Many believe that bioequivalence testing is necessary for only a handful of medications. In reality, it should be the norm for virtually all drugs.
The prime minister’s recent proposal to make it compulsory for doctors to prescribe generic drugs has provoked a welcome debate on the quality of drugs being sold in India. Until now, it has been the norm to paint those of us raising these issues of drug quality as agents of foreign, vested interests. The recent debate has however exposed the fact that a vast majority of Indian doctors lack faith in the country’s drug supply and its drug regulator’s ability to ensure uniformity and consistency in the quality of generic drugs sold in the country.
A pertinent issue now that the administration has recently made bioequivalence studies mandatory for a certain class of drugs is whether we should allow discretion to the regulator to provide waivers to the industry from this requirement. We have argued in our previous writings that bioequivalence testing is of paramount importance because it establishes that the generic drug has a therapeutic effect that is identical or similar to that of the innovator drug that has been tested through clinical trials.
However there are others, like George Thomas and S. Srinivasan, who dismiss concerns regarding bioequivalence testing as “misinformed”. They state, in pertinent part “Of the approximately 800 useful drugs known to modern medicine, bioequivalence is really only important for a few drugs with low solubility and high or low permeability, so the debate about BA and BE is somewhat misinformed.”
This is a dangerous line of argument that trivialises the importance of bioequivalence and we would like to counter these assertions.
The reason for bioequivalence testing
Bioequivalence testing was introduced in the US and EU in the 1980s to ensure that generics were not required to repeat large-scale clinical trials in order to prove efficacy and safety of a drug that had already received marketing approval. This testing was required by all formulations administered orally and expected to dissolve in the bloodstream. The purpose was to test whether the generic drug dissolved at the same rate in the bloodstream of a volunteer and acted in a manner similar to the innovator product that was evaluated through clinical trials. Such testing is required because although the active ingredient of the generic and innovator are the same, inactive ingredients and the method of manufacture can influence the manner in which the drug behaves physiologically. For example, if the generic manufacturer uses different excipients or adds greater quantities of a binding agent, it is possible that a drug will not dissolve in the blood stream at the rate comparable to the innovator drug for which clinical studies establish therapeutic action.
Although much cheaper than clinical trials, bioequivalence testing still costs a pretty penny and takes time to conduct. This is one of the reasons that Indian companies have been caught fudging bioequivalence studies. The second author of this piece discovered large scale manipulation of BE studies at Ranbaxy and worked with the US FDA to hold the company accountable for this fraud. The Indian government at the time famously dismissed the Ranbaxy fraud as a “documentation” issue despite the company pleading guilty to seven counts of criminal felony and paying $500 million to the US government.
Thomas and Srinivasan, in their piece, argue that bioequivalence studies are required for only “few drugs with low solubility and high or low permeability” and hence they argue that the debate is “misinformed”. There are several factual and logical problems with their line of argument.
On facts, it should be noted that after initially insisting on bioequivalence testing for all drugs administered orally, the USFDA released guidance in 2000 on granting “bio-waivers” based on a “Biopharmaceutics Classification System” (BCS) that it developed. The BCS created 4 categories of drugs based on their solubility and permeability: Class I (high solubility, high permeability), Class II (low solubility, high permeability), Class III (high solubility, low permeability) & Class IV (low solubility, low permeability). For drugs in Class I & Class III, generic companies can request the waiver of ‘in-vivo’ bioequivalence studies i.e. testing on human volunteers. Rather generic companies could test these drugs ‘in-vitro’ i.e., use the solubility of the drugs as a surrogate for their physiological behavior. Such waivers are not automatically granted; they are evaluated on certain factors to be assessed by the regulator on a case by case basis. For example, even if a drug rapidly dissolves in the stomach acid and is rapidly absorbed into the blood stream, how much of it is available in the body to treat the illness varies widely.
An additional factor to be considered in India is that the supply chain is littered with irrational fixed dose combinations (FDC). The US FDA guidance issued in 2015 states categorically that biowaivers cannot be granted if there is any pharmacokinetic interaction between the components of the FDC. The Kakote Committee report tells us how little we know about such interactions.
Most importantly, there appears to be very little faith in the system of ‘bio-waivers’. As per figures attributed to a study by the European Federation for Pharmaceutical Sciences Global Bioequivalence Harmonisation Initiative, the number of bio-waiver requests submitted to the USFDA, between 2000 and 2015 have averaged approximately two per year – a drop in the ocean. Another study attributes the lack of enthusiasm in the bio-waiver pathway to the lack of a global consensus between the three most important agencies, the USFDA, the European Medicines Agency (EMA) and WHO. The situation was similar in Europe, with an EMA document from 2007 noting that “Although frequently discussed, BCS-based biowaivers are still rarely used probably attributed to uncertainties on both, pharmaceutical companies and regulatory authorities.” In other words, bioequivalence testing is the norm for virtually all drugs, with only a miniscule few escaping this requirement.
This may change in the future because the EMA and the International Pharmaceutical Federation have started the long drawn process of classifying all drugs under BCS. This requires extensive research and will take several years.
In any case, it is pertinent to note that the argument put forth by Thomas and Srinivasan that the debate on bioequivalence is important for only a few drugs misses the point. Several important drugs fall outside BCS Class I and Class III. According to the EMA, this includes important cancer medication like Dastinib, Erlotinib, Sorafenib and diabetes medication like Repaglinide. For a few of the other drugs studied by the EMA, like Imatinib (Glivec ®) and antibiotics like Telithromycin, it was unable to classify them in any of the categories and required applicants to generate their own data.
The Indian position on bioequivalence was scandalous until April 3, 2017 when the government made bioequivalence testing mandatory for all generics. The problem with the government’s new position is that it falls backs on the BCS system created by the USFDA and grants a blanket exemption from bioequivalence testing for all drugs in Category I and Category III without paying any attention to the regulatory uncertainty faced by far more experienced regulators who insist on a case-by-case determination of such waivers. And it assumes that the CDSCO has the scientific expertise to analyze the data presented to determine whether a company’s claim of their product conforming to BCS Class I or III is adequate. History shows that such discretion was the primary reason for we are straddled with such a dysfunctional regulatory system for drug approval in India .The 59th Parliamentary Standing Committee report on the functioning of the CDSCO adequately addresses this question.
For far too long, the Indian debate on access to medicine, exemplified by the approach adopted by Thomas and Srinivasan, has focused solely on price with no attention to quality. But of what use is affordable medicine if it doesn’t work as intended? Is an Indian life any less valuable than an American or European life?
Prashant Reddy T. is a research associate at the School of Law, Singapore Management University. Dinesh S. Thakur is a public health activist and chairman of Medassure Global Compliance Corporation.