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toxicology in drug development presentation
- 1. Toxicology in DrugDevelopment 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.
- 2. Outline Outline Regulatory Overview RegulatoryOverview Drug/biologic development process Drug/biologic development process Resources Resources Questions (and answers?) Questions (and answers?)
- 3. Parties involved inDrug Development Parties involved in Drug Development FDA Sponsor Contract Labs Clinical Sites Manufacturing Sites Consultants Other…
- 4. Sponsors Sponsors Pharmaceutical/Biotechnology Firms Practicing Physicians and Dentists Academic Institutions NIH Other
- 5. The FDA The 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
- 6. Drug Drug Center for DrugEvaluation and Research (CDER) Center for Drug Evaluation and Research (CDER) – Conventional synthetic chemicals Conventional synthetic chemicals – Antibiotics, natural and recombinant hormones Antibiotics, 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)
- 7. Center for BiologicsEvaluation and Research (CBER) Center for Biologics Evaluation and Research (CBER) – Blood and blood products Blood and blood products – Vaccines and allergenics Vaccines and allergenics – Conventional biotechnology-derived products Conventional biotechnology-derived products – recombinant proteins, monoclonal antibodies, antigenic peptides recombinant proteins, monoclonal antibodies, antigenic peptides – Novel biotechnology-derived products Novel biotechnology-derived products – cellular or gene therapies, tissue-engineered therapies cellular or gene therapies, tissue-engineered therapies – DNA vaccines, xenotransplantation DNA vaccines, xenotransplantation Biologic Biologic
- 8. Proteins Proteins Small Molecules SmallMolecules Drug substance Heterogenous mixture Broad specs during development Specs may change Single entity; high chemical purity Exception: racemic mixtures Specs well-defined early Drug product Usually IV or SC Usually oral Impurities Difficult to standardize Standards well established Bridging requirements Significant for drug substance Bioequivalence procedures Biological activity May mimic naturally occurring molecules Primary MOT Predictive based on MOA Less predictive Nonspecificity Variable significance Usually significant Drug-druginteraction Chronic Toxicity Lack of models; species specificity and antigenicity Models sometimes relevant Impurities Toxicity not a major issue, may impact immunogenicity May be significant Purity standards well established
- 9. FDA Organizational Chart(Partial) Center for Devices and Radiological Health Office of Vaccines Research and Review Karen M idthun, MD DIvision of Cell and Gene Therapy Phillip Noguchi, MD DIvision of Therapeutic Proteins Am y Rosenburg, MD Division of Monoclonal Antibodies Katy Stein, PhD Division of A pplication Review and Processing Glen Jones, PhD Division of Clinical Trial Design and Analysis Karen Weiss, MD Office of Therapeutics Research and Review Jay Siegal, MD Office of Blood Research and Review Jay Epstein, MD Center for Biologics Evaluation and Research Kathryn Zoon, PhD Center for Drug Evaluations and Research FDA
- 10. CDER Review Divisions CDERReview 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
- 11. What Types ofNonclinical What 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?
- 12. Guidance, Guideline, orRegulation 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
- 13. The ICH Process TheICH 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
- 14. ICH Nonclinical GuidanceTopics ICH 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)
- 15. FDA Nonclinical GuidanceTopics FDA 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
- 16. Types of ToxicologyStudies Recommended Types 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
- 17. Impact of NonclinicalStudies on Drug Impact of Nonclinical Studies on Drug Development Development 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
- 18. Drug Development Process DrugDevelopment Process PRELEAD PRELEAD IND IND NDA NDA “ “Discovery” Discovery” Development Development Investigational New Drug Investigational New Drug New Drug Application New Drug Application Research Research
- 19. Toxicology Testing Process ToxicologyTesting Process PRELEAD PRELEAD IND IND NDA/BLA NDA/BLA Discovery Discovery Development Development Clinical trials Clinical trials P1 P1 P2 P2 P3 P3 Nonclinical tox studies in animals Nonclinical tox studies in animals
- 20. What are Phase1, 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
- 21. Nonclinical Information Flow NonclinicalInformation Flow In vitro/Animal Models In vitro/Animal Models Application Application Trial Trial J. Lipani, 1998 J. Lipani, 1998 Hypothesis testing Hypothesis testing Mechanism of Mechanism of action action Safety assessment Safety assessment Develop surrogate Develop surrogate markers markers ADME/PK ADME/PK Potential for effect Potential for effect Toxicity profile Toxicity profile Dose/regimen Dose/regimen Route of administration Route of administration
- 22. Contract Research Organizations ContractResearch Organizations • Formulation/Manufacture/Fill and Finish Formulation/Manufacture/Fill and Finish • Metabolism/distribution (ADME/PK) Metabolism/distribution (ADME/PK) • In vitro In vitro – Activity/high throughput screening Activity/high throughput screening – Toxicity (non-GLP and GLP) Toxicity (non-GLP and GLP) • In vivo In vivo – Research Research – Model development Model development – Proof of concept/efficacy Proof of concept/efficacy – Development Development – GLP toxicology testing for regulatory submission GLP toxicology testing for regulatory submission
- 23. Good Laboratory Practice(GLP) for Nonclinical Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies Laboratory Studies 21 CFR Part 58 21 CFR Part 58 Regulatory guidelines for conduct of toxicology (safety) Regulatory guidelines for conduct of toxicology (safety) studies in support of regulatory submission studies 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…”
- 24. GLP Overview GLP Overview Cover food additives, human and animal drugs, biologics, Cover food additives, human and animal drugs, biologics, devices, and electronics devices, and electronics Define terms Define terms Define responsibility of facility management, study Define responsibility of facility management, study director, quality assurance unit director, quality assurance unit Describe facility requirements Describe 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.
- 25. Toxicology CRO Toxicology CRO Independent research facility Independent research facility Specialized facility designed to meet Specialized 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 testing Provide general or specialized testing – Discovery Discovery – Development (GLP toxicology testing for regulatory Development (GLP toxicology testing for regulatory submission) submission)
- 26. Study Director Study 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
- 27. Study Director • Often,but not always, a toxicologist • Often, but not always, MS or PhD (depends on experience) • DABT or equivalent a plus – marketable
- 28. Types of NonclinicalStudies Reviewed by FDA Types of Nonclinical Studies Reviewed by FDA Basic pharmacology – primary and secondary mechanisms of action – nonclinical efficacy studies Safety pharmacology Pharmacokinetics Toxicology Genotoxicology Carcinogenicity
- 29. What Does FDAExpect 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
- 30. What Does FDAExpect 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
- 31. What Does FDAExpect 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
- 32. What Does FDAExpect 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
- 33. Timing of NonclinicalStudies - Phase 1 Timing 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
- 34. Timing of NonclinicalStudies - Phase 1/2 Timing 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
- 35. Timing of NonclinicalStudies - Phase 3 Timing of Nonclinical Studies - Phase 3 Phase 3 Clinical Trials – repeat dose toxicity studies of appropriate length – male and female fertility – post-natal development
- 36. • 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
- 37. • 32 cynomolgusnonhuman 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
- 38. Questions Asked by QuestionsAsked 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?
- 39. 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?
- 40. Career Opportunities forFDA Career Opportunities for FDA Toxicologist Toxicologist Pre-IND Consulting Review nonclinical protocols Serve on intra- and inter-agency expert working committees Generate guidance and policy documents Professional development
- 41. For Online Informationon FDA For Online Information on FDA http://www.fda.gov/ – CDER News – Guidelines – ICH Documents – Employment Opportunities