Regulatory Challenges for the Licensure of Future Vaccines Tong Wu, Ph.D. Bacterial & Combination Vaccine Division, BGTD, Health Canada June 26-29, 2018, Seoul, Korea, the Global Bio Conference 1
Disclaimer The views and opinions expressed in the following presentation are those of the individual presenter and should not be attributed to Health Canada. 2
Outline Introduction Potency assay Reference standard Specification Clinical development to support quality specifications 3
Introduction 4
Challenges in vaccine development What does it take to market a new vaccine? 15-20 years on average. an investment of $US 800 million or more. thousands of individuals or more in clinical studies. regulatory scrutiny is unpredictable and not always science-based. Overall, the development of a new vaccine, especially the first against an infectious agent, is a complicated, time-consuming, expensive, risky, and competitive process. 5
Regulatory framework in Canada Life cycle approach Source: The Progressive Licensing Framework Concept Paper for Discussion, Health Canada, 2006; www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfbdgpsa/pdf/prodpharma/proglic_homprog_concept-eng.pdf. 6
Requirements for regulatory approval of vaccines in Canada Regardless of manufacturing platform, target population or disease to be prevented, a vaccine must be: safe (acceptable safety profile) efficacious (or effective) of suitable quality No prescriptive or product-specific requirements guided by up-to-date science and technology Considerations for review and approval Case by case Risk/benefit assessment 7
Our goal is Quality Safety Efficacy Vaccine availability Science based regulatory standards and risk benefit based decision making are essential for ensuring timely access to new vaccines as well as managing vaccine supply postapproval. 8
Potency Assay 9
Why are potency assays required? A suitable potency assay, combined with a well managed reference standard and an appropriate specification: provides a bridge between clinical lots and commercial lots. assures that commercial lots are comparable to clinical lots that are shown to be safe and efficacious/effective in clinical studies. is a critical tool for life cycle management of a vaccine product. 10
Potency assays in vivo vs in vitro In vivo challenge models Relevance to clinical efficacy In vivo functional serological assays In vitro immunoassays In vitro physicochemical methods Assay sensitivity and consistency 11
Strategy for potency assessment throughout product life cycle At early development stage, in vivo potency assay is critical for Proof of concept Decision on excipients (e.g. adjuvant) and final formulation At clinical development stage, both in vivo and in vitro potency assays may be used to characterize antigenicity and stability of the vaccine verify suitability of in vitro potency assay for stability monitoring establish potency specifications Post-approval commercial manufacturing in vitro potency assay preferred assay for routine lot release, stability monitoring, supporting manufacturing changes in vivo potency assay may be used to support manufacturing changes (demonstrate product comparability) 12
Why in vitro potency assay for commercial manufacturing? Quality of commercial vaccine lots is assured through a combination of cgmp compliance, validated manufacturing process and QC testing. Consistency approach The goal of potency assessment assure that commercial lots have comparable potency results to that of clinical lots shown to be effective in clinical trials, therefore, expected to perform similarly in clinical. Use of in vivo potency assay (even challenge assays) alone can t predict clinical outcome, due to differences in immune systems (human vs animal models) 13
Why in vitro potency assay for commercial manufacturing? (cont d) A potency assays suitable for quality control of commercial lots should have consistent performance (low variability). Highly variable in vivo assay likely leads to high invalidity rate, and delays decision for lot release. adds challenge to management of reference standards In recent years, rejection of lots were largely due to method and references related issues (use of highly variable in vivo assay), not vaccine quality issues. Test issues, rather than vaccine quality, have led to vaccine shortages. Both vaccine manufacturers and regulatory scientists are currently working towards replacing in vivo potency assay with suitable in vitro potency assay. 14
Potency assay method development Research Understand mechanism of action Development Incorporate new science and technology Prevalidation Optimize assay parameters Validation Determine assay performance Regulatory scrutiny Regulatory review and approval 15
Points to consider when developing and validating potency assay In vivo potency assays are highly variable and less sensitive, it is critical to select appropriate immunization schedule. In general, one injection is preferred, and multiple injections should be justified. The immunization schedule should ensure that the immune response are within dose response curve. In vitro potency assay select appropriate antibody to ensure assay is stability indicating (e.g. monoclonal antibody specific to functional epitopes) For both in vivo and in vitro potency assays Establish assay sensitivity (e.g. using samples with known antigen content) Use appropriate reference standard 16
Reference Standard 17
Reference standard critical reagent for potency assay A carefully managed reference standard for potency is essential for assuring comparable vaccine potency throughout its life cycle. Reference standard for potency assay is used to: Calculate relative potency, in which the biological activity of a test sample is directly compared to that of the reference standard Set test validity criteria to ensure consistent performance of the potency assay over time Management of potency reference standard is challenging, especially when the new vaccine is the 1 st against an infectious agent. 18
Reference standard - challenges Vaccines are complex biologics Development and maintenance of vaccine reference standards is often more challenging when compared with those for well characterized biologics or small molecule drugs. Use of highly variable in vivo assays for reference calibration difficult to ensure accuracy Complex formulation/matrix difficult to preserve potency as freezingthaw may impact product integrity Critical QC tests are relative design lack of appropriate tools for stability monitoring All the above affect the values assigned to subsequent reference replacement, and impact the validity or the comparability of the test results. 19
Reference standard selecting suitable candidate material ICH Q6B requires that candidate material be representative of production and clinical materials Alternatively, a reference standard may be different from the test vaccine lots in its composition and/or storage conditions. However, the candidate material should have the following characteristics: The dose response curve of the candidate material is comparable to that of commercial vaccine lots to allow the calculation of the relative strength of the test sample The candidate material can be stored for a long period of time without decay. 20
Reference standard ensuring stability The composition and storage conditions (frozen, lyophilized or added stabilizer) of a reference standard should be carefully selected in order to preserve the integrity of the reference avoid the need for frequent replacement that may lead to drift/shift of the reference standard. Stability monitoring should be meaningful. Implement and trend a test readout, that is independent of the reference standard, if possible (e.g. ED 50 ) Link potency unit, especially arbitrary unit, to other quality attribute measured independently (e.g. protein content based on total nitrogen). 21
Specification 22
Potency specification regulatory expectation Specific to each vaccine product. ICH Q6B requires that specifications be linked to: clinical studies ensure specifications at end of shelf life (lowest for potency and highest for degradation impurities) not worse than those of clinical lots demonstrated to be safe and efficacious in clinical trials manufacturing process ensure comparable quality attributes of commercial and clinical lots stability of both drug substance and drug product set different specifications for release and end of shelf life for quality attributes that change during storage. analytical procedure comparable test performance (clinical development vs commercial production) and assay variability. 23
Potency specification: based on product release model WHO TRS 999, Annex 5 24
Potency specification: based on product release model (cont d) Different specifications for release and end of shelf-life for potency that declines through shelf-life. Potency specification at end of shelf-life (lower limit) should be supported by clinical lots demonstrated to be safe and efficacious (or immunogenic) in clinical studies. Potency specification at release should ensure vaccine lots meet specification at the end of shelf-life, based on rates of changes during storage be within manufacturing capability 25
How to support the lowest potency specification? Ideal situation: Vaccine lots with potency at the lower limit are tested in clinical study and shown to be efficacious or immunogenic. Reality: The lower boundary of potency, for most licensed vaccines, has not been tested in clinical studies. Flexibility is required to set a practical potency range for commercial manufacturing. Consider age of clinical materials at the point of use, combined with established potency decay rate, were considered during licensure. Commitment for post-licensure studies. For future vaccines: clinical development program should incorporate elements to support quality specifications. 26
Support quality specifications with clinical experience 27
How to support quality specifications with clinical experience? Test aged lots or lots stored under forced degradation conditions in clinical trials. This approach is ethical. Study subjects are monitored closely. The aged/degraded materials are likely to be safe and effective based on existing experience and knowledge. This type of clinical studies have been approved by other agencies (e.g. FDA for live attenuated viral vaccines), as well as by our division recently (intend to support the upper limit for free polysaccharide). Consider the results of dose-ranging study. The dose-ranging study should include a lose lower than what is intended for commercial product. Lots with different antigen content should be tested using the potency assay account for the performance of potency assay. 28
How to support potency specification when correlate of protection has not been established? It is impractical and cost prohibitive to conduct dose-ranging study using protection as end point. To support potency specification: Characterize and assess the immune responses globally of each dosing group, covering both cellular and humoral immunity. If both cellular and humoral immunity induced by the vaccine dose intended for commercial product is similar to that induced by vaccine with lower antigen content, the potency result of the vaccine with lower antigen may be used to set lower potency limit (assuming that efficacy of the vaccine candidate is demonstrated in Phase III clinical study). Preserve clinical samples for further studies, as correlate of protection may be established in future efficacy trials, or through advances in basic research. 29
Conclusion Developing a new vaccine is technically challenging and financially risky. Regulators must facilitate vaccine development process, and continue to enhance benefit-risk assessment in regulatory decision-making. promote science-based regulatory standards. Remove outdated requirements Implement improved quality control methods support innovation in vaccine development, manufacturing and quality control. 30
Thank you!? 31