‘Phase IV studies have to be scientific and ethical’

Queries on GCP

A MONTHLY COLUMN By Dr Arun D Bhatt

Do IEC/IRB members face legal/financial liability for clinical trials approved by them? Is there a legal provision in India granting them immunity from the same? If not, what can be done to safeguard them from liability?

Dr A A Mundewadi, Mumbai

Traditionally, IRB / IEC has rarely been named in lawsuits. One of reasons has been that the IEC is not as visible an actor as the trial sponsor, doctors, and hospital involved in administering the protocol. This invisibility, however, is already changing in light of extensive media coverage of high profile cases of alleged research abuse of subjects leading to serious consequences e.g. death.

IRBs/IECs are vulnerable to law suit in such situations. (Reference: The Suitability Of IRB Liability Sharona Hoffman & Jessica Wilen Berg Http://ssrn.com/abstract=671004 Case Western Reserve University)

Please note that GCP guidelines protect the subject’s rights to take action in case of negligence of any stakeholder in the trial.

ICH GCP 4.8.4: None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject’s legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.

Following actions would help in reducing the risk of litigation:

• Having SOPs and documentation of all meetings, minutes and decisions
• Archival of documents for adequate period as per the regulatory requirements
• Adhering to regulatory/ICMR/GCP guidelines in functioning
• Having a member with legal background/a legal advisor for the institution
• Careful legal and ethical review of research in special areas e.g. AIDS, pregnant women vulnerable subjects
• Prompt review and ethically appropriate decisions, when there is a potential for harm to subjects e.g. serious adverse events, new information on drug which could change the risk: benefit ratio, unethical or negligent behaviour of investigator.

For post-marketing surveillance (PMS) study, is it mandatory to have a study protocol approved by ethics committee? As number of private practitioners from different parts of the country would be involved, which ethics committee should be approached for approval? Is it necessary to obtain the informed consent from the patients in PMS study? Can the company provide the drug? Is it officially permitted to give compensation to the participating doctors for spending time in filling the case record forms?

Dr Balaji More, Mumbai

If this is a regulatory PMS, it is desirable to take approval of Ethics Committee (EC). One can approach an independent ethics committee for a study in private practice. As per ICMR guidelines, phase IV studies are out of the purview of EC. However, ICMR guidelines recommend that the adverse reactions induced by drugs, if any, should be brought to the notice of the EC.

The need for EC approval also depends on the indications to be studied and proposed study plan. Please see to definition of phase IV in Indian GCP guidelines and amended Schedule Y.

Indian GCP phase IV: Studies performed after marketing of the pharmaceutical product. Trials in phase IV are carried out on the basis of the product characteristics on which the marketing authorisation was granted and are normally in the form of post-marketing surveillance, assessment of therapeutic value, treatment strategies used and safety profile.

Phase IV studies should use the same scientific and ethical standards as applied in pre-marketing studies. After a product has been placed on the market, clinical trials designed to explore new indications, new methods of administration or new combinations, etc are normally considered as trials for new pharmaceutical products.

Schedule Y post-marketing trials (phase IV): Post-marketing trials are studies (other than routine surveillance) performed after drug approval and related to the approved indication(s). These trials go beyond the prior demonstration of the drug’s safety, efficacy and dose definition. These trials may not be considered necessary at the time of new drug approval but may be required by the Licensing Authority for optimising the drug’s use. They may be of any type but should have valid scientific objectives.

Phase IV trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s), e.g. mortality/morbidity studies, epidemiological studies etc. It is necessary to obtain informed consent if the study requires investigations, follow-ups which are not routinely carried out and which could lead to potential inconvenience or harm.

The company can provide drug. However, in this case the study will be more a phase III study and less like a prescription based surveillance. There is no official guideline on compensation for the participating doctor. However, it is an industry practice to compensate the doctor for the time and efforts.

What happens in a multi-centric trial where one centre has not obtained ethics committee approval? What is the repercussion for data obtained from other centres? Does it mean that such a trial cannot be published? Is there a way to salvage this trial?

Dr Sanjay Karkhanis, Mumbai

The editor of the journal may consider the article, if the data are analysed without the centre with EC approval. There is no repercussion on data of other centres, except, that the editor may ask for a proof that the EC approval was taken for all the centres.

Dr Arun D Bhatt, well-known clinical pharmacologist from Mumbai, and currently president, ClinInvent Research India Pvt Ltd, answers your questions on Good Clinical Practices. Please send in your questions at: arunbhatt@clininvent.com All queries should ideally reach him by the 15th of each month