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Clinical Development – Drugs
Darrin Cowley PhD
Executive Director Amgen
BioBoot Camp 2015
Product Development:
Preclinical Phase 1 Phase 2 Phase 3 Lifecycle
Management
Development process:
• It can take 15+ years to develop a new medicine from discovery to
approval
• The clinical space from first in human (FIH) to approval on average
takes 5-9 years
• Average cost of research and development is estimated between
1-1.5 billion dollars for a program that gets approved
Drug
Discovery
File Approval
safety efficacy pivotal
Regulations
Code of Federal Regulations (CFR)
– Good Manufacturing Practices (GMP): 21 CFR 211
– Biologic Products 21 CFR 600
– Additional Standards for Viral Vaccines 21 CFR 630
FDA website (development and approval process): http://www.fda.gov/Drugs/DevelopmentApprovalProcess/default.htm
FDA website (formal meeting requests process): http://www.fda.gov/downloads/Drugs/Guidances/ucm153222.pdf
Guidance's
Product class specific guidance
– Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use
International Conference on Harmonization (ICH)
– ICH Q2: Validation of Analytical Procedures: Text and Methodology;
– ICH Q3: Impurities;
– ICH Q5: Quality of Biotechnological Products;
Q5A: Viral Safety…..
Q5C: Stability testing.....
Q5D: Comparability….
– Q6: Specifications
Documentation
Internal Documentation (SOP)
– Manufacturing
– Specifications
– Testing
– Stability
– Protocols and reports
Quality Agreements
Contract Development and Manufacturing
Nonclinical testing and timelines
– Clinical Research Organizations (CRO)
Clinical Molecule Development through MA
Preparing for First in Human
– Clinical formulation
– Assessment of comparability
– Filing of CTA (IND)
Development of Commercial Process
– Molecule assessment
– Upstream and downstream process
– Drug Substance and Drug Product characterization
– Assessment of comparability
– Filing of Pivotal CTA
Preparing for Commercial Production
– Tech transfer and scale up
– Assessment of comparability
Filing MA (BLA)
Preparing for First in Human Studies
A working cell bank (WCB) is derived from the master cell bank (MCB) and is used to initiate a production batch – Characterization of Cell Banks
Stability, sterility, adventitious agents, viability, etc..
Scale up to support phase 1-2 clinical studies – GMP manufacturing
Drug Substance and Product
In-house or CMO
– Material should be consistent with tox material
Consider comparability assessment
– Molecule characterization
In-process and release testing – Bioburden and endotoxin
– Specification tests
Assess drug substance and drug product specification(s) and update if necessary
FIH material should be placed on stability – Define stability protocol
– Recommended storage 1-3 lots of DS and DP
– Accelerated stability 1-6 months
CLINICAL USE SUPPORT STUDIES
– Finalize FIH formulation
– Support delivery and use in Phase 1 clinical studies.
– Typically assess the feasibility of drug administration
intravenous (IV), IV bag study
subcutaneous (SC) injection Syringe and Diluent Compatibility Study.
Preparing for First in Human Studies
It all comes down to safety and efficacy
Analytical methods are fit for purpose – Release and characterization assays
– Assay qualification well underway
Comparability assessment – Biophysical
– Biochemical
– biological
Quality systems in place – Release and distribution of product
– Documentation of deviations
– Change control system
Filing CTD (IND)
Preparing for First in Human Studies
Clinical Trials:
Phase 1: First in Human (FIH)
Clinical development is about getting high potential candidate molecules into the clinic as quickly as possible without sacrificing patient safety
Safety and tolerability study
– Performed in healthy subjects or patients
– Starting dose may be defined by animal toxicity studies and/or molecule knowledge
Phase 2: Dose ranging and efficacy
– Establishing a clinical dose that is safe and efficacious
– Usually placebo controlled
Clinical Trial Applications:
Used to meet regulatory requirements for initiating clinical studies
Typically contain one or more of the following:
– Scientific rationale for proposed use
– Preclinical data showing product is reasonably safe for testing in humans
– CMC data demonstrating that:
Physical & chemical properties are not similar to toxic substances
Manufacturer can produce consistent supply of product
– Plans for clinical program
Protocols
Investigator & site information
Strategic use of the Clinical Trial Application Process:
•Opportunity to engage the agency in product development plans
• FDA review = 30 days
•Authorization is implicit unless otherwise notified
•Opportunity to set stage for future clinical program
• Begin working with “the-end-in-mind”
Module 1
– Regional Information Label
Module 2
– Quality overall summary, non-clinical and clinical overview and summary
Module 3
– Quality section
Module 4
– Non-clinical study reports
Module 5
– Clinical study reports
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/CTD_triangle.pdf
CTD Format
Development of Commercial Process
A determination will need to be made to proceed to the development of a commercial process
– Decision typically occurs during phase 2 studies
This is a very costly proposition, an organization needs the right clinical data and knowledge that the molecule is well behaved that they want to invest in the future development
Develop a process that is scalable to working cell culture volumes of 12,000+ liters
Scale down DOE studies to evaluate all aspects of the cell culture process to control critical quality attributes of the molecule
– Dissolved gasses
– Mixing speeds
– Culture media and periodic feeds of needed nutrients
– Cell growth and viability
– pH and temperature
Develop the final drug product formulation
– Vial, syringe, IV, (liquid, lyo)
Perform a Molecule Assessment
Consideration of manufacturing, stability, and product attributes when designing/selecting protein candidates for commercialization
Understand what process steps could impact critical molecule attributes
Initiate a risk assessment that links product and process together
Develop a control strategy for critical process steps
Cell Culture Process (Upstream)
1000 L
Bioreactor
1000 L
Bioreactor
Cell Culture graphic curtsey of Ingrid Markovic, Ph.D FDA
Purification Process (Downstream)
Purification graphic curtsey of Ingrid Markovic, Ph.D FDA
Drug Substance Characterization
Drug Substance should be positive for identity and have specified criteria for purity, potency and microbial contamination
Acceptance criteria for release and stability attributes should be re-assessed
– Often broader early in the development and subject to revisions (e.g., narrowed down) as manufacturing process develops
Results from release and stability testing should be provided in the INDa
Raw data supporting Drug Substance characterization should be provided in the INDa
Drug Substance Characterization (cont’)
Safety
– Ensured by the specified limits for bioburden and endotoxin, misc. process-related contaminants
Purity & Characterization
– Assesses capability of purification process to remove process-related impurities (e.g., endogenous viruses, host-cell proteins, DNA, leachables, anti-foam, antibiotics, toxins, solvents, heavy metals, etc.)
– Product-related impurities (e.g., aggregates, breakdown products, product variants due to: oxidation, deamidation, denaturation, loss of C-term Lys in MAbs etc.)
– Product substances (product variants that are active)
Identity
– Unique for protein of interest, especially relevant for closely related proteins manufactured in the same facility
Drug Substance Characterization (cont’)
Potency
– Required to assess biological activity of the product
– Assay should be relevant for protein mechanism of action
– For MAb or Fc fusion proteins - a binding assay may be sufficient for early development, but a functional assay relevant for the mechanism of action should be developed
– If mechanism of action unknown - multiple bioactivities plus elucidating higher order structure may be required
Strength
– Protein content
Stability
– Drug Substance stability should be demonstrated with appropriate stability-indicating assays
Drug Substance Characterization – Methodology Safety
– LAL test, rabbit pyrogen test, bacterial culture methods
Purity & Characterization including but not limited to: – Reversed-phase HPLC, Peptide mapping, MS
– SDS-PAGE, Western analysis, capillary electrophoresis
– SEC, AUC, FFF, light scattering
– Ion Exchange Chromatography
– Carbohydrate analysis (capillary electrophoresis, high-pH anion-exchange chromatography, etc…)
Identity – N-terminal sequencing
– Peptide mapping
– Immunoassays (ELISA, Western blotting)
Potency – Animal-based assays, cell-based assays, reporter gene, biochemical (e.g.,
enzyme activity)
Protein content – RIA, ELISA, UV absorbance, Bradford
Drug Product Characterization
Drug Substance thaw
Formulation (pooling and mixing)
Sterile Filtration
Filling
Stopper placement
Capping and Crimping (vials only)
Inspection
Packaging
Drug Product Characterization
Safety
– Final Drug Product for injection should be sterile
– Within specified limits for endotoxin
– Immunogenicity should be screened and monitored
Successfully reduced in MAb by replacing murine with human sequences
Purity & Characterization
– Product and process-related impurities & product-related substances should be within specified limits
Identity
– Unique for protein of interest, especially relevant for closely related proteins manufactured in the same facility
Drug Product Characterization (cont’)
Potency
– Assay should be relevant for protein mechanism of action
– For MAb or Fc fusion proteins, a binding assay may be sufficient for early development, but a functional assay relevant for the mechanism of action should be developed
– If mechanism of action unknown - multiple bioactivities plus elucidation of higher order structure may be required
Strength
– Protein content
Stability
– Drug Product should maintain stability for the duration of the clinical trial
Container closure compatibility
– Primary function - barrier to microbial ingress
– Extractables/Leachables studies – requirement for licensure
Drug Product Characterization (cont’)
Determination of final dose(s)
– Liquid
– Lyophilized
Route of administration
– Subcutaneous
– Intravenous (IV)
Container type and delivery device
– Vial
– Syringe (combination product)
– Device (combination product)
Must provide assurance that the product submitted to a pivotal clinical study is comparable to the Phase 1 and Phase 2 studies
Impact of Changes Introduced Throughout Product Development Must be Assessed
Operational and/or supply requirements change e.g., scale up, manufacturing site, final commercial presentation
Assessment of Comparability
Comparability should: Illustrate the product has highly similar quality
attributes before and after process changes
Ensure the process maintains or improves it
capabilities
Conclude that existing knowledge ensures
changes have no impact on safety and
efficacy or is not sufficient and requires
additional studies, PK/PD clinical studies
Comparability ensures that the results from toxicology, nonclinical evaluation, and previous clinical evaluation (safety and efficacy)remain applicable
throughout product development and commercialization
Filing update to use the commercial process material in clinical studies
Process updates for drug substance and drug product
Process and product related impurities
Comparability of commercial process material to Phase 1 and Phase 2
Analytical methods qualified/validated
Stability program update
Pre-filing meeting with agency
– Up to sponsor, can discuss potential issues and request feedback
Filing update (INDa Phase 3)
Determine scale and site of commercial drug substance and drug product production
– Analytical testing lot release location
Facility assessment and process fit
Technology transfer
Validate drug substance and drug product processes
Transfer and validate analytical methods
Comparability assessment back to pivotal material
Complete molecule characterization
– Elucidation of structure
– Impurities
Place validation lots (DS and DP) on stability to support MA
– Typically 3 lots DS and DP
Preparing for Commercial Production
Pre-BLA meeting with Agency
– Opportunity to discuss any unresolved issues
– FDA notification of intent to file 75 days in advance
– Briefing package due 4 weeks in advance
Modular CTD format, accepted in ICH regions
Electronic filing preferred
Opportunities for expedited review
Review process can take 6-18 months
– Potentially many rounds of questions
Frequent interactions with FDA
Label negotiations critical
May have Advisory Committee meeting
Marketing Application
The Format of the Common Technical Document
Module 1
Regional
Information Label
Module 2
Module 3 Module 4 Module 5
TOC Introduction
Quality Section Nonclinical Study
Reports
Clinical Study
Reports
Quality
Overall
Summary Nonclinical
Summaries
Clinical
Overview
Clinical
Summary
Nonclinical
Overview
• Defined Format
• Flexibility for
Regional Content
Requirements
Figure from ICH.org
Commercial Manufacturing Controls BLA
Major Module 3 sections drug substance
– S.1, nomenclature, structure, general properties
– S.2, manufacturing process, control of materials
– S.3, elucidation of structure, impurities
– S.4, specification, analytical procedures, justification of specification
– S.5, reference standard
– S.6, container closure
– S.7, stability summary, protocol, stability data
Commercial Manufacturing Controls BLA
Major Module 3 sections drug product
– P.1, composition of drug product
– P.2, formulation
– P.3, manufacturing process, control of critical steps
– P.4, excipients
– P.5, specification, analytical procedures, justification of specification
– P.6, reference standard
– P.7, container closure
– P.8, stability summary, protocol, stability data
United States FDA Structure
Center for Drug Evaluation & Research (CDER)
Center for Biologics Evaluation & Research (CBER)
Center for Devices & Radiological Health (CDRH)
Center for Food Safety & Applied Nutrition (CFSAN)
Vaccines (CBER)
National Center for Toxicological Research
Office of the Commissioner
Office of Regulatory Affairs
Acknowledgements
Barry Cherney
Chantal Cazeault
Andy Spasoff
Tim Brown
Ingrid Markovic
Randy Steiner
Alex Mercier