Skip to main content

FDA’s Benefit–Risk Framework for Human Drugs and Biologics: Role in Benefit–Risk Assessment and Analysis of Use for Drug Approvals

Therapeutic Innovation & Regulatory Science volume 55, pages 170–179 (2021)Cite this article

Abstract

Background

Structured, descriptive approaches are utilized by drug regulatory agencies to support and communicate approval decisions about human drugs and biologics. The US Food and Drug Administration (FDA) uses the Benefit–Risk Framework (BRF), which has been integrated into its drug review process. This paper reviews how FDA review teams have used the BRF to communicate approval decisions.

Methods

This paper (1) uses content analysis to systematically review the decision factors communicated by FDA review teams in all BRFs associated with novel drugs approved by FDA in 2017–2018 and (2) presents a case study about how the BRF was used for three drugs approved for HIV-1 in 2018–2019.

Results

The content analysis found most BRFs for novel drug approvals communicate what we call an “urgent” context and complicating decision factors around benefit and/or risk; the HIV-1 case study highlights the flexibility of the structured BRF tool.

Conclusions

FDA’s BRF provides a flexible mechanism for communicating important decision factors, allowing it to support the diversity of drug approval decisions made by FDA.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

Figure 1.
Figure 2.
Figure 3.

References

  1. US Department of Health and Human Services. Adequate and well-controlled studies. 21 CFR §314.126 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.126.

  2. Gassman AL, Nguyen CP, Joffe HV. FDA regulation of prescription drugs. N Engl J Med. 2017;376(7):674–82.

    Article  Google Scholar 

  3. Smith MY, Benattia I, Strauss C, Bloss L, Jiang Q. Structured benefit-risk assessment across the product lifecycle: practical considerations. Ther Innov Regul Sci. 2017;51(4):501–8.

    Article  Google Scholar 

  4. Wang J, Wolka A, Bullok K, Anglin G, Radawski C, Noel R. Implementation of structured benefit–risk assessments in marketing authorization applications: lessons learned. Ther Innov Regul Sci. 2016;50(6):718–23.

    Article  Google Scholar 

  5. Juhaeri J. Benefit-risk evaluation: the past, present and future. Ther Adv Drug Saf. 2019;10:2042098619871180.

    Article  Google Scholar 

  6. Pharmaceuticals & Medical Devices Agency. Points to Be Considered by the Review Staff Involved in the Evaluation Process of a New Drug April 17, 2008. https://www.pmda.go.jp/files/000153830.pdf#page=1.

  7. International Converence on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Revision of M4E Guideline on Enhancing the Format and Structure of Benefit-Risk Information in ICH: Efficacy M4E(R2). June 15, 2016. https://database.ich.org/sites/default/files/M4E_R2__Guideline.pdf.

  8. Centre for Innovation in Regulatory Science. The CIRS-BRAT Framework 2014. https://www.cirs-brat.org/.

  9. Levitan B, Phillips LD, Walker S. Structured approaches to benefit-risk assessment: A case study and the patient perspective. Ther Innov Regul Sci. 2014;48(5):564–73.

    Article  Google Scholar 

  10. Nixon R, Dierig C, Mt-Isa S, Stockert I, Tong T, Kuhls S, et al. A case study using the PrOACT-URL and BRAT frameworks for structured benefit risk assessment. Biom J. 2016;58(1):8–27.

    Article  Google Scholar 

  11. Mt-Isa S, Hallgreen CE, Wang N, Callreus T, Genov G, Hirsch I, et al. Balancing benefit and risk of medicines: a systematic review and classification of available methodologies. Pharmacoepidemiol Drug Saf. 2014;23(7):667–78.

    Article  Google Scholar 

  12. Miller KL, Woodcock J. Value assessment in the regulatory context. Value Health. 2017;20(2):296–8.

    Article  Google Scholar 

  13. Food and Drug Administration. Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making: Draft PDUFA V Implementation Plan Fiscal Years 2013–2017. February 2013. https://www.fda.gov/media/84831/download.

  14. Food and Drug Administration. Benefit-Risk Assessment in Drug Regulatory Decision-Making: Draft PDUFA VI Implementation Plan (FY 2018–2022). March 30, 2018. https://www.fda.gov/media/112570/download.

  15. Food and Drug Administration. Benefit-Risk Assessment Throughout the Drug Lifecycle: FDA Discussion Document. May 3, 2019. https://healthpolicy.duke.edu/sites/default/files/2020-07/discussion_guide_b-r_assessment_may16_0.pdf.

  16. Lee Abbott M, McKinney J. Understanding and Applying Research Design. Hoboken: Wiley; 2013.

    Google Scholar 

  17. Rosenthal R, Rosnow RL. Essentials of Behavioral Research: Methods and Data Analysis. 2nd ed. New York: McGraw Hill; 1984.

    Google Scholar 

  18. Food and Drug Administration. Advancing Health Through Innovation: 2017 New Drug Therapy Approvals. January 2018. https://www.fda.gov/media/110526/download.

  19. Food and Drug Administration. Advancing Health Through Innovation: 2018 New Drug Therapy Approvals. January 2019. https://www.fda.gov/media/120357/download.

  20. Hughes D, Waddingham E, Mt-Isa S, Goginsky A, Chan E, Downey GF, et al. Recommendations for benefit-risk assessment methodologies and visual representations. Pharmacoepidemiol Drug Saf. 2016;25(3):251–62.

    Article  Google Scholar 

  21. Raju GK, Gurumurthi K, Domike R, Weinstock C, Singh H, Kluetz P, et al. Using a benefit risk analysis approach to capture regulatory decision-making: renal cell carcinoma. Clin Pharmacol Ther. 2019;107:495–506.

    Article  Google Scholar 

  22. European Medicines Agency. <Co>Rapporteur day <60*><80> critical assessment report: Overview and list of questions. 2019. https://www.ema.europa.eu/documents/template-form/day-80-assessment-report-overview-d120-loq-template-guidance-rev-1019_en.doc.

  23. Walker S, McAuslane N, Liberti L, Leong J, Salek S. A universal framework for the benefit-risk assessment of medicines: is this the way forward? Ther Innov Regul Sci. 2015;49(1):17–25.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the Division of Antiviral Products (Office of New Drugs, CDER, FDA) for helpful discussion to inform the case study. We also thank staff and leadership in the Office of New Drugs (CDER, FDA) for helpful feedback.

Funding

No funding was obtained for this research.

Author information

Authors and Affiliations

  1. Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, USA

    Leila Lackey, Graham Thompson & Sara Eggers

  2. 10903 New Hampshire Ave, WO Bldg 51 Rm 1141, Silver Spring, MD, 20993, USA

    Leila Lackey

Authors
  1. Leila Lackey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Graham Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara Eggers
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors had substantial contributions to all aspects of authorship, including conception and design, data acquisition, analysis, and interpretation; drafting and revising the work; final approval of the published version; and agreement to be accountable for all aspects of the work.

Corresponding author

Correspondence to Leila Lackey.

Ethics declarations

Conflict of interest

The authors are employed by the Center for Drug Evaluation and Research at the FDA. They have no other conflicts to disclose. This publication reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lackey, L., Thompson, G. & Eggers, S. FDA’s Benefit–Risk Framework for Human Drugs and Biologics: Role in Benefit–Risk Assessment and Analysis of Use for Drug Approvals. Ther Innov Regul Sci 55, 170–179 (2021). https://doi.org/10.1007/s43441-020-00203-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43441-020-00203-6

Keywords

  • Benefit–risk assessment
  • FDA
  • Content analysis
  • HIV
  • Decision-making