“Make Global Pharma Responsible in Homeland for Objectionable Conduct in Clinical Trials Elsewhere”

In the context of his recent meeting with Commissioner Margaret A. Hamburg of US-FDA, the Drug Controller General of India (DCGI) reportedly expressed his concern to ‘The Economic Times’ on the ‘objectionable conduct’ of global pharma in new drug trials in India, as follows:

“US and other global drug makers who conduct clinical trials at different locations across the globe need to be made responsible in their home country for their objectionable conduct in clinical trials elsewhere.”

He further added:

“While conducting trials, drug makers cannot discriminate on the basis of nationality, because patient safety is top priority for every regulator – US or India”

The above report also mentioned that there is already a law in place in the United States that makes companies accountable in their homeland, if they are found to be indulging in corruption overseas.

‘Uncontrolled clinical trials are causing havoc to human life’:

That is exactly what the Supreme Court of India observed last year in response to a Public Interest Litigation (PIL) filed by the Human Rights group ‘Swasthya Adhikar Manch (SAM)’.

At the same time, revoking the power of the ‘Central Drugs Standard Control Organization (CDSCO)’ under the Drug Controller General of India (DCGI), the apex court directed the Health Secretary of India to be personally responsible for all ‘Clinical Trials (CT)’ of new drugs conducted in the country in order to control the ‘menace’ of poorly regulated trials on a war-footing.

Earlier in May 2012, the Parliamentary Committee on Health and Family Welfare in its report on the CDSCO, also stated as follows:

“There is sufficient evidence on record to conclude that there is collusive nexus between drug manufacturers, some functionaries of CDSCO and some medical experts.”

Inaction on CT related deaths:

According to the Ministry of Health, between 2005 and 2012, around 475 new drugs were approved for CT, out of which only 17 obtained the regulatory approval for market launch. Though 57,303 patients were enrolled for CT, only 39,022 could complete the trials. During CT, 11,972 patients suffered Serious Adverse Events (SAE) and 2,644 died. 506 SAEs out of the total and 80 deaths had clearly established link to CTs. However, only 40 out of 80 trial related deaths had their respective families meagerly compensated.

An independent investigation:

Interestingly, an investigation  in 2011 by ‘The Independent’, a newspaper of global repute, also highlighted the recruitment of hundreds of tribal girls for a drug study without any parental consent.

Stringent regulatory action followed:

Following high voltage indictments, alleging wide spread malpractices, from all corners – the Civil Society, the Supreme Court and the Parliament, the Ministry of Health constituted an experts committee last year chaired by Professor Ranjit Roy Chaudhury. The committee, after due consultation with all stakeholders, submitted its report recommending a robust process for CTs in India. Besides many other, the experts committee also recommended that:

  • CTs can only be conducted at accredited centers.
  • The principal investigator of the trial, as well as the Ethics Committee of the institute, must also be accredited.
  • If a trial volunteer developed medical complications during a CT ‘the sponsor investigator’ will be responsible for providing medical treatment and care.

Further, in October 2013, the Supreme Court reportedly ordered the government to video record clinical trials of new drugs, making it even tougher for pharma MNCs and the CROs to avoid responsibility on informed consent of the participating volunteers, as required by the regulator.

Consequent industry uproar and recent Government response:

Following all these, as the ball game for CTs in India changed significantly, there were uproars from Big Pharma, the CROs and their lobbyists crying foul.

As the caustic comments and the directive of the Supreme Court of India triggered the regulatory changes in CT, the Union Ministry of Health did not have much elbowroom to loosen the rope. Consequently, the pharma industry and the CROs reportedly made some angry comments such as:

“The situation is becoming more and more difficult in India. Several programs have been stalled and we have also moved the trials offshore, to ensure the work on the development does not stop.”

In response to shrill voices against the stringent drug trial regime in India, Mr Keshav Desiraju, Secretary, Union Ministry of Health and Family Welfare, reportedly said recently:

“While it is not our intention to impose unrealistic barriers on industry, it is equally our intention not to take risks, which may compromise the safety of the subjects of clinical trials.”

During the same occasion, the Union Health Minister Ghulam Nabi Azad also remarked:

“The industry has complained that the regulations are too stringent, but there have also been complaints by parliamentarians, NGOs and others that they are too lax, which the Supreme Court had taken note of.”

He further said without any elaboration, “The Indian regulatory regime governing clinical trials needs to balance the interests of all stakeholders.”

Conclusion:

According to the Indian Society for Clinical Research (ISCR), pharma companies conduct around 60 percent of CTs and the rest 40 percent are outsourced to Contract Research Organizations (CROs) in India.

With the Supreme Court laying stringent guidelines and the regulatory crackdown on CTs, the number of new drug trials in India has reportedly come down by 50 percent. According to Frost & Sullivan, the Indian CT industry was worth US$ 450 million in 2010 -11. Currently, it is growing at 12 percent a year and is estimated to exceed the US$1 billion mark in 2016, with perhaps some hiccups in between due to recent tightening of the loose knots in this area.

Some experts reportedly argue that laxity of regulations and cost arbitrage were the key drivers for global players to come to India for CTs. Thus, there should not be any surprise that with the costs of drug trials going north, in tandem with stringent regulations in the country, some business may shift out of the country. As Mr. Desiraju epitomized in his interview succinctly, as quoted above, this shift would result in much increased costs for the respective companies, which his ministry would ‘regret greatly.’

That said, would the recent anguish of the DCGI, when he expressed “Make global pharma also responsible in their respective homelands for objectionable conduct in CTs elsewhere”, be also construed as a clear signal for shaping up, sooner?

By: Tapan J. Ray

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.

New ‘Patient Compensation’ Norms on Clinical Trials in India: Overdue Action, Sharp Reaction and Ethical Issues

Responding to the damning stricture made by the Supreme Court on January 3, 2013, the Ministry of Health, as expected, by a gazette notification of January 30, 2013 has made the norms of compensation to patients participating in Clinical Trials (CT) more stringent.

‘Patient Compensation’ will now include injury or death, even if those are not related to the drugs being tested in the CT.

It is worth mentioning that these guidelines have been reportedly worked out after due consideration of around 300 comments received from the stakeholders on the draft proposal circulated by the Ministry of Health in July 2011, couple of rounds of discussion with the members of the civil society, expert groups and against reported ‘stiff opposition from the drug companies’.

Just a day after, on February 1, 2013, the Ministry of Health also notified final regulations on the conditions under which CT sites will be authorized by the local licensing and the inspection authorities of the Central Drugs Standard Control Organization (CDSCO).

Key features of the new Government ‘Action’ on patient compensation:

Following are the key features in the new norms for patient compensation:

1. The sponsors of CTs will now be liable for injuries or deaths, which will take place during the course of a clinical trial and will be required to pay compensation to the patients or their families.

2. The investigator of the CT must inform the concerned pharmaceutical company, the Clinical Research Organization (CRO) and the Ethics Committee regarding injury or death during CT within 24 hours.

3. It will be mandatory for all CT Ethics Committees to be pre-registered with the Drug Controller General of India (DCGI), unlike the old system where this was not required and trial sponsors reportedly could staff the committee.

4. The pharmaceutical companies and the CROs will get 10 days time to submit a detailed report on related serious adverse event to the Ethics Committee, which in turn will get another 10 to 11 days to convey its evaluation on compensation to be paid to the independent expert committee. The Expert Panel will then advise the DCGI of an appropriate financial compensation within 30 days from the date of receiving the above report.

5. It will no longer require inclusion of specific amount of compensation for injury or death in the informed consent form and does not refer to insurance coverage for potential liability.

6. It requires the sponsors of CTs to provide the trial subject with free “medical management” for as long as it will require.

Will make CT more expensive in India:

Clinical Trials (CT), as we know, are of critical importance for obtaining marketing approval of any new drug and at the same time forms a major cost component in the new drug development process, across the world.

Any savings in this area, both in terms of time and money, will add significantly to the profit margin of the product. In that context the above notification will now make CT more expensive in India.

Sharp ‘reaction’ of CT related industry:

Understandably, reacting to this notification, some Clinical Research Organizations have expressed concerns in areas like:

  1. Lack of distinction between study-related injuries and non-study related injuries
  2. The use of placebos in placebo-controlled trials,
  3. Lack of any arbitration mechanism in case of disagreement on causality/quantum of compensation and the lack of clarity on who constitutes the Expert Committee and its composition.

Some other Experts related CT industry do highlight a few more troubling issues in the notification, as follows:

1. Compensation to be paid for ‘failure of an investigational product to provide intended therapeutic effect.’ This, they expressed, is intriguing as the very nature of a CT is to ascertain whether the investigational drug is efficacious or not.

2. If compensation is not paid as required, a sponsor or CRO may be banned from conducting any further trials in the country. This, they feel, provision could make India a challenging place to conduct CT.

3. There should also be clarity on the formula to determine compensation, the process for determining a compensation amount, and how an appeal process would work.

The bottom-line is, due to this new policy on ‘Patient Compensation’ CT expenses may go up considerably in India.

Other expert views:

On the other hand, some other experts opined to the International Weekly Journal on Science – ‘nature’ as follows:

“These reforms should go further to restore public confidence and the Indian government should establish special courts to deal quickly with allegations of medical misconduct, such as not fully disclosing to participants the risks involved in a clinical trial”.

Global concern on ethical issues with ‘Placebo Controlled’ studies:

In this context, though issues related to ‘Placebo Controlled’ trials have been raised by the CT related industry in India, very interestingly a paper of Research Administration of the University of California on the ethical issues with ‘Placebo Controlled’ studies’ clearly articulates that the use of a placebo in clinical research has remained a contentious issue in the medical community since long.

Some strongly argue that use of placebos is often unethical because alternative study designs would produce similar results with less risk to individual research participants. Others argue that the use of placebos is essential to protect society from the harm that could result from the widespread use of ineffective medical treatment.

However, as per the Office for Human Research Protections (OHRP) guidebook, “Placebos may be used in clinical trials where there is no known or available (i.e. US-FDA-approved) alternative therapy that can be tolerated by subjects.”

This issue also needs to be deliberated and effectively addressed by the Indian drug regulator in the debate of patient compensation for ‘placebo controlled trials’.

A perspective on CT in India:

Interestingly, in this critical area India is fast evolving as a major hub. This is vindicated by a study conducted by Ernst & Young and the Federation of Indian Chambers of Commerce and Industry of India (FICCI), which states that India now participates in over 7 per cent of all global phase III and 3.2 per cent of all global phase II trials. The key points of attraction of the global players, so far as India is concerned, were reported as follows:

1. Cost of Clinical Trial (CL) is significantly less in India than most other countries of the world

2. Huge patient pool with different disease pattern and demographic profile

3. Easy to enroll volunteers, as it is easy to persuade poor and less educated people as ‘willing’ participants.

Such opportunities, experts believe, should have ideally made the clinical research industry to demonstrate greater responsibility to ensure that patients’ safety needs are adequately taken care of. Unfortunately, despite such expectations, some important areas like ‘patient compensation’ have still remained blatantly neglected.

It has now come to light with the help of ‘Right To Information (RTI)’ query that more than 2,000 people in India died as a result of Serious Adverse Events (SAEs) caused during drug trials from 2008-2011 and only 22 of such cases, which is just around 1 percent, received any compensation. That too was with a meager average sum of around US$ 4,800 per family.

It has been widely reported that pharmaceutical companies often blame deaths that occur during trials on a person’s pre-existing medical condition and not related to CT.

DCGI had hauled-up 9 companies for blatant negligence:

According to another report quoting the Drug Controller General of India (DCGI), 25 people died in clinical trials conducted by nine pharmaceutical companies, in 2010. Unfortunately, families of just five of these victims received” compensation for trial related death, which ranged from Rs 1.5 lakh (US$ 3000) to Rs 3 lakh (US$ 6000).

This report also highlighted that arising out of this critical negligence, for the first time ever, the then DCGI was compelled to summon these nine pharmaceutical companies on June 6, 2011 to question them on this issue and with a clear directive to pay up the mandatory compensation for deaths related to clinical trial by June 20, 2011, or else all other CTs of these nine companies, which were ongoing at that time or yet to start, will not be allowed.

The report also indicates that after this ultimatum all the nine companies as mentioned therein had paid the compensation to the families of the patients who had died related to the CT.

Long exploitation of the fragile CT regulations in India:

For all these reasons, the subject of CT in India has created a huge ruckus, mainly for wide spread alleged malpractices, abuse and misuse of fragile CT regulations of the country by some players in this field. The issue is not just of GCP or other CT related standards but more of ethical mind-set and reported rampant exploitation of uninformed patients, especially in case of trial related injuries or even death.

The Bulletin of the World Health Organization (WHO) in an article titled, “Clinical trials in India: ethical concerns” reported as follows:

“Drug companies are drawn to India for several reasons, including a technically competent workforce, patient availability, low costs and a friendly drug-control system. While good news for India’s economy, the booming clinical trial industry is raising concerns because of a lack of regulation of private trials and the uneven application of requirements for informed consent and proper ethics review.”

“Pharmaceutical industry seeks to run studies in countries with lower costs”:

There seems to be nothing basically wrong in this approach per se. However, a recent report does highlight as follows:

“Clinical trials conducted by global drug makers and their proxies have generated increased scrutiny in recent years as the pharmaceutical industry seeks to run studies in countries with lower costs and populations where patients are not exposed to as many medications that can confound results. India has been a prime example”.

A lesson to learn by the Indian Drug Regulator:

It is worth noting that US-FDA in a communication meant for the consumers has stated as follows:

“The Food and Drug Administration’s job is to make sure medical treatments are safe and effective for people to use. FDA staff members meet with researchers, and perform inspections of clinical trial study sites to protect the rights of participants and to verify the quality and integrity of the data.”

The above approach seems to be drastically missing with the drug regulator in India as on date.

Conclusion:

Over a long period of time, a blatant negligence on reasonable care and financial compensation was allowed to continue by the Drug Regulator and the sponsors alike on the CTs conducted in India. A perceptible intent of justice to the patients, with the enforcement of stricter compensation laws and regulations for CT though belated, could dramatically change the CT scenario in India for the better in the years ahead.

In the fine balance of national priority for this area, patients’ safety and interest, I reckon, should always weigh more than the possibility of increase in the costs of CT in India. Thus,  the new norms of Patient Compensation indeed bring with it a breath of fresh air for the concerned stakeholders.

That said, the lose knots in some areas of the new norms, as discussed above, must be properly addressed and adequately tightened for greater clarity of the CT process, for all concerned.

By: Tapan J. Ray

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.