Difference between Indian GCP and ICH GCP

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 sponsors 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 (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 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 (2.4.3.2) also cover issues of biological samples. The consent has to include:

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:

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:

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. Monitors 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!

Monitors 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 (2.3.1.6), 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 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

Indian GCP are indirectly became the law it needs to be in line with the ICH GCP. Following are the some concerns with the recommendations need to follow to remain in line with the ICH GCP. ? Investigator qualifications:According to the section 3.3.1 of Indian GCP, investigator must be qualified as per the requirement of the Medical council of India.[4] So pharmacists can not become investigator for the BA/BE studies. Even knowledgeable investigators having medical degree of the foreign university are not approved by Medical council of India. This guideline is major issue for selection of the Investigators by the sponsor and need to be change as per the ICH GCP. ? Investigator and Sponsors SOP;According to the section 3.1.3 of Indian GCP it is mandatory for the sponsor and the investigator should sign a copy of the SOPs.[4] Practically, it is impossible for sponsor to obtain the signature in each copy of the SOPs.[3] There are many SOPs and many of them revised periodically which led to obtaining signature again. Where as ICH GCP are mainly expecting that investigator to comply with the SOPs. [1] ICH GCP expecting investigator should provide the summary of the outcome of the trial to the IEC.[1] Where as Indian GCP needs that the investigators should sign and forward data like CRF, results, analysis and report it to the sponsor.[4] ? Authority of ethical committee. As per section 2.4.2.6 of Indian GCP the EC has authority to stop the a trial if ethical committee finds that the objective of the trial have been obtain midway or unrelated results have been obtained.[4] According to ICH GCP it is the duty of the Independent data-monitoring committee. [1] ? Essential wording of the Informed consent:-

In the Informed consent document following wording are necessary as per Indian GCP; Subjects have right to retain his/her biological sample at any time of trial.[4] Risk of discovery of biologically sensitive information.[4] These wording is making difficult to obtain consent which may discourage the subjects from participating in trial. [3] ? Compensation;The Indian GCP mentions that when a subject is withdrawn from research for medical reason then he/she should get full compensation.[4] This is true for healthy subject involve in BE study but for the cancer and HIV subjects in long clinical study then this may results into much costlier trial.[3] ? Monitors responsibility:According to Indian GCP, it is the responsibility of the Monitor to inform sponsor and Ethical committee for protocol violation which is practically impossible because monitor is not in contact with ethical committee.[4] As India going to be hub for Clinical research there is severe needs to update the guideline and should be incorporate country specific guideline to ICH-GCP guideline. Conclusion/Recommendation As discussed in background I would like to conclude that Good clinical practice is the gold standard for clinical research industry. [6] But there are several needs to update the ICH-GCP. Following are the some recommendation which needs to be implemented. Provide one set of GCP guideline for all trial i.e. for all class of medical device. There is severe need to give standard for phase IV trial and also needs to give importance to the same. [2] There are severe misleading issues in the ICH-GCP which sometimes became the hurdle in the process of patients recruitment. Give more specific guideline for inform consent process and mention the issues that are included in the informed consent especially for trials on cancer patients. There are severe needs to improve the terminology used in the ICH-GCP.[2] Because clinical trial not only involves the medical persons but it involve the professional from different educational background. As regulatory authority are not in regular touch with the industry and there is very less communication between the reg. authority and industry.[5] This communication gap should be filled and any issues

related to product development need to be resolve.[5] Documentation is essential part of trail as per ICH GCP which did not give an assurance that trial is reliable and valid. [5] Documentation part also needs improvement by systematic inspection of audit trail and by two-way comparison between original documents and CRF.[5] To ensure that ICH GCP has been followed in clinical trial, inspection by the regulatory authority is necessary. Following are the some recommendation for GCP inspection by authority. ? Normally, a trial site has less than 2% chance of getting inspection by the authority.[5] Even CRO and IEC have very less chance of being inspected. So, more number of inspections is needed. ? Regulatory authorities have very few trained inspectors for ensuring compliance with the ICH GCP. So, there is severe need to ensure that inspectors get trained on ICH-GCP. As way to ensuring compliance is only inspection as per GCP. Training can also increase the efficiency for inspection.[5]

It is suggested that GCP should not be implemented on the researcher when research is not conducted for economical purpose but conducted for knowledge purpose.[5] So many valuable thoughts can come out which otherwise remain hidden under the pressure of the cost for implementation of ICH GCP.[5] As ICH-GCP is very informative but it is not having reference mention in it so it needs to revises.[5] It should be necessary to have delegate from academia and health care professional into the revision of ICH-GCP. So it needs to update like other guidelines.[5] Finally, I conclude that All trials should be done well but good clinical practice might not the only method to make sure that trial was conducted by good ways but Many researchers are not following the acceptable standards so in such cases it should be mandatory to follow the ICH GCP, and have better ways to ensure conduct of trial is right or wrong. [5]

Q.1 What are the difference between Indian GCP and ICH-GCP with respect to: 1. Investigator qualification 2.Investigator responsibility for data analysis 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. 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