PHARM 532 Regulation of Pharmaceuticals II

Transcription

1 FDA s Regulatory Structuret PHARM 532 Regulation of Pharmaceuticals II Spring 2009 Center(s) for Biologics Evaluation & Research (CBER) 1 Drug Evaluation & Research (CDER) 2 Device & Radiological Health (CDRH) 2 Veterinary Medicine (CVM) 2 Food Safety & Applied Nutrition (CFSAN) 2 1.Public Health Service Act 2. Food, Drug & Cosmetic Act 1 2 FDA Regulatory Structure Medical Products Development Drugs/Biologics Preclinical IND NDA BLA PLA/ELA ANDA (generics) SNDA Medical Devices quality system requirements Class I mostly notification Class II mostly 510(k) demonstration of substantial equivalence Class III IDE PMA 3 4

2 PRE-CLINICAL RESEARCH CLINICAL STUDIES PRE-CLINICAL RESEARCH CLINICAL STUDIES FDA REVIEW SYNTHESIS AND PURIFICATION SYNTHESIS AND PURIFICATION PHASE 1 ING DISCO OVERY/S SCREEN ANIMAL TESTING SHORT-TERM DISCO OVERY/S SCREEN NING ANIMAL TESTING SHORT-TERM PHASE 2 PHASE 3 LONG-TERM LONG-TERM INDUSTRY TIME FDA TIME IND FDA & INDUSTRY TIME SPONSOR/FDA MEETINGS ENCOURAGED NDA 5 INDUSTRY TIME FDA TIME IND FDA & INDUSTRY TIME SPONSOR/FDA MEETINGS ENCOURAGED NDA/ BLA FDA ACTION 6 PRE-CLINICAL RESEARCH CLINICAL STUDIES FDA REVIEW POST MARKETING SCOVER RY/SCRE EENING DI SYNTHESIS AND PURIFICATION ANIMAL TESTING SHORT-TERM PHASE 1 PHASE 2 PHASE 3 ACCELERATED APPROVAL TREATMENT USE PARALLEL TRACK ADVERSE REACTION SURVEILLANCE PRODUCT DEFECT REPORTING PHASE 4 SURVEYS/ SAMPLING TESTING Medical Device Approval process with thanks to Dave Pettenski, USFDA LONG-TERM POST APPROVAL INSPECTIONS S INDUSTRY TIME FDA TIME FDA & INDUSTRY TIME IND NDA BLA ACTION SPONSOR/FDA MEETINGS ENCOURAGED 7 8

3 Medical Device Approvals Origin i of Classification System Medical Device Amendment to the FD&C Act of 1976 May 28, 1976 Provided classification for regulatory purposes A priority of control/oversight Early form of risk based approach 9 10 Basis for Classification of Devices Amount of information known about device for intended use & indications for use Scalpel: intended use - cut tissue. Indication in labeling "for making incisions in the cornea". What level of controls are necessary to assure Safety & Effectiveness of device Support or sustain human life OR important in preventing impairment of human health Risk of causing illness or injury 11 Medical Device Classification & Regulatory Requirements Class I - General Controls (with & w/o exemptions) Class II General Controls and Special Controls (with & w/o exemptions) Class III General Controls and Premarket Approval 12

4 Class I - General Controls Known information provides reasonable assurance of safety & effectiveness using General Controls OR Known information does not assure S & E, BUT the device Does not support or sustain human life, OR Is not used to prevent impairment of human health AND No unreasonable risk of illness or injury 13 General Controls FD&C Act Sec. 510: Registration, Listing, 510(k) FD&C Act Sec. 518: Notification & Other Remedies FD&C Act Sec. 519: Records & Other Reports (MDR, Tracking. Corrections/Removals) FD&C Act Sec. 520: General Provisions (GMPs/QSR) 14 General Controls FD&C Act Section 510 Establishment Registration General Controls FD&C Act Section 518 Notification Product Listing Repair, Replace, or Refund 510(k) - Premarket Notification, unless exempt Recall Authority 15 16

5 General Controls FD&C Act Section 519 Medical Device Reporting Device Tracking (as required) Reports of Removals and Corrections General Controls FD&C Act Section 520 Good Manufacturing Practices/Quality System Regulations, unless exempt Design Controls (as applicable) All class II & III medical devices plus the five class I devices listed in 21 CFR Examples of Class I Devices Class II - Special Controls Examination Gloves 21CFR Dental Hand Instrument 21CFR Elastic Bandages 21CFR Pacemaker Charger 21CFR Ultrasonic Cleaner for Medical Instruments 21CFR Hand-held (Manual) Surgical Instruments 21CFR General Controls alone are insufficient to provide assurance of Safety & Effectiveness HOWEVER: Information exists to establish Special Controls 20

6 Special Controls Examples of Class II Devices General Controls + Special Labeling Requirements Performance Standards Postmarket t Surveillance Patient Registries Guidelines Recommendations Any other appropriate actions 21 Cardiac Monitor 21CFR Elbow Joint Metal/Polymer Constrained Cemented Prosthesis 21CFR Pediatric hospital bed 21CFR Infusion Pump 21CFR Powered Wheelchair 21CFR Surgical Drapes 21CFR TENS device 21CFR Class III - Premarket Approval Premarket Approval Not enough information to classify as either Class I or II Device usually supports/sustains life, Is of substantial importance in preventing impairment of human health or Presents a potential, ti unreasonable risk of illness or injury Extensive submission including data showing Safety & Effectiveness Conditions of Approval Annual Reports 23 24

7 Examples of Class III Devices Implantable pacemaker pulse generator 21CFR Replacement heart valve 21CFR Cranial electrotherapy 21CFR Implanted electrical urinary continence device 21CFR Silicone gel-filled breast implant 21CFR Implanted cerebella stimulator 21CFR Pre May 28, 1976 Products Intent to classify all products on the market Class I and II No 510(k) required Class III No PMA required until called for Marketed with a 510(k) Post May 28, 1976 Products Automatic Class III Unclassified Device What regulations apply? Introduced onto market after May 1976 Not substantially equivalent to a pre-may 1976 device Not already Classified as I or II Similar product for same intended use already on market or is it brand new? Product P d t Classification Database Search: infusion i 27 28

8 Current Issues Risk-Based Approach Pediatric Labeling Therapeutic Biological Products Sub-part th A Accelerated dapproval of fnew Drugs for Serious or Life-Threatening Illnesses Exploratory IND Studies Follow-on biologics (biosimilars) Risk-Based Approach Precedent: CDRH Quality Systems Inspection Technique Premarketing Risk Assessment Process Analytical Technology (PAT) Development and Use of Risk Minimization Action Plans how long is FDA s arm? Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment CDER Risk-Based Inspection Prioritization Score (Compliance Program ) Pediatric i Labeling Best Pharmaceuticals for Children Act (BPCA) Establish a process for studying on-patent and off-patent drugs for use in pediatric populations Improve pediatric therapeutics through collaboration on scientific investigation, clinical study design, weight of evidence, and ethical and labeling issues Rewards (penalties) to manufacturers for (non) compliance Therapeutic Biological i l Products CBER CDER well-characterized biologicals and generic equivalence 31 32

9 CBER CDER Categories of Therapeutic Biological Products Transferred to CDER Monoclonal antibodies for in-vivo use Proteins intended for therapeutic use, including cytokines (e.g. interferons), enzymes (e.g. thrombolytics), and other novel proteins, except for those that are specifically assigned to CBER (e.g., vaccines and blood products). Immunomodulators (non-vaccine and non-allergenic products) Growth factors, cytokines, and monoclonal antibodies... hematopoietic cells in vivo Categories of Therapeutic Biological Products Remaining in CBER Cellular products, including products composed of human, bacterial or animal cells, or from physical parts of those cells Vaccines Allergenic extracts used for the diagnosis and treatment of allergic diseases and allergen patch tests Antitoxins, antivenins, and venoms Blood, blood components, plasma derived products, including recombinant and transgenic versions of plasma derivatives, blood substitutes, plasma volume expanders, human or animal polyclonal antibody preparations including radiolabeled or conjugated forms, and certain fibrinolytics such as plasma-derived plasmin, and red cell reagents... when the patent runs out... biosimilars for typical drugs ANDA what is the appropriate basis for comparability? bioequivalence [Orange Book] 33 Schellekens H. TRENDS in Biotechnology Vol.22 No.8 August Therapeutic Biological i l Comparability Part 314 Subpart H & Part 601 Subpart E: Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses the manufacturing process analytical procedures manufacturing equipment manufacturing facilities container closure systems process analytical technology (PAT) immunogenicity issues Comparability Protocols - Protein Drug Products and Biological Products - Chemistry, Manufacturing, and Controls Information. USFDA CFR Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. NDA approval adequate and well-controlled clinical trials effect on a surrogate endpoint reasonably likely... to predict clinical benefit 36

10 CBER & CDER Approval Stats New Molecular Entity Drugs/Biologics Calendar Year Approved Priority Median FDA Time Median Total Approval Time Approved Standard Median FDA Time Median Total Approval Time Exploratory IND Studies Pharm Tox * * * * * high within-ind failure rate 1 exploratory studies could 2 mechanism of action and treatment of disease improved understanding pk/pd improve selection of most promising... candidate explore bio-distribution characteristics using imaging technologies * Includes BLAs Innovation or Stagnation, Challenge & Opportunity on the Critical Path to New Medical Products USFDA Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies, USFDA Safety Program Designs... What Ails the FDA? pk or imaging microdose* studies in animals to support single dose studies in humans pharmacological effects more extensive preclinical trials of specified design to better predict starting and maximum doses in clinical trials clinical studies of mechanism of action clinical starting doses and dose escalation schemes surveillance authority leadership (several layers) PDUFA pressures clock information flow, culture of fear decisions based on insufficient evidence politicization *<1/100 of dose calculated to yield a pharmacological effect; maximum 100 mcg; see European Medicines Agency Evaluation of Medicines for Human Use and ICH S7A 39 Okie N Engl J Med 2005;352(11):