Friday, April 25, 2014

A damning indictment of drug regulation in India - How the CDSCO handled new drug approvals

(This post is the second part of a series examining the functioning of India's drug regulatory authority, the CDSCO).

Having examined the mandate, organization structure and operational procedures of the CDSCO, the Committee moved on to investigate one of the most important activities the CDSCO undertakes - New Drug Approvals. In order to do so, the CDSCO was asked to provide detailed reports on 42 new medicines that had received their approval - a mere 2% of all drugs approved by them from January 2001 to October 2010. And this is where things started to get very murky indeed.

Three of the drugs on the list (pefloxacin, lomefloxacin and sparfloxacinhappened to be somewhat controversial, having either never been marketed in Western countries, or withdrawn from the market due to serious side effects. They are still sold in India. Naturally, one would expect a higher level of monitoring of these medications. Instead, the Ministry had no files for them at all. That's right, nothing. In government-speak, the files were "untraceable". So there is no record of how such controversial drugs got approved, what kind of safety profile they had with regards to the Indian population, and whether any adverse effects were reported in clinical trials, if they were performed at all.

Things were not much better for the remaining 39 drugs either, with a litany of missing or poorly performed studies. In contravention of existing rules, 11 drugs had not been tested in Phase III clinical trials at all. Two drugs had been tested in a very small number of people, well below the statutory requirement of at least 100 patients. One drug had been tested at only two hospitals, whereas the rules specify a minimum of three to four testing sites. Four drugs had not only not undergone clinical trials, but had not even been evaluated by outside experts. In the Committee's words, "The decision to approve these drugs was taken solely by the non-medical staff of CDSCO on their own." 

13 drugs had not received approval for sale in any major developed country (such as the USA, Canada and Australia). For 24 drugs, medical experts had not been consulted for their opinions prior to approval. In cases where experts had been consulted, only 3-4 opinions had been sought, far fewer than is considered necessary to arrive at a rational and well-informed decision.

Even more troubling, a total of 33 drugs had received CDSCO approval during the period of Jaunary 2008 to October 2010 without any clinical trials being conducted in the Indian population. The Ministry explained that in special cases, drugs could be approved without clinical trials in the "Public Interest". As the Committee pointed out rather acerbically, "No explanation is available as to what constitutes Public Interest". It was equally critical of such explanations as were offered by the Ministry:
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 USFDA 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). 
The law has been designed to allow for certain drugs to be approved rapidly without necessarily undergoing clinical trials in India. This loophole was meant to be used in emergency situations, such as an epidemic of a new disease - say, bird flu - where there may not be sufficient time to carry out detailed investigations. But as the report points out, none of the 33 drugs could be classified as "emergency" drugs, and in fact had been launched in foreign markets well before they were introduced in India, allowing for plenty of time to conduct clinical trials. The lack of information on how these drugs perform in Indian populations extends to expert opinions and post-marketing surveillance data, which were inadequate at best and non-existent at worst. As the report states, "The interest is in those ethnicities that live in India, not Slavs, Caucasians, Hispanics and Negroes." Skipping clinical trials in India makes life simpler for drug manufacturers and cuts costs, but puts the Indian population at risk for adverse effects that may not be detected if the drug has been tested on a mix of Western ethnicities.

Upon examination, the Committee also found that those Phase III trials that had been conducted in India were often carried out in small towns, which were most likely to have a homogenous population. Given that there are multiple ethnicities in India (for example, Indo-Aryan and Dravidian, among others), for a trial to satisfactorily cover a representative sample of the Indian population, it would need to be conducted in urban areas with heterogenous populations, as well as in geographically disparate centres so that all ethnicities could be included. Given the way they were conducted at the time the report was prepared, the Committee concluded that ,"...such trials do not produce any useful data and merely serve to complete the formality of documentation."

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