# Presentation: 139315

## The Critical Path Initiative: The Division of Therapeutic Proteins’ Perspective

- Amy S. Rosenberg, MD
- Director, Division of Therapeutic Proteins
- ACPS Meeting, October 19, 2004

## Incentive for Critical Path: the Decrease in Novel Drug and Biological Product License Applications

## The Primary Problem: Failure to Develop Therapeutics and Vaccines to Address Difficult Diseases 

- High candidate drug failure rate
- 99.9% of candidate drugs fail;
- <20% of drugs entering human testing get approved;
- a drug entering phase I in 2000 less likely to reach market than one entering Phase I in 1985
- ~50% of phase 3 studies fail due to lack of efficacy

**Notes:**
Although many articles in the recent literature bemoan the diminution in submission of novel product license applications, the real problem, in my mind, is the failure to develop therapeutics and vaccines to treat difficult diseases. This of course, in spite of the wealth of information arising from novel technologies

## New Chemical Entities Lag Significantly Behind R&D Expenditures(Science, Drug Discovery 19 March 2004)

**Notes:**
This isn’t for lack of trying. As shown in this figure, R&D expenditures have risen exponentially but the numer of new chemical entity approvals is essentially flat lined

## Factors Contributing to Decline in New Product Applications(Glassman and Sun. Nature Rev Drug Discovery 2004)

- Failure of novel methodologies and treatments to achieve practical applications
- High throughput screening and combinatorial chemistry
- Antisense
- Pharmacogenomics
- Genomics based target identification
- Gene therapy
- Immunotherapy of cancer
- Antiangiogenesis treatments for cancer

## Practical Medical Applications of Proteomic and Genomic Data: Industry Perspective

- “I think we got too enamored of technology and lost focus of what to do”. The 1990s were really a boon for us in terms of science. We forgot that we needed to link all of that to disease”
- (Lee Babiss, Roche)
- “We thought we would very quickly validate targets that were critical to disease and agonize or inhibit them as a way to start to find a drug...What we found in fact is that validating targets takes a lot of time. This is one of the big disappointments of this era”
- (Frank Douglas, Aventis)

## Slide 7

**Notes:**
1975 Kohler and Millstein Hybridoma technology

## Lengthening Clinical Times Have Increased Total Times for Approval of New Biological Drugs (Tufts Outlook 2003)

## Small Molecular Drugs: Both Clinical Phase and Review Times have Diminished Since the Early 1990s 

## Factors Contributing to Decline in New Biological Product Applications

- Shift in disease indications:
- chronic diseases; longer trials to assess effects and durability of response
- Shift to therapeutic products whose mechanism of action and toxicities were less well understood
- Unexpected and difficult toxicities
- Difficulty of developing surrogate endpoints

## FDA-Industry Share Common Goals but Make Distinct Contributions(JM Reichert, Nature Reviews Drug Discovery, 2003)

- “ The ultimate goal of both the FDA and industry is to provide patients with access to new, safe and effective treatments. ***Coordination and cooperation*** between industry and FDA will be required.”
- “The FDA can only assist in the process though. The development of innovative products is actually accomplished by the pharmaceutical and biopharmaceutical industry.”

**Notes:**
So how can FDA and Industry can work together to improve drug development? First is to acknowledge that we have a common goal. Second, is understanding each others’ roles in achieving that goal

##  The “NIH Road Map”: Participation by Industry, NIH, and FDA

**NIH Initiatives**
- “New Pathways to Discovery”
- “Research Teams of the Future”
- “Re-engineering the Clinical Research Enterprise”
-    FDA needs to work with NIH as well as Industry to address Road Map and Critical Path Initiatives

**Notes:**
In addition to FDA industry interactions, we also have a third co partner for development of new products to address poorly treated disease and that is the NIH that recently evolved the “ROAD MAP” initiative

## Role of FDA

- FDA uniquely positioned to identify and overcome challenges to product development:
- Reviewers can identify common themes and systematic weaknesses across similar products
- Based on such knowledge reviewers formulate guidance documents: availability fosters development and innovation; improves chances of an initial success of a marketing application; shortens time to approval

## FDA Strategies for Speeding Innovative Therapeutics to Market

- 2002 Improving Innovation in Medical    		    Technology: Beyond 2002
- Highlighted importance of guidance documents to avoid multi-cycle reviews
- 2004 Critical Path Initiative

**Notes:**
FDA efforts to improve efficiency in DD are encapsulated in two initiatives: Critical Path and Improving Innovation

## Critical Path Initiative: Support of Research for Product Development

- Support research for applied sciences needed for medical product development
- Develop new tools to improve predictions regarding safety and effectiveness of new products in faster time frames at lower cost

**Notes:**
CPI arose from the following set of premises

## Research Support for Product Devlopment

## Critical Path: Targeted Areas 

**Notes:**
Neglected areas are safety follow up and mass production. Assessing Safety: show that the product is safe for each stage of development: preclinical: product is safe enough for early human testing; eliminate products with safety problems early Clinical Development: show that product is safee enough for commercial distribution
Demonstrating Medical Utility: Show that the product benefits people. Preclinical: select appropriate biological with high probability of effectiveness. Clinical: show effectiveness in people. 

Industrialization: Go from a lab concept or prototype to a manufacturable product. Design a high quality product: physical design, characterization, specifications; Develop mass production capacity: manufacturing scale up; quality control

## The Researcher/Reviewer: Ideally Positioned to Advance Critical Path

**Regulation**
- Product expert: integral to regulatory process at all stages of product development.
- Provides scientific expertise on multiple levels:
- product manufacture (including inspections)
- product characterization including mechanism of action, in vivo bioactivity and toxicities;
- expert in analytical methods;
- expert in animal models
- key role in policy formation; guidances

## The Researcher/Reviewer: Ideally Positioned to Advance Critical Path

- Basis for regulatory expertise is engagement in high quality research program
- Maintenance of active laboratory research in field relevant to review area
- Publishes findings in peer reviewed, high quality journals
- Undergoes site visit evaluation of program every 4 years and yearly internal evaluation

## Report of the Subcommittee to FDA Science Board 1998

- “*It is the concensus of the Committee that FDA requires a strong laboratory research focus and not a virtual science review process; otherwise we risk the potential to damage  not only the health of the population of the US but also the health of our economy...”*

**Notes:**
Strong support for the researcher reviewer was evidenced in the last critical review of research activities at FDA, the Subcommittee to the FDA Science Board in 1998.

## Importance of Intramural Research: Researcher Reviewer(FDA Science Board Subcommittee Report)

- Regulators and policy makers require expert knowledge and first hand experience with the latest technology being applied to biological products
- An intramural research program is required to assess risks of new therapies, to develop assays and new approaches to increase efficacy and safety, and reduce risks.
- A strong well maintained intramural research program provides _*the basis for a climate of science and scientific communication within FDA*_ that enhances the ability of the Agency to recruit and retain high quality scientific staff

## Support for Intramural Research(FDA Subcommittee Report)

- The research program facilitates the ability of FDA to address existing regulatory issues and to anticipate future problems to keep pace with rapidly emerging and complex cutting edge technology.
- It facilitates a response in a timely, flexible and competent way to new policy issues that require new “Points to Consider” documents, that suggest approaches to companies preparing IND and BLA applications.
- The research program must be primarily staffed with full time, permanent personnel (rather than visiting and post-doctoral scholars) to capture the value of their research experience in regulatory submission reviews.

## The Division of Therapeutic Proteins

## DTP Licensed Products

**Product Diversity**:
- 30 novel molecular entities/37 total licensed products
- many naturally derived products but mostly recombinants
- minimal “me too” products: IFNs.
- engineered versions of prototype products to enhance PK or other product characteristics: pegylation; site directed mutagenesis for hyperglycosylation, other enhancements
- diverse cell substrates: bacteria, yeast, insect cells, rodent, human, transgenic animals
- manufacturing process unique for each product

## DTP Products

- Interferons
- Interleukins
- Thrombolytics
- Anti-thrombotics
- Therapeutic Enzymes
- Hematologic Growth Factors
- Neurotrophic Growth Factors
- Chemokines
****

- Wound healing products
- Toxin-fusion molecules
- Angiogenesis/Anti-angiogenesis agents
- Immunomodulators
- Immune Adjuvants
- Receptor Antagonists
- Lectins

## Principal Scientific and Regulatory Challenges in DTP

- Comparability/Follow on Biologics
- Immunogenicity
- Potency Assessments
- Product Counterfeit
- Novel transgenically produced products: chicken eggs, plants
- Infectious Disease Transmission

##  Keen Knowledge of Pitfalls in Product Development: 

- Pre-clinical studies:
- optimal drug delivery route not explored: cytokines/growth factors microenvironment considerations: act locally, not globally
- lack of appropriate animal models or failure to develop species specific product: safety and efficacy
- Phase I/2:
- immunogenicity: thrombopoietins; CNTF;
- Unexpected adverse events (IL-12)
- animal models poorly reflective of human disease: lack of biological activity in human disease
- MOA not fully evaluated; most appropriate endpoints not sufficiently investigated***;***

## Pitfalls in Product Development

- Phase 3:  Product Issues
- development of validated potency assay
- changing manufacture during phase III studies
- Lack of adequate process validation

## Pitfalls in Product Development: Insight into Clinical Issues

- Phase 2/3: Clinical Issues (R. Temple)
- Insufficient dose ranging studies;
- Overoptimism regarding less than adequate phase 2 (“confirm” before you’ve “learned”)
- failure to continue dose finding in phase 3, choosing wrong single dose or regimen based on too little data
- no valid biomarker, so no possible early insight until phase 3
***surprise infrequent adverse effect***
***adverse effects showing up with longer exposure***

## DTP’s CP Focus: Support Ongoing Critical Path Projects

- Entry of products with novel mechanisms of action into drug development pipeline:
***Research that investigates mechanism of action of new products  ***
***Research that establishes new animal models for assessment of safety/efficacy***
***Research that provides new or improved products to pipeline***

## DTP’s Focus: Support Ongoing Critical Path Projects

- Barriers/hurdles to product development including immunogenicity, potency assessment:
***research that overcomes these barriers to product development***
***activities to standardize assays; compare immunogenicity across products in same class***
- Identification of surrogate endpoints/ biomarkers for safety and efficacy:
-  ***research that identifies novel biomarkers for safety and efficacy***
***activities to gain concensus on appropriate surrogate markers ***

## Research on Novel Products:CpG Oligonucleotides

- Development as immunomodulators for infectious diseases
- Principal Investigator: Daniela Verthelyi, Ph.D., M.D.
- Investigation of immunomodulatory activities of innate immune response: CpGs; other Toll Like Receptor (TLR) agonists
- Identification of surrogate markers of immune protection in primate models of infectious disease
- Development of novel TLR agonists
- Application to bioterrorism situations: “animal rule”

**Research on Novel Products: Chemokines**

- Chemoattractant cytokines -critical for cell migration: inflammation,metastasis, angiogenesis, allergy, atherosclerosis
- Principal Investigator: Mike Norcross, MD
- Development of methods to assay potency of chemokine products
- Cellular and molecular regulation of chemokines and chemokine receptors in HIV infection.
- Methods for non-clinical screening of antiviral biological products.
- Development and validation of biomarkers and surrogate endpoints for immune base therapies for HIV infection.

**Notes:**
Matastasis:SDF-1
Allgraft rejection: 
Would healing:
Arthrosclerosis:
Angiogenesis:

## Cell Migration is Controlled by Chemokines

- Chemokines

- _Cell Migration is Controlled by Chemokines_

## Research on Novel Products: Novel Cytokine Development

- Signaling pathways of novel interleukins and interferons:
- Principal Investigator: Raymond Donnelly, Ph.D.
- Defining signal transduction pathways and receptors for Interleukins 19,20,22,
- Defining biological properties of IFN-

## Research that Provides New and Improved Products to Pipelines 

- Enhance specificity and sensitivity of     oligonucleotide microarrays** **for multiple purposes
- Principal Investigator: Serge Beaucage, Ph.D
**detection and quantification of bacterial and viral nucleic acid contaminants in biologics including blood products**
** ****high-throughput screening of point mutations or single nucleotide polymorphisms in genomic DNA that predispose human to diseases. **
**gene expression assays to evaluate the safety and efficacy of drugs**

## Critical Path Projects Promoting Novel Anti-Cancer Treatments

- Principal Investigator: Emily Shacter, Ph.D.
- Modulation of signal transduction pathways to enhance tumor cell death in response to cancer chemotherapy agents
- Investigation of antioxidants as potential chemoprotective agents to limit side-effects from chemotherapy
- Principal Investigator: Gibbes Johnson, Ph.D.
- Enzymology of EGFR signaling
- Identification of novel signaling molecules

## Immunogenicity Issues Along the Critical Path

- All protein therapeutics potentially immunogenic
- IgE antibodies can cause anaphylaxis
- IgG antibodies can neutralize a therapeutic protein, or can block action of endogenous homolog
- Immunogenicity
- has killed products in development: TPO, CNTF, GM-CSF-IL-3 fusion molecule
- limits efficacy for many biological therapeutics: therapeutic enzymes, IFNs , asparaginase
- poses ongoing concern for licensed products following changes in manufacture, packaging, and clinical indication: Epo
- lack of standardized assays for comparison across products in same class

## The Immunogenicity Barrier

**The Immunogenicity Barrier**

## Critical Path Activities: Immunogenicity Concerns 

- Research to understand the mechanism by which antibody responses to proteins are switched to cause anaphylaxis or to neutralize protein therapeutic (Edward Max, Ph.D., MD)
- Research to develop better animal models of immune tolerance and autoimmunity (Wendy Shores, Ph.D.)
- Research to dissect immune responses to embryonic stem cells (Amy Rosenberg, MD)
- Participation in international efforts to standardize antibody assays for erythropoietin products

## DTP Focus: New Critical Path Project Proposals

- Immunogenicity-
- Nanotechnology: novel antigen presenting mechanisms could facilitate immunogenicity or tolerogenicity
- Therapeutic enzymes: tolerance induction in CRIM negative patients
- Protein aggregates in therapeutic protein products: risk assessment. Specifications set on manufacturing experience, not on risk: how much, what kinds, how delivered incur risk?
- Development of Guidance Documents where appropriate

## DTP Focus: New Critical Path Project Promoting Treatment for Sepsis(Emily Shacter, Ph.D.)

- Development of protein S as an adjunct to activated protein C (XigrisTM) to improve survival from sepsis
- Activated protein C (APC; Xigris) is an approved biologic used to decrease mortality from sepsis.
- Protein S is an anticoagulant plasma glycoprotein required for APC activity.
- Both proteins are depleted during DIC of sepsis, but only APC is given as a therapeutic.
- CDER research suggests that addition of protein S to the treatment protocol will improve efficacy, supporting the idea that recombinant protein S should be developed as a therapeutic protein.

**Notes:**
However, Critical path is not totally focused on research, a very important component of it also concerns communicating with industry. Both face to face and technology enhanced communications are vital for timely submission and product approval Moreover, the issuance of guidance is critical, as this has been shown to reduce the need for multi cycle reviews

## Open, honest communication
Informal communication/formal documentation of agreements
Regular status updates
Timely communication of issues as they arise
Clear, concise FDA response with explanation of position

CBER, DODP, DCRDP, DOTC, DPDP, DAVDP, DMEDP

- Open, honest communication
- Informal communication/formal documentation of agreements
- Regular status updates
- Timely communication of issues as they arise
- Clear, concise FDA response with explanation of position
- CBER, DODP, DCRDP, DOTC, DPDP, DAVDP, DMEDP

**Notes:**
Highlights the “climate of science” 

## Reviewers and Decision Makers
Direct access to reviewers
Timely access to decision makers at critical points
Timely communication of issues as they arise
The final stages:
Frequent telecons to resolve outstanding issues
Scheduled labeling meetings and post-approval commitment discussions
Potential discussion 30 days prior to action date
Allow sufficient time for management reviews

CBER, DMEDP, DCRDP, DGCDP, OMP, OIM

- Reviewers and Decision Makers
- Direct access to reviewers
- Timely access to decision makers at critical points
- Timely communication of issues as they arise
- The final stages:
- Frequent telecons to resolve outstanding issues
- Scheduled labeling meetings and post-approval commitment discussions
- Potential discussion 30 days prior to action date
- Allow sufficient time for management reviews
- CBER, DMEDP, DCRDP, DGCDP, OMP, OIM

## Other DTP Critical Path Activities

- ICH Q5e comparability guidance:  led by  Barry Cherney, Ph.D., DTP Deputy Director
- Standardization of antibody assays for Erythropoietin products: Susan Kirschner, Ph.D.
- Support of risk based approach to GMP and inspectional issues: Barry Cherney, Ph.D., and Ralph Bernstein, Ph.D.

## Summary

- DTP strongly supports Critical Path efforts to facilitate development of new products for poorly treated diseases
- DTP research efforts elaborated
- Other activities include development of guidance, adoption of risk based approach to GMPs, and maintenance of communication format with industry