Issues with recent changes to clinical trials’ regulations

Bhavik Narsana	Sameer Sah	Arijeet Mukherjee

To develop a new drug, it is sine qua non that clinical research must be carried out. Clinical research is a fundamental building block of innovation in the field of science and medicine. It is fair to say that India was looked at as one of the potential top destinations worldwide to carry out clinical research. However, in the last couple of years, on account of issues raised by NGOs and patient welfare organisations, the Supreme Court of India1 had to intervene and the Indian government has introduced various measures to regulate the clinical research industry in India. The Central Drug Standards Control Organisation (CDSCO) had also established an expert committee under the chairmanship of Prof Ranjit Roy Chaudhury to formulate a policy and guidelines on clinical trials and this report was submitted in 2013. Presently, this report is under consideration by the Government of India.2

The new measures have attracted a mixed response and based on information in public domain, have led to quite a few pharmaceutical companies moving their clinical research programmes out of India. In this Article, we aim to identify the recent changes to the legal framework and issues relating to: (a) informed consent; (b) SAE reporting; and (c) compensation for clinical trials in India.

Informed consent in clinical trials

Clinical trials in India are regulated by the Drugs and Cosmetics Act, 1940 (Act). The Drugs and Cosmetics Rules, 1945 (Rules) formulated under the Act provide detailed provisions for regulating clinical trials in India. The Rules define ‘clinical trials’ as systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and/or adverse effects with the objective of determining safety and/or efficacy of the new drug.3 The Rules provide for various requirements that have to be satisfied prior to conducting any clinical trials. These include requirements related to informed consent and specify the format of the consent to be obtained along with details to be specified therein.

In June 2013, the Government released draft rules proposing to make audio visual (AV) recording mandatory. Eventually, in October 2013, the Supreme Court ordered that AV recording must be made mandatory for all consent recording and this was followed by an order from Drugs Controller General (India) on November 19, 2013 requiring the AV recording of the informed consent process of each trial subject, including the procedure of providing information to the subject and the subject’s understanding of such consent. CDSCO released Draft Guidelines on Audio-Visual Recording of Informed Consent Process in Clinical Trial dated January 9, 2014 (Draft Guidelines) which provides for the procedure for the AV recording.

The salient aspects of the procedure include:

• Explaining the research process, time duration, benefits, reasonably foreseeable risks, etc., in a language that is non-technical and understandable to the study subjects, this also includes appraising the subject of alternate therapies available to him / her, and also explaining to the subject that there could be certain unforeseeable risks that the subject could encounter in the process.
• The investigator has to identify the protocol, the subject/legally acceptable representative/impartial witness (as the case may be) and the language understood by such person. If the investigator does not know the language, a member of the study team who understands the language, would have to become the interpreter.

The introduction of compulsory AV recording has received a mixed response from the pharma industry and the scientific community. While there are some apparent advantages of such recording, there are numerous logistical and other implementation issues which may impede the attainment of the legislative intent. These logistical and implementation issues inter alia include:

• Investigators have been reported to state that volunteers are weary of being filmed while discussing details pertaining to their ill health. This arises on account of several factors including fear of leakage misuse or tampering of the recordings.
• It appears that certain subjects are uncomfortable on account of socio-religious factors or on account of an apprehension of physical ill-appearance from being recorded.
• Given the conservative nature of Indian society, it is possible that women may not be comfortable being videographed, and if they agree, they may request the presence of a male member of their family which may defeat the purpose of ensuring that the subject is herself aware of the risk, etc., associated thereof.
• There is a social stigma associated with certain diseases (including leprosy, STDs such as AIDS, etc.) and subjects may not be comfortable being video graphed.
• The order applies to all clinical trials. Therefore, AV recording of field study also becomes mandatory, which may be difficult considering that the Draft Guidelines require the AV recording to be conducted in a room conducive to recording of disturbance-free audio and video of the consent process.

Bearing in mind the larger picture, the regulation appears to be slightly lopsided. The AV recording is intended to achieve two purposes: (i) ensuring that the subjects are orally explained the potential risks and other details pertaining to the study as opposed to the subjects simply signing a lengthy standardised form carrying all these details, and (ii) enforcing implementation as AV recordings would be available for future scrutiny as well. From what is apparent, industry sources do not sense an issue with discussing risks, etc., with subjects. Rather, this would probably be in the interests of both the patients as well as the investigators. The concern is on the recordings. Therefore, considering the issues associated with the AV recording, an alternate option that could be considered would be an investigator administering the information to provide sworn affidavits that the process has been duly completed. Nevertheless, given the fact that there is a Supreme Court order mandating such AV recording, it is unlikely that such AV recording can be removed as a requirement unless the Supreme Court withdraws the order. Hopefully, once empirical data is available regarding the difficulties being faced, the Government may understand the issues and petition the Supreme Court again.

SAE reporting and compensation

The Rules were amended in January 2013 to provide for obligations concerning reporting of ‘special adverse events’ (SAEs) and to provide for compensation in case of injury or death of a subject during a clinical trial. The Ministry of Health and Family Welfare has also issued certain draft rules for public comments by a notification dated 24 April 2014 (Draft Rules).

SAE reporting

In relation to SAE reporting, investigators are required to report SAEs within 24 hours of occurrence, and sponsors are required to report them within 10 calendars days of occurrence. Industry participants have reacted to the timelines as being very tight, especially considering that these are linked to occurrence and not knowledge. As per the Draft Rules, the investigator has been provided the opportunity to explain the reasons for the delay to the satisfaction of the licensing authority. Further, for sponsors to report the SAE, the time period is proposed to be increased from 10 calendar days to 14 calendars days of occurrence. However, as the linkage to the occurrence as opposed to knowledge of occurrence has been retained, it is unclear whether this would solve the issues being raised by industry participants.

Medical management

The Rules provide for expenses related to medical management of the subject and for separate compensation in the case of injury and / or death. The obligation to provide free medical management applies to any injuries sustained during the clinical trial, whether or not these are related to the clinical trial. It remains questionable whether the medical expenses should be provided only for injuries related to the clinical trial, or for all injuries sustained by the subject whether or not sustained in the process of the clinical trial. The Draft Rules seek to amend the Rules, and while they retain the right of the subject to receive medical treatment until it is established that the injury is not related to the clinical trial, it has still not been clarified as to who would decide whether the injury is related to the trial (whether it would be the investigator or the ethics committee). Theoretically, however, non-trial related injuries will be excluded from the ambit of receipt of free medical assistance once this is established.

Further, it is not really clear whether the sponsors could consider medical insurance for the subjects given their existing ailments and the fact that they would be participating in such research.

Compensation

With respect to financial compensation available to subjects suffering from clinical trial related injuries, the Draft Rules have sought to create degrees of injuries and the commensurate financial compensation thereof. At the outset, the Draft Rules categorise the injuries as permanent and non-permanent; in case of injury of non-permanent nature, the compensation will be quantified proportionate to the nature of the non-permanent injury, loss of wages and transportation.

Under the Rules, the primary responsibility of the compensation lies on the sponsor. Further, the liability of the sponsor is attracted even in cases where there is negligence, etc., by the investigator. To this some sponsors had claimed that compensation for certain instances such as therapeutic failure, adverse effects due to concomitant medication, and placebo related issues, violated principles of clinical legal research. Taking these points into consideration, under the Draft Rules, injuries or death occurring due to therapeutic failure or placebo related issues can be claimed for compensation, only if it is established that standard care, even though available, was not provided to the subject as per the clinical trial protocol.

The Independent Expert Committee constituted for examination of SAE of deaths had suggested a compensation formula. The formula takes into account a factor that varies with the age of the subject and is based on the Workmen Compensation Act, 1923. It also takes into account a risk factor based on the risk associated with the subject (the lowest multiple being for terminally ill patients and the highest multiple being for healthy volunteers having little or no risk). Further, for patients where the expected mortality is 90 per cent or more within 30 days, a fixed amount of Rs 2,00,000 should be given.

A separate committee was constituted for clinical trial related injury (other than death) and this was published by the CDSCO on May 1, 2014 seeking comments by May 16, 2014. The committee has recommended using the formula for death related compensation and discounting it by 80 per cent and 50 per cent, respectively, in the case of SAE leading to permanent disability or a congenital defect. For SAEs that lead to life threatening diseases or where SAEs are reversible, the compensation would be linked to the number of days when the subject is affected by the condition.

From a broader perspective, these stipulations have the potential to increase costs for sponsors. Further, there is some potential for misuse in these provisions (for instance, injuries caused to subjects which are unrelated to the clinical trials would also be covered by the medical management provision). Considering that clinical research forms a part of the costs associated with drug development, sponsors are likely to want to understand their maximum bottomline exposure. Hopefully, the Government will work towards striking a balance between patient welfare and the sponsors’ commercial requirements.

Conclusion

The Indian clinical research industry is a very important part of the Indian pharma industry and market, and also has the potential to provide independent economic support to the country. The Government of India has time and again raised a concern for the sale and supply of essential medicines in India at affordable pricing and this has manifested in various results, including, the introduction of a new pricing regime in 2013, granting of compulsory licenses for patented products that are not available in a sustainable manner to the Government. To that extent, drugs would be introduced in India either by domestic manufacturers or by foreign manufacturers. Historically, the CDSCO has been known to approve drugs without the submission of clinical data, but this is a practice that was frowned upon by the Standing Committee of the Ministry of Health and Family Welfare in its scathing report on the functioning of the CDSCO submitted to the Rajya Sabha in 2012. Therefore, the CDSCO is now bound to increasingly insist on clinical data. This by itself translates into a tremendous need and opportunity for the clinical research industry in India to be robust. Apart from this, where Indian subjects participate in global studies, this represents an economic opportunity for the subjects as well as the Indian contract research organisations. Therefore, understandably, industry participants have reason to look forward to the authorities to strike a balance between robust regulation and operational flexibility. The Draft Rules suggest a step is being taken in the direction of balancing interests, but the industry participants definitely expect more.

(The views of the authors are personal and should not be attributed to the firm.)

References:
1. Swasthya Adhikar Manch, Indore & Anr v. Ministry of Health & Family Welfare & Ors, Hon’ble Supreme Court of India, W.P. (C) No 33/2012.
2. http://www.cdsco.nic.in/writereaddata/ Report_of_Dr_Ranjit_Roy.pdf
3. Rule 122-DAA of the Drugs and Cosmetics Rules, 1945