However, the full text of the SC order made public a couple of days later revealed that the SC had held back these approvals for two weeks to enable the Additional Solicitor General to ‘place on record a recently released report of Prof Ranjit Roy Chaudhury and details of the existing regime which ensures safety to the subjects of clinical trials and avoid any serious adverse event by such clinical trials.’
Thus the full text of the SC order was quite different from the initial reports, reflecting both the heightened public awareness of clinical trials as well as the industry’s anxiety that more regulations can only mean more bad news.
Continuing regulatory reform …
The clinical research industry in India has been in the throes of regulatory reform for the past year. The latest salvo is a compensation formula to determine the quantum of compensation in the cases of clinical trial related serious adverse events (SAEs) of deaths recommended by an expert committee set up by the Drug Controller General (India) (DCGI).
And prior to the compensation formula, the DCGI had issued an order asking sponsors to provide details of agreements with investigators/institutions pertaining to payments for conducting trials and these aimed to bring better transparency in the system.
Apurva Shah Chairman, Association of Contract Research Organisations |
Commenting on both these developments, Apurva Shah, Chairman, Association of Contract Research Organisations (ACRO) mentions, “There will not be any ambiguity in calculating the compensation. And while the disclosure of CRO-investigator agreements is a good thought, the practical aspects of implementation must be viewed seriously. Also, the intent of doing so must be transparently shared and communicated with all stakeholders including the industry, CROs and investigators. This will enable us to calculate the per subject compensation limit, hence better planning of study insurance and budget. And the insurance premium will be much higher now, as the compensation may go up to Rs 4 – 73.6 lakhs.”
Terming the DCGI’s order related to disclosure of financial consideration of investigators at the time of applying for permission to conduct the clinical trial in India as a welcome step, Dr Milind Antani – Head, Pharma & Life Science Practice, Nishith Desai Associates (NDA), a law firm, says, “It is indisputable that the common man views India’s clinical trial industry with suspicion today. Disclosure of financial interest of investigators will bring transparency to the process which in turn will help the industry in the long run. That said, we feel that the order will inconvenience the industry a lot.”
… and their impact
Dr Milind Antani Head, Pharma & Life Science Practice Nishith Desai Associates |
There is indeed no question that the industry is concerned about the impact of these notifications. Commenting on the adverse impact on approval timelines, Suneela Thatte, President, Indian Society for Clinical Research (ISCR) says, “Disclosure of CRO-investigator agreements being furnished at the time of clinical trial applications, will in our opinion, only add more delays and logistical challenges to the clinical trial applications and we do not understand the rationale for a decision like this. Such delays are unwarranted at a time when the industry is looking at faster and more effective ways to bring drugs to market for the benefit of patients.”
Dr Shoibal Mukherjee Chief Medical Officer, Quintiles India & Head, Asia Medical Sciences Group |
Dr Shoibal Mukherjee, Chief Medical Officer, Quintiles India & Head, Asia Medical Sciences Group states that disclosure of details of financial terms of agreements with investigators to the regulator might be a positive development. “However, it is not clear what the regulator intends to do with this information. There are currently no guidelines or regulations relating to research grants, so requirement for submission of this data is not a matter of checking on compliance. Release of this data to the public or press without adequate context and explanation, as has happened with adverse event data in the past, can lead to negative consequences,” he points out.
Mukherjee suggests that the Government should perhaps make up its mind about what they want to do with the data before beginning to collect the information. As an alternative, he points out that submitting these to the regulator at any time prior to initiation of patient recruitment at the site should serve the purpose as the regulator can always put a hold on the study if it finds anything amiss.
Anay Shukla Member, Pharma Team, Nishith Desai Associates |
Explaining legal ramifications of this diktat, Anay Shukla, Member, Pharma Team, Nishith Desai Associates warns, “Owing to this order, the industry is now pondering whether sponsor/ CRO is required to establish contractual relationships before applying for permission to conduct clinical trial. If it was the other way round, that is, if the contract was entered into before it received permission, and the permission did not come through, or came with prohibitory conditions, then it would result in loss of precious time, negotiations and paperwork for the sponsor/CRO.”
Shukla therefore recommends that the requirement of furnishing financial details should be inserted as a condition of permission given to conduct clinical trials in India. According to him, “The permission letter must clearly state that the permission is contingent on furnishing financial details of the arrangement with investigators upon finalisation of the agreement, failing which the permission may be revoked at any time.”
Hariani opines that while bringing in transparency in disclosure of financial details it is important to avoid manipulation in results or adoption of unethical practices. While the notification presently does not need amendment, he feels that the authorities should be open to make changes in the future, based on the experience gained in implementation.
Suneela Thatte President, Indian Society for Clinical Research |
ISCR’s suggestion according to Thatte, is that if this information is required by the DCGI’s office, they should ask for it post approval and prior to initiation of a study at site.
Also, given the clinical trial process, it does not sound feasible to reveal all the details before the trial begins. As Shah comments, “The details of CRO-investigator contracts isn’t operationally feasible before the onset of clinical trials as sites are finalised only after approval by expert committee (NDAC) appointed by DCGI. An important point that we must raise is that issuance of orders without discussion with various stakeholders, whose viewpoint, if considered as well, can make the implementation of guidelines and/or rules and regulations much more simpler for the authorities.”
Dr S M Sapatnekar Chief Executive Officer, Savishree Consultants |
Raising more queries on the notifications, Dr SM Sapatnekar, Chief Executive Officer, Savishree Consultants asks, “What is the purpose of revealing the details of CRO-investigator contracts? How will the Government decide whether the amount is fair or hyper inflated? Can it refuse permission for recorded reasons if the compensation is too high?”
Then there is the other concern about the regulator’s capability to actually implement these rules. Does the DCGI’s office have the time and manpower to evaluate SAE reports, asks Sapatnekar. Further, what if the proposed trial is an investigator-initiated one? He concedes that seeking information can be understood; why does the Government want the entire contract? Is such information sought from any other profession?
The compensation formula saga
Ameet Hariani Managing Partner, Hariani & Co Advocates and Solicitors |
Till 2012, compensation sums paid to victims of clinical trials in most instances, have been as low as Rs 1.5 lakh to Rs 3 lakh. Following public outcry at this data, the DCGI had constituted three independent expert committees on March 14 this year, chaired by Dr AK Agarwal, Maulana Azad Medical College. The committees were asked to examine the SAEs of deaths occurring during clinical trial and to recommend the cause of death, as well as determine the quantum of compensation to be paid by the sponsor or his representative. The compensation formula uploaded last month on the DCGI’s website was a fruit of these deliberations.
Commenting on the formula Thatte opines, “A standardised compensation formula that is transparent, objective and all encompassing is something that all stakeholders of the clinical research process have been waiting for several months now. The issue of compensation has been a contentious one for a long while, largely because of the lack of clarity on what needed to be compensated and by how much. However, a compensation formula on its own will be ineffective until such time as we have more clarity on the compensation guidelines that were introduced on January 30, 2013.”
Hariani informs, “Disclosure of information pertaining to financial support, fees, honorarium, payments in kind, etc., to be paid to the investigator as per contract entered into by the sponsor with the investigator or institution in clinical trials, would bring in transparency and ensure that unfair means are not adopted by companies to manipulate clinical trial data or engage in any unethical practices.”
Mukherjee feels that the formula adopted for the compensation is partially determined by its actual mechanism and points out that it is only one part of the ecosystem being created around clinical trials with a focus on monetary payments to patients or their relatives for “study-related injuries.” He says that while the intentions are laudable, many of those who are closely involved with clinical trials are still uncomfortable with the idea as “the practice of medicine is too complex to allow for easy adjudication of the cause of adverse events.”
He informs that a case-by-case compensation formula is not adopted anywhere in the world as, “it is very easy to be biased, one way or another, in linking or not linking a trial to an individual instance of an adverse event. This is the very reason why clinical trials were devised as an unbiased way of determining the efficacy and safety of medicines. If it were so easy to judge whether a medicine was effective or not, and whether it caused serious side effects, we would not have to go through the elaborate process of a clinical trial and wait till its end to analyse the data and reach a conclusion regarding its efficacy and safety.”
Cause for misuse
The document released by the office of the DCGI states that the base amount of compensation was fixed at Rs 8 lakhs with a view that this would ensure that the family received an amount equivalent to the minimum wages per month by way of interest. And it will not be wrong to anticipate that it might be misused by subjects or their family members, given the socio-economic realities of India. As Shah puts it, “Once the compensation values are seen to be so high it will induce people to participate in trials.”
Sharing similar concerns, Mukherjee says, “There may be potential for misuse if the family has significantly more to gain monetarily from the patient’s death than by the patient staying alive, and the misuse potential would increase in direct proportion to the value of the payout in comparison to the actual monetary loss suffered by the family. In the present case, while the approach in ensuring that the family receives at least the minimum wages is sound, the mechanism chosen is flawed.”
Antani, however, feels that there is little or no likelihood of it being misused by family members since the compensation is contingent upon proof that the SAE of death was related to clinical trial in ways prescribed in law. Moreover, he points out that a participant in the clinical trial is required under law to provide a written free informed consent for participation which negates the possibility of coercion by family members. His misgiving is that the high monetary compensation resulting from the formula decided by the expert committee may induce people to participate in clinical trial.
Hariani points out that companies will have to take extra care while evaluating the subjects and recording their previous medical history before enrolling them in clinical trial as the new formula takes into consideration the age of the subject and the risk factor depending on the seriousness and duration of the disease at the time of enrolment in the clinical trial while deciding compensation.
The base amount is defined as the compensation that would be paid to a 65-year-old patient with a maximum of two years’ life expectancy. If the intention was to ensure that the family received the minimum wages every month for the expected duration of the patient’s life, then the amount of compensation should have been fixed at Rs 1.85 lakhs (being minimum wages of Rs 7,744 per month for 24 months), opines Mukherjee of Quintiles. Thus he points out that the base amount of compensation is fixed at a level disproportionate to the intention and logic of the argument. For younger patients, the compensation amount calculated by this formula will be higher and the mismatch even greater, he concludes.
“We would suggest that compensation be calculated simply by multiplying minimum wages with the number of months of expected earning life. A minimum amount may be fixed for those above the age of 65. This would provide substantial relief for families of younger healthy volunteers and patients with non-life-threatening diseases while reducing the potential for misuse,” suggests Mukherjee.
Suggesting a solution, Thatte says, “With regard to the compensation formula, we must apply the same approach in ensuring that participants in a clinical trial are not being coerced or induced into participating in a trial with the promise of large compensation. This is a responsibility that both ethics committees and investigators in particular must take on and ensure.”
Impact on growth
Industry observers point out that even though there is now a formula to compute compensation, it is silent on some issues. For instance, the compensation formula covers SAE of death only and no other adverse effects. Further, the provisional nature of the formula as well as the absence of a fixed formula for determining compensation for clinical trial related injury continues to cast a cloud of uncertainty over the issue of trial related compensation, forecasts Antani of NDA. Such uncertainty may slow down clinical trials in India.
Dr Shubhangi Desai Head, Clinical Operations, Asia Pacific, SIRO Clinpharm |
There are also signs that some stakeholders feel unfairly targeted by these regulations while alleging that others escape censure. Highlighting this concern, Dr Shubhangi Desai, Head, Clinical Operations, Asia Pacific, SIRO Clinpharm points out that the responsibilities of the two key stakeholders in a trial, i.e. the principal investigator (PI) and the patient, have not been considered while drafting the regulations. “This lacuna can be misused and can result in rampant false claims and may lead to increase in claims for medical management of adverse events (AEs) which might not be related to the investigational product. The onus for medical negligence must be on the PI and not on the legal applicant as this can lead to possibility of lack of oversight by the PI, leading to safety concerns for the clinical trial patients/participants,” she avers.
Legal eagle Antani feels that the formula is in the right direction as it will help sponsors and CROs estimate costs associated with conducting a clinical trial in India and therefore plan the trial better. It would have had a much larger impact had the formula not been ‘provisionally final’.
Expressing his concerns, Mukherjee says, “Given the strong potential for bias and the large monetary value of compensation payouts mandated by the recently introduced formula, it is likely that international sponsors may like to avoid India in their global clinical development programmes, and undertake trials in the country only when such trials are unavoidable for commercial entry into the Indian market. Local sponsors too may prefer to undertake trials outside their home country, as many of them have already started doing. This will take us back to the time when few doctors in the country had any experience of participating in the global drug development process.”
Steps under way
Desai affirms, “We as a country have always had good laws and policies. What we have lacked is implementation and strong action against the violators within a specified time frame.”
Media reports on unethical clinical trials have industry spokespersons refuting these charges. As the ISCR’s spokesperson, Thatte comments, “We would like to dispel the notion that there are ‘many unethical clinical trials under way’ in India. As in every profession and industry, there will always be players who operate at both ends of the spectrum and so while there may be a few in India who do not follow the requisite guidelines, we must acknowledge that there are several hundreds of clinical trials taking place in the country in utmost compliance with international and local guidelines.”
Commenting on the regulatory reforms under way in the sector, Desai says, “Today, the Government has taken some positive steps like undertaking inspections, registration of the ethics committees (ECs), laying down compensation guidelines and so on. The next few months will be very critical as the various steps taken should be continued and action initiated against all parties where unethical trials are conducted.”
Today, steps are being taken in the right direction for curbing unethical practices. However, implementation remains a challenge. Hariani is hopeful, considering the speed at which changes are being carried out, that the authorities will not leave any stone unturned to curb unethical trials. However, he comments that it is pretty shameful that the authorities have to be monitored by the Supreme Court. It clearly shows a Government without a will to act.
Mukherjee is willing to concede that the regulations planned could have a positive impact. For instance, as he points out, “The recent orders would ensure that investigators are not vilified by activists and media for receiving a legitimate grant from commercial entities for the conduct of extramural research. Copies of financial agreements between sponsors and investigators submitted to the regulator can then be checked for compliance with these norms. Through this initiative, the government should encourage the use of publicly funded healthcare and research facilities for extramural research in a transparent manner as is done elsewhere in the world. This will help the cash-starved public healthcare and research-education sector attract private funding and improve their facilities without additional burden on the public exchequer while ensuring that there is no misuse of these facilities.”
Clearing the perceptions
Will these two recent orders, coming after so many others in the same vein, clear the unfortunate perception that the clinical trial/research industry is treating Indian patients/volunteers as ‘guinea pigs’?
Reacting to this Mukherjee opines, “This is a perception that is not supported by the facts and is one that we Indians have created and fuelled for ourselves. Only when we shed this perception will it change for others. We must ask this question to those among us who have nurtured this perception, but I suspect that deep-seated insecurities that went into creating this perception will be hard to eradicate.”
Though the clinical trial industry in India is at a relatively nascent stage compared to other global locations, it still needs to be compliant with global norms. The industry perspective voiced on various occasions is that volunteers who participate in a clinical trial receive a greater degree of medical care and attention than they would under regular treatment because of the high level of investigation and patient management that a clinical study protocol requires. So, there are already several checks and balances in place to safeguard the rights and privacy of patients in a clinical trial which is at times little understood by the public at large.
Calling the use of such terms as as ‘misleading and unfortunate’ Thatte avers that it maligns the image of clinical trial participants as well as casts aspersions on the intent of those involved in the clinical research process.
Desai feels these perceptions will change after implementation of Indian good clinical practice (GCP) strongly, i.e. by ensuring proper consenting at site, strict adherence to protocol and most importantly educating our people about clinical trials.
Sapatnekar in fact points out that the term ‘guinea pig’ spreads a paranoia to the effect that ‘all sponsors are out to exploit India’ when in actual case, India did not have even two per cent of global clinical trials market.
Building a better future
The industry provides the rationale that volunteers who participate in a clinical trial already have an underlying disease which could be mild or serious. They may participate in a clinical trial due to various reasons but their participation is guided by ICH-GCP as well local GCP guidelines. These clearly indicate what a volunteer must understand prior to enrolling in a clinical trial. This process, called the informed consent process, is a crucial step in ensuring that the participant is informed about all aspects of the trial relevant to the subject’s decision to participate, points out Thatte.
Highlighting the crucial role of the media to convey the right message to the public, she reasons that the term ‘guinea pigs’ will not disappear “until the media plays a more responsible role in reporting on clinical trials and educating the larger public about clinical research, while also highlighting the rights and responsibilities of patients.”
There seems to be a general view that the introduction of the new formula would definitely see an uptick in the range of compensation. It would have a positive impact and would relatively increase the amount of compensation payable to the subject in the event of any clinical trial death/injury. It is also hoped that there would now be relative clarity on the amount of compensation that a person participating in the trial and suffering any injury/death, would obtain.
But some issues still need to be ironed out. While commenting on the changes that need to be incorporated in the set compensation formula, Sapatnekar highlights some of these saying, “Unless maximum amount of compensation is known, no insurer can name the premium. There is no way a genuine investigator initiated trial will start. If the procedure of claim settlement is ad infinitum, sponsor has many destinations other than India where the trials are faster, better and cheaper.”
The industry also feels that there is a need to highlight the many benefits clinical research offers ordinary people in the long run. Desai avers, “People must be made aware about the importance of clinical research, the difference in the number of trials done in India vis-a-vis those done globally and about the guidelines followed in India, which are much more stringent than those used internationally. Since large swathes of India’s population have unmet medical needs, the government and the media should also highlight the advantages of participating in clinical trials. This notification alone cannot wipe out the perception.”
‘No gain without pain’ seems a trite summation of the industry’s current situation but in this case, it fits the bill completely. In conclusion, as Hariani points out, while the apex court’s observations on the subject has increased awareness, the notifications are only the first step towards changing the perception in the global market and prompting transparency. Both sides will have to take many more such steps in the same direction to reach the right balance.