Clinical Research: Building Trust

“Come what may, you have to pay.” The compensation guidelines recently put in place by the regulators for study related injuries seems to have only this message for the clinical research industry, says Dr Arun Bhatt, President Clininvent Research

But Bhatt is not against regulation per se. He is all for a “transparent and fair regulatory process”, with a “reasonable timeframe: three months”. Considering that the current timeline is around nine months, Bhatt’s concern is understandable.

And the flight of trials from India to other geographies is apparently already happening (See Market cover: Trial(s) by fire: page 17). As Dr Shubhangi Desai, Head Clinical Operations- Asia Pacific, SIRO Clinpharm confirms, in the last three years, pharmaceutical companies don’t mind spending the extra buck to conduct trials in other South East Asian countries, in order to get approvals in the given timeline.

Giving their views in their individual capacity, Dr Viraj Suvarna and Dr Partha Gokhale make the point that clinical trials generally ensure better patient care than normal clinical practice and it is unfortunate that Indians are losing out on the good quality care accorded by clinical studies/trials.

Regulations ok, delays not

Industry associations have welcomed the efforts by regulators to frame new policy guidelines and refine those already in existence and have in fact been a key part of the drafting process.

“We have been concerned about over the last year on the uncertainty and unpredictability of the regulatory environment.” Suneela Thatte President, Indian Society for Clinical Research (ISCR)

Stating ISCR’s position, President Suneela Thatte, says they believe there is need for better governance of clinical trials in the country and have welcomed the intent of the Ministry of Health & Family Welfare and the Central Drugs Standard Control Organisation (CDSCO) to create a more robust framework for the conduct of clinical research in the country. “Any steps, therefore, to ensure the practice of the highest standards of ethics and quality and the protection of patient rights and safety is welcomed by us.”

Apurva Shah, Chairman, Association of Contract Research Organisations (ACRO) feels that these recent changes are a welcome step and will go a long way in plugging the holes in the system and give a feeling of comfort to the patients/volunteers that the system is in place to ensure their safety and well being.

“We can’t want clinical trials for our benefit but ignore the way the industry works.” Apurva Shah Chairman, Association of Contract Research Organisations (ACRO)

However Shah cautions that there are a lot of finer points in the process that the regulators need to look at before finalising these laws so that they don’t create a system that doesn’t work and the local industry just can’t function. Of course, that has nothing to do with the safety or quality, he avers.

Thatte too says that they have been concerned about over the last year on the “uncertainty and unpredictability of the regulatory environment and more recently, the compensation guidelines which have acted as a disincentive to do clinical research in the country.”

She says most organisations and institutions are adopting a wait and watch approach at the moment and while they may not see an immediate impact of the compensation guidelines, in the long run it could impact business if the regulatory authorities do not address the concerns of stakeholders on priority. Taking a broader view, she says their greater concern is about the impact on patients. A slow down in clinical research will impact patients and the future availability of effective and affordable medicines in our country, she opines.

“The problem is that all these actions have come in a span of few months creating a sense of panic amongst all stakeholders.” Dr Arun Bhatt President, Clininvent Research

What seems to have spooked the industry is the timing and frequency of the recent changes after years of relative inaction. As Bhatt says, the problem is that all these actions have come in a span of few months as a result of a Supreme Court order, creating a sense of panic amongst all stake holders – ethics committee (ECs), investigators, and sponsors.

In spite of their concerns over the implementation of regulatory guidance, industry would like more rather than less regulatory oversight, a fact borne out when ISCR’s Thatte mentions that they have also drawn the Ministry’s attention to four more areas which are equally important components of research governance: investigator site registration and accreditation, CRO registration and accreditation, regulatory capacity building, and credibility of the informed consent process.

Sounding the alarm

Shah emphasises that the majority of industry players who do a good quality job are in favour of high quality checks so that the weaker players who don’t take ethics and quality seriously are weeded out. Right now due to the wrong doings of a few, the whole industry gets a bad name but what worries him is that the regulators and lawmakers seem to lack an “understanding of how the global industry works and the demands of the market. We can’t want clinical trials for our benefit but ignore the way the industry works,” he says. Spelling out the issues involved, he says, “India has proven its quality to a large extent but its been failing miserably on time predictability. Regulatory delays are due to lack of manpower, training and understanding of the functioning of the industry.”

He charges that most times, delays and uncertainty due to timing is due to external issues like politics and media heat. Thus it is seen that most times, it is these issues that control the drug development process in India rather than it being driven and controlled by scientific issues and concerns. Shah cautions that other smaller countries like South Korea who have a planned approach are beating India on every front.

Viraj Suvarna

Sounding a warning, he says,“The net result is that our local capability of developing new drugs is diminishing fast and it will become a distant dream. That’s a pity because clinical research could have been a huge socio-economic opportunity for India and would have helped solve some of our country’s problems such as lowering the cost of healthcare, improving the delivery of medical care, offering employment and foreign exchange earnings.”

Suvarna and Gokhale bring forth another related reason for the decrease in clinical trials coming to India: the unreasonable demands of the National Drug Advisory Committee (NDAC) with respect to protocol amendments, site selection etc. which add to the delays.

Impacting innovation

Partha Gokhale

Bridging the sponsor/CRO and the patient, lies the investigator community, comprising doctors and other clinical staff who actually conduct the clinical research study and are therefore possibly the most vital link in a clinical trial. On the shoulders of the principal investigator (PI) lies the responsibility of doing right by the patients he recruits to trials as well as to corporates who sponsor the trial. (See testimonials from PIs on pages 80- 81)

But not all trials are initiated by corporates. As Thatte of ISCR points out, “There is a lot of institution-initiated and investigator-initiated research being done in India and they are perhaps the most impacted in particular by the new compensation guidelines. We believe that these guidelines could negatively impact the spirit of innovation and research that exists in many of our best medical institutions.”

Investigator issues

“Some of the points (in the compensation guidelines) will in fact induce the patient to participate in the clinical trial.” Dr Shubhangi Desai Head Clinical Operations- Asia Pacific, SIRO Clinpharm

Going into more detail, Suvarna and Gokhale say that PIs are worried because of the unreasonable regulations put forth by the current amendment to the Schedule Y of Drugs and Cosmetics Act, 1940. For example, as per the new amendment, PIs need to report serious adverse events (SAEs) to licensing authority, EC and the sponsor/ its representatives within 24 hours of occurrence.

They contend that this is unreasonable and unrealistic, as investigators will be able to report a SAE only once they become aware about it through the patient or the relative of patient, as the case may be, making this regulation impossible to follow.

Desai of Siro Clinpharm too highlights the cumbersome nature of this request, and cites one rule which requires different colour envelopes for different types of SAEs, which only stretches timelines further.

This will be an additional workload for the PI predicts Bhatt and in addition, they also have to consider issues related to compensation guidelines when they carry out their own clinical research. Additionally, there is apprehension about surprise regulatory inspections. Most investigators might become reluctant to take part in trials because of these issues, feels Bhatt.

An IT raid or site visit?

Suvarna and Gokhale also point out that PIs are concerned regarding the lack of training and background (i.e. expertise/profession etc.) of drug inspectors who come to inspect their clinical trial sites.

Sharing their experiences, the duo point out that the observations shared by global regulatory staff like the US FDA inspectors, are to generally develop the quality of research at the site. At the end of the inspection, an inspection site report is shared which not only points out the deficiencies but also the good practices followed by the site. The report encourages the site to correct the deficiencies and improve the quality of research for future trials, they explain.

On the other hand, they allege that the attitude of Indian drug inspectors is like conducting a sting operation or an Income Tax raid. Further, many of the inspectors are not from the field of clinical trials/ studies and have a background of conducting good manufacturing practice (GMP) inspections and the duo allege that they use the same yardstick for good clinical research practice (GCP) inspections.

If the industry is unhappy with the quality of regulation and the regulators, is self regulation the answer? To some extent, internal checks already exists. As Desai points out, all ethical companies already have best practices on maintaining quality and compliance in GCP guidelines through periodic audits to demonstrate compliance to the framework.

But self regulation is not the full answer. Thatte believes that “self-regulation cannot and should not replace regulations and policies. Rather it will add an extra layer of governance for the industry and an extra layer of protection for patients, and should co-exist with government regulation. The role of robust governance mechanisms by the regulator cannot be over-emphasised,” is her reasoning.

Industry believes that they are unnecessarily maligned and the perception that they are trying to escape the regulator’s net is baseless.

For instance, Suvarna and Gokhale make the point that the DCGI and Indian media also need to realise that global multinationals who conduct clinical trials in India are not only governed by Schedule Y of Drugs and Cosmetics Act, 1940 and Indian Good Clinical Practices but also by international guidelines like US-FDA, EMEA, Health Canada etc which have much more stringent regulations. They state that there have been a number of international site inspections conducted by global regulators like US-FDA, EMEA, Japan, UK-MHRA till date and no major concerns have been seen in any of their Indian sites. The point seems to be that with so much at stake, playing by the rules is in the interest of industry.

Media’s role?

Besides the regulators, the industry directs equal censure on the media for its reportage on the sector. As Thatte comments, the continuous negative reporting of clinical research and, at times misrepresentation of information, has done little to encourage investigators to pursue clinical research. She adds that this does not mean misconduct should not be reported … but the value and role of clinical research and positive benefits it has brought to hundreds and thousands of patients in our country needs to be and should be highlighted.”

Bhatt says that it is likely that due to recent media stories focusing on deaths in clinical trials, patients would be afraid of taking part in clinical trials.

So what approach would industry like media to take? Thatte believes media can and should play an important role in educating patients about their rights and responsibilities in a clinical trial so that they can make a more discerning choice.

Learning to co-exist

Inspite of the ‘gloom and doom’ scenario painted above, each stakeholder still seems to be hoping for a ‘happily ever after’; of course after some ‘prescribed’ medicine.

Thatte expresses ISCR’s appreciation of the various efforts taken by CDSCO but also highlights how more needs to be done on each front. For instance, while the CSDCO’s intention was to bring clarity and robustness in the clinical trial approval process with the setting up of the Apex Committee, Technical Committee and Expert Committees, ISCR has requested for complete clarity on the functioning of these committees, perhaps alluding to a lack of transparency.

“While these committees re- evaluate the current approval processes, the routine functioning of the CDSCO should not be compromised, thereby leading to unpredictability in the review and approval process of clinical trials,” highlights Thatte.

The common refrain seems to be that more regulations and a review of the existing process are welcome but this should not slow down the routine process. So what measures need to be taken to end the impasse?

Thatte’s suggestions as the ISCR spokesperson range from the need for more consistency and stability in the regulatory office; openness and transparency; to continued industry dialogue; quicker responsiveness and action on issues addressed.

She also asks for a policy framework that provides clarity of the Ministry’s intent and larger vision. “We also believe that those found guilty of violating existing rules and guidelines should be brought to task and blacklisted. We do not condone violation of any guidelines,” asserts Thatte.

Desai too advocates measures like a system of de-accreditation or penalising companies, sites, CROs, investigators, for non-compliance, just like US FDA. She suggests that industry must also consider leveraging IT to better the process (for instance, its easy to envisage that improved IT processes could ease and speed up the safety reporting process). Her other suggestions include regular periodic inspections of sites, CROs and ECs to ensure compliance and requiring training certifications for participation of a principal investigator in a clinical trial.

Suvarna and Gokhale believe that the answer lies is more empowerment of the DCGI (Drugs Controller General of India) who should be brought to a level of a joint secretary in the health ministry. Only once the DCGI is empowered will it have the authority to answer parliamentary queries.

Manpower is the next target, with the duo calling for a ramp up of the department with input of people who understand and/or have necessary professional background of medicine and pharma science. They point out that only medical and scientific people could answer some of the “out of context questions” raised by our parliamentarians. Haring back to Desai’s point about leveraging IT, they opine that the records management of the (DCGI’s) office needs a complete overhaul with computerisation in key areas.

Shah signs off expressing the hope that if we can plug these regulatory holes in India, we soon have a chance to compete and secure a place in the industry as a preferred destination.

The last word belongs to Bhatt, as he probably speaks for all stakeholders when he calls for a regulatory system with a balance of safeguarding clinical trial subjects and supporting innovation, with the the inspection process being used to improve the quality of clinical trials and train various stakeholders.

As the industry comes together on International Clinical Trials Day on May 20, let’s hope the occasion spurs more solutions and productive debate rather than a re-hash of previous issues.

(With inputs from Usha Sharma)

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