Accelerating Therapeutic Development through a look at current Regulatory Applications A Non-Clinical Perspective

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1 Accelerating Therapeutic Development through a look at current Regulatory Applications A Non-Clinical Perspective Imran M. Khan, Ph.D. Division of Psychiatry Center for Drug Evaluation and Research FDA 1

2 Views expressed in this presentation are those of the speaker and do not necessarily represent those of the Food and Drug Administration 2

3 Outline IND Regulations Nonclinical studies to support standard IND for New Molecular Entity (NME) First in human Previous human experience Products marketed in the U.S. Biologic products Exploratory IND Pediatric Trials Clinical Holds Nonclinical deficiencies How to avoid / remove Development and Regulatory Acceptance of Scientific Tools in Drug Development Programs 3

4 IND Regulations (21 CFR ; 21 CFR (a)(8)) Pharmacology and Toxicology information Adequate information involving laboratory animals or in vitro assays, on the basis of which the sponsor has concluded that the proposed clinical trial is safe to proceed. Pharmacology PK/ADME Toxicology: repeat dose toxicity, genetic toxicology, fertility/reproductive/developmental toxicity, carcinogenicity, other Guidance documents with detail information are available at FDA.gov 4

5 NME: First-In-Human (FIH) Typically, a single-dose trial in healthy volunteers Pharmacology in vitro receptor binding screen, in vitro PD (functional) assays, in vivo animal efficacy models Safety Pharmacology CNS, cardiovascular (including herg assay), respiratory PK/ADME PK in animal species used for toxicity testing Tissue distribution whole body autoradiography in vitro metabolism data in animals and human Toxicology (with TK) 2 species; of similar or longer duration Genetic Toxicology API and impurities 5

6 NME: previous human experience Standard nonclinical studies may not be needed. Occasionally, when previous human experience is adequately documented with respect to safety, the data could support the conduct of the initial clinical trial in absence of some nonclinical studies e.g. safety pharmacology The nonclinical safety studies should be equal to or exceed in duration of the clinical trial in the rodent (6 month) and non-rodent (9 month) species Depending on clinical trial protocol, may need: Reproductive and developmental studies and completion of the genetic toxicology battery 6

7 U.S. Marketed Product Additional nonclinical studies are not needed, if: The proposed dose and duration are consistent with those for the approved product. The intended route of administration is the same as for the marketed product. The patient population is sufficiently similar to that for which the product is approved. The marketed product or the clinical formulation and the predicted PK/ADME are sufficiently similar to the marketed product. 7

8 Biologic Products Nonclinical studies to support biologics may differ in some aspects from those for small molecules, e.g., May not need genotoxicity studies (e.g., mabs). May not need two species (only one species may be pharmacologically relevant). May need to assess for antidrug antibodies, particularly if no toxicity is observed at an adequate high dose. Criteria for adequate high dose may be different (e.g., saturation of pharmacodynamic effect). May need to incorporate assessment of pharmacodynamic effect(s) into toxicity studies. Acute-dose toxicity studies may not be adequate to support a single-dose clinical trial if a long t 1/2 in humans is anticipated. 8

9 Exploratory IND Intended for clinical trials of limited Dose and Duration ICH M3(R2) provides description of five approaches: Total clinical dose 100 g AND total dose 1/100 th NOAEL and 1/100 th pharmacologically active dose (Approach 1) Dosing up to 14 days not to exceed duration of dosing in nonrodent; into therapeutic range but not intended to evaluate clinical MTD (Approach 5) Nonclinical studies are conducted under GLP In U.S. once the proposed clinical trial(s) is completed, the Exploratory IND has to be withdrawn. 9

10 Pediatric Trials The need for nonclinical studies will depend on the nature of the clinical trial and previous human (adult or pediatric) experience. FIH Similar to those to support FIH in adult in addition to conducting toxicity study(ies) in juvenile animals Previous human experience Adult data may support single-dose and some repeat-dose trials Juvenile animal toxicology study in one species (typically, rat) prior to expanded clinical trials in pediatric patients For primary pediatric indication, chronic dosing in humans may be supported by chronic toxicity studies in juvenile animals (6 month rodent and/or 12 month non-rodent). Studies in juvenile animals should take into consideration age range of pediatric population. 10

11 Nonclinical Deficiencies Warranting Clinical Hold Lack of nonclinical studies Inadequate nonclinical studies: Inadequate documentation (e.g., individual animal line listings) Too few animals tested Standard parameters not assessed or data not provided Inadequate doses Conducted using route other than that proposed for humans without justification Inadequate duration No no-effect dose for serious toxicity Serious toxicity with no or inadequate strategy for monitoring in humans CMC issues identified that require nonclinical safety testing (e.g., impurities with structural alert for genotoxicity; novel excipient in clinical formulation not adequately tested in animals) Inadequate Clinical Investigator s Brochure 11

12 How to Avoid a Clinical Hold In some cases, cannot In other cases: Provide justification and adequate response to clinical hold issues, e.g. Revise the clinical protocol e.g. Limit dose and/or plasma exposure to provide a sufficient safety margin, Limit duration of dosing, For un-monitorable toxicity in animals may ascend clinical dose slowly with careful monitoring or, limit duration if this toxicity occurs after prolonged administration, Add or increase clinical monitoring to address safety issue(s) of concern Provide scientific justification to support clinical protocol e.g. the toxicity in animals is not relevant to humans ( -2 -globulin-associated nephropathy in male rats); inadequate high dose in pivotal toxicity study due to excessive emesis, saturation of absorption, etc. 12

13 Development and Regulatory Acceptance of Scientific Tools in Drug Development Programs Drug Development Tools Qualification Programs Biomarkers Animal models - under the Animal Rule Clinical outcome assessments (COAs) 13

14 Biomarker Qualification Proposals Nonclinical qualifications completed PSTC Translational Biomarkers of Nephrotoxicity ILSI/HESI Nephrotoxicity Biomarkers Preclinical Application of Cardiac Troponins Review Stage Galactomannan for Aspergillosis Consultation and Advice Stage Clinical Biomarkers of Nephrotoxicity Toxicogenomic Analysis to Explore + Chromosome Ab Circulating Tumor Cells in Metastatic Breast Cancer Circulating Tumor Cells in Prostate Cancer Translational Biomarkers of Hepatotoxicity Translational Biomarkers of Skeletal Muscle Toxicity Imaging Biomarkers in Oncology: SUV (quantitative FDG-PET/CT) and VLA (quantitative chest CT)

15 Guidance documents may be found at: Follow links to Drugs; Guidance, Compliance & Regulatory Information; Guidances (Drugs) Follow links to Work Products; ICH Guidelines; nonclinical guidances are under S (Safety) and M (Multidisciplinary) Guidelines 15