinical practice guidelines for management of patients.

Observations   A clinical practice guideline is a published statement that includes recommendations that are intended to optimize patient care. In the guideline development process, a panel of experts formulates recommendation questions that guide the retrieval of evidence that is used to inform the recommendations. Typically, methods of guideline development, a summary of the supporting evidence, and a justification of the panel’s decisions accompany the recommendations. To use such guidelines optimally, clinicians must understand the implications of the recommendations, assess the trustworthiness of the development process, and evaluate the extent to which the recommendations are applicable to patients in their practice settings. Helpful recommendations are clear and actionable, and explicitly specify whether they are strong or weak, are appropriate for all patients, or depend on individual patients’ circumstances and values. Rigorous guidelines and recommendations are informed by appropriately conducted, up-to-date systematic reviews that consider outcomes important to patients. Because judgments are involved in the interpretation of the evidence and the process of moving from evidence to recommendations, useful guidelines consider all relevant factors that have a bearing in a clinical decision and are not influenced by conflicts of interest.

Conclusions and Relevance   In considering a guideline’s recommendations, clinicians must decide whether there are important differences between the factors the guideline panel has considered in making recommendations and their own practice setting.

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Brignardello-Petersen R , Carrasco-Labra A , Guyatt GH. How to Interpret and Use a Clinical Practice Guideline or Recommendation : Users’ Guides to the Medical Literature . JAMA. 2021;326(15):1516–1523. doi:10.1001/jama.2021.15319

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Clinical Trials and Clinical Research: A Comprehensive Review

Venkataramana kandi.

1 Clinical Microbiology, Prathima Institute of Medical Sciences, Karimnagar, IND

Sabitha Vadakedath

2 Biochemistry, Prathima Institute of Medical Sciences, Karimnagar, IND

Clinical research is an alternative terminology used to describe medical research. Clinical research involves people, and it is generally carried out to evaluate the efficacy of a therapeutic drug, a medical/surgical procedure, or a device as a part of treatment and patient management. Moreover, any research that evaluates the aspects of a disease like the symptoms, risk factors, and pathophysiology, among others may be termed clinical research. However, clinical trials are those studies that assess the potential of a therapeutic drug/device in the management, control, and prevention of disease. In view of the increasing incidences of both communicable and non-communicable diseases, and especially after the effects that Coronavirus Disease-19 (COVID-19) had on public health worldwide, the emphasis on clinical research assumes extremely essential. The knowledge of clinical research will facilitate the discovery of drugs, devices, and vaccines, thereby improving preparedness during public health emergencies. Therefore, in this review, we comprehensively describe the critical elements of clinical research that include clinical trial phases, types, and designs of clinical trials, operations of trial, audit, and management, and ethical concerns.

Introduction and background

A clinical trial is a systematic process that is intended to find out the safety and efficacy of a drug/device in treating/preventing/diagnosing a disease or a medical condition [ 1 , 2 ]. Clinical trial includes various phases that include phase 0 (micro-dosing studies), phase 1, phase 2, phase 3, and phase 4 [ 3 ]. Phase 0 and phase 2 are called exploratory trial phases, phase 1 is termed the non-therapeutic phase, phase 3 is known as the therapeutic confirmatory phase, and phase 4 is called the post-approval or the post-marketing surveillance phase. Phase 0, also called the micro-dosing phase, was previously done in animals but now it is carried out in human volunteers to understand the dose tolerability (pharmacokinetics) before being administered as a part of the phase 1 trial among healthy individuals. The details of the clinical trial phases are shown in Table ​ Table1 1 .

This table has been created by the authors.

MTD: maximum tolerated dose; SAD: single ascending dose; MAD: multiple ascending doses; NDA: new drug application; FDA: food and drug administration

Clinical research design has two major types that include non-interventional/observational and interventional/experimental studies. The non-interventional studies may have a comparator group (analytical studies like case-control and cohort studies), or without it (descriptive study). The experimental studies may be either randomized or non-randomized. Clinical trial designs are of several types that include parallel design, crossover design, factorial design, randomized withdrawal approach, adaptive design, superiority design, and non-inferiority design. The advantages and disadvantages of clinical trial designs are depicted in Table ​ Table2 2 .

There are different types of clinical trials that include those which are conducted for treatment, prevention, early detection/screening, and diagnosis. These studies address the activities of an investigational drug on a disease and its outcomes [ 4 ]. They assess whether the drug is able to prevent the disease/condition, the ability of a device to detect/screen the disease, and the efficacy of a medical test to diagnose the disease/condition. The pictorial representation of a disease diagnosis, treatment, and prevention is depicted in Figure ​ Figure1 1 .

This figure has been created by the authors.

The clinical trial designs could be improvised to make sure that the study's validity is maintained/retained. The adaptive designs facilitate researchers to improvise during the clinical trial without interfering with the integrity and validity of the results. Moreover, it allows flexibility during the conduction of trials and the collection of data. Despite these advantages, adaptive designs have not been universally accepted among clinical researchers. This could be attributed to the low familiarity of such designs in the research community. The adaptive designs have been applied during various phases of clinical trials and for different clinical conditions [ 5 , 6 ]. The adaptive designs applied during different phases are depicted in Figure ​ Figure2 2 .

The Bayesian adaptive trial design has gained popularity, especially during the Coronavirus Disease-19 (COVID-19) pandemic. Such designs could operate under a single master protocol. It operates as a platform trial wherein multiple treatments can be tested on different patient groups suffering from disease [ 7 ].

In this review, we comprehensively discuss the essential elements of clinical research that include the principles of clinical research, planning clinical trials, practical aspects of clinical trial operations, essentials of clinical trial applications, monitoring, and audit, clinical trial data analysis, regulatory audits, and project management, clinical trial operations at the investigation site, the essentials of clinical trial experiments involving epidemiological, and genetic studies, and ethical considerations in clinical research/trials.

A clinical trial involves the study of the effect of an investigational drug/any other intervention in a defined population/participant. The clinical research includes a treatment group and a placebo wherein each group is evaluated for the efficacy of the intervention (improved/not improved) [ 8 ].

Clinical trials are broadly classified into controlled and uncontrolled trials. The uncontrolled trials are potentially biased, and the results of such research are not considered as equally as the controlled studies. Randomized controlled trials (RCTs) are considered the most effective clinical trials wherein the bias is minimized, and the results are considered reliable. There are different types of randomizations and each one has clearly defined functions as elaborated in Table ​ Table3 3 .

Principles of clinical trial/research

Clinical trials or clinical research are conducted to improve the understanding of the unknown, test a hypothesis, and perform public health-related research [ 2 , 3 ]. This is majorly carried out by collecting the data and analyzing it to derive conclusions. There are various types of clinical trials that are majorly grouped as analytical, observational, and experimental research. Clinical research can also be classified into non-directed data capture, directed data capture, and drug trials. Clinical research could be prospective or retrospective. It may also be a case-control study or a cohort study. Clinical trials may be initiated to find treatment, prevent, observe, and diagnose a disease or a medical condition.

Among the various types of clinical research, observational research using a cross-sectional study design is the most frequently performed clinical research. This type of research is undertaken to analyze the presence or absence of a disease/condition, potential risk factors, and prevalence and incidence rates in a defined population. Clinical trials may be therapeutic or non-therapeutic type depending on the type of intervention. The therapeutic type of clinical trial uses a drug that may be beneficial to the patient. Whereas in a non-therapeutic clinical trial, the participant does not benefit from the drug. The non-therapeutic trials provide additional knowledge of the drug for future improvements. Different terminologies of clinical trials are delineated in Table ​ Table4 4 .

In view of the increased cost of the drug discovery process, developing, and low-income countries depend on the production of generic drugs. The generic drugs are similar in composition to the patented/branded drug. Once the patent period is expired generic drugs can be manufactured which have a similar quality, strength, and safety as the patented drug [ 9 ]. The regulatory requirements and the drug production process are almost the same for the branded and the generic drug according to the Food and Drug Administration (FDA), United States of America (USA).

The bioequivalence (BE) studies review the absorption, distribution, metabolism, and excretion (ADME) of the generic drug. These studies compare the concentration of the drug at the desired location in the human body, called the peak concentration of the drug (Cmax). The extent of absorption of the drug is measured using the area under the receiver operating characteristic curve (AUC), wherein the generic drug is supposed to demonstrate similar ADME activities as the branded drug. The BE studies may be undertaken in vitro (fasting, non-fasting, sprinkled fasting) or in vivo studies (clinical, bioanalytical, and statistical) [ 9 ].

Planning clinical trial/research

The clinical trial process involves protocol development, designing a case record/report form (CRF), and functioning of institutional review boards (IRBs). It also includes data management and the monitoring of clinical trial site activities. The CRF is the most significant document in a clinical study. It contains the information collected by the investigator about each subject participating in a clinical study/trial. According to the International Council for Harmonisation (ICH), the CRF can be printed, optical, or an electronic document that is used to record the safety and efficacy of the pharmaceutical drug/product in the test subjects. This information is intended for the sponsor who initiates the clinical study [ 10 ].

The CRF is designed as per the protocol and later it is thoroughly reviewed for its correctness (appropriate and structured questions) and finalized. The CRF then proceeds toward the print taking the language of the participating subjects into consideration. Once the CRF is printed, it is distributed to the investigation sites where it is filled with the details of the participating subjects by the investigator/nurse/subject/guardian of the subject/technician/consultant/monitors/pharmacist/pharmacokinetics/contract house staff. The filled CRFs are checked for their completeness and transported to the sponsor [ 11 ].

Effective planning and implementation of a clinical study/trial will influence its success. The clinical study majorly includes the collection and distribution of the trial data, which is done by the clinical data management section. The project manager is crucial to effectively plan, organize, and use the best processes to control and monitor the clinical study [ 10 , 11 ].

The clinical study is conducted by a sponsor or a clinical research organization (CRO). A perfect protocol, time limits, and regulatory requirements assume significance while planning a clinical trial. What, when, how, and who are clearly planned before the initiation of a study trial. Regular review of the project using the bar and Gantt charts, and maintaining the timelines assume increased significance for success with the product (study report, statistical report, database) [ 10 , 11 ].

The steps critical to planning a clinical trial include the idea, review of the available literature, identifying a problem, formulating the hypothesis, writing a synopsis, identifying the investigators, writing a protocol, finding a source of funding, designing a patient consent form, forming ethics boards, identifying an organization, preparing manuals for procedures, quality assurance, investigator training and initiation of the trial by recruiting the participants [ 10 ].

The two most important points to consider before the initiation of the clinical trial include whether there is a need for a clinical trial, if there is a need, then one must make sure that the study design and methodology are strong for the results to be reliable to the people [ 11 ].

For clinical research to envisage high-quality results, the study design, implementation of the study, quality assurance in data collection, and alleviation of bias and confounding factors must be robust [ 12 ]. Another important aspect of conducting a clinical trial is improved management of various elements of clinical research that include human and financial resources. The role of a trial manager to make a successful clinical trial was previously reported. The trial manager could play a key role in planning, coordinating, and successfully executing the trial. Some qualities of a trial manager include better communication and motivation, leadership, and strategic, tactical, and operational skills [ 13 ].

Practical aspects of a clinical trial operations

There are different types of clinical research. Research in the development of a novel drug could be initiated by nationally funded research, industry-sponsored research, and clinical research initiated by individuals/investigators. According to the documents 21 code of federal regulations (CFR) 312.3 and ICH E-6 Good Clinical Practice (GCP) 1.54, an investigator is an individual who initiates and conducts clinical research [ 14 ]. The investigator plan, design, conduct, monitor, manage data, compile reports, and supervise research-related regulatory and ethical issues. To manage a successful clinical trial project, it is essential for an investigator to give the letter of intent, write a proposal, set a timeline, develop a protocol and related documents like the case record forms, define the budget, and identify the funding sources.

Other major steps of clinical research include the approval of IRBs, conduction and supervision of the research, data review, and analysis. Successful clinical research includes various essential elements like a letter of intent which is the evidence that supports the interest of the researcher to conduct drug research, timeline, funding source, supplier, and participant characters.

Quality assurance, according to the ICH and GCP guidelines, is necessary to be implemented during clinical research to generate quality and accurate data. Each element of the clinical research must have been carried out according to the standard operating procedure (SOP), which is written/determined before the initiation of the study and during the preparation of the protocol [ 15 ].

The audit team (quality assurance group) is instrumental in determining the authenticity of the clinical research. The audit, according to the ICH and GCP, is an independent and external team that examines the process (recording the CRF, analysis of data, and interpretation of data) of clinical research. The quality assurance personnel are adequately trained, become trainers if needed, should be good communicators, and must handle any kind of situation. The audits can be at the investigator sites evaluating the CRF data, the protocol, and the personnel involved in clinical research (source data verification, monitors) [ 16 ].

Clinical trial operations are governed by legal and regulatory requirements, based on GCPs, and the application of science, technology, and interpersonal skills [ 17 ]. Clinical trial operations are complex, time and resource-specific that requires extensive planning and coordination, especially for the research which is conducted at multiple trial centers [ 18 ].

Recruiting the clinical trial participants/subjects is the most significant aspect of clinical trial operations. Previous research had noted that most clinical trials do not meet the participant numbers as decided in the protocol. Therefore, it is important to identify the potential barriers to patient recruitment [ 19 ].

Most clinical trials demand huge costs, increased timelines, and resources. Randomized clinical trial studies from Switzerland were analyzed for their costs which revealed approximately 72000 USD for a clinical trial to be completed. This study emphasized the need for increased transparency with respect to the costs associated with the clinical trial and improved collaboration between collaborators and stakeholders [ 20 ].

Clinical trial applications, monitoring, and audit

Among the most significant aspects of a clinical trial is the audit. An audit is a systematic process of evaluating the clinical trial operations at the site. The audit ensures that the clinical trial process is conducted according to the protocol, and predefined quality system procedures, following GCP guidelines, and according to the requirements of regulatory authorities [ 21 ].

The auditors are supposed to be independent and work without the involvement of the sponsors, CROs, or personnel at the trial site. The auditors ensure that the trial is conducted by designated professionally qualified, adequately trained personnel, with predefined responsibilities. The auditors also ensure the validity of the investigational drug, and the composition, and functioning of institutional review/ethics committees. The availability and correctness of the documents like the investigational broacher, informed consent forms, CRFs, approval letters of the regulatory authorities, and accreditation of the trial labs/sites [ 21 ].

The data management systems, the data collection software, data backup, recovery, and contingency plans, alternative data recording methods, security of the data, personnel training in data entry, and the statistical methods used to analyze the results of the trial are other important responsibilities of the auditor [ 21 , 22 ].

According to the ICH-GCP Sec 1.29 guidelines the inspection may be described as an act by the regulatory authorities to conduct an official review of the clinical trial-related documents, personnel (sponsor, investigator), and the trial site [ 21 , 22 ]. The summary report of the observations of the inspectors is performed using various forms as listed in Table ​ Table5 5 .

FDA: Food and Drug Administration; IND: investigational new drug; NDA: new drug application; IRB: institutional review board; CFR: code of federal regulations

Because protecting data integrity, the rights, safety, and well-being of the study participants are more significant while conducting a clinical trial, regular monitoring and audit of the process appear crucial. Also, the quality of the clinical trial greatly depends on the approach of the trial personnel which includes the sponsors and investigators [ 21 ].

The responsibility of monitoring lies in different hands, and it depends on the clinical trial site. When the trial is initiated by a pharmaceutical industry, the responsibility of trial monitoring depends on the company or the sponsor, and when the trial is conducted by an academic organization, the responsibility lies with the principal investigator [ 21 ].

An audit is a process conducted by an independent body to ensure the quality of the study. Basically, an audit is a quality assurance process that determines if a study is carried out by following the SPOs, in compliance with the GCPs recommended by regulatory bodies like the ICH, FDA, and other local bodies [ 21 ].

An audit is performed to review all the available documents related to the IRB approval, investigational drug, and the documents related to the patient care/case record forms. Other documents that are audited include the protocol (date, sign, treatment, compliance), informed consent form, treatment response/outcome, toxic response/adverse event recording, and the accuracy of data entry [ 22 ].

Clinical trial data analysis, regulatory audits, and project management

The essential elements of clinical trial management systems (CDMS) include the management of the study, the site, staff, subject, contracts, data, and document management, patient diary integration, medical coding, monitoring, adverse event reporting, supplier management, lab data, external interfaces, and randomization. The CDMS involves setting a defined start and finishing time, defining study objectives, setting enrolment and termination criteria, commenting, and managing the study design [ 23 ].

Among the various key application areas of clinical trial systems, the data analysis assumes increased significance. The clinical trial data collected at the site in the form of case record form is stored in the CDMS ensuring the errors with respect to the double data entry are minimized.

Clinical trial data management uses medical coding, which uses terminologies with respect to the medications and adverse events/serious adverse events that need to be entered into the CDMS. The project undertaken to conduct the clinical trial must be predetermined with timelines and milestones. Timelines are usually set for the preparation of protocol, designing the CRF, planning the project, identifying the first subject, and timelines for recording the patient’s data for the first visit.

The timelines also are set for the last subject to be recruited in the study, the CRF of the last subject, and the locked period after the last subject entry. The planning of the project also includes the modes of collection of the data, the methods of the transport of the CRFs, patient diaries, and records of severe adverse events, to the central data management sites (fax, scan, courier, etc.) [ 24 ].

The preparation of SOPs and the type and timing of the quality control (QC) procedures are also included in the project planning before the start of a clinical study. Review (budget, resources, quality of process, assessment), measure (turnaround times, training issues), and control (CRF collection and delivery, incentives, revising the process) are the three important aspects of the implementation of a clinical research project.

In view of the increasing complexity related to the conduct of clinical trials, it is important to perform a clinical quality assurance (CQA) audit. The CQA audit process consists of a detailed plan for conducting audits, points of improvement, generating meaningful audit results, verifying SOP, and regulatory compliance, and promoting improvement in clinical trial research [ 25 ]. All the components of a CQA audit are delineated in Table ​ Table6 6 .

CRF: case report form; CSR: clinical study report; IC: informed consent; PV: pharmacovigilance; SAE: serious adverse event

Clinical trial operations at the investigator's site

The selection of an investigation site is important before starting a clinical trial. It is essential that the individuals recruited for the study meet the inclusion criteria of the trial, and the investigator's and patient's willingness to accept the protocol design and the timelines set by the regulatory authorities including the IRBs.

Before conducting clinical research, it is important for an investigator to agree to the terms and conditions of the agreement and maintain the confidentiality of the protocol. Evaluation of the protocol for the feasibility of its practices with respect to the resources, infrastructure, qualified and trained personnel available, availability of the study subjects, and benefit to the institution and the investigator is done by the sponsor during the site selection visit.

The standards of a clinical research trial are ensured by the Council for International Organizations of Medical Sciences (CIOMS), National Bioethics Advisory Commission (NBAC), United Nations Programme on Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) (UNAIDS), and World Medical Association (WMA) [ 26 ].

Recommendations for conducting clinical research based on the WMA support the slogan that says, “The health of my patient will be my first consideration.” According to the International Code of Medical Ethics (ICME), no human should be physically or mentally harmed during the clinical trial, and the study should be conducted in the best interest of the person [ 26 ].

Basic principles recommended by the Helsinki declaration include the conduction of clinical research only after the prior proof of the safety of the drug in animal and lab experiments. The clinical trials must be performed by scientifically, and medically qualified and well-trained personnel. Also, it is important to analyze the benefit of research over harm to the participants before initiating the drug trials.

The doctors may prescribe a drug to alleviate the suffering of the patient, save the patient from death, and gain additional knowledge of the drug only after obtaining informed consent. Under the equipoise principle, the investigators must be able to justify the treatment provided as a part of the clinical trial, wherein the patient in the placebo arm may be harmed due to the unavailability of the therapeutic/trial drug.

Clinical trial operations greatly depend on the environmental conditions and geographical attributes of the trial site. It may influence the costs and targets defined by the project before the initiation. It was noted that one-fourth of the clinical trial project proposals/applications submit critical data on the investigational drug from outside the country. Also, it was noted that almost 35% of delays in clinical trials owing to patient recruitment with one-third of studies enrolling only 5% of the participants [ 27 ].

It was suggested that clinical trial feasibility assessment in a defined geographical region may be undertaken for improved chances of success. Points to be considered under the feasibility assessment program include if the disease under the study is related to the population of the geographical region, appropriateness of the study design, patient, and comparator group, visit intervals, potential regulatory and ethical challenges, and commitments of the study partners, CROs in respective countries (multi-centric studies) [ 27 ].

Feasibility assessments may be undertaken at the program level (ethics, regulatory, and medical preparedness), study level (clinical, regulatory, technical, and operational aspects), and at the investigation site (investigational drug, competency of personnel, participant recruitment, and retention, quality systems, and infrastructural aspects) [ 27 ].

Clinical trials: true experiments

In accordance with the revised schedule "Y" of the Drugs and Cosmetics Act (DCA) (2005), a drug trial may be defined as a systematic study of a novel drug component. The clinical trials aim to evaluate the pharmacodynamic, and pharmacokinetic properties including ADME, efficacy, and safety of new drugs.

According to the drug and cosmetic rules (DCR), 1945, a new chemical entity (NCE) may be defined as a novel drug approved for a disease/condition, in a specified route, and at a particular dosage. It also may be a new drug combination, of previously approved drugs.

A clinical trial may be performed in three types; one that is done to find the efficacy of an NCE, a comparison study of two drugs against a medical condition, and the clinical research of approved drugs on a disease/condition. Also, studies of the bioavailability and BE studies of the generic drugs, and the drugs already approved in other countries are done to establish the efficacy of new drugs [ 28 ].

Apart from the discovery of a novel drug, clinical trials are also conducted to approve novel medical devices for public use. A medical device is defined as any instrument, apparatus, appliance, software, and any other material used for diagnostic/therapeutic purposes. The medical devices may be divided into three classes wherein class I uses general controls; class II uses general and special controls, and class III uses general, special controls, and premarket approvals [ 28 ].

The premarket approval applications ensure the safety and effectiveness, and confirmation of the activities from bench to animal to human clinical studies. The FDA approval for investigational device exemption (IDE) for a device not approved for a new indication/disease/condition. There are two types of IDE studies that include the feasibility study (basic safety and potential effectiveness) and the pivotal study (trial endpoints, randomization, monitoring, and statistical analysis plan) [ 28 ].

As evidenced by the available literature, there are two types of research that include observational and experimental research. Experimental research is alternatively known as the true type of research wherein the research is conducted by the intervention of a new drug/device/method (educational research). Most true experiments use randomized control trials that remove bias and neutralize the confounding variables that may interfere with the results of research [ 28 ].

The variables that may interfere with the study results are independent variables also called prediction variables (the intervention), dependent variables (the outcome), and extraneous variables (other confounding factors that could influence the outside). True experiments have three basic elements that include manipulation (that influence independent variables), control (over extraneous influencers), and randomization (unbiased grouping) [ 29 ].

Experiments can also be grouped as true, quasi-experimental, and non-experimental studies depending on the presence of specific characteristic features. True experiments have all three elements of study design (manipulation, control, randomization), and prospective, and have great scientific validity. Quasi-experiments generally have two elements of design (manipulation and control), are prospective, and have moderate scientific validity. The non-experimental studies lack manipulation, control, and randomization, are generally retrospective, and have low scientific validity [ 29 ].

Clinical trials: epidemiological and human genetics study

Epidemiological studies are intended to control health issues by understanding the distribution, determinants, incidence, prevalence, and impact on health among a defined population. Such studies are attempted to perceive the status of infectious diseases as well as non-communicable diseases [ 30 ].

Experimental studies are of two types that include observational (cross-sectional studies (surveys), case-control studies, and cohort studies) and experimental studies (randomized control studies) [ 3 , 31 ]. Such research may pose challenges related to ethics in relation to the social and cultural milieu.

Biomedical research related to human genetics and transplantation research poses an increased threat to ethical concerns, especially after the success of the human genome project (HGP) in the year 2000. The benefits of human genetic studies are innumerable that include the identification of genetic diseases, in vitro fertilization, and regeneration therapy. Research related to human genetics poses ethical, legal, and social issues (ELSI) that need to be appropriately addressed. Most importantly, these genetic research studies use advanced technologies which should be equally available to both economically well-placed and financially deprived people [ 32 ].

Gene therapy and genetic manipulations may potentially precipitate conflict of interest among the family members. The research on genetics may be of various types that include pedigree studies (identifying abnormal gene carriers), genetic screening (for diseases that may be heritable by the children), gene therapeutics (gene replacement therapy, gene construct administration), HGP (sequencing the whole human genome/deoxyribonucleic acid (DNA) fingerprinting), and DNA, cell-line banking/repository [ 33 ]. The biobanks are established to collect and store human tissue samples like umbilical tissue, cord blood, and others [ 34 ].

Epidemiological studies on genetics are attempts to understand the prevalence of diseases that may be transmitted among families. The classical epidemiological studies may include single case observations (one individual), case series (< 10 individuals), ecological studies (population/large group of people), cross-sectional studies (defined number of individuals), case-control studies (defined number of individuals), cohort (defined number of individuals), and interventional studies (defined number of individuals) [ 35 ].

Genetic studies are of different types that include familial aggregation (case-parent, case-parent-grandparent), heritability (study of twins), segregation (pedigree study), linkage study (case-control), association, linkage, disequilibrium, cohort case-only studies (related case-control, unrelated case-control, exposure, non-exposure group, case group), cross-sectional studies, association cohort (related case-control, familial cohort), and experimental retrospective cohort (clinical trial, exposure, and non-exposure group) [ 35 ].

Ethics and concerns in clinical trial/research

Because clinical research involves animals and human participants, adhering to ethics and ethical practices assumes increased significance [ 36 ]. In view of the unethical research conducted on war soldiers after the Second World War, the Nuremberg code was introduced in 1947, which promulgated rules for permissible medical experiments on humans. The Nuremberg code suggests that informed consent is mandatory for all the participants in a clinical trial, and the study subjects must be made aware of the nature, duration, and purpose of the study, and potential health hazards (foreseen and unforeseen). The study subjects should have the liberty to withdraw at any time during the trial and to choose a physician upon medical emergency. The other essential principles of clinical research involving human subjects as suggested by the Nuremberg code included benefit to the society, justification of study as noted by the results of the drug experiments on animals, avoiding even minimal suffering to the study participants, and making sure that the participants don’t have life risk, humanity first, improved medical facilities for participants, and suitably qualified investigators [ 37 ].

During the 18th world medical assembly meeting in the year 1964, in Helsinki, Finland, ethical principles for doctors practicing research were proposed. Declaration of Helsinki, as it is known made sure that the interests and concerns of the human participants will always prevail over the interests of the society. Later in 1974, the National Research Act was proposed which made sure that the research proposals are thoroughly screened by the Institutional ethics/Review Board. In 1979, the April 18th Belmont report was proposed by the national commission for the protection of human rights during biomedical and behavioral research. The Belmont report proposed three core principles during research involving human participants that include respect for persons, beneficence, and justice. The ICH laid down GCP guidelines [ 38 ]. These guidelines are universally followed throughout the world during the conduction of clinical research involving human participants.

ICH was first founded in 1991, in Brussels, under the umbrella of the USA, Japan, and European countries. The ICH conference is conducted once every two years with the participation from the member countries, observers from the regulatory agencies, like the World Health Organization (WHO), European Free Trade Association (EFTA), and the Canadian Health Protection Branch, and other interested stakeholders from the academia and the industry. The expert working groups of the ICH ensure the quality, efficacy, and safety of the medicinal product (drug/device). Despite the availability of the Nuremberg code, the Belmont Report, and the ICH-GCP guidelines, in the year 1982, International Ethical Guidelines for Biomedical Research Involving Human Subjects was proposed by the CIOMS in association with WHO [ 39 ]. The CIOMS protects the rights of the vulnerable population, and ensures ethical practices during clinical research, especially in underdeveloped countries [ 40 ]. In India, the ethical principles for biomedical research involving human subjects were introduced by the Indian Council of Medical Research (ICMR) in the year 2000 and were later amended in the year 2006 [ 41 ]. Clinical trial approvals can only be done by the IRB approved by the Drug Controller General of India (DGCI) as proposed in the year 2013 [ 42 ].

Current perspectives and future implications

A recent study attempted to evaluate the efficacy of adaptive clinical trials in predicting the success of a clinical trial drug that entered phase 3 and minimizing the time and cost of drug development. This study highlighted the drawbacks of such clinical trial designs that include the possibility of type 1 (false positive) and type 2 (false negative) errors [ 43 ].

The usefulness of animal studies during the preclinical phases of a clinical trial was evaluated in a previous study which concluded that animal studies may not completely guarantee the safety of the investigational drug. This is noted by the fact that many drugs which passed toxicity tests in animals produced adverse reactions in humans [ 44 ].

The significance of BE studies to compare branded and generic drugs was reported previously. The pharmacokinetic BE studies of Amoxycillin comparing branded and generic drugs were carried out among a group of healthy participants. The study results have demonstrated that the generic drug had lower Cmax as compared to the branded drug [ 45 ].

To establish the BE of the generic drugs, randomized crossover trials are carried out to assess the Cmax and the AUC. The ratio of each pharmacokinetic characteristic must match the ratio of AUC and/or Cmax, 1:1=1 for a generic drug to be considered as a bioequivalent to a branded drug [ 46 ].

Although the generic drug development is comparatively more beneficial than the branded drugs, synthesis of extended-release formulations of the generic drug appears to be complex. Since the extended-release formulations remain for longer periods in the stomach, they may be influenced by gastric acidity and interact with the food. A recent study suggested the use of bio-relevant dissolution tests to increase the successful production of generic extended-release drug formulations [ 47 ].

Although RCTs are considered the best designs, which rule out bias and the data/results obtained from such clinical research are the most reliable, RCTs may be plagued by miscalculation of the treatment outcomes/bias, problems of cointerventions, and contaminations [ 48 ].

The perception of healthcare providers regarding branded drugs and their view about the generic equivalents was recently analyzed and reported. It was noted that such a perception may be attributed to the flexible regulatory requirements for the approval of a generic drug as compared to a branded drug. Also, could be because a switch from a branded drug to a generic drug in patients may precipitate adverse events as evidenced by previous reports [ 49 ].

Because the vulnerable population like drug/alcohol addicts, mentally challenged people, children, geriatric age people, military persons, ethnic minorities, people suffering from incurable diseases, students, employees, and pregnant women cannot make decisions with respect to participating in a clinical trial, ethical concerns, and legal issues may prop up, that may be appropriately addressed before drug trials which include such groups [ 50 ].

Conclusions

Clinical research and clinical trials are important from the public health perspective. Clinical research facilitates scientists, public health administrations, and people to increase their understanding and improve preparedness with reference to the diseases prevalent in different geographical regions of the world. Moreover, clinical research helps in mitigating health-related problems as evidenced by the current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic and other emerging and re-emerging microbial infections. Clinical trials are crucial to the development of drugs, devices, and vaccines. Therefore, scientists are required to be up to date with the process and procedures of clinical research and trials as discussed comprehensively in this review.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.

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Article Contents

Introduction, terminology, development, determining the strength of the body of evidence, quality appraisal, presentation and communication, implementation, configuring cpgs to different settings: adopting, contextualizing or adapting, shared decision-making, authors’ contribution.

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Guide to clinical practice guidelines: the current state of play

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Tamara Kredo, Susanne Bernhardsson, Shingai Machingaidze, Taryn Young, Quinette Louw, Eleanor Ochodo, Karen Grimmer, Guide to clinical practice guidelines: the current state of play, International Journal for Quality in Health Care , Volume 28, Issue 1, February 2016, Pages 122–128, https://doi.org/10.1093/intqhc/mzv115

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Extensive research has been undertaken over the last 30 years on the methods underpinning clinical practice guidelines (CPGs), including their development, updating, reporting, tailoring for specific purposes, implementation and evaluation. This has resulted in an increasing number of terms, tools and acronyms. Over time, CPGs have shifted from opinion-based to evidence-informed, including increasingly sophisticated methodologies and implementation strategies, and thus keeping abreast of evolution in this field of research can be challenging.

This article collates findings from an extensive document search, to provide a guide describing standards, methods and systems reported in the current CPG methodology and implementation literature. This guide is targeted at those working in health care quality and safety and responsible for either commissioning, researching or delivering health care. It is presented in a way that can be updated as the field expands.

CPG development and implementation have attracted the most international interest and activity, whilst CPG updating, adopting (with or without contextualization), adapting and impact evaluation are less well addressed.

High-quality, evidence-informed clinical practice guidelines (CPGs) offer a way of bridging the gap between policy, best practice, local contexts and patient choice. Clinical guidelines have been upheld as an essential part of quality medical practice for several decades. An early definition of CPGs by the Institute of Medicine (IOM) [ 1 ] described it as ‘systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.’ This definition was updated in 2011 to more strongly emphasize rigorous methodology in the guideline development processes: ‘Clinical guidelines are statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options’ [ 2 ]. In this rapidly evolving field of research, a more recent definition suggested a modern twist to the guideline description: ‘Guidelines are a convenient way of packaging evidence and presenting recommendations to healthcare decision makers’ [ 3 ].

Guidelines have a range of purposes, intended to improve effectiveness and quality of care, to decrease variations in clinical practice and to decrease costly and preventable mistakes and adverse events. They generally include statements of expected practice; provide benchmarks or standards against which individuals can audit; compare and potentially improve their practices; or guidance regarding undertaking particular tasks [ 4 , 5 ]. Quality improvement initiatives are linked with CPGs, as evidence-informed recommendations form the basis for identifying core outcomes and measurable standards of care [ 6 ]. Internationally, over the past decade in particular, an industry seems to have developed around CPG development, reporting, adoption, contextualization or adaptation, evaluation and implementation. The growing volume of evidence and the acronyms used in this field can be overwhelming, even for those involved. This article is targeted at individuals and organizations working in health care quality and safety; and responsible for either commissioning, researching or delivering health care. We aim to provide a guide describing common standards, methods and systems used in current international CPG activities and the various activities to produce and communicate them.

Guidelines, CPGs, protocols and care pathways are commonly used terms, but without common agreement about their definitions [ 7 ]. Definitions that we have found useful are that guidelines relate to broader systems, such as those found in primary care (e.g. water or air quality, food security, incident reporting and investigation, etc.) and are generally developed and used by policy-makers, service organizations, funders or regulatory authorities. CPGs relate to clinical matters, generally dealing with clinical conditions or symptoms, and are typically intended for use by health care providers and clinic managers [ 4 ]. They can include best-practice statements for any one or combination of concerns regarding screening, diagnosis, management or monitoring. The term ‘protocol’ is commonly used to prescribe behaviours at diplomatic and societal events. In health, it has the meaning of rules or instructions about how to do a particular process explicitly, and without error. Care pathways generally relate to a series of evidence-informed steps, which can involve a multidisciplinary team at various care levels (i.e. primary, secondary), which should underpin the journey of care of patients with a particular diagnosis [ 8 , 9 ]. Whilst broadly similar to CPGs, clinical pathways differ by being more explicit about the sequence, timing and provision of interventions. They are usually based on CPGs and contextualized for use within specific environments or circumstances [ 9 ].

There are detailed processes available for developing a CPG. Notably, there are well-credentialed international and national guideline development groups, including the World Health Organization (WHO) [ 10 ], the Scottish Intercollegiate Guidelines Network (SIGN) [ 11 ], the National Institute for Health and Care Excellence (NICE) [ 12 ] and the Australian National Health and Medical Research Council (NHMRC) [ 13 ], each with their own approach to guideline construction and writing, usually described in a guideline development manual.

Globally, potentially many hundreds more health departments, insurers and other health care organizations, professional associations, hospitals, specialty colleges and individuals have attempted to produce recommendations to improve and/or standardize local clinical practices, all using their own interpretations of the best way to construct and write CPGs. The most common approach to CPG development seems to come from the efforts of small teams of dedicated volunteers, often working with minimal funding and variable understanding of CPG development methods, to produce recommendations for practice in local settings, based on a range of evidence sources. These include peer-reviewed literature, grey literature, other CPGs and expert opinion. Historically, CPGs were built mostly on expert opinion, which included variable (and often selective) reference to research evidence [ 14 , 15 ]. Such CPGs are still found today, albeit in decreasing numbers, as transparently constructed evidence-informed approaches integrated with expert opinion and patient values have rapidly gained acceptance over the past two decades as the best approach to CPG development [ 14 , 15 ]. To add to the complexity of the evolution of CPG development, developers around the world have used a range of different and purpose-built approaches to identify, appraise, synthesize and describe the evidence base underpinning best-practice statements. Thus, there is no standard approach to any aspect of CPG activity.

However, evidence of a maturing CPG development culture internationally is seen in recent attempts to standardize practices. In 2011, the Institute of Medicine (IOM) introduced eight standards for CPG development [ 16 ], which are similar to those promoted by the Guidelines International Network (G-I-N) [ 17 ] (Table  1 ).

Comparing the elements of clinical practice guideline development between the Institute of Medicine (IOM) and the Guidelines International Network (G-I-N)

In addition, a recent enterprise, conducted by McMaster University, systematically and comprehensively reviewed the methodological content of 35 international CPG development manuals, to identify key CPG development components. This work included the G-I-N and IOM criteria. The McMaster Group developed a checklist of 18 topics and 146 items [ 18 ]. This project, Guidelines 2.0, itemized all potentially relevant CPG steps, linked to primary resources and is able to be contextualized or adapted to local contexts. This provides a comprehensive resource; however, given the extensive list of items included, it may not be user-friendly. In another example of efforts to standardize methods, a step-by-step manual was developed to assist CPG developers in the area of head and neck cancer surgery [ 19 ].

Given these widely available best-practice approaches to CPG development that are now available to all, it seems sensible to reconsider the need for future ad hoc CPG development that does not comply with recommendations from at least one of these approaches [ 16 ]. Moreover, there is a wealth of freely accessible, good-quality CPGs from internationally respected development agencies [ 9–12 ] that can be adopted and then configured to meet local needs, using emerging CPG contextualization or adaptation methods (refer to ‘adopting, contextualising, adapting’ section) [ 10–13 ]. Thus there seems little merit in producing new CPGs, unless a true gap exists in available guidance. This gap should be verified by a comprehensive search of CPG repositories before any de novo activities take place. Where de novo CPGs are required, there are many comprehensive evidence-synthesis resources available (such as the Cochrane database of systematic reviews), which should make the CPG development processes less demanding. Given these efficiencies in sourcing the research evidence, the key issues for discussion by the development teams could then be oriented to the use and inclusion of local contextualized evidence regarding resource requirements, feasibility, cultural issues, patient preferences, values and approaches for shared decision-making.

A critical methodological quality issue in CPG development is how best to describe the strength of the evidence underpinning recommendations. Numerous approaches to grading evidence have been developed. However, in the last few years, two main approaches have emerged to support systematic and comprehensive evidence synthesis: Grading of Recommendations Assessment, Development and Evaluation (GRADE) [ 20–23 ] and the Australian NHMRC approach, Formulating Recommendations Matrix (FORM) [ 24 ]. The GRADE approach has gained momentum internationally, with acceptance by, among other organizations, the WHO's Guideline Review Committee [ 10 ]. The GRADE and FORM approaches not only assist CPG developers to summarize the evidence body for a recommendation and consider its local relevance but also provide advice on how to proceed from evidence to recommendations in a standardized and transparent manner.

Similar to evidence grading, a number of tools have been developed to support critical appraisal of CPG quality. Many of them have focused on structural issues such as the composition of the CPG team, the review dates, the layout and the CPG purpose and end use, whilst others focus on rigour of methodological development and applicability [ 25–27 ]. The AGREE II instrument (Appraisal of Guideline ResEarch and Evaluation) [ 28 , 29 ] emerged internationally five years ago. It comprises six domains with a total of 23 items, each scored 1–7 (Strongly Disagree through to Strongly Agree). More than one scorer is required to determine a valid score, and a scoring rubric is required to combine scores into one composite score for each domain. A new, simplified tool, the iCAHE CPG quality checklist, was recently developed as an alternative to the AGREE approach [ 30 ]. The iCAHE instrument items were based on perspectives of CPG quality of busy clinicians, educators and policy-makers. It has similar domains to AGREE II, but only 14 questions, each with a binary response (Yes/No), requiring one scorer, and the overall score is the sum of the ‘Yes’ responses. Both instruments include questions regarding the CPG process, that is, the identification and reporting of the body of evidence underpinning the CPG. The two instruments show moderate to strong correlation in pilot testing ( r = 0.89) with the iCAHE tool requiring significantly less time to administer.

Considering the substantial international effort invested in CPG development, there has been much less research into the process of CPG updating. Whilst the importance of updating is noted in most CPG development manuals, specific processes for doing so are poorly described [ 31 ]. Examples of guidance on updating from the G-I-N and IOM development standards are provided in Table  2 .

Examples of guidance for updating from the Institute of Medicine (IOM) and the Guidelines International Network (G-I-N)

A recently published systematic review aimed to identify best practices for updating CPGs [ 31 ]. The review authors systematically identified and appraised 35 CPG development handbooks which included information on CPG updating. They concluded that the available guidance on updating processes was lacking in detail, used variable terminology, and that more rigorous and explicit guidance would increase the trustworthiness of updated CPGs. This review did not include the systematic approach published in 2003 by Johnston et al. from the Cancer Care Ontario Practice Guidelines Initiative, which reports four criteria for use after an updated literature review has been performed. These criteria provide clear guidance regarding how recent literature might alter the earlier strength of the body of evidence (p. 648) (Table  3 ) [ 32 ]. These criteria have been used for the last three updates of the Acute pain management CPG by the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine [ 33 ].

Clinical Practice Guideline Update elements [ 32 ]

Technologies for ‘dynamic updating’ of CPGs are also emerging [ 34 ]. The GRADE group is currently piloting an international collaborative initiative in CPG writing with corresponding implementation plans, aimed at ready implementation of recommendations – DECIDE: Developing and Evaluating Communication strategies to support Informed Decisions and practice based on Evidence [ 3 ]. This Consortium has supported the development of two interactive CPG development tools, the GDT ( http://gdt.guidelinedevelopment.org/ ) [ 35 ] and ‘Making GRADE the Irresistible Choice’ MAGICapp ( http://www.magicapp.org/ ) [ 36 ]. These multi-layer development and dissemination software tools could put up-to-date CPGs literally ‘in the pockets’ of clinicians via smartphones and tablets. These tools also allow for dynamic updating of evidence sources, and integration of evidence with electronic medical record tools [ 34 ].

Concurrent with the evolution of standardized CPG development principles, there has been increasing interest in the manner in which recommendations are written and presented to best support uptake. This interest has stemmed from concerns with the need to address structural barriers to CPG uptake, in the way recommendations are worded and presented, as well as external barriers to implementation such as access and relevance [ 37 ]. To address this, a specific tool was developed for CPG developers and implementers (GuideLine Implementability Appraisal (GLIA)) that provided 10 dimensions of 31 items, including decidability and executability, global, presentation and formatting, measurable outcomes, apparent validity, flexibility and effect on process of care [ 38 ]. The DECIDE consortium is exploring methods to ensure effective communication of evidence-based recommendations targeted at key stakeholders: health care professionals, policy-makers and managers, as well as patients and the general public. Their multi-layer development and dissemination software tools allow one-click adaptation of display of content depending on the audience [ 3 ].

Another recently launched tool, GUIDE-M, is intended to enhance quality, implementability and acceptability of CPGs, the ‘Guideline Implementability for Decision Excellence Model’ ( www.guide-m.ca ) [ 39 ]. This tool was developed to reflect an evidence-informed, international and multidisciplinary perspective to putting CPGs into practice.

There is surprisingly little decisive guidance on how CPGs can be successfully implemented , and the knowledge gap regarding the effectiveness of CPGs on patient health outcomes is substantial. More is known about the effectiveness of various implementation strategies on process outcomes (how the system works) rather than clinical outcomes, although this impact is often modest [ 37 , 40 ]. An overview by Grimshaw (2012) showed effects of evidence implementation strategies (not specific to CPGs) such as educational measures, audit and feedback, opinion leaders and tailored interventions, which resulted in 4.3–12% in median absolute improvements in care [ 41 ]. CPG implementation often requires behaviour change by health care professionals, patients and other stakeholders within the health care system, because they may need to change or discard ‘usual’ practices in light of current best-evidence recommendations.

CPG recommendations often include the introduction of new technologies or interventions or discontinuation of ineffective, costly or harmful interventions. To do this requires significant and often swift changes in clinician behaviour. For behaviour change to be successful, consideration of the context in which the CPG is to be used is paramount [ 42–44 ]. Several implementation theories account for context explicitly, e.g. the Promoting Action on Research Implementation in Health Services framework [ 45 ], the Consolidated Framework for Implementation Research [ 46 ] and the Theoretical Domains Framework (TDF) [ 47 , 48 ]. The TDF is a validated framework that includes 14 domains of theoretical constructs and has been tested for developing complex interventions to implement changes in health care settings [ 49 ].

Theoretical frameworks of implementation can facilitate planning and executing implementation of CPG recommendations, as well as support evaluation of CPG impact [ 50–53 ]. However, few published CPG implementation interventions use specific theories. A recent systematic review reported that only one-fifth of the 235 CPG implementation studies reviewed used a specific theory [ 54 ]. Moreover, critics of implementation theories have highlighted the poor evidence supporting them and suggested that a common-sense approach may do just as well [ 55 , 56 ]. However, there seems to be emerging evidence that behaviour-change processes applied in CPG implementation, that are informed by theory are more effective than those that are not and that theory should be used to establish causal relationships between theoretical constructs and effects of aspects of implementation [ 56 , 57 ]. Further research is required to understand the practical aspects of how CPG recommendations can be effectively and efficiently implemented in ways that produce improvements in processes and clinical outcomes.

Since the early 2000s, there has been increasing international recognition of the potential for efficiency and value of taking CPGs developed in one country and applying them to other countries. This is intended to avoid duplication of effort in de nov o guideline development, when useful CPGs may exist elsewhere [ 26 , 58 ]. There is no consensus on the appropriate terminology to use for transferring CPGs from one health system or health setting to another, or for subsequent configuration of CPGs for local contexts and needs. The ADAPTE Collaboration, a strategic collaboration between two international CPG research groups (ADAPTE and Practice Guideline Evaluation and Adaptation Cycle) proposes an ‘adaptation’ approach in their resource manual (distributed via G-I-N (ADAPTE Collaboration 2009)) [ 59 ]. Their work describes the direct transfer of CPGs across similar income and health systems settings.

Another approach, that of adopting and then contextualizing, underpinned an innovative Filipino CPG implementation project [ 60 ]. The ADAPTE process lacked detail on the specifics of ‘how to’ transfer recommendations from CPGs developed in high-income to low-income country settings, where health care policy and contexts, funding, workforce, resources and training are significantly different. The CPG working group from the Philippines Academy of Rehabilitation Medicine differentiated between the notions of ‘adaptation’ and ‘contextualization’ and proposed an innovative adoption and contextualization approach, by mapping recommendations from multiple CPGs into a typical Filipino patient pathway, and then developing local ‘context points’ to support local uptake [ 61 ]. This work has since been recognized as best practice for lower- and middle-income countries by the International Society of Physical and Rehabilitation Medicine (ISPRM) and provides a practical, cost-effective and efficient alternative approach to developing local context de novo CPGs.

Shared decision-making occurs when patients and their health care providers make joint decisions about health care interventions based on best research evidence, and layered by patient preferences, values, clinical judgement and local contexts [ 62 , 63 ]. When done well, shared decision-making and mutual agreement on the way forward for the management of a patient's condition could be considered the desired end-point of CPG implementation [ 62 , 64 ]. Where high-quality evidence is lacking, shared decisions will rely more heavily on clinician perspectives and patient preferences [ 65 ]. Barriers to effective shared decision-making include lack of time, skills, knowledge, mutual respect and effective communication processes [ 63 , 66 ]. A Cochrane review evaluating shared decision-making interventions reported low-quality evidence for the effectiveness of any intervention targeting health care professionals, patients or both. However, the authors conclude that despite the low-quality evidence, any intervention targeting both parties is consistently better than targeting either one or no intervention [ 63 ].

Decision aids are tools designed specifically to help with decision-making, with particular application in the context of low-quality or uncertain evidence [ 66 ]. These tools have been reported to increase absolute knowledge of patients amongst other benefits; however, effects on clinical outcomes are to date uncertain [ 67 ]. Rapid developments in evidence mean that decision aids may be out-of-date, and the process for updating may be onerous and, in many cases, not done [ 66 ]. There is a move to use new technology to support this process. Point-of-care decision aids include short one-page summaries as in ‘Option Grids’ ( www.optiongrid.co.uk ) [ 68 ]. Technology in development includes the previously mentioned MAGICapp group, where the layered approach extends to patient end-user tools for use in consultation, linked with the SHARE-IT project evaluating the value of the decision aid in clinical care ( http://magicproject.org/share-it/ ) [ 69 ].

This paper explores the standards, methods and systems in use by those involved with CPGs and provides a synthesis of the current state of play of international guideline activity. It also highlights the immense efforts being made by researchers, clinicians and policy-makers who are committed to optimizing ways in which evidence is packaged to improve care.

The tools described in this paper are not all uniformly accessible or user-friendly. They have variable evidence of psychometric properties and utility, and many require additional research to ensure that they can be applied appropriately in different CPG contexts.

CPG activities are evolving processes. We anticipate that the next decade will see significant further research into tools to underpin best practices in CPG activities. Given the increasing number of high-quality CPGs that are freely available internationally for a range of health conditions, we propose that the growth areas in CPG methods in the next decade will be in updating, adopting, contextualizing and/or adapting, and implementing. Moreover, the next generation of CPG activities should build on knowledge of current activities in development, advance processes of end-user engagement, and evaluate CPG impact on health outcomes.

K.G. lead the design and execution of the paper. Q.A.L., T.Y., T.K., S.M., S.B. and E.O. contributed to the conception or execution of the paper. All authors approved the final version

This project was supported by the South African Medical Research Council Flagship Grants, 2014–2017 for the project South African Guidelines Excellence (SAGE), Cochrane South Africa, South African Medical Research Council.

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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.

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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.

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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 .

Here’s how you know

• U.S. Department of Health and Human Services
• National Institutes of Health

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• TRIPOD+AI: an updated...

TRIPOD+AI: an updated reporting guideline for clinical prediction models

Linked research methods & reporting.

TRIPOD+AI statement: updated guidance for reporting clinical prediction models that use regression or machine learning methods

Linked Opinion

Making the black box more transparent: improving the reporting of artificial intelligence studies in healthcare

• Related content
• Peer review
• Jérémie F Cohen , senior researcher in clinical epidemiology 1 2 ,
• Patrick M M Bossuyt , professor of clinical epidemiology 3
• 1 Centre of Research in Epidemiology and Statistics (CRESS), INSERM, EPOPé Research Team, Université Paris Cité, 75014 Paris, France
• 2 Department of General Pediatrics and Pediatric Infectious Diseases, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France
• 3 Department of Epidemiology and Data Science, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands
• Correspondence to: J F Cohen jeremie.cohen{at}inserm.fr

New update promotes best practice in this important area of clinical research

Clinical prediction models emerged in the 1990s as tools to support medical decision making through individual diagnostic and prognostic predictions based on structured clinical information. Clinical prediction rules such as the FeverPAIN score for pharyngitis 1 or the PECARN rule for children with head trauma 2 are based on prediction models and aid clinicians in prescribing antibiotics and ordering computed tomography (CT) scans, respectively.

In a linked paper (doi: 10.1136/bmj‑2023‑07837), Collins and colleagues introduce TRIPOD+AI, an updated version of the TRIPOD statement to improve the reporting of studies on the development and evaluation of clinical prediction models. 3 Transparent, accurate, and complete reporting is a prerequisite to any form of quality assessment of a study—including evaluating the risk of bias and applicability of study results—and increases the value and usability of scientific reports. 2 Given evidence of suboptimal reporting in studies of clinical prediction models, the TRIPOD group released a reporting guideline in 2015. 4 TRIPOD 2015 and its 22 item checklist are currently recommended by about 20% of high impact medical journals. 5 As with other reporting guidelines, TRIPOD does not prescribe how studies should be conducted but highlights essential items that should be present in study reports.

Traditionally, most clinical prediction models were developed using a regression framework, such as logistic regression for binary diagnostic outcomes or Cox regression for time dependent prognostic outcomes. More recently, artificial intelligence has gained momentum because of the availability of large and diverse datasets, the wide dissemination of software in healthcare settings, and new statistical approaches capable of handling complex relationships between variables and high dimensional datasets. Machine learning, a branch of artificial intelligence, has been particularly dynamic and has found several applications in clinical prediction. 6

The new TRIPOD+AI guideline incorporates recent advances in clinical prediction modelling, notably in the realm of machine learning. The update also reflects changes in research practice standards, such as the growing emphasis on fairness, reproducibility, and research integrity, as well as the principles of open science, including public and patient involvement in research. Furthermore, efforts have been made to improve consistency in terminology between machine learning and traditional clinical research communities.

To update the original TRIPOD statement, the authors established a steering committee that conducted literature reviews to identify potential new items. The group then relied on input from a large and diverse panel of 200 international experts who participated in a two round, modified online Delphi exercise to achieve consensus on the final set of 27 items retained in the checklist. TRIPOD+AI also provides a short 12 item checklist for journal and conference abstracts.

The benefits of TRIPOD+AI will extend to primary researchers, readers, and systematic reviewers of clinical prediction model studies, editors and peer reviewers, patients, funders, public health decision makers, and the public. Beyond its goal to enhance reporting, the guideline also offers educational value through its glossary, explaining terms used in the checklist, and an abridged explanation and elaboration document that provides brief explanations for each subitem.

The authors of TRIPOD+AI must be complimented for their efforts. Yet, some elements of the reporting guideline warrant further consideration. The length of the TRIPOD+AI checklist, which has grown to 27 items and 52 subitems, could be a barrier to implementation. Two influential reporting guidelines, CONSORT 2010 for randomised trials 7 and PRISMA 2020 for systematic reviews, 8 have 38 and 42 subitems, respectively. While items in TRIPOD+AI covering ethics, conflicts of interest, patient and public involvement, and open science might contribute to promoting best research practices, they are not all specific to studies of clinical prediction models and could overlap with standard instructions for authors.

Despite the additions, TRIPOD+AI provides little guidance for studies evaluating clinical prediction models in comparison with or incremental to alternative clinical pathways. Demonstrating added value, in terms of reclassification and accuracy gains, might be critical to justify adoption. Such evaluations will require careful consideration of the proposed role of the model in the clinical pathway, whether as a triage, replacement, add-on, or new test. 9

While beyond the scope of TRIPOD+AI, we encourage researchers and users to also consider other dimensions of clinical prediction models, such as their readiness for deployment, interface between man and machines, acceptability by clinicians and patients, and effects on patient centred outcomes. For studies examining such outcomes, researchers could combine TRIPOD+AI with other reporting guidelines, such as DECIDE-AI 10 and CONSORT-AI. 11

Reporting guidelines are pivotal to ensuring that healthcare decisions are based on sufficiently robust and trustworthy evidence. We are confident that TRIPOD+AI will not only enhance the completeness and informativeness of reporting of studies on clinical prediction models, but also benefit the entire research ecosystem and patients by promoting best research practices in prediction modelling.

Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: JC has received research grants from Sauver la Vie (Fondation Université Paris Cité) for projects in the field of artificial intelligence in healthcare.

Further details of The BMJ ’s policy on financial interests is here: https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf .

Provenance and peer review: Commissioned; not externally peer reviewed.

• PRISM investigators
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New guidelines reflect growing use of AI in health care research

by NDORMS, University of Oxford

The widespread use of artificial intelligence (AI) in medical decision-making tools has led to an update of the TRIPOD guidelines for reporting clinical prediction models. The new TRIPOD+AI guidelines are launched in the BMJ today.

The TRIPOD guidelines (which stands for Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis Or Diagnosis) were developed in 2015 to improve tools to aid diagnosis and prognosis that are used by doctors. Widely used, their uptake by medical practitioners to estimate the probability that a specific condition is present or may occur in the future, has helped improve transparency and accuracy of decision-making and significantly improve patient care.

But research methods have moved on since 2015, and we are witnessing an acceleration of studies that are developing prediction models using AI, specifically machine learning methods. Transparency is one of the six core principles underpinning the WHO guidance on ethics and governance of artificial intelligence for health. TRIPOD+AI has therefore been developed to provide a framework and set of reporting standards to boost reporting of studies developing and evaluating AI prediction models regardless of the modeling approach.

The TRIPOD+AI guidelines were developed by a consortium of international investigators, led by researchers from the University of Oxford alongside researchers from other leading institutions across the world, health care professionals , industry, regulators, and journal editors. The development of the new guidance was informed by research highlighting poor and incomplete reporting of AI studies, a Delphi survey, and an online consensus meeting.

Gary Collins, Professor of Medical Statistics at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, and lead researcher in TRIPOD, says, "There is enormous potential for artificial intelligence to improve health care from earlier diagnosis of patients with lung cancer to identifying people at increased risk of heart attacks. We're only just starting to see how this technology can be used to improve patient outcomes.

"Deciding whether to adopt these tools is predicated on transparent reporting. Transparency enables errors to be identified, facilitates appraisal of methods and ensures effective oversight and regulation. Transparency can also create more trust and influence patient and public acceptability of the use of prediction models in health care."

The TRIPOD+AI statement consists of a 27-item checklist that supersedes TRIPOD 2015. The checklist details reporting recommendations for each item and is designed to help researchers, peer reviewers, editors, policymakers and patients understand and evaluate the quality of the study methods and findings of AI-driven research.

A key change in TRIPOD+AI has been an increased emphasis on trustworthiness and fairness. Prof. Carl Moons, UMC Utrecht said, "While these are not new concepts in prediction modeling, AI has drawn more attention to these as reporting issues. A reason for this is that many AI algorithms are developed on very specific data sets that are sometimes not even from studies or could simply be drawn from the internet.

"We also don't know which groups or subgroups were included. So to ensure that studies do not discriminate against any particular group or create inequalities in health care provision, and to ensure decision-makers can trust the source of the data, these factors become more important."

Dr. Xiaoxuan Liu and Prof Alastair Denniston, Directors of the NIHR Incubator for Regulatory Science in AI & Digital Health care are co-authors of TRIPOD+AI explained, "Many of the most important applications of AI in medicine are based on prediction models. We were delighted to support the development of TRIPOD+AI which is designed to improve the quality of evidence in this important area of AI research."

TRIPOD 2015 helped change the landscape of clinical research reporting bringing minimum reporting standards to prediction models. The original guidelines have been cited over 7500 times, featured in multiple journal instructions to authors, and been included in WHO and NICE briefing documents.

"I hope the TRIPOD+AI will lead to a marked improvement in reporting, reduce waste from incompletely reported research and enable stakeholders to arrive at an informed judgment based on full details on the potential of the AI technology to improve patient care and outcomes that cut through the hype in AI-driven health care innovations," concluded Gary.

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National COVID-19 guidelines vary widely, often promote ineffective treatments

digicomphoto/iStock 

A comparative analysis yesterday in  BMJ Global Health shows that national clinical guidelines for treating COVID-19 vary significantly around the world, and nearly every national guideline (NG) recommends at least one COVID-19 treatment proven not to work.

The authors considered the gold standard for clinical guidelines to be the World Health Organization's (WHO's) 2022 updated guidelines—the 11th version of the WHO guideline.  

They looked at NGs for 109 of the 194 WHO member states after the summer of 2022. Of the 85 countries not included in the final analysis, 9 did not have any NGs.

Regionally, Europe had the most countries with easily identifiable guidelines (69.8%), followed by Africa (53.2%). A country's ministry of health published 73.4% of guidelines, while 12.8% of the guidelines were published by a national disease organization.  

The 11th WHO guidelines recommend that clinicians categorize disease severity as non-severe, severe, and critical. However, 84.4% of reviewed NGs defined COVID-19 severity differently from the WHO, and 6.4% of the guidelines did not define severity at all.  

Just 10 countries (9.2%) had NGs that published severity definitions comparable to the WHO.

Steroids most widely recommended  

The WHO guidelines recommend 10 therapeutics or medications, but NGs recommended 1 to 22 therapeutics. The therapies recommended in NGs were graded in 25 (23.8%) of the guidelines assessed. Most (77%; 84) guidelines did not include an assessment of the strength of the therapeutic recommendation.

"The most commonly recommended drugs were corticosteroids; 92% (100/109) of the NGs featured corticosteroids, and 80% (88/109) recommended corticosteroids for the same disease severity as did the WHO," the authors wrote.  

Corticosteroids were not recommended in severe disease in nearly 10% of guidelines, however, despite strong evidence of their benefit.

Several countries, especially those in poorer regions, in 2022 continued to recommend treatments that had been disproven and were not recommended by the WHO, including chloroquine, lopinavir–ritonavir, azithromycin, vitamins, and zinc.

Why do NGs differ so much in their treatment guidance for such a widespread and potentially serious infection when all have access to the same information?

"Why do NGs differ so much in their treatment guidance for such a widespread and potentially serious infection when all have access to the same information?" the authors wrote. "Apart from the prohibitive cost of some medications for low-resource settings, we do not have a satisfactory explanation."

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TRIPOD+AI: Updated Reporting Guidelines for Clinical Prediction Models

Sherri Rose is part of a global consortium of experts who have updated  the TRIPOD guidelines for prediction algorithms to include machine learning and AI methods. The new TRIPOD+AI guidelines were recently published in BMJ with the ultimate goal of improving patient care.

The first TRIPOD—or Transparent Reporting of multivariable prediction model for Individual Prognosis or Diagnosis—statement was published in 2015 to provide recommendations for studies developing or evaluating the performance of prediction models. These algorithms are widely used to predict health outcomes and support clinical decision-making.

But it’s been nearly a decade since the TRIPOD guidelines for prediction algorithms were published and there have been many methodological advances using artificial intelligence powered by machine learning methods. Thousands of these predictive models are published each year and there have been longstanding concerns about the transparency and accuracy of these models, giving editors and peer reviewers of medical journal articles incomplete or even inaccurate reporting.

“Poor reporting of a model might also mask flaws in the design, data collection, or conduct of a study that, if the model was implemented in the clinical pathway, could cause harm,” they wrote. “Better reporting can create more trust and influence patient and public acceptability of the use of prediction models in healthcare.”

The global consortium of researchers wrote that the new guidelines supersede the TRIPOD 2015 guidelines. They presented a 27-item checklist with detailed explanations of each reporting recommendation, and the TRIPOD+AI for Abstracts checklist.

Read BMJ Article

Using Artificial Intelligence Tools and Health Insurance Coverage Decisions

The safe inclusion of pediatric data in ai-driven medical research, sherri rose honored with president's award for commitment to equity & diversity.