Tuesday, April 29, 2014

A damning indictment of drug regulation in India - Drug safety in India versus the world, the CDSCO way

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

As mentioned earlier, there are several drugs that continue to be sold in the Indian market even though they have been withdrawn elsewhere. The Committee decided to look into allegations that some such drugs had been approved unlawfully, and found several cases where drugs had been approved in contravention of the existing laws.


  • Buclizine, an anti-histamine, was approved for appetite stimulation in children without any expert consultation or clinical trials. As per the law, if a drug approved for one condition is proposed for the treatment of a different condition, it must be treated as a new drug, following all the required procedures and meeting all regulatory requirements. This was not done for buclizine. The Ministry also claimed that buclizine had been previously approved in other countries, when in fact it had either been discontinued or banned in those countries.
  • Letrozole, an anti-cancer drug, is to be used for the treatment of breast cancer only in women of post-menopausal age. Yet, India was the only country where letrozole was approved for improving female fertility in women of reproductive age. No Phase II studies were conducted, an especially crucial requirement since this drug had not been tested for its impact on female fertility anywhere else in the world. Phase III trials were approved without any Phase II information being provided, and were conducted on a small group of women, far fewer than the number specified in Good Clinical Practice rules. No post-marketing surveillance reports were provided by the manufacturer to determine whether this novel use of letrozole had any adverse impact, either on the women taking the drug or the babies born to them. When the entire episode received negative coverage in the media, CDSCO took no action against any erring officials or the manufacturer, and instead referred the matter to experts to determine drug efficacy and safety. The drug has since been banned for use in improving female fertility, and the report sternly demands that the DGCI "...take action against those CDSCO functionaries who colluded with private interests and got the drug approved in violation of laws."

  • A fixed dose combination of two drugs (flupenthixol and melitracen), one of which (melitracen) has never been used in India, was approved without any documents on file relating to the regulatory process. Moreover, melitracen has been banned for sale and use in Denmark, where it was first manufactured. As per Indian law, this means melitracen cannot be imported and sold in India. Thus, the approval granted to this FDC is in violation of Indian law and therefore illegal. The Committee also points out that the manufacturer has been trying to market the drug in smaller markets with poorer drug regulatory authorities (such as Myanmar, Bangladesh, Trinidad and sadly, India) instead of in developed countries with larger markets and more potential for profit, implying that the manufacturers knew that this FDC would not pass the more stringent requirements of competent regulatory authorities.
  • Placenta extract gel, a new formulation, received an illegal certification from the CDSCO that it was not a new drug and could be used for multiple novel indications, despite the fact that new formulations of an existing drug or a proposed use for a new indication must be treated as "new drugs" as per the law. Moreover, the list of new proposed uses ends with what the Committee calls "...the term “etc.” (An unknown and unheard of terminology in the history of drug approval)", allowing for many more indications to be tacked on with ease while circumventing regulatory requirements. For this deliberate violation of the rules, the Committee recommends that an enquiry be instituted and the guilty parties be punished appropriately.
  • Nimesulide, a non-steroidal anti-inflammatory drug (NSAID), was approved for use in children of all ages in India in 1996. It was later banned worldwide for use in children due to reported cases of fatal liver injury in patients, an event which received extensive media coverage in India. Instead of taking the expected route of banning the drug in India as well, the CDSCO merely referred the matter to an expert committee for "efficacy and safety issues". The Committee members were clearly deeply disturbed at the callousness exhibited by the CDSCO, going so far as to state on record that, "The Committee takes special notice of this case of persistent insolence on the part of CDSCO and hopes that never again shall the DCGI approve drugs in violation of laws, that too for use in neonates and young children...The Committee expresses its deep concern, extreme displeasure and disappointment at the state of affairs as outlined above."
Many of the cases mentioned above concern drugs that have been banned in other countries but were still widely available in India until recently. A few of them were finally banned by the Central government, years after the rest of the world had done so. The Committee decided to examine the cases of a few such controversial drugs, and took a closer look at analgin (metamizole), an NSAID.


This drug was found to have potentially serious side effects in the 1970s, and has subsequently been withdrawn or banned in several countries, including the USA, Sweden and France. In India, the drug is easily available over the counter and does not require a medical prescription, despite its risk profile. Far safer alternatives are available in the Indian market, so that the withdrawal of this drug will not have a negative impact on consumers. As the Committee points out, "...a drug becomes a candidate for withdrawal not only due to serious side effects but also when safer, more efficacious drugs are launched. Unfortunately, no attention is being paid to this issue."

In some cases, CDSCO officials defended their decision not to withdraw certain drugs since no adverse effects had been reported from India. The Committee shot down this flimsy defence by pointing out that the only way to detect major side effects is to run a large scale phase IV (post-marketing) trial. Expecting either individual medical practitioners or larger medical centres to spontaneously report adverse events is completely unrealistic. As mentioned earlier, there have been many cases in India where Phase IV trials were either not conducted at all or done so incorrectly; in the absence of any home-grown mechanism to unearth serious side effects, the Committee recommended that the "CDSCO should keep a close watch on regulatory developments that take place in countries with well developed regulatory systems in the West and take appropriate action in the best interest of the patients."

Similar to new drug approvals, banning a drug also requires consultation with qualified experts. The Committee found that the Ministry had no standardized process to carry out such consultations, and indeed the explanations from the Ministry were found to be "vague, not convincing and not to the point." Some drugs were referred to an expert committee, some to the Drugs Technical Advisory Board (DTAB), and some weren't referred to any external experts at all before being banned. Oddly enough, no new drugs awaiting approval were referred to the DTAB; would it not make more sense for the same body that approved a drug to also ban it if serious side effects were later reported? The Committee certainly thought so, and also wondered why all the external experts contacted (if at all) were located in New Delhi - were there no qualified individuals anywhere else in the country?

Another issue with drug approvals has been the lax oversight of fixed drug combinations (FDCs), which should be treated like new drugs and follow the necessary regulatory procedures. This includes obtaining approval from CDSCO and then approaching state authorities for manufacturing licences to begin producing the drug. However, the Committee found that in many cases, state authorities had granted manufacturing licences without any prior CDSCO approval, which is against the law. The Central government was found to have taken no action on the matter, even though the issue was first discussed in 2000, over a decade before the report was issued. Clearly, the procedure for approving FDCs, and banning them if needed, needs to be streamlined and made transparent.

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