# Presentation: 120326

## Perspective on Pharm/Tox Assessment for Cell and Gene Therapy Products

- Pharmacologist
- Center for Biologics Evaluation and Research
- FDA

**Perspective on Pharm/Tox Assessment ****for Cell and Gene Therapy Products**

## Presentation Outline

- Regulatory expectations
- OCTGT regulated CT and GT products
- Preclinical evaluation
- Potential safety concerns for CT and GT products
- Pharm/Tox study designs
- The use of animal species/models
- Preclinical data in the IND
- Communication with the FDA

## Safety is Always Primary

-  **FDA Regulatory & Scientific Input **
** ****ICH documents**
** ****FDA guidance/PTCs/21 CFR**

-  **Basic Research**
** ****POC Studies**

-  **Biodistribution**
** ****Toxicology**

**Clinical Trials**

**Biologics License Application**
**(BLA)**

**Product License Granted**

***Discovery Phase / Safety Assessment***

** ****PreIND discussion with FDA**

**IND Submission For **
**Early Phase**** Clinical Trial**

## How Are Animal Studies Integrated into the Proposed Clinical Plan? 

- 21 CFR, part 312.23(a)(8)
**Pharmacologic & Toxicologic Studies**
- “...adequate information about the pharmacological & toxicological studies...on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations.  The kind, duration, & scope of animal and other tests required varies with the duration & nature of the proposed clinical investigations.”

## CT and GT IND/IDE Submissions in CBER

- CT = cell therapy, GT = gene therapy, XP = xenotransplantation

## OCTGT-Regulated Products

**OCTGT-Regulated Products**

- Somatic cell therapies
- Gene Therapies
- Viral therapies, e.g. oncolytic viruses
- Immunotherapies, e.g. tumor vaccines
- Xenotransplantation
- Tissue engineering*
- OCTGT Product + device*
-  * in conjunction with CDRH

## Product Examples

**Product Examples**

- Cell Therapy Products
- Progenitor cells, e.g. stem cells derived from various types of human tissues, embryos, and hematopoietic stem cells...
- Differentiated cells, e.g. islet cells, cartilage cells, dendritic cells, T lymphocytes...
- Gene Therapy Products
- Many types of replication deficient viral vectors
- Plasmid DNA vectors
- Various types of transgenes delivered by those vectors

## Product Examples (cont.)

- Oncolytic Vectors
- Replication competent or attenuated viruses for the treatment of various type of cancers via viral lysis of tumor cells
- Therapeutic Vaccines
- Tumor vaccines for cancer immunotherapy
- Vaccines for the treatment of nononcology diseases such as Alzheimer’s disease

## Types of Vectors for GT

- Plasmid DNA:
- Naked DNA
- Lipid-DNA complex
- Ligand-DNA complex
- Others, e.g. bacteria-based gene transfer

## Types of Vectors for GT (cont.)

- Replication Deficient Viral Vectors
- Retroviruses
- Adenoviruses
- Adeno-associated viruses
- Vaccinia/fowlpox viruses
- Herpes simplex viruses
- Lentivirus
- Other newer vectors on the horizon ....

## Routes of Gene Transfer

*Ex vivo* (transduction of cells *in vitro*)
- Transduced somatic cells
- Transduced hematopoietic cells
*In situ* (local delivery)
- Direct administration into specific tissues (e.g. intratumoral injection, s/c injection, etc.)
*In vivo* (systemic delivery)
- Intravenous administration, etc...

## Regulatory expectations

- OCTGT regulated CT and GT products
- Preclinical evaluation
- Potential safety concerns for CT and GT products
- Pharm/Tox study designs
- The use of animal species/models
- Preclinical data in the IND
- Communication with the FDA

## Preclinical Expectations for Early Phase Clinical Trials

- Scientific basis for conducting clinical trial
- Feasibility/establishment of rationale
- “Proof-of-concept” [POC]
- Establish pharmacologically effective dose(s)
- Optimize ROA/dosing regimen
- Rationale for species/model selection for further tests

## Preclinical Expectations (cont.)

- Recommend initial safe dose & dose escalation scheme in humans
- Potential target tissue(s) of toxicity/activity
- Parameters to monitor clinically
- Eligible patient population

## Preclinical Evaluation – CT/GT Agents vs. “Traditional” Biologics

- Similar general requirements for safety
- Pharmacologic profiles
- Proof-of-Concept (POC)
- Dose-response relationship
- Toxicology profile

## Preclinical Evaluation – CT & GT Agents

- BUT... the approach by which safety data are obtained will differ
**Gene Therapy............Cell Therapy**

-  Biodistribution of
-    vector
-  Kinetics of gene
-    expression

- Migration potential
- Differentiation
- Phenotype expressed
- Anatomical/functional integration  into host physiology
- Post-transplant survival

## Preclinical Evaluation – CT & GT Agents (cont.)	

**Gene Therapy................Cell Therapy**
- Long-term toxicity

-  Carcinogenicity/
-    insertional mutagenesis:

-  Tumorigenicity/
-    proliferative potential:

-  Depends on the product
-  Consider the ROA
-  Include appropriate study duration

## Preclinical Evaluation – CT & GT Agents (cont.)

- Reproductive Toxicity
- Consider a tiered approach
- Based on the BD data of the vector
- Determine the need to address the risk of germline transfer, then
- Determine the need to conduct reproductive and developmental toxicology studies
- ICH S5(R2) guideline should be consulted for the  overall design of these studies

**Preclinical Evaluation – ****CT & GT Agents (cont.)**

**Gene Therapy................ Cell Therapy**
- Long-term toxicity

## Potential Safety Concerns for CT Products

- Risk analysis based on CT products
- Cell survival status following delivery
- Cell migration/trafficking to non-target site(s)
- Cell differentiation to undesired cell types
- Immunogenicity to xenogeneic/allogeneic cells
- Uncontrolled cell proliferation or tumorigenicity
- Host response (physiologic, anatomic, the use of immunosuppressants, etc.)

## Potential Safety Concerns for GT Products

- Risk analysis based on GT products:
- Phenotype/activation state of target cell(s)
- Type of vector, mode of introduction
- Vector biodistribution to non-target cells
- Level and/or persistence of vector genome
- Level of viral replication in non-target tissues
- Inappropriate immune activation
- Potential for insertional mutagenesis and/or oncogenicity

## Potential Safety Concerns forGT Products (cont.)

- Transgene related concerns
- Expression of endogenous or recombinant enzymes, receptors, ligands, hormones, growth factors, oligonucleotides (anti-sense, siRNA, etc...)
- Local vs. systemic activities
- Acute or chronic effects
- Immunogenicity
- Autoimmunity

## Pharm/Tox Studies

- Pharmacology/POC studies
- Relevance of animal species/models
- Dose levels/regimen at which the desired biological activity can be observed via the proposed ROA
- Toxicology (T) studies in a healthy animal that is biologically relevant for safety assessment
- Hybrid pharmacology-toxicology study design
- POC + T – Obtain toxicology endpoints in an animal model of disease

## Toxicology Study Design

- Appropriate controls
- Mimic clinical scenario as closely as possible
- Product, formulation, ROA, dose regimen, etc.
- Reasonable group size to provide adequate interpretation of the data
- The number of animals will vary depending on the species, disease model, delivery system, product class, etc.

## Sufficient duration, depending on the biology of the test product, to allow for appearance of any toxicities...and the potential for resolution of toxicities 
Use several time points to evaluate early, middle and late findings following dosing
Include the time point at which the toxicities are expected to be reversed/resolved

- Use several time points to evaluate early, middle and late findings following dosing
- Include the time point at which the toxicities are expected to be reversed/resolved

**Toxicology Study Design (cont.)**

## Selection of dose levels
Include multiple dose levels in order to determine No-Observed-Adverse-Effect-Level (NOAEL)
NOAEL will help to determine a safe starting dose level and dose escalation scheme in the clinical trial
Need repeat dose toxicology study to support safety of a repeat dosing regimen in the clinical trial

- Include multiple dose levels in order to determine No-Observed-Adverse-Effect-Level (NOAEL)
- NOAEL will help to determine a safe starting dose level and dose escalation scheme in the clinical trial
- Need repeat dose toxicology study to support safety of a repeat dosing regimen in the clinical trial

**Toxicology Study Design (cont.)**

## Standard Toxicology Endpoints
Mortality 
Clinical observations, body weights, appetite
Hematology and coagulation
Serum chemistry
Immune effects (humoral or cellular immune responses)
Gross pathology (scheduled and unscheduled deaths)
Microscopic pathology 
Scheduled and unscheduled deaths
Examine both target and non-target tissues
Specific immunohistochemistry staining

- Mortality
- Clinical observations, body weights, appetite
- Hematology and coagulation
- Serum chemistry
- Immune effects (humoral or cellular immune responses)
- Gross pathology (scheduled and unscheduled deaths)
- Microscopic pathology
- Scheduled and unscheduled deaths
- Examine both target and non-target tissues
- Specific immunohistochemistry staining

**Toxicology Study Design (cont.)**

## Pharm/Tox Study Design for CT Products

- The guiding principles for POC and safety studies remain the same for CT and GT products
- Specific safety endpoints include cell survival, undesired cell differentiation and proliferation, immunogenicity to xenogeneic/allogeneic cells, host tissue/organ response...
- Safety endpoints may vary
- Depending on the product
- Considering the ROA
- Appropriate study duration may also vary

## ‘Hybrid’ studies may be conducted to provide rationale and safety data
Cell trafficking data may be needed depending on the product and ROA
The advisory committee recommendations (e.g. BRMAC* for cardiac CT) are also an important source of information for guiding safety assessment		

			*Now called CTGTAC

- Cell trafficking data may be needed depending on the product and ROA
- The advisory committee recommendations (e.g. BRMAC* for cardiac CT) are also an important source of information for guiding safety assessment
- 			*Now called CTGTAC

**Pharm/Tox Study Design for****CT Products (cont.)**

## Vector Biodistribution (BD) Studiesfor GT Products 

- Use of a relevant species, *e.g.* the same species as used in the toxicology study
- Usually the maximum feasible dose and/or NOAEL dose levels used in toxicology study
- Administered via the clinical ROA, i.e. used in toxicology study
- Biodistribution profile in both target and non-target tissues, including the blood
- Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events

## Vector BD Studies for GT Products – Specific Considerations

- Novel GT products: the BD data need to be completed prior to initiation of clinical trials to assess vector persistence & kinetic profile
- GT products similar to those previously used in humans:
- Safety database in humans
- BD data in animals by cross-reference to other INDs
- Conduct of BD study in parallel with early phase clinical trials
- BD data using the clinical material are needed for license application and labeling

## CT & GT Dose Extrapolation

- The objective is to recommend a starting clinical dose level and dose escalation scheme that are safe and biologically plausible
- Dose extrapolation between animals and humans based on:
- POC data – minimally active dose level
- Safety data from animal studies (e.g. toxicology, vector BD, cell migration) - NOAEL
- Calculation of clinical dose levels based on
- Fixed dose level (e.g., absolute dose)
- Body weight
- Organ mass (volume/weight)

## Preclinical Safety Evaluation – Other Issues – Devices

- Is this device approved/cleared for the intended use?
- If not - has an IDE/MF been submitted to CDRH?
- Yes - Need to include  a letter of cross reference in your IND
- No - Need to consult with CDRH as to what data are required for submission
- Perform preclinical safety evaluation studies using the intended clinical device, if possible

## Selection of Appropriate Animal Species

- The use of NHPs is **not** required
- The use of multiple species (e.g. a rodent and a non-rodent) is **not** required
- 			.....BUT.....

- Scientific justification must be provided for the selection of the animal species/model

## Selection of Animal Species/Model

- Use of relevant species/model
- Traditional
- Normal animals; rodent & non-rodent
- Non-traditional
- Spontaneous disease
- “Non-spontaneous” disease (induced, challenge)
- Genetically modified animals (e.g. “humanized” or transgenic animals)

## Selection of Animal Species/Model (cont.)

- Use of large animal models may be needed for preclinical assessment of CT/GT products
- Depends on the product
- Depends on the ROA
- Depends on the delivery system

## Preclinical Summary

- Pharm/Tox studies for CT & GT should be:
- Rational, problem-solving in study design
- Assessments based on the best available technology, methods to date
- Conclusions are data-driven
- Scientifically designed & judicious use of animals
- Should allow for early initiation of clinical trials
- Should allow uninterrupted clinical development

## Preclinical Summary (cont.)

- Some limitations of preclinical studies for CT and GT products
- Information on mechanism of action is often limited
- Biologically relevant animal species or model(s) of disease are not always available
- Limited information is available to support the validity of extrapolation from animal to human
**No one species will be representative or predictive for all humans, including humans**

## Regulatory expectations

- OCTGT regulated CT and GT products
- Preclinical evaluation
- Potential safety concerns for CT and GT products
- Pharm/Tox study designs
- The use of animal species/models
- Pharm/Tox data in the IND
- Communication with the FDA

## Sources of Preclinical Pharmacology Data

- Pharmacology data in support of a clinical trial can come from:
- Well-controlled studies conducted in-house
- Published data in peer-reviewed journals
- Cross-reference to similar products in previously submitted MF/INDs

## Sources of Toxicology Data

- Toxicology data in support of a clinical trial can come from:
- GLP-compliant toxicology studies
- Well-controlled studies conducted in-house
- Published data in peer-reviewed journals
- Cross-reference to similar products in previously submitted MF/INDs

## Perils of Using Published Animal or Human Studies as Sole Support for Initiation of Clinical Trials

- Often they were **not designed to answer a toxicologic question**, and therefore, adequate toxicology endpoints may not have been incorporated into the design
- Published reports often **do not provide sufficient information for independent review**
- Products **were not** comparable/substantially similar

## Submit Complete Study Reports

**Not just summarized statements**
**Detailed** description of the study performed
- Test system (i.e. animal species/model)
- Test articles/ROA/delivery system
- Study methodology - dose levels; dose schedule; dose procedure; test parameters, etc...
- Complete data sets for all parameters evaluated
- Submit **individual animal data** for all parameters evaluated
- Submit summarized and tabulated results

## Regulatory expectations

- OCTGT regulated CT and GT products
- Preclinical evaluation
- Potential safety concerns for CT and GT products
- Pharm/Tox study designs
- The use of animal species/models
- Pharm/Tox data in the IND
- Communication with the FDA

## Early Communication

- Pre-preIND interactions
- Non-binding, informal scientific discussions between Pharm/Tox in OCTGT/CBER and sponsor
- Pre-IND meetings
- Submit a pre-IND package to include:
- Product development/characterization – Chemistry, Manufacturing and Controls (CMC)
- Summary of preclinical information – Pharmacology, Toxicology study protocol/plan
- Proposed clinical protocol outline
- Schedule a pre-IND teleconference

## Selected Guidance Documents

- Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological products _www.fda.gov/cder/guidance/1397fnl.pdf_
- Guidance for Industry: Guidance for Human Somatice Cell Therapy and Gene Therapy (1998) _www.fda.gov/cber/gdlns/somgene.pdf_
- The ICH S6 document: Preclinical Safety Evaluation of Biotechnology Derived Pharmaceuticals _www.fda.gov/cder/guidance/1859fnl.pdf_
- Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events _www.fda.gov/cber/gdlns/gtclin.pdf_

## The Pharm/Tox Branch (PTB) at OCTGT/DCEPT

- Mercedes Serabian, M.S. DABT, Branch Chief; Initial contact for pre-preIND interactions
- A total of 7 reviewers including the BC: Interdisciplinary scientists - biologist, chemist, pharmacologist, toxicologist, and ORISE Fellow
- (301) 827-5102 [phone]; (301) 827-9796 [fax]

## CME Questions

- For the development of a replication-deficient adenoviral vector expressing the extracellular domain of the HER2 gene as a tumor vaccine for immunotherapy to treat cancer patients,
- What preclinical studies or endpoints might be useful in supporting the clinical proof of concept?
- What types of preclinical studies are needed to support safety of the proposed clinical trial?
- Please propose your scheme for scaling from animal to human safe doses.