Presentation on theme: "Office of Hematology and Oncology Products"— Presentation transcript:
1Office of Hematology and Oncology Products Ann T. Farrell, M.D.Division DirectorDivision of Hematology ProductsOffice of Hematology and Oncology ProductsCenter for Drug Evaluation and Research
2DisclosureI have nothing to disclose and will not discuss off-label uses.
3FDA Missionprotect 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
4FDA 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 divisionsCenter for Biologic Evaluation and Research (CBER)Cellular therapies - Office of Cellular, Tissue and Gene TherapyVaccines – Office of VaccinesBlood and Plasma Products – Office of Blood Research and Review
5Four Main Areas that Impact Public Determine whether protocols submitted under an investigational new drug (IND) application are safe to proceedApprove Drugs/Biological Products for widespread commercial marketingWork with Pharmaceutical Manufacturers to manage production and safety issues that arisePermit access to drugs or biological products in development for compassionate use
6FDA and You Patient Advisors – Special Government Employees ConsultationAdvisory Committee Meetings -- ODACPatient 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 EngagementFederal Register Notice – 11/4/14 – wants suggestionsProfessional 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.
7Division Structure Divisions organized by area of expertise Project Manager (PM) coordinates multidisciplinary teamsDiscipline-specific teamsPrimary and secondary reviewWithin 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.
8Staff with Significant Expertise Reviewers are Clinicians – Medical Officers, Physician Assistants, Nurse PractitionersChemists, Biologists, MicrobiologistsPharmacologists/ToxicologistsClinical PharmacologistsStatisticiansEpidemiologistsSocial Scientists, EthicistsRegulatory Expertise - Lawyers, Project ManagersExternal Advisors (Special Government Employees)
9Drug Development Timeline End ofPhase IMeetingEnd ofPhase IIMeetingINDSubmissionClinicalStartPre-NDAMeetingNDA/BLAIND ReviewAnnual reportsIND Amendments30 daysClinicalholdPhase IPhase IIPhase III
10Orderly and Logical Progression of Studies Lab studies first, then animal, then humanSmall studies before largeShort studies before longLow dose before high doseEach step builds on prior experienceAs 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 generalSmall studies before largeShort studies before longLow dose before high doseEach step builds on prior experience
11Oncology Drug Development Lab studies first, then animal, then humanSmall studies before large onesPhase 1 (dose escalation accelerated titration 1 by 1 or 3 plus 3)Phase 2 (sometimes main trial for accelerated approval)Available therapyUnmet needRisk/benefitPhase 3 (usually one trial – pivotal trial)Each step builds on prior experiencePhase 4 studies post-approval to address safety/efficacy issues
12Investigational New Drug (IND) Determine whether protocols submitted under an investigational new drug (IND) application are safe to proceedResearch (physician working at a university/center)Commercial (Pharmaceutical Sponsors or other)Expanded AccessIntermediate protocolSingle PatientEmergency
13IND Formal application to the Agency to conduct research Requirements for submissionFDA has 30 days to get back to the sponsor regarding whether the trial is safe to proceed or notTeam reviewsDeficiencies – notify the sponsor and recommend how to correct themIf not corrected --- clinical hold
14INDs Fast Track Designation – nonclinical data Break Through Designation – clinical dataFocused attention on the development program
15Basis for NDA and BLA Approval Demonstration of efficacy with acceptable safety in adequate and well-controlled studiesAbility to generate product labeling thatDefines an appropriate patient population for treatment with the drugProvides adequate information to enable safe and effective use of the drugSo 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 descriptionwe have to be able to describe a dosing regimen, what the expected benefits and what the expected risks are
16Requirements 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)
17Approval Accelerated or Regular Regular Approval Accelerated Approval Based on clinical benefitAccelerated ApprovalAffect a surrogate endpoint other than mortality or irreversible morbiditySurrogate endpoint must be reasonably likely to predict clinical benefit, based on epidemiologic, therapeutic, pathophysiologic, or other evidenceAdditional studies confirming clinical benefit must be completed after approval
18Clinical Benefit Improvement in survival Improvement how a patient feelsImproved functioningClinical 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.1818
19Accelerated Approval Serious and life-threatening illness New therapy must provide advantage over available therapyability to treat patients unresponsive to or intolerant ofimproved patient response
20Evidence for Accelerated Approval Substantial evidence from well-controlled clinical trials regarding a surrogate endpointNOT: Borderline evidence regarding a clinical benefit endpoint
21Greatest Potential for Problems Chemistry, Manufacturing and ControlEfficacy DataSafety DataClinical Data goes to an Oncologics Drug Advisory Committee (AC) Meeting or other ACMeet several times a year to discuss scientific issues
22How 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 evidence1998 FDA Effectiveness Guidance:Statistically strong evidenceMulticenter trialImportant clinical benefitAdditional trials not ethical
23Review Time Standard 10 months plus 2 months Priority 6 months plus 2 monthsExpedited less than 6 months (usually)
24Oncologic Drugs Advisory Committee Meetings November – Panobinostat and Triferic ApplicationsSeptember 2013 – Perjeta in combination with trastuzumab/docetaxel demonstrating neoadjuvant pathologic CRMay 2013 – Animal data for approval of agents to treat radiation-induced myelosuppression associated with a radiological/nuclear incidentNovember 2011 – Facilitating anticoagulant drug development in pediatrics
26Permit accessPermit access to drugs or biological products in development for compassionate usewidespread – commercial marketingnot marketed – emergency INDs, Single Patient INDsphysician working with a pharmaceutical sponsorprocess which includes providing documentation, letters, etc.
28Ponatinib- 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 therapyThe 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.
30Ponatinib approvalOctober 2013 – voluntarily withdrawn from market available via expanded access protocolDecember 2013 – returns to marketEfficacy – unchangedSafety –Changed Box Warning to reflectIncrease in Vascular Occlusive Events – 27%New warning for Heart Failure
31Ponatinib – 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.