Clinical Trials: Benefits, Types and Phases | Medical Science

In this article we will discuss about:- 1. Introduction to Clinical Trials 2. Protection of Participants in Clinical Trials 3. Eligibility Criteria 4. Informed Consent 5. Benefits 6. Risks 7. Types 8. Phases.

Introduction to Clinical Trials:

Clinical trials include any investigation done on human subjects to determine:

1. The clinical, pharmacological, pharmacokinetic of an investigational agent;

2. and/or other pharmacodynamic effects of an investigational agent;

3. And/or to identify any adverse reactions to an investigational agent;

4. And to assess the agent’s safety and efficacy.

In fact, clinical trials may also be considered as bioassays where actions and interaction(s) of a molecule (likely to be used as drug) are observed in human volunteers/patients. Clinical trials are conducted to evaluate the efficacy and safety of the drug molecule/molecules in human subjects before commercialisation.

A clinical trial (also clinical research) is a research study in human volunteers to answer specific health questions. Carefully conducted clinical trials are the fastest and safest way to find treatments that work in people and ways to improve health.

Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environmental conditions. Observational trials address health issues in large groups of people or populations in natural settings. Participants also receive up-to-date care from the scientists/experts/investigators.

Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research.

Research in clinical trials involving human subjects is conducted according to strict scientific and ethical principles. Based on these principles and guidelines, an action plan i.e. protocol is prepared which acts like a recipe for conducting the trial. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. It describes what would be done in the study, how it would be conducted, and why each part of the study is necessary. The same protocol in used in every study under multi-centre trials in the same project.

The clinical trial process depends on the kind of trial being conducted. The clinical trial team includes pharmacologists, pharmaceutical scientists, physicians, clinical pharmacologists, statisticians and nurses as well as social workers and other health care professionals.

They check the health of the participant at the beginning of the trial. They gives specific instructions for participating in the trial, observe various parameters of the study in the participant as indicated in the protocol and continue to stay with the participants even after the trial is completed.

Protection of Participants in Clinical Trials:

All federally funded clinical trials and trials to evaluate a new drug or medical device are subject to the Food and Drug Administration (FDA) regulation or the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines.

In India such statutory requirement is outlined in Schedule Y of the Drugs and Cosmetics Act and Rules where it is necessary to get the protocol approved or reviewed by the Institutional Review Board (IRB) or the Institutional Ethical Committee (IEC). Many institutions require that all clinical trials, regardless of funding, be reviewed and approved by a local IRB/IEC.

The Board or Committee, which includes physicians, researchers, community leaders, medical professionals, non-medical members and other members of the community, reviews the protocol to make sure the study is conducted fairly and that the participants are not exposed to risk, endangering the health. The legal status, composition, function, operations and regulatory requirements pertaining to the IRB/IEC may differ among countries.

The IRB/IEC also decides how often to review the trial once it has begun. Based on this information, the IRB/IEC decides whether the clinical trial should continue as initially planned and, if not, what changes should be made. An IRB/ IEC can stop a clinical trial if the study centre is not following the protocol or if the trial appears to be causing unexpected harm to the participants.

Eligibility Criteria for Clinical Trials:

Each study protocol has guidelines for who can or cannot participate in the study. These guidelines, called eligibility criteria, describe characteristics that must be shared by all participants. The criteria differ from study to study. Using inclusion/exclusion criteria is an important principle of medical research that helps to produce reliable results.

The factors that allow someone to participate in a clinical trial are called “inclusion criteria” and those that disallow one from participating are called “exclusion criteria”. These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, current health status and other medical conditions.

Before joining a clinical trial, a participant must qualify for the study. Some research studies seek participants with illnesses or conditions to be studied in the clinical trial, while others need healthy participants. It is important to note that inclusion and exclusion criterias are based on scientific norms. Thus, the criterias are used to identify appropriate participants and keep them safe. The criterias are so chosen and grouped so that at the end of the study, researchers would be able to answer the questions they plan to study.

Enrolling participants with similar characteristics ensures that the results would be due to what is under study and not because of other factors. In this way, eligibility criterias help researchers achieve accurate and meaningful results. These criteria also make certain that people who are seriously ill but participating in the study, are not exposed to the risk.

Informed Consent in Clinical Trials:

Informed consent is the process by which participants learn the key facts about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout the study so as to provide information to the participants. To help someone decide whether or not to participate, the physicians and nurses involved in the trial explain the details of the study.

The informed consent form should be bilingual. If the participant’s native language is not English, translation assistance should be provided. The research team should provide an informed consent document that includes details about the study, such as its purpose, duration, required procedures, and key contacts.

Risks and potential benefits should be explained in the informed consent document. The participant then decides whether or not to sign the document. Informed consent is not a contract, and the participant may withdraw from the trial at any time. People who agree to take part in the study are asked to sign the informed consent form.

However, signing the form does not mean that the person must stay in the study. People can leave the study at any time either before the study starts or at any time during the study or the follow-up period. If new benefits, risks, or side-effects are discovered during the study, the researchers must inform the participants. They may also be asked to sign new consent forms if they want to stay in the study.

Place:

Clinical trials usually take place in hospitals, medical or pharmaceutical institutions, cancer centres, other medical centres, clinics and military hospitals in cities and towns across India and in other countries. Clinical trials may include participants at one or two highly specialised centres, or they may involve hundreds of locations at the same time.

Sponsors:

Clinical trials are sponsored or funded by a variety of organisations or individuals such as physicians, medical and pharmaceutical institutions, foundations, voluntary groups, and pharmaceutical companies, in addition to federal agencies such as the National Institutes of Health (NIH), the Department of Defense (DOD), and the Department of Veteran’s Affairs (VA). Trials can take place in a variety of locations, such as hospitals, universities, doctors’ offices, or community clinics.

Benefits of Clinical Trials:

Clinical trials that are well-designed and well-executed are the best approach for eligible participants to:

1. Play an active role in their own health care.

2. Gain access to new research treatments before they are widely available.

3. Receive regular and careful medical attention from a research team that includes doctors and other health professionals.

4. Help others by contributing to medical research.

5. Be the first to benefit from the new method under study. The approach being closely studied and properly monitored may be more effective than the standard approach.

Risks Involved in Clinical Trials:

There are also risks to clinical trials.

1. There may be unpleasant, serious or even life-threatening side-effects to experimental treatment.

2. The experimental treatment may not be effective for the participant.

3. The protocol may require more of their time and attention than would a non-protocol treatment, including trips to the study site, more pathological tests, more treatments, hospital stays or complex dosage requirements.

4. New drugs or procedures under study are not always better than the standard care to which they are being compared.

5. Participants in randomised trials will not be able to choose the approach they receive.

6. Health insurance and managed care providers may not cover all patient care costs in a study.

Types of Clinical Trials:

Treatment Trials:

Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy to evaluate the efficacy of the treatment. They are designed to answer specific questions about, and evaluate the effectiveness of, a new treatment or a new way of using a standard treatment.

Prevention Trials:

Prevention trials look for better ways to prevent diseases in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.

Diagnostic Trials:

Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. Diagnostic trials usually include people who have signs or symptoms of disease.

Screening Trials:

Screening trials test the best way to detect certain diseases or health conditions. They involve people who do not have any symptoms of disease.

Quality of Life Trials (or Supportive Care Trials):

These trials explore ways to improve comfort and the quality of life for individuals with a chronic illness.

Phases of Clinical Trials:

The trials at each phase have a different purpose and help scientists answer different questions.

Phase I Trial (Clinical Pharmacological Evaluation):

Phase I trials are the first step in testing a new approach in humans. In Phase I trials, researchers test an experimental drug or treatment in a small group of healthy human volunteers (20-80) for the first time to evaluate its safety, minimum effective dose, determine a safe dosage range, and identify side-effects. Drugs with significant potential toxicity, for example, cytotoxic drugs are usually studied in patients instead of healthy volunteers.

Diseases, which are incurable including AIDS, are also studied in patients. Phase I trials usually take place at a few locations only. The volunteers are divided into smaller groups, called cohorts. Each cohort is treated with an increased dose of the new therapy or technique. The highest dose with an acceptable level of side-effects is determined to be appropriate for further testing.

Early phase I clinical trials are always of “open” design. Scientists start by giving a single dose, which is one-twentieth to one-tenth of the predicted therapeutic dose based on experiments to a smaller group of people, a slightly larger dose to the next group, and so on, while closely monitoring the patients for side-effects.

Generally, the trial is only intended to determine the maximum tolerated dose and the toxicity of the drug. This stage is also used to determine the best method of administration of the drug. Some phase I trials test new combinations or new dose schedules of drugs that are already shown to be effective. Cross-over designs are also followed in this phase.

Pharmacokinetic studies conducted at this stage provide basic data for subsequent phase II and phase III trials.

Phase II Trials (Controlled Clinical Evaluation):

Phase II trials study the safety and effectiveness of an investigating molecule or agent or intervention, and evaluate how it affects the human body. In phase II trials, the experimental study drug or treatment is given to a large group of patients (50-300). Phase II trials are done to determine if a drug is actually effective or not.

Most phase II studies are well-controlled, randomised trials following “cross-over” design. Here one group of patients (subjects) receives the experimental drug, while a second “control” group receives a standard treatment or placebo. Placement of the subject into the drug treatment or placebo group is by random chance (as if by the flip of a coin).

Many investigators feel that the double blind protocol—neither the patient nor the researchers (investigator, coordinator, etc.) know who is getting the experimental drug—which is used in phase III trials should also be used in phase II studies.

Additionally, phase II studies are often designed to determine the correct dosage, that is, the dosage with the least number of side-effects that is most effective. These are often referred to as dose-ranging studies. In general, the purpose of phase II studies is to provide the pharmaceutical company and the FDA comparative information about the relative safety of the experimental drug, the proper dosage, and the drug’s effectiveness. The main targets of a “late” phase II clinical trial are to find out the appropriate clinical dosage schedule and to establish the incidence of beneficial and undesirable effects in the patient population.

In certain cases, phase II clinical studies may not be randomised and patients in an advanced stage of a disease may get a promising treatment at the best dose as can happen in a phase III study. Only about one-third of experimental drugs successfully complete both phase I and phase II studies.

Phase III Trials (Extended Clinical Evaluation):

In phase III trials, the experimental study drug or treatment is given to large groups of people (250-1000) to confirm its effectiveness, monitor side-effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. Comparison of the new drug with the standard current therapy is carried out using randomly assigned groups.

This method, called randomisation, helps to avoid bias and ensures that human choices or other factors do not affect the study results. Randomisation is important to the scientific validity of the research. “Placebo controlled double blind cross­over design” procedures are preferred. Undesirable interactions of the new drug with other drugs are also studied. Further studies may have to be conducted to find out the mechanism of action of the drug in humans.

In most cases, studies move into phase III testing only after they have shown promise in phases II and I.

Phase IV Trials (Post-Marketing Surveillance):

Phase IV trials are conducted to further evaluate the long-term safety and effectiveness of a treatment. They usually take place after the treatment has been approved for standard use. Several hundred to several thousand people may take part in a phase IV study.

These studies are less common than phase I, II, or III trials. They may also monitor the use of the drug or treatment in different populations, or look at quality-of-life issues. The main aim is to monitor efficacy and safety under prescription use. Adverse drug reaction(s) and toxicity are also revealed in this trial.

Schedule Y which lays down guidelines for undertaking clinical trials was amended in December 2000 and published in January 2005. 

Bioavailability and Bioequivalence:

Bioavailability is defined as the rate and extent to which a substance reaches the systemic circulation. Bioavailability testing is a means of predicting the clinical efficacy of a drug. They are designed to determine either an absolute bioavailability or relative bioavailability i.e. bioequivalence (with a reference dosage form which has good absorption characteristics). It is required by law to undertake bioequivalence studies whenever a new formulation of an existing drug product is introduced into the market.

Besides being legally necessary, bioequivalence studies are required for a variety of reasons:

1. Results from clinical studies indicate that different drug products produce different therapeutics results.

2. Results from bioavailability studies indicate that different products are not bioequivalent.

3. Drug has a narrow therapeutic range.

4. Some drugs have a low solubility and/or a large dose is required.

5. Absorption is considerably less than 100%.

6. High excipient/active drug ratio present in the drug product.

Bioequivalence Criteria:

The FDA (Food and Drug Administration) criteria for establishing bioequivalence between two formulations is that the 90% confidence interval for the ratio of the mean AUC and mean C_max for the test product must be between 80-120% of the respective mean values for the reference or the innovator product.

Methods of Assessing Bioavailability:

There are several methods, which determine the bioavailability or bioequivalence of a drug product. The vast majority of bioavailability studies involve the administration of the test dosage form to a group of healthy human subjects, followed by the collection and assay of the drug concentration in blood (plasma or serum) samples. The second most frequent method utilises urinary excretion measurements.

Occasionally, other types of biological material, such as saliva, cerebro-spinal fluid, bile, or faeces are also collected. For those drugs, for which assay methods are not available for the determination of drug concentrations in biological fluids, a pharmacological response may be measured.

Finally, some bioavailability assessments are made on the basis of a determination of the therapeutic response of patients to a given dosage form. FDA (US) recognises pharmacokinetic, pharmacodynamic, clinical, and in vitro studies as acceptable approaches to document the bioavailability or bioequivalence of a drug product.

Good Clinical Practice:

It is vital to have a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.

Guidelines for good clinical practices (GCP) are given in ICH topic E6. These were adopted by FDA (US) as “Guideline for good clinical practice ICH harmonised tripartite” in May 1996 and became operational in January 17, 1997. The objective of this ICH GCP guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

GCP is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

“Ethical principles for medical research involving human subjects” was adopted by the 18th WMC (World Medical Association) General Assembly Helsinki, Finland in June 1964 and amended many times. The latest amendment was by the 52nd WMA General Assembly, Edinburgh, Scotland in October 2000.

The guideline was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO).

This guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities. The principles established in this guideline may also be applied to other clinical investigations that may have an impact on the safety and well-being of human subjects.

Principles of ICH GCP:

i. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

ii. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

iii. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

iv. The available non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

v. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

vi. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval or favourable opinion.

vii. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

viii. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

ix. Freely given informed consent should be obtained from every subject prior to clinical trial participation.

x. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.

xi. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

xii. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GP). They should be used in accordance with the approved protocol.

xiii. Systems with procedures that assure the quality of every aspect of the trial should be implemented.