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Advanced Prostate Cancer: Developing Gonadotropin- Releasing Hormone Analogues Guidance for Industry

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Advanced Prostate Cancer: Developing Gonadotropin- Releasing Hormone Analogues Guidance for Industry Advanced Prostate Cancer: Developing Gonadotropin- Releasing Hormone Analogues Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document, contact Elaine Chang at 240-402-2628. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2019 Clinical/Medical Advanced Prostate Cancer: Developing Gonadotropin- Releasing Hormone Analogues Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: [email protected] https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2019 Clinical/Medical TABLE OF CONTENTS I. INTRODUCTION..................................................................................................1 II. BACKGROUND ....................................................................................................1 III. DEVELOPMENT PROGRAM ............................................................................2 A. Product Development ........................................................................................................ 2 B. Nonclinical Development .................................................................................................. 3 C. Phase 3 Efficacy Trial Considerations ............................................................................. 4 1. Trial Design ......................................................................................................................... 4 2. Trial Population .................................................................................................................. 5 3. Dose Selection ..................................................................................................................... 5 4. Trial Procedures and Timing of Assessments ..................................................................... 5 5. Pharmacokinetics and Pharmacodynamics ........................................................................ 6 6. Efficacy Endpoints ............................................................................................................... 7 7. Statistical Considerations .................................................................................................... 7 D. Labeling Considerations ................................................................................................... 8 APPENDIX .........................................................................................................................9 Contains Nonbinding Recommendations Draft — Not for Implementation 1 Advanced Prostate Cancer: Developing 2 Gonadotropin-Releasing Hormone Analogues 3 Guidance for Industry1 4 5 6 7 8 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 9 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 10 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 11 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 12 for this guidance as listed on the title page. 13 14 15 16 17 I. INTRODUCTION 18 19 This guidance describes the Food and Drug Administration’s (FDA’s) current recommendations 20 regarding the overall development program to establish the effectiveness and safety of 21 gonadotropin-releasing hormone (GnRH) analogues for treating advanced prostate cancer. 22 23 In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 24 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 25 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 26 the word should in Agency guidances means that something is suggested or recommended, but 27 not required. 28 29 30 II. BACKGROUND 31 32 GnRH analogues, both agonists and antagonists, remain a mainstay for treating patients with 33 prostate cancer. Both are intended to reduce testosterone (T) levels in the blood, a major driver of 34 prostate cancer growth, but they have different properties. GnRH agonists cause a transient surge 35 in luteinizing hormone (LH) and testosterone. This surge desensitizes the LH receptors and is 36 followed by a sustained decrease in T levels. Patients whose LH receptors have not been fully 37 desensitized will develop a surge in testosterone during subsequent administration of a GnRH 38 agonist. This increase is referred to as the acute-on-chronic effect. GnRH antagonists bind to the 1 This guidance has been prepared by the Division of Oncology Products 1 in the Center for Drug Evaluation and Research at the Food and Drug Administration. 1 Contains Nonbinding Recommendations Draft — Not for Implementation 39 GnRH receptor, preventing production of LH and the resultant production of testosterone. 40 Subsequent administration of a GnRH antagonist does not result in a testosterone surge.2 41 42 New drug applications for GnRH analogues typically rely, in part, on FDA’s finding of safety 43 and/or effectiveness for a previously approved GnRH analogue and are submitted through the 44 pathway described by section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act. These 45 505(b)(2) applications generally have included product-specific data from a clinical trial and 46 nonclinical general toxicology studies. This guidance addresses the current regulatory 47 requirements for the approval of these agents and the use of a standardized approach to trial 48 design. 49 50 51 III. DEVELOPMENT PROGRAM 52 53 A. Product Development 54 55 GnRH analogues typically contain a peptide similar to naturally occurring GnRH. The product is 56 often marketed in the form of a polymer (such as freeze-dried powder (microspheres) that a 57 provider must mix with a solvent in a prefilled syringe to be reconstituted into a suspension) in a 58 single-dose delivery system for intramuscular administration. Chemistry, manufacturing, and 59 controls (CMC) information for this peptide and the materials necessary to provide an extended- 60 release formulation can be provided within an application or as a cross reference to a drug master 61 file. The CMC information submitted in the investigational new drug application (IND) during 62 drug development should follow relevant FDA guidance documents: 63 64 • Guidance for industry Content and Format of Investigational New Drug Applications 65 (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, 66 Biotechnology-derived Products3 (November 1995) 67 68 • Guidance for industry INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing, 69 and Controls Information (May 2003) 70 71 For products entering clinical trials, the product development program should be aligned with the 72 following applicable ICH guidance documents: 73 74 • Guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products 75 (November 2003) 76 77 • Guidance for industry Q1B Photostability Testing of New Drug Substances and Products 78 (November 1996) 2 TN Clinton, SL Woldu, and GV Raj, 2017, Degarelix versus Luteinizing Hormone-Releasing Hormone Agonists for the Treatment of Prostate Cancer, Expert Opin Pharmacother 18(8): 825–832; LG Gormella, 2009, Effective Testosterone Suppression for Prostate Cancer: Is There a Best Castration Therapy?, Rev Urol 11(2): 52–60. 3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 2 Contains Nonbinding Recommendations Draft — Not for Implementation 79 80 • Guidance for industry Q2(R1) Validation of Analytical Procedures: Text and 81 Methodology (November 2005) 82 83 • Guidance for industry Q3A(R) Impurities in New Drug Substances (June 2008) 84 85 • Guidance for industry Q3B(R2): Impurities in New Drug Products (July 2006) 86 87 • Guidance for industry Q3C Impurities: Residual Solvents (December 1997) 88 89 • Guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for 90 New Drug Substances and New Drug Products: Chemical Substances (December 2000) 91 92 Because the active ingredient is intended to be released over 1 to 6 months, ensuring adequate 93 and continuous product release is critical to successful development. During product 94 development, in vitro tests are conducted to evaluate and characterize the quality and 95 performance of the proposed drug
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