Regulatory Considerations on Patient Specific Cell Therapies Central New York Biotechnology Symposium 2011 Don Handley, MSc, MBA Administrative Director, Research Subject Protection Roswell Park Cancer Institute June 3, 2011 Basic Drug Development Pathway But… Preclinical Drug Development Drug Development Takes Longer Than It Did in the Past Developing a new medicine takes an average of 10–15 years; the Congressional Budget Office reports that “relatively few drugs survive the clinical trial process” ~ 5,000 – 10,000 Preclinical Clinical Trials 250 FDA Review Scale-Up to Mfg. Post-Marketing Surveillance 5 COMPOUNDS 3 – 6 YEARS PHASE 1 PHASE 2 PHASE 3 NUMBER OF VOLUNTEERS 20–100 100–500 6 – 7 YEARS 1,000–5,000 NDA SUBMITTED ONE FDAAPPROVED DRUG IND SUBMITTED PRE-DISCOVERY Drug Discovery 0.5 – 2 YEARS Sources: Drug Discovery and Development: Understanding the R&D Process, www.innovation.org; CBO, Research and Development in the Pharmaceutical Industry, 2006. INDEFINITE Regulations affecting product development and commercialization Development – Investigational New Drug Application (IND) • Submitted to FDA prior to initiation of first human clinical study • IND includes: – Chemistry & Manufacturing Information: • Active ingredient characterization, synthesis, • specifications and analytical methods, stability Drug product composition, manufacturing process, specifications and analytical methods, stability – Animal study reports: pharmacology, pharmacokinetics, toxicology – Proposed clinical protocol • A dynamic application: – Information amendments with new studies / data – Annual update reports on progress of studies – Clinical protocol amendments – new protocols / revised protocols Regulations affecting product development and commercialization Animal studies – Good Laboratory Practices • Regulations on the conduct of certain types of animal studies – Safety (toxicology) and PK studies • Applies to studies conducted before and after an IND is submitted • Covers: – – – – – – – – Organization and Personnel – management and quality assurance Facilities – animal care and supply, labs, specimen and data storage Equipment – design, maintenance and calibration Testing Facilities Operation – SOPs, animal care Test and Control Articles, characterization, handling Protocol for and Conduct of a Nonclinical Laboratory Study Records and Reports – reporting, storage, retention of data Disqualification of Testing Facilities Regulations affecting product development and commercialization Clinical studies – Good Clinical Practices • Regulations on the conduct of human clinical studies • Informed consent of study subjects • Institutional review boards • Responsibilities of study sponsor – – – – – Study protocol and regulatory study file / documentation Transfer of obligations to contract research organizations Selecting, training and monitoring Recordkeeping and retention Disposition of study supplies • Responsibilities of clinical investigators – – – – Selecting, training study staff Control of investigational drug Recordkeeping and retention Communications with sponsor and IRB Regulations affecting product development and commercialization Manufacturing – Good Manufacturing Practices • Regulations on the manufacture of drugs to be administered to humans or • • animals Applies to manufacture of investigational drug supplies and commercial production Covers: – Organization and Personnel – QC unit, personnel qualifications and responsibilities – Buildings and Facilities - Design and construction features, sanitation and maintenance – Equipment - design, size, and location, construction, cleaning and maintenance – Control of Components and Drug Product Containers and Closures – receipt, testing, use, rejected materials – Production and Process Controls – procedures, deviations, sampling, testing, control of contamination, reprocessing – Packaging and Labeling Controls – operations, inspection, expiration dating – Holding and Distribution - warehousing and distribution procedures – Laboratory Controls – sample testing, release for distribution, stability testing – Records and Reports - equipment cleaning and use log, production and control records, laboratory records, distribution records, complaint files – Returned and Salvaged Drug Products Regulations affecting product development and commercialization Marketing – New Drug Application (NDA) • Submitted to FDA to gain marketing approval of a drug • NDA includes: – Chemistry & Manufacturing Information: • Active ingredient characterization, synthesis, specifications and analytical methods, stability • Drug product composition, manufacturing process, specifications and analytical methods, stability – Animal study reports: pharmacology, pharmacokinetics, toxicology – Clinical study reports – Proposed labeling • A dynamic application: – – – – – Post-approval manufacturing or product changes Lifecycle changes – new indications, labeling changes Annual reports Adverse reaction reports Advertising and promotional materials Regulations affecting product development and commercialization Marketing – New Drug Application (NDA) FDA review: – Is the drug safe? Is it effective? – Is the risk/benefit ratio of the drug acceptable? – Is the chemistry of the drug well characterized? – Is the manufacturing and controls of the drug and quality systems of the manufacturing sites adequate? – Does the proposed labeling reflect the risks of the drug and convey it’s intended uses? Patient Specific Cell Therapies Regulatory Basis • 1993 - FDA issues official notice outlining basis • • for regulation of somatic cell therapy products. “Somatic cell therapy is the prevention, treatment, cure, diagnosis or mitigation of disease or injuries in humans by the administration of autologous (self), allogeneic (intra-species), or xenogeneic (inter-species) cells that have been manipulated or altered ex vivo.” Therefore, these products must comply with the same regulations as other biologics and drugs. Patient Specific Cell Therapies Examples of cellular products Regulated by: Office of Cellular, Tissue and Gene Therapies • Stem cells and stem cell-derived products • – hematopoietic, mesenchymal, embryonic, umbilical cord blood, etc Cancer vaccines and immunotherapies – E.g., dendritic cells, activated T lymphocytes (TIL, LAK), B lymphocytes, monocytes, cancer cells chemically modified or unmodified Patient Specific Cell Therapies OPPORTUNITIES • Cells are dynamic. They migrate, proliferate, differentiate, and respond to their environment in vitro and in vivo • Therapeutic outcome can be curative and permanent – Repair, replace, regenerate CHALLENGES • No terminal sterilization – requires aseptic processing • Limited shelf life (due to cell viability) • Small lot size/limited sample volume • Limited availability of starting material for process, product, and test method development • Patient to patient variability and cellular heterogeneity Patient Specific Cell Therapies Safety concerns • Cell migration/trafficking to non-target site(s) • Cell differentiation to undesired cell types • • • • Ex vivo manipulation (i.e. expansion, genetic modification) Potential inflammatory/immune response to allogeneic/ xenogeneic cells Inappropriate cell proliferation (i.e. tumor formation) Interactions with concomitant therapies (i.e. immunosuppressive agents) Patient Specific Cell Therapies Preclinical Considerations Obtain proof-of-concept in relevant animal models Show comparability of product lots used in various studies Use same route of administration and delivery method Cellular fate post transplantation Tumorigenicity potential OCTGT offers Pre-Pre-IND meetings for early, non-binding advice to help with development plans. Patient Specific Cell Therapies Manufacturing and Control – Starting Material and Reagents • Source of cells • Ancillary products that act on the cells – bioreactors, cell culturing, drug/biologics used to activate/change biological characteristics of the cells – Product Manufacturing - adequate facility and equipment performance standards and monitoring plans • Ensure aseptic environment for cell processing through design and monitoring • Use closed systems where possible • Use disposable equipment and process aids – Product Testing and Characterization • Need meaningful measures of sterility, identity, purity, and potency • Define and monitor/control all cell types present in the product • Detection of phenotype-specific cell surface antigens • Genomic / proteomic analysis • Panel of tests to assess cellular impurities profile – Detect discrete cell populations with unwanted features • Potency: specific ability or capacity of the product…to effect a given result (via a quantitative biological assay) – Product Stability Patient Specific Cell Therapies Clinical – – – Patients with advanced, refractory disease Data to support initial dose levels, dosing schedule Patients need to have fairly stable disease after cell collection and during manufacturing process of vaccine – Need optimized manufacturing process to shorten time to treatment of patient – Potential for disease progression after administration and prior to biological effect of cancer vaccine Questions? Don Handley Roswell Park Cancer Institute 716.845.3455 donald.handley@roswellpark.org