Drug Development Lynnda Reid, Ph.D. Pharmacology/Toxicology Reviewer Center for Drug Evaluation and Research (CDER) Rafael Ponce, Ph.D., DABT Scientific Director Amgen

Outline Regulatory Overview Drug/biologic development process Resources Questions (and answers?)

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

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

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

Center for Drug Evaluation and Research (CDER) Office of New Drugs Cardiovascular and renal Neurology Psychiatry Anesthesia, Analgesia, Rheumatology Metabolism and endocrinology Pulmonary and allergy Gastroenterology Dermatology and dental Urology Anti-infectives and ophthalmology Anti-viral Special pathogens and transplant products Drug oncology Biological oncology Medical imaging and hematology Nonprescription

Driving issues for nonclinical assessment Nonclinical development Clinical development Discovery What is a safe starting dose? How shall I dose escalate? What are the primary toxicological consequences of treatment? Are they reversible? Can I monitor for these adverse effects (i.e., are there useful premonitory indicators)?

Is there an ideal toxicological model? Yes

In the absence of the ideal, what next? Informative alternative species What is a safe starting dose? How shall I dose escalate? What are the primary toxicological consequences of treatment? Are they reversible? Can I monitor for these adverse effects (i.e., are there useful premonitory indicators)? Is my animal model a reliable biological model for human response? What limitations does my species have as a surrogate for humans?

Proteins Small Molecules

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

Impact of Nonclinical Studies on Drug 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

Development Process Discovery Development PRELEAD IND NDA/BLA Pharmacology, Lead ID Process Development Pharmacokinetics Nonclinical safety Clinical trials P1 P2 P3

What are Phase 1, 2, and 3 Trials? Safety and pharmacokinetics Generally 20 to 80 subjects Closely controlled Phase 2: Efficacy and safety Usually no more than several hundred subjects Closely controlled Phase 3: Efficacy and safety Several hundred to several thousand subjects Controlled and uncontrolled

Nonclinical Information Flow In vitro/Animal Models Application Trial Hypothesis testing Mechanism of action Safety assessment Develop surrogate markers ADME/PK Potential for effect Toxicity profile Dose/regimen Route of administration J. Lipani, 1998

Contract Research Organizations Formulation/Manufacture/Fill and Finish Metabolism/distribution (ADME/PK) In vitro Activity/high throughput screening Toxicity (non-GLP and GLP) In vivo Research Model development Proof of concept/efficacy Development GLP toxicology testing for regulatory submission

Types 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? 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? 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 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 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 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 1/2 Phase 1-2 Clinical Trials repeat dose toxicity studies of appropriate length Phase 2 Clinical Trials complete genotoxicity assessment (in vivo and in vitro)

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

Questions Asked by 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: 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?

Why does species selection matter? Use of an unsuitable species may lead to false conclusions False positive There is an observed toxicity in a nonclinical species that will not develop in humans Consequence: Resource wasting Increased clinical monitoring, evaluation/investigation Decision to slow or terminate program Management: Investigative tox, clinical confirmation False negative Toxicity that will develop in humans is not predicted by nonclinical species Consequence: Increased (unknown) risk to humans Development of an unexpected toxicity Not easily managed

Our collective interest Minimize the risk of a false negative Identify toxicological liabilities of a candidate therapeutic as early as possible Kill unsuitable candidates early Distribute resources to best candidates Informed risk-benefit assessment Appropriate monitoring Efficient dose escalation and candidate progression

Nonclinical support for FIH dosing Drug exposure and distribution to the target site (PK): First step in animal to human extrapolation Nonclinical study mimics dose route Appropriate allometry to scale dose from nonclinical species to humans Adjustment for known differences in protein binding, metabolism, clearance, etc.

Nonclinical support for FIH dosing Drug action at target site (PD, Tox) Second step in animal to human extrapolation Similar underlying physiology for target/pathway Presence of biological target at site of action in nonclinical species Similar drug-target interaction (e.g., KD) Similar pharmacological potency of drug (e.g., Emax, ED50)

MABEL/PAD vs NOAEL

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The 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 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 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