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

Division Structure

• Divisions organized by area of expertise

• Project Manager (PM) coordinates multidisciplinary teams

• Discipline-specific teams

• Primary and secondary review

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

IND Review

Clinical Start

Annual reports

End of Phase IMeeting

End of Phase IIMeeting

IND Amendments

Pre-NDAMeeting

NDA/BLA INDSubmission

30 daysClinicalhold

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

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

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

– 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

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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

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.

References

• www.fda.gov