Methods for Expediting Innovative Novel Drugs to Market

Transcription

1 1 Methods for Expediting Innovative Novel Drugs to Market Presented by: Ada Kung, ( 龔曉嘉博士 ) Ph.D. DABT, MBA akung@expedient-solutions.com

2 2 FDA Guidance for Industry Expedited Programs for Serious Conditions - Drugs and Biologics (May 2014) To facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life- threatening condition. Four expedited programs: 1. Fast track designation 2. Breakthrough therapy designation 3. Accelerated approval 4. Priority review designation

3 3 Concepts for Expedited Programs A. Serious Condition Serious Condition : A disease or condition associated with morbidity that has substantial impact on day-to-day functioning. The Drug Is Intended to Treat a Serious Condition : A drug must be intended to have a direct effect on a serious manifestation or symptom of a condition or other intended effects. B. Available Therapy A therapy that is approved or licensed in the United States for the same indication being considered for the new drug and Is relevant to current U.S. standard of care (SOC) for the indication.

4 4 Concepts for Expedited Programs (Cont.) C. Unmet Medical Need There Is No Available Therapy. There Is Available Therapy : Has an effect on a serious outcome of the condition that is not known to be influenced by available therapy Has an improved effect on a serious outcome(s) of the condition compared with available therapy Has an effect on a serious outcome of the condition in patients who are unable to tolerate or failed to respond to available therapy Addresses an emerging or anticipated public health need The Only Available Therapy Was Approved Under the Accelerated Approval Program Based on a Surrogate Endpoint or an Intermediate Clinical Endpoint and Clinical Benefit Has Not Yet Been Verified.

5 5 Comparison of FDA s Expedited Programs for Serious Conditions Fast Track Breakthrough Therapy Accelerated Approval Priority Review Nature of program Designation Designation Approval Pathway Designation 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 OR A drug that has been designated as a qualified infectious disease product 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 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 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) An application (original or efficacy supplement) for a drug that treats a serious condition AND, if approved, would provide a significant improvement in safety or effectiveness OR Any supplement that proposes a labeling change pursuant to a report on a pediatric study under 505A OR An application for a drug that has been designated as a qualified infectious disease product OR Any application or supplement for a drug submitted with a priority d review voucher

6 6 Comparison of FDA s Expedited Programs for Serious Conditions (Cont.) Fast Track Breakthrough Therapy Accelerated Approval Priority Review Nature of program Designation Designation Approval Pathway Designation When to submit request With IND or after Ideally, no later than the pre-bla or pre- NDA meeting With IND or after Ideally, no later than the end-of-phase 2 meeting The sponsor should ordinarily discuss the possibility of accelerated approval with the review division during development, supporting, for example, the use of the planned endpoint as a basis for approval and discussing the confirmatory trials, which should usually be already underway at the time of approval With original BLA, NDA, or efficacy supplement Features Actions to expedite development and review Rolling review Intensive guidance on efficient drug development Organizational commitment Rolling review Other actions to expedite review Approval based on an effect on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict a drug s clinical benefit Shorter clock for review of marketing application (6 months compared with the 10- month standard review)

7 7 Drug Indication Company Fast Track (36%) Breakthrough Therapy (32%) Accelerated Approval (27%) Priority Review (68%) Months to Approval Anthim Inhalational anthrax Elusys Therapeutics V 12 Sixteen PET imaging for prostate Blue Earth Axumin of The 2016 Novel Drugs (73%) Were Designated cancer Diagnostics Vin One Or More Expedited Programs Defitelio Hepatic Veno-Occlusive Disease 8/5 (review) Jazz Pharmaceuticals V V 8 Epclusa HCV Inhibitor Gilead Sciences V V V 8 Exondys 51 Duchenne muscular dystrophy Sarepta Therapeutics V V V 15 Lartruvo Soft tissue sarcoma Eli Lilly V V V V 8 Netspot Nuplazid Ocaliva Rubraca PET imaging for neuroendocrine tumors Parkinson s disease Primary biliary cholangitis BRCA mutation associated advanced ovarian cancer Advanced Accelerator Applications USA V 11 ACADIA Pharmaceuticals V V 8 Intercept Pharmaceuticals V V V 11 Clovis Oncology V V V 6 Spinraza Spinal muscular atrophy Biogen V V 3 Tecentriq Urothelial carcinoma Genentech V V V 3 Venclexta Chronic lymphocytic leukemia AbbVie V V V 6 Xiidra Dry eye disease Shire Development V 17/6 Zepatier HCV Inhibitor Merk V V 8 Zinplava Clostridium difficile infection Merk V V 11

8 8 General Considerations A. Manufacturing and Product Quality Considerations Pursue a more rapid manufacturing development program to accommodate the accelerated pace of the clinical program. Be prepared to propose a commercial manufacturing program that will ensure availability of quality product at the time of approval. Estimated market demand and the commercial manufacturing development plan Manufacturing facilities and a lifecycle approach to process validation Include a timeline for development of the manufacturing capabilities with goals aligned with the clinical development program

9 9 General Considerations (Cont.) B. Nonclinical Considerations Sponsors should initiate early communication with FDA for their nonclinical study programs. study protocol modifications sequence and scheduling of studies the need for specific studies (e.g., long-term toxicity)

10 10 General Considerations (Cont.) C. Clinical Inspection Considerations Sponsors should anticipate the Agency s need to inspect clinical trials, including the analytical component of bioavailability or bioequivalence studies. Sponsors should be prepared for inspections to be scheduled by the Agency early in the application review process. It is important for reviewers to have timely access to adequate and accurate data in BLA, NDA, or supplement submissions. D. Companion Diagnostics Sponsors using one of the expedited programs for a product that involves an in vitro companion diagnostic device should consult FDA s guidance on the topic.

11 FDA Special Protocol Assessment (SPA) Guidance For Industry (May 2016) 11

12 12 Special Protocol Assessment (SPA) Guidance for Industry (May 2016) SPA, a process in which sponsors may request to meet with FDA to reach agreement on the design and size of certain clinical trials, clinical studies, or animal trials to determine if they adequately address scientific and regulatory requirements. Process: Sponsors submit specific questions (protocol design, scientific and regulatory requirements. FDA SPA review FDA issues an SPA Letter (assessment of the protocol, agreement or nonagreement with the proposed protocol, answers to the sponsor s relevant questions.)

13 13 Special Protocol Assessment (SPA) Guidance for Industry (May 2016) An SPA agreement indicates concurrence by FDA with the adequacy and acceptability of specific critical elements of overall protocol design (e.g., entry criteria, dose selection, endpoints, and planned analyses). Feedback on these issues provides the greatest benefit to sponsors in planning late-phase development strategy. It is hoped that trial quality will be improved by the SPA process.

14 14 Special Protocol Assessment (SPA) Guidance for Industry (May 2016) However An SPA agreement does not indicate FDA concurrence on every protocol detail. Because SPA provides for the evaluation of protocols for trials that have not been initiated, the conduct and results of the subsequent trial are not part of the evaluation. The existence of an SPA agreement does not guarantee that FDA will file (accept) a new drug application (NDA) or biologics license application (BLA), or that the trial results will be adequate to support approval.

15 15 Eligible Protocols Request Animal carcinogenicity protocols. Drug substance and drug product stability protocols. Animal efficacy protocols. Protocols for trials intended to form the primary basis of an efficacy claim. In addition, protocols for clinical or animal trials of bioequivalence or bioavailability that will form the basis of an efficacy claim are considered to meet this criterion and are eligible for an SPA. Any necessary trials to prove biosimilarity and/or interchangeability.

16 16 General Information Meeting With FDA Before Submission of a Request To discuss the proposed trial and its regulatory context. Sufficient information should be provided in the meeting request to permit detailed discussion. Reaching SPA Agreement With FDA An SPA agreement with FDA does not imply that FDA has reviewed or concurs with each detail of the protocol. The presence of an SPA agreement does not guarantee that a marketing application will be filed or approved. Sponsors should make every effort to identify unusual or potentially problematic aspects of the protocol and submit specific questions in their Request.

17 17 Procedures for Submission of a Request Notice of Intent Sponsors should notify FDA of their intent to submit a Request. (via developmental meeting, or as an informal fax or to the regulatory project manager) Timing of a Request At least 90 days before the anticipated start of the trial. Format of a Request Submit each protocol for an SPA as a separate amendment with Form FDA 1571 and a cover letter attached. Where to Send a Request To the appropriate CDER or CBER division.

18 18 Content of a Request and Submission Materials Animal Carcinogenicity Protocols Drug Substance and Drug Product Stability Protocols Animal Rule Efficacy Protocols Clinical Trial Protocols

19 19 FDA Assessment Process Determining Whether a Submission Is Appropriate for an SPA Appropriate : the division proceeds with the assessment. Not appropriate : notify the sponsor of the reasons. Assessment of the SPA Submission FDA s review focuses on critical protocol design features For animal carcinogenicity protocols, ECAC renders a final judgment. Sponsor can resubmit the Request after deficiencies in the supporting information are resolved, or continue without formal FDA agreement.

20 20 FDA Assessment Process (Cont.) Revisions During FDA Assessment FDA will incorporate timely responses addressing easily correctable deficiencies into the 45-day review timeline. FDA will consider submission of a revised protocol, or revised or additional supporting materials, to be a new SPA submission with a new 45-day timeline for response. FDA Response to Sponsor FDA committed to sending an SPA Letter to the sponsor within 45 calendar days of receipt of the SPA submission.

21 21 FDA Assessment Process (Cont.) Potential for Delay of FDA Response Input obtained from advisory committee review or consultants is critical. FDA should advise the sponsor of: (1) FDA s reasons for the delay; and (2) an anticipated date of FDA s response.

22 22 Sponsor Options After Receipt Of Nonagreement SPA Letter Initiate Trial Without SPA Agreement FDA agreement is not required before proceeding with critical trials intended to form primary evidence of effectiveness. FDA reviews marketing applications on the basis of submitted data, regardless of whether FDA previously agreed with the design of the protocol in an SPA agreement.

23 23 Sponsor Options After Receipt Of Nonagreement SPA Letter (Cont.) Do Not Initiate Trial and Respond in Writing to Address Nonagreement Sponsors can respond in writing to amend the protocol or provide additional supporting information to address the reasons for the nonagreement expressed by FDA. Will be considered an SPA resubmission. Request a Type A or BPD Type 1 Meeting to Discuss Nonagreement FDA and the sponsor should discuss any remaining issues and uncertainties regarding the protocol but may not necessarily come to final agreement on all remaining issues.

24 24 Documentation The primary documentation should consist of the SPA Letter that includes: Agreement Nonagreement Comments or questions to the sponsor ECAC minutes (If applicable)

25 25 References Guidance for Industry Expedited Programs for Serious Conditions - Drugs and Biologics, May 2014 Special Protocol Assessment (SPA) Guidance for Industry, May 2016 U.S. Food and Drug Administration, 2016 Novel Drugs Summary, January ovation/ucm htm

26 Thanks for listening!! 26