Nonclinical Development of Combination Drugs

  • Alberto LodolaEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1641)


We define “combination drugs” as “fixed-dose combinations” (FDCs), that is, two or more drugs (marketed or not) combined in a single pill or two or more separate drugs packaged together. FDCs have been available commercially for many years but only relatively recently have nonclinical development guidelines been released by a number of regulatory authorities and the World Health Organization; as yet there are no ICH guidelines specific to combination drugs. In general however, the ICH guidelines for monotherapy development provide a framework for FDC development. Depending on the type of drug combination (marketed drug/marketed drug; marketed drug/NME and NME/NME) the scope and complexity of toxicity studies will vary greatly. In all cases however, a key issue is the potential for pharmacokinetic and/or toxicologic interaction between the components. For a marketed drug/marketed drug combination a detailed review of the nonclinical data available may suffice, particularly when the components have a history of coadministration at about the same dose and ratio as that of the proposed combination. For a marketed drug/NME combination, in addition to a review of the data for the marketed drug, a full ICH program of studies will be required for the NME, and a study of up to 90-day duration (in one species) for the combination. With an NME/NME combination each component will require a full ICH battery of studies and a combination study in one species. In all cases additional studies may be needed to address data gaps. Given the many novel and complex issues which arise when developing FDCs we recommend that, whenever possible, the nonclinical study strategy is discussed with the regulatory authorities.

Key words

Combination drugs Fixed-drug combinations Regulatory guidelines Nonclinical issues Study design Dose selection Development strategies 


  1. 1.
    FDA (2006) Nonclinical safety evaluation of drug or biologic combinations.
  2. 2.
    EMA (2008) Guideline on the non-clinical development of fixed combinations of medicinal products.
  3. 3.
    TGA (2014) Fixed combination prescription medicines.
  4. 4.
    CADTH (2014) CADTH common drug review. Submission guidelines for the CADTH common drug review.
  5. 5.
    CDSCO (2010) Guidance for industry on fixed dose combinations (FDCs).
  6. 6.
  7. 7.
    Segal SA (1999) Device and biologic combination products. Understanding the evolving regulation. Medical Device and Diagnostic Industry. January. pp 180–184Google Scholar
  8. 8.
    Portnoy S, Koepke K (2005) Regulatory strategy. Preclinical testing of combination products. Medical Device and Diagnostic Industry. May. pp 152–157Google Scholar
  9. 9.
    Herxheimer H (1975) The danger of fixed drug combinations. Int J Clin Pharmacol Biopharma 12(1–2):70–73Google Scholar
  10. 10.
    Shenfield GM (1982) Fixed combination drug therapy. Drugs. 23(6):462–480CrossRefPubMedGoogle Scholar
  11. 11.
    Sica DA (2002) Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs 62(3):443–462CrossRefPubMedGoogle Scholar
  12. 12.
    Moulding T, Dutt AK, Reichman LB (1995) Fixed-dose combinations in antituberculous medications to prevent drug resistance. Ann Intern Med 122(12):955–956CrossRefGoogle Scholar
  13. 13.
    Majori G (2004) Combined antimalarial therapy using artemisinin. Parasitologia 46(1–2):85–87Google Scholar
  14. 14.
    Fechtner RD, Realini T (2004) Fixed combinations of topical glaucoma medications. Curr Opin Ophthalmol 15(2):132–135CrossRefPubMedGoogle Scholar
  15. 15.
    Prescott J, Manalo B (2011) Considerations for fixed-dose combination products in cardiometabolic disease.
  16. 16.
    Kararli TT (2010) Fixed dose combination (fdc) products overview.
  17. 17.
    Wertheimer A, Morrison A (2002) Combination drugs: innovation in pharmacotherapy. P&T 27(1):44–49Google Scholar
  18. 18.
    Hommer A (2011) Role of fixed combinations in the management of open-angle glaucoma. Exp Rev Pharmacoecon Outcomes Res. 11(1):91–99CrossRefGoogle Scholar
  19. 19.
  20. 20.
    Kararli TT, Sedo K, Bossart J (2014a) Fixed-dose combination products—a review (part 1—introduction).
  21. 21.
    Kararli TT, Sedo K, Bossart J (2014b) Fixed-dose combination products—a review (part 2—analysis).
  22. 22.
    Kararli TT, Sedo K, Bossart J (2014c) Fixed-dose combination products—what’s in the clinic? (part 3—pipeline).
  23. 23.
    ICH Guidelines (2007)
  24. 24.
    ICH (2009) Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2).
  25. 25.
    ICH (2012) M3(R2) Implementation Working Group M3(R2) guideline: guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. Questions & answers (R2).
  26. 26.
    FDA (2013) Guidance for industry. Codevelopment of two or more new investigational drugs for use in combination.
  27. 27.
    FDA (2006) Fixed dose combinations, co-packaged drug products, and single-entity versions of previously approved antiretrovirals for the treatment of HIV.
  28. 28.
    Liminga U, Silva L (2003) Non-clinical development of fixed combinations. A European regulatory perspective. Int J. Pharm Med 18(3):135–138Google Scholar
  29. 29.
    Japanese Pharmaceutical Association (2015) Pharmaceutical administration and regulations in Japan.
  30. 30.
    Hunt L (2003) Fixed-combination medicines: an Australian perspective. WHO Drug Inform 2:110–112Google Scholar
  31. 31.
    Therapeutic Products Directorate (2000) Guidelines for preparation of new drug submissions for products used for estrogen-progestin replacement therapy in menopause (HRT).
  32. 32.
    WHO (2005) WHO Expert Committee on Specifications for Pharmaceutical Preparations Guidelines for registration of fixed-dose combination medicinal products Technical Report Series. WHO Tech Rep Ser 929:93–142Google Scholar
  33. 33.
    Rogge MC, Taft DR (eds) (2005) Preclinical drug development. Taylor & Francis Group, Boca Raton, FLGoogle Scholar
  34. 34.
  35. 35.
    ICH (2000) Safety pharmacology studies for human pharmaceuticals S7A.
  36. 36.
    FDA (2000) DRAFT ICH Consensus principle for clinical evaluation of new antihypertensive drugs E12A.

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  1. 1.ToxAdvantageNoizayFrance

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