Protection of Subjects

Protection of Subjects and Regulation of Clinical Trials in India
by
Deepthi Pandiri
Submitted to The College Of Health And Human Services
Eastern Michigan University
In partial fulfillment of the requirements
for the degree of
MASTER OF SCIENCE
In
Clinical Research Administration
March 10, 2014
Ypsilanti, Michigan
Dedication
I dedicate this research paper to my loving parents, Mrs. Sujatha and Venkata Reddy Pandiri,
whose words of encouragement and push for tenacity ring in my ears. Without their continued
support, love, and affection, I could not have completed my course of study in the United States.
I am indebted to my husband, Sunil Reddy Kattagummula, for his strong belief and hope in me
and for providing me assistance. I also thank my family and friends who encouraged me during
my stay at Eastern Michigan University.
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Acknowledgements
I thank my mentor, Dr. Irwin G. Martin, for his endless support, confidence, and innovative
thoughts throughout my master’s program.
I thank Dr. Stephen Sonstein, our academic advisor, for his support throughout my study
at Eastern Michigan University.
I also acknowledge and thank my EMU Graduate School division for allowing me to
conduct my research and for providing any assistance requested. I give a special thanks to the
members of staff development and the College of Human and Health Services for their continued
support.
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Abstract
Access to better healthcare and payment may provide powerful incentives to participate in
clinical research in developed countries. In India, however, problems may arise in obtaining
consent due to language and cultural differences. While India has been a preferred destination to
perform clinical trials, serious concerns exist, such as failure to obtain informed consent, a lack
of attentive regulatory authorities, insufficient infrastructure, and a failure to follow International
Conference on Harmonization-Good Clinical Practices (ICH-GCPs). Research projects that
violated ethical norms have taken place in India during and after the release of regulatory
guidelines. Hence, there is a need for regulatory agencies to enforce these guidelines to ensure
subject protection.
In many developing countries, such as India, there is no agency that exclusively protects
clinical trial subjects or regulates clinical trials, as there are in developed countries. This study
suggests proposals such as strengthening regulatory bodies, developing a plan to address
deficiencies in the current Indian model, and protecting subjects during subject recruitment.
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Table of Contents
Dedication .............................................................................................................................. i
Acknowledgements ............................................................................................................... ii
Abstract ................................................................................................................................iii
List of Tables ........................................................................................................................ v
Introduction ........................................................................................................................... 1
Background ........................................................................................................................... 3
Methods................................................................................................................................. 5
Results ................................................................................................................................... 6
Discussion ........................................................................................................................... 20
Conclusion .......................................................................................................................... 26
References ........................................................................................................................... 27
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List of Tables
Table Page
1. Laws and Regulations in developed countries ................................................................ 6
2. Laws and Regulations governing India........................................................................... 8
3. Examples of unethical trials took place in India ........................................................... 13
4. Death during trails in India ........................................................................................... 17
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Introduction
The U.S. Food and Drug Administration (FDA) approves new drugs for marketing by
pharmaceutical companies after reviewing clinical trial results generally containing more than
4000 patients. This is one of the greatest challenges for pharmaceutical companies in the United
States because less than 5% of patients are willing to participate in clinical trials (Garg et al.,
2011; Cekola, 2007). The main reason for this disinclination among American patients is
because of their physician’s discouragement for participation (Cekola, 2007). Many patients are
also worried about treatment with placebo rather than the active product (Garg et al., 2011;
Cekola, 2007). Additionally, of Americans willing to participate, many may be disqualified from
a study because they already take drugs that may confound the experiment (Cekola, 2007). As
result, pharmaceutical companies may move their studies to other countries with populations that
are more viable and willing to participate to find a large enough pool of subjects.
Developing countries have become the preferred location to conduct clinical trials (Garg
et al., 2011). Clinical trials in India often cost 40% of the price of American drug trials (Cekola,
2007). The lack of access to adequate health care in developing countries has created a desperate
environment in which many individuals can only receive the treatment they need through clinical
trials. In developing countries, the large populations, lower costs of technical services, spectrum
of diseases, lower per-patient trial costs, and wide range of races offer pharmaceutical companies
an attractive location to conduct clinical trials (Garg et al., 2011). Hence, there are great
opportunities to conduct clinical trials in developing countries compared to developed countries.
India has an environment that is suitable for conducting clinical trials. In 2005, India
became such a popular destination for clinical trials it acquired the nickname “Guinea pig of the
world” (Nundy et al., 2005). Unlike many other favorite destinations for clinical trials, India
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provides highly regarded institutions with a sophisticated technological infrastructure that can
accommodate foreign studies. Additionally, these facilities are organized with responsible
medical professionals who speak English and are willing to conduct clinical trials for less money
than an American with similar training (Bhatt, 2011).
Additionally, India is stratified. Many medical facilities are too expensive for the poor to
afford. The majority of India’s population is desperate for affordable medical attention (Cekola,
2007). For many sick individuals in developing countries such as India, clinical trials are their
only access to health care (Bhatt, 2011; Cekola, 2007; Glickman et al., 2009).
Regulations and guidelines on international research are important because they (a)
inform researchers what is acceptable, and (b) regulations and guidelines provide a crucial point
for researchers and other professionals to discuss issues in international health research (RTI
International, 2004). One quarter of clinical trials conducted in developing countries fail to
undergo an ethical review (Fleck, 2004). Only about one half of the large hospitals have
Institutional Review Board (IRBs), and as per Indian Pharmacological Society, these few boards
have not yet formulated standard operating procedures (Prakash, S. 2009). An Informed consent
is a process for getting permission before conducting a clinical trial on a person. It is a way to
educate the subject about the research. An informed consent must be obtained from the subject or
his or her legally authorized representative prior to the onset of a clinical trial (FDA, 1981).
Some unethical trials were being conducted in developing countries due to absence of adequate
regulations and proper laws in these countries (Srinivasan, 2004). Due to this, there is a need to
protect the subjects and regulate the trials.
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Background
It is estimated that 20-30% of global clinical trial activities are conducted in developing countries
(Bhatt, 2004). Seven percent of all global phase 3 trials and 3.2% of all global phase 2 trials are
performed in India (Jayasheel, B. G., 2010). The availability of a large patient population, a
lower cost of technical services, limited health-care services, a spectrum of diseases, and a wider
range of races have made India an attractive place for conducting clinical trials (Bhatt, 2004).
However, concerns exist regarding the current Indian model. For example, deficiencies exist in
functioning of ethics committees, regulatory bodies, and investigators’ unethical approaches to
recruiting subjects (Bhatt, 2004). As a consequence, Indian participants assume a greater risk
than patients in developed countries.
Each country has its own regulatory authority that is responsible for enforcing the rules
and regulations for the drug development process, including the licensing, registration,
manufacturing, marketing and labeling of pharmaceutical products. The Central Drugs Standard
Control Organization (CDSCO) is the national regulatory body for Indian pharmaceuticals and
medical devices. The Drug Controller General of India (DCGI) is part of CDSCO and regulates
the pharmaceutical industry in India (Desai & Naik 2011). The functions of the DCGI include
approval of trial and sending biological overseas for testing (Desai & Naik 2011). In India, the
Indian Council of Medical Research (ICMR) is the highest authority for formulation and
promotion of biomedical research (ICMR, 2006). The Indian Council of Medical Research
(ICMR) established its “Ethical Guidelines for Biomedical Research on Human Subjects” in
2000 (ICMR, 2006). These guidelines covered general principles such as voluntariness, informed
consent, privacy and confidentiality, risk minimization, community agreement, general ethical
issues, non-exploitation by providing remuneration to the research participants irrespective of the
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social and economic condition, and institutional arrangements such as ensuring research reports
and materials connected with the research are to be made in a transparent manner (ICMR, 2006).
Good Clinical Practices (GCP) guidelines were developed by the International Conference on
Harmonization (ICH). In 1996, the ICH published this set of standards and technical
requirements for the registration of pharmaceuticals for human use. This publication was
harmonized by FDA for research efforts across the United States. Regulatory bodies at clinical
research sites, serve as safeguards of ethical research conduct. Currently, ICH regions such as the
United States, Japan, and European countries have stringent rules and regulations (Guideline for
Good Clinical Practice, 1996).
Developing countries must protect their citizens that participate as subjects in clinical
trials. Most developing countries lack a strong organization that exclusively protects clinical
trials’ subjects and regulates clinical trials. The purpose of this paper is to explore unethical
clinical practices, their impact on human subjects and summarize ways in which regulatory
agencies can protect the subjects and regulate the clinical trials in India. This paper also focuses
on measures that can be taken to overcome the problem.
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Methods
This paper contains a brief review of the protection of subjects and regulation of clinical trials in
developed countries such as US and developing countries such as India. This review contrasted
the procedures and processes in developed and developing countries using the US and India as
examples. The sources for the study included a combination of papers which include published
research articles, textbooks, and international guidelines, ethical and regulatory policies. The
literature was searched for topics concerning laws and regulations regarding conduct of clinical
trials in US and India and examples of unethical trials that took place in India. The databases for
health sciences pubmed, cinahl and googlescholar were used for literature search. This paper
aimed to collect information from several publications with regard to unethical trials that took
place in India. Keywords such as protection of subjects, developing countries, developed
countries, regulations, unethical trials, etc., were used and all such retrieved information from
search results were carefully scrutinized and applicable information for this project was
collected. All such findings from literature review and publicly available clinical trials data were
summarized.
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Results
The literature review discovered the regulatory and ethical principles and bodies in developed
countries (see Table 1) and India (see Table 2).
Table 1. Laws and Regulations Concerning Conduct of Clinical Trials in Developed Countries
Laws and Regulations Important Points
Good Clinical Practice A worldwide ethical and scientific quality standard for creating, recording
(GCP)
and verifying assessments that includes the participation of human subjects.
GCP standards ensure that rights, security and well-being of clinical trial
subjects are properly secured (European Commission, 1997).
The Principles of ICH GCP: Before a clinical study is initiated, expected
threats and distractions should be weighed against the advantages for the
individual subject, topic, and community. A clinical trial should be
performed in compliance with the protocol was established by IRB/IEC
approval (European Community, 1997).
Independent Data A separate data-monitoring panel that may be established by the sponsor to
Monitoring Committee assess the improvement of a trial, protection information, and crucial
efficacy endpoints, and to suggest to the sponsor whether to proceed, change

(IDMC)
or quit a trial (European Commission, 1997).
Institutional Review Protects human rights and well-being of all clinical trial subjects. The
Board/ Independent IRB/IEC should contain a reasonable number of members who jointly have
Ethics Committee the credentials and experience to evaluate and assess the technology, medical
factors, and values of the suggested clinical trial (European Commission,

(IRB/IEC)
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Responsibilities 1997).
Public Health Service This act was passed, and protected a wide variety of health issues, including
Act of 1944 the regulation of biological products and control of communicable illnesses
(FDA, 2012).
Regulations for Human In 1981, the FDA and the Division of Health and Individual Services
Subject Protections modified regulations for human subject protections, based on the 1979
Belmont Review, which had been from the Nationwide Percentage for the
Security of Individual Topics of Biomedical and Behavior Analysis (FDA,
2012).
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Table 2: Laws and Regulations Governing the Conduct of Clinical Trials in India.
The Pharmacy This act regulates the pharmacy profession in India. The act controls the
Act of 1948 registration of pharmacists, education regulations, and cancellation of
registrations.
Good Clinical Good Clinical Practice is an international quality standard for the design,
Practice monitoring, auditing, and recording and reporting of clinical trials. In 1996,
Guidelines Indian GCP guidelines were issued by the ICMR with WHO, ICH, USFDA and
European GCP guidelines (Gupta & Kohli, 2006).

(GCP)
Central Drug The national drug authority is the Central Drug Standards Control Organization
Standards (CDSCO) in New Delhi, which is controlled by the Drug Controller General of
Control India (DCGI). This system is responsible for medical devices, clinical trials,
Organization and quality standards, and it also registers all imported drugs, new drugs, and
biological drugs. The main regulatory bodies in India include CDSCO and
(CDSCO) and
Drug DCGI. The Federal CDSCO is responsible for the safety, efficacy, and quality
of drugs supplied to the public. The DCGI is an important body in the

Controller
pharmaceutical industry for the approval of clinical trials, test licenses, drug
General of
testing, bioequivalence studies, registration for importing and exporting NOCs,
India (DCGI)
biological sample, drugs, licensing of blood banks, r-DNA products, vaccines
and medical devices, amendments in drugs and cosmetic acts. To conduct a
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clinical trial in India, the regulatory authority of India (i.e., DCGI) must give
permission and also companies where the trials must be conducted (Desai and
Naik 2011).
Schedule Y of This act was enacted in 1945, and improved in 2005 (Desai and Naik, 2011).
the Drugs and To conduct a trial, an applicant should submit the study’s details, such as the
Cosmetic Act protocol of the clinical trial, with a consent form, chemical and pharmaceutical
data, generic and chemical names, dosage form, composition, animal
pharmacology and toxicity data, and also Phases I, II, III, and IV data to the
DCGI.
Expert DCGI composed independent Expert Committees to frame guidelines for

Committee
clinical trials. These committees used to examine the reports of serious adverse
(EC)
events also it will decide the cause of death. These committees will work under
the provisions as mentioned in Appendix XI1 of Schedule Y of Drugs &
Cosmetics (D&C) Rules (Shankar, 2013).
Indian GCP guidelines are not completely in line with ICH-GCP. There are significant
differences in some of the areas (Bhatt, 2010). Indian guidelines mandate that the sponsor and
investigator sign a copy of the standard operating procedures (SOPs) and be aware of and
comply with SOPs. However, ICH-GCP expects the investigator to comply with the protocol and
leaves the task of monitoring compliance with SOPs to monitors and auditors. Another example
is that Indian GCP requires that an investigator sign and forward the study’s data (e.g., case
report forms, results and interpretations), analyses, and reports from his or her center to the
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sponsor and ethics committee. However, ICH-GCP mandates that when the trial is completed,
the investigator must provide the IEC with a summary of the trial’s outcome (Bhatt, 2010).
According to Indian GCP, the IEC has the power to order the discontinuation of a trial if
it finds that the goal of the trial has been achieved midway or unequivocal results were obtained.
However ICH-GCP mandates that this is the responsibility of the independent data monitoring
committee (IDMC). Additionally, the monitor is supposed to inform the sponsor and the IEC of
any unwarranted deviation from protocol or any transgression from GCP principles. However,
ICH-GCP states that the monitor must verify that the documents provided by the investigator are
legible. India is considering adopting ICH-GCP guidelines, but it has not yet adopted a complete
set of guidelines as described by ICH-GCP (Bhatt, 2010).
The Central Drug Standards Control Organization (CDSCO) built an expert committee in
consultation with clinical experts and formulated GCP guideline for generation of clinical data
on drugs, based on its recommendation these guidelines will be updated in a timely manner. The
DCGI also checks the regulatory status of the drug in other countries, such as the names of the
countries where the drug was approved or where the investigational new drug program was filed.
It typically takes between 10 and 12 weeks for approval, as compared to an average of 30 days
with the U. S. Food and Drug Administration (USFDA) and 60 to 90 days in Europe (Desai and
Naik 2011). Once approval is given, the sponsor must send the safety reports and annual report
of that particular year with all of the details of the study in India. Once the study is completed, a
detailed report to be submitted to the DCGI. The DCGI also ensures that trials are conducted as
per the protocol and ethical guidelines (Sarda et al., 2012).
Indian Penal Code 1860, Sections 52, 80, 81, 83, 88, 90, 91, 92 304-A, 337, and 338
contain the laws for medical malpractice to protect patients from treatment adversities (Med
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India, n.d.). This section enables hospitals to be held responsible for treatments; this section also
applies to physicians. Additionally, the physicians and hospitals can be penalized for any
irresponsibility and carelessness. In 2011, the Ministry of Health and Family Welfare proposed
amendments to the Drugs and Cosmetic Rules, 1945, to ensure payment of compensation to the
study subject for clinical trial related injuries or death. After more than a year, the final
amendments were notified and effective in 2013, resulting in the Clinical Trials Compensation
Law (Desai & Naik, 2011).
The Law states
a. Clinical trial subjects are entitled to free medical management as long as required and
financial compensation for clinical trial related injury or death.
b. The sponsor or its representative, whosoever so is conducting the clinical trial in India, is
compelled to bear the expenses of the subject’s medical management and provide
financial compensation. With respect to compensation, the sponsor, whether a
pharmaceutical company or an institution, is also required to give an official declaration
to the DCGI, stating that they will provide compensation in the case of clinical trial
related injury or death.
c. The Sponsor, Investigator and Ethics Committee have to submit their report with an
analysis on the cause of the adverse event to the Experts Committee (in case of death or
injury, the DCGI appoints such Committee) and the DCGI within a stipulated time. The
Experts Committee would be set up by DCGI and would investigate the cause of death or
injury (if required by DCGI), and recommend financial compensation.
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d. The DCGI is authorized to decide the cause of the serious adverse event as well as pass
an order on payment of compensation, if applicable, taking into account
recommendations of the Experts Committee.
e. The time frame for determination of the cause of the serious adverse event and order of
financial compensation is three months from the date of report of the serious adverse
event by the investigator.
f. The sponsor or sponsor representative is given a time frame of 30 days from receipt of
the order of the DCGI to provide compensation to the subject.
g. Failure of the sponsor or sponsor representative to provide free medical management
and/or financial compensation, as ordered, may lead to the Failure of the sponsor or
sponsor representative to provide free medical management and/or financial
compensation, as ordered, may lead to the suspension or cancellation of the existing and
further scheduled clinical trials in India.
h. The Informed Consent Form was modified to include relevant details for the purpose of
determination of compensation such as occupation, annual income and qualification of
the subject. It is obligatory to hand over a copy of the informed consent sheet and duly
completed informed consent form to the subject or his or her attendant (Desai, 2013).
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Examples of unethical practices in India
Clinical trials in India require DCGI and Ethics committees’ approval and can be performed only
at certified center by qualified investigators. In Practice, DCGI and Ethics review committee are
approving without duly reviewing protocol and adverse events. Table 3 summarizes the 7 major
cases that were available publicly out of 10 cases where DCGI gave permission for phase 3 trials
without phase 2 trials, trials conducted without DCGI and ethical review committee approval,
subjects involved in unethical trials without their knowledge or informed consent.
Table 3: Examples of Unethical practices in India.
Trail Name Description
Letrozole Trials Novartis anti cancer drug Letrozole is to be used only in post
menopausal women and not intended nor permitted to use for
reproductive health in women. As per Indian law Phase 3 studies can
be conducted only after phase 2 studies, however DCGI gave
permission to clinical trial sponsor company Sun Pharma to conduct
phase 3 studies prior to phase 2. These trails were also conducted in
private hospital by three doctors on only 55 subjects. On April 10,
2007 DCGI approved usage Letrozole improving fertility (Sinha,
2012). On October 12, 2011 Indian Ministry of Health and Family
Welfare banned the drug based on its findings as per section 26A of
the Drug and Cosmetics Act, 1940(23 of 1940) (CDSCO, 2011).
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Streptokinase Trials Without prior approval from DCGI and Genetic Engineering
Committee, Bangalore based Biocon and Hyderabad based Shanta
conducted phase III trials of genetically engineered drugs (insulin
for diabetes by Biocon and streptokinase for heart attacks by
Shantha) (Srinivasan, 2004).
As a result of the trials eight people died. Based on this event, Aadar
Destitute and Old People’s Home (a Delhi based social organization)
has filed Public Interest litigation in the Supreme Court of India and
Court against the above two companies (Basu, 2004).
Risperidone Trials In 2003 Johnson and Johnson conducted Risperidone trials in
Gujarat, India to treat acute mania. A subject explained that he
signed a form as advised by his doctor, but he did not know he was
participating in a clinical trial.
Violated norms: Not all subjects were informed they were
participating in a trial. Informed consent was not properly obtained
from all participants (Parth et al., 2013).
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NDGA Trials In collaboration with Indian doctors, the Johns Hopkins University
tested NDGA in Indian patients before its safety was established in
animal tests. Between the time periods November 1999 to April
2000 this drug was injected into 26 oral cancer patients.
A Radiobiologist, Dr. V. Narayan Bhattathiri, at the clinical trial
center accused his colleagues of violating ethics by conducting
clinical trials without informed consent for drugs which are not
approved and using patients as guinea pigs. He reported the issue to
Human Rights Commission. Indian health ministry appointed a
committee and submitted its finding to the government. The Johns
Hopkins University committee then agreed that safety testing of the
NDGA drug in animals was inadequate and it also confirmed Dr
Bhatathiri’s accusations were valid regarding informed consent
(Mudur, 2011).
Zoniporide Trials In 2000, Pfizer conducted Zoniporide trials to treat perioperative
cardiac events. Although Phase II trials were not completed in the
United States, the DCGI gave it’s the approval for Phase III trials in
India. This implied the following violations: Schedule Y of the
Indian Drug and Cosmetic Act: Before 2005, the act prohibited
Phase II clinical trials outside the country. Phase III trials of drugs
were allowed only if the drug had already been tested (Parth et al.,
2013).
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Cilostazol Trails Cilostazol is an oral phosphodiesterase type 3 inhibitor with
antiplatelet and vasodilating activity. This drug helps in reduction of
intermittent claudicating symptom in patients with peripheral
vascular disorder (Rao, 2013). DCGI gave clearance for this drug to
Otsuka America Pharmaceutical, Inc with insufficient information
on its adverse effects such as diarrhea, headache, hypoglycemia,
hypotension, and palpitations (Kumar & Chandy, 2006).
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Salbutamol Ipratrpium Ethics Committee of governments Mahatma Gandhi Memorial
Inhaler Medical College's had given approval for Salbutamol Ipratrpium
Inhaler drug trial on September 12, 2005 to Mumbai-based company
Cipla and trials were conducted by contract research organization —
LAMBDA. Anwar Bi complained to DCGI, Medical Council of
India and the National Rights Commission (NHRC) as her husband
Abdul Rasheed died on April 21, 2010 due to drug trials. According
to Anwar Bi Rasheed went to Manorama Raje TB hospital for
treatment where TB specialist Salil Bhargava took Rasheed to his
private clinic Gyanpushp Research Centre for Chest and Allergy
Diseases and tested an unknown medicine on him as part of drug
trial without patient consent. He treated Rasheed for chronic
obstructive pulmonary disease from 2005-2010 with a new drug
Salbutamol Ipratrpium Inhaler. This matter was raised in the State
Assembly, following which the Medical Education Department had
sent a list of patients on October 29, 2010, to three Members of
Legislative Assembly, including Leader of Opposition Ajay Singh,
Paras Saklecha and Pratap Grewal. The list, which was prepared on
the directives of Assembly Speaker Ishwardas Rohani, contained
names of patients, including Rasheed's, on whom the drug trial was
carried out since the last five years (The Hindu, 2012).
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According to the data available from the Drugs Controller General of India (DCGI) for
the year 2011 there were 159 deaths in clinical trials. The below (see Table 4) shows the
list of pharmaceutical companies named in clinical trial death list.
Table 4: Death during Trials in India (Dey, 2012).
Deaths During Trials in 2011 as per DCGI
Deaths Company
57 Novartis
32 Quintiles Technologies
20 Bayer
20 Pfizer
19 Bristol Mayer Squibb India
10 MSD Pharmaceutical
1 Dr Reddy’s Laboratories
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Supreme Court asked the Center to investigate 'unauthorized' clinical trials in a
judgement on a Public Intrest Litigation (PIL). The Supreme Court of India issued a notice to
Government of India. According to this appeal, GlaxoSmithKline had conducted unauthorized
trails of a vaccine for cervical cancer on 24000 tribal girls in Andhra Pradesh and Gujarat states.
The PIL also alleged that the vaccine has an adverse reaction on the girls health followed by
companies’ failure in providing treatment, which lead to death of seven girls. The Supreme Court
also directed Christian Medical College, Vellore to scrutinize the medical records of the girls and
submit a report to the court (Manjesh, 2013).
The Government of India is planning to amend the Drugs & Cosmetics Act to add 10
years of imprisonment and cancellation of license for violating norms of clinical trials on
humans. This act would ensure that those who do not follow the norms set by the Drug
Controller General of India (DCGI) for conducting clinical trials on humans will be punished
(Dey, 2009).
A probe by Government of India against drug trials in 2010 found six tribal children died
after administration of Human Papilloma Virus (HPV) vaccines as part of clinical trials. The
Government of India took disciplinary action against medical professionals who had allegedly
been conducting these trials. Following this incident, the government ordered suspension of
clinical trials on April 7, 2010. Thirteen thousand seven hundred and ninety one (13,791) and
9,637 girls were vaccinated in Andhra Pradesh and Gujarat states, respectively. A three-member
committee was then appointed by the ministry to probe issues of ethics (Patro, 2012).
In response to queries of health activists under Right to Information Act (2005), State
Government exposed drugs and herbal treatments that were tested on mentally challenged
patients and children. Following a legal investigation, the Government fined 12 doctors 5000
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($99) each under State Nursing Homes Act. However private doctors were exempted from fines
as they are not covered under this Act (Reporter, 2012a).
Some pharmaceutical companies that have conducted clinical trials in India have granted
meager compensations, sometimes as low as 50,000 ($820), to the legal heirs of the victims. In
2010, compensation was given to 22 cases of death by firms, mostly foreign, such as Merck,
Quintiles, Lilly, Bayer, Amgen, Bristol Myers Squibb, Sanofi, Pfizer and Wyeth. In 2011,
35.21 lakh ($57721) was offered as compensated for 16 cases for drug trial deaths by
Pharmaceutical companies such as ICON, VEEDA, Pfizer, Sanofi, Fresenius and Sun Pharma.
Total compensation of 70.33 lakh ($115295) paid for all cases (The Hindu, 2013). Independent
Expert Committee (formed by DCGI) prepared a formula to pay compensation in case of adverse
event of death. Compensation was calculated based on 3 factors, age, risk and base amount.
Compensation= B*F*R/99.37
In the above formula B represents base amount (i.e., 8 lacs), F represents factor (depending on
the age of the subject), and R represents risk factor (depending on severity of disease)
(Kavitarana, 2013).
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Discussion
Based on the above findings, there is a need to develop a new plan that addresses deficiencies in
current Indian Model. The results Risperidone and NDGA trials of the Parth el al. (2013) and
Mudur (2011) shows that due to illiteracy, patients signed informed consents without
understanding the procedures, benefits or risks involved in clinical trials. Not all subjects were
informed they were participating in a trial. Clinical trial investigators should explain the
informed consent to subjects, the nature and purpose of the study, the duration of research, the
risk factors and the freedom to withdraw from the trial at any time. There are instances where
patients have signed the informed consent however not aware that they have an option to
withdraw the clinical trial at any point of time (Berne Declaration, 2013). The company should
obtain proper informed consent from an eligible adult participant. Additionally, there should be
reasonable distribution of the problems and advantages of research and equal attention for all
subjects in a trial, and risk of harm should be minimal. Researchers should develop techniques to
ensure that participants can better understand the information provided in the consent process
and should describe the procedures in the protocols. While taking the informed consent from the
subject, family members should provide consent also for mentally retarded subjects. In the
absence of a family member’s permission, an individual’s voluntary informed consent should
suffice. The researcher should use the same procedure while taking the informed consent process
for women and men. The government should provide awareness programs for people regarding
the pros and cons of clinical trials and ensure that ethical clinical practices are in place. Since the
literacy rate in developing countries such as India is comparatively low, it has to advantage of
latest technology and implement recording of audio and video of informed consent process of
each trial subject. Poverty, low literacy, and pressure from sponsors for early completion of
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patient enrollment leads to unethical subject recruitment. Therefore, a need exists to enroll only
participants who have basic education qualifications, so that can increase the awareness of
informed consent in the subjects. Therefore, the GCP should stress the implementation and
documentation of the informed consent process. Good Clinical Practice should be considered as
the universal ethical and scientific quality standard to conduct a clinical trial. The GCP should
emphasize following strict adherence to the study at the sites to protect the subjects during
subject recruitment. Recruitment policies to be made available in English as well as the regional
languages to improvise the patient’s awareness. Developing countries should follow the system
of protections that is at least equal to that of developed countries. Continuous monitoring of the
safety of the research studies should require more qualified human resources. Decision-making
choices must be clear and all of the information and decisions should be available for review by
public. Failures of the trials should be advertised to public, as safety and transparency of clinical
trials is the most important concern in India. Reports by The Hindu (2012) illustrates that ethical
committees are not effectively working, so it needs to improve in below areas. Ethical
committees should be entrusted with review of the proposed clinical research protocols prior to
the start of the study. They should also extend their responsibility to monitor approved projects
regularly for the compliance of ethics until the studies are completed. An ethics manual should
be followed by ethics committees across both high resource and low resource regions. It should
tie international standards, such as Council for International Organization of Medical Sciences
(CIOMS) and the Declaration of Helsinki. In this way, an ethics manual should be used as a deep
background reference in a clinical trial design and ethics committee operations. The role of
ethics committees should include review of the proposed study and regular monitoring for the
compliance of the ethics of the approved studies until the same are completed. This ongoing
22 | P a g e
review should be in accordance with international guidelines and standard operating procedures
of the WHO. There is a need to develop a national Central Ethical Monitoring Cell for
monitoring clinical trials sponsored by developed countries and local IRBs. All local IRBs
should be required to be registered under the Central Ethical Monitoring Cell. When assigning a
site for a clinical trial, caution should be followed by the Central Ethical Monitoring Cell and it
should not be under the control of sponsors or CROs. Reviewing and approving protocol,
standard of care, and liabilities of IRBs should be clearly declared in ethical guidelines. Reports
by Kumar & Chandy (2006) shows that DCGI gave clearance for this drug to Otsuka America
Pharmaceutical, Inc with insufficient information on its adverse effects such as diarrhea,
headache, hypoglycemia, hypotension, and palpitations. So DCGI should give the permission
only after scrutinizing the activity of the drug. The DCGI should help strengthen the
pharmaceutical industry in India by updating its laws and regulations in a timely manner based
on their findings after each clinical trial submissions. For instance, DCGI finds a new process is
required for a specific trial based on their findings; it has to amend regulations accordingly. The
Indian regulatory system should start adapting the demands of quality and accountability of
global trials. Regulatory bodies should make sure that clinical trials are started only after getting
written permission from DCGI and an IEC. The results of Sinha (2012) and Parth et al., (2013)
shows that DCGI gave permission to clinical trials sponsor company to conduct phase 3 studies
prior to phase 2 trials. DCGI should give permission for phase 3 trials only after phase 2 trials. It
has been recommended that whenever clinical trials sponsored by the developed countries insure
their participants from international insurance companies, pharmaceutical companies should
prefer insurance to subjects from local insurance companies which will give an opportunity for
clinical trial participants to visit their offices and settle issues if any. One of the major concerns
23 | P a g e
for participants when dealing with foreign insurance companies is communicating with them and
this can be addressed by opting local insurance companies. A collaborative partnership between
researchers and sponsors of developed countries should build policies for developing countries to
minimize the exploitation. India should follow and adopt stringent regulations. This would result
in a reduction in exploitation of subjects. Clinical trial sites in India should improve the
information infrastructure by developing databases to maintain details of potential trial
participants, providing sophisticated laboratories, and continuing medical education as a
common approach to improving clinical practice. Current policies should be reviewed and
amended to address present day challenges by considering the aforementioned models. Those
models should be included in the current model and embedded into law to ensure that no clinical
company or organization is exempt from following ethical standards. Due to the lack of
resources, ethics review committees find difficulty in complying with U.S regulations.
Therefore, companies that sponsor the research in developing countries should provide financial
support for operating and managing the trial. India should have the capacity to conduct clinical
trials independently and have their own ethical and scientific reviews. India should adopt new
techniques, such as targeted education, case-based learning, and interactive and multimodality
teaching techniques for conducting any clinical trials. A thorough review and proper assessment
of governing bodies in India is required to get international acclaim in the field of clinical trials.
Companies should increase spending on clinical trials so that ethical issues can be dealt with
easily. Proper training should be given to the investigators in India regarding ethical and
scientific considerations, as well as in the design and process of clinical trials. There was no right
to information act to demand documented evidence and instructions of clinical trials procedures
and consequences from pharmaceutical companies before participating in clinical trials
24 | P a g e
(Mohapatra & Kachhwaha, 2013), which may leads to unethical clinical trials. To avoid this,
there is an urgent need to implement right to information act. Banned drugs in any other country
should not be used for clinical trials in developing countries. Sponsors, media, health care
providers and the public should arrange open communication to overcome real and perceived
barriers to clinical study participation. The role of lawyers before the commencement of any
clinical trial occurs when there is a precautionary approach taken by the pharmaceutical
company of obtaining legal opinions from their in-house lawyers and legal practitioners.
Acquiring such legal opinion is not available for patients participating in clinical trials.
There is a need to strengthen the regulatory bodies in India and the following are
suggestions for strengthening the drug regulatory mechanism in India. Regulations could include
educating the population, providing public health initiatives, producing public service
announcements, following the company’s GCP ethics policies, strengthening oversight boards,
and establishing international agreements between countries, like the World Health Organization.
To monitor the clinical trials in the pharmaceutical industry, regulatory bodies should be
strengthened by setting up new offices in new locations, creating new central drugs laboratories,
equipping them with state-of-the-art technology to enable them to carry out sophisticated
analysis of drugs, upgradation of the existing 6 central drugs testing laboratories, skill
development of the regulatory officials, increasing transparency in decision-making of CDSCO.
Awareness must be created among all stakeholders of the guidelines set down for clinical trials
by the Central Drugs Standard Control Organization. The CDSCO should make the guidelines
available to the public on its websites in order to ensure fair practices. The CDSCO and the State
Drug Control Administration should be adequately staffed to supervise clinical trials across the
country. Since the CDSCO has a small technical staff, they face challenges in reviewing and
25 | P a g e
increasingly mounds of data that are submitted for clinical trials and drug approval. The CDSCO
should gain knowledge on the pharmaceutical company’s role in the health care sector, which
would help protect the wellness of the people and address larger public health problems. The
CDSCO should implement an e-governance program, which would enable the pharmaceutical
companies or clinical trial sites to file, track, and review the clinical trial application online.
Understanding drug efficiency and adverse drug reactions would help in offering better treatment
for patients. Regulatory bodies in India should be ready to meet the challenges worldwide by
staffing qualified and academically sound resources to discuss necessary strategies. The national
regulatory authority should become more pro-industry, vigilant, and efficient, which would
translate to a more USFDA-like regulatory system. The Indian government should work closely
with international bodies to update the regulatory guidelines. Established regulatory bodies in
various countries should redefine their guidelines and laws, as global pharmaceutical companies
are becoming more competitive and aggressive. New updated regulatory bodies should be
introduced, as needed, by the government. It needs to frame a more systematic regulatory
process of drugs before initiating the study. The regulatory bodies recognize the need to frame
guidelines and regulatory approval processes as per with international standards. The Ministry of
Health and Family Welfare should monitor clinical trials in accordance with the procedure
prescribed in Schedule‘Y’of the Drugs and Cosmetics Act, 1940. Currently, in India Ministry of
Health and Family Welfare is responsible only for four departments 1. Department of health and
family welfare, 2. Department of AYUSH, 3. Department of Health Research and 4. Department
of AIDS control.
26 | P a g e
Conclusion
India can protect its people from unethical clinical trials if a few simple suggestions are
implemented. Unless laws are fairly implemented, the current unethical and illegal trials will
pave the way for private practitioners to make money, which may leave many Indian patients
diseased, deformed, or dead. India is considering ICH-GCP guidelines; however, it has not yet
adapted a complete set of guidelines as described by ICH-GCP.
The research suggests that ICH should monitor and recommend the concerned
governments to start implementing the ICH-GCP guidelines. Informed consent should be made
mandatory to protect human subjects from any harm that may be posed during the research. The
Indian government should implement a right to information act to demand documented evidence
and instructions of clinical trial procedures and consequences from pharmaceutical companies
before participating in clinical trials. Indian government should amend clinical trial laws by
adding new rules that will oblige pharmaceutical companies that sponsor trials to pay
compensation in cases where volunteers suffer trial-related death or injury and also trial sponsors
will need to pay in cases of trial-related injuries and deaths. Current policies should be reviewed
and amended to address present day challenges. India should adopt new techniques, such as
targeted education, case-based learning, and interactive and multimodality teaching techniques
for conducting any clinical trials. Ethical committees should be entrusted with review of the
proposed clinical research protocols prior to the start of the study.
27 | P a g e
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Protection of Subjects and Regulation of Clinical Trials in India

Submitted to The College Of Health And Human Services

Eastern Michigan University

In partial fulfillment of the requirements

for the degree of

Clinical Research Administration

March 10, 2014

my stay at Eastern Michigan University.

thoughts throughout my master’s program.

at Eastern Michigan University.

of attentive regulatory authorities, insufficient infrastructure, and a failure to follow International

Conference on Harmonization-Good Clinical Practices (ICH-GCPs). Research projects that

suggests proposals such as strengthening regulatory bodies, developing a plan to address

List of Tables ........................................................................................................................ v

1. Laws and Regulations in developed countries ................................................................ 6

2. Laws and Regulations governing India........................................................................... 8

3. Examples of unethical trials took place in India ........................................................... 13

4. Death during trails in India ........................................................................................... 17

opportunities to conduct clinical trials in developing countries compared to developed countries.

than an American with similar training (Bhatt, 2011).

protect the subjects and regulate the trials.

functioning of ethics committees, regulatory bodies, and investigators’ unethical approaches to

than patients in developed countries.

issues, non-exploitation by providing remuneration to the research participants irrespective of the

Good Clinical Practice, 1996).

on measures that can be taken to overcome the problem.

place in India. Keywords such as protection of subjects, developing countries, developed

countries (see Table 1) and India (see Table 2).

Laws and Regulations Important Points

subjects are properly secured (European Commission, 1997).

The Principles of ICH GCP: Before a clinical study is initiated, expected

individual subject, topic, and community. A clinical trial should be

performed in compliance with the protocol was established by IRB/IEC

approval (European Community, 1997).

efficacy endpoints, and to suggest to the sponsor whether to proceed, change

factors, and values of the suggested clinical trial (European Commission,

Security of Individual Topics of Biomedical and Behavior Analysis (FDA,

Act of 1948 registration of pharmacists, education regulations, and cancellation of

European GCP guidelines (Gupta & Kohli, 2006).

of drugs supplied to the public. The DCGI is an important body in the

and medical devices, amendments in drugs and cosmetic acts. To conduct a

data, generic and chemical names, dosage form, composition, animal

Expert DCGI composed independent Expert Committees to frame guidelines for

the provisions as mentioned in Appendix XI1 of Schedule Y of Drugs &

Cosmetics (D&C) Rules (Shankar, 2013).

set of guidelines as described by ICH-GCP (Bhatt, 2010).

per the protocol and ethical guidelines (Sarda et al., 2012).

Law (Desai & Naik, 2011).

The Law states

financial compensation for clinical trial related injury or death.

financial compensation. With respect to compensation, the sponsor, whether a

pharmaceutical company or an institution, is also required to give an official declaration

related injury or death.

injury (if required by DCGI), and recommend financial compensation.

an order on payment of compensation, if applicable, taking into account

recommendations of the Experts Committee.

event by the investigator.

the order of the DCGI to provide compensation to the subject.

g. Failure of the sponsor or sponsor representative to provide free medical management