On September 30, 2013, with a damning stricture to the Drug Regulator, the Supreme Court, in response to a Public Interest Litigation (PIL) filed by the NGO Swasthya Adhikar Manch, stayed approvals for 162 applications for local Clinical Trials (CTs) of new drugs approved by the Drugs Controller General of India (DCGI) earlier.
The apex court of the country granted the DCGI two weeks time to furnish evidence to the court that adequate patients’ safety and other related mechanisms have been put in place for CTs of all New Chemical Entities (NCEs) and New Molecular Entities (NMEs) in the country.
According to reports, during July and August 2013, the DCGI received 1,122 CT applications, out of which, 331 related to approval of global CTs. The New Drug Advisory Committee (NDAC) approved 285 drugs in AIDS, oncology, cardiology, neurology, psychiatry, metabolism and endocrinology therapy areas. Finally, 162 drugs received the green signal from the DCGI. Now all these trials have come to a halt.
At the same time, the court also directed the Ministry of Health to come out with a plan within 10 weeks to strengthen the regulatory framework for CTs in India based on various suggestions received from the state governments, other stakeholders and experts groups.
A casual approach?
Just to recapitulate, prior to this, on January 3, 2013, against the PIL, the bench of Honorable Justices R.M Lodha and A.R Dave of the Supreme Court reportedly observed that uncontrolled Clinical Trials (CT) are creating ‘havoc’ to human lives causing even deaths to many subjects in India.
In an interim order, the bench directed the Government that CTs could be conducted only under the supervision of the Health Secretary of India. Holding the Government responsible, the bench further observed, “You (Government) have to protect health of citizens of the country. It is your obligation. Deaths must be arrested and illegal trials must be stayed.”
Thereafter, though the Health Secretary of India approved the above 162 CTs, presumably following the above Supreme Court directive, it is an irony that when asked by the Apex Court, the government could not immediately explain precisely what systems and mechanisms have been put in place for proper conduct of these 162 CTs. It sought 2 weeks’ time to justify the action taken by the drug regulator in this regards.
Compromise on patients’ safety continues unabated:
During another hearing early in October 2013 on a petition filed by the NGO ‘Swasthya Adhikar Manch regarding violations of norms during CTs, the Supreme Court reportedly sought details from the Union Government on the irregularities during the drug trial using Human Papilloma Virus (HPV) vaccines by the Seattle (USA) based organization PATH in Andhra Pradesh and Gujarat states of India.
This intervening application by the NGO was based on the 72nd Parliamentary Standing Committee (PSC) on Health and Family Welfare report dated August 30, 2013, where it was recommended that action should be taken against PATH, state governments of Andhra Pradesh, Gujarat, Indian Council of Medical Research (ICMR) and other government officials including Drug Controller General of India (DCGI) for alleged violations on the subject.
The report highlights, HPV vaccines were given to 14,091 girls in Khammam district of Andhra Pradesh and 10,686 girls in Vadodra, Gujarat. These girls were between age group of 10 and 14, of which seven girls died due to such illegal vaccine trials.
Eventually, these trials were stopped, but only after the matter received media attention.
As per reports, the vaccines were provided by two pharma MNCs – Merck and GlaxoSmithKline through PATH. It also stated as follows:
“Vaccines were given to children irrespective of age in the case of Merck’s Gardasil vaccine. While permission was given to use GSK’s Cervarix vaccine in children of 10 to 14 years, CTs had been conducted on subjects in the age group of 18 to 35 years. Thus the safety and well being of subjects were completely jeopardized.”
No options but to shape-up:
It is worth mentioning, the above PIL had alleged that large scale drug trials being conducted across the country, mainly by the pharma MNC, are using Indian patients as ‘guinea pigs’, as it were. The NGO also told the Supreme Court that several pharmaceutical companies continue to conduct CTs quite indiscriminately, in various states of India, endangering lives of poorly/un-informed trial subjects.
In an affidavit to the Court, the Government admitted that between 2005 and 2012, 2,644 people died during CTs of 475 NCEs/NMEs with serious adverse events related deaths taking 80 lives.
Thus, coming under immense pressure from the civil society and now the scrutiny of the Supreme Court for so many CT related deaths and consequential patients’ compensation issues, the Government does not seem to have any other options left now but to bring US$ 500 million CT segment of the country, which is expected to cross a turnover of US$ 1 Billion by 2016, under stringent regulations.
Experts believe that the growth of the CT segment in India is driven mainly by the MNCs for easy availability of a large treatment naive patient population with varying disease pattern and demographic profile at a very low cost, as compared to many other countries across the world.
CT related deaths in India:
As per the Ministry of Health following are the details of deaths related to CTs registered in India from 2008 to August 2012:
| Year | Total no of deaths | CT related deaths | Compensation paid to patients: |
| 2012 (up to August) | 272 | 12 | NA |
| 2011 | 438 | 16 | 16 |
| 2010 | 668 | 22 | 22 |
| 2009 | 737 | NA | NA |
| 2008 | 288 | NA | NA |
It is estimated that over the last four years, on an average, 10 persons have died every week in India related to CT.
DCGI hauled-up 9 MNCs on patients’ compensation:
It is worth noting, absolutely unacceptable level of compensation, by any standard, are being paid by the concerned companies, including large MNCs, for the lives lost during CTs.
According to another report quoting the Drug Controller General of India (DCGI), 25 people died in clinical trials conducted by 9 pharma MNCs, in 2010. Unfortunately, families of just five of these victims received” compensation for trial related deaths, which ranged from an abysmal Rs 1.5 lakh (US$ 2,500) to Rs 3 lakh (US$ 5,000) to the families of the diseased.
This report also highlighted that arising out of this critical negligence, for the first time ever, the then DCGI was compelled to summon the concerned nine pharma MNCs on June 6, 2011 to question them on this issue and give a clear directive to pay up the mandatory compensation for deaths related to CTs by June 20, 2011, or else all CTs of these nine MNCs, which were ongoing at that time or yet to start, will not be allowed.
The 9 pharma MNCs summoned by the DCGI to pay up the mandatory compensation for deaths related to CTs were reported as Wyeth, Quintiles, Eli Lilly, Amgen, Bayer, Bristol-Myers Squibb (BMS), Sanofi, PPD and Pfizer.
The report also indicated that after this ultimatum, all the 9 MNCs had paid compensation to the concerned families of the patients, who died related to the CTs.
Prior indictment by Indian Parliamentary Committee:
On May 8, 2012, the department related ‘Parliamentary Standing Committee (PSC)’ on Health and Family Welfare presented its 59th Report on the functioning of the Indian Drug Regulator – the Central Drugs Standard Control Organization (CDSCO) in both the houses of the Parliament.
The report made the following scathing remarks on CDSCO under its point 2.2:
“The Committee is of the firm opinion that most of the ills besetting the system of drugs regulation in India are mainly due to the skewed priorities and perceptions of CDSCO. For decades together it has been according primacy to the propagation and facilitation of the drugs industry, due to which, unfortunately, the interest of the biggest stakeholder i.e. the consumer has never been ensured.”
Action just not enough yet:
Acting on the damning stricture by the Supreme Court, the Ministry of Health by a gazette notification of January 30, 2013 made the norms of compensation to patients participating in CTs more stringent. ‘Patient Compensation’ was proposed to include injury or death, even if those are not related to the drugs being tested in the CTs.
Understandably, reacting to this notification, some pharma companies, industry lobby groups and also Clinical Research Organizations (CROs) expressed concerns in areas like:
- Lack of distinction between study-related injuries and non-study related injuries.
- Use of placebos in placebo-controlled trials.
- Lack of any arbitration mechanism in case of disagreement on causality/quantum of compensation and also lack of clarity on who constitutes the Expert Committee and its composition.
In addition, the DCGI requested the stakeholders’ to share their inputs to the independent experts advisory committee chaired by Prof. Ranjit Roy Chaudhury along with six other distinguished members namely, Dr V. P. Kamboj, Dr BT Kaul, Dr Vasantha Muthuswamy, Dr Mira Shiva and Dr Uma Tekur, to help formulating policy, guidelines and SOPs for approval of NCEs/NMEs and procedures for CTs, including the conduct of ethics committees, the accreditation of trials sites, inspections of trials sites, the ongoing monitoring of trials and banning of drugs. The Government on February 6, 2013 constituted this Committee.
This decision of the regulator, though under pressure, was praiseworthy. Unfortunately nothing substantially changed on the ground for CTs in India even thereafter, as no substantive action has yet been taken on the above expert committee recommendations.
The report of the experts committee:
Prof. Ranjit Roy Chaudhury experts committee in its 99-page report has reportedly recommended some radical changes in the CT space of India. Among others, the report includes the following:
- Setting up of a Central Accreditation Council (CAC) to oversee the accreditation of institutes, clinical investigators and ethics committees for CTs in the country.
- Only those trials, which will be conducted at centers meeting these requirements, be considered for approval by the DCGI.
- For speedy clearance of applications, a broad expertise based Technical Review Committee (TRC) will replace 12 New Drug Advisory Committees (NDACs), which are currently functioning for NCE/NME approvals.
- The TRC would be assisted, as required, by appropriate subject experts selected from the ‘Roster of Experts’.
- For any Adverse Effects (AEs) or Serious Adverse Effects (SAEs) during a CT, the sponsor investigator will be responsible for providing medical treatment and care to the patient at its/their cost till the resolution of the AEs/SAEs.
- This is to be provided irrespective of whether the patient is in the control group, placebo group, standard drug treatment group or the test drug administered group.
- A Special Expert Committee should be set up independent of the Drug Technical Advisory Board (DTAB) to review all drug formulations in the market and identify drugs, which are potentially hazardous and/or of doubtful therapeutic efficacy.
- A mechanism should be put in place to remove these drugs from the market by the CDSCO at the earliest.
Though some of the above provisions were vigorously objected by the industry during stakeholders’ consultations, the committee in its final report has upheld those recommendations.
The main worry – costs of CTs will go up:
CTs, 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 suggestions, if implemented to create a safety net for the patients participating in CTs, will make these trials more expensive for the concerned companies with increased liability.
Hence, we hear a hue and cry, especially from the pharma MNCs. This is mainly because, India was, thus far, a low cost CT destination for them with virtually no liability for the drug trial patients. This is because, the poor and ill-informed subjects are left in the lurch by many companies exploiting the gaping holes existing in the fragile CT system of the country. After the intervention of the Supreme Court in this regard, some foreign players have reportedly suspended their CTs in India for reasons best known to them.
Exploitation of CT regulations:
The system of CT in India has created a huge ruckus, as it has long been tainted with widespread malpractices, abuses and misuses by many players, both global and local. The issue is not just of GCP or other CT related standards but more of an ethical mind-set and well-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.”
Industry reactions:
Very interestingly, there have been a divergent sets of reactions from the industry on this issue.
An influential section in the CT space of the country has reacted, with gross indiscretion, to the most recent SC order banning CTs for NCEs/NMEs till a robust mechanism in India is put in place.
Commenting on the verdict, an industry leader has reportedly said:
“A black day for Indian science and a sad reflection on our judiciary”.
Such comments probably vindicate much talked about crony capitalistic mindset of this class. They do not hesitate a bit to display their scant respect even to the highest judiciary of the country, leave alone their glaring indifference to the important public health interest related issue. All such actions possibly emanate from the intense greed to protect and further the vested interests, not withstanding the gross injustice being meted out to the drug trial subjects as a consequence.
On the other hand, supporting the Supreme Court’s view, The Indian Society for Clinical Research (ISCR) reportedly has said:
“As a professional organization representing clinical research professionals across the stakeholder spectrum, ISCR is fully supportive of the need for a more robust and regulated environment for the conduct of clinical trials in India which ensures the practice of the highest standards of ethics and quality and where patient rights and safety are protected”.
ISCR further said, “As in every profession and industry, there will always be players who operate at both ends of the spectrum. While we do not condone any irregularities, we must acknowledge, there are several hundreds of clinical trials taking place in the country in compliance with international and local guidelines. There have been over 40 US FDA clinical trial audits done in India with no critical findings reported. There have also been several European regulatory audits of Indian clinical trial sites, again with no critical findings.”
That said, Indian Parliamentary Standing Committee, had commented on a ‘nexus between the industry and the drug regulator’ for continuation of such sorry state of affairs, since long.
‘Industry-pharma nexus’ in the USA too?
Recently, similar tricky relationship between the regulator and the pharma companies was unearthed again with the later paying hefty fees to attend meetings of a panel that advises the US FDA.
The article highlighted, an investigative report in the ‘Washington Post’ found that pharma companies paid as much as US$ 25,000 to attend sessions convened by a scientific panel on painkillers, and has led to claims that the industry was being given an opportunity to influence federal policy in this area.
Expected Government action:
The Supreme Court is expected to hear the matter on October 24, 2013.
Meanwhile, the Ministry of Health reportedly held meetings with concerned officials to chalk out the strategy before the Court, when this case would come up for hearing after two weeks.
The report says, the Government is planning to place before the court a comprehensive plan with details of the existing mechanism and ongoing efforts like, bringing the the new Drugs and Cosmetic (Amendment) Bill 2013 and incorporation of Prof. Ranjit Roy Chaudhury expert committee recommendations, to plug the loopholes in the new drug trial mechanism of the country.
Conclusion:
While the importance of CTs to ensure better and more effective treatment for millions of patients in India is immense, it should not be allowed at the cost of patients’ safety, under any garb. If the regulator overlooks this critical factor and some pharmaceutical players keep exploiting the system, judiciary has no option but to effectively intervene in response to PILs, as happened in this particular case too.
Thus, I reckon, appropriate safety of human subjects participating in CTs and a fairplay in compensation, whenever justified, should be non-negotiable for the indian drug regulator. Despite reactions with indiscretion from a section of the industry, the Supreme Court is absolutely right to direct the DCGI to stop CTs for all NCEs/NMEs until the apex judiciary is satisfied that a robust system is in place for such trials in India. This will ensure, the scientific objectives of the CTs are properly achieved without any compromise on patients’ safety.
Breaking the nexus decisively between a section of the powerful pharmaceutical lobby group and the drug regulator, as highlighted even in the above Parliamentary Committee report, the Ministry of Health should, without any further delay, put in place a robust and transparent CT mechanism in India, come what may.
This well thought-out new system, besides ensuring patients’ safety and fairplay for all, will have the potential to help reaping a rich economic harvest through creation of a meaningful and vibrant CT industry in India, simultaneously benefitting millions of patients, as we move on.
That said, the moot question still remains: Will the drug regulator be able to satisfy the Supreme Court, as the two weeks expire, that appropriate mechanisms are in place to resume smooth conduct of CTs for the new drugs in India?
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.