Anne M. Pilaro, Ph.D. Center for Drug Evaluation and Research FDA Nonclinical Safety Testing for Biological Therapeutics for Cancer Treatment Anne M. Pilaro, Ph.D. Center for Drug Evaluation and Research FDA

Disclaimer The opinions expressed by Dr. Pilaro in this presentation are the presenter’s, and do not reflect official policy of the FDA Information presented was obtained from publicly available sources, including published literature, labeling, and/or SBA documents No official support or endorsement by FDA is intended or should be inferred

Objectives for Today’s Presentation Discuss review responsibilities for biological therapies for cancer Review approaches to obtain IND-enabling, nonclinical safety data for protein therapeutic agents for cancer Introduce current guidance for toxicology testing of biological therapeutic products

What is a Biological Product? Substances derived either from living organisms – including humans, animals, plants, and microorganisms – or produced by biotechnology methods Photo from www.gene.com

Who is Responsible for Regulating Biologic Cancer Therapies? CBER, OCTGT adoptive cell transfers (i.e., stem cells, embryonic stem cells [ESC], leukocytes with or without gene modification) gene therapies tumor vaccines (e.g., pDNA-based, viral vector-based, or autologous/allogeneic tumor with or without gene modification) siRNAs delivered using gene transfer technology combination therapies

Who is Responsible for Regulating Biologic Cancer Therapies? CDER/OODP/DDOP hormones and metabolic factors synthetic peptides oligonucleotides and siRNA CDER/OODP/DBOP monoclonal antibodies recombinant proteins e.g., cytokines, growth factors, fusion proteins extracted proteins

Who is Responsible for Regulating Biologic Cancer Therapies? For the purposes of this presentation, focus today will be on products regulated in CDER/OODP/DBOP monoclonal antibodies for cancer treatment cytokines and/or growth factors e.g., interleukin-2 for cancer treatment recombinant hematopoietic factors for treatment and/or prophylaxis of chemotherapy side effects fusion proteins for cancer treatment combination antibody~ or protein~small molecule drug conjugates

What Do I Need to Start an IND for a New Anti-Cancer Agent? Product characterization manufacturing and quality control issues Nonclinical testing in animals biologic or pharmacologic activity pharmacokinetic profile toxicology testing in animals Phase 1 clinical trial

What are Pharmacology Studies for Anti-Cancer Biologics? Evaluation of ability of a new agent to induce the desired therapeutic effect in vitro studies of product binding, tumor cell killing, and other effects in vivo studies of anti-tumor activity e.g., human tumor xenograft models Demonstration of pharmacologic and/or biologic activity is the first step in the development of ANY new drug or biologic

Why are Pharmacology Studies Important? Establish basis for conducting trial interaction with target receptor, tissue, or organ degree of pharmacodynamic (P/D) effect correlation of P/D effect with exposure Optimize dosing, regimen for the clinic Optimize route of administration Selection of species for further testing

Where do Pharmacology Data Come From? Most biologic activity/pharmacology data come from studies conducted in the sponsor’s own laboratory need to include appropriate control groups should include sufficient “n” in treatment groups to attain statistical relevance should be described in the IND in adequate detail that FDA can judge appropriateness of model, findings to proposed human study Published literature may also serve as data source data in article must be of sufficient detail, as above For previously tested agents, access to data may be obtained by permission to cross-reference existing IND or DMF

How are Pharmacology Data Used to Support a New IND? Data from nonclinical bioactivity and/or pharmacology studies are used to establish the rationale for conducting the first clinical trials in humans for anti-cancer biologic agents, most early trials are done in the index (patient) population, NOT healthy volunteer subjects

What are Pharmacokinetic Studies for Anti-Cancer Biologics? Measurement of in vivo disposition of a new biologic agent studies of product concentration, exposure, clearance, and half-life determined from blood, plasma, or serum levels of agent at various times after dosing differences following different routes of dosing

Why are Pharmacokinetic Studies Important? Demonstration of the pharmacokinetics of a new biologic allows estimation of: exposure to agent after any given dose correlation with pharmacologic/therapeutic effect duration of exposure (half-life) dosing interval for the clinical study time to reversal of any biologic or toxic effects development of anti-product antibodies both total and neutralizing activity

Where do Pharmacokinetic Data Come From? Serum levels of anti-cancer biologic measured during in vivo pharmacology studies Stand-alone pharmacokinetic studies in responsive species Adjunct to single- and repeat-dose toxicology studies in animals toxicokinetics

What are Toxicology Studies for Anti-Cancer Biologics? Dedicated in vivo studies that provide data describing the safety profile of the agent, at doses greater than those that produce the therapeutic effect single- and repeat-dose paradigms sub-chronic and chronic duration include measurements of exposure, antibody development, and reversibility

Why is Toxicology Testing for Any New Biologic Important? Provides information regarding the safety of single and/or repeated exposure to the biologic anti-cancer agent toxicities related to the dose of product given toxicities related to the duration of product administration identification of target organs reversibility of toxicities after clearance of the biologic product after development of neutralizing antibodies

What Does a Nonclinical Toxicology Study Tell Me? Single dose (acute) studies designed to maximize exposure to agent (mimic overdose) high doses, frequently i/v administration limited endpoints – 14 days clinical observations, body weights gross necropsy with no histology clinical pathology not usually done

What Does a Nonclinical Toxicology Study Tell Me? Repeat-dose administration Designed to support the intended clinical usage of the agent doses “bracket” those planned for clinic dosing for at least the same number of planned administrations duration may vary from 14 days to 6+ months should include recovery group(s)

Where do Toxicology Data Come From? Data in support of a clinical trial may come from: GLP-compliant toxicology studies conducted by a contract laboratory well-controlled studies conducted in house (“GLP-like”) published data in peer-reviewed journals cross-reference to previously submitted IND or DMF

What Do I Need to Measure in Toxicology Testing? Monitoring in-life clinical observations, behavior signs/symptoms of toxicity body weights, weight changes feed and water consumption clinical pathology serum enzyme, electrolyte, glucose and lipid profiles as evidence of organ toxicity hematology urinalysis these can all also be monitored in man!

What Do I Need to Measure in Toxicology Testing? Pharmacokinetics/toxicokinetics correlation of serum levels of biologic with toxicity, pharmacodynamic activity identification of elimination half-life and antibody development (reversibility) Pathology gross and microscopic evaluation of tissue damage most sensitive indicator, but final! confirmation of target organ toxicity detected biochemically

What Else Do I Need to Include in My Toxicology Studies? Administration/dose selection route & dosing regimen should mimic proposed clinical use alternative routes/regimens acceptable in some cases attainment of toxic dose, no observable adverse effect level (NOAEL) desirable multiples of human dose needed to determine adequate safety margins can vary with product class and/or clinical indication

Are There Any Specific Safety Concerns for my Biologic Agent? Monoclonal antibodies (naked or conjugated) cross-reactivity with normal tissue exaggerated pharmacodynamic effects chronicity of exposure and toxicity immunogenicity/antibody production “bystander” toxicity of radiolabel or small molecule drug in conjugates

Are There Any Specific Safety Concerns for my Biologic Agent? Cytokines and/or growth factors demonstration of species-specificity evaluation of interaction with host endogenous cascade tumor-promoting potential immunogenicity/antibody production effects on neutralization of endogenous counterpart to test agent

How Are Toxicology Studies Used to Support a New IND? Nonclinical toxicology data are used to make recommendations regarding the conduct of the clinical trial, based on the safety data obtained initial safe starting dose, dose-escalation scheme target organ(s), reversibility of toxicity appropriate parameters for clinical monitoring identify “at risk” patient populations (inclusion/exclusion criteria)

What Else Do I Need to Know for Safety Testing of Biologics? Data from preclinical pharm/tox studies must meet the regulatory requirements set forth in 21 CFR data must be of unquestionable integrity, quality to support safety of agent for entry into clinical trials animal studies may be done in house as long as meet the requirements of 21 CFR 312.23(8) full compliance with GLP (21 CFR 58) expected for any pivotal toxicity studies

What Else Do I Need to Know for Safety Testing of Biologics? Product development allowed during preclinical testing phase use of non-GMP protein products allowed need to demonstrate comparability with clinical grade material(s) as development progresses Protein therapeutics are not expected to differ from small molecule cancer drugs in the requirements for demonstration of safety, just in the approach used to obtain the data

Where Can I Find Guidance for Safety Testing of Biologics? The ICH S6 Document Title: Preclinical Testing of Biotechnology-Derived Pharmaceuticals Scope: Covers protein and other biological therapeutics produced by biotechnology methods Does not address: cellular, tissue or gene therapies, blood or plasma products, traditional vaccines 34

ICH-S6 – What it Doesn’t Do Does NOT provide a “one size fits all” or “cookbook” approach to toxicology study design provides a framework for design of animal studies to address safety of biotechnology derived products, based on characteristics of the product and intended clinical use 26 42 26

ICH-S6 – What it Does Do Recognizes that conventional approaches to toxicity studies used for small molecule drugs are often NOT appropriate for protein therapeutics unique issues of species restriction, dose and formulation limitations, antibody formation limit utility of standard toxicity paradigms offers alternative approaches to obtain adequate safety data to support human use 26 42 26

ICH-S6 – What it Does Do Provides guidance to sponsors regarding the design of toxicology studies, including: usage of pharmacologically relevant vs. nonrelevant animal species usage of animal models of disease immunogenicity testing and its implications genotoxicity, chronic toxicity, carcinogenicity, and reproductive and developmental toxicity testing GLP compliance 26 42 26

Additional Guidance from FDA Coming soon… Guidance for Industry and Reviewers: Nonclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals FDA general guidance on necessary studies to support development of protein therapies expands upon the framework of ICH S6 adds FDA experience with unique issues includes Q&A section to address common questions encountered by sponsors in field 31 47 31

Additional Guidance from FDA Coming soon… Guidance for Industry, Investigators and Reviewers: Nonclinical Studies for Anticancer Drugs and Biologics OODP-specific guidance on necessary studies to support development of anti-cancer therapies identifies differences in nonclinical study approaches for small molecule versus protein cancer therapeutics addresses issues of timing of studies relative to duration of clinical trial, indication incorporates principles of both ICH S6 and FDA Guidance for protein therapeutics 31 47 31

Summary What do I need to start an IND for a new anti-cancer biologic agent? The “Three R’s” of nonclinical testing: pharmacology = RATIONALE toxicology = RECOMMENDATIONS demonstration of safety = REGULATORY EXPECTATIONS

Take-Home Messages Animal testing determines safety…but caveats exist for biological products Toxicology programs for anti-cancer biological therapeutics require novel approaches to obtain data no “one size fits all” paradigm for biologics traditional animal toxicology models may not be appropriate or feasible studies may have to be “individualized” to address specific safety concerns

Take-Home Messages Toxicology studies for anti-cancer biological therapeutics should: follow guidance set forth by ICH S6, and additional guidances as available be rational, scientifically designed, and problem solving employ careful design, judicious use of animals

Take-Home Messages But... animal studies really only give you a “best guess” of what to expect no animal model, including humans is 100% predictive of response in man sometimes animal studies can give a false sense of security however, these models may be useful in evaluation of mechanism, other toxicities

Some Further Resources ICH Guidances ICH S6: Safety Studies for Biotechnological Products ICH M3: Timing of Pre-clinical Studies in Relation to Clinical Trials ICH S5a: Detection of Toxicity to Reproduction for Medicinal Products ICH S2b: Standard Battery of Genotoxicity Testing also available at: www.ich.org/cache/compo/276-254-1.html

Some Further Resources Points to Consider Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use - 2/28/97 www.fda.gov/cber/gdlns/ptc_mab.pdf Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use Derived from Transgenic Animals – 1995 www.fda.gov/cber/gdlns/ptc_tga.txt

Further Questions? Please Contact the DBOP Toxicologists Anne M. Pilaro, Ph.D. Supervisory Toxicologist DBOP Staff Andrew McDougal, Ph.D. Brenda Seidman, Ph.D. (301) 796-2320