A petition to reform the legal framework for bioequivalence testing requirements for generic drugs

Continuing with our campaign to improve the quality of generic medicines made in India, we filed one more petition with the Minister of Health on the issue of bioequivalence testing for new generic drugs being approved in India. The petition can be accessed over here.

The simple aim of bioequivalence testing is to ensure that a generic medicine has the same bioavailability in a patient’s bloodstream as the innovator drug which is evaluated through a clinical trial. In essence, bioequivalence testing measures the solubility and permeability of a drug i.e., can the drug permeate through the intestinal membrane to enter the bloodstream and if so, at what rate.  Such testing is important because although a generic drug will have the same active ingredient as the innovator drug, the manufacturer may use different excipients, binders etc. which will affect the ability of the drug to dissolve into the bloodstream; this is called bioavailablity. Every drug displays a dose-response, meaning its concentration increases once it is administrered and then the body excretes it through normal bodily functions. The highest concentration of the drug in the bloodstream and the total drug available before it is excreted are key measurement criteria to demonstrate equivalence between the innovator formulation and the generic formulation. This information determines the dosage, for example when you are prescribed 100 mg of Ibuprofen, clinical trials were used to arrive at this number. Once such bioequivalence is established between an innovator and generic drug, the latter can be clinically prescribed as a substitute for the former. This testing to establish bioequivalence is carried on healthy human volunteers rather than patients with the disease as is the case with clinical trials. One of the reasons, that generic drugs are more affordable is because of the fact that bioequivalence studies are simpler and cheaper to conduct than full-fledged clinical trials needed to get regulatory approval for new drugs.

As explained in our earlier post on stability testing, India for long has had two different regulatory structures for generic drugs – one for ‘new drugs’ (the ‘new’ being an issue of whether the drug was previously approved for the Indian market) which extends for a four year period subsequent to such approval during which period, additional approvals are granted only by the Central Drug Regulator, the DCGI. After the expiry of this four year period, new manufacturing applications for the drug are approved by state drug regulators. Shockingly the latter category of generic drugs, which were approved by state drug regulators were never required under the law to establish their bioequivalence. There is no scientific basis for not requiring these drugs NOT to go through bioequivalence testing.

In 2013, the Ranjit Roy Committee recommended that bioequivalence testing be made compulsory for all generic drugs. The next year, the Drugs Consultative Committee (DCC), while agreeing that such testing was important, did not want to make it a mandatory rule as they felt India lacked the infrastructure to carry out these tests. In 2016 I had submitted a report to the Ministry of Health to make bioequivalence testing compulsory. A few months later the Drugs Technical Advisory Board formally recommended that government make it compulsory for all generic drugs to go through bioequivalence testing. In 2017, the government finally amended the Drugs & Cosmetics Rules, to bring in the new bioequivalence testing norms. There are however major lacunae with these rules which is why we are petitioning government for a review of the rules by an expert committee.

Our first major objection is regarding the manner in which “bio-waivers” have been granted under the bio-pharmaceutical classification system (BCS). The BCS system classifies all drugs into 4 categories (Classes I, II, III & IV) based on two demonstrable chemical characteristics,  their solubility and permeability. There is  scientific basis to assert that two of these categories of drugs can be exempted from in-vivo (human testing) bioequivalence studies because the data required to ensure that they will become bioavailable in the right dosage can be generated sufficiently through in-vitro testing (lab testing), thus greatly bringing down costs and time even further. This exemption is called a ‘bio-waiver”. The in-vitro testing can be conducted in the laboratory by testing solubility in aqueous solutions maintained at the pH levels of the human stomach and permeability can be tested on animal models or epithelial cells in a laboratory setting. Although the BCS system offers generic companies an opportunity to lower costs, it is not really used very frequently in most countries. This is most likely because regulators have to scrutinize every application for a bio-waiver to scrutinize the ingredients in the formulation and make an assessment on whether a bio-waiver can be granted. Moreover since bio-waiver protocols are not standardized across the world, it made sense for most companies to conduct regular in-vivo bioequivalence studies because while they may ask for a biowaiver in one market, a different market may not agree and ask them to conduct a bioequivalence study nonetheless. The problem with the amendments of 2017 was that it gave a blanket waiver to all Class I and Class III drugs without specifying what process will the regulator employ to evaluate such formulations as to how the waivers would be granted and what in-vitro data would be scrutinized by the regulators.  Ideally, the law should prescribe a scientifically rigorous and administratively transparent process to grant for a bio-waiver for any formulation for drugs that fall into Classes I & III.

Our second objection is the silence in the rules on the categories of drugs in Class I and III that do not qualify for bio-waivers. For example, the USFDA guidelines (which are the pioneering guidelines for bio-waivers) forbid the grant of bio-waivers to drugs which have a Narrow Therapeutic Index (NTI) or those which are consumed through the oral cavity.    

Our third major objection with the amendments of 2017 is that it is silent on existing drugs in the Indian market. The Indian market is awash with generic drugs that were never put through bioequivalence testing. In its 2016 meeting, the DTAB had agreed to give a three year window for all existing drugs to submit their bioequivalence data but that policy decision never got translated into the law. It is critical that all existing drugs be reviewed for their bio-equivalence.

A fourth issue, which although not directly associated with the rules, is the manner in which the DCGI is selecting the ‘reference product’ i.e., the product against which the bioequivalence testing is conducted. Usually this should be the innovator product that has gone through full-fledged a clinical trial. A few months ago, the DCGI did kick-start process to list the reference products but the process is simply not transparent enough. The entire process needs a comprehensive relook.

Due to the above objections, and a few more issues that are listed in our petition, we have asked the Health Minister to constitute an expert interdisciplinary committee to conduct an in-depth study of the legal framework to govern bioequivalence studies for our drug supply.   

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