# Presentation: 120328

## 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?

**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

## ICH-S6 – What it Doesn’t Do

**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

## ICH-S6 – What it Does Do

**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

## ICH-S6 – What it Does Do

**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

## Additional Guidance from FDA

**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

## Additional Guidance from FDA

**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

## 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