Performance Based Regulatory Assessment

Transcription

1 Performance Based Regulatory Assessment Leveraging the Depth of Industry Knowledge with the Breadth of Regulator Knowledge FDA/PQRI Conference 6 October 2015 Bethesda, MD roger nosal Vice President & Head of Global CMC

2 Disclaimer The views & opinions expressed are those of the individual presenter. The content is the intellectual property of the individual presenter & protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Pharmaceutical Quality Research Institute & PQRI are registered trademarks. All other trademarks are the property of respective owners. 2

3 PQRI Workshop Objective To To communicate, exchange & devise and a devise harmonized a globally and value harmonized added and path value forward added towards path forward global quality. towards quality through the product lifecycle. 3

4 Content Performance-Based Regulatory Assessment 1. What is the Desired State? 2. What is the Current State? 3. What is the Path to Desired State? 4. What are Barriers & Next Steps? 4

5 What is the Desired State? Risk Performance Quality Expectations Risk-Based Regulatory Review

6 Performance-Based Regulation A regulatory approach that focuses on desired, measurable outcomes, rather than prescriptive processes, techniques, or procedures. Performance-based regulation leads to defined results without specific direction regarding how those results are obtained.. Performance-based regulatory actions focus on identifying performance measures that ensure an adequate safety margin and offer incentives for companies to improve safety without formal regulatory intervention by the agency. 6

7 Translating Risk into Performance RISK Transparency Uncertainty Robustness Control strategy QRM Consistency Balance (Benefit:Risk) PERFORMANCE Reliability Sustainability Continual Improvement 7

8 Desired State: Quality Expectations FDA & Industry are generally aligned... Patients expect their medicines: Are safe, efficacious & have correct identity Deliver the performance described on the label Perform consistently over their shelf-lives Are made in a manner that ensures quality Are available when needed Industry provides appropriate transparency regarding risk (QRM) such that regulators have confidence a control strategy is appropriately established & maintained through the product lifecycle 8

9 What Constitutes Good Risk-based Regulatory Review? Increase use of Annual Reports & control w/in PQS Integrate regulatory review w/inspection to transparently link the relationship of PQS to Established Conditions Delineate level of risk according to product type & product categories, i.e., complex vs. simple dosage forms Identify & communicate quality risks relevant to patient safety & efficacy Do not penalize firms for transparently sharing risk assessments & additional development data Appropriate level of detail in regulatory submissions Reduce post approval supplements Establish unified approach & expectations across industry globally 9

10 What is the Current State? Characterization of Risks 10

11 FDA concerns: Current State: Lack of detailed transparency in risk assessments Absence of coherent & complete description & rationale of a product control strategy Uncertainty in lifecycle & Management Industry concerns: Inconsistency in regulatory assessments Integration between inspections & assessments is clunky Overlap of IR queries w/inspection observations Increased scrutiny of development studies Absence of incentives for flexible regulatory approaches for post-approval changes, i.e., w/in PQS Inconsistency in assessment of individual CQA controls Global divergence 11

12 Concerns We ve Heard About Risk Regulators want to understand how & when industry performs risk assessments What is the level of expertise & process to establish a product control strategy & manage changes through development & after commercialization? How are manufacturing process changes managed? Are formal risk assessment approaches used to evaluate changes? Are changes systematically managed under a QRM paradigm & robust change management system? Who participates in risk assessment exercises? How is knowledge/experience captured & transferred? 12

13 Risk Companies perform risk assessments to: Understand the product quality attributes Establish appropriate control strategies Establish a baseline for subsequent process improvements Evaluate impact of process trending & adjustments Evaluate process optimization proposals Distinguish risk & characterize uncertainty Determine & confirm predictability Regulators evaluate risk assessments To ensure appropriate control strategy is established To ensure robustness of RA approach NOT to repeat risk assessments 13

14 Value of Risk Assessments Component Sub-component Response Observed or Predicted Score Severity Biological activity (CB ELISA) Pharmacokinetics Immunogenicity Safety Uncertainty Prior Knowledge 0 - <20% % change to activity 5 >40-100% change to activity 10 0 to < 20% % 5 > 50% change 10 None detected 1 Potential validated? for immunogenicity based on 5 literature and other product knowledge Detected and limits therapeutic efficacy or safety 10 No known adverse events 1 Reversible adverse event 5 Irreversible adverse events 10 Impact of specific isoform established in 1 Can Risk Assessments be Do Risk Assessments adequately predict whether a control reliably mitigates a risk? clinical study In-vivo non-clinical 3 in-vitro data 5 Platform data, Relevant Literature 7 No information 10 CQA Scoring (RPN #) Severity (highest) x Uncertainty = RPN [ 5, non-cqa]; [> 5, CQA] 14

15 What is the Path to Desired State? Leveraging Knowledge & Experience Emphasis on Control Strategy 15

16 Opportunity for Alignment? Leverage Industry/Regulator Knowledge Interface: Evaluate the combination of registration content & the Pharmaceutical Quality System Is Quality Risk Management robust? Does the product control strategy assure quality, safety, efficacy & supply reliability? Will & management provide assurance of requisite quality through the product lifecycle? Performance-based regulatory assessment should: Focus on relevant risks Appropriately address uncertainty Ensure Established Conditions are scientifically justified, not arbitrarily contrived 16

17 Leveraging Knowledge & Experience Regulatory Authorities Pharmaceutical Industry Regulatory Authorities possesses a breadth of knowledge. Pharmaceutical Industry possesses a depth of knowledge. 17

18 Control Strategy by Design Start with the Patient Understand patient needs TARGET PRODUCT PROFILE Understand the process Does it deliver what the patient needs? What needs to be controlled to assure quality for the patient? Develop analytical method(s) to monitor quality risks Assess materials & process risks to quality Understand criteria (CQAs) needed to assure product quality Process understanding (Not all critical parameters carry equal risk) Differentiate CPP/change management based on residual risk Determine which risks to quality require a test How does process deal with risks to quality ENHANCED knowledge? Determine where optimal control is positioned Control on inputs, parameters, IPCs, outputs OR a mix Establish specification for all critical controls Test method + acceptance criterion OR Rationale for how CQA is controlled w/o testing Can Control Strategy provide a measure of product performance? 18

19 Risk-Based Regulatory Review of Control Strategy Performance Control Strategy =? Quality Assurance & Risk Mitigation A robust control strategy in conjunction w/robust & management will demonstrate quality through the product lifecycle. Evaluate control strategy relative to the quality of the risk assessments used to establish it. Review & assess & management processes & systems at inspection. Focus on functional relationships that are relevant to product CQAs. Reduce &/or eliminate focus on unnecessary low risk issues. Assess control strategy relative to consistency, supply reliability & sustainability through the product lifecycle. 19

20 Functional Relationship of Product CQAs to CPPs 20

21 What are Barriers & Next Steps? Barriers What is Lost w/o Risk-Based Regulatory Review? Next Steps 21

22 Barriers to Risk-Based Regulatory Lack of transparency Review Omission of risks in regulatory submissions Regulatory expectations & queries Discontinuity in & management thru lifecycle Unaccommodating submission format: How to effectively present risk assessments & QRM approach? How to holistically convey product control strategy? How can industry align content with IQA template? QOS? Increasing global regulatory divergence 22

23 What is Lost w/o Risk-Based Regulatory Review? Opportunities to... Improve confidence in quality Expedite regulatory reviews & approvals Reduce post approval change submissions Reconcile risk with performance Embrace continual improvement Increase mutual trust Align global regulatory expectations Enhance efficiency 23

24 Next Steps Joint industry & regulator QRM workshop Pilot alternative regulatory submission options Repurpose CTD-QOS Emphasize product control strategy as a reflection of quality performance Reconcile integrated submission & inspection criteria Collaborate on ICH development & expansion ICH Q12 Mutual Recognition & transparency 24

25 Acknowledgements Mary Oates Ron Ogilvie Lynne Krummen Ann Subashi PhRMA LDKIT - RbRR Sarah Pope Miksinski John Lepore Moheb Nasr Graham Cook Jean-Louis Robert Christine Moore Øyvind Holte G. K. Raju Mark Rosolowsky Diane Zezza Jeff Baker 25