toxicology in drug development lynnda reid, ph.d. pharmacology/toxicology reviewer center for drug...

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Toxicology in Drug Development Toxicology in Drug Development Lynnda Reid, Ph.D. Pharmacology/Toxicology Reviewer Center for Drug Evaluation and Research (CDER) Rafael Ponce, Ph.D., DABT Senior Scientist ZymoGenetics, Inc.

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Toxicology in Drug DevelopmentToxicology in Drug Development

Lynnda Reid, Ph.D.

Pharmacology/Toxicology Reviewer

Center for Drug Evaluation and Research (CDER)

Rafael Ponce, Ph.D., DABT

Senior Scientist

ZymoGenetics, Inc.

OutlineOutline

Regulatory OverviewRegulatory Overview Drug/biologic development processDrug/biologic development process ResourcesResources Questions (and answers?)Questions (and answers?)

Parties involved in Drug DevelopmentParties involved in Drug Development FDA Sponsor Contract Labs Clinical Sites Manufacturing Sites Consultants Other…

SponsorsSponsors

Pharmaceutical/Biotechnology Firms Practicing Physicians and Dentists Academic Institutions NIH Other

The FDAThe FDA

Center for Drug Evaluation and Research (CDER)

Center for Biologic Evaluation and Research (CBER)

Center for Devices and Radiological Health (CDRH)

Center for Veterinary Medicine (CVM)

Center for Food Safety and Applied Nutrition (CFSAN)

National Center for Toxicological Research (NCTR)

Office of Regulatory Affairs

DrugDrug

Center for Drug Evaluation and Research (CDER)Center for Drug Evaluation and Research (CDER)– Conventional synthetic chemicalsConventional synthetic chemicals– Antibiotics, natural and recombinant hormonesAntibiotics, natural and recombinant hormones– Novel drugs such as antisense oligonucleotides Novel drugs such as antisense oligonucleotides

and synthetic peptides (< 40 AA)and synthetic peptides (< 40 AA)

Center for Biologics Evaluation and Research (CBER)Center for Biologics Evaluation and Research (CBER)– Blood and blood productsBlood and blood products

– Vaccines and allergenicsVaccines and allergenics

– Conventional biotechnology-derived products Conventional biotechnology-derived products

– recombinant proteins, monoclonal antibodies, antigenic peptidesrecombinant proteins, monoclonal antibodies, antigenic peptides

– Novel biotechnology-derived productsNovel biotechnology-derived products

– cellular or gene therapies, tissue-engineered therapiescellular or gene therapies, tissue-engineered therapies

– DNA vaccines, xenotransplantationDNA vaccines, xenotransplantation

BiologicBiologic

ProteinsProteins Small Molecules Small MoleculesProteinsProteins Small Molecules Small MoleculesDrug substance Heterogenous mixture

Broad specs during developmentSpecs may change

Single entity; high chemicalpurityException: racemic mixturesSpecs well-defined early

Drug product Usually IV or SC Usually oral

Impurities Difficult to standardize Standards well established

Bridgingrequirements

Significant for drug substance Bioequivalence procedures

Biological activity May mimic naturally occurringmoleculesPrimary MOTPredictive based on MOA

Less predictive

Nonspecificity Variable significance Usually significantDrug-drug interaction

Chronic Toxicity Lack of models; species specificityand antigenicity

Models sometimes relevant

Impurities Toxicity not a major issue, mayimpact immunogenicity

May be significantPurity standards wellestablished

Drug substance Heterogenous mixtureBroad specs during developmentSpecs may change

Single entity; high chemicalpurityException: racemic mixturesSpecs well-defined early

Drug product Usually IV or SC Usually oral

Impurities Difficult to standardize Standards well established

Bridgingrequirements

Significant for drug substance Bioequivalence procedures

Biological activity May mimic naturally occurringmoleculesPrimary MOTPredictive based on MOA

Less predictive

Nonspecificity Variable significance Usually significantDrug-drug interaction

Chronic Toxicity Lack of models; species specificityand antigenicity

Models sometimes relevant

Impurities Toxicity not a major issue, mayimpact immunogenicity

May be significantPurity standards wellestablished

FDA Organizational Chart (Partial)

C en ter for D evices an d R ad io lo gica l Hea lth

O ffice o f V acc in es R esearch an d R eviewK aren M id th un , M D

D Ivis io n o f C e ll an d G en e T herapyP h illip N o g uch i, M D

D Ivisio n of T herapeu tic P rote insA m y R o sen b u rg , M D

D ivisio n o f M o n oc lo na l An tib od iesK aty S te in , P hD

D ivis io n o f A p plica tion R eview an d P ro cess ingG len Jo n es , P hD

D ivis io n o f C lin ica l T r ia l D esig n an d A na lys isK aren W e iss , M D

O ffice o f Th erap eu tics Research an d ReviewJay S ieg a l, M D

O ffice o f B lo o d R esearch an d ReviewJay E p ste in , M D

C en ter for B io lo g ics E va lu atio n an d R esearchK athryn Zo o n, P hD

C en ter for D ru g Eva lua tion s an d R esearch

F DA

CDER Review DivisionsCDER Review Divisions

Anesthetic, Critical Care, and Addiction

Anti-Viral Anti-Infective Anti-Inflammatory,

Analgesic, and Ophthalmic Cardio-Renal Dermatologic and Dental Gastrointestinal and

Coagulation

Metabolic and Endocrine Medical Imaging and

Radiopharmaceutical Neuropharmacological Oncology Over-the-Counter Pulmonary Reproductive and Urologic Special Pathogens and

Immunologic

What Types of NonclinicalWhat Types of Nonclinical Studies Should Sponsors Conduct? Studies Should Sponsors Conduct?

ICH (International Conference on Harmonization) Guidelines Drug class specific guidance FDA Consultations General Toxicology?

Genotoxicity?Carcinogenicity?

General toxicity? Genotoxicity? Carcinogenicity?

Guidance, Guideline, or Regulation Guidance, Guideline, or Regulation

A guidance and a guideline are the same. Provide direction and a course(s) of action Not legally binding Public comments are considered, but responses are optional

Regulation A rule or a law by which conduct is governed Legally binding Published through notice and rulemaking, e.g., CRF, FR Substantive public comments MUST be responded to in the

preamble of the final rule

The ICH ProcessThe ICH Process

Established in 1990 to improve efficiency of the new drug approval process in Europe, Japan, and the United States

Regulators and industry representatives from all three regions participated

The harmonized topics are safety, quality, and efficacy

ICH Nonclinical Guidance TopicsICH Nonclinical Guidance Topics

Nonclinical safety studies for pharmaceuticals

Timing of nonclinical safety studies

Phase 1 studies (2)

Pharmacokinetics

Safety Pharmacology

Acute and Repeat dose toxicity studies (3)

Toxicokinetics

Reproductive toxicology (3)

Genotoxicity (2)

Carcinogenicity (4)

Duration of chronic toxicity testing

Biotechnology products

Impurities & Stereorisomers (4)

FDA Nonclinical Guidance TopicsFDA Nonclinical Guidance Topics

Published Guidance Documents:

– Content and Format of INDs for Phase 1 Studies

– Single Dose Acute Toxicity Testing for Pharmaceuticals

– Product Specific guidance anti-virals

vaginal contraceptives and STD preventatives

– Special Protocol Assessment

– Submission in Electronic Format (2)

Published Draft Guidances:– Carcinogenicity study protocols– Immunotoxicology– Photosafety testing– Statistical evaluation of carcinogenicity studies

Types of Toxicology Studies RecommendedTypes of Toxicology Studies Recommended

General Toxicology

– acute and repeat dose toxicology studies

Special Toxicology Studies

– local irritation studies, e.g., site specific, ocular

– hypersensitivity studies for inhalation and dermal drug products

Reproductive and Developmental Toxicology Studies

– male and female fertility

– embryonic and fetal development

– post-natal reproductive and developmental effects

Impact of Nonclinical Studies on Drug Impact of Nonclinical Studies on Drug DevelopmentDevelopment

Setting Initial Doses in Humans Identification of Possible Adverse Effects Identification of Reversible vs Irreversible Effects Identification of Useful Biomarkers for Monitoring Toxicity

during Clinical Trials Drug Labeling

Drug Development ProcessDrug Development Process

PRELEADPRELEAD IND IND NDA NDA

““Discovery”Discovery”

DevelopmentDevelopment

Investigational New Drug Investigational New Drug New Drug ApplicationNew Drug Application

ResearchResearch

Toxicology Testing ProcessToxicology Testing Process

PRELEADPRELEAD IND IND NDA/BLA NDA/BLA

DiscoveryDiscovery

DevelopmentDevelopment

Clinical trialsClinical trials

P1P1 P2P2 P3P3

Nonclinical tox studies in animalsNonclinical tox studies in animals

What are Phase 1, 2, and 3 Trials? What are Phase 1, 2, and 3 Trials?

Phase 1: Safety and pharmacokinetics Generally 20 to 80 subjects Closely controlled

Phase 3: Efficacy and safety Several hundred to several thousand subjects Controlled and uncontrolled

Phase 2: Efficacy and safety Usually no more than several hundred subjects Closely controlled

Nonclinical Information FlowNonclinical Information Flow

In vitro/Animal ModelsIn vitro/Animal Models ApplicationApplication TrialTrial

J. Lipani, 1998J. Lipani, 1998

Hypothesis testingHypothesis testing Mechanism of Mechanism of

actionaction Safety assessmentSafety assessment Develop surrogate Develop surrogate

markersmarkers ADME/PKADME/PK

Potential for effectPotential for effect Toxicity profileToxicity profile Dose/regimenDose/regimen Route of administrationRoute of administration

Contract Research OrganizationsContract Research Organizations

• Formulation/Manufacture/Fill and FinishFormulation/Manufacture/Fill and Finish• Metabolism/distribution (ADME/PK)Metabolism/distribution (ADME/PK)• In vitroIn vitro

– Activity/high throughput screeningActivity/high throughput screening– Toxicity (non-GLP and GLP)Toxicity (non-GLP and GLP)

• In vivoIn vivo– ResearchResearch

– Model developmentModel development– Proof of concept/efficacyProof of concept/efficacy

– DevelopmentDevelopment– GLP toxicology testing for regulatory submissionGLP toxicology testing for regulatory submission

Good Laboratory Practice (GLP) for Nonclinical Good Laboratory Practice (GLP) for Nonclinical Laboratory StudiesLaboratory Studies

21 CFR Part 5821 CFR Part 58 Regulatory guidelines for conduct of toxicology (safety) Regulatory guidelines for conduct of toxicology (safety)

studies in support of regulatory submissionstudies in support of regulatory submission Guidelines “intended to assure the quality and integrity of Guidelines “intended to assure the quality and integrity of

the safety data…”the safety data…”

GLP OverviewGLP Overview

Cover food additives, human and animal drugs, biologics, Cover food additives, human and animal drugs, biologics, devices, and electronicsdevices, and electronics

Define terms Define terms Define responsibility of facility management, study Define responsibility of facility management, study

director, quality assurance unitdirector, quality assurance unit Describe facility requirementsDescribe facility requirements

– Animal care, test/control articles, lab operations, Animal care, test/control articles, lab operations, specimen and data storage, equipment, SOPs, records, specimen and data storage, equipment, SOPs, records, etc.etc.

Toxicology CROToxicology CRO

Independent research facilityIndependent research facility Specialized facility designed to meetSpecialized facility designed to meet

– Animal care requirements (Dept. of Agriculture)Animal care requirements (Dept. of Agriculture)– Quarantine requirements (CDC)Quarantine requirements (CDC)– Facility/study GLP requirements (US FDA)Facility/study GLP requirements (US FDA)– Safety and health regulations (OSHA, state, region)Safety and health regulations (OSHA, state, region)

Provide general or specialized testingProvide general or specialized testing– DiscoveryDiscovery– Development (GLP toxicology testing for regulatory Development (GLP toxicology testing for regulatory

submission)submission)

Study DirectorStudy Director

Responsible to Sponsor, Facility, FDA Single point of control Responsible for overall technical conduct of study Interprets, analyzes, documents, and reports results

SD does not necessarily conduct all aspects of these activities, but has ultimate responsibility

Study Director

• Often, but not always, a toxicologist• Often, but not always, MS or PhD (depends on

experience)• DABT or equivalent a plus – marketable

Types of Nonclinical Studies Reviewed by FDATypes of Nonclinical Studies Reviewed by FDA

Basic pharmacology

– primary and secondary mechanisms of action

– nonclinical efficacy studies

Safety pharmacology

Pharmacokinetics

Toxicology

Genotoxicology

Carcinogenicity

What Does FDA Expect from Nonclinical Studies?What Does FDA Expect from Nonclinical Studies?

Pharmacology– proposed mechanism of action– identification of secondary pharmacologic effects– Proof of Concept studies for serious indications

Safety Pharmacology– effects on neurological, cardiovascular, pulmonary,

renal, and gastrointestinal systems – abuse liability

What Does FDA Expect from Nonclinical Studies?What Does FDA Expect from Nonclinical Studies?

Pharmacokinetics– comparison of ADME in species used for toxicology

studies– identification of bioaccumulation potential– identification of potential differences in gender– generation of PK parameters, e.g., Cmax, Tmax,

AUC(o-inf.), half life

What Does FDA Expect What Does FDA Expect in General Toxicology Studies?in General Toxicology Studies?

Acute and repeat toxicology studies in two species

Duration of repeat dose nonclinical studies should be at least equal or greater than the duration of the proposed clinical study

A control and at least 3 drug concentrations

– identification of the NOAEL and MTD

– identify shape of the dose-response curve

Doses/systemic exposure should exceed clinical dose/exposure

What Does FDA Expect What Does FDA Expect in General Toxicology Studies?in General Toxicology Studies?

Formulation should be the same as the clinical formulation

Route of exposure:

– should be the same as clinical route

– additional routes of exposure may be needed to achieve systemic toxicity

Histopathology examination of all animals and standard tissues

Lymphoproliferative tissues should be assessed for unintended effects on the immune system

Toxicokinetic information

Timing of Nonclinical Studies - Phase 1Timing of Nonclinical Studies - Phase 1

Prior to “First Time in Humans” – safety pharmacology– pharmacokinetics/toxicokinetics (exposure data)– single dose toxicity studies in 2 mammalian species– expanded acute or repeat dose toxicity studies in a rodent

and a nonrodent– local tolerance– in vitro evaluation of mutations and chromosomal damage– hypersensitivity for inhaled and dermal drugs– teratogenicity studies

Timing of Nonclinical Studies - Phase 1/2Timing of Nonclinical Studies - Phase 1/2

Phase 1-2 Clinical Trials– repeat dose toxicity studies of appropriate length

Phase 2 Clinical Trials– complete genotoxicity assessment (in vivo and in vitro)– repeat dose toxicity studies of appropriate length

Timing of Nonclinical Studies - Phase 3Timing of Nonclinical Studies - Phase 3

Phase 3 Clinical Trials– repeat dose toxicity studies of appropriate length– male and female fertility– post-natal development

• 10 rats (5M/5F)

• Control + 4 Dose groups

• Single exposure, IV

• Monitor clinical observations, food consumption, serum chemistry, hematology, coagulation over 7 days (+ baseline)

• Serum PK

• Gross observations, histopathology on major organs and tissues

Acute dose range finding in rats

• 32 cynomolgus nonhuman primates (16M/16F)

• Control (5M/5F), Low (3M/3F), Med (3M/3F), High (5M/5F)

• Repeated exposure over 4 weeks, Sac 3M/3F, 4 week recovery

• Monitor clinical observations, food consumption, serum chemistry, hematology, coagulation over 56 days (+ baseline)

• Monitor PK, antibody formation

• Gross observations, histopathology on major organs and tissues

• Include other clinical endpoints as appropriate (EKG, ophthalmology, BP)

• Perform specialty testing on tissues/blood (immunohistochemistry, FACS)

Chronic GLP Tox in Cynos

Questions Asked byQuestions Asked by Review Pharmacologist/Toxicologist Review Pharmacologist/Toxicologist

Validity of study design: – Was the appropriate animal model used?– Were dose(s) and duration sufficient to

support the proposed clinical study or labeling?

– Were adequate systemic exposures achieved?

– Was the route of administration relevant to clinical used?

More Questions:More Questions:

Did the test system exhibit any effects? Were the effects treatment-related? Are the effects biologically significant? Are the effects reversible? Are the effects clinically relevant? Can the effects be monitored clinically?

Career Opportunities for FDA Career Opportunities for FDA ToxicologistToxicologist

Pre-IND Consulting

Review nonclinical protocols

Serve on intra- and inter-agency expert working committees

Generate guidance and policy documents

Professional development

For Online Information on FDAFor Online Information on FDA

http://www.fda.gov/

– CDER News

– Guidelines

– ICH Documents

– Employment Opportunities