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The Division of Therapeutic Proteins:Regulatory and Research Programs

Cellular, Tissue, and Gene Therapies Advisory Committee Meeting, April 17, 2013

Amy S. Rosenberg, MD

Director, DTP

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Mission Statement

The Division of Therapeutic Proteins (DTP) is responsible for protecting and advancing the public health by assuring the quality, safety and efficacy of biological therapeutic products, helping to ensure their security, and helping to speed innovations that make them safer, more effective and available.

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The Future of Drug Safety: Promoting andProtecting the Health of the Public

(Institute of Medicine Report 2006)

“The committee affirms that a strong program of intramural scientific research provides an essential foundation for sound, scientifically based regulatory policy and performance”

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Commissioner’s StatementsMargaret A. Hamburg, M.D., Commissioner of Food and Drugs, AAAS Forum on

Science and Technology Policy May 14, 2010

• “But not only is more scientific knowledge required, but also a culture in which many scientific perspectives and opinions are sought and brought to bear on complex regulatory science problems.”

• “No matter what, FDA must be a science based, science-driven agency in all we do.”

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Benefits of Researcher-Reviewer Model: Credibility of Regulation

• Hands on expertise for novel technologies, scientific approaches; insight into on and off target mechanisms of action; enhances regulatory evaluations

• Interactions with scientists in academia and industry facilitate acceptability of regulatory recommendations and policies

• Direct access for addressing critical regulatory questions that require research investigation

Division of Therapeutic Proteins, CDER, FDA

Amy RosenbergDivision Director

Amy RosenbergDivision Director

Gibbes JohnsonDeputy Division Director

(Acting)

Gibbes JohnsonDeputy Division Director

(Acting)

Daniela VerthelyiChief

Lab of Immunology

Daniela VerthelyiChief

Lab of Immunology

Serge BeaucageChief, Lab of Chemistry

(Acting)

Serge BeaucageChief, Lab of Chemistry

(Acting)

Susan KirshnerBranch Chief I

(Acting)

Susan KirshnerBranch Chief I

(Acting)

Associate ChiefLab of Chemistry

TBD

Associate ChiefLab of Chemistry

TBD

Gibbes JohnsonPI

Gibbes JohnsonPI

Baolin ZhangPI

Baolin ZhangPI

Ashutosh RaoPI

Ashutosh RaoPI

Serge’s labStaff

Serge’s labStaff

Lab staffLab staff

Lab staffLab staff

Lab staffLab staff

Associate ChiefLab of Immunology

TBD

Associate ChiefLab of Immunology

TBD

Amy RosenbergPI

Amy RosenbergPI

Mike NorcrossPI

Mike NorcrossPI

Ed MaxPI

Ed MaxPI

Daniela’s lab

Staff

Daniela’s lab

Staff

Lab staffLab staff

Lab staffLab staff

Lab staffLab staff

Jack RaghebPI

Jack RaghebPI

Ray DonnellyPI

Ray DonnellyPI

Lab staffLab staff

Lab staffLab staff

Secondary Reviewer

TBD

Secondary Reviewer

TBD

Full Time ReviewersFull Time

Reviewers

Juhong LiuJuhong Liu

Full Time ReviewersFull Time

ReviewersFull Time

ReviewersFull Time

Reviewers

Emanuela LacanaBranch Chief II

(Acting)

Emanuela LacanaBranch Chief II

(Acting)

Kathy LeeBranch Chief III

(Acting)

Kathy LeeBranch Chief III

(Acting)

Secondary Reviewer

TBD

Secondary Reviewer

TBD

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Scientific Activities of DTP

• Weekly seminar series: DTP and outside speakers

• Site visits every 4 years; yearly evaluation for mission relevance and scientific productivity

• Participation in NIH Scientific Activities: interest groups, retreats, seminars and journal clubs, symposia, study sections, advisors for initiatives.

• Participation in FDA Scientific Activities: science rounds, Research Coordinating Committee, Science Forum, Promotion and Conversion Evaluation Committee, Adventitious Agent Working Group (with CBER)

• Service on Editorial Boards of Journals, Reviewers for journals

• Internal Research Grants Evaluation and Awards: Critical Path, Office of Women’s Health, Regulatory Science Research, Medical Countermeasures

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Not the NIH, not Academia…

• Most research personnel have significant regulatory load:– Dramatic increase in regulatory load including

novel regulatory paradigms eg biosimilars– Non-research workload not predictable; can’t

be managed as in academia– Limited ability to hire support staff (internal

grants)– Research productivity affected across the

division

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Major Regulatory Scientific Challenges Confronting DTP

• Comparability of biological therapeutics following manufacturing changes by same manufacturer: – seemingly minor manufacturing changes can have major

impact on critical product attributes and clinical behavior

• Biosimilars: same class therapeutic protein product produced by different manufacturer: physicochemical and biological similarity to innovator product reduce the number/dimensions of clinical trials needed for approval

– DTP provides recommendations regarding the extent of pre-clinical and clinical studies to evaluate similarity in safety/efficacy based on the extent of physicochemical comparability

– All biosimilars require a clinical immunogenicity study: DTP/LI scientists consult on immunogenicity evaluations of candidate biosimilar products

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Biosimilar Applications in DTP

• 18 preIND/INDs in the Laboratory of Chemistry– 5 reference products

• Much more intensive review than other IND/pre IND applications: coordinated meetings by Biosimilar Review Committee (5 meetings total)

• Dr. Johnson overseeing DTP’s biosimilar review• Participation of DTP staff on Biosimilar policy

issues and guidance documents• LI reviewers perform immunogenicity reviews on

all biosimilar products

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Major Regulatory Scientific Challenges Confronting DTP: Requirement for Scientific Expertise

• Biobetters: engineered versions of prototype products to enhance PK or other product characteristics

• Enhanced PK/PD: pegylation, hyperglycosylation• Enhanced substrate binding: site directed mutagenesis (eg enhanced fibrin specificity)• Enhanced cellular targeting : use of receptor specific ligands or glycoform engineering for improved

uptake in target cells

• Novel technology products• Nanotechnology• Ankyrin repeat domains and avimers• Device/biologic combination products

• Breakthrough Therapeutics: FDA Safety and Innovation Act (FDASIA)• Ensuring that product quality and manufacturing issues keep pace with

speed of clinical development• Immune responses to therapeutic protein products/novel technology

products: LI research-reviewers consult across the agency on these issues • Immediate hypersensitivity responses; • Abrogation of efficacy of life saving or highly effective therapeutics• Clinical deficiency syndrome due to cross reactive neutralization of endogenous protein• Immune tolerance induction

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DTP Approved Products• Product Diversity

– Wide diversity in product origin, cell substrate production systems, mechanism of action, and complexity

– Mostly recombinants, some naturally derived

• 80 approved products– All therapeutic proteins other than mAbs, most Ig fusion

proteins and classical endocrine hormones: • Hematologic and somatic cell growth factors (eg Epo, G-CSF)• Thrombolytics and anti-thrombotics (eg tPA)• Therapeutic enzymes: intracelluar (LSDs) and extracellular

targets (eg asparaginase, urate oxidase): rare diseases• Botulinum toxins: toxicity, counterfeit• Toxin conjugates• Interferons, interleukins, immunomodulatory agents• Receptor antagonists• Combination biologic/device (eg bone morphogenic proteins)

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Products Approved by DTP 2009-2012

1) Kalbitor (Ecallantide); plasma kallikrein inhibitor: LC 2) Xiaflex: Collagenase clostridium H: LC3) Dysport (abobotulinumtoxin A): LI4) Xeomin (Incobotulinumtoxin A): LI5) Extavia (Interferon beta-1b): LI6) Pancreaze (Pancrelipase): LC: from porcine pancreas glands7) Creon (Pancrelipase): LC. “8) Zenpep (Pancrelipase): LC. “9) Pertzye (Pancrelipase) LC10) Ultresa (Pancrelipase) LC11) Viokace (pancrelipase) LC12) Lumizyme (Alglucosidase alfa): LC-rare disease indication13) VPRIV (Velaglucerase alfa): LC-rare disease indication: first plant cell based approval14) Krystexxa (pegloticase; pegylated urate oxidase):LC 15) Belatacept (CTLA4-Ig): LI16) Erwinase (asparaginase Erwinia): LC17) Voraxaze (glucarpidase): LC18) Elelyso (taliglucerase alpha): LC. Novel carrot cell production system19) JETREA (ocriplasmin) Intravitreal Injection: for the treatment of symptomatic vitreomacular

adhesion including macular hole-LC20) Tbo-filgrastim LC21) Albuferon: IFN-HSA fusion protein NOT APPROVED22) 4 additional BLAs and NDAs reviewed but not approved

Ongoing BLA Approval Submissions

• Metroleptin: leptin analog for Type II DM and obesity-LI

• Lipefilgrastim, pegylated G-CSF-LC: neutropenia

• Balugrastim, G-CSF fusion protein-LC: neutropenia

• Calasparagol pegol, pegylated asparaginase: Acute Lymphocytic Leukemia

• Albiglutide: type II diabetes

• Vimizim, galactosamine 6 sulfatase: Morquio syndrome type A

Laboratory of Chemistry:Regulatory Oversight of Approved Products

– Enzyme Replacement Therapies (ERT): Rare and Orphan Diseases

• Lysosomal storage diseases (Gaucher, Pompe, Fabry),• Pancreatic enzyme insufficiency

– Concerns• Small patient populations;• Control and enhancement of critical quality attributes important for safety

and efficacy • immunogenicity • Zoonotic transmission of viruses

• Products – Glucocerebrosidase (3 products)– Alpha-galactosidase A– Alpha-glucosidase (2 products, 1 approved for infants and one for

adults)– Alpha-L-iduronidase– N-Acetylgalactosamine4-sulfatase– Iduronate 2-sulfatase– Pancreatic enzyme extracts (7 products)– Sacrosidase

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Challenges in the Development of Therapeutics for Rare Diseases

• Sensitivity of critical quality attributes, known to impact clinical performance, to manufacturing changes: e.g. sialic acid and mannose-6P.

• Most rare disease therapeutics are complex products, with multiple moieties contributing to the mechanism of action, thus requiring multiple potency assays. Some potency assays (eg cellular uptake assays,) may be technically complex and challenging.

• Given the rarity and seriousness of the diseases, clinical development is accelerated. Product quality and manufacturing consistency issues a challenge for accelerated development: – few product lots are used in the clinical trials, particularly in the pivotal

clinical trial causing difficulty in establishing release and stability acceptance criteria that ensure consistent clinical performance.

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Laboratory of Chemistry: Regulatory Oversight of Approved Products

Extracellular substrate degrading enzymes:• Treatment of leukemia (asparaginase), • Treatment of methotrexate toxicity (carboxypeptidase) • Treatment of tumor lysis and gout (urate oxidase)• Dispersion of drugs in tissues/degradation of extracellular matrix

(hyaluronidases) Concerns

• Stability of PEG-protein link• Immune responses to enzyme and/or PEG• Consistency of manufacturing• Old legacy products, need for modernization of manufacturing

processes

Laboratory of Chemistry: Regulatory Oversight of Approved Products

• Hematologic growth factors: erythropoietins, granulocyte and granulocyte-macrophage colony stimulating factors

• Somatic cell growth factors: bone morphogenic proteins, keratinocyte growth factors, platelet derived growth factors

• Thrombolytics: tPA, TNKase• Combination products: eg BMP devices

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– Pegylation chemistry: pegylation of protein therapeutics is used to extend pharmacokinetics and may diminish immunogenicity: consultative reviews provided to DTP, DMA

– Oligonucleotide chemistry: to ONDQA

– Bioassays

– Guidances: Pancreatic Enzyme Products, Drug Master Files and Botanicals

Laboratory of Chemistry: Regulatory Contributions Across the Center

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Conclusions• Strong research program needed to support

optimal regulation of protein therapeutic products: IOM report, Commissioner

• Research program viability threatened by growing regulatory load and insufficient support

• Opinion/recommendations of external review committee extremely valuable in supporting the science base of the agency.

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Researcher/Reviewer Model: Research Scientist and Product Expert

Product expert: scientific expertise on product manufacture, qualities, and biological activities

mechanism of action; in vivo bioactivity and toxicities; analytical methods,

Maintains active laboratory research program in field relevant to review area

Publishes research findings in peer reviewed, high quality journals

Undergoes site visit evaluation of program and yearly internal scientific evaluation

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