EMA: FDC products (lenghty post) [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2020-07-17 14:30 (95 d 18:32 ago) – Posting: # 21733
Views: 676

Hi A.Shtaiwi,

the EMEA (European Agency for the Evaluation of Medicinal Products) was renamed to EMA (European Medicines Agency) back in 2005. ;-)

Since you have two APIs, you have to assess both in all studies. See the EMA’s Guideline on clinical development of fixed combination medicinal products, Section 4.5:

[…] bioequivalence with the reference fixed combination medicinal product […] should be demonstrated for all active substances in the fixed combination medicinal product according to the relevant guidelines.


[image]One caveat: Some European agencies are increasingly concerned about ‘drifting’ of bioavailability (as mentioned in the GL) and may ask additionally for BE of the new combo versus single components or a justification why such a potential drift is clinically not relevant.
See Marina Feřtek’s presentation (BioBridges, Prague 2017). In your case that might not be possible if either the 1st API (IR component) or the 2nd API (MR component) are not – or no more – marketed as mono products.
Recently I supported an adjusted indirect comparison a,b for Czechia’s SÚKL;  outcome pending  accepted. c


  1. Adjusted indirect comparison because an adjustment is performed for different sample sizes and (optionally) within-subject variances which might differ between studies.
    Most papers1–11 on the topic were co-authored by regulators. The CI will always be wider than in a hypothetical head-to-head study because variances are additive. Furthermore, studies were not powered for such a comparison. Hence, a wider acceptance range of 70.00–142.86% was proposed.5
  2. Example
    1. Information
      1. PAR of the originator: Combo (TAB) vs. single components (RA, RB).
        Sample size, PE, and 90% CI of A(TAB) vs. RA and B(TAB) vs. RB.
      2. BE study: Generic combo (TAB) vs. originator’s combo (RAB).
        ANOVAs: A(TAB) vs. A(RAB) and B(TAB) vs. B(RAB).
    2. Indirect comparison
      1. Assume that TAB of the originator’s study = RAB of the BE study. Cross fingers that the reference does not show large batch-to-batch variability.
      2. Calculate PE and 90% CI of the generic combo vs. the components.

      • Simple example assuming equal sample sizes (point estimates only, the CI is tricky):
        Originator’s study (a.1.)
          Component A: PE =   95%
          Component B: PE = 110%
        Generic combo (a.2.)
          Component A: PE =  90%
          Component B: PE = 105%
        Indirect comparison
          Component A: PE = (  90 ×   95) / 100 =   85.5%
          Component B: PE = (105 × 110) / 100 = 115.5%

  3. Submitted mid June, accepted end of August. :thumb up:
    • Assessment of the Applicant’s Response:
      The Applicant provided in the response results of indirect comparison of treatments with respect to pharmacokinetic (PK) parameters Cmax, AUC0–t and AUC0–inf both for ░░░░░░ and ░░░░░░. The Applicant also provided computational formulas for such indirect comparisons which are acceptable.
      For comparison scenario “▒▒▒▒ Study vs. PAR”, indirect comparison led to conclusion of BE as 90% confidence interval (CI) for treatment ratio was entirely within standard BE limits (80%, 125%) for all PK parameters both for ░░░░░░ and ░░░░░░.
      Thus, the issue regarding BE drift is resolved. The Applicant adequately justified that no potential risk of “drifting” of bioequivalence exists in this case.
      The issue is resolved.


  1. Gwaza L, Gordon J, Welink J, Potthast H, Hansson H, Stahl M, García-Arieta A. Statistical approaches to indirectly compare bioequivalence between generics: a comparison of methodologies employing arte­me­ther / lume­fan­trine 20 / 120 mg tablets as prequalified by WHO. Eur J Clin Pharmacol. 2012; 68(12): 1611–8. doi:10.1007/s00228-012-1396-1.
  2. Herranz M, Morales-Alcelay S, Corredera-Hernández MA, de la Torre-Alvarado JM, Blázquez-Pérez A, Suá­rez-Gea ML, Álvarez C, García-Arieta A. Bioequivalence between generic tacrolimus products marketed in Spain by adjusted indirect comparison. Eur J Clin Pharmacol. 2013; 69(5): 1157–62. doi:10.1007/s00228-012-1456-6.
  3. Gwaza L, Gordon J, Welink J, Potthast H, Leufkens H, Stahl M, García-Arieta A. Adjusted Indirect Treatment Comparison of the Bioavailability of WHO‐Prequalified First‐Line Generic Antituberculosis Medicines. Clin Pharmacol Ther. 2014; 96(5): 580–8. doi:10.1038/clpt.2014.144.
  4. Yu Y, Teerenstra S, Neef C, Burger D, Maliepaard M. Investigation into the interchangeability of ge­neric formulations using immunosuppressants and a broad selection of medicines. Eur J Clin Pharmacol. 2015; 71(8): 979–80. doi:10.1007/s00228-015-1878-z. [image] Open access.
  5. Gwaza L, Gordon J, Potthast H, Welink J, Leufkens H, Stahl M, García-Arieta A. Influence of point estimates and study power of bioequivalence studies on establishing bioequivalence between generics by adjusted indirect comparisons. Eur J Clin Pharmacol. 2015; 71(9): 1083–9. doi:10.1007/s00228-015-1889-9.
  6. Gwaza L. Adjusted Indirect Treatment Comparisons of Bioequivalence Studies. PhD Thesis: Utrecht. 2016. [image] Open access.
  7. García Arieta A, Potthast H, Leufkens H, Welink J, Gordon J, Gwaza L, Maliepaard M, Stahl M. Assessment of the interchangeability between generics. GaBI J. 2016; 5(2): 55–9. doi:10.5639/gabij.2016.0502.015. [image] Open access.
  8. Gwaza L, Gordon J, Leufkens H, Stahl M, García-Arieta A. Global Harmonization of Comparator Products for Bioequivalence Studies. AAPS J. 2017; 19(3): 603–6. doi:10.1208/s12248-017-0068-6.
  9. Zheng J, Chow S-C, Yuan M. On assessing bioequivalence and interchangeability between generics based on indirect comparisons. Stat Med. 2017; 36(19): 2978–93. doi:10.1002/sim.7326.
  10. Wang YL, Hsu LF. Evaluating the Feasibility of Use of a Foreign Reference Product for Generic Drug Applications: A Retrospective Pilot Study. Eur J Drug Metab Pharmacokinet. 2017; 42(6): 935–42. doi:10.1007/s13318-017-0409-y.
  11. Pejčić Z, Vučićević K, García-Arieta A, Miljković B. Adjusted indirect comparisons to assess bioequivalence between generic clopidogrel products in Serbia. Br J Clin Pharmacol. 2019; 85: 2059–65. doi:10.1111/bcp.13997.

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