More Regulatory Rigour on the cards

In the past year, the pharmaceutical sector seems to have attracted more than its fair share of attention from the Supreme Court (SC) of India, be it the finalising the drug pricing policy or conducting clinical trials in the country. While it is perusing the pricing policy finally released by the Group of Ministers, the SC seems as determined to keep an eagle eye on the conduct of clinical trials of drugs in the country.

A public interest litigation (PIL) filed in February last year by NGO Swasthya Adhikar Manch, Indore alleged illegal and unethical drug trials involving mentally challenged patients at the MGM Medical College in Madhya Pradesh.

While hearing its PIL, alleging malpractices in clinical trials by Government and non-Government as well as by independent investigators, the SC in its order dated October 8, 2012 had asked either the Secretary, Ministry of Health and Family Welfare (MoH&FW), Government of India or Central Drugs Standard Control Organisation (CDSCO) through Director General of Health Services, Government of India to submit information, from January 2005 to June 2012, on the number of clinical trials approved, number of deaths, if any, recorded during the trials, the number and nature of side effects recorded and compensation, if any, paid to the victims or their family members. The SC’s most recent missive was on January 3 when it ordered that an additional affidavit filed by the Deputy Drugs Controller (India) in the CSDCO in response to its October 8 order, should be disregarded as it should have been filed by either the Secretary, MoH&FW, Government of India or CDSCO through Director General of Health Services, Government of India. The SC has now given these authorities four weeks to file this information. Meanwhile it has accepted the application filed by Siddharth Luthra, Additional Solicitor General that until further order by this Court, clinical trials of new chemical entity shall be conducted strictly in accord with the procedure prescribed in Schedule ‘Y’ of Drugs & Cosmetics Act, 1940 under the direct supervision of the Secretary, Ministry of Health and Family Welfare, Government of India.

Damning data

As per available data in public domain, the number of serious adverse events (SAEs) resulting in deaths during clinical trials reported in the last three years viz. 2010, 2011 and up to June 2012 were 668, 438 and 211 respectively. However, of these deaths and basis data available with the DCGI, 22 and 16 in 2010 and 2011 respectively were deemed to be due to clinical trials while the rest were found to be due to other concurrent conditions including a natural progression of the disease which is often the case when the subjects were cancer patients, a new illness that patient may have developed, age related disorders or a complication totally unrelated like an accident.

Ghulam Nabi Azad, Minister for Health and Family Welfare had presented the findings of the 59th Report of the Parliamentary Standing Committee on the functioning of the CDSCO to the Rajya Sabha which has raised various issues pertaining to the functioning of the organisation, including alleged approval of drugs without clinical trials. In response to the outcry from parliamentarians as well as health activist groups, the Government constituted a three member expert committee on May 11, 2012 to examine the issues raised by the Parliamentary Committee. The expert committee comprising Dr VM Katoch, Secretary (Department of Health Research) and Director General, ICMR, Dr PN Tandon, President, National Brain Research Centre, Department of Biotechnology, Manesar and Dr SS Aggarwal, former Director, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow submitted their report and Azad indicated that it is under consideration.

A consultative approach

The regulators seem to have adopted a consultative approach, at least on some fronts. Take for example guidelines on compensation to be given to subjects who suffered SAEs or died during clinical trials. On August 3, 2012, the CDSCO put up its guidelines for compensation, compiled in consultation with representatives of industry bodies like the ISCR (Indian Society for Clinical Research), etc. asking for recommendations and suggestions from the public. The guidelines sought to determine quantum of financial compensation to be paid in case of clinical trial related injury or death as well as determine when an SAE or death could be considered trial-related.

In a follow up to the above move, the DCGI’s office had issued an another order dated August 16, 2012, which placed more emphasis on informed consent forms (ICF) highlighting that what ought to be valued was the process. It directs the ethics committee (EC) to “exercise particular care to protect the rights, safety and well being of all trial subjects”. The August 16 order requested all ECs involved in clinical trials in India to “keep vigil on clinical trials being conducted under their jurisdiction”. Further it allows EC members to make surprise visits (to sites where the trial is being conducted) to ensure that the clinical trial is being conducted as per schedule ‘Y’, GCP guidelines and other applicable regulations.

On December 12, the DCGI issued an another order which addressed all concerned, including ECs and also marked copies to all zonal and sub-zonal offices of CDSCO and State and Union Territory Drugs Control Authorities, to play a watchdog role when it came to approving clinical trial protocols and monitoring ongoing clinical trials in their jurisdiction.

Though there was no direct communication between the DCG(I)’s office to the State and Union Territory Drugs Control Authorities, the fact that they have been copied did not escape the notice of industry observers who pointed out that Madhya Pradesh state authorities had sought to absolve themselves of responsibility for the alleged illegal and unethical drug trials involving mentally challenged patients at the M G M Medical College in Madhya Pradesh, on the grounds that the trials were approved by the DCG(I)’s office at the Centre.

This order was a follow up to the points discussed at the 44th meeting of the Drugs Consultative Committee (DCC) held on July 20, 2012. In the inaugural deliberations, Sanjay Prasad, Director, Ministry of Health and Family Welfare made the point that the drug regulatory frame work at both the Centre and State levels is an important part of healthcare system.

Confirming this stance, while commenting on the CDSCO order dated December 12, Dr GN Singh, DCG(I) said, “As we have issued copies of this letter to State and Union Territory Drugs Control Authorities as well, it is equally their responsibility to keep an eye on clinical trial activities in their territories.”

Industry reactions

Dr S M Sapatnekar

Analysing the situation, Dr SM Sapatnekar, Medical Director, Karmic Lifesciences, a Mumbai-based CRO, points out that since August 2012, there has been a spate of notices and orders from the office of DCGI. “With mass media outcry on unethical practices, observations of the parliamentary committee and displeasure of the Supreme Court of India, some action from the DCG(I) was anticipated. However, what is notified (and is expected to be enforced) does not seem to be either effective or specific. At their best, these notices and orders are reiterative. At their worst, these are open to contest in the courts on interpretation of statute,” he avers.

Sapatnekar opines, “The order tries to ensure that clinical trials conducted in the country are conducted strictly in accordance with Schedule ‘Y’ etc. How that is to be attained is left to imagination. While keeping vigil, if an EC member comes across what is a permissible deviation or objectionable default, the order makes it binding to alert the DCG(I) and take remedial measures too! Is this possible and is this done? There are doubts.”

Suneela Thatte

Suneela Thatte, President, Executive Director, Customer Operations, Quintiles Research (India) a CRO headquartered out of Bangalore, says, “The order from the DCG(I) appears to serve as a reminder to ECs of their role in according and approving clinical trial protocols and reiterates their responsibility in safeguarding the rights and safety of patients. The contents of the two orders are not in any variance with what is currently laid down in policies and guidelines that govern the conduct of clinical trials in the country.”

The overall impression seems to be that the DCG(I)’s office would like ECs and their members to take a more proactive rather than passive and reactive stance. But this raises other issues.

Dr Arun Bhatt

For example, Sapatnekar asks, “Do we expect even the mandatory “lay person” and “philosopher” on the EC to keep vigil befitting Schedule ‘Y’ and GCP guidelines? ‘Specificity’ is an important quality of an order; the wording “and applicable regulations” makes it vague. It also raises practical questions. If the EC keeps an “active vigil” it will be carrying out an executive function. In such a case, will the EC act as an auditor? If so, on whose behalf? Who will decide on a surprise visit? What is the statutory force for entry to and inspection of the clinical sites? What happens to confidentiality of patient identity? Also, he points out that since the copy is marked to zonal and sub-zonal offices of CDSCO, a question arises about undefined relationship of EC members vis-à-vis the CDSCO. Dr Arun Bhatt, President of Mumbai-based CRO Clininvent Research too comments that while the December 12 order mandates monitoring of compliance to Schedule Y/GCP, this would require inspection of the clinical trial sites. As per the inspection guidelines released by CDSCO, CDSCO HQ will issue instruction to the CDSCO Officers/ Inspectors to conduct the inspection. Hence, its not clear what is the role of state drug control authorities vis—vis new order, he concludes.

Thatte highlights, “It is not clear from the order what, if any, role is to be played by local drug control authorities within States and Union Territories as they have only been copied on the Order. I believe we will need to wait for more clarity from the DCG(I)’s Office on this.”

She feels that at a time when the DCG(I)’s office is serious in its intent to tighten the regulatory environment, it is unlikely that the DCG(I) will expect local drug authorities to take on additional responsibility without providing them the resources, both in terms of manpower and expertise.

Thatte points out that there have been questions raised in the past on the role (or lack of) of State and Union Territory drug authorities in clinical trials. Perhaps by copying the order to these authorities, the DCGI expects them to have some oversight of trials in their respective states but again one cannot deduce this from the orders. “However, in the long run, it would be good to have State and Union Territories’ drug authorities more involved in clinical trials in their respective regions even if it were only to provide oversight,” she concludes. The flurry of directives from the DCG(I)’s office as well as critical oversight from the highest court in the land combined with activist NGOs, seems to have put the clinical research industry in India on the defensive.

But of more serious concern is the fact that the industry, specifically CROs, have been left guessing as to the roles of state and centre, as well as the newly envisaged role for EC members. It is clear that 2013 will see more action on this front as regulators try to finetune regulations and responsibilities and industry tries to interpret the new lay of the land.

[email protected]