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FDA recommends bioequivalence standards for 26 drugs

Great Blog post from RxObserver

As part of its efforts to further standardize the application process for generic drugs, the U.S. Food and Drug Administration (FDA) has published new guidance detailing the recommended bioequivalence studies for 26 new products. This draft is the latest addition to over 1,100 such documents intended to facilitate the approval process of abbreviated new drug applications (ANDA) used for the introduction of generics.

Bioequivalence (BE) between a generic drug and its brand-name predecessor (i.e. reference-list drug) is established by evidence of ‘bioavailability’. This is the observation that clinically, the two versions release essentially the same amount of active pharmaceutical ingredient (API) at the same speed. Different delivery methods for the same drug, like transdermal patches and tablets, would require different sets of BE standards. Generic products that have passed the comparability test on “dosage form, strength, route of administration, quality, performance characteristics and intended use” are deemed interchangeable with their innovator counterpart and listed in the FDA’s orange book titled “Approved Drug Products with Therapeutic Equivalence Evaluations”.

The “26 bioequivalence” recommendations outline suggested study design, study population, analytical procedure, acceptable parameters and other relevant parameters for the API of interest. Since the active ingredient has already gone through efficacy and safety tests during the brand-name drug application, generic sponsors only need to demonstrate that the API in the generic version behaves the same way as in the brand-name version. Usually, a small number of volunteers are recruited during a bioequivalence study where some are given the brand name and others given the generic. Researchers take blood samples from the participants at designated intervals and measure the amount of API in the samples. To gain approval, generic sponsors must show innovator-generic equivalence for two central measures: extent of absorption (maximum API concentration in the blood) and rate of absorption (the time it took to achieve such concentration). The FDA’s guidance does not cover inactive ingredients, which means generic manufacturers have some leeway in how they flavor, color or coat the drug as long as these modifications do not affect the API measures.

According to a 2013 report from the Generic Pharmaceutical Association, healthcare savings through generic substitutions increased at approximately 17% each year since 2007, totaling $1.2 trillion in dollars saved between 2003 and 2012. In 2012 alone, generics shaved $217 billion off the U.S. healthcare bill. Interestingly, 72% of those savings were from newer generics that came to the market as a result of the much hyped ‘patent cliff.’ The FDA’s proposed bioequivalence guidance contains recommendations for generic versions of several popular brand-name drugs set to go off-patent over the next six years. These include a kidney cancer treatment from Pfizer called Inlyta (API: Axitinib, expected expiration in 2020); a painkiller from Purdue Pharma labeled Butrans (API: Buprenorphine, expected expiration in 2015); and an anti-seizure medication used to treat certain types of epilepsy by Lundbeck named Onfi (API: Clobazam, expected expiration in 2018). Onfi currently costs between $110 and $900 for a 30-day supply (depending on dosage)while a potential generic alternative could be priced as low as $10 for the lowest dosage, generating over 90% in savings for payers.

The FDA’s bioequivalence guide has faced criticism for the strength of its statistical analysis guidelines. Under the agency’s standards, the API profiles for brand-name drugs and their generic counterparts do not need to be identical; some minor variation is acceptable.In practice, however, high variability is virtually non-existent. Analysis of 2,070 bioequivalence studies from 1996 to 2007 revealed an average variability of 4.35% for maximum API concentration and 3.56% for time to maximum concentration.

The market value of the U.S. pharmaceutical industry is expected to increase 30% over the next decade, reaching $475 billion by 2020. Over the same time period we can expect multiple market forces to continue the drive to generics. Among these factors, exploding healthcare expenditures are putting downward pressure on drug prices. More than 80% of prescription drugs dispensed today are generics, and the percentage may grow to 87% over the next five years. The patent expiration of multiple big name brand drugs will take place over the next few years. Starting in 2014, we will see patents expire for Nexium, Cymbalta, Celebrex, Actonel, Gleevec, Avodart, Crestor, and Benicar, just to name a few. The combined global sales of these drugs is in the hundreds of billions of dollars. It is not unreasonable to assume that generic equivalents for many of these compounds are being developed now. The FDA’s bioequivalence guidance is yet another regulatory effort that addresses industry interest in generic development as the FDA strives to not only save time and money during the review process, but also ensure the safety and efficacy of generics before market introduction.

Topics: Industry News