“In the case of sertindole , an anti-psychotic drug, three experts located at three different places wrote letters of recommendation [to the DCGI] in nearly identical language. And, not surprisingly, all of them used the incorrect full form of DCGI in the address! Is such a coincidence possible unless the person behind the scene who actually drafted the letters is one and the same person?”
“Letters of opinion recommending approval for pirfenidone of Cipla – from a Professor of Pulmonary Medicine, AIIMS, New Delhi, dated 19th June 2010; a Consultant Chest Physician, Lilavati Hospital, Mumbai, dated May 25, 2010; an Additional Professor of Pulmonary Medicine, PGI, Chandigarh, dated 14th June 2010; and a Pulmonologist of Yashoda Hospital, Secunderabad, dated 12th June 2010 – were all received exactly on the same day, July 2, 2010, and diarised by the DCGI office under consecutive references 4877, 4878, 4879 and 4880. Is the Committee mistaken in coming to the conclusion that all these letters were collected by the interested party… and handed over to office of the DCGI on the same day?... it is obvious that the interested party was in the loop in the entire process of consultation with experts.”
Similar were the cases regarding approvals of dapoxetine and nimesulide injection.
In the above particular case, observed the Committee, “to conclude that there is collusive nexus between drug manufacturers, some functionaries of the CDSCO and some medical experts.”
In its submission to the Committee, the CDSCO apparently admitted that it did not have a data bank of experts and that there were no guidelines on how experts were to be identified and opinions sought. Observing that many actions by experts in the above cases are clearly unethical, and in violation of the Code of Ethics of the Medical Council of India (MCI), the Committee has referred the matter to the MCI for necessary follow-up and action. In addition, in the case of government-employed doctors, it has asked the Ministry to take up the matter with medical colleges and hospital authorities for suitable action.
The Committee came across these cases of irregularities when it sought details of the approval process with regard to 42 randomly selected drugs from the list of new drugs put by the CDSCO on its website. The sample size accounted for fewer than 2 per cent of the 2,167 drugs approved by the CDSCO during the period between January 2001 and November 2010. Interestingly, however, the Ministry could not produce documents relating to three controversial drugs – pefloxacin, lomefloxacin and sparfloxacin – on the grounds that their files were untraceable. These were approved on different dates and are currently sold in India. Doubting that the disappearance of the files was accidental, the Committee has asked for a reconstruction, review, and updating of the files on these drugs with new data relating to their safety profile, contra-indications, dosage, and so on. These drugs are not marketed in the United States, Britain, Canada, Australia and other developed countries with well-developed drug regulatory systems.
On examining the remaining 39 cases, the Committee found that in the case of 11 drugs (28 per cent), the mandated Phase III pre-approval clinical trials under the Drugs and Cosmetics Act Rules had not been conducted. The Rules require that, besides specified documentation (such as on pharmacology, toxicology, animal studies and overseas clinical trials), the applicant for new drugs developed outside India should conduct Phase III trials on not fewer than 100 patients at three or four different hospitals in India to test their efficacy and safety for the proposed indication(s). The rationale for Phase III trials before approving any drug of foreign origin is to “determine if there are any ethnic differences that can alter the metabolism, safety and efficacy of the drug when administered to patients of different ethnicities living in India”, the Committee’s report notes.
In the case of two drugs, trials were conducted on just 21 and 46 patients respectively against the mandated requirement of at least 100 persons. In one case, trials were conducted at just two hospitals as against the requirement of three or four sites. In the case of four drugs (10 per cent) – everolimus of Novartis, a drug for the treatment of certain kinds of cancer but known to have side effects; buclizine of UCB Pharma, an unsuccessful antihistamine which has now reappeared in the market as an appetite stimulant; pemetrexed of Eli Lily, an anti-cancer chemotherapeutic agent with side effects; and FDC's pregabalin, a neuropathic drug, with other agents of Theon – not only were the mandatory Phase III trials not conducted but even the opinions of experts were not sought. “The decision to approve these drugs,” says the report, “was taken solely by the non-medical staff of the CDSCO on their own.”
Drugs without licence
The Committee further notes that of the 39 drugs, 13 drugs (33 per cent) did not have a licence to be sold in any of the major developed countries. It points out that none of these has any special or specific medical relevance to India. In 25 cases (64 per cent), opinions of medical experts were not obtained before approval. In the remaining 14 cases, only three or four experts were consulted, far fewer than the usual numbers in countries with well-developed regulatory systems, such as the U.S. “In a country where some 700,000 doctors of modern medicine are in practice, such a minuscule number of opinions is hardly adequate to get diverse views and come to a well-considered rational decision, apart from the possibility of manipulation by interested parties,” observes the parliamentary panel. In the case of drug approvals without trials, the panel has brought out ample evidence for overt and covert manipulation.
According to the report, between January 2008 and October 2010, a total of 33 drugs were approved without clinical trials on Indian patients. The CDSCO seems to have exploited a provision in Schedule Y of the Rules, which allows a waiver of these trials in the “public interest”. Specifically, the Rules say that for drugs that are indicated in life-threatening/serious diseases or diseases of special relevance to the Indian health scenario (but have been approved elsewhere), “the toxicological and clinical data requirement may be abbreviated, deferred or omitted”. But the report notes that the CDSCO could not offer any explanation for what constituted “public interest”. Approving on an average one drug every month without trials cannot be in the “public interest” by any stretch of the imagination, the Committee has commented.
The reasons that the CDSCO gave included “serious disease”, “rare disease status according to the U.S. Food and Drugs Administration” (FDA) and “orphan drug status in Europe and the USA”. (An orphan drug is one that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease.) The Committee, however, was not convinced with the reasons given, and rejected them. The Ministry stated that in cases where Phase III trials were being waived off in the “public interest”, the status of regulatory approval in other countries and opinions from medical specialists in the relevant field were obtained before taking a decision.
Invisible hands
It was while reviewing the expert opinions received by the CDSCO in some random cases described earlier that the Committee realised that not only were an overwhelming majority of recommendations based on personal perception rather than hard scientific evidence or data, but there was adequate documentary evidence to show that many opinions were actually written by the invisible hands of drug manufacturers and there was collusion between the industry, medical experts and the regulatory authorities, with the experts merely obliging by putting their signatures.
The Committee notes that the provision for waiving Phase III trials was perhaps included in the Drugs and Cosmetics Act Rules to expedite the introduction of new drugs in emergency situations such as the outbreak of a new disease like SARS (severe acute respiratory syndrome), bird flu or swine flu when there is no alternative but to take a calculated risk. But, the Committee observes, none of the 33 drugs scrutinised by it fell in that category. Further, most of these drugs had been launched in overseas markets years ago with ample time to conduct trials in India. The Rules also require that in cases where drugs are approved without Phase III trials, post-marketing surveillance data (PMSD) are mandatory, apart from expert opinions. However, according to the report, expert opinion was sought only in five of the 33 cases of drug approval without trials. The Ministry also failed to produce PMSD even for one case out of four randomly selected drugs approved without trials.
The fundamental issue with regard to drug approvals, the report notes, is that without well-laid-down guidelines on when expert opinions are required, too much is left to the absolute discretion of CDSCO officials. The decision to seek expert opinion or not on a new drug lies exclusively with non-medical functionaries of the CDSCO, as a result of which irrational and incorrect decisions are taken that may harm public health, the Committee says. Apart from the waiver of Phase III trials, the Committee has highlighted several other violations of the laws on drug approvals.
When an old drug is approved for a new disorder, it is to be deemed as a new drug and all mandatory requirements for a new drug have to be met. The case of buclizine was mentioned earlier, where an anti-allergic drug was now being marketed as an appetite stimulant in children. Similar is the case of letrozole of Novartis, a drug for breast cancer for use only in post-menopausal women and contra-indicated for women of reproductive age. The DCGI, however, approved the drug in April 2007 for improving female fertility on the basis of Phase III trials on just 55 women by three doctors in private clinics and without meeting the mandatory requirement of Phase II trials for a new drug. Worse still, in this case the company had not even carried out such trials abroad as it did not envisage such new use for the drug elsewhere! Belatedly, however, the drug has now been banned for use in female fertility.
There are several other instances of approvals in violation of regulations. For placenta extract gel, the CDSCO went out of its way to unlawfully and wrongly certify in writing that it was not a new drug and cleared it for a large number of indications. Nimesulide was approved in India in 1996 for use in children of 0-12 years without any trials being conducted. Even though, following deaths due to liver injury in Europe, the drug was banned nearly seven years ago, it continued to be sold in India until February 2011, when a media outcry led to an inquiry and it was banned.
A major and long-standing concern in India is that drugs that are withdrawn or banned abroad are available here. For example, the anti-diabetic drug phenformin was available for over 30 years after it was banned abroad in the 1970s because of unacceptable side effects, until the Delhi High Court intervened and ordered its withdrawal in 2003. Similar is the case of the pain-killer analgin, which has been withdrawn in a large number of countries following the finding, in the 1970s, that it has serious and potentially fatal side effects, but continues to be marketed in India. There are several other examples, and in each of them the ban is enforced rather belatedly, and that too as a result of a media outcry or court orders or some expert committee decisions.
Regulatory failure
The availability of many Fixed Dose Combinations in the Indian market is another area of regulatory failure. When two or more drugs, already approved individually, are combined for the first time as an FDC formulation, the product is deemed to be a new drug under the Indian law and therefore has to undergo clinical trials (all phases) and satisfy other regulatory requirements. And once an FDC is approved by the CDSCO, manufacturers can obtain manufacturing licences from State Drug Authorities.
There have been several irregular approvals of FDCs at the level of the CDSCO itself. Besides the two cases mentioned earlier, perhaps the most serious one is that of a drug called Deanxit (an FDC of flupenthixol and melitracen). Interestingly, the CDSCO failed to produce any documents on the regulatory process followed in approving this drug, which should not have been approved for two reasons. Melitracen had never been approved in India before and a combination (even if the ingredients had been individually approved) is considered a new drug and so must undergo all three phases of trials. But there was a violation on another count as well. The drug is prohibited for sale in the country of its origin, Denmark, and Rule 30-B of the Indian law prohibits import and marketing of any drug not approved in the country of its origin.
There have also been many cases of State authorities granting manufacturing licences for FDCs even before CDSCO approval. The Drugs and Cosmetics Act provides for directives to the States by the Centre under Section 33P or a direct ban by the Centre under Section 26A. But the CDSCO or the government has never invoked these provisions to remove from the Indian market unauthorised FDCs that can be harmful, the report points out. The Committee has expressed grave concern over such serious shortcomings in Centre-State coordination in the implementation of the Drugs and Cosmetics Act and the Rules.
In the wake of this Parliamentary Standing Committee’s report, an expert committee – comprising V.M. Katoch, Secretary and Director-General, Indian Council for Medical Research (ICMR); P.N. Tandon, president, National Brain Research Centre, Manesar, Haryana; and S.S. Aggarwal, former Director, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow – has been asked to examine the validity of the scientific and statutory basis adopted for approval of new drugs without clinical trials, outline appropriate measures to bring about systemic improvements in the processing and grant of statutory approvals, and suggest steps to institutionalise improvements in other procedural aspects of the CDSCO’s functioning. The Committee has been asked to submit its report within two months. Further action will be taken on the basis of this committee’s report.
The Parliamentary Standing Committee itself has made several recommendations with regard to drug trials and new drug approvals. Phase III trials, it has said, should be approved only after the DCGI has ensured the availability of facilities and the trials should be spread across the country so that the sample is truly representative. It has recommended that trials should be conducted in well-equipped medical colleges and large hospitals with research expertise and 24x7 emergency services, and not in private clinics.
Given India’s large population and its enormous ethnic diversity, unlike in most Western countries, the question of increasing the minimum number of subjects in Phase III pre-approval clinical trials should be accorded a certain urgency, the Committee has said. Since the major objective is to determine the applicability or otherwise of the data generated abroad to the Indian population, it has stressed the need to ensure that sites selected for trials are able to cover diverse ethnic groups. Even for indigenously developed drugs, the number of trial subjects should be increased by bringing about changes in the norms of Good Clinical Practice (GCP), it has said.
The Committee has also called for well-laid-down guidelines for the selection of outside experts with emphasis on expertise in the specific therapeutic area including published research, instead of the CDSCO choosing them arbitrarily on the basis of hierarchy. It has also emphasised that experts should give hard evidence to support their recommendations and should also file a “Conflict of Interest” declaration. The Ministry informed the Committee that 12 new and permanent specific subject-oriented Drug Advisory Committees (DACs), each with 10 experts, were being constituted to provide technical inputs and advise the CDSCO in examining applications for new drugs. However, the Committee expressed its reservations as the procedure for selection of the experts was not transparent enough.
The Committee also considered the more basic issues affecting the functioning of the CDSCO, including the lack of technical and administrative infrastructure and human resources to handle India’s huge pharmaceutical market.
More than 10,500 drug manufacturers with an estimated turnover of over Rs.50,000 crore from domestic sales alone operate in the country. The pharmaceutical industry, the Ministry told the Committee, was growing at the rate of about 10 per cent and the workload of the CDSCO was increasing at the rate of 20 per cent a year, with no corresponding rise in the required human resources and infrastructure. Endorsing this, the Committee has also expressed serious concern that the CDSCO is substantially understaffed. Calling for urgent redress, the Committee has said that if the human resource available to the CDSCO is not proportionate to its volume of work, it will not be able to discharge its regulatory functions efficiently.
“Strengthening of drugs regulatory mechanisms cannot be achieved by human resource augmentation alone,” the Committee has said.
It has underlined the importance of capacity building in the organisation by setting up new offices, creating new drug-testing laboratories and equipping them with state-of-the-art technology, upgrading the existing six Central Drug-testing Laboratories, developing the skills of the regulatory officials, implementing an effective pharmacovigilance programme and increasing transparency in decision-making at the CDSCO. The Committee has also recommended that the Ministry should work out a Centrally sponsored scheme for improving the infrastructure and human resource at the State level, given the paucity of resources in States.
It must be pointed out that many of these recommendations for upgrading and strengthening the CDSCO are not new. They were made by the Mashelkar Committee in 2003. Specifically, it had called for a Central Drug Administration (CDA), a national umbrella body to coordinate regulatory functions at the Central and State levels. In November 2011, a High Level Expert Group constituted by the Planning Commission also endorsed the idea of an umbrella regulatory body called the National Drug Regulatory and Development Authority. The government failed to realise the importance and urgency of those proposals and act upon them. The Parliamentary Committee has only reiterated and reinforced them.
But, at a more fundamental level, there is an anomaly in the CDSCO’s organisational structure and an apparent contradiction between its mandated functions and its mission statement, which need to be corrected first. The minimum qualification for the post of the DCGI is only a B.Pharm “with a minimum 5-year experience in the manufacture or testing of drugs or enforcement of the provisions of the Drugs Act”. This is greatly in contrast with the qualifications required of the heads of the regulatory bodies in the U.S. and the the United Kingdom. The Indian requirement, the Committee has observed, virtually excludes qualified medical doctors from occupying the post of the DCGI. On the other hand, the Deputy Drug Controller (DDC) has to be a postgraduate in the field of medicine. Because of this, the Committee has observed, highly qualified medical doctors may be reluctant to work under a higher officer with lesser qualification.
Pro-industry bias
More pertinently, the CDSCO’s mission statement is itself skewed in favour of the industry. Its mission, according to a report of the Ministry, is to “meet the aspirations… demands and requirements of the pharmaceutical industry”. This is in sharp contrast to the public health centric mission statements of the U.S.-FDA and the Medicine and Health regulatory Authority (MHRA) of the U.K. “Most of the ills besetting the system of drugs regulation in India are mainly due to the skewed priorities and perceptions of the CDSCO. For decades together it has been according primacy to the propagation and facilitation of drugs industry, due to which, unfortunately, the interests of the biggest stakeholder, the consumer, has never been ensured,” the Committee has said. So the CDSCO has to first reformulate its mission perspective, which must be to protect the interests of public health, before it looks to reform its other aspects.
