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