Skip to main content

Advertisement

SpringerLink
Log in

Implementation of a Pregnancy Prevention Programme (PPP) with a Controlled Distribution System (CDS) for the Generic Teratogenic Phthalimides Thalidomide, Lenalidomide and Pomalidomide

  • Review
  • Published:
Therapeutic Innovation & Regulatory Science Aims and scope Submit manuscript

Abstract

Thalidomide (α-phthalimidoglutaride) was marketed in the 1950s and early 1960s; it was promoted as a sedative-hypnotic agent with minimal hangover. It was available in some countries as an over-the-counter medicine. Publications reporting profound teratogenic effects with thalidomide brought about major revisions to the monitoring of the safety of medicines. As a consequence of previously unrecognised teratogenic effects, it has been estimated that over 12,000 children were born with a range of defects and disabilities, including severe congenital anomalies. Notably, it has been hypothesised that around 40% of babies with thalidomide-induced malformations born during the 1950s and 1960s died in the neonatal period. The commonest causes of death were atresia of the small bowel, cardiac or renal malformations. Nevertheless, phocomelia (as a typical manifestation of thalidomide´s teratogenic effects) has been reported once again after thalidomide was approved for use in areas where leprosy is endemic. As a result, thalidomide embryopathy remains an important topic in countries such as Brazil. Nowadays thalidomide is approved around the world for the treatment of a wide range of conditions, including leprosy, Crohn's disease, multiple myeloma, and certain malignant solid tumours. Second-generation immunmodulatory drugs including lenalidomide and pomalidomide have received approval for use in the management of various forms of neoplastic disease. Based on clinical experience with thalidomide and its derivatives, learnings have been transferred to further research on a subset of substituted phthalimides each of which has a high risk of causing teratogenic effects. This group of phthalimides is classified within regulatory science as human teratogens. In order to gain approval, a Pregnancy Prevention Programme (PPP), along with a Controlled Distribution System (CDS) is required. The challenges of PPPs in particular for a generic manufacturer have been described, including Raising of awareness, and education; Special aspects of data collection and evaluation; Ethically and socially relevant aspects, and Utilising existing information technology and infrastructure. This paper highlights the risks of unplanned pregnancies, provides information on the regulatory background, and regulatory expectations. Our aim is to provide insights and practical learnings that have impacted operational risk management with the teratogenic phthalimides. Opportunities are presented that may support the implementation of harmonised approaches for PPP and CDS using existing IT-systems across countries and companies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

References

  1. McBride WG. Thalidomide and congenital abnormalities. Lancet. 1961;278(7216):1358. https://doi.org/10.1016/S0140-6736(61)90927-8.

    Article  Google Scholar 

  2. Speirs AL. Thalidomide and congenital abnormalities. Lancet. 1962;1(7224):303–5. https://doi.org/10.1016/s0140-6736(62)91248-5.

    Article  CAS  PubMed  Google Scholar 

  3. Matthews SJ, McCoy C. Thalidomide: a review of approved and investigational uses. Clin Ther. 2003;25(2):342–95. https://doi.org/10.1016/s0149-2918(03)80085-1.

    Article  CAS  PubMed  Google Scholar 

  4. Bwire R, Freeman J, Houn F. Managing the teratogenic risk of thalidomide and lenalidomide: an industry perspective. Expert Opin Drug Saf. 2011;10(1):3–8. https://doi.org/10.1517/14740338.2011.527331.

    Article  CAS  PubMed  Google Scholar 

  5. Lenz W. A short history of thalidomide embryopathy. Teratology. 1988;38(3):203–15. https://doi.org/10.1002/tera.1420380303.

    Article  CAS  PubMed  Google Scholar 

  6. Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res. 2015;105(2):140–56. https://doi.org/10.1002/bdrc.21096.

    Article  CAS  Google Scholar 

  7. Vargesson N. Thalidomide. In: Gupta RC, editor. Reproductive and developmental toxicology. 2nd ed. New York: Academic Press; 2017. p. 467–79.

    Chapter  Google Scholar 

  8. Schuler-Faccini L, Franca Soares RC, Moreira de Sousa AC, Maximino C, Luna E, Doderlein Schwartz IV, et al. New cases of thalidomide embryopathy in Brazil. Birth Defects Res. 2007;79(9):671–2. https://doi.org/10.1002/bdra.20384.

    Article  CAS  Google Scholar 

  9. World Health Organization, Model List of Essential Medicines, 19th edition. https://www.who.int/publications/i/item/WHOMVPEMPIAU2019.06. Accessed 31 Dec 2020

  10. Zeldis JB, Williams BA, Thomas SD, Elsayed ME. S.T.E.P.S.: a comprehensive program for controlling and monitoring access to thalidomide. Clin Ther. 1999;21(2):319–30. https://doi.org/10.1016/s0149-2918(00)88289-2.

    Article  CAS  PubMed  Google Scholar 

  11. Castaneda CP, Zeldis JB, Freeman J, Quigley C, Brandenburg NA, Bwire R. RevAssist: a comprehensive risk minimization programme for preventing fetal exposure to lenalidomide. Drug Saf. 2008;31(9):743–52. https://doi.org/10.2165/00002018-200831090-00003.

    Article  CAS  PubMed  Google Scholar 

  12. Wills S. Teratogenesis and Infection. In: Carachi R, Doss S, editors. Clinical embryology. Cham: Springer; 2019.

    Google Scholar 

  13. Group ECW. Why after 50 years of effective contraception do we still have unintended pregnancy? A European perspective. Hum Reprod. 2018;33(5):777–83. https://doi.org/10.1093/humrep/dey089.

    Article  Google Scholar 

  14. Office of Women´s Health (USA), Factsheet: Menstruation and the Menstrual Cycle. 2014. https://web.archive.org/web/20150629023922; http://www.womenshealth.gov/publications/our-publications/fact-sheet/menstruation.pdf. Accessed 15 Jan 2021

  15. European Medicines Agency, Summary of Product Characteristics_Thalidomide-Celgene. https://www.ema.europa.eu/en/documents/product-information/thalidomide-celgene-epar-product-information_en.pdf. Accessed 14 Jan 2021

  16. European Medicines Agency, Summary of Product Characteristics_Revlimid. https://www.ema.europa.eu/en/documents/product-information/revlimid-epar-product-information_en.pdf. Accessed 10 Feb 2021

  17. European Medicines Agency, Summary of Product Characteristics_Imnovid. https://www.ema.europa.eu/en/documents/product-information/imnovid-epar-product-information_en.pdf. Accessed 10 Feb 2021

  18. Doss SH, Sneddon SF. General embryology. In: Carachi R, Doss S, editors. Clinical embryology. Cham: Springer; 2019.

    Google Scholar 

  19. Garg RC, Bracken WM, Hoberman AM, Enright B. Tornesi B (2017) Reproductive and developmental safety evaluation of new pharmaceutical compounds. In: Gupta RC, editor. Reproductive and developmental toxicology. 2nd ed. Academic Press: New York; 2017. p. 101–27.

    Chapter  Google Scholar 

  20. Estevan C, Pamies D, Vilanova E, Sogorb MA. OECD guidelines for in vivo testing of reproductive toxicity. In: Gupta RC, editor. Reproductive and developmental toxicology. 2nd ed. Academic Press: New York; 2017. p. 163–78.

    Chapter  Google Scholar 

  21. Tomson T, Battino D, Perucca E. Teratogenicity of antiepileptic drugs. Curr Opin Neurol. 2019;32(2):246–52. https://doi.org/10.1097/WCO.0000000000000659.

    Article  CAS  PubMed  Google Scholar 

  22. Sales Luiz Vianna F, de Oliveira MZ, Sanseverino MTV, Morelo EF, de Lyra Rabello Neto D, Lopez-Camelo J, et al. Pharmacoepidemiology and thalidomide embryopathy surveillance in Brazil. Reprod Toxicol. 2015;53:63–7. https://doi.org/10.1016/j.reprotox.2015.03.007.

    Article  CAS  PubMed  Google Scholar 

  23. Sales Luiz Vianna F, Kowalski TW, Fraga LR, Sanseverino MT, Schuler-Faccini L. The impact of thalidomide use in birth defects in Brazil. Eur J Med Genet. 2017;60(1):12–5. https://doi.org/10.1016/j.ejmg.2016.09.015.

    Article  PubMed  Google Scholar 

  24. Ridings JE. The thalidomide disaster, lessons from the past. Methods Mol Biol. 2013;947:575–86. https://doi.org/10.1007/978-1-62703-131-8_36.

    Article  CAS  PubMed  Google Scholar 

  25. World Health Organization, Factsheets, Leprosy. https://www.who.int/news-room/fact-sheets/detail/leprosy. Accessed 19 Feb 2021.

  26. Yang YT, Chen B, Bennett CL. Thalidomide, drug safety, and off-label prescribing: lessons learned from Celgene’s settlement. JAMA Oncol. 2018;4(7):915–6. https://doi.org/10.1001/jamaoncol.2018.0808.

    Article  PubMed  Google Scholar 

  27. Pan American Health Organization, The importance of pharmacovigilance. 2002. www.paho.org. Accessed 31 Dec 2020

  28. European Medicines Agency, Guideline on Good Pharmacovigilance Practices (GVP). Module XVI. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-xvi-risk-minimisation-measures-selection-tools_en-3.pdf. Accessed 15 Jan 2021

  29. Castaneda C, Minton N, Mezo M, Hirsch D, Phillips L, Sheehan P, et al. False-positive pregnancy tests in females of reproductive potential receiving lenalidomide in the United States. Leuk Lymphoma. 2018;59(4):1025–6. https://doi.org/10.1080/10428194.2017.1361030.

    Article  PubMed  Google Scholar 

  30. European Medicines Agency., Revlimid: EPAR - Risk-management-plan summary. https://www.ema.europa.eu/en/documents/rmp-summary/revlimid-epar-risk-management-plan-summary_en.pdf. Accessed 06 Jan 2020

  31. European Medicines Agency, Thalidomide Celgene: EPAR - Risk Management Plan Summary. https://www.ema.europa.eu/en/documents/rmp-summary/thalidomide-celgene-epar-risk-management-plan-summary_en.pdf. Accessed 06 Jan 2021

  32. European Medicines Agency, Imnovid: EPAR - Risk-management-plan summary. https://www.ema.europa.eu/en/medicines/human/EPAR/imnovid. Accessed 06 Jan 2021

  33. Orange Book, Approved Drug Products with Therapeutic Equivalence Evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm. Accessed 06 Jan 2021

  34. Wieland A, Marcus WC. Dealing with supply chain risks: Linking risk management practices and strategies to performance. Int J Phys Distrib Logist Manag. 2012;42(10):887–905. https://doi.org/10.1108/09600031211281411.

    Article  Google Scholar 

  35. CT. EU Clinical Trial Register. https://www.clinicaltrialsregister.eu/. Accessed 06 Jan 2021.

  36. Noyelle RM. No blood, no drug. BMJ. 1991;302(6787):1276. https://doi.org/10.1136/bmj.302.6787.1276-b.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Addressing Challenges in Access to Oncology Medicines. Health Division, OECD Directorate for Employment, Labour and Social Affairs. https://www.oecd.org/health/health-systems/addressing-challenges-in-access-to-oncology-medicines.htm. Accessed 10 Feb 2021

  38. Federal Institue for drugs and Medical Devices, T-Prescriptions. https://www.bfarm.de/EN/FederalOpiumAgency/T-Prescriptions/_node.html. Accessed 19 Jan 2021

  39. Hammar T, Nilsson AL, Hovstadius B. Patients’ views on electronic patient information leaflets. Pharm Pract (Granada). 2016;14(2):702. https://doi.org/10.18549/PharmPract.2016.02.702.

    Article  Google Scholar 

  40. Jesus SM, Santana RS, Leite SN. The organization, weaknesses, and challenges of the control of thalidomide in Brazil: A review. PLoS Negl Trop Dis. 2020;14(8): e0008329. https://doi.org/10.1371/journal.pntd.0008329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zipursky J. REMS in pregnancy: System perfectly designed to the get the results it gets. BMJ Qual Saf. 2020. https://doi.org/10.1136/bmjqs-2019-010588.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Amalia Alexe for her careful review of our manuscript and for her insightful comments and suggestions.

Funding

This article was not funded.

Author information

Authors and Affiliations

  1. Global Risk Management Plan Manager, Safety Risk Detection and Management, Novartis Pharma AG, Basel, Switzerland

    Marion Mueller

  2. Chief Medical Office and Patient Safety, Global Drug Development, Novartis Pharma GmbH, Wehr, Germany

    David J. Lewis

  3. Department of Pharmacy, Pharmacology and Postgraduate Medicine, University of Hertfordshire, Hatfield, AL10 9AB, Herts, UK

    David J. Lewis

Authors
  1. Marion Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MM and DJL conceived of the ideas presented. The authors discussed the information in the article, and both contributed to the final manuscript.

Corresponding author

Correspondence to Marion Mueller.

Ethics declarations

Conflict of interest

The authors work for different departments of a pharmaceutical company undertaking work related to the content of the article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mueller, M., Lewis, D.J. Implementation of a Pregnancy Prevention Programme (PPP) with a Controlled Distribution System (CDS) for the Generic Teratogenic Phthalimides Thalidomide, Lenalidomide and Pomalidomide. Ther Innov Regul Sci 55, 1155–1164 (2021). https://doi.org/10.1007/s43441-021-00327-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43441-021-00327-3

Keywords

Search

Navigation