National University of study and

research in law, Ranchi

HEALTH LAW
CONTINUOUS ASSESSMENT TEST - II

A CRITICAL EVALUATION OF CLINICAL TRIAL

IN INDIA

Submitted By: Submitted To:

Name – Rakesh Kumar Sahoo Name – Mr. Kaushik Bagchi

Roll No – 342, Sec – B Assistant Prof., NUSRL

Semester – VIII Health Law Faculty

Introduction

A clinical trial in simple terms can be defined as a set of practice that helps certify a new drug
molecule as safe and efficacious before reaching the market. In fact "any research study that
prospectively assigns human participants or groups of humans to one or more health-related
interventions to evaluate the effects on health outcomes" can be defined as a clinical trial.
Clinical interventions include drugs, cells and other biological products, surgical procedures,
radiologic procedures, devices, behavioural treatments, process-of-care changes, preventive
care, etc. To determine the safety and efficacy of drug research on humans is always warranted,
but one needs to be cautious and vigilant as to how the players in this field undertakes the
process. Adherence to the principles of good clinical practices or GCPs, including adequate
human subject protection universally recognized as a critical requirement to the conduct of
research involving human subjects. In India, compliance with GCP guidelines issued by the
Central Drugs Standard Control Organization or the CDSCO is recommended.

History

Perhaps the first ever clinical trial was James Lind’s demonstration that citrus fruits cure
scurvy. He compared the effects of various different acidic substances, ranging from vinegar
to cider, on groups of afflicted sailors, and found that the groups who were given oranges and
lemons has largely recovered from scurvy after 6 days. Two ancient scripts Charaka Samhita
and Sushruta Samhita, compiled as early as 200 B.C. and 200 A.D. respectively shows that
medical research is not a new concept for India.

International Guidelines

1. The Nuremburg Code (The 1st International Code of Ethics)

The disclosure of the unacceptable human experimentation carried out upon prisoners of war
and civilians during the Second World War led to the Nuremburg Code of 1949. This reflected
an understanding of the value of research in humans balanced against the need to establish legal
and moral boundaries in order to protect the interest of the research subject.

The basic principles laid down by the Code are as follows:-

1. Required is the voluntary, well-informed, understanding consent of the human subject

in a full legal capacity.
 2. The experiment should aim at positive results for society that cannot be procured in
some other way.
3. It should be based on previous knowledge (like, an expectation derived from animal
experiments) that justifies the experiment.
4. The experiment should be set up in a way that avoids unnecessary physical and mental
suffering and injuries.
5. It should not be conducted when there is any reason to believe that it implies a risk of
death or disabling injury.
6. The risks of the experiment should be in proportion to (that is, not exceed) the expected
humanitarian benefits.
7. Preparations and facilities must be provided that adequately protect the subjects against
the experiment’s risks.
8. The staff who conduct or take part in the experiment must be fully trained and
scientifically qualified.
9. The human subjects must be free to immediately quit the experiment at any point when
they feel physically or mentally unable to go on.
10. Likewise, the medical staff must stop the experiment at any point when they observe
that continuation would be dangerous.

2. The Declaration of Helsinki

In June 1964, the World Medical Assembly adopted the Declaration of Helsinki containing
recommendations guiding Physicians in biomedical research involving human subjects. It
stated that the purpose of biological research involving human subjects must be to improve
diagnostic, therapeutic and prophylactic procedures and the understanding of the etiology and
pathogeneses of disease.

Some of the basic principles are –

The fundamental principle is respect for the individual (Article 8), their right to self-
determination and the right to make informed decisions (Articles 20, 21 and 22) regarding
participation in research, both initially and during the course of the research. The investigator's
duty is solely to the patient (Articles 2, 3 and 10) or volunteer (Articles 16, 18), and while there
is always a need for research (Article 6), the subject's welfare must always take precedence
over the interests of science and society (Article 5), and ethical considerations must always
take precedence over laws and regulations (Article 9).

The recognition of the increased vulnerability of individuals and groups calls for special
vigilance (Article 8). It is recognised that when the research participant is incompetent,
physically or mentally incapable of giving consent, or is a minor (Articles 23, 24), then
allowance should be considered for surrogate consent by an individual acting in the subject's
best interest, although their consent should still be obtained if at all possible (Article 25).

3. Drugs and Cosmetics Rules, 1945

Under this rule, it is mandatory to obtain license before manufacturing or importing or

marketing a new drug in India and generally, clinical trials are necessary pre-requisite for the
issue of such a license. Schedule Y governs the manner and mode of conducting clinical trials
in India. In the year 2002, certain amendments were made to the Act which are necessary before
any clinical trial:-

1. Post Marketing Surveillance (PMS), study has been made mandatory.

2. It is mandatory to obtain prior approval from the DGCI before any institution conducts
clinical trials for a new drug, whether for clinical investigation or any clinical
experiment.
3. Concurrent Phase trials are now allowed in India, allowing phase 2 and 3 trials for drugs
discovered outside India can now be conducted concurrently with international trials.

Phases of Clinical Trial

Phase-O (Pre-clinical studies) are actually non-clinical studies involving in vitro and trials on
animal populations. Wide ranging doses of the compound are introduced to the animal subjects
or to an in-vitro substrate in order to obtain preliminary pharmacokinetic information and to
assist pharmaceutical companies in decisions regarding further development of the test agents.

Phase-I studies assess the safety of a drug or device. This initial phase of testing, which can
take several months to complete, usually includes a small number of healthy volunteers (20 to
80), who are generally paid for participating in the study. The study is designed to determine
the effects of the drug or device on humans including how it is absorbed, metabolized, and
excreted. This phase also investigates the side effects that occur as dosage levels are increased.
About 70% of experimental drugs pass this phase of testing.
Phase-II studies test the efficacy of a drug or device. This second phase of testing can last from
several months to two years, and involves up to 100-300 patients. Most phase II studies are
randomized trials where one group of patients receives the experimental drug, while a second
"control" group receives a standard treatment or placebo. Often these studies are "blinded"
which means that neither the patients nor the researchers know who has received the
experimental drug. This allows investigators to provide the pharmaceutical company and the
FDA with comparative information about the relative safety and effectiveness of the new drug.
About one-third of experimental drugs successfully complete both Phase I and Phase II studies.

Phase III studies involve randomized and blind testing in 1000 to 3000 patients. This large-
scale testing, which can last several years, provides the pharmaceutical company and the FDA
with a more thorough understanding of the effectiveness of the drug or device, the benefits and
the range of possible adverse reactions. 70% to 90% of drugs that enter Phase III studies
successfully complete this phase of testing. Once Phase III is complete, a pharmaceutical
company can request FDA approval for marketing the drug.

Phase IV studies, often called Post Marketing Surveillance Trials, are conducted after a drug
or device has been approved for consumer sale. Pharmaceutical companies have several
objectives at this stage: (1) to compare a drug with other drugs already in the market; (2) to
monitor a drug's long-term effectiveness and impact on a patient's quality of life; and (3) to
determine the cost-effectiveness of a drug therapy relative to other traditional and new
therapies. Phase IV studies can result in a drug or device being taken off the market or
restrictions of use could be placed on the product depending on the findings in the study.

Types of Clinical Trial

There are three types of Clinical Trials –

1. Blinded – Single, Double or Triple Binding

2. Placebo
3. Controlled

Placebo Controls – Placebo is the term given to a chemically inert substance given in the guise
of medicine for its psychologically suggestive effect, used in controlled clinical trials to
determine whether improved and side effect may reflect imagination or anticipation rather the
actual power of drug. In other words, we can say that in placebo, the patient is used as a dummy
in such a trial for which he never consented. He is denied the benefit of the vaccine without his
knowledge.

Regulatory Framework for Approval of CTs

New chemical entities cannot be administered to human subjects in a clinical trial without
permission from the Drugs Controller General of India. Such permission may be obtained by
submitting to the DCGI an application for a clinical trial. The application must include a
protocol for the study, a draft of the Informed Consent Document, a list of proposed
investigators who have agreed to participate in the study, and background information about
the drug in accordance with Schedule Y of the Drugs & Cosmetics Rules. It takes almost 12
weeks to obtain permission for a clinical trial for most investigatory drugs. If clinical supplies
are to be imported, a "Test-Import License" must also be applied for. Import and manufacture
of clinical trial supplies is governed by Rules 33 & 34 and provisions contained in Part X-A of
the rules.

The procedure for applying for marketing approval depends on the status of the new drug,
which broadly fall within three categories:

1. New drug substances discovered that are already approved/marketed in other countries,
for which it is sufficient if phase III or confirmatory trials are conducted to obtain data
about the efficacy and safety of the drug in a sufficient number of patients
2. New drug substances discovered but are not approved/marketed in other countries. It
means that permission to conduct phase I trial is allowed only if the drug has completed
phase I and moved to phase II in other countries.
3. New drug substances discovered in India; for which clinical trials have to be carried
out as human or clinical pharmacology trials. Exploratory trials, or phase II trials, are
carried out on limited number of patients to determine therapeutic uses, effective dose
range and further evaluation. Confirmatory trials, or phase III trials, are conducted to
obtain sufficient data about the efficacy and safety of the drug in a larger number of
patients, again in comparison with a standard drug or a placebo, to confirm efficacy and
safety claims made in the product monograph. If the new drug substance is not marketed
in any other country, phase III trials should be conducted on a minimum of 500 patients
spread across 10-15 centres. In the case of new drug substances discovered that are not
approved or marketed in other countries, clinical trials are now allowed to be carried
out in India simultaneously with trials abroad.
Regulation of Trials in India

For registering new drugs for marketing in India, submission of data generated on Indian
patients is essential. For this purpose, a 100-patient non-comparative open-label study on
patients treated for the primary indication is sufficient. For drugs that treat rare conditions, a
lower sample size is usually adequate.

The Indian Council of Medical Research (ICMR) plays a significant role in controlling clinical
trials in India. The Drugs and Cosmetics Act and The Medical Council of India Act states that
all clinical trials in India should follow the ICMR guidelines, 2000. The ICMR has a
mechanism of review for its own institutions, and so do other government agencies.

The Drugs Controller General of India or the DCGI is responsible for regulatory approvals of
clinical trials in India. The DCGI's office depends on external experts and other government
agencies for advice. The ICMR has a Central Ethics Committee on Human Research. This
committee audits the functioning of this Institutional Ethics Committee or the IEC. The
recently amended Schedule Y of Drugs and Cosmetic Rules order the composition of the IEC
as per the ICMR guidelines.

Compliance with GCP guidelines issued by the Central Drugs Standard Control Organization
or the CDSCO is recommended although this does not have statutory status at the present time.
A report on the status of the study with details of enrolment and safety issues also needs to be
submitted annually and on completion of every study.

These measures suggest that India do have guidelines and regulations at par with the
international standards; but, the insufficiency lies with regard to the implementation of these
control mechanisms. The shortfall is mainly due to the lack of sanction attached to such
provisions in case of violations. The regulatory mechanisms available in the country are
scattered in various guidelines having less or sometimes no force of sanction.

Legal and Ethical Issues in Clinical Research

1. Financial Inducement

A case study undertaken by Dateline shows that a pharmaceutical company paid $12 per patient
for voluntary involvement in clinical trials. Due to their economically poor background and
lack of education, the patients are not aware of their involvement and the possible risk of
injuries. The payment works as an inducement. In fact, the patient can earn up to $400
depending on the length of study and this payment outstrips their general income. The unethical
practice of financial inducement—though seemingly an incentive—leads to enrolment of
volunteers in more than one study at a time. This not only puts their lives in danger, but can
also skew the accuracy of test results. Until now, many people have fallen sick and several
deaths have occurred.

2. Death & Inadequate Compensation

The Indian government reports that across the country more than 2500 people have died in
clinical trials since 2005, many participating in studies for Western pharmaceutical companies.
But it is unclear that how many people died or were injured due to their involvement in clinical
trials because in many cases there are no proper systems of documentation of death registration.
The pharmaceutical companies conduct investigations only to ascertain the cause of death:
whether it was the result of a clinical trial or simply because of a pre‐existing disease.
Compensation is to be given only if a death is said to have been caused due to clinical trial.
Also, the amount of compensation varies across different companies. But now, the government
is in the process of fixing a minimum compensation amount in case of death or injuries
sustained during the course of the trials. The Ministry of Health and Family Welfare has
authorised DGCI to determine the amount of compensation to be given in case of death or
injuries sustained during trials

3. Simultaneous Conduction of Phase II & Phase III

Another unethical practice is the simultaneous conduct of Phase II and Phase III trials by CROs.
Clinical trial laws were amended in 2005 to help familiarize India with international clinical
research activities as well as allow for Phase II and Phase III trials to be conducted
concurrently. Before 2005, Phase II and Phase III trials were allowed with a phase lag—that
is, after their gross safety aspects were somewhat known abroad. These concurrent clinical
trials may have a serious adverse effect on the trial participants, for instance, causing disability
or permanent damage or death.

Government Regulation on Clinical Trials

Clinical trials are regulated by the government under the Drug and Cosmetics Act 1945, which
is amended from time to time. Civil societies and many social activists complained to the court
that Indian citizens are being used as guinea pigs during the course of drug development.
Accordingly, the Supreme Court has ordered the government to make audio‐video recording
of informed consent mandatory for companies intending to conduct clinical trials. It also
mandates them to inform patients about the possible adverse health effects of the drug under
trial. According to the new guidelines, a manufacturer, before requesting an individual to
participate in clinical trial of a new drug, must inform the individual of any reasonably
foreseeable risks or discomforts as well as of the possible benefits. For further regulation, the
Department of Health and Family Welfare has appointed an expert committee for setting
guidelines for CTs. The committee produced and published its report which suggested:-

1. Clinical trials can only be carried out at accredited centres.

2. Both the principal investigator of the trial and the ethics committee of the institute
should be accredited.
3. Only those trials conducted at such centres should be accepted by the Drugs Controller
General of India (DCGI).
4. An informed consent from each participant is a prerequisite for a clinical trial. In
circumstances where informed consent has to be obtained from special groups of people
who have diminished capacity to protect their interests or give consent for themselves,
the consent given by the guardian should be witnessed by an independent person who
also has to sign the informed consent document.
5. Audio‐visual recording of the informed consent process should be undertaken and the
documents preserved, adhering to the principles of confidentiality. The audio‐visual
recording of informed consent process and other related documents should be safely
preserved after the completion of the study for at least a period of 5 years.
6. If any adverse effect or serious adverse effect occurs during a clinical trial, the sponsor
investigator should be responsible for providing medical treatment and care to the
patient at his own cost and also provide proper compensation for disability or death of
the participant.
7. Central Drugs Standard Control Organisation (CDSCO) is responsible for providing
written assurance to the pharmaceutical house or investigator seeking approval for a
clinical trial that if all the papers needed for the review are complete, then a decision,
either interim of full, will be given within three months.
8. For all new chemical entities (NCEs) that are developed and 16 marketed in India, all
trial phases (Phases I–IV) will have to be carried out in India. In case of NCEs
developed outside India, which is of relevance to our population, it is presently not
 always necessary to carry out Phase I trials in our country, provided Phase I trials have
either been done or are being done in the country of origin.
9. All NCEs undergoing clinical trials in any country can also undergo parallel Phase II
and Phase III trials in India, after testing for “safety” in Phase I trials. However, Phase
I trials should have been done in the country of origin if the disease is prevalent there.

Conclusion
With an exponentially growing clinical trial market, India promises to be one of the hottest
destinations for global clinical trials. But, at the same time, to rely simply on minimum
standards of non-binding and vague medical ethics is both naive and culturally insensitive. To
address the challenges and key issues, India should devise policies and ensure implementation
in legislative, Intellectual Property Rights structure and regulatory issues.

There is also a need to develop Clinical Research Organizations with adequate capacity and
competency in carrying out research activities in compliance with ICH/GCP guidelines.
Many of the new initiatives for regulating pharma industry in India has been in the charts for
quite a long time. What required is speedy implementation and, necessary investment and
infrastructure support. India should realize the fact that laws alone would not suffice, there
should be a proper administrative and monitory mechanism to ensure its working.

Lack of regulatory jurisdiction over private trial sites and absence of uniform application of the
need for informed consent and proper ethics review have raised concerns about trials conducted
in India. What we need here is to establish authorities such as the proposed Central Drug
Authority and central licensing mechanism for manufacturing approvals. This would
essentially help us keep a check over the activities of firms conducting drug trials in India.