In a random scrutiny, the Parliamentary Standing Committee on Health has found that as many as 33 drugs were approved without clinical trial on Indian patients by the Drug Controller General of India (DCGI), during the period of January 2008 to October 2010.

“According to information provided by the Ministry, a total of 31 new drugs were approved in the period January 2008 to October 2010 without conducting clinical trials on Indian patients. The figure is understated because two drugs 29 (ademetionine and FDC of pregabalin with other ingredients) were somehow not included in the list.  Thus there is no scientific  evidence to show that these 33 drugs are really effective and safe in Indian patients,” said the report which is likely to create ruckus in the coming days.

In order to scrutinize new drug approvals, the Committee sought details [sponsors; pre-approval phase III clinical trials; overseas regulatory status in US, Canada, Britain, Australia and European Union; indications; names of experts if  consulted and Post-Marketing Safety Update Reports  (PSURs)] in respect of  randomly selected 42 medicines from the list of new drugs uploaded by CDSCO on its website.  Of these, 38 drugs were approved in the years 2004 to August 31, 2010; one drug had been approved earlier in 2001. Three drugs had been approved earlier in mid 90s. In all DCGI had approved 2,167 drugs in the period January 2001 to 30-11-2010. Thus the sample size for random scrutiny was less than 2 percent, said the panel headed by Brajesh Pathak report said.

``Out of 42 drugs picked up randomly for scrutiny, the Ministry could not provide any documents on three drugs (pefloxacin, lomefloxacin and sparfloxacin) on the grounds that files were non-traceable. 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. It is not possible to monitor if manufacturers  are abiding by the conditions of approval viz. indications, dosage, contraindications, precautions etc. Updation of product monographs and safety information in the light of recent developments is also not possible putting patients at risk. Before being withdrawn, major changes in safety profile, including Black Box Warnings (meant to draw attention to serious side effects), were incorporated to the prescribing guidelines of the two drugs sold in the United States but later withdrawn from the market,’’ the report said.

Excerpts from the Report:

7.14   On scrutiny of 39 drugs on which information was available, the Committee found the following shortcomings:

• In the case of 11 drugs (28 per cent) 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, ethylcobolamine, 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 per cent) (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.

• Of the cases scrutinized, there were 13 drugs (33 per cent) 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 28 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).

• In the case of 25 drugs (64 per cent), opinion of medically qualified experts was not obtained before approval.

• In those cases (14 out of 39 drugs), where expert opinion was sought, the number of experts consulted was generally 3 to 4, though in isolated cases the number was more. In a country where some 700,000 doctors of modern medicine are in practice such a miniscule number of opinions are hardly adequate to get diverse views and come to a well considered rational decision apart from the possibility of manipulation by interested parties. As against this, to review just the dose of popular pain-killer paracetamol, the United States Food and Drug Administration (US FDA) constituted a panel of 37 experts drawn from all over the country. After extensive debate 20 members sought ban on the combination of paracetamol with narcotics (17 opposed), 24 members sought reduction of dose from 500mg to 325mg (13 opposed) and 26 members advised to make high dose (1000mg) formulation a prescription only medicine (11 opposed). The voting pattern shows independent application of mind by each member. The opinions and decisions are in public domain (website of US FDA) so that anyone is free to scrutinize, offer comments and give suggestions. In India, every discussion and document is confidential away from public scrutiny. This matter needs to be reviewed to ensure safety of patients, fair play, transparency and accountability.

7.15   Unless there is some legal hitch, the Committee is of the view that there is no justification in withholding opinions of experts on matters that affect the safety of patients from public. Consideration should be given to upload all opinions on CDSCO website.

7.16   According to information provided by the Ministry, a total of 31 new drugs were approved in the period January 2008 to October 2010 without conducting clinical trials on Indian patients. The figure is understated because two drugs 29 (ademetionine and FDC of pregabalin with other ingredients) were somehow not included in the list.  Thus there is no scientific  evidence to show that these 33 drugs are really effective and safe in Indian patients.

7.17   The Ministry explained that under the rules, DCGI has the power to approve drugs without clinical trials in “Public Interest.” No explanation is available as to what constitutes Public Interest. How can approvals given to foreign drugs without testing on Indians be in Public Interest? Some of the reasons given for irregular approvals are: “Serious disease” (all the more reason to conduct clinical trials to ensure that patients in India really benefit from such imported, exorbitantly expensive drugs), “Rare disease status according to United States Food and Drugs Administration” (How can US FDA decide which is rare disease in India?), “Orphan drug status in Europe and USA” (There is no provision in Indian laws to give special treatment to such foreign drugs).

7.18  When asked about the reasons for approving New Drugs without clinical trials, the Health Secretary, during the course of oral evidence, stated that approval of new drugs without phase-III clinical trials in “public interest” was being done with the support of technical advice.  Explaining about the basis for deciding to waive off the condition of local clinical trials for manufacture/import of new drugs, the Ministry stated that the Drugs and Cosmetics Rules do not prescribe specific situation under which clinical trial exemption can  be granted due to “public interest”.  However, the DCGI can abbreviate, defer or omit the toxicological and clinical data requirements for drugs meant for life-threatening/serious diseases and diseases of special relevance to Indian health scenario.  It was further claimed that in such cases status of regulatory approval of the said drug in other countries and opinion from the medical specialists of the relevant field is obtained for taking decision.  Further, the marketing approval is conditional to applicants submitting post-marketing surveillance data.

7.19   In cases where foreign drugs were approved without clinical trials in the country, the Ministry offered the following explanation:  “Most of the drugs are approved in other countries based on multinational clinical trials…. on various ethnic/racial populations” implying that Indians would be included and hence conducting trials in India was not necessary. However, this presumptive remark is not accompanied by 30 any evidence. The interest is in those ethnicities  that live in India, not Slavs, Caucasians, Hispanics and Negroes. The information in the Status Note on the very first drug of a total of 31 in the list of new drugs permitted in “public interest” without clinical trials, daptomycin, shows that pre-approval studies conducted by the American innovator recruited just 558 patients  in United States, South Africa, Europe, Australia and Israel. There is absolutely no evidence of major ethnic groups of India being enrolled in these small trials.

7.20   It would appear that the intention of those who framed the Act and Rules was to leave a small door ajar for entry of new drugs without undergoing trials in serious emergency situations such as epidemic of a new hitherto unknown disease (e. g. SAARS, Bird Flu or Swine flu) where there may not be time enough to test new drugs and there is no alternative but to take calculated risk. None of the 33 drugs fall in this category of emergency treatments. Besides many drugs were launched in overseas markets years ago with ample time to conduct trials in India.  The following are some examples:

• Daptomycin (Cubicin) of Novartis was launched overseas on 13-9-2003 and approved in India on 28-1-2008 after a gap of over four years. There was no tearing hurry to approve the drug without trials.

• Pemetrexed (Alimta) of Eli Lilly was approved on 5-2-2004 in the United States. After a gap of more than two years, it was approved by DCGI on 28-6-2006 without trials. There was more than adequate time to conduct phase III trials in India and yet undue favour was shown to the manufacturer.

• Raltegravir (Isentress) of Merk Sharp and Dhome was launched abroad on 12-10-2007 and approved in India on 27-01-2010 without conducting clinical trials even though there was adequate time to conduct mandatory clinical trials.

7.21 Such irregular approvals spare drug producers the cost and efforts but put Indian patients at risk. On an average DCGI is approving one drug every month without trials. This cannot be in public interest by any stretch of imagination. Moreover it was stated that in such cases (i) expert opinion is sought and (ii) Post Marketing Surveillance Data is mandatory.

• However a look at the information on approvals given by DCGI shows that expert opinion was sought in only 5 of 33 such out-of- the-way approvals.

• With regard to Post-Marketing Surveillance data, the Ministry failed to provide even one out of randomly selected 4 drugs approved without trials.

7.22   As stated earlier, the very purpose of phase III trials is to determine any ethnic/racial differences in the safety, efficacy and metabolism of drugs. Hence to serve any useful purpose, patients of different ethnicities living in India should be enrolled. For example, the results of a trial conducted only on Indo-Aryans may not be applicable to Mongoloids or Dravidians due to genetic differences.