ECs/ IRB Are mere Rubber stamp

INTRODUCTION
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.
2

INTRODUCTION
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
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
4

QUESTIONS WE ARE SUPPOSED TO ASK...

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
5

EC/IRB in India
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.
6

EC/IRB in India
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.
7

EC/IRB in India
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.
8

EC/IRB in India
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
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

10

EC/IRB in India
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 members 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.

11

EC/IRB in India
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.

12

EC/IRB in India
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.

13

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.
14

 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.

15

EXAMPLES
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.

16

 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.

17

THE CONTROVERSY ON TRIALS IN INDORE

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.
18

Diabetes drug tested on humans before toxicology studies completed 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.
19

Experimental cancer drug tested without people's consent 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.
20

21

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 22 patients, but that wasn't done

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.
23

RECENT CHANGES
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.
24

RECENT CHANGES
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

25

MEASURES
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

26

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.

27

28