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ECs/ IRB Are mere Rubberstamp

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The first appearance of need of ethics committee (EC) was

made in Declaration of Helsinki in 1964,

In India it appeared in 1980 in the ICMR Policy Statement.

EC also called as the Institutional Review Board or the

Ethics Review Board stands as the bridge between the

researcher and the ethical guidelines of the country.

The establishment of EC requires 5-15 members

Individuals carrying out research can approach to

independent ECs.

INTRODUCTION

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Independent Review Boards (IRBs) or Ethics Committees (ECs)

have been entrusted with the responsibility to safeguard the

rights

safety

and well-being of all trial subjects.

They are responsible for ongoing review and monitoring of

trial activities to ensure that patients rights, safety and well-

being are protected

INTRODUCTION

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Constraints like

• lack of space

• infrastructure

• Time

• Funds and

• administrative support

This results in most EC activities being

restricted to an initial review and approval of

study protocol although

INTRODUCTION

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Is the clinical research responsive to the health needs and priorities of the communities in which the research is conducted?

Are trial results accurate and valid, and can they be extrapolated to other settings?

Is the financial compensation and health benefits provided to research participants an undue inducement?

A major concern is the ethical oversight of research involving human subjects to ensure that these concerns are addressed

QUESTIONS WE ARE SUPPOSED TO ASK...

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• DCGI designates the EC as an important regulator of ethical

research;

both the bodies seem to work in isolation.

•There is no proper communication network between the Ecs

functional in the country and the DCGI.

• Both the ICMR and DCGI do not have any autonomy over the

research reviewed and approved by the ECs in our country.

•There is no central public authority that is responsible for

supervising the proper and competent functioning of ECs.

• This result in ECs functioning as self-sufficient bodies

concerned with approval of research conducted in their

institutes, with no accountability whatsoever.

EC/IRB in India

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• IRBs are the one entity that is still neglected with inadequate training, limited resources and no legal teeth.

Due to this lack of training in bioethics, EC members do not have a clear understanding of complex ethical issues like

•reduced autonomy• cultural specificities in obtaining informed consent• vulnerable population• therapeutic misconception•conflict of interest• use of placebo• distributive justice•management of and compensation for study-related injury and •post trial access.

EC/IRB in India

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There were no legal experts on most of the ECs and a lack

of clarity in the appointment procedures of EC members.

The study also noted that record keeping was poor, and the

independence and competence of EC questionable.

The scarcity of legal experts and lay persons on the EC

quorum, which is mandatory as per Schedule Y

specifications, also makes arrangement of regular periodic

meetings with the presence of these members a difficult

task.

It is seen that most often the Head of the Institution's

function as chairperson of its EC, thus compromising its

independent status.

EC/IRB in India

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As per a survey conducted by ICMR

• there are more than 200 institutions with functional ECs in India

• many of the existent ECs do not have their standard operating

procedures in place and are not constituted as per Schedule Y

recommendations

• ECs do not have adequate representation of members during

their meetings, which is likely to generate a biased opinion

• the irregular schedule of meetings, with no process in place for

expedited review.

EC/IRB in India

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ICMR also conducted in 2003, where a 20-point

questionnaire was circulated to 1200 institutions

only 223 responded.

It concluded among other points that many research

institutions in India either do not have an EC or there is

inadequate representation in it by persons other than

those of the medical fraternity

EC/IRB in India

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In the last quarter of year 2010, the FDA has issued warning letters to two IRBs.

The first was for issues such as the following.

• Failure to ensure that the IRB is composed of at least five members, at least one IRB member’s primary concerns are in nonscientific areas, and no IRB member participates in the initial or continuing review of any projects in which the member has a conflict of interest

• Failure to have adequate written procedures governing the functions and operations of the IRB.

EC/IRB in India

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The second enumerated the following

• Failure to require that information given to subjects as part of informed consent is in accordance with 21 CFR 50.25.

• Failure to follow written procedures for conducting its initial and continuing review of research.

• Failure to include at least one member whose primary concerns are in a nonscientific area when reviewing proposed research at convened meetings. • Failure to prepare and maintain adequate documentation of IRB activities, including minutes of IRB meetings.

EC/IRB in India

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•The ICMR guidelines are not legislated, hence, the ECs cannot

act against those who violate the prescribed guidelines.

•The role of the EC is merely restricted to being an advisory or

to facilitate research.

•The DCGI has given ECs the power to reject trials not

conforming to the recommended ethical standards.

•The DCGI provides clearance only to those trials that have

been reviewed and approved by the concerned EC.

•The EC also plays a significant role of an ethical regulator for

the DCGI. However, the lack of a national ethics body, with a

strong regulatory control, has further hampered the

establishment of a legal ethics policy.

EC/IRB in India

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Previous issues noted include

failure to conduct continuing review in a timely or appropriate

fashion;

conflict of interest of IRB members;

inappropriate use of expedited review;

failure to inform IRB members of expedited approvals;

inadequate attendance at and documentation of IRB

meetings;

standard surgical informed consent documents lacking the

required elements;

inappropriate granting of exempt status for studies involving

prospectively collected specimens, data, documents, or records;

and

inappropriate granting of waivers of consent without

documentation of compliance with the required criteria for

approval.

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There is an increased scrutiny of clinical research quality from regulators, media and whistleblowers.

Despite major strides taken in most aspects, including clear ethical guidelines, awareness and training of investigators and stringent monitoring by sponsors, adverse coverage by the media continues to plague the clinical research scenario in India.In the developed world, a critical observation during an auditor regulatory inspection could mean loss of reputation, being blacklisted from clinical research and even no marketing authorization for the drug.

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• As many as 436 people died last year due to serious

adverse events (SAE) during clinical trials and the Union

Health Minister has said the deaths could be due to life-

threatening diseases such as cancer, heart failure and

stroke or the side-effects of the drugs or their

administration to terminally ill patient or critical patients

• In 2011, 438 cases of SAE were reported, of which 16

were believed to be due to clinical trials while the

previous year, 668 cases of SAE were reported, of which

22 were caused due to trials.

EXAMPLES

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• Certain pharma companies had conducted illegal drug tests of a

cervical cancer vaccine on tribal girls.

• The petition alleges that big pharma companies including Glaxo

Smithkline and MSD Pharmaceuticals tested two unproven HPV

vaccines – gardasil and cervarix – on almost 24,000 tribal girls in

Andhra Pradesh and Gujarat, including 44 people at the Maharaja

Yeshwantrao Hospital (MYH). Of these 44, ten were males!

• The PIL filed by Kalpana Mehta of Indore and two people – Nalini

Bhanot and V Rukmini Rao of the  Gramya Resource Centre for

Women alleges that the testing had an adverse effect on the girls’

health and the pharma companies ignored their further treatment.

• They allege that seven girls succumbed to their illness during

the vaccine trial.

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The recent reporting of controversial drug trials being

conducted by doctors of the government medical college and

private practitioners on ‘mentally challenged’ patients in Indore

has caused uproar.

It was alleged that for more than two years, from 2008 to 2010,

trials were conducted flouting ethics guidelines.

The Madhya Pradesh government levied a fine of Rs 5000 each

on the doctors involved, and this was seen widely as being paltry

and insufficient punishment.

As details emerged, questions were raised about the role of

independent or commercial (as compared to institutional) ethics

committees, improper documentation of consent, vulnerability of

research participants as well as the thorny issue of private practice

(and in this case, research in private clinics) by government

doctors.

THE CONTROVERSY ON TRIALS IN INDORE

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In 2002, the multinational company Novo Nordisk conducted

multi-centre phase III clinical trials of a diabetes drug before

receiving the results of animal studies.

The study report found that the drug, ragaglitazar, caused urinary

bladder tumors in rats -- and this should have been known before

the drug went for phase I trials, let alone phase II and phase III.

Ragaglitazar was developed by Dr Reddy's Laboratories,

Hyderabad, and licensed to Novo Nordisk which conducted the

trials.

The trials were conducted on 650 people from North America,

200 from Latin America, 100 from Australia / New Zealand, 800

from the European Union, and 200 from non EU Europe- -and 550

from Asia -- including 130 people from eight centers in India.

Half of these people received the experimental drug.

Diabetes drug tested on humans before toxicology studies completed

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In November 1999, 25 people with oral cancer who went to

the government-run Regional Cancer Centre in

Thiruvananthapuram were given an experimental drug, the

chemical tetra-O-methyl nor-dihydro-guaiaretic acid (M4N) or

tetraglycinyl nor-dihydro-guaiaretic acid (G4N), though there

was an established treatment for their condition.

They were not told that they were taking part in an

experiment or that they were being denied an established

treatment.

Only later did it become known that the trial had not been

approved by the Drugs Controller of India (approval was

obtained retroactively).

Further, the sponsor institution, the Johns Hopkins University

in the United States, had not given ethical clearance to the

study, but managed to release the money for research

anyway.

Experimental cancer drug tested without people's consent

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The court issued notice to Indian Council of Medical Research and Govt of Madhya Pradesh, on the application of Bhopal Gas Peedith Mahila Udyog Sangathan (BGPMUS) and Bhopal Gas Peedith Sangarsh Sahayog Samiti, who joined the petition as interveners. 

They petitioned that 250 survivors of the Bhopal Gas Tragedy were subjected to clinical trial of new chemical entity from 2004 to 2008, and that it was withdrawn only in 2008 on directions given by the Director of Bhopal Memorial Hospital and Research Centre (BMHRC). 

The Hospital BMHRC reportedly earned Rs. 100 Lacs for conducting such clinical trials.

BGPMUS claimed it had documents to prove that the trials were conducted without the patients' knowledge and some of them may have even died during the tests at Bhopal Memorial Hospital and Research Centre, which works under the Supreme Court's supervision.

Most victims couldn't read English and were asked to sign papers in the language," he said. "A copy of the consent statement should have been given to the patients, but that wasn't done

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RECENT CHANGES

• Ethics Committees should be approved with the

Licensing Authority before they accept any clinical trials

for review, and all clinical trials would have to be

registered at the Clinical Trials Registry of India before

enrolling the first patient for the study.• The preliminary scrutiny of the applications will be done by

a committee of officers of the Central Drugs Standard Control

Organisation (CDSCO) who will ensure that it contains all the

required administrative as well as technical information in

proper manner as per the checklist.

If the applications are not submitted in accordance with the

format and the checklist, it will not be accepted by CDSCO

for further examination.

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• The Ethics Committee will have to allow inspectors or

officials authorised by the CDSCO to enter its premises to

inspect any record, data or any document related to clinical

trials and provide adequate replies to any query raised by

the inspectors.

• The Committee will also have to inform in writing the

Licensing Authority if there is any change in its membership.

• If the Ethics Committee fails to comply with any of the

conditions of registration, the Licensing Authority can after

giving an opportunity to show cause, suspend or cancel its

registration. The registration, unless suspended or cancelled

earlier, shall be valid for three years.

RECENT CHANGES

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• The Ethics Committees will have to maintain a record for

at least five years after the completion of the trial.

• The annual status of each clinical trial, as to whether it is

ongoing, completed or terminated, shall be submitted to the

Licensing Authority and in case of termination, the details

and reasons will also have to be informed.

• In the case of any serious adverse event occurring to the

clinical trial subjects during the trial, the Ethics Committee

will inform the authorities within 10 days. In case of an injury

to the subject, the applicant shall provide complete medical

management and compensation

RECENT CHANGES

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Measures should be taken for proper functioning like the following:

•GOVERNMENT INITIATIVES

•PROPER TRAINING

•NEED FOR CENTRAL REGISTRATION OF ETHICS COMMITTEES

•OVERSIGHT MECHANISMS

•NEED FOR A NATIONAL FORUM

MEASURES

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CONCLUSION

•We can hence see how the ethical committees have just

become formalities or mere rubber stamps which could have

saved many lives if would have functioned in a proper manner.

• Research ethics is an essential part of good research

practice to protect participants in clinical studies.

• It is our optimistic belief that these challenging issues

will be resolved through a consensus in the future.

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