# Presentation: 275180

## Moving Novel Concepts From Research Laboratory To Clinical Proof-of-Principle

- Biopharmaceutical Development Program
- Biological Resources Branch
- Developmental Therapeutics Program
- National Cancer Institute
- Frederick, Maryland

## Mission

- To produce clinical-grade biopharmaceuticals under current Good Manufacturing Practices (cGMPs) appropriate for Phase I/II (dose-ranging safety and efficacy) and “proof of principle” clinical trials of innovative biopharmaceutical concepts.
- To manufacture high-quality laboratory-grade material to support preclinical development for selected innovative projects.

## Key Assumptions

- Concepts are selected for novelty and innovation over derivatives of existing approaches.
- Many projects have been previously considered by Pharma and declined due to uncertain technology, regulatory hurdles, or small markets.
- Clinical production is focused on meeting requirements for initial proof-of-concept trials, NOT final product requirements for commercial development.
- Approximately 1/10-1/20 clinical projects may eventually be licensed.
- Desired size of program is based on assumptions #1-4, i.e., 10-20+ projects/year to clinic.
- Intellectual Property to be retained by Project Originator(s).

## Where Does The Program Get Its Projects?

- Peer-reviewed Extramural Research
- Special Competitions
- 	Rapid Access to Intervention Development (RAID) Program
- 	Inter-Institute Program (IIP) for AIDS Projects
- 	National Cooperative Drug Discovery Groups
- Intramural NCI Research
- Other NIH Programs (NIAID)
- Commercial Collaborations with Government
- The NCI Selects and Prioritizes Candidate Projects
- BDP Provides Feasibility Analyses and Cost Estimates that are used in the Selection

## Capabilities And Resources

**Fermentation For Recombinants:  20L, 80L, 100L and 1,000L**
**Natural Products Fermentation:  30, 300, 3,000 Gallons**
**Hollow Fiber Mammalian Cell Production (8 Pathways)**
**Packed Bed Mammalian Cell Production**
**Process Development and Optimization**
**	****Fermentation**
**	****Recovery**
**	****Refolding**
**	****Purification**
**	****Assays**
**	****Etc.**
**Clean Room Suite**
**BL3 Suite**
**QA**
**QC**
**Management of Required Out-Source Production and Testing**
**CMC Documentation for IND Submission**

## Major Milestones In A Typical Clinical-Grade Production Project

- Pre-Proposal Communications With Potential Investigator-Applicants
- Proposal Received by NCI
- Initial Review by Staff
- 	Clarify Projects by Posing “Generic Questions” to Applicants
- 	Make Preliminary Feasibility Analysis & Cost Estimates
- 	Identify Any Special Concerns

## Major Milestones (Continued)

- Peer Review by Selection Committee
- 	Committee May Re-define Project Scope
- 	Staff Re-examines Feasibility & Cost Estimates
- Oversight Committee Review
- 	Staff Present Cost and Feasibility Analysis
- 	Determination of Scope of Project
- 	Re-evaluation of Progress at Key Milestones

## Major Milestones (Continued)

- Initial Meeting of Staff With Outside Investigator
- Initial Project Team Meeting
- 	Define Deliverables
- 		Material Requirements
- 		Formulation
- 		Filling
- 	Special Concerns
- 		Safety
- 		Regulatory
- 		Production
- 		Assays
- 		Special Consultants
- Outline Major Milestones
- Determine Which Efforts Should be In-house Versus Out-Source

## Many Projects Require SubstantialAttention At The Outset

**Expression System**
- 	Ampicillin Selection Pressure
- 	Lab-scale Affinity Purification
- 	Protein Solubility Problems
- 	Low Yield
- 	Errors in Genetic Sequence
- 	Extraneous Genetic Material
- 	Poorly Defined Production System
**Analytical Approaches**
**	**Unvalidated or Non-Existent *In Vitro* Potency Assay
- 	Lack of Key Reagents, e.g., Antibodies to Desired Product
- 	Poor Biochemical Characterization

## Many Projects Require Substantial Attention At The Outset (Continued)

**Regulatory and Safety**
- 	Inappropriate Cell Banks
- 	Difficult or Unidentified Toxicology Systems
- 	Failed Vendor Qualification
**Other**
- 	Intellectual Property Concerns
- 	Delays in Material Transfer Agreements
- 	Contracting Delays

## Typical Results Of One Review Cycle Of Project Candidates

**20 Projects Submitted for Review**
**6 Selected**
- 	2 – Clinical Development for Phase I Trials
- 	2 – Further Preclinical Development.  May be re-reviewed
- 	     for clinical production.
- 	2 – Production to support Preclinical Development Only

## Examples Of BDP Projects In Various Stages During 12-Month Interval

- Monoclonal Antibodies (19)
- Other Mammalian Cell Products (3)
- Recombinant Proteins (14)
- Natural Products (1)
- DNA Vaccines (3)
- Genetically-modified Organisms for Vaccines (4) or Gene Therapy (2)
- Oligonucleotides (3)
- Synthetic Peptides (Many)
- Other (1)

## Summary Of Major cGMP Project Milestones During Past 12 Months

- Ch-EB6 MoAb (Affinity Purification Reagent)	       6 gms
- Ch14.18 MoAb (Clinical)		         	1,473 Vials
- PCLUS 3-18MN Peptide Vaccine (HIV)		   145 Vials
- PCLUS 6.1-18MN Peptide Vaccine (HIV)	   145 Vials
- LMB-2 (Anti-TAC PE38) Immunotoxin (2 Lots)	3,155 Vials
- 1D12 MoAb (Affinity Purification Reagent)	     15 gms
- He-Fi 1 MoAb (Clinical) (2 Lots)			1,070 Vials
- Geldanamycin (Antitumor Antibiotic) (4 Lots)	   700 gms

## Summary Of Major cGMP Project Milestones During Past 12 Months (Continued)

- HPV-16 E7 (12-20) Peptide Vaccine (HPV)	711 Vials
- HPV-16 E7 (86-93) Peptide Vaccine (HPV)	740 Vials
- HPV-16 E6 Peptide Vaccine (HPV)		180 Vials
- HPV-18 E6 Peptide Vaccine (HPV)		954 Vials
- MuB3 MoAb (Clinical)				  49 gms
- HSV-863 MoAb (Clinical)			  32 gms
- Patient-Specific Id Vaccines (Lymphoma)	  18 Vaccines
- Patient-Specific Peptide Vaccines		    6 Vaccines

## Selected Examples Of Projects Leading To Commercial Development

**IL-2 DPT (DABL-IL2)**  R&D supported through National Cooperative Drug Discovery Group mechanism.  Licensed for cutaneous T-cell lymphoma
**Anti-EGFR Antibody**  Manufacture of preclinical material and chimerization of antibody.  Currently in licensing trials in head and neck cancer, other malignancies.
**Anti-GD2-IL2 Fusion Protein (Melanoma)**  R&D supported under National Cooperative Drug Discovery Group Mechanism.  Manufacture of first clinical lot.  Further development underway by company.

## Selected Examples Of Projects Leading To Commercial Development (Continued)

**Patient-Specific Id Vaccines for Myeloma & Lymphoma**  Manufacture of 30+ vaccines/year.  Entering controlled trials in lymphoma.  CRADAs signed for development for lymphoma and myeloma indications.
**Anti-CD22/PE38 Immunotoxin for Lymphoma****  **Manufacture of clinical material for initial trials.  Being developed by company.
**Anti-CD25/PE38 Immunotoxin for Lymphoma**  Manufacture of clinical material for initial trials.  Licensed by company.
**IL7 Cytokine**  Manufacture of preclinical and clinical material for initial clinical studies.  CRADA signed with company.

## The Idea Is Not Enough: Characteristics Of Projects With Eventual Commercial Development (With Some Exceptions)

**What The Investigator Has Already Done**
- 	Defined Candidate Molecule
- 	Comparisons With Similar Products
**	**Characteristics of molecule consistent with pharmaceutical requirements
- 	Production adequate
- 	Product characterization adequate
- 	Laboratory standard
- 	*In vitro* potency assay
- 	Stability studies
- 	Reproducible model systems
- 	Early animal work includes some toxicology
**Scale-up Requirements Practical for Initial Clinical Trials**
**General:  Previous Experience of Investigator**

## Summary

**A flexible and adaptive approach to facilitation**
**of clinical proof-of-concept evaluation of promising **
**new biopharmaceutical concepts appears to be a **
**cost-effective approach to increasing the number of **
**innovative clinical development candidates.**

## Our next speaker is:

**Dr. Rao Vishnuvajjala**
**Pharmaceutical Resources Branch**
**Developmental Therapeutics Program**