In a long overdue move the Ministry of Health and Family Welfare has finally amended the law to make bioequivalence studies compulsory for certain classes of generic drugs manufactured in India. The government first advertised the draft amendments in early February for public comment and then formally amended the Drugs & Cosmetics Rules, 2017 through a notification on April 3 to incorporate the change.
Bioequivalence studies are studies conducted to establish that two medicines, normally the original patented drug and a generic version, have the same biological equivalence – that is, that they work the same way, to the same extent and for the same purpose. The new law required bioequivalence studies to be performed on drugs with low solubility. Although it is preferable to have a system of by which bioequivalence should be established for all drugs, this requirement is often waived for drugs that are highly water soluble as they are likely to with high solubility are considered to be more easily absorbed in the body.
In order to understand the significance of these amendments it is necessary to understand the history of modern drug regulation, especially in the context of generic medicines. The modern drug regulatory framework can be traced to the sixties when the United States amended its law to require drug manufacturers to demonstrate proof of efficacy of their new drugs. Until then the main policy objective of regulation was to ensure quality of drugs per the manufacturer’s specifications. Proof of efficacy required the conduct of extensive clinical trials, often requiring thousands of patients and the cost these days runs into hundreds of millions of dollars. The cost of clinical trials created a new entry barrier for competitors to enter the market after the patents over the original drug expired.
The United States Congress responded by enacting the Hatch Waxman Act in 1984 creating a new regulatory pathway that would enable competitors to introduce generic versions of the proprietary drugs without the requirement of repeating expensive clinical trials. The one mandatory requirement to gain approval for a generic under this new regulatory pathway was the conduct of bioequivalence studies. These studies are aimed at studying whether the generic drug behaves in the same manner as the innovator drug – that is, whether it dissolves at the same rate into the bloodstream thereby demonstrating similar therapeutic properties as the innovator.
Lower costs of generics
These studies are usually conducted on a much smaller group of healthy volunteers than is the case with clinical studies which are conducted on patients suffering from the disease in question. As a result, the cost of a bioequivalence study is only a small fraction of conducting full-fledged clinical trials. This practice of approving generics based on bioequivalence studies is one of the reasons that generic drugs are much more affordable than patented versions of the drugs.
The legal requirement in India under the Drugs & Cosmetics Rules, 1945 for conducting bioequivalence studies has, so far, been limited to only those generics that are approved by the Drug Controller General of India within the first four years of the innovator drug being approved in India. For example, if Pfizer has a new drug approved in 2012 after submitting clinical trial data, manufacturers of all generics versions for that drug to be launched in the market between 2012 and 2016 must seek permission from the Drug Controller General of India and submit data on bioequivalence studies in cases where there is no valid patent. For those generics entering the market after the four year process only require permission from state licensing authorities, who are not required to demand data on bioequivalence studies under the Drugs & Cosmetics Rules, 1945.
This distinction between generics approved within the first four years and those approved from the fifth year, has no basis in science and has without doubt jeopardised public health because state licensing authorities were in effect approving generics with absolutely no data on their performance. As a result doctors have been prescribing generics without having any data on the performance of these drugs. As a result most domestic manufacturers catering for the Indian market would wait till the fifth year and get approval to manufacture and sell generics without conducting bioequivalence studies.
Those manufacturers exporting to the US and the European Union would still be required to conduct these studies in order to gain marketing approval for those jurisdictions. In fact, even these companies have faced serious allegation of fraud regarding the manner in which these bioequivalence studies are conducted as exposed in the Ranbaxy scandal and more recently the GVK Bio scandal.
The Indian debate
In 2013, an expert committee headed by Dr Ranjit Roy Choudhary had recommended making bioequivalence studies compulsory for all generics irrespective of when they were approved. Surprisingly when this recommendation was discussed by the Drug Consultative Committee, which has all state drug controllers and the Drug Controller General of India as members, the recommendation was rejected not on the basis of science but on commercial feasibility. At its 47th meeting held in July, 2014 the Drug Consultative Committee stated the following while rejecting the Choudhary Committee recommendation:
“The recommendations of the Prof Ranjit Roy Chaudhury Committee in respect of Bioavailability or Bioequivalence (BA / BE) studies conducted in India were deliberated in detail. The members were of the view that BA / BE studies in respect of drugs manufactured in the country shall be insisted whenever there are issues relating to patient safety and variable bioavailability. As the infrastructure for conduct of such studies is not uniformly available in the country it cannot be implemented as a rule.”
The rejection of this view that bioequivalence studies should be undertaken on case by case basis was yet another egregious example of how decisions related to patient safety are guided by the commercial interests of the Indian pharmaceutical industry rather than public health. Even more egregious perhaps was the Drug Consultative Committee’s claim that India lacked the infrastructure to conduct such studies. At that point in time India had one of the largest clinical research establishments in the world.
Last year, Ranbaxy whistleblower Dinesh Thakur had filed two PILs before the Supreme Court seeking, amongst other prayers, that the government make bioequivalence studies mandatory for the approval of all generics (full disclosure: I was his lawyer in the case). A bench headed by the then Chief Justice TS Thakur dismissed the PILs as raising issues of mere “academic interest”. The same judge however did admit a PIL on banning sardar jokes.
Thereafter, Thakur and I prepared a comprehensive report and submitted the same to the Ministry of Health where we specifically highlighted the issue of bioequivalence studies.
It is not clear what influenced the government to change its mind and make bioequivalence studies compulsory but the health ministry certainly deserves credit for making the decision.
The challenge for the future will be to ensure that clinical research organisations that conduct bioequivalence studies do not commit fraud. This is a daunting task given the list of organisations that have been caught red-handed by foreign regulators.
The writer is a research associate at the School of Law, Singapore Management University.