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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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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 in December 2001 led to a lot of discussion but little implementation. Being guidelines, most companies ignored them. The international pharmaceutical companies in India, which were conducting clinical trials in compliance with International Conference on Harmonisation - Good Clinical Practices (ICH-GCP), continued to follow the same. Similar was the attitude of big Indian pharma companies competing 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 become law and have to be followed for clinical trials in India. In general, Indian GCP guidelines are in line with ICH-GCP. However, there are significant differences in some of the areas, which will make the task of compliance difficult for the sponsors, investigators and ethics committees. Investigator qualifications The Indian GCP (3.3.1) insists that the investigator should be qualified as per the requirement of the Medical Council of India (MCI). This means that non-medical scientists e.g. pharmacists who organise the bio-equivalence studies, cannot become investigators. Even in the medical field, several eminent investigators have medical degrees from UK or US, which are not prescribed by MCI. The qualifications of some of the senior investigators were not recognised as the medical institutions 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 the investigators for proof that their qualifications are in line with MCI. This provision can become a major hurdle for sponsors in selecting investigators and needs to be modified in line with ICH-GCP. Investigator and sponsor¶s SOPs The Indian guideline (3.1.3) mandates that the sponsor and the investigator should sign a copy 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 all investigators in a trial on its large number of SOPs. Imagine the task of making multiple copies 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

As per ICH-GCP, when the trial is completed, the investigator has to provide the Independent 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 like Case Report Forms (CRF), results and interpretations, analyses and reports of the study from his/her centre to the sponsor and the ethics committee. Usually data analysis is the function of the sponsor. However, this provision makes it a responsibility of the investigator, increasing his burden. The CRFs are never sent to IEC unless 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 to cope with large number of bulky documents submitted for their approval. This provision will increase IECs¶ troubles, as they will have to create space for bulky CRFs and the clinical trial reports. Powers of IEC According to Indian GCP (, 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 unequivocal results obtained. As 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 clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend the sponsor whether to continue, modify, or stop a trial. This is possible, as the sponsor has to provide regular feedback and interim analysis of trial data on efficacy and safety to IDMC. For most global trials, the sponsor establishes an IDMC in a western country. As Indian centres are part of global trials, they are reviewed by IDMC. This means that Indian IECs at different sites will not be involved in this process and cannot fulfill this requirement of Indian GCP. IDMC is also recommended in Indian GCP (3.1.5). Hence, these two 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 scope for 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 are in line with the international clinical trial data. If a sponsor finds that the results are comparable to international data in initial 25-30 patients, he can submit this data to IEC to request them to stop the trial and later present the IEC recommendation to the regulatory authorities for obtaining registration. Essential documents for IEC In the appendix V, essential documents for IEC files are listed. This means the sponsor and the investigator have to provide additional copies of most documents to IEC and also ensure that they are filed. It will bedifficult for the monitor and the auditor to check compliance to this 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 ( also cover issues of biological samples. The consent has to include: y y Right to prevent use of his/her biological sample (DNA, cell-line, etc) at any time during the conduct of the research Foreseeable extent of information on possible current and future uses of the biological material and of the data to be generated from the research and if the material is likely to be used for secondary purposes or would be shared with others, clear mention of the same Risk of discovery of biologically sensitive information


These items will make the consent form more complex to explain to the subject and may discourage him from participating in the research. Compensation In the essential items for consent, there are also mandatory clauses on compensation, which are as follows: y y Free treatment for research related injury by the investigator/ institution Compensation of subjects for disability or death resulting from such injury In addition, 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 reasons related 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-equivalence study, it could lead to issues in a clinical trial of a chronic disease in patients. A cancer patient taking part in a long trial of a new product is assured of regular follow up and costly investigations. If he is withdrawn because of a medical reason e.g. adverse event, he receives 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 free investigations 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 provide compensation for any serious physical or mental injury or to provide insurance coverage Research subjects who suffer physical injury in a trial are entitled to financial/other assistance to compensate them equitably for any temporary or permanent impairment or disability subject to confirmation from IEC. In cases of death, their dependents are entitled to material compensation These provisions, probably, are an attempt to protect Indian patients, who are often illiterate and from lower socio economic class. Monitor¶s Qualifications Indian GCP guidelines (3.2) suggest that the monitor should have adequate medical, pharmaceutical and/or scientific experience. As most monitors are pharmacists or



science graduates, they would not have adequate medical experience and hence will not qualify as monitors! Monitor¶s responsibilities Monitor is supposed to inform the sponsor and IEC in case any unwarranted deviation from protocol or any transgression from principles of GCP. The monitor is not in contact with IEC and hence this requirement cannot be fulfilled. Monitor is also responsible for ensuring that CRFs are legible. As per ICH-GCP monitor has to verify that the documents provided by the investigator are legible. There is a glaring omission in the functions of the monitor. It does not include verification of informed consent. Drug label In the section on protocol (, it is mentioned that drug label should include name and contact numbers of investigator and name ofinstitution. This is not a global practice. This will lead to practical difficulties in global trials where the labels are uniform with minor changes made if required by local laws and practice. Document retention Indian GCP (3.1.5) mandates that the sponsor should make arrangements for safe and secure custody of all study related documents and material for a period of three years after the completion of the study or submission of the data to the regulatory authority (ies) whichever is later. If the company does not get marketing approval within 3 years of completion of trial and if there is a need for regulator inspection after marketing approval, the records will not be available. It is desirable, as in the case of ICH-GCP, to link the records to marketing approval. Recommendations Time has to come to review some of the provisions of Indian GCP guidelines, as they are soon to become a law. Some of the sections related to the investigator, IEC, monitor, drug label and documentation have to be viewed pragmatically from compliance and practical considerations. Some others - informed consent and compensation ² need discussion on global practices vis-«-vis Indian socioeconomic realities. Overall, there is an urgent need for another harmonisation between Indian GCP and ICH-GCP!

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