Clinical trials in India Uncertainty lingers

Clinical trials are an essential component of the drug discovery research process. This is the stage when volunteers or patients are first exposed to the new drug/device on trial so it is only to be expected that the regulatory authorities would want to be very sure that they are well protected.

Consequently, in the past year the Indian contract research organisation (CRO) industry witnessed several new regulatory initiatives and legislative measures all aimed to safeguard the safety and well-being of clinical trial participants

“It may be mentioned that India may be the only country in the world where AV recording of each trial patient is mandatory.” Dr Renu Razdan Vice Chairperson, Association of Contract Research Organisations

But it seems the pace of change has got industry concerned. As Dr Renu Razdan, Vice Chairperson, Association of Contract Research Organisations (ACRO) puts it, “More than 21 orders and 13 notifications were issued by the higher authorities and the industry has been asked to implement them without any lead time. One more bill introduced in the Parliament is the Central Drugs Authority (CDA) bill.” She avers that most of these have already been implemented though in a majority of cases, no lead time was given to the industry.

“Nearly 50 per cent of the subjects, particularly female patients, have refused to get their consent recorded as per the AV recording norms.” Dr Kiran Marthak Member of Board of Directors and Global Head of Clinical Development, Lambda Therapeutic Research

Since the rules and orders need to be followed and maintained by the industry, the Government did take inputs from industry stakeholders to understand the issues in more detail and continues to do so. Speaking about this ongoing consultative process, Dr Kiran Marthak, Member of Board of Directors and Global Head of Clinical Development, Lambda Therapeutic Research says, “The industry gets an opportunity to interact with the government officials including Drug Controller General (India) (DCGI), Directorate General of Health Services (DGHS), Indian Council of Medical Research (ICMR), Health Secretary to convey the impractical aspects of the new laws.”

“We are very supportive of the need for a regulatory framework that has its focus quality, ethics and patient safety.” Dr Shoibal Mukherjee Chief Medical Officer, Quintiles India and Head, Asia Medical Sciences

Industry accepts the rules but protests the method of implementation. Dr Shoibal Mukherjee, Chief Medical Officer, Quintiles India and Head, Asia Medical Sciences agrees for the need to operate in a system which is safeguarded with regulations and points out, “We are very supportive of the need for a regulatory framework that has its focus quality, ethics and patient safety. However, many of the regulations introduced in 2013, such as the regulation on compensation and on audiovisual (AV) recording of informed consent deviate from global practices and may actually hinder research.”

A hasty reaction?

In the past few years, clinical trials have become the focus of NGOs and activists and this has put the authorities on the back foot. For instance, the Supreme Court of India order mandating AV recording of the informed consent process came in response to a case filed by Indore-based NGO Swasthya Adhikar Manch, Indore along with other like organisations, regarding five global clinical trials approved by CDSCO between January 2013 and August 2013.

The SC passed an order requiring that before clinical trials are conducted, ‘appropriate provision shall be made or administrative direction shall be issued which ensures that AV recording of the informed consent process of the participants is done and the documentation preserved, adhering to the principles of confidentiality.’ The ruling specifies that this is applicable to new subjects to be enrolled in clinical trials, including global clinical trials. The document also provided guidelines for stakeholders for AV recording of informed consent process in clinical trials.

Following the order from the SC, CDSCO issued a directive on November 19 that in all clinical trials, in addition to the requirement of obtaining written informed consent, AV recording of the informed consent process of each trial subject, including the procedure of providing information to the subject and his/her understanding on such consent is required to be done while adhering to the principles of confidentiality. Such AV recording and related documentation would be preserved.

Mukherjee while commenting on the orders, says, “As the order on AV recording is very recent and the number of new clinical trials in India is negligible, it will take a few months before we get a better and deeper understanding of the practical challenges in AV recording of informed consent. In addition, it will be important for them to get a clear guidance on how such materials are stored and how associated data privacy concerns are addressed. Lastly, we are yet to see a perceptible improvement in regulatory approval timelines.”

“In situations where patients refuse to be videotaped, there is not much one can do, except to disallow such a patient from participating in the trial as the guidance states.” Suneela Thatte President, Indian Society for Clinical Research (ISCR)

The order dated November 19 aims to bring more transparency and create confidence among patient groups but appears to be doomed to failure. Suneela Thatte, President, Indian Society for Clinical Research (ISCR) says, “With the new requirement for AV recording of the informed consent process, patients are refusing to be videotaped due to several reasons. Discomfort with and suspicion of being videotaped as well as hesitancy into entering into a videotaped discussion on a serious illness or illness with a stigma as the case might be.”

Marthak agrees with Thatte and says, “Nearly 50 per cent of the subjects,particularly female patients, have refused to get their consent recorded as per the AV recording norms.”

Implementation challenges

The challenges of implementation become clear during the patient enrollment process. Some patients have second thoughts about participating in trials when they are informed about the mandatory video tapping of consent. Thatte reveals, “In situations where patients refuse to be videotaped, there is not much one can do, except to disallow such a patient from participating in the trial as the guidance states, ‘Only those subjects who give the consent for the AV recording shall be included in the clinical trial process.’”

This reaction from patients has worried investigators too as they face an ethical dilemma. As Thatte reasons, “Disallowing a patient from participating in a clinical trial and accessing more effective treatment on account of his or her refusal to be videotaped is a violation of medical ethics and the rights of a patient to fair treatment. We therefore hope this will be revoked.”

Though in most cases Indian regulators take their cue from guidelines being implemented in western countries, on this count they seem to have gone a step further. Apart from India, no other country in the world has mandated AV recording of the informed consent process. As Razdan reveals, “It may be mentioned that India may be the only country in the world where AV recording of each trial patient is mandatory. Even in the US, this is recommended in extreme situations, for example, for totally illiterate subjects.”

Dr YK Gupta, Professor & Head, Dept of Pharmacology, All India Institute of Medical Sciences (AIIMS) agrees that AV recording is a good step towards empowering clinical trail subjects but there are logistical issues in some cases. For instance, studies related to HIV/AIDS medication, contraceptive methods and consenting in emergency situation like heart attack etc. He reveals that groups of experts across the country are making a case that ethics committees should be empowered to grant waivers (of the AV recording of the consent process) in such situations.

Another major ethical issue posed by the AV recording mandate is the need to maintain confidentiality. Mukherjee stresses that the AV recording of informed consent is a big challenge due to confidentiality and the socio-cultural environment in India. Razdan avers that while all attempts are made to maintain confidentiality, it is not clear how these recordings can be monitored or audited.

Thatte agrees and says, “Confidentiality is a real issue and challenge that investigators are facing. Confidentiality of data is also of prime importance and it is the investigator’s responsibility to ensure that all patient data is treated keeping patient safety, rights and privacy uppermost. Building trust amongst patients in videotaping informed consent is a major challenge particularly where misguided activism and misleading reports have already created an environment of mistrust amongst the general public. So there are no easy solutions.”

However, Arun Bhatt, President, Clininvent Research differs on this count saying, “There are no confidentiality issues as the information exchange is between the doctor and the patient. No third party, except ethics committee and regulators, can view the video.”

Bottlenecks galore

Commenting on the slew of actions being taken by the Ministry of Health and Family Welfare and CDSCO to create a vigorous framework for clinical research, Thatte says, “What has concerned us with the regulatory guidelines and notifications introduced last year is that some of them have been hastily introduced and not well thought through. They have acted as a deterrent to stakeholders and have impacted the willingness and interest of sponsors (who include academic and teaching institutions, NGOs, CROs and biopharma companies) to do clinical research in the country.”

The compensation formula is another well discussed topic among the CRO fraternity. Mukherjee says, “The compensation regulations contain several clauses that are making sponsors reluctant to conduct clinical research in India. There have also been recent notifications with regard to the representation of sites in a trial and the number of trials an investigator can undertake.”

Besides the AV recording issue, there are many bottlenecks in the Indian CRO industry today. Listing some of these, Marthak highlights the limitation on number of protocols per investigator, reporting of Serious Adverse Events (SAE) within 24 hours of occurring, and compensation for the SAE even if it is not related to clinical trial drug and also for inadequate response to the trial drug. Adding to this list, Thatte spotlights composition of NDACs and pre-determined allocation of trial sites by type of site.

All the above mentioned barriers are prevalent in the system due to less regulated mechanisms. However, investigators also feel that too much regulations will become an obstacle to growth. Razdan enlights, “There have been a number of incidences where leading investigators / doctors have refused to participate in trials due to numerous changes that have been brought in. While many changes have been good for patient’s welfare, others like putting a cap on the maximum number of trials that an investigator can do, is actually a regressive step. It is actually the ethics committee, infrastructure and investigator’s expertise that should determine the upper limit of trials and can be done by an investigator only. It is important to mention that clinical research involves not only medical but scientific bent of mind and every clinician can undertake research activities. Hence putting this upper cap is a big bottleneck.”

Hoping for the best

“There are no confidentiality issues as the information exchange is between the doctor and the patient. No third party, except ethics committee and regulators, can view the video.” Arun Bhatt President,Clininvent Research

Many guidelines and regulations have been introduced to safeguard Indian patients and regulatory agencies are continuously working to address these issues. Still there are a lot of ambiguity present which is leading the industry no where. As Razdan says, “There are a number of grey areas which need to be addressed. One is the medical management for clinical trial patients. This area is very ambiguous and providing medical management for ‘as long as required’ is construed in different ways by different people.”

Mukherjee hopes for a balanced work environment and comments, “We hope that equilibrium will soon be brought in balancing the interest of patients and other stakeholders with the national health agenda of the country. We will see a more regulated, but conducive environment created for the conduct of clinical research in our country. We need to secure the progress of an industry that is committed to drug discovery and development for diseases endemic to our region and the growing lifestyle diseases that are affecting our population.”

Thatte too feels, “We need the ecosystem to be encouraged and motivated to do clinical research in India.”

With the acceptance of recommendations of the Prof Ranjit Roy Chaudhury expert committee submitted to the Union Health Ministry of India gives a new direction to the system. The committee was constituted by the Ministry and the core function was to formulate the policy and guidelines for approval of new drugs, clinical trials and banning of drugs. Bhatt anticipates, “Some of the recommendations of Dr Roy Chaudhury Committee will become rules / guidelines. Their impact can be judged only after the rules are framed and implemented.”

Building trust

In western countries there are websites announcing the trials and with this information, volunteers/ patients are comfortable signing up for the trials, whereas in India, patient groups lack confidence in Indian clinical trials and CROs. The few that do, are unfortunately put off.

According to Mukherjee, “Like elsewhere in the world, many patients in India seek clinical trials as they look for different treatment options. It is not unusual for clinical researchers and investigators to receive queries direct from patients seeking access to investigational therapies.”

Unfortunately, he avers that misleading media reports and requirements such as compulsory video recording of informed consent and announcement of large compensation payouts for ‘injuries’ have made patients suspicious of research activities.

Looking to the future, he says, “Patients must see the regulatory authorities as a reliable gate-keeper capable of ensuring patient safety without compromising patient access to clinical trials, so that they feel confident that trials approved by the authorities and conducted by doctors are authorised to do so will be safe to participate in. Ultimately all stakeholders involved in the clinical trial process need to be committed to high quality clinical research which has safeguarding patients’ health at its core.”

Razdan feels, “There is a need for education and information which should be transparent with the patients. Regulators and the industry have to ensure that patients are given enough education and information regarding clinical trials so that they opt for participating in these trials.” She further elaborates, “One only has to look at the advances that medical sciences has made in past few decades and clinical research and trials have become an intrinsic part of this development.”

“Patients coming forward to share experiences of how important clinical research is in addressing their unmet medical needs is also a critical need and would help build greater awareness and credibility. Better governance and action by regulatory authorities with regard to proven irregularities in the conduct of clinical research will also go a long way in instilling confidence amongst the public at large,” adds Thatte.

Resolving the grey areas

While individual companies have been complying with all the notifications and guidelines issued by DCGI to the best of their abilities, associations like ISCR and ACRO are working towards more long term solutions to address the loop holes.

Thatte informs that there have been and continue to be various stakeholder representations to the regulators to draw attention to the lack of clarity and ambiguity in some of these guidelines. The hope is that the requisite changes will be affected soon in the interest of patients in particular for many of whom participation in a clinical trial is the only hope of cure or a better quality of life. Many organisations and institutions are therefore adopting a wait and watch approach at the moment, according to her.

Similarly, after internal debate, ACRO too has represented the views of its members on the suggested changes through representations to the parliamentary standing committee along with other industry stakeholders. While DCGI has reviewed the timeline for approval of clinical trials, timeline for Bioavailability and Bioequivalence (BA/BE) studies would be further looked into. ACRO has submitted feedback both from within the CRO community as well as from investigators.

When the Health Ministry was striving to strengthen and streamline the clinical trial regulations in India, industry too has taken steps to self-regulate. The ISCR released its code of conduct for members earlier this year (see box) and while this is restricted to its members, it is a step in the right direction. This indicates the industry’s seriousness and their positive approach to adhere to the regulations for the betterment. Hopefully, such measures will multiply and ultimately form the basis of a more transparent and trustworthy ecosystem for clinical trials.

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