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Bioequivalence of Highly Variable Drugs: A Comparison of the Newly Proposed Regulatory Approaches by FDA and EMA

Pharmaceutical Research volume 29, pages 1066–1077 (2012)Cite this article

ABSTRACT

Purpose

To explore the comparative performance of the recently proposed bioequivalence (BE) approaches, FDAs and EMAs, by the FDA working group on highly variable drugs and the EMA, respectively; to compare the impact of the GMR-constraint on the two approaches; and to provide representative plots of % BE acceptance as a function of geometric mean ratio, sample size and variability.

Methods

Simulated BE studies and extreme GMR versus CV plots were used. Three sequence, three period crossover studies with two treatments were simulated using four levels of within-subject variability.

Results

The FDAs and EMAs approaches were identical when variability was <30%. In all other cases, the FDAs method was more permissive than EMAs. The major discrepancy was observed for variability values >50%. The GMR-constraint was necessary for FDAs, especially for drugs with high variabilities. For EMAs, the GMR-constraint only became effective when sample size was large and variability was close to 50%.

Conclusions

A significant discrepancy in the performances of FDAs and EMAs was observed for high variability values. The GMR-constraint was essential for FDAs, but it was of minor importance in case of the EMAs.

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Abbreviations

90% CI:

90% confidence interval

AUC :

area under the curve

BE:

bioequivalence

C max :

peak plasma concentration

CV w :

coefficient of variation

CV wR :

coefficient of variation corresponding to s 2 wR

EMAnc :

modified EMA approach without GMR-constraint

EMAs :

scaled approach proposed by EMA

FDAnc :

modified FDA approach without GMR-constraint

FDAs :

scaled approach proposed by FDA scientists

GMR:

geometric mean ratio

HVDs:

highly variable drugs

k :

scaling factor of the limits proposed by EMA

PK:

pharmacokinetic(s)

R:

reference product (i.e., the innovator’s product)

s 2 w :

within-subject variability

s 2 wR :

within-subject variability of the reference product

s 2 wT :

within-subject variability of the test product

s w0 :

constant referring to regulatory standardized variation of FDAs limits

s wR :

standard deviation corresponding to s 2 wR

T:

test product (i.e., product under evaluation)

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ACKNOWLEDGMENTS & DISCLOSURES

The authors wish to thank the reviewers for their constructive critique and helpful comments which improved the quality of this manuscript.

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Authors and Affiliations

  1. Laboratory of Biopharmaceutics-Pharmacokinetics Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, 15771, Greece

    Vangelis Karalis, Mira Symillides & Panos Macheras

Authors
  1. Vangelis Karalis
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  2. Mira Symillides
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  3. Panos Macheras
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Correspondence to Vangelis Karalis.

APPENDIX

APPENDIX

Three period, three sequence crossover (3x3) bioequivalence studies, with equal number of subjects in each sequence, were simulated using the FDAs and EMAs approaches. The design of these studies was: TRR, RTR, RRT. In each simulated BE study, determination of bioequivalence was based on the 90% CI around the GMR of T and R drugs. Several levels of sample size were assumed: 18, 24, 30, 36, 48, 60, 72, 84, 96, 108, 120, and 150 subjects. Within-subject variability of the R was set equal to T. For the simulations, several levels of variability were considered: 20%, 40%, 50%, and 70%. The percentages of acceptance, for the FDAs (27) and EMAs (3) methods, were recorded and plotted as a function of GMR.

These power curves are shown in Figs. 5 and 6 for FDAs and EMAs, respectively. Only the region where the GMR lies between 0.80 and 1.25 is depicted in Figs. 5 and 6. This range of GMR was deliberately chosen, since it corresponds to the area defined by the complementary constraint criterion on GMR.

Fig. 5
figure 5

Percent of studies accepted as a function of GMR for the FDAs approach (27). Sample size (from bottom to top) is: 18, 24, 30, 36, 48, 60, 72, 84, 96, 108, 120, and 150. Four levels of within-subject variability are shown: 20%, 40%, 50%, and 70%.

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Fig. 6
figure 6

Percent of studies accepted as a function of GMR for the EMAs approach (3). Sample size (from bottom to top) is: 18, 24, 30, 36, 48, 60, 72, 84, 96, 108, 120, and 150. Four levels of within-subject variability are shown: 20%, 40%, 50%, and 70%.

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Karalis, V., Symillides, M. & Macheras, P. Bioequivalence of Highly Variable Drugs: A Comparison of the Newly Proposed Regulatory Approaches by FDA and EMA. Pharm Res 29, 1066–1077 (2012). https://doi.org/10.1007/s11095-011-0651-y

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KEY WORDS

  • bioequivalence
  • European Medicines Agency
  • Food and Drug Administration
  • highly variable drugs
  • replicate design