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
–
–
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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