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

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

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

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

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

FDA and You Patient Advisors – Special Government Employees Consultation Advisory Committee Meetings -- ODAC Patient Focused Drug Development Meetings – 5th 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 Professional Affairs and Stakeholder Engagement -a focal point for advocacy, to enhance two-way communication and collaboration with healthcare professionals, patients, patient groups, and others on CDER issues concerning drug development, drug review, and drug safety.

Division Structure Divisions organized by area of expertise Project Manager (PM) coordinates multidisciplinary teams Discipline-specific teams Primary and secondary review Within the Center for Drug Evaluation and Research, there are 16 different divisions which are organized by areas of expertise. The RHPM or CSO coordinates a multidisciplinary team. Discipline specific teams exist with a primary reviewer and a team leader who performs primary and secondary reviews respectively.

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)

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

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 As outlined on the slide, drug development is an orderly process. The process starts with lab studies and then progresses into animal studies and then clinical humans trials. In general Small studies before large Short studies before long Low dose before high dose Each step builds on prior experience

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

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

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

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

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 So when we approve a drug or biologic product, we generally have sufficient information from adequate and well-controlled studies to generate product labeling. The product labeling must define the patient population for whom the treatment is used and adequate information to enable safe and effective use. I am going to stress a couple of points here: we have to be able to describe for whom the treatment should be prescribed and that is guided by the data submitted for review because in general the study population is what goes into the description we have to be able to describe a dosing regimen, what the expected benefits and what the expected risks are

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)

Approval Accelerated or Regular Regular Approval Accelerated 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

Clinical Benefit Improvement in survival Improvement how a patient feels Improved functioning Clinical benefit must be demonstrated to receive regular approval. Clinical benefit is defined as prolonged patient survival or an improvement in how a patient feels or functions. Cancer and hematologic conditions often cause symptoms that lead to patient suffering. Improvement in symptoms of cancer, properly measured, using an instrument that is ‘fit for purpose’ in the intended patient population, could provide evidence of clinical benefit and support a regular approval. A symptom endpoint may support a claim of treatment benefit if it is used as a primary or secondary endpoint in adequate and well-controlled oncology or hematology clinical trials and if the studies also demonstrate a favorable treatment effect on the disease. The Office of Hematology and Oncology Products works with Sponsors to incorporate Clinical Outcome Assessments into their drug development plans when appropriate. 18 18

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

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

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

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

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

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

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

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.

Risk/Benefit

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 The indication on this slide is for the original approval of Iclusig. There is no test specified here because the requirement for a test was not considered necessary for the product to be used. Although much of the development was for patients whose disease had the T315I mutation, there was data showing a similar response rate for those without the mutation.

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)

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

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. The Agency takes its post-marketing surveillance seriously, and after the percentage of adverse events appeared to triple in a short time frame, we felt it best to restrict the drug for those patients who truly needed it. Those who were T315I positive or those who had no other options. The decision on whether it was absolutely necessary for a test can be summed up this way – you can get here either by multiple trials with various approved TKIS or get mutation testing done in either instance you would be a candidate for this product. So the indication was felt to be low risk from a CDRH perspective for a companion diagnostic.

References www.fda.gov