What are clinical trials?

• Clinical trials are scientific studies conducted to find better ways to prevent, screen for, diagnose, or
treat disease.

• These clinical trials may also show which medical approaches work best for certain illnesses or groups of
people.

• Clinical trials produce high-quality data for healthcare decision making.

• The purpose of clinical trials is to answer scientific questions. Therefore, these studies follow strict,
scientific standards which protect patients and help produce reliable clinical trial results.

• Clinical trials are one of the final stages of a long and careful research and development process. The
process often begins in a laboratory, where scientists first develop and test new ideas.
Who is in the research team?

• A principle investigator, who is usually a medical doctor, will lead each clinical study.

• The research team may include: doctors, nurses, social workers, health care professionals, scientists, data
managers, clinical trial coordinators

Where are clinical trials conducted?

• The location will depend on the type of study and who is organizing it. Some common locations include:
hospitals, Universities, medical centers, doctors’ offices, community clinics, federally-funded and industry-
funded research sites
Clinical trials related to drugs are classified into four phases.

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

 Phase I trials test an experimental drug, vaccine or device in a small group of people (20 to 80) to evaluate safety, possible
side effects, and to determine how the drug should be used or delivered.
 Phase II trial uses more people (100 to 300). While the emphasis in Phase I is on safety, the emphasis in Phase II is on
effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease
or condition. These trials also continue to study safety, including short-term side effects. This phase can last several years.

• Phase III trials are usually large studies with many participants usually ranges from several hundred to about 3,000 people.
This phase compares the experimental drug or vaccine to a placebo or standard treatment, to evaluate safety and efficacy.
Some side effects that were not identified in Phase II may be identified in a Phase III trial because many more people are
evaluated. The regulatory health authority, such as the U.S. Food and Drug Administration, will consider the results of
clinical trials up to and including Phase III trials when determining whether to approve a new drug or vaccine.
• Phase IV trials take place after a regulatory health authority, such as the U.S. Food and Drug Administration, has approved
the use of the drug or vaccine. A drug's effectiveness and safety are monitored in large, diverse populations.
If you’ve ever looked up clinical trials or applied for one, you may have come across these terms. So, what exactly do they
mean?

Controlled/Comparative design
• A controlled study is one in which there are at least two groups of participants – one group receives the new
treatment and one group receives a comparison treatment (or no treatment) and is known as the “control” group. To
have something to compare the treatment to makes for a much more powerful study with more clinically meaningful
results.
• In clinical trials that involve patients and healthy participants, the healthy group is the control group. If it is unethical
to include healthy controls, the control group may:
• Receive a standard, comparison treatment that is commonly prescribed for the same condition; or
• Receive physical therapy only; or
• Not receive any treatment; or
• Receive a placebo.
Placebo
• A placebo is an inactive control that looks identical to the study treatment.
• For example, a sugar pill or an injection of saline.
• The point of a placebo is to determine if the effects of the study treatment are related to the actual biological/chemical
properties of the treatment, versus the psychological effects – the “placebo effect”.
• A person who receives any treatment, whether placebo or an active treatment, may experience effects (whether good
or bad) simply because they believe they are receiving something that will improve their condition or may give them
side effects. These effects are psychological and they are real, but they are not related to the actual
biological/chemical/physical mechanisms of the treatment and usually disappear quite quickly.
• Placebo effects are common for drugs and devices such as spinal cord stimulators.

A placebo is a very powerful comparator, but it is not always appropriate to use a placebo and may be considered
ethically questionable. For example, a placebo for a surgical study is called a “sham” This is when a fake surgery is
performed so that the control participants still believe they are being surgically treated. The use of sham surgery is highly
controversial and rarely performed in humans.
Blinded
• A controlled trial will usually be “blinded”.
• Naturally, placebo-controlled trials are always blinded. This means that participants are unaware of which treatment they
receive until the study is complete.
• A study is double-blinded if the study investigator(s) are also unaware of which treatment the participants receive.
• Blinding ensures that the outcomes are not biased by participants’ or investigators’ preconceptions – that is, what they
think the outcome will be if they know which treatment they are receiving.
• For example, a person who receives a new treatment versus an already available or a standard treatment may think that
they will experience more side effects or better results.
Randomized
• Randomization is the process of randomly allocating participants to either the treatment or control / comparison
groups (also known as “treatment arms”).
• This is generally performed by a computer program.
• Randomization ensures that the process of assigning participants to different groups is not biased (i.e. an investigator
that decides to put a certain patient into the treatment group because their condition appears particularly bad).
• Randomization also ensures that the groups are balanced, which makes them more comparable, and that participants
have an equal chance of receiving the treatment or control / placebo / comparison treatment.
Crossover
• In most controlled clinical trials, participants will receive either the new treatment or the control/comparison treatment
and that’s it.
• Another word for this is a “parallel” study. In a crossover study, all participants get to experience both the new
treatment and the control/comparison treatment.
• After a certain period of being on the new treatment or the control treatment, participants will swap groups. Usually, a
crossover study involves a washout period, during which participants stop taking the treatment or control that they were
on, for a certain amount of time in order to “wash away” any lasting effects before swapping treatments.
• This type of clinical trial is usually much longer than a parallel clinical trial.
• The main advantage is that participants become their own controls and makes for a better comparison between
treatment and control. Participants are also much more likely to join a placebo-controlled trial if they will definitely get
to trial the new treatment too.
Clinical trial benefits & risks
The potential benefits of participating in a clinical trial may include the following:
• Access to promising new treatments often not available outside the clinical-trial setting
• Treatment that may be more effective than the standard approach
• Close monitoring, advice, care, and support by a research team of doctors and other health care professionals who
understand your disease or condition
• The opportunity to be the first to benefit from a new method under study
• The chance to play an active role in your own health care and gain a greater understanding of your disease or condition
• The chance to help society by contributing to medical research. Even if you don't directly benefit from the results of the
clinical trial you take part in, the information gathered can help others and adds to scientific knowledge. People who take
part in clinical trials are vital to the process of improving medical care.
The potential risks of participating in a clinical trial may include the following:

• The clinical trial may require more time than a non-clinical trial treatment such as more visits
to the clinical trial site, more treatments, hospital stays, etc.

• There may be unpleasant, serious or life threatening side effects to experimental treatments.
Clinical Trial Informed Consent
Informed consent is the process of learning about the clinical trial before deciding to participate. Before someone can
participate in a clinical trial they must review and sign an informed consent form.
As part of the informed consent process, participants also will be able to review the trial protocol with the clinical trial
team.
The informed consent form will include the following information:
• Clinical trial process, including tests that may be conducted
• Known risks and benefits of experimental treatment
• Length of clinical trial
• Clinical trial contact information

Even after signing the informed consent form, participants may choose to stop participating in the clinical trial at any
time.
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 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.
Clinical Trials Regulations in India

• In India, the Central Drugs Standard Control Organization (CDSCO) which comes under the Ministry of Health and Family
Welfare is the main body which works on development of regulatory procedures and standards for drugs, cosmetics,
diagnostics and devices.

• It lays down regulatory guidance by amending acts and rules; and regulates new drug approval process. Its main
objective is to standardize clinical research and bring safer drugs to the Indian market.

• The Drug Controller General of India DCG(I) is responsible for giving regulatory permissions for the conduct of clinical
trials and is responsible for approval of marketing licenses for drugs in India. When an application is filed, the office of
the DCG(I) reviews it; the required time for approval depends on the trial’s regulatory status in other countries.

• To expedite the approval process, for studies already approved by other countries’ regulatory agencies, the DCG(I) office
has divided all applications into two categories: A and B.
• Category A includes clinical trials whose protocols have been approved by EMEA or regulatory agencies in the US, UK,
Switzerland, Australia, Canada, Germany, South Africa or Japan.

• For such studies, permission is granted, accepting the protocol approval of those countries. For category A applications,
review and approval are projected to take two to four weeks.

• The category B clinical trial applications, are reviewed following the regular approval system by an expert committee.
This process usually takes eight-twelve weeks for approval of application.

• The DCG(I) at times also requests guidance from other independent government agencies viz., ICMR or Department
of Biotechnology (for biotech products) on a case-by-case basis, thus extending the review period.
Other regulatory bodies

 U.S. Food and Drug Administration (FDA): The Food and Drug Administration (FDA) is a government
agency responsible for ensuring the safety and effectiveness of all medications, vaccines, medical
equipment used for prevention, diagnosis, and treatment.

 Institutional Review Board (IRB): An Institution Review Board (IRB) is a committee of health care
professionals and community members, who review, approve, and monitor clinical trials to make
sure potential risks are as low as possible and that the clinical trial follows ethical and legal codes for
medical practice.
New Drug Application
A drug sponsor will complete a New Drug Application (NDA) to ask the FDA to consider approving a new drug for
marketing in the U.S. An NDA includes: all animal and human data, analysis of data, information regarding drug
behavior in the body, manufacture details
The FDA has 60 days to decide whether to file it to be reviewed. If they decide to file the NDA, the FDA review team is
assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.
The following steps must then take place.
• Drug labeling: The FDA reviews the drug’s professional labeling and confirms appropriate information is shared with
consumers and health professionals.
• Facility inspection: The FDA inspect the facilities where the drug will be manufactured.
• Drug approval: FDA reviewers either approve the application or issue a response letter.
KEY DOCUMENTS IN CLINICAL RESEARCH

 Drugs and Cosmetics Act (1940) and Drugs and Cosmetics Rules (1945)

This act first came into being in 1940 and regulates the import, manufacture and distribution of drugs in the country to
ensure that drugs and cosmetics sold in the country are safe, effective and conform to essential quality standards.

It has Chapters, Rules and Schedules and is amended at regular intervals to ensure greater safety, efficacy and drug
quality. It has 12 appendices, formats for clinical trial protocols, informed consent forms, ethics committee (EC) approval
templates and a format for serious adverse event (SAE) reporting.

 Ethical Guidelines of the Indian Council of Medical Research (2006)

The revised ICMR guidelines released in 2006 is called the 'Ethical Guidelines for Biomedical Research on Human
Participants' and remains valid as of today, and a revised version is expected in 2017.

This guideline covers two broad aspects of clinical research – the general principles that need to be followed and guidance
regarding special areas of research (e.g., research in children or herbal research). Researchers are expected to be familiar
with both these documents and abide by the requirements in the former and the guidance in the latter.
 Indian Good Clinical Practice Guideline (2001)

A good clinical practice (GCP) guideline was released in 2001 by the CDSCO that attempted to be India specific, but
unlike the ICH GCP guideline, has not been revised since.

How are participants protected?

Safety of participants is a high priority issue. In every trial, scientific oversight and patient rights contribute to their
protection. Good clinical practice (GCP) aims to ensure that ethical and appropriate procedures are followed in trials.

Good Clinical Practice (GCP)

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the design, conduct,
performance, monitoring, auditing, recording, analyses and reporting of clinical trials. GCP provides assurance that the
data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are
respected and protected. It was finalised in 1996 and became effective in 1997, but was not enforced by law at that time.
Purpose

The principles of Good Clinical Practice (GCP) help assure the safety, integrity, and quality of clinical trials by addressing
elements related to the design, conduct, and reporting of clinical trials.

GCP training describes the responsibilities of investigators, sponsors, monitors, and IRBs in the conduct of clinical trials.

GCP training aims to ensure that:

 The rights, safety, and well-being of human subjects are protected

 Clinical trials are conducted in accordance with approved plans with rigor and integrity
 Data derived from clinical trials are reliable

It is also important to mention the participants of GCP in clinical trials and their respective responsibilities.
Regulatory Authorities Review submitted clinical data and conduct inspections

The sponsor Company or institution/organization which takes responsibility

for initiation, management and financing of clinical trial
The project monitor GCP training aims to ensure that: Usually appointed by sponsor
 The rights, safety, and well-being of human subjects are
protected
 Clinical trials are conducted in accordance with approved
plans with rigor and integrity
 Data derived from clinical trials are reliable

It is also important to mention the participants of GCP in

clinical trials and their respective responsibilities.

The investigator Responsible for conduct of clinical trial at the trial site. Team
leader.

The pharmacist at trial location Responsible for maintenance, storage and dispensing of
investigational products eg. Drugs in clinical trials

Patients Human subjects

Ethical review board or Committee for protection of subjects Appointed by Institution or if not available then the
Authoritative Health Body in that Country will be responsible

Committee to monitor large trials Overseas Sponsors eg. Drug Companies

ICH-GCP
The ICH-GCP is a harmonised standard that protects the rights, safety and welfare of human subjects, minimises human
exposure to investigational products, improves quality of data, speeds up marketing of new drugs and decreases the cost to
sponsors and to the public. Compliance with this standard provides public assurance that the rights, safety and well-being
of trial subjects are protected and consistent with the principles of the Declaration of Helsinki. There are 13 core principles
of ICH-GCP and they are as follows:
1. Clinical trials should be conducted in accordance with ethical principles that have their origin in the Declaration of
Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).
2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against anticipated benefit for the
individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the
risks.
3. The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over
interest of science and society.
4. The available non-clinical and clinical information on an investigational product should be adequate to support the
proposed clinical trial.
5. Clinical trials should be scientifically sound, and described in clear, detailed protocol
6. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/
independent ethics committee (IEC) approval/favourable opinion
7. 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.
8. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform
his or her respective task(s)
9. Freely given informed consent should be obtained from every subject prior to clinical trial participation.
10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting,
interpretation and verification.
11. 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).
12. Investigational products should be manufactured, handled and stored in accordance with applicable Good
Manufacturing Practice (GMP). They should be used in accordance with the approved protocol.
13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.