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• W2026948045 abstract "Immunosuppressants are considered critical dose/narrow therapeutic index drugs and there is the lingering suspicion among physicians and patients that generic versions may differ in quality and therapeutic efficacy from the brand name drug. The innovator's and the generic active drug molecule are exactly the same and are produced following exactly the same tight rules of good manufacturing practice. Upon oral administration, the drug molecule separates from the formulation and passes the membranes of gut mucosa cells; from this point on, the formulation has no influence on the kinetics of a drug and its biological effects. As formulations may differ, bioequivalence testing in healthy volunteer studies establishes equal relative oral bioavailability. Due to the number of patients required to achieve sufficient statistical power, to test the therapeutic equivalence of two formulations of the same drug with the same bioavailability is an unrealistic goal. An often overlooked fact is that the approval by drug regulatory agencies of several post-approval versions of the innovators’ immunosuppressants is based on the identical guidelines used for approval of generics. The FDA has issued specific guidelines describing the requirements for approval of generic versions of tacrolimus, sirolimus, and mycophenolic acid. The standard average bioequivalence approach is recommended and in the cases of tacrolimus and sirolimus, the effect of food should also be tested. No studies in the patient population are requested. Immunosuppressants are not regarded as drugs that require a special status to establish bioequivalence between generic and the innovator's versions. Immunosuppressants are considered critical dose/narrow therapeutic index drugs and there is the lingering suspicion among physicians and patients that generic versions may differ in quality and therapeutic efficacy from the brand name drug. The innovator's and the generic active drug molecule are exactly the same and are produced following exactly the same tight rules of good manufacturing practice. Upon oral administration, the drug molecule separates from the formulation and passes the membranes of gut mucosa cells; from this point on, the formulation has no influence on the kinetics of a drug and its biological effects. As formulations may differ, bioequivalence testing in healthy volunteer studies establishes equal relative oral bioavailability. Due to the number of patients required to achieve sufficient statistical power, to test the therapeutic equivalence of two formulations of the same drug with the same bioavailability is an unrealistic goal. An often overlooked fact is that the approval by drug regulatory agencies of several post-approval versions of the innovators’ immunosuppressants is based on the identical guidelines used for approval of generics. The FDA has issued specific guidelines describing the requirements for approval of generic versions of tacrolimus, sirolimus, and mycophenolic acid. The standard average bioequivalence approach is recommended and in the cases of tacrolimus and sirolimus, the effect of food should also be tested. No studies in the patient population are requested. Immunosuppressants are not regarded as drugs that require a special status to establish bioequivalence between generic and the innovator's versions. In the United States and many other countries in the world, companies are free to manufacture interchangeable generic products once the innovator's patent protection of a ‘brand name’ drug expires. However, since the availability of generic versions of brand name drugs, there has always been the lingering suspicion among physicians and patients that generic drugs may differ in quality and therapeutic efficacy and may put patients at risk.1.Shrank W.H. Cox E.R. Fisher M.A. et al.Patient's perception of generic medications.Health Affairs. 2009; 28: 546-556Crossref PubMed Scopus (179) Google Scholar,2.Shrank W.H. Cadarette S.M. Cox E. et al.Is there a relationship between patient beliefs or communication about generic drugs and medication utilization?.Med Care. 2009; 47: 319-325Crossref PubMed Scopus (65) Google Scholar It cannot be denied that in several cases, such fears have been encouraged by innovators to protect their market share and pricing. Early scientific evidence, mostly from the 1970s, recognized that even when two drug products contained the same active component at the same dose, small changes in the product formulation could result in significant differences in oral bioavailability. Several cases of lack of effect or intoxication after administration of pharmaceutically equivalent generic drug products were reported.3.Gleiter C.H. Gundert-Remy U. Bioinequivalence and drug toxicity: How great is the problem and what can be done?.Drug Safety. 1994; 11: 1-6Crossref PubMed Scopus (26) Google Scholar As a response to these reports, in 1974, in the United States, the Office of Technology Assessment established the Drug Bioequivalence Study Panel to develop clinical and statistical procedures for establishing bioequivalence between pharmaceutical equivalents. The recommendations were implemented by the Food and Drug Administration (FDA) and codified in 21 CFR Part 320.4.Barrett J.S. Batra V. Chow A. et al.PhRMA perspective on population and individual bioequivalence.J Clin Pharmacol. 2000; 40: 561-570Crossref PubMed Google Scholar Pharmaceutical equivalents contain the same active ingredient, are administered by the same route in the same dosage form, and are of identical strength and concentration.5.Benet L.Z. Understanding bioequivalence testing.Transplant Proc. 1999; 31: 7S-9SAbstract Full Text Full Text PDF PubMed Google Scholar In 1984, the Drug Price Competition and Term Restoration Act6.Drug Price Competition and Patent Term Restoration Act. Public law 98–417, 98.Stat. 1984; : 1585-1605Google Scholar permitted the FDA to use a simplified approval process for generic products of drugs, so-called abbreviated new drug applications (ANDA).7.Code of Federal Regulations, 21, Food and Drugs, Part 314.94, Content and format of an abbreviated application, 1995, pp 134. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314&showFR=1 (accessed 14 September 2009).Google Scholar In summary, a generic drug product has to meet compendial, bioequivalence, and good manufacturing standards. Although the approval of generics is a tightly regulated and proven process with an excellent safety track record,5.Benet L.Z. Understanding bioequivalence testing.Transplant Proc. 1999; 31: 7S-9SAbstract Full Text Full Text PDF PubMed Google Scholar as of today, frequent arguments against generic drugs mentioned by physicians and patients alike are the following:●The quality of generics is sometimes lower than that of the originator drug.●The FDA acceptance limits for generics are 80–125%. This is a potential difference of as much as 45%!●Generic drugs are tested only in healthy volunteers and may act differently in the target disease population, resulting in uncontrolled clinical risks.●Generics of so-called ‘critical dose’ drugs are especially dangerous. It is the goal of our review to address these arguments in detail. Today, demonstration of average bioequivalence between the brand name drug (reference) and a generic drug product (test drug) is a requirement for approval by drug regulatory authorities in the United States8.Center for Drug Evaluation and Research, U.S. Department of Health and Human Services. Guidance for industry. Bioavailability and bioequivalence. Study for orally administered drug products. General considerations. March 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070124.pdf (accessed 14 September 2009).Google Scholar and most other countries. The components of a drug product can be divided into two major components: the drug molecule (this may be the active drug or a prodrug, such as mycophenolate mofetil, which is converted into the active principle in the body) and the drug formulation. Whereas the drug molecule is responsible for therapeutic effects and potential drug-related adverse effects, the only purpose of the formulation is to deliver the drug into the system. It is critical to understand that, on oral administration, the drug molecule is separated from the formulation and passes the membranes of the gut mucosa cells, and hereafter, the formulation has no influence on the kinetics of a drug and its biological effects. The overall therapeutic/toxicological effects of a drug are determined by two basic principles: its kinetics (pharmacokinetics/toxicokinetics) and its dynamics (pharmacodynamics/toxicodynamics). Pharmacokinetics/toxicokinetics describes the way the body handles the drug molecule, including its absorption, the time-dependent concentration changes of the drug in blood and tissues, and the elimination of the drug from the body. Pharmacodynamics and toxicodynamics describe the effects that a drug has in the body that can treat a disease and/or that may cause toxic effects. This includes the drug molecule's interactions with its target molecules such as enzymes and receptors. The term bioequivalence describes both equivalence of pharmacokinetics/toxicokinetics and equivalence of pharmacodynamics/toxicodynamics. Bioequivalence is defined as ‘the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or 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.’8.Center for Drug Evaluation and Research, U.S. Department of Health and Human Services. Guidance for industry. Bioavailability and bioequivalence. Study for orally administered drug products. General considerations. March 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070124.pdf (accessed 14 September 2009).Google Scholar If bioequivalence has been established, drugs will be therapeutically equivalent and will exhibit equivalent tolerability and safety profiles. The FDA guidance assumes bioequivalence when the same bioavailability can be demonstrated.8.Center for Drug Evaluation and Research, U.S. Department of Health and Human Services. Guidance for industry. Bioavailability and bioequivalence. Study for orally administered drug products. General considerations. March 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070124.pdf (accessed 14 September 2009).Google Scholar Oral bioavailability is defined as ‘the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action…’. This assumption is correct for the following reason: Once absorbed, a drug molecule's behavior is completely independent of the formulation by which it was delivered across the gut mucosa. This includes its pharmacodynamics (its therapeutic potency and efficacy), its tolerability, safety, and its elimination (clearance) from the body. As the efficacy and safety of an innovator's drug has already been established, the FDA regulations are promulgated without repetition of the same studies of the generic version of the drug, as it contains exactly the same molecular entity as the innovator's product. Oral delivery of a drug may be affected by its formulation, but also by interactions in the gut including the presence of food or gut bacteria, gut motility, and gut disease processes such as infections and inflammation. The only drug-specific component with the potential to differ between an innovator's version of the drug and a generic version is the formulation. The goal of bioequivalence testing is to demonstrate that this is not the case.9.Center for Drug Evaluation and Research, U.S. Department of Health and Human Services. Guidance for industry. Bioequivalence recommendations for specific products. Draft May 2007. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072872.pdf (accessed 14 September 2009).Google Scholar As aforementioned, bioequivalence studies typically aim to demonstrate that two pharmaceutical equivalents have similar pharmacokinetics.10.Schall R. Luus H.G. On population and individual bioequivalence.Stat Med. 1993; 12: 1109-1124Crossref PubMed Scopus (149) Google Scholar The standard bioequivalence trial is conducted according to a randomized 2-period crossover design and typically includes between 12 and 36 healthy adults with an appropriate washout between study periods. The key issue in bioequivalence testing is to demonstrate similar oral bioavailability. As pharmaceutical equivalents are orally administered, absolute bioavailability cannot be determined directly. Area under the time concentration curve (AUC) measurements serve as a surrogate for the extent of absorption or systemic exposure. The maximum plasma concentration (Cmax) and the time of its occurrence (tmax) together characterize the rate of absorption.11.Garbe E. Röhmel J. Gundert-Remy U. Clinical and statistical issues in therapeutic equivalence trials.Eur J Clin Pharmacol. 1993; 45: 1-7Crossref PubMed Scopus (48) Google Scholar Test and reference product are considered equivalent when the 90% confidence interval for the true formulation means (μtest/μreference) falls within the acceptance limits of 0.8–1.25.12.Schuirmann D.J. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability.J Pharmacokinet Biopharm. 1987; 15: 657-680Crossref PubMed Scopus (1962) Google Scholar,13.Food and Drug Administration (FDA)Bioavailability and bioequivalence requirements.Fed Regist. 1992; 57: 17997-18001Google Scholar In practice, the confidence interval approach is carried out using log-transformed data.14.Sauter R. Steinijans V.W. Diletti E. et al.Presentation of results from bioequivalence studies.Int J Clin Pharmacol Ther Toxicol. 1992; 30: 233-256PubMed Google Scholar The 0.8–1.25 bioequivalence acceptance range translates into a difference of -20 to +25% in the rate and extent of absorption between the two drug products. These acceptance limits are arbitrary and are based on the observation that a -20 to +25% difference in the concentration of the active ingredient in blood will not be clinically significant.5.Benet L.Z. Understanding bioequivalence testing.Transplant Proc. 1999; 31: 7S-9SAbstract Full Text Full Text PDF PubMed Google Scholar,15.Benet L.Z. Bioavailability and bioequivalence: definitions and difficulties in acceptance criteria.in: Midha K.K. Blume H. Bio-International Bioavailability: Bioequivalence and Pharmacokinetics. Medpharm, Stuttgart1993: 27-35Google Scholar It is important to recognize that it is the upper and lower limit of the 90% confidence interval for the true mean ratios and not only the mean ratio (point estimate) that must be within the bioequivalence acceptance limits.5.Benet L.Z. Understanding bioequivalence testing.Transplant Proc. 1999; 31: 7S-9SAbstract Full Text Full Text PDF PubMed Google Scholar The 90% confidence interval is a measure of total variability, which is influenced by both inter- and intra-individual variability.16.Midha K.K. Rawson M.J. Hubbard J.W. The bioequivalence of highly variable drugs and drug products.Int J Clin Pharmacol Ther. 2005; 43: 485-489Crossref PubMed Scopus (65) Google Scholar,17.Patnaik R.N. Lesko L.J. Chen M.L. et al.FDA Individual bioequivalence Working GroupIndividual Bioequivalence: new concepts in the statistical assessment of bioequivalence metrics.Clin Pharmacokinet. 1997; 33: 1-6Crossref PubMed Scopus (70) Google Scholar Variability is a factor that has a significant impact on acceptance or rejection in average bioequivalence testing. The width of the 90% confidence interval is dependent on both the magnitude of the within-subject variability of the reference drug and the number of subjects. Bioequivalence testing compares the quality of reference and test formulations. Therefore, the tighter the intra-subject variability of the oral bioavailability of the brand name drug, the more difficult it is for the generic version to meet bioequivalence acceptance criteria. The FDA's approval process of generic drugs evaluates chemistry, manufacturing and controls, in vivo bioequivalence, labeling, in vitro dissolution, if applicable, and includes inspection and auditing of all facilities. Identical to the innovator's regulatory submission, the manufacturer of a generic drug must submit a chemistry, manufacturing, and control package to the FDA for review. The required testing includes, but is not limited to, quality and purity of the drug, stability of the drug substance and formulated drug, batch reproducibility, and the establishment of a quality system for batch release. Manufacturing of a generic drug, just as for manufacturing the brand name drug, has to comply with the rules of good manufacturing practice.18.Dighe S.V. A review of the safety of generic drugs.Transplant Proc. 1999; 31: 23S-24SAbstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar As aforementioned, it is the upper and lower limit of the 90% confidence interval for the true mean ratios and not only the mean ratio (point estimate) that must be within the bioequivalence acceptance limits.5.Benet L.Z. Understanding bioequivalence testing.Transplant Proc. 1999; 31: 7S-9SAbstract Full Text Full Text PDF PubMed Google Scholar To fit the 90% confidence interval within the 80–125% acceptance limits, the generic drug and the innovator have to be almost identical. The only theoretical exception is if the generic drug formulation has a markedly lower variability than the innovator's formulation. However, even then, a deviation of 15% is almost impossible and additional studies would most likely be requested. Indeed, an analysis of 224 approved generic drugs showed the mean difference of the point estimates of the area under the time concentration curves to be within 3.5% of that of the innovator's formulation and 80% of the area under the time concentration curve point estimates to be within ±5% of those of the innovator's formulations.19.Nightingale S.L. Morrison J.C. Generic drugs and the prescribing physician.J Am Med Assoc. 1987; 258: 1200-1204Crossref PubMed Scopus (72) Google Scholar When assessing these numbers, it should also be considered that the bioanalytical assays used for these studies are allowed to have a total imprecision of up to 15% and a between-day accuracy of between 85 and 115%.20.Center for Drug Evaluation and Research, U.S. Department of Health and Human Services. Guidance for industry. Bioanalytical method validation. May 2001. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf (accessed 14 September 2009).Google Scholar Even if modern bioanalytical assays usually perform better and samples are run in as few batches as possible to reduce variability, considering that bioanalytical assays still add to the overall variability of the results, it seems reasonable to assume that relative bioavailability of most innovators’ formulations and generic formulations is almost identical. Even if the innovator's batches or even the same batch of an innovator's drug is compared, the results are not always exactly the same.21.Christians U. First M.R. Benet L.Z. Recommendations for bioequivalence testing of cyclosporine generics revisited.Ther Drug Monit. 2000; 22: 330-345Crossref PubMed Scopus (32) Google Scholar An adjunct question on this topic is why use relative bioavailability as a surrogate marker instead of establishing therapeutic equivalence? It is important to note that it is necessary to establish relative bioavailability in a healthy volunteer population first. To avoid exposing patients to undue risks due to a potential lack of therapeutic efficacy or toxicity, bioequivalence between the innovator drug and a generic must be shown before the drugs can be compared in a patient population. To test for therapeutic equivalence, patients should be randomly divided into two separate study groups, with one group of patients treated with the reference formulation and the other receiving the test product. Parameters included in the analysis would be the incidence and severity of side effects and therapeutic efficacy. An acceptable sensitivity would be about ≤10% difference between the study groups receiving the test and reference formulation. Taking that into consideration, after a successful comparison in healthy volunteers, two bioequivalent drug formulations will be compared. The number of study subjects required to result in reasonable statistical power (≥80%) would easily exceed those required for phase III clinical trials and be prohibitive in terms of time and costs.22.McGilveray I.J. Gallicano K. Generic drugs: the Canadian perspective.Transplant Proc. 1999; 31: 16S-18SAbstract Full Text Full Text PDF PubMed Google Scholar Although several therapeutic efficacy studies between alternative bioequivalent formulations of immunosuppressants have been described, it is reasonable to assume that, statistically speaking, these studies were severely underpowered and would not have detected potential differences. A good example of such a study was the comparison of the efficacy and safety of Neoral with that of Sandimmune in 466 renal transplant patients.23.Taesch S. Niese D. Safety and tolerability of a new oral formulation of cyclosporin A, Sandimmun Neoral, in renal transplant patients.Transplant Int. 1994; 7: S263-S266Crossref PubMed Scopus (42) Google Scholar Although Sandimmune and Neoral are not bioequivalent, the overall incidence of adverse events was similar, even with an increase in the exposure of patients to cyclosporine in the test group after a 1:1 switch to Neoral. In addition, there was no difference in kidney function. Nephrotoxicity is a frequent side effect of cyclosporine. The results of this study comparing two not-bioequivalent cyclosporine formulations indicated that the detection or exclusion of differences in the safety and efficacy of two bioequivalent cyclosporine formulations with reasonable sensitivity and statistical power would be practically impossible using this quantity of patients. The few studies that claimed to show a difference24.Qazi Y.A. Forrest A. Tornatore K. et al.The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function.Clin Transplant. 2006; 20: 313-317Crossref PubMed Scopus (32) Google Scholar, 25.Haug III, M. Wimberley S.L. Problems with the automatic switching of generic cyclosporine oral solution for the innovator product.Am J Health Syst Pharm. 2000; 57: 1349-1353PubMed Google Scholar, 26.Taber D.J. Baillie G.M. Ashcraft E.E. et al.Does bioequivalence between modified cyclosporine formulations translate into equal outcomes?.Transplantation. 2005; 80: 1633-1635Crossref PubMed Scopus (49) Google Scholar were statistically underpowered and/or flawed in other ways and have not prompted drug regulatory authorities to take any action. With very few exceptions such as direct interactions of the formulation with drugs in the gut lumen with drugs such as chelators, resins, or ion exchangers, once the drug is absorbed, most clinically significant drug–drug interactions occur in the gut and/or the liver, at the drug-metabolizing enzymes, and/or active drug transporters. Again, on absorption, the drug molecule will behave in exactly the same manner after delivery, regardless of its formulation. For this reason, the effects of genetic polymorphisms, drug–drug and disease–drug interactions in the liver or other organs will be similar and independent of whether the active molecule was delivered by a generic or the innovator's formulation. It should be noted that ethnic differences in pharmacokinetics are mostly due to different distribution patterns of polymorphisms of drug-metabolizing enzymes and/or active drug transporters in specific populations. A single isolated report showed that sirolimus absorption was affected differently by generic than by the innovator's cyclosporine formulations.27.Kovarik J.M. Noe A. Wang Y. et al.Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus.Eur J Clin Pharmacol. 2006; 62: 361-366Crossref PubMed Scopus (16) Google Scholar Intestinal drug–drug interactions are a general problem in transplantation and can occur when foods, herbal drugs, and other drug formulations are taken in at the same time as the immunosuppressants. Changing the cyclosporine concentration will also affect sirolimus blood concentrations. This will happen with both the innovator and generic formulations. Even the most extensive new drug development will not be able to predict or study all possible interactions. Most of the coadministered drugs with the potential to interact with immunosuppressants have never been specifically tested in a transplant population but, regardless, they have safely been used. Drug–drug interactions greatly depend on factors such as pharmacogenomics, the presence of other drugs, and liver function. The extent of a drug–drug interaction will depend on the nature, dose, and duration of administration of the interacting drug rather than on the formulation of the immunosuppressant, and will also require blood concentration measurement and possibly dose adjustments. Owing to confounding factors, it is more difficult to detect potential differences between two formulations in a patient population that exhibits significant variability. For this reason, a rigorously controlled study in healthy individuals is more likely to show potential differences between a brand name immunosuppressant and a generic version than studies in the more variable and less well-controlled target patient population. The terms ‘narrow therapeutic’ and ‘critical dose’ drugs are often used interchangeably. Benet and Goyan28.Benet L.Z. Goyan J.E. Bioequivalence and narrow therapeutic index drugs.Pharmacotherapy. 1995; 15: 433-440PubMed Google Scholar defined narrow therapeutic index drugs as ‘those for which small changes in pharmacokinetic response lead to marked changes in pharmacodynamic response.’ This means that, in general, narrow therapeutic index drugs have a steep dose–response curve (for a detailed discussion, see 29.Levy G. What are narrow therapeutic index drugs?.Clin Pharmacol Ther. 1998; 63: 501-505Crossref PubMed Scopus (40) Google Scholar). The FDA defines narrow therapeutic index drugs as follows: (1) there is a less than twofold difference in median lethal dose (LD50) and median effective dose (ED50) values or (2) there is less than a twofold difference in the minimum toxic concentrations and minimum effective concentrations in blood, and (3) safe and effective use of the drug product requires careful titration.29.Levy G. What are narrow therapeutic index drugs?.Clin Pharmacol Ther. 1998; 63: 501-505Crossref PubMed Scopus (40) Google Scholar,30.Williams R.L. FDA position on product selection for ‘narrow therapeutic index drugs’.Am J Health Syst Pharm. 1997; 54: 1630-1632PubMed Google Scholar There seems to be a general consensus that immunosuppressive drugs such as cyclosporine, tacrolimus, the proliferation signal inhibitors such as sirolimus and everolimus, and probably also mycophenolate and its derivatives should be considered narrow therapeutic index drugs.31.Johnston A. Belitsky P. Frei U. et al.Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients.Eur J Clin Pharmacol. 2004; 60: 389-395Crossref PubMed Scopus (25) Google Scholar On the other hand, highly variable drugs have been defined as a drug with a within-subject variability equal to or exceeding 30% of the maximum concentration (Cmax) or the area under the time concentration curve.16.Midha K.K. Rawson M.J. Hubbard J.W. The bioequivalence of highly variable drugs and drug products.Int J Clin Pharmacol Ther. 2005; 43: 485-489Crossref PubMed Scopus (65) Google Scholar Approved high variability drugs are generally safe and often have relatively flat dose–response curves. In the case of drugs with high within-subject variability and a steep dose–response curve, patients will frequently experience episodes of a lack of therapeutic effect (drug exposure too low) or toxicity (drug exposure too high). These drugs typically fail during clinical drug development.28.Benet L.Z. Goyan J.E. Bioequivalence and narrow therapeutic index drugs.Pharmacotherapy. 1995; 15: 433-440PubMed Google Scholar Therefore, approved drugs with a steep dose–response curve such as narrow index drugs have relatively low within-subject variability. Although bioequivalence testing for highly variable drugs is a challenge that requires large numbers of subjects to achieve adequate statistical power, testing the bioequivalence of narrow therapeutic index drugs is comparatively straight forward. It is important to remember that the within-subject variability of the reference drug determines the bioequivalence acceptance limits. Low intra-subject variability of the reference drug raises the bar for the test formulation and the generic version must meet these tight acceptance criteria. Although the significant subject–formulation interaction of highly variable drugs may cause a subset of subjects to respond differently to the test and reference formulations, this is hardly ever the case with two bioequivalent formulations of a narrow therapeutic index drug. In addition, owing to the narrow inter-subject variability, testing would reveal that the formulations ar" @default.
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