NTI drugs are drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. Drugs are considered to have an NTI when comparison of the 50% median effective dose (ED50) and 50% median lethal dose (LD50) is ≤2 [2]. The European Medicines Agency (EMA) requires bioequivalence of 90%–111% [3] for NTI drugs, but even this represents >23% variation.

The US Food and Drug Administration (FDA) accepts bioequivalence if the ratio of AUC_generic to AUC_branded and C_{max generic} to C_{max branded}, for the average of the sample of participants lies between 0.80%–1.25% of the originator medication, at the 90% confidence level for AUC and C_max [4, 5]. Despite this acceptable variation of between 80%–125%, some investigators confirmed a true variation of as much as ~70%–140% (namely 74%–142%), amounting to halving or doubling the true comparison [6, 7].

While the active ingredients, in the generic compound, may equate to that within the originator formulation, it may be reconstituted in a different format (referred to, by FDA, as pharmaceutical alternatives [7]. It may contain a different salt or ester of the active moiety or alternatively different dosages or strengths, e.g. the amlodipine salt may be besylate or camsylate, ferrous sulphate or gluconate [7]. This may result in different bioavailability with altered absorption or solubility characteristics directly modifying efficacy and safety [7].

Bioequivalent studies do not compare batch-to-batch variability nor country-to-country variations. In complex diseases, such as Parkinson’s disease, patients may absorb the medication more slowly, because of delayed gastric motility and possible co-medications, such as dopamine agonists, anticholinergic, monoamine oxidase inhibitors and antipsychotics, which may affect medication availability [8]. In addition, drug interactions, in conjunction with co-medications, may also not have been adequately addressed by simple bioequivalence studies in healthy volunteers [8].

Conflict of interest
The author of the research paper [1] declared that there was no conflict of interest.

Abstracted by Professor Roy G Beran, Neurology Department, Liverpool Hospital, Liverpool, Australia.

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References
1. Beran RG. Generic substitution in patients whose illness has a narrow therapeutic index, such as epilepsy. APHE. 2020;1(2):1-5.
2. Crawford P, Feely M, Guberman A, et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006;15(3):165-76.
3. European Medicines Agency. Guideline on the investigation of bioequivalence. Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** 20 January 2010 [homepage on the Internet]. [cited 2022 May 20]. Available from: www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf
4. Hill AM, Barber MJ, Gotham D. Estimated costs of production and potential prices for the WHO Essential Medicines List. BMJ Glob Health 2018;3(1):e000571.
5. Yu LX, Jiang W, Zhang X, et al. Novel bioequivalence approach for narrow therapeutic index drugs. Clin Pharmacol Ther. 2015;97(3):286-91.
6. American Academy of Neurology. Assessment: generic substitution for antiepileptic medication. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1990;40(11):1641-3.
7. Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand name psychoactive drugs. Clin Ther. 2003;25(6):1578-92.
8. Go CL, Rosales RL, Schmidt P, et al. Generic versus branded pharmacotherapy in Parkinson’s disease: does it matter? A review. Parkinsonism Relat Disord. 2011;17(5):308-12.

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