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New medicines, new principles
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As a medical scientist on vacation in India, my interest was drawn to two recent articles that appeared in the Indian press, both referring to generic drugs and the issue of bioequivalence.
The landmark passage in 1984 of the Hatch-Waxman Act in the US changed the way generic drugs were approved by the Food and Drug Administration (FDA). Prior to 1984, generic drug manufacturers were required to conduct the same safety and efficacy tests demanded from manufacturers of branded drugs. To increase the availability of lower- cost drugs, the Hatch-Waxman Act reduced the requirements for approval of generics by accepting the concept of “bioequivalence" as a surrogate for safety and efficacy. Traditionally, the US FDA has been the health authority which sets benchmarks used around the world. In the 1980s, most of the marketed drugs whose loss of patent protection qualified them for substitution through generics had a relatively wide spectrum of pharmacological activity, resulting in efficacy over a wide dosage range. Thus, demonstrating bioequivalence (with its inherent limits) resulted in generic versions of drugs which would probably show approximately similar pharmacological efficacy, but not necessarily similar therapeutic equivalence.
Advances in drug discovery through significant advances in research into the molecular basis of disease processes have led to the introduction of new drugs targeting specific molecular entities such as receptors and enzymes whose high potency, selectivity and high therapeutic efficacy requires well-controlled, extensive clinical trials of safety and efficacy for their approval. These new drugs are effective within a narrow dose range, making bioequivalence, which works best for drugs effective over wider dose ranges, no longer an appropriate surrogate. Since generic versions of these newer drugs are still approved based on bioequivalence, their efficacy varies widely. This variability is not documented by the manufacturers of generics (as they are not required to assess efficacy), but is passed on to the patient, who now becomes the sole and individual documenter of the efficacy of generics.
Patients seldom have an effective lobby, making it difficult for them to document their individual experiences with a generic drug. Recently, websites such as PillGirlReport.com, whose creator Naomi Wax, a journalist, wrote a piece titled “The depressing truth about generics: Medical professionals are wrong to claim that these drugs are as good as brand names"—it appeared recently in several leading US newspapers, including the Los Angeles Times—document a growing dissatisfaction with the efficacy of newer generics compared with their branded counterparts. As the Hatch-Waxman Act requirements were never intended to assess the safety or efficacy of the generic version, it falls as a burden to the patient to determine whether the generic is therapeutically as effective as its branded counterpart.
Issues relating to price, methods of testing generic drugs and general access of populations in emerging countries to drugs have been extensively discussed in the media by manufacturers of both branded and generics drugs. Now is the time to address the needs of patients for access to effective drugs. This requires the national health authorities to open a discussion forum enabling patient advocacy groups, the scientific community and patients to discuss issues relating to the availability of safe and effective drugs, whether they are branded or generic. It needs to be emphasized that under the present requirements, the generic product is not required to satisfy the regulator about any aspect of its safety or efficacy before approval.
The sole requirement is that of bioequivalence, which at the present time, for the reasons stated above, is no longer sufficient as a surrogate for safety and efficacy. Thus, generic drugs should now be required to document, in some appropriate form, for example therapeutic equivalence, their safety and efficacy.
Since the government of India is contemplating the recommendations of the Mashelkar report on creating an FDA-type agency in India, the time is right for a discussion on the requirements for approval of generics in India.
Generics will continue to gain importance as the mainstay of therapeutic health care, making it relevant that the considerations outlined above also be discussed. It is time for India, which stands poised to become an economic engine for world growth, to look to the future and to set the benchmarks for a variety of issues, in this case the standards for approval of branded and generics drugs in future.
It is the primary responsibility of health authorities to protect the health of citizens. It is imperative that they reassess the acceptability of bioequivalence as a surrogate for efficacy and suggest cost-effective ways for making therapeutic equivalence rather than bioequivalence the appropriate surrogate for safety and efficacy, especially as it appears that generic drugs will be the mainstay of health care in the future.
Ajay Bhatnagar is a scientist who led the team that discovered the anti-cancer drug Letrozole at Novartis. Comments are welcome at theirview@livemint.com
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