American Journal of Law & Medicine

Deficiencies of the FDA in Evaluating Generic Formulations: Addressing Narrow Therapeutic Index Drugs

     A. Generics and Abbreviated New Drug Applications
     B. Bioequivalence
     A. BE Changes
     B. Confusion Among Healthcare Providers
     C. Global Standards for BE
     D. Automatic Substitution
     E. BE Concerns for NTI Drugs
        1. Antiepileptic Drugs (AEDs)
        2. Warfarin
        3. Wellbutrin
     A. Prohibit Autosubstitution of NTI Drugs
     B. Appropriate Scaling
     C. Globalization of BE Guidelines
     D. Continuing Professional Education

Generic drugs represent a significant portion of the medical arsenal in treating disease. As copies of originator drugs, these drugs have been permitted abbreviated approval under the Hatch-Waxman Act. Yet with the current cost focus upon generic formulations, potential safety issues with generics have arisen. Although there is an established criterion of "bioequivalence " that generic formulations must demonstrate, narrow-therapeutic index drugs for sensitive clinical circumstances such as epilepsy, antiplatelet therapies, and mental health treatments may require different regulatory treatment than other generic drugs. Further, in these circumstances, differences in generic formulations may lead to adverse clinical outcomes due to less stringent bioequivalence tolerances. Yet there is no mandate for comparison between different generic formulations. Countries outside the United States advocate for narrowing tolerance ranges for these high risk health situations and the drugs for their treatment. We argue in this paper that additional patient safety matters must be taken into account for narrow therapeutic disease drugs, and regulatory bodies should emphasize greater tightness in bioequivalence before these narrow-therapeutic drug generic formulations are approved.


Innovator drugs take years of research, clinical trials, and testing to pass the U.S. Food and Drug Administration (FDA) approval process, while generics must only pass bioequivalence (BE) tests to be deemed equivalent to the original product and safe for public use. Hence, if bioequivalent, generic drugs offer great promise to minimize costs and increase drug accessibility.

The definition of a generic drug is: "A drug product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." (1) The cost of a generic drug can be 80% to 85% lower than the brand name product and, hence generic drugs are rapidly substituted after patent expiration (2) and can save consumers an estimated 8 billion to 10 billion dollars a year. (3) Consequently, the use of generic drugs has rapidly increased and now dominates the medication landscape for patient use. (4) Indeed, doctors will prescribe a generic alternative over a brand drug when available 93% of the time. (5)

Under healthcare reform, the use of generic drugs is expected to increase not only due to consumer desire for lower prices, but also by government through cost savings initiatives. (6) For this reason, investigating the BE criteria is critically important, as more people will be exposed to generics than ever before.

Regulations regarding BE have been in place for over twenty years. However, there have been and currently are controversies over BE among both clinicians and research scientists. (7) For example, case studies have demonstrated when patients on "Narrow Therapeutic Index Drugs" (NTI drugs) are switched to generics, a change in therapeutic dosing and side effects occurs--yet randomized, double-blinded controlled studies fail to prove that any differences exist, (8) NTI drugs are drugs with small differences between therapeutic and toxic doses. (9) These tests, however, are often underpowered, casting doubt upon their significance. (10) This situation creates a divide between those who see no need for change in BE standards and those who believe better standards are necessary. This debate is most charged in the areas of antiepileptics, anticoagulents, and antidepressants, although this last group of drugs is not specifically NTI drugs.

In the context of ever-increasing use, it is critically important to understand the criteria by which generic drugs are evaluated and the key BE issues attendant in generic drug use. Although BE appears to be a safe and effective determinant for the interchangeability of most brand drugs for generic alternatives, its use also raises important questions: Are current BE standards the best possible way to evaluate interchangeability for all drugs? Or is there a better approach?

What is needed is both information and changes based on regulatory science. Beyond FDA potential tightening in NTI drug requirements, physicians should not only have access to BE education, but such education should also be required through continuing education state requirements. In addition, any "mandatory" generic substitution of NTI drugs at the pharmacy level should therefore not be permitted. (11)

This Article reviews these concerns. Part II discusses the background of FDA and generic regulation. Part III investigates the challenges to BE criteria. Part IV proposes solutions to improve the current BE criteria. Finally, Part V summarizes the findings of this Article.



Since the Food, Drug, and Cosmetic Act (FDCA) (12) was passed in 1938, several amendments have been added to make drugs safer for Americans. In 1962, the FDCA required "substantial evidence" of both safety and efficacy, obtained in "adequate and well-controlled" studies, for all drugs, (13) This mandate included the development of the New Drug Application (NDA), retroactive evaluations of drugs developed pre-1962, and expert panels established by the Drug Efficacy Study Implementation (DESI) Review to make further recommendations. (14) The NDA applied to generic drugs and required preclinical and clinical data establishing the active ingredient's safety and efficacy (i.e., the ability of a drug to produce the desired effects under expert hands and under ideal circumstances). (15) Developing new drugs involves pre-clinical and clinical trials that are both costly and time consuming for manufacturers. Consequently, DESI developed the Abbreviated New Drug Application (ANDA) as an affordable mechanism for approval of generic versions for drug products approved between 1938 and 1962. (16) The ANDA enabled approval based on active ingredients and BE rather than more costly safety and efficacy data. (17) The ANDA was the first time BE was introduced into FDA regulations. (18)

The original ANDA did not apply to generic forms of drugs marketed after 1962, and as patents expired in the 1970s on post-1962 drugs, the ANDA of 1962 did not offer a viable generic drug testing approval process. (19) Manufacturers of post1962 generic drugs had to submit complete safety and efficacy data. (20)

After 1978, manufacturers no longer had to submit efficacy and safety data if they could cite published reports of such trials documenting safety and efficacy. (21) Since published reports with the required information were usually unavailable to the public, this option offered little solution to the problem of proving safety and efficacy of generic drugs. This issue gave rise to the Drug Price Competition and Patent Term Restoration Act of 1984, (22) also known as the Hatch-Waxman Act, under which generic drugs are approved today. (23)


The Hatch-Waxman Act modifies the ANDA process to allow BE to be used for generic drugs post-1962 in place of safety and efficacy data. This approach offered a cost- and time-efficient solution for generic drug manufacturers to prove that their generic drugs were as safe and effective as the brand name reference drugs. (24) The definition of BE is "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents of pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an ... appropriately designed study." (25)

BE enables generic drugs to bypass clinical studies by assuming the same active ingredient, if absorbed into the blood stream at the same rate and to the same extent, will act identically to the innovator product. (26) BE compares the rate and extent of active ingredient absorption between generic and innovator products. (27)

BE uses pharmacokinetic measures from an accessible biological matrix such as blood, plasma, or serum. This allows measurement of the release of the active ingredient from the drug product into the systemic circulation. (28)

Calculation of BE uses a statistical method of analysis employing log-transformed average ratios of the rate and extent of drug absorption. (29) The rate of absorption is evaluated by maximum concentration ("Cmax") and the time required to achieve this value ("Tmax"). (30) The extent of absorption is the "area under the concentration-time curve, [known as] AUC." (31)

The AUC for the reference drug is measured, and then the AUC for the test drug is measured. (32) Those two measurements are put into a ratio: AUC(test) divided by AUC(ref) and log transformed. (33) This is also done for Cmax measurements. (34) Both measurements must fall within a 90% confidence interval within the BE limits of 0.8 to 1.25 to be declared BE. (35) The 80% to 125% (reciprocal of 80%: (100/80) x 100=125%) boundaries reflect the range of the 90% confidence interval. (36) Both the ratios for Cmax and AUC must be within the 0.8 to 1.25 limits of the 90% confidence interval for the drug to be BE. (37)

BE studies are usually done in a two-way crossover study with a minimum of twenty-four subjects. (38) An absence of significant difference is required to declare BE. (39) Note that the 0.8 to 1.25 limit is not a measurement of absolute difference in blood plasma levels between generic and brand name drugs; this is a common misconception and does not address the real concerns with the BE tests. (40)

The actual difference between generic and brand name drugs when the active ingredient in blood plasma is compared, according to the AUC test, is usually about 3.5%. (41) Hence, if generic drugs were to have active ingredient in blood plasma compared to the innovator product of more than 12% to 13%, they are unlikely to fall within the BE range of 80% to 125%. Thus, a true variation of plus or minus 20% should not meet BE criteria. (42) Several sources speak of 40% to 50% variation based on the broad confidence interval limits of 0.8 to 1.25. (43) Such large variation among drugs would fall outside the 90% confidence interval and not meet BE requirements for generic approval. While some studies claim Cmax variation of more than 15%, other studies claim this would be impossible if both the 90% confidence interval and the BE limits of 0.8 to 1.25 are met. (44)

In addition to BE, products approved under the ANDA must be "pharmaceutically equivalent." (45) Pharmaceutical equivalence is defined as use of the same active ingredients, route of administration, dosage, form, and strength as the reference drug. (46) The FDA considers drugs "therapeutic equivalents" if they are pharmaceutical equivalents and show BE. (47)



It should be noted that the approaches to BE have been altered over the past several decades. Some recommendations for approaches to BE were included in the 1992 guidance on "Statistical Procedures for Bioequivalence Studies." (48) The specific recommendations were: 1) logarithmic transformation of pharmacokinetic data, 2) methods to evaluate sequence effects, and 3) methods to evaluate outlier data. (49) The guidance also recommended that statistical analysis be based on two one-sided crossover tests to determine whether the average values for the pharmacokinetic measures were comparable for generic and brand name drugs. (50) These recommendations have been influential for current BE standards. These current BE standards, however, have created confusion and debate, particularly in the context of NTI drugs.


BE was put into place to eliminate seemingly unnecessary and costly safety steps in the drug approval process. As a result, the criteria for BE are important in maintaining high drug safety standards. Many scientists and clinicians are confused about BE ranges and what they actually mean. Dr. Janet Woodcock, Director of the FDA's Center for Drug Evaluation and Research, said, "[T]he FDA permits generic drugs to absorb at a 25% different rate and extent than the original copy." (51) As previously noted, an acceptable difference in blood plasma levels between most generics and brand name drugs is 3. …

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