In what is probably a first of its kind report in independent India, the Parliamentary Standing Committee on Health & Family Welfare has tabled before Parliament a unanimous, damning report on the state of drug regulation in India and the manner in which it severely compromises the safety of Indian patients. The 118 pages report which is exhaustive, thoroughly researched and cross-referenced, and at times forensic in its examination of the evidence before it, raises very serious issues of subversion of Indian drug regulatory laws by the Drug Controller General of India and several pharmaceutical companies, both Indian and international pharmaceutical companies. The report can be accessed on the website of Parliament over here.
The international companies indicted by the report are Novartis, Phamasset Inc. (a subsidiary of Gilead), Lundbeck, Bayer, UCB, Eli Lilly, GlaxoSmithKline, Sanofi, Merck, Ranbaxy & Pharmacia (acquired by Pfizer). The Indian companies indicted by the report are Cipla, Sun Pharmaceuticals, Themis, Theon, Centaur, Venus, Emcure, Hetero, Macleods and Mars.
Before proceeding any further, let me clarify that the report does not pertain to the standards of manufacture at the plants of either Indian or international companies. The Report instead focuses on the manner in which regulatory approvals are sought for marketing of drugs for the Indian market and how the DCGI and the Central Drug Standards Control Organization (CDSCO) have failed to enforce the law either through collusion or blatant negligence. The problems highlighted herein are thus unique to the Indian market and this report should not be used to question the quality of Indian exports to foreign markets.
Listed below is a very brief summary of the numerous issues raised by the Parliamentary Standing Committee:
(i) The role of the CDSCO in drug regulation: While the statutory head of the Indian drug regulatory system is the Drug Controller General of India, setup under the Drugs & Cosmetics Act, 1940, the organization that he heads is called the Central Drug Standards Control Organization (CDSCO). The first target of the Standing Committee’s report is the CDSCO itself.
In pertinent part the report states: 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.
This one statement of the Committee accurately identifies the core problem of regulation of the Indian drug industry. The entire legal and regulatory framework has been setup to serve the industry and not the patient.
(ii) The lack of local clinical trials for new drugs: This is one of the most serious issues raised by the Report. I’ve discussed this problem earlier in the context of the data exclusivity debate. To briefly recount the main issue: Rule 122 and Schedule Y of the Drugs & Cosmetics Act, 1940 requires all new drugs being introduced in the Indian market to undergo local Phase III clinical trials on at least 100 patients, in order to prove their safety and efficacy on the Indian population. The reason for this requirement is that different patient populations react differently to the same drugs. In pertinent part the Parliamentary report states the following:
The basic purpose of Phase III trials is to determine if there are any ethnic differences that can alter the metabolism, efficacy and safety of the drug when administered to patients of different ethnicities living in India (such as Indo-Aryans, Dravidians, Mongoloids, Tribals etc.). There is evidence that the effect of some drugs can vary among various ethnic groups. For example, the blood levels reached after intake of lipid lowering agent rosuvastatin are far higher in Asians, compared to Europeans and North American Caucasians, Hispanics and Blacks needing lowering of dosage. Failure to lower dose in Indians can result in severe toxicity, including life-threatening muscle injury leading to fatalities. Hence, testing drugs in the Indian ethnic groups is of paramount importance before approving any drug of foreign origin.
The proviso to Rule 122A however allows the DCGI to waive this requirement in ‘public interest’. In pertinent part the proviso states the following: “Provided that the requirement of submitting the results of local clinical trials may not be necessary if the drug is of such a nature that the Licensing Authority may, in public interest decide to grant such permission on the basis of data available from other countries.”
When I had written about this issue earlier, I was unable to access any information on whether the DCGI was waiving these trials or whether it was demanding information on local clinical trials. A part of the reason for this lack of information is that hardly anybody in India does any independent research on the drug regulatory systems. The other reason is because the DCGI has pretty much exempted itself from the RTI Act. The Parliamentary Standing Committee Report however has damning evidence on how the DCGI has constantly invoked the proviso to Rule 122A to simply waive the requirement for local clinical trials on the basis of ‘public interest’. Of the 39 drug approvals scrutinized by the Committee, it found the following shortcomings:
In the case of 11 drugs (28%) Phase III clinical trials mandated by Rules were not conducted. These drugs are i, Everolimus (Novartis), ii. Colistimethate (Cipla), iii. Exemestane (Pharmacia), iv. Buclizine (UCB), v. Pemetrexid (Eli Lilly), vi. Aliskiren (Novartis), vii. Pentosan (West Coast), viii. Ambrisentan (GlaxoSmithKline), ix. Ademetionine (Akums), x. Pirfenidone (Cipla), and xi. FDC of Pregabalin, Methylcobolamine, Alpha Lipoic Acid, Pyridoxine & Folic Acid (Theon);
In the case of 2 drugs (Dronedarone of Sanofi and Aliskiran of Novartis), clinical trials were conducted on just 21 and 46 patients respectively as against the statutory requirement of at least 100 patients;
In one case (Irsogladine of Macleods), trials were conducted at just two hospitals as against legal requirement of 3-4 sites;
In the case of 4 drugs (10%) (Everolimus of Novartis; Buclizine of UCB; Pemetexid of Eli Lilly and FDC of Pregabalin with other agents), not only mandatory Phase III clinical trials were not conducted but even the opinion of experts was not sought. The decision to approve these drugs was taken solely by the non-medical staff of CDSCO on their own;
When the Parliamentarians questioned the Health Ministry the basis for determining ‘public interest’ in waiving local clinical trials, they were not provided with a reasonable answer.
In conclusion to this point the Standing Committee made the following recommendation:
The Committee is of the view that taking into account the size of our population and the enormous diversity of ethnic groups there is an urgent need to increase the minimum number of subjects that ought to be included in Phase III pre-approval clinical trials to determine safety and efficacy of New Drugs before marketing permission is granted. In most western countries the required numbers run into thousands. However since the major objective in India is to determine the applicability or otherwise of the data generated overseas to Indian population, the requirement should be re-assessed and revised as per principles of medical statistics so that major ethnic groups are covered. A corresponding increase in the number of sites so as to ensure a truly representative sample spread should also be laid down in black and white. Furthermore, it should be ensured that sites selected for clinical trials are able to enroll diverse ethnic groups. For domestically discovered drugs, the number of subjects should be revised as well. This can be easily achieved by changes in the Good Clinical Practice (GCP) guidelines.
While the above recommendation of the Standing Committee is very pertinent, the Government needs to explain how and why pharmaceutical companies are going to conduct such trials in India without a proper ‘data exclusivity’ law. Why will pharmaceutical companies who lack patent protection in India, invest money in conducting local clinical trials when their competitors are entitled to use their data without paying them any money?
(iii) The missing files from the CDSCO: When the Standing Committee decided to scrutinize the drug approvals granted by the CDSCO, it randomly picked 42 drugs for scrutiny. Of these 42 drugs, the Ministry could not provide the files for 3 drugs (pefloxacin, lomefloxacin and sparfloxacin) on the grounds that the files were untraceable. The Committee then makes the following stinging observation: All these drugs had been approved on different dates and different years creating doubt if disappearance was accidental. Strangely, all these cases also happened to be controversial drugs; one was never marketed in US, Canada, Britain, Australia and other countries with well developed regulatory systems while the other two were discontinued later on. In India, all the three drugs are currently being sold.
(iv) Marketing drugs not marketed anywhere in the world: Another major issue raised by the Standing Committee is on how drugs not marketed anywhere else in the world are still sold in India. In pertinent part the Committee notes:
Of the cases scrutinized, there were 13 drugs (33%) which did not have permission for sale in any of the major developed countries (United States, Canada, Britain, European Union nations and Australia). None of these drugs have any special or specific relevance to the medical needs of India. These drugs are: i. Buclizine for appetite stimulation (UCB); ii. Nimesulide injection (Panacea); iii. Doxofylline (Mars) iv. FDC of Nimesulide with Levocetirizine (Panacea); v. FDC of Pregabalin with other agents (Theon); vi. FDC of Tolperisone with Paracetamol (Themis); vii. FDC of Etodolac with Paracetamol (FDC); viii. FDC of Aceclofenac with Thiocolchicoside (Ravenbhel); ix. FDC of Ofloxacin with Ornidazole (Venus), x. FDC of Aceclofenac with Drotaverine (Themis); xi. FDC of Glucosamine with Ibuprofen (Centaur); xii. FDC of Diclofenac with Serratiopeptidase (Emcure) and xiii. FDC of Gemifloxacin with Ambroxol (Hetero).
As you will note that apart from UCB, the major defaulters in this segment are Indian companies.
(v) The ‘invisible hand’ behind expert medical opinions: While scrutinizing drug approvals the Committee shockingly discovered that most of the expert opinions provided by so called independent doctors were ‘personal’ in the sense that they were not backed by any hard scientific evidence or data. The most damning revelation however is the evidence which indicates that some of the medical opinions were written by drug manufacturers and the medical experts merely affixed their signatures on those opinions without applying their minds. The Committee identified 8 such instances of the ‘invisible hand’ where supposedly independent doctors situated thousands of kilometres apart from each other provided the DCGI with identical opinions and in some cases they even had the same mistakes such as the wrong address of the DCGI. Further, several of these opinions despite being written by individual doctors on different dates were all received by the DCGI on the same date indicating that the opinions were delivered to the CDSCO together by one individual. These approvals involved the following companies: Phamasset Inc., Lundeck, Bayer, Cipla, Mars, Akums, Pancea.
In pertinent part the Committee notes A review of the opinions submitted by the experts on various drugs shows that an overwhelming majority are recommendations based on personal perception without giving any hard scientific evidence or data. Such opinions are of extremely limited value and merely a formality. Still worse, there is adequate documentary evidence to come to the conclusion that many opinions were actually written by the invisible hands of drug manufacturers and experts merely obliged by putting their signatures…………… Is the Committee mistaken in coming to the conclusion that all these letters were collected by interested party from New Delhi, Mumbai, Chandigarh and Secunderabad and handed over to office of the DCGI on the same day? If so, it is obvious that the interested party was in the loop in the entire process of consultation with experts. (Annexure 6)………….It is inconceivable that a letter dated 17-6-2005 from New Delhi will be delivered to the office of DCGI also in New Delhi after more than two months. The conclusion, as in aforementioned cases, is obvious.
The one approval which really ‘outraged’ the Committee was the case of approval of a FDC manufactured by Themis Medicare Ltd. Apparently not only did the DCGI ask Thermis Medicare Ltd. to select experts but also get their opinions and deliver it to the DCGI!
The Committee recommended strict action against the pharmaceutical companies and the doctors involved in these approval and also ordered the CDSCO to put in place mechanisms to ensure the selection of independent medical experts. While concluding this portion of the report the Committee notes: There is sufficient evidence on record to conclude that there is collusive nexus between drug manufacturers, some functionaries of CDSCO and some medical experts.
Conclusion: The contents of this post cover only about 50% of the issues raised by the 118 page report of the Parliamentary Standing Committee. There are several more interesting issues raised by the Committee which I’ll hopefully cover in a later post.