Regulatory Issues and Strategies: U.S. FDA

Transcription

1 Regulatory Issues and Strategies: U.S. FDA Aliza Thompson, MD Division of Cardiovascular and Renal Products Center for Drug Evaluation and Research Food and Drug Administration United States

2 Disclaimers and Disclosures The views expressed in this talk represent my opinions and may not represent the views of the FDA. I have no financial relationships to disclose.

3 On the one hand There is great unmet medical need for therapies to treat kidney diseases. There are many challenges associated with developing therapies for kidney diseases.

4 On the other hand There are important efforts underway to address these challenges. There are also regulatory initiatives and programs meant to speed innovation and facilitate the development of therapies for diseases with unmet medical need.

5 Today s talk Obviously, it is impossible to cover all of the regulatory challenges all of the important efforts all of the Agency s programs and initiatives in one talk.

6 Today s Talk Drug development tools Endpoints for drug approval Clinical trial enrichment Expedited programs for serious conditions

7 Drug development relies on tools We need a better toolbox.

8 Drug Development Tools The Drug Development Tools Qualification Program was created by the Center for Drug Evaluation and Research at FDA to provide a framework for the development and regulatory acceptance of scientific tools for use in drug development programs. The Center has developed qualification programs for: Biomarkers Clinical Outcome Assessment (measures a patient s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions) Animal Models

9 What is qualifica;on? Qualification is a conclusion that within the stated context of use, the drug development tool can be relied upon to have a specific interpretation and application in drug development and regulatory review. Once qualified, the drug development tool will be publicly available to be used in any drug development program for the qualified context of use.

10 Goals of Biomarker Qualifica;on Program Provide a framework for scientific development and regulatory acceptance of biomarkers for use in drug development Facilitate integration of qualified biomarkers in the regulatory review process Encourage the identification of new and emerging biomarkers for evaluation and utilization in regulatory decision-making Support outreach to relevant external stakeholders to foster biomarker development

11 The promise of a becer toolbox for drug development Many important effort underway to develop new tools and optimize the use of existing tools for kidney diseases Will focus on the renal safety biomarkers as an example

12 Nonclinical biomarkers of drug- induced nephrotoxicity

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14 Challenges How can we better leverage other sources of data to support the use of particular biomarkers as drug development tools? How can we better engage the academic community in this effort? Who will take on the task of defining key data elements and data structure so that we can assimilate disparate sources of information on renal biomarkers? Can we come up with better mechanisms to enable and promote data sharing?

15 The Endpoint Issue Often the endpoints we care most about are also late and/or infrequent outcomes. Very long or very large trials may be needed to detect a treatment effect if rates of disease progression are low or an early stage of disease is targeted. Considerable interest in surrogate endpoints as the answer.

16 Surrogate Endpoints Surrogate endpoint- a biomarker that can be used in therapeutic trials as a substitute for a clinically meaningful endpoint. Treatment effects on a surrogate endpoint are expected to predict treatment effects on the outcomes of clinical interest. The appeal of surrogate endpoints- faster, cheaper, more efficient drug development programs. May be viewed as the only feasible option for a therapy targeting an early stage of a disease or a slowly progressive disease.

17 Surrogate endpoints as a basis for drug approval in the U.S. Surrogates used as a basis for full approval the definitive endpoint used to establish a therapy s efficacy Surrogates used as a basis for accelerated approval of a therapy for a serious or life-threatening illness which provides a meaningful advantage over existing therapies surrogate is reasonably likely based on epidemiologic, therapeutic, pathophysiologic, or other evidence to predict clinical benefit comes with post-marketing commitment to complete studies verifying therapy s clinical benefit

18 The problem with surrogates Disease processes are complex and drugs have effects beyond those that are intended. Identifying surrogate endpoints that can reliably predict a treatment s effect on a clinical outcome is a challenge. When surrogate endpoints are used, there is always some residual uncertainty about the nature of a treatment s benefit (i.e., whether a treatment s effect on the surrogate endpoint will translate into a clinical benefit in the intended population and the size of that benefit).

19 The Endpoint Issue Surrogate endpoints can facilitate drug development, but before a biomarker is accepted as a surrogate endpoint, there needs to be strong evidence supporting its use. There is greatest confidence in a candidate surrogate when there are data from intervention trials showing that treatment effects on the surrogate reliably predict treatment effects on the clinical outcome of interest. Identifying suitable surrogate and clinical endpoints for drug development can be challenging. It takes the ongoing involvement of all stakeholders.

20 Tackling the Endpoint Issue Total Kidney Volume in Polycystic Kidney Disease - Polycystic Kidney Disease Outcomes Consortium GFR decline in Chronic Kidney Disease- National Kidney Foundation Outcome Measures in Lupus Nephritis- Kidney Health Initiative Patient Reported Outcome Measures in Glomerular Diseases/ Nephrotic Syndrome- NephCure Foundation Complete and Partial Remissions in Idiopathic Membranous Nephropathy- Patrick Nachman and Dan Cattran Clinical Trial Endpoints in Vascular Access- Kidney Health Initiative

21 Trial design is cri;cal Enrichment: the prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population Includes: strategies to decrease heterogeneity, prognostic enrichment strategies, and predictive enrichment strategies

22 guidancecomplianceregulatoryinformation/ guidances/ucm pdf

23 Challenges Can we do a better job of using enrichment strategies in trials of kidney diseases to select patients who are more likely to benefit (or less likely to develop an important adverse drug effect)? How do we balance the benefits of a targeted approach against concerns about generalizability and applicability? How do we determine the optimal approach for a particular drug that is being developed to treat a particular disease?

24 FDA s Expedited Programs for Serious Condi;ons Programs: Fast Track Breakthrough Therapy Accelerated Approval Priority Review All draw on principle of addressing unmet medical need in the treatment of a serious condition. Guidance document addresses qualifying criteria and features.

25 GuidanceComplianceRegulatoryInformation/Guidances/ UCM pdf

26 Fast Track Designa;on Qualifying Criteria: A drug that is intended to treat a serious condition AND nonclinical or clinical data demonstrate the potential to address unmet medical need Features: Opportunities for more frequent interactions with the review team, product could be eligible for Priority Review or Rolling Review (Agency reviews portions of a marketing application before the complete application is submitted)

27 Breakthrough Therapy Designa;on Qualifying Criteria: A drug that is intended to treat a serious condition AND preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies Features: Intensive guidance on efficient drug development during IND phase, organizational commitment involving senior managers, all fast track designation features

28 Priority Review Designa;on Qualifying Criteria: An application for a drug that treats a serious condition AND if approved, would provide a significant improvement in safety or effectiveness; there are also other settings in which an application may qualify Features: Shorter clock for review of marketing application

29 Accelerated Approval Pathway Qualifying Criteria: a drug that treats a serious condition AND generally provides a meaningful advantage over available therapies AND demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit OR on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit (i.e., an intermediate clinical endpoint)

30 Accelerated Approval Pathway Features: Approval based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a drug s clinical benefit Other Considerations: For drugs granted accelerated approval, postmarketing confirmatory trials are generally required to verify and describe the anticipated clinical benefit or effect on IMM Approval of a drug may be withdrawn if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug

31 Closing comments There is great unmet medical need for therapies to treat kidney diseases. There are many challenges associated with developing therapies for kidney diseases. To succeed, we will need the involvement of all stakeholders.

32 Thanks.