Regulatory Process Biobootcamp CBSA / Fitzsimons / FBBp / Holland & Hart Lauren C. Costantini, Ph.D. LCC Consulting, LLC

Transcription

1 Regulatory Process Biobootcamp CBSA / Fitzsimons / FBBp / Holland & Hart Lauren C. Costantini, Ph.D., LLC

2 This Discussion Regulatory Processes Rationale for requirements to move a product through development R & D, Preclinical, Manufacturing, IND, Clinical, NDA, Commercialization *Lessons learned Success stories and what it took Failure stories and what went wrong How to avoid potential challenges 2

3 The Food and Drug Administration Help for the little guys: Small Business Assistance Programs in 5 FDA regional offices; workshops Small business assistance offices in each of the Centers opmentapprovalprocess/ SmallBusinessAssistance/ default.htm Pragmatic; dialogue; prepare 3

4 Interacting with the Agency Answer questions rather than assume Months of project time and money can be wasted due to guessing what the FDA will say. Pre-IND Meeting Not required but nip issues in the bud Ensure preclinical package supports planned clinical trials *Lesson Learned no pre-ind mtg - LT tox for polymer as well as drug Prepare well The Bibles Freedom of Information (FOI) Summary Basis of Approval (SBA) Advisory Panel meetings Go in with YOUR plan, not open arms! Critical to get FDA buy-in prior to trial start re: sample size, endpoints, stats (what is success?) 4

5 The Bibles Code of Federal Regulations The rules by the executive departments and agencies of the Federal Government. It is divided into 50 titles that represent areas subject to Federal regulation Examples: President, Domestic Security, Aliens and Nationality, Federal Elections, Banking, Aeronautics, Commerce and Foreign Trade, Securities Exchanges, Customs, Foreign Relations, Food and Drug, etc Guidance Documents Represent the Agency's current thinking on a particular subject. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. International Conference on Harmonization Regulatory authorities & industry experts from Europe, Japan and US; to achieve greater harmonisation in requirements, reduce duplicate testing, make more economical use of resources, and eliminate unnecessary delay in global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations. 5

6 The Bibles : CFR FDA Jurisdiction: Title 21 Parts 1 to 99. General regulations for the enforcement of the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act. Color additives. Parts 100 to 169. Food standards, good manufacturing practice for foods, low-acid canned foods, acidified foods, and food labeling. Parts 170 to 199. Food additives. Parts 200 to 299. General regulations for drugs. Parts 300 to 499. Drugs for human use. Parts 500 to 599. Animal drugs, feeds, and related products. Parts 600 to 799. Biologics and cosmetics. Parts 800 to Medical devices and radiological health. Regulations under the Federal Import Milk Act, the Federal Tea Importation Act, the Federal Caustic Poison Act, and for control of communicable diseases and interstate conveyance sanitation. Parts 1300 through end. Drug Enforcement Administration regulations and requirements. 6

7 The Bibles : Guidance Documents Divided into Drug, Device, Vaccines/Blood/Biologics Content and Format for IND (BLA, PMA, etc) Applications Nonclinical Studies for the Safety Evaluation of a Pharmaceutical, Animal Models Microbiology, Pharm/Tox, Clinical Pharmacology Clinical Data for Marketing Application, Clinical Endpoints for Indications, Special Protocol Assessment, Drug Safety, Adverse Event Reporting, Bioequivalence, Drug Interaction Studies, Using IRBs Chemistry, Manufacturing, and Controls (CMC) Good Manufacturing Practice (GMP), Release Specs, Combination Products Labeling, Advertising, Promotion Generics, Over-the-counter Electronic Submissions Formal Meetings, Formal Disputes, Clinical holds Specifics: Clinical Development Programs for Drugs, Devices, and Biologics for the Treatment of Osteoarthritis 7

8 The Bibles : ICH Safety Carcinogenicity, Genotoxicity battery, Toxicokinetics, ReproTox, Pharmacokinetics, Dose and Duration; Quality Stability, Dissolution, Sterility, Validation of Analytical Procedures, Impurities, Extractables, Particulate Contaminants, Microbiology, Analysis of Expression Constructs in Cell Lines, GMP Efficacy General Considerations for Clinical Trials, Statistical Principles for Clinical Trials, Choice of Control Group in Clinical Trials, Dose-Response Information to Support Drug Registration, Clinical Safety Data Management, Case Safety Reports, Post-Approval Safety Data Management, Content of Clinical Study Reports, Factors in Acceptability of Foreign Clinical Data, Studies for Special Populations (Geriatric, Pediatric), Pharmacogenomics, Biomarkers related to Drug Response, GCP, Specifics: Extent of population exposure to assess clinical safety for drugs intended for long-term treatment of non-life-threatening conditions 8

9 The Bibles : CFR and ICH Handbooks online US FDA Code of Federal Regulations & EU ICH Handbooks Mix & Match CFRs, Guidance Documents, Manuals 9

10 The Bibles : Guidance Documents online Drugs: ances/default.htm Devices: cedocuments/default.htm Vaccines, Blood, and Biologics: yinformation/default.htm 10

11 R & D No regulatory requirements, however DOCUMENT EVERYTHING Start the SOP (Standard Operating Procedures) process Go/no-go decision for a candidate takes into consideration The Funnel 11

12 Preclinical: Product Development No regulatory requirements at this PRECLINICAL stage, however DOCUMENT EVERYTHING CMC section of IND requires history of where the product came from For example, cell therapies: Donor documentation Cell banking Safety testing (sterility, endotoxin, viability) Tracking and follow up 12

13 Preclinical: GLP Good Laboratory Practice (Non-clinical laboratories) In the 1970s, FDA inspections of nonclinical laboratories revealed that some studies submitted in support of the safety of regulated products had not been conducted in accord with acceptable practice, and that accordingly data from such studies was not always of the quality and integrity to assure product safety. Regular inspections and data audits to monitor laboratory compliance with the GLP requirements (~every 2yrs) Organization, personnel, Quality Assurance (QA), facilities, equipment, operations, reagents/solutions, animal care, test and control articles, protocols and conduct, records and reports, computer systems Establishment inspection reports (EIRs): FDA 483 lists inspectional observations 13

14 Preclinical: Product Development Non-GLP/GMP for most of this process API, Excipients, Materials Formulation dev Analytical method dev Stability & Dissolution Product Specs GLP Batch & Scale up 14

15 Preclinical: Animal Studies Animal POC/prelim safety Proof your candidate works and is safe Lab or CRO Animal PK/PD/ ADME Bioanalytical assay dev and validation CRO validate Reprotox/ Mutagenicity/ Carcinogenic. Proof your candidate is safe CRO - GLP Compatibility Devices, combo products, drug delivery CRO - GLP Animal Tox Full safety; therapeutic index for initial clinical starting dose; acute and chronic ; 2 species CRO - GLP 15

16 Manufacturing: GMP for Clinical Good Manufacturing Practice for clinical trial product CGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product. The regulations make sure that a product is safe for use, and that it has the ingredients and strength it claims to have. Assures: Identity, Strength, Quality, Purity of drug products Personnel, QC, Facility, Equipment, Record keeping, Controls, Packaging and Labeling, Inventory FDA inspects facilities before a drug can be approved 16

17 Manufacturing: GMP for Clinical *Lesson Learned new equipment was sticky This will be QC Product release specs GMP CMO selection Batch records API and Product specs GMP Active and placebo production Tech transfer; order equipment; practice run ; Sponsor and CMO are responsible for quality *Lesson Learned sausage knife; cheese Packaging and Labeling for clinical trial Equipment cleaning validation Stability GMP Active and placebo release Separate vendor; coordination is key 17

18 Manufacturing: Common Problems Raw Material Qualification Failed Vendor Qualification Intellectual Property Concerns Solubility Problems Low Yield Poorly Defined Production System Inadequate Purification Schemes Unvalidated or Non-Existent In Vitro Potency Assay Lack of Key Reagents Stability Difficulty doing in vitro 18

19 Clinical Trials: GCP Good Clinical Practice for clinical trials Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects. Compliance with GCP assures that the rights, safety, and well-being of trial subjects are protected and that the clinical trial data are credible. This International Conference on Harmonization (ICH) guidance provides a unified standard for the European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in those jurisdictions IRB, Protocol Format, Investigator, ICF, Records, Safety Reporting, Sponsor, QA and QC, CROs, Trial Design, Data Management and Monitoring Committee, Compensation to Subjects and Investigators, Submission to agency, AE Reporting, Monitoring, Statistics, Ethics, IB, Essential documents before, during, and after the trial 19

20 The Meetings : Getting the most out of your tax dollars Type A (highest priority): Critical path meeting immediately necessary for an otherwise stalled development program (clinical holds, dispute resolution, special protocol assessment) Type B: Pre-IND meetings, some Ph1 meetings, End-of-PhII meetings, Pre-NDA/BLA meetings Type C (lowest priority): Other than a Type A or Type B meeting 20

21 Pre-IND Meeting: Sleep better at night Not required for submission of IND Address issues critical to filing an IND (and approval) Decreases chance of clinical hold due to CMC, toxicology or clinical trial design issues Particularly important for novel products/indications 21

22 Pre-IND Meeting: Logistics Telecon or face-to-face Sponsor sends request; FDA schedules mtg w/in 60d of request; mtg date determined w/in 14d of request Pre-IND package due 30d prior to mtg Similar to IND package (next slide) but only tox PLANS Thus do not request until you have package almost complete! FDA may cancel mtg if incomplete package FDA sends responses Sponsor can keep or cancel meeting (keep!) 22

23 Pre-IND Meeting: When to go? Prior to initiating GLP toxicology studies ($$) Obtain FDA s input regarding: Choice of animal model Dose and regimen Sample size Assessment parameters Too early: not enough preclinical data to have meaningful discussion; FDA may change requirements by the time Sponsor submits IND Too late: insufficient time to incorporate FDA s advice into IND 23

24 IND Table of Contents 1 Form FDA 1571 [21 CFR (a)(1)] 2 Table of contents [21 CFR (a)(2)] 3 Introductory statement [21 CFR (a)(3)] 4 General investigational plan [21 CFR (a)(3)] 5 Investigator's brochure [21 CFR (a)(5)] 6 Protocol(s) [21 CFR (a)(6)] a. Study protocols [21 CFR (a)(6)] b. Investigator data [21 CFR (a)(6)(iii)(b)]a c. Institutional review board data [21 CFR (a)(6)(iii)(b)]a 7 Chemistry, manufacturing, and control data[21 CFR (a)(7)] 8 Pharmacology and toxicology data [21 CFR (a)(8)] 9 Previous human experience [21 CFR (a)(8)] 10 Additional information [21 CFR (a)(10)] IND is in effect after 30 days, unless placed on clinical hold by FDA 24

25 Pre-IND Meeting: Your questions Go in with YOUR plan, not open arms! What feedback do you want and need? Be specific Size of safety database? Requirements for special population trials? Drug-drug interactions? Divide them by subject Preclinical, Clinical, CMC Critical to get FDA buy-in prior to trial start re: sample size, endpoints, stats (what is success?) Listen! The agency often has recent and valuable information 25

26 After Pre-IND Meeting Conduct GLP toxicology studies and final reports for IND submission Finalize clinical protocol for IND submission Prep for clinical trial (Timelines!) Confirm CMC/GMP manufacturing for clinical trial Write IND Most is finished if you had a pre-ind mtg! 26

27 NDA Pre-NDA meeting nip remaining issues in the bud Submission of NDA (volumes and volumes of information) Tell drug's whole story: what happened during clinical tests, what are the ingredients, results of animal studies, how drug behaves in body, how it will be labeled, how manufactured, processed and packaged. Submission is still not a guarantee Advisory Committee Meetings (next slide) Label negotiations Politics *Lesson learned - politics of stem cells and GMO Review: FDA accepts the filing or sends Sponsor a refusal-to-file letter within 60d; if accepted for filing, various sections undergo concurrent review; approval time differs... 27

28 FDA Advisory Committees Novel or complex products or indications Meetings occur prior to approval Sponsor: prepares briefing packet summarizing clinical data Committee: experts in the field FDA: reviewers assigned to NDA present their interpretation of data; ask questions to committee FDA sometimes takes recommendation, but not always *Lessons Learned - if bad news, do not fret - APPROVED! 28

29 Approved! PARTY! Label negotiations Post-Market safety Post-market trials (Phase IV, surveillance, registries) Post-market compliance RMP Sales and Distribution 29

30 Label Negotiations You already drafted an ideal label early in development to assure the studies conducted will support your indication Final label may look very different from initial label Labels have become increasingly complex and lengthy 30

31 Balancing Act Valley of Death Tight budgets often call for short cuts in development Pay now or Pay later Taking too many shortcuts may require additional studies ($) later, or may inhibit partnering with those that have $ *Lesson learned too many to count! 31

32 Conclusions DOCUMENT DOCUMENT DOCUMENT Review FDA Regulations early in development The translation of discoveries to products will occur more efficiently (and with less stress!) Start with the final product label in mind Global submission strategy 32

33 BACKUP/DETAILED SLIDES 33

34 Pre-IND package - CMC Chemistry: description, physical and chemical characteristics, biological activity (potency) Manufacturing: general outline of the manufacturing procedure, raw materials, cellular and animal source materials, process description, process control, consistency of manufacture Control: methods, release specifications, reference standards, impurities profile, stability Other CMC issues: differences between product used in preclinical studies and clinical studies, immunogenicity assay development 34

35 Pre-IND package - Preclinical Goal of the pharmacology/toxicology program is to support the safety of the proposed clinical study Pharmacology: desired pharmacological effect Toxicology: rationale for starting dose, dose range, safety Drug distribution Include summary data for completed preclinical studies Provide overview of proposed/ongoing preclinical studies 35

36 Pre-IND package - Preclinical Address which studies conducted under GLP GLP required for pivotal toxicology studies GLP not necessary for proof-of-concept and preliminary toxicology studies Need for special evaluations: histopathology, recovery samples Need for long-term studies: reproductive toxicology, carcinogenicity, mutagenicity 36

37 Pre-IND package - Clinical The proposed IND study is usually a Phase 1, first-in-human study If clinical studies have already been initiated outside the US The proposed study may be a Phase 2 or Phase 3 study Package will include presentation and discussion of clinical data 37