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Office of Hematology and Oncology Products Ann T. Farrell, M.D. Division Director Division of Hematology Products Office of Hematology and Oncology Products.

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Presentation on theme: "Office of Hematology and Oncology Products Ann T. Farrell, M.D. Division Director Division of Hematology Products Office of Hematology and Oncology Products."— Presentation transcript:

1 Office of Hematology and Oncology Products Ann T. Farrell, M.D. Division Director Division of Hematology Products Office of Hematology and Oncology Products Center for Drug Evaluation and Research

2 Disclosure I have nothing to disclose and will not discuss off-label uses.

3 FDA Mission protect the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices. responsible for the safety and security of most of our nation’s food supply, all cosmetics, dietary supplements and products that give off radiation. responsible for regulating tobacco products

4 FDA Structure Center for Drug Evaluation and Research (CDER) –Regulate Drugs and Biologics except for vaccines, blood and plasma products and cellular based therapies – 16 review divisions Center for Biologic Evaluation and Research (CBER) –Cellular therapies - Office of Cellular, Tissue and Gene Therapy –Vaccines – Office of Vaccines –Blood and Plasma Products – Office of Blood Research and Review

5 Four Main Areas that Impact Public Determine whether protocols submitted under an investigational new drug (IND) application are safe to proceed Approve Drugs/Biological Products for widespread commercial marketing Work with Pharmaceutical Manufacturers to manage production and safety issues that arise Permit access to drugs or biological products in development for compassionate use

6 FDA and You Patient Advisors – Special Government Employees –Consultation Advisory Committee Meetings-- ODAC Patient Focused Drug Development Meetings – 5 th authorization of Prescription Drug User Fee Act/Food Drug Administration Safety and Innovation Act (July 9, 2012) – 5 years (lung cancer – July 2013, sickle cell disease – February 2014) CDER’s Center Director Office – Professional Affairs and Stakeholder Engagement Federal Register Notice – 11/4/14 – wants suggestions

7 Division Structure Divisions organized by area of expertise Project Manager (PM) coordinates multidisciplinary teams Discipline-specific teams Primary and secondary review

8 Staff with Significant Expertise Reviewers are Clinicians – Medical Officers, Physician Assistants, Nurse Practitioners Chemists, Biologists, Microbiologists Pharmacologists/Toxicologists Clinical Pharmacologists Statisticians Epidemiologists Social Scientists, Ethicists Regulatory Expertise - Lawyers, Project Managers External Advisors (Special Government Employees)

9 Drug Development Timeline IND Review Clinical Start Annual reports End of Phase I Meeting End of Phase II Meeting IND Amendments Pre- NDA Meeting NDA/BLA IND Submission 30 days Clinical hold Phase I Phase II Phase III

10 Orderly and Logical Progression of Studies Lab studies first, then animal, then human Small studies before large Short studies before long Low dose before high dose Each step builds on prior experience

11 Oncology Drug Development Lab studies first, then animal, then human Small studies before large ones Phase 1 (dose escalation accelerated titration 1 by 1 or 3 plus 3) Phase 2 (sometimes main trial for accelerated approval) –Available therapy –Unmet need –Risk/benefit Phase 3 (usually one trial – pivotal trial) Each step builds on prior experience Phase 4 studies post-approval to address safety/efficacy issues

12 Investigational New Drug (IND) Determine whether protocols submitted under an investigational new drug (IND) application are safe to proceed –Research (physician working at a university/center) –Commercial (Pharmaceutical Sponsors or other) –Expanded Access Intermediate protocol Single Patient Emergency

13 IND Formal application to the Agency to conduct research Requirements for submission FDA has 30 days to get back to the sponsor regarding whether the trial is safe to proceed or not Team reviews Deficiencies – notify the sponsor and recommend how to correct them If not corrected --- clinical hold

14 INDs Fast Track Designation – nonclinical data Break Through Designation – clinical data Focused attention on the development program

15 Basis for NDA and BLA Approval Demonstration of efficacy with acceptable safety in adequate and well-controlled studies Ability to generate product labeling that –Defines an appropriate patient population for treatment with the drug –Provides adequate information to enable safe and effective use of the drug

16 Requirements for Drug Approval Safety (FDAC 1938) Efficacy established in adequate and well-controlled investigations (FDAC 1962) Use of data from one trial plus supportive evidence (FDAMA 1997)

17 Approval Accelerated or Regular Regular Approval –Based on clinical benefit Accelerated Approval –Affect a surrogate endpoint other than mortality or irreversible morbidity –Surrogate endpoint must be reasonably likely to predict clinical benefit, based on epidemiologic, therapeutic, pathophysiologic, or other evidence –Additional studies confirming clinical benefit must be completed after approval

18 Clinical Benefit Improvement in survival Improvement how a patient feels Improved functioning 18

19 Accelerated Approval Serious and life-threatening illness New therapy must provide advantage over available therapy –ability to treat patients unresponsive to or intolerant of –improved patient response

20 Evidence for Accelerated Approval Substantial evidence from well-controlled clinical trials regarding a surrogate endpoint NOT: Borderline evidence regarding a clinical benefit endpoint

21 Greatest Potential for Problems Chemistry, Manufacturing and Control Efficacy Data Safety Data Clinical Data goes to an Oncologics Drug Advisory Committee (AC) Meeting or other AC Meet several times a year to discuss scientific issues

22 How many trials? Usually more than one trial is needed. Substantial evidence: “Adequate and well-controlled investigations” Sometimes a single trial may suffice. –FDAMA (1997) single trial plus other supportive evidence –1998 FDA Effectiveness Guidance: Statistically strong evidence Multicenter trial Important clinical benefit Additional trials not ethical

23 Review Time Standard 10 months plus 2 months Priority 6 months plus 2 months Expedited less than 6 months (usually)

24 Oncologic Drugs Advisory Committee Meetings November 2014 – Panobinostat and Triferic Applications September 2013 – Perjeta in combination with trastuzumab/docetaxel demonstrating neoadjuvant pathologic CR May 2013 – Animal data for approval of agents to treat radiation-induced myelosuppression associated with a radiological/nuclear incident November 2011 – Facilitating anticoagulant drug development in pediatrics

25 2014 NME Recent Approvals Cyramza (ramucirumab) – gastric cancer Sylvant (siltuximab) – multicentric Castleman’s disease Zykadia – non-small cell lung cancer Belodaq (bellinostat) – peripheral t-cell lymphoma Zydelig – CLL, Follicular B-cell non-Hodgkins Lymphoma, small cell lymphocytic lymphoma Keytruda – melanoma

26 Permit access Permit access to drugs or biological products in development for compassionate use widespread – commercial marketing not marketed – emergency INDs, Single Patient INDs physician working with a pharmaceutical sponsor process which includes providing documentation, letters, etc.

27 Risk/Benefit

28 Ponatinib- original indications kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy

29 Ponatinib original approval Efficacy (MCyR) for CML –Relapsed CML – 49% –CML with T315I -70% –Accelerated Phase CML (CHR) – 47% –Blast Phase CML (CHR) – 21% –Ph+ Acute Lymphoblastic Leukemia – 34% Safety –Arterial thrombosis – 8% (MI, Stroke, gangrene)

30 Ponatinib approval October 2013 – voluntarily withdrawn from market available via expanded access protocol December 2013 – returns to market Efficacy – unchanged Safety – –Changed Box Warning to reflect –Increase in Vascular Occlusive Events – 27% –New warning for Heart Failure

31 Ponatinib – latest indications Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315Ipositive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

32 References


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