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From Guidelines to Law Arun Bhatt

From Guidelines to Law Arun Bhatt

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Published by Ranajita Ghanty

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Published by: Ranajita Ghanty on May 09, 2011
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05/29/2011

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From guidelines to law
Dr Arun Bhatt discusses some of the issues affecting the key stakeholders in the GCP compliance
The Indian Good Clinical Practices (GCP) guidelines which were released inDecember 2001 led to a lot of discussion but little implementation. Beingguidelines, most companies ignored them. The international pharmaceuticalcompanies in India, which were conducting clinical trials in compliance withInternational Conference on Harmonisation - Good Clinical Practices (ICH-GCP),continued to follow the same. Similar was the attitude of big Indian pharma companiescompeting globally. The new revised schedule Y, likely to come into effect in near future,links most provisions to the Indian GCP. This means that Indian GCP guidelines will becomelaw and have to be followed for clinical trials in India.In general, Indian GCP guidelines are in line with ICH-GCP. However, there are significantdifferences in some of the areas, which will make the task of compliance difficult for thesponsors, investigators and ethics committees.
I
nvestigator qualifications
The Indian GCP (3.3.1) insists that the investigator should be qualified as per therequirement of the Medical Council of India (MCI). This means that non-medical scientistse.g. pharmacists who organise the bio-equivalence studies, cannot become investigators.Even in the medical field, several eminent investigators have medical degrees from UK orUS, which are not prescribed by MCI.The qualifications of some of the senior investigators were not recognised as the medicalinstitutions from where these investigators studied were not approved by MCI at that time.Implementation of this provision will require the monitors and auditors to ask theinvestigators for proof that their qualifications are in line with MCI. This provision canbecome a major hurdle for sponsors in selecting investigators and needs to be modified inline with ICH-GCP.
I
nvestigator and sponsor¶s SOPs
The Indian guideline (3.1.3) mandates that the sponsor and the investigator should sign acopy of the Standard Operating Procedures (SOPs). Besides, the investigator and his staff have to be aware and comply with SOPs.This provision is practically impossible, as the sponsor will have to obtain signatures of allinvestigators in a trial on its large number of SOPs. Imagine the task of making multiplecopies of hundreds of SOPs, delivering them to investigators, and obtaining their signatures!Besides, SOPs also get revised periodically and the whole cycle have to be repeated.ICH-GCP expects the investigator to comply with the protocol and leaves the task of monitoring compliance to SOPs to monitors and auditors.Investigators responsibility for data analysis
 
A
s per ICH-GCP, when the trial is completed, the investigator has to provide theIndependent Ethics Committee (IEC) with a summary of the outcome of trial.In contrast, Indian GCP demands that the investigator should sign and forward the data likeCase Report Forms (CRF), results and interpretations, analyses and reports of the studyfrom his/her centre to the sponsor and the ethics committee.Usually data analysis is the function of the sponsor. However, this provision makes it aresponsibility of the investigator, increasing his burden. The CRFs are never sent to IECunless the IEC asks for them for some specific purpose e.g. suspected fraud. The IECs of major institutes, which are involved in several international trials, are already struggling tocope with large number of bulky documents submitted for their approval. This provision willincrease IECs¶ troubles, as they will have to create space for bulky CRFs and the clinical trialreports.
Powers of 
IEC
 
A
ccording to Indian GCP (2.4.2.6), the IEC has power to order discontinuation of a trial if the IEC finds that the goals of the trial have already been achieved mid-way or unequivocalresults obtained.
A
s per ICH-GCP, this is the responsibility of independent data-monitoring committee(IDMC). The sponsor may consider establishing an IDMC to assess the progress of a clinicaltrial, including the safety data and the critical efficacy endpoints at intervals, and torecommend the sponsor whether to continue, modify, or stop a trial. This is possible, as thesponsor has to provide regular feedback and interim analysis of trial data on efficacy andsafety to IDMC. For most global trials, the sponsor establishes an IDMC in a westerncountry.
A
s Indian centres are part of global trials, they are reviewed by IDMC. This means thatIndian IECs at different sites will not be involved in this process and cannot fulfill thisrequirement of Indian GCP. IDMC is also recommended in Indian GCP (3.1.5). Hence, thesetwo provisions are likely to create a conflict of responsibilities between IEC and IDMC!This provision also could become a nightmare for regulatory authorities, as there is scopefor misuse of this provision by sponsors of local Schedule Y open registration trial.The goal of these local trials is to confirm whether the Indian safety and efficacy results arein line with the international clinical trial data. If a sponsor finds that the results arecomparable to international data in initial 25-30 patients, he can submit this data to IEC torequest them to stop the trial and later present the IEC recommendation to the regulatoryauthorities for obtaining registration.
E
ssential documents for
IEC
 
In the appendix V, essential documents for IEC files are listed. This means the sponsor andthe investigator have to provide additional copies of most documents to IEC and also ensurethat they are filed. It will bedifficult for the monitor and the auditor to check compliance tothis provision, as the sponsor does not have direct access to IEC documents.Essential items for informed consent
 
Besides the essential items for informed consent listed in ICH-GCP, Indian guidelines(2.4.3.2) also cover issues of biological samples.The consent has to include:
y
 
Right to prevent use of his/her biological sample (DN
A
, cell-line, etc) at any timeduring the conduct of the research
y
 
Foreseeable extent of information on possible current and future uses of thebiological material and of the data to be generated from the research and if thematerial is likely to be used for secondary purposes or would be shared with others,clear mention of the same
y
 
Risk of discovery of biologically sensitive informationThese items will make the consent form more complex to explain to the subject and maydiscourage him from participating in the research.
C
ompensation
In the essential items for consent, there are also mandatory clauses on compensation,which are as follows:
y
 
Free treatment for research related injury by the investigator/ institution
y
 
Compensation of subjects for disability or death resulting from such injury Inaddition, there is a whole section on compensation related issues (2.4.5 and 2.4.7).Indian GCP mandates that when a subject is withdrawn from research for medical reasonsrelated to the study, the subject should get the benefit for full participation.While this provision seems appropriate for studies in healthy volunteers e.g. bio-equivalencestudy, it could lead to issues in a clinical trial of a chronic disease in patients.
A
cancerpatient taking part in a long trial of a new product is assured of regular follow up and costlyinvestigations. If he is withdrawn because of a medical reason e.g. adverse event, hereceives free medical treatment for the event but does not receive any other benefit.However, such a patient can cite this provision and insist on regular follow up and freeinvestigations assured for the trial for the whole duration of trial!The other provisions for compensation are prescriptive:
y
 
The sponsor (company, government, institution) should agree to providecompensation for any serious physical or mental injury or to provide insurancecoverage
y
 
Research subjects who suffer physical injury in a trial are entitled to financial/otherassistance to compensate them equitably for any temporary or permanentimpairment or disability subject to confirmation from IEC.
y
 
In cases of death, their dependents are entitled to material compensation Theseprovisions, probably, are an attempt to protect Indian patients, who are oftenilliterate and from lower socio economic class. Monitor¶s Qualifications Indian GCPguidelines (3.2) suggest that the monitor should have adequate medical,pharmaceutical and/or scientific experience.
A
s most monitors are pharmacists or

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