Quality and Regulatory Affairs


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Part of the MaRS Best Practices Series - Pre-Clinical development workshop

Speaker: James Ault, VP Regulatory Affairs, Ricerca BioSciences

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Quality and Regulatory Affairs

  1. 1. Regulatory IND Process James Ault, RAC, RQAP-GLP VP Quality and Regulatory Affairs Ricerca Biosciences, LLC May 23, 2007 Quality and Regulatory Affairs
  2. 2. Regulatory IND Process <ul><li>So, you’ve got the next Blockbuster Product! </li></ul><ul><li>What now? </li></ul><ul><li>PROVE IT! </li></ul>
  3. 3. Regulatory IND Process <ul><li>Overview/Summary </li></ul><ul><li>Requirements for a regulatory submission </li></ul><ul><li>Regulatory strategy </li></ul><ul><li>IND application contents </li></ul><ul><li>Reasons for clinical hold </li></ul><ul><li>Interaction with the regulators/meetings </li></ul>
  4. 4. Fundamental Principle <ul><li>No medical product can be marketed in the United States until “substantial evidence” of the safety and effectiveness has been provided to the FDA’s satisfaction </li></ul>
  5. 5. What is “Substantial Evidence”? <ul><li>Test product in animals and humans; see if it works and if it does any harm </li></ul><ul><li>Use “controlled conditions of testing” to eliminate possibility that results are wrong </li></ul><ul><li>Apply rigorous scientific, medical and regulatory standards throughout </li></ul><ul><li>Assure identity, quality, purity, strength, reproducibility of manufacturing and ability to pass an FDA inspection </li></ul>
  6. 6. Here’s What the FDA Wants from You <ul><li>Description of the product </li></ul><ul><li>How do you make the product? </li></ul><ul><li>What does your product do? How do you know? </li></ul><ul><li>How did you test it? - animals and humans </li></ul><ul><li>Did you follow ALL the regulations? </li></ul><ul><li>Show us the data! ALL the data </li></ul><ul><li>We may need to inspect - for cause </li></ul>
  7. 7. When Do You File an IND? <ul><li>Whenever clinical studies are initiated: </li></ul><ul><ul><li>on a new drug or biologic in the US </li></ul></ul><ul><ul><li>for a new indication or different route of administration of an already approved drug </li></ul></ul>
  8. 8. Regulatory Strategy <ul><li>A regulatory strategy is a reverse-engineered document. Start from the outcome desired and work backward through a schedule of key pieces that are necessary to realize that outcome. </li></ul><ul><li>The key pieces are: </li></ul><ul><ul><li>Indication </li></ul></ul><ul><ul><li>Route of administration </li></ul></ul><ul><ul><li>Dose </li></ul></ul><ul><ul><li>Safety data </li></ul></ul>
  9. 9. Regulatory Strategy <ul><li>The regulatory strategy is developed by key players in the development process. Each area needs planning and coordination with the other players to ensure that the required information or materials are assembled and available at the appropriate times. The key players are Chemical Syntheses, Toxicology/Biology, Clinical and Regulatory. </li></ul>
  10. 10. Regulatory Strategy <ul><li>Chemistry – necessary components </li></ul><ul><li>Route of synthesis – identify the RSM </li></ul><ul><li>Specifications – for Raw Mats and Product </li></ul><ul><li>Reference standards </li></ul><ul><li>Analytical Methods – Release and In-Process </li></ul><ul><li>Quantity needed? GLP and Clinical? </li></ul><ul><li>Formulation </li></ul><ul><li>Stability </li></ul>
  11. 11. Regulatory Strategy <ul><li>Biology – necessary components </li></ul><ul><li>Preliminary pK/TK, in-vitro data </li></ul><ul><li>Species and duration based on intended clinical dose and duration </li></ul><ul><li>GLP Toxicology studies, two species </li></ul><ul><li>Schedules – animals, rooms, test material availability, pathology and reporting </li></ul>
  12. 12. Regulatory Strategy <ul><li>Clinical – necessary components </li></ul><ul><li>Route of administration – oral, IV, topical </li></ul><ul><li>Lead clinician selected </li></ul><ul><li>Phase I protocol developed </li></ul><ul><li>Previous human experience (if any) </li></ul><ul><li>Clinical sites? International will require BSE/TSE Certifications and Quality Person to release in EU </li></ul>
  13. 13. Regulatory Strategy <ul><li>Regulatory – necessary components </li></ul><ul><li>Form 1571 – IND Application </li></ul><ul><li>Draft Introductory Statement </li></ul><ul><li>CMC writing – copies of labeling for clinic and environmental waiver </li></ul><ul><li>Toxicology/Pharmacology writing – data summaries </li></ul><ul><li>Clinical Protocol </li></ul><ul><li>Investigator Brochure </li></ul><ul><li>Form 1572 – Statement of Investigator </li></ul><ul><li>Format? FDA or CTD </li></ul><ul><li>Accommodation for Annual reports that are required </li></ul>
  14. 14. IND Application <ul><li>Content and Format </li></ul><ul><li>Cover Sheet (Form FDA 1571) </li></ul><ul><li>Table of Contents </li></ul><ul><li>Introductory Statement </li></ul><ul><li>General Investigational Plan </li></ul><ul><li>Investigator’s Brochure </li></ul><ul><li>Clinical Protocols </li></ul><ul><li>Chemistry, Manufacturing and Controls Data </li></ul><ul><li>Pharmacology and Toxicology Data </li></ul><ul><li>Previous Human Experience </li></ul><ul><li>Additional Information </li></ul>
  15. 15. IND Item 7: Chemistry, Manufacturing and Controls <ul><li>Introductory Statements </li></ul><ul><ul><li>Includes signals of known potential risks: chemistry and manufacturing differences between the drug product for clinical use and drug substance used in toxicology trials…. How they affect the safety (impurity) profile </li></ul></ul>
  16. 16. IND Item 7: Chemistry, Manufacturing and Controls <ul><li>Drug Substance </li></ul><ul><li>Description of the properties, formula, structure, and reference standards </li></ul><ul><li>Name of Manufacturer </li></ul><ul><li>Synthesis or formulation </li></ul><ul><li>Specifications/Methods used </li></ul><ul><li>Stability (some data on representative lots) </li></ul>
  17. 17. IND Item 7: Chemistry, Manufacturing and Controls <ul><li>Drug Products </li></ul><ul><li>List of componentsquantitative composition </li></ul><ul><li>Name and address of Manufacturer </li></ul><ul><li>Method of manufacture and packaging (brief) </li></ul><ul><li>Specifications/methods (usually tentative) </li></ul><ul><li>Stability (general) </li></ul><ul><li>Investigational labeling </li></ul><ul><li>Placebo information </li></ul><ul><li>Environmental Assessment (request Exemption) </li></ul>
  18. 18. What is cGMP? Good Manufacturing Practices Shipping/Receiving Raw Mats/Supplies Quarantine-Test-Release Processing - batch records Validated facilities/equip. Good documentation Test product Documentation reviewed by QA - Release/Reject Label and ship to client Archive data and records Wait for FDA to appear
  19. 19. IND Item 8: Non-clinical Pharmacology and Toxicology <ul><li>Pharmacology </li></ul><ul><li>Description of pharmacological effects and mechanisms of action </li></ul><ul><ul><ul><li>- intended use </li></ul></ul></ul><ul><ul><ul><li>general safety </li></ul></ul></ul><ul><li>In Vitro and In Vivo </li></ul><ul><li>Extrapolation to humans </li></ul>
  20. 20. IND Item 8: Non-clinical Pharmacology and Toxicology <ul><li>Toxicology: Integrated Summary </li></ul><ul><li>Description of design and dates when conducted </li></ul><ul><li>Systematic presentation of findings from animal toxicology and toxicokinetic studies - related to any risks </li></ul><ul><li>Signatures, testing locations and compliance statements (GLP) </li></ul>
  21. 21. IND Item 8: Non-clinical Pharmacology and Toxicology <ul><li>Toxicology - Full Data Tabulations </li></ul><ul><li>For each toxicology study that is intended to support safety of the proposed clinical investigation: </li></ul><ul><li>Full tabulation of data suitable for detailed review </li></ul><ul><li>- line listings </li></ul><ul><li>- methods description or study protocol </li></ul>
  22. 22. What is GLP? Good Laboratory Practices Adequate Facility Qualified Personnel - Technical and Quality Unit Protocol and SD Unique Suitable Test Systems Characterized Test Materials/Controls Effective SOPs Accurate/Timely Data Accurate/Complete Report Secure Archives
  23. 23. FDA’s Role Reviewing IND Submissions <ul><li>Regulatory/Scientific Role in Assuring </li></ul><ul><li>Safety of Subjects/Patients </li></ul><ul><li>Adequate clinical program/protocol design </li></ul><ul><li>Quality and integrity of the data </li></ul>
  24. 24. Grounds for IND Clinical Hold <ul><li>Clinical trial or program can be placed on hold for the following reasons: </li></ul><ul><li>IND does not contain enough data to assess safety </li></ul><ul><li>Human subjects are exposed to unreasonable risk </li></ul><ul><li>Investigators not qualified </li></ul><ul><li>Investigator’s brochure is incorrect, misleading, erroneous, or materially incomplete </li></ul>
  25. 25. Causes for Rejection <ul><li>No. 1 cause - safety or excessive risk to patients </li></ul><ul><li>Inadequate or incomplete manufacturing description </li></ul><ul><li>Premature submission - not all data or protocols provided </li></ul><ul><li>Inadequate reports of previous studies </li></ul><ul><li>Inadequate investigational plan </li></ul>
  26. 26. FDA’s Regulatory Aspect - IND <ul><li>Will the product expose human subjects to unreasonable risks when used in limited, early-stage clinical studies? </li></ul><ul><ul><li>Animal pharmacology and toxicology studies </li></ul></ul><ul><ul><li>Manufacturing information </li></ul></ul><ul><ul><li>Clinical protocols and investigator information </li></ul></ul>
  27. 27. Agency Interaction/Meetings <ul><li>As currently codified, there are three meetings that can be requested: </li></ul><ul><li>Pre-IND (PIND) submission meeting – to clarify potential questions concerning any part of the application </li></ul><ul><li>End of Phase II (EOPII) – to develop Phase Three protocol </li></ul><ul><li>Pre-NDA review – to clarify expectations of upcoming submission </li></ul>
  28. 28. Agency Interaction/Meetings <ul><li>In FDA speak: </li></ul><ul><li>Communicate early and often – don’t need to have a formal meeting to get advise </li></ul><ul><li>Agency open to novel approaches to development – witness the GMPs for the 21 st Century initiative, especially risk management approaches in ICH documents </li></ul><ul><li>Honesty – put problems “out there”; they will likely find them anyway and you will lose the “trust” of the reviewers </li></ul><ul><li>Don’t bring your lawyers – the regulators have more </li></ul><ul><li>than you do! </li></ul>
  29. 29. Regulatory IND Process <ul><li>Thank you for your invitation to </li></ul><ul><li>present at your meeting. </li></ul><ul><li>Are there any questions that I may address? </li></ul>