An Integrated Bioinformatics and Quantitative Modeling Approach to Investigate Potential Claims of Oral Generic Drug Product Bioinequivalence: Introduction

It has been reported that 88% of prescriptions filled in the United States are for generic drugs, and this has saved the US health system $1.68 trillion from 2005 to 2014.1 Over the same time period, the number of approvedAbbreviatedNewDrugApplications for generic drugs increased by 44%.2 Generic drugs are considered safe, effective, and substitutable for the reference-listed drug under all clinical use conditions. This is because the Food and Drug Administration (FDA) mandates that they be pharmaceutically equivalent and bioequivalent through vigorous testing; therefore, they are considered to be therapeutically equivalent to the reference-listed drug (or brand-name) product.3,4 However, the FDA’s Office of Generic Drugs will occasionally receive complaints from patients and/or healthcare providers that a generic drug was either not as effective or safe as the brand name product that they were taking or prescribing previously. Such was the case with a generic version of bupropion.5 Under these circumstances, because many diseases are difficult to treat, and these reports are lacking controls, it is extremely challenging for the FDA to determine if complaints about benefits or risks of generic drugs are real or due to other factors related to disease progression or to some other factors. A related point is that the FDA interprets drug safety as a benefit-to-risk ratio. A drug is safe if its benefits favorably outweigh its risks. If patients receiving a bioinequivalent generic drug product fail to gain the benefits provided by a brand-name product, then its benefit-to-risk ratio is overstated, and failure to provide benefits may be considered a safety issue. Therefore, it is imperative that complaints about generic drug substitution be investigated thoroughly to determine if the generic drug is actually meeting bioequivalence standards and if there is a rational, mechanistic explanation for the purported reduction in benefits or increase in risks attributed to the generic drug. Through this process of investigation, the regulatory science supporting the approval criteria for all drugs, including both generic and brand-name products, continues to evolve and remain rigorous and comprehensive. In the commitment letter of the Generic Drug User Fee Act (GDUFA) of 2012, the FDA committed to consult with industry and the public to create an annual list of regulatory science initiatives specific to research on generic drugs. The research studies conducted under these initiatives will advance the public health by providing access to safe and effective generic drugs. The regulatory science results will provide new tools for the FDA to evaluate generic drug equivalence and for industry to efficiently develop new generic products in all product categories. The Office