Clinical Program Director UCB BioSciences Principal Advisor reus BioPharma

Transcription

1 Clinical Program Director UCB BioSciences Principal Advisor reus BioPharma J. Margaretha Oortgiesen ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

2 Strategic Planning in Regulatory Affairs J. Margaretha Oortgiesen Clinical Program Director UCB BioSciences Principal Advisor Qureus BioPharma

3 Regulatory Intelligence USA: Strategic Regulatory Considerations 11 December 2014

4 Learning outcomes USA BACKGROUND: The US FDA, mission, organization, scope of products TACTICAL CONSIDERATIONS: IND/NDA applications & implications for non-us companies STRATEGIC CONSIDERATIONS: Regulatory mechanisms, working with the FDA; Working with Partner organizations & CROs 4

5 Agenda BACKGROUND The US Food and Drug Administration (FDA) TACTICAL CONSIDERATIONS IND Applications Marketing Applications STRATEGIC CONSIDERATIONS Regulatory mechanisms Working with the FDA 5

6 Food and Drug Administration United States FDA Part of US Department of Health & Human Services Lead be commissioner Margaret Hamburg Website: 6

7 FDA Mission and Activities MISSION: To promote and protect the public health (helping safe and effective products reach the market in a timely way). To monitor products for continued safety (post-authorization) To advance public health (helping to speed innovations that make medicines more effective, safer and more affordable) To help the public receive accurate science-based information (to improve their health) ACTIVITIES: New Product Review -Review of Data Keeping Watch -Safe manufacturing, distribution and handling Keeping Watch Monitoring for New Risks Standards and Regulations Research Enforcement: Actions to Protect Public Health

8 Scope of Products Regulated Drugs (Prescription and Over-The-Counter) Biologics Vaccines Blood products Biotechnology products, cell products, and gene therapy Medical Devices Food Veterinary products Consumer and Medical Radiation Products Cosmetics 8

9 How does FDA achieve its mission? For prescription drug/biologics products: IND regulatory process NDA/BLA regulatory process Postmarketing surveillance of drug safety

10 FDA Organization and Centers Eight Centers/Offices: Office of the Commissioner (OC) Office of Regulatory Affairs (ORA) Center for Biologics Evaluation and Research (CBER) Center for Drug Evaluation and Research (CDER) Center for Devices and Radiological Health (CDRH) Center for Food Safety and Applied Nutrition (CFSAN) Center for Veterinary Medicine (CVM) National Center for Toxicological Research (NCTR) 10

11 Center for Drug Evaluation and Research (CDER) CENTER DIRECTOR: Janet Woodcock, M.D. (DBNA) Offices: OFFICE OF REGULATORY POLICY OFFICE OF MANAGEMENT OFFICE OF COMMUNICATIONS OFFICE OF COMPLIANCE OFFICE OF MEDICAL POLICY OFFICE OF TRANSLATIONAL SCIENCES OFFICE OF EXECUTIVE PROGRAMS OFFICE OF COUNTER-TERRORISM AND EMERGENCY COORDINATION OFFICE OF SURVEILLANCE AND EPIDEMIOLOGY OFFICE OF NEW DRUGS OFFICE OF PHARMACEUTICAL SCIENCE OFFICE OF PLANNING AND INFORMATICS 11

12 Center for Biologics Evaluation and Research (CBER) CENTER DIRECTOR: Karen Midthun, M.D. Management: DEPUTY DIRECTOR ASSOCIATE DIRECTOR FOR MEDICINE ASSOCIATE DIRECTOR FOR POLICY ASSOCIATE DIRECTOR FOR QUALITY ASSURANCE ASSOCIATE DIRECTOR FOR RESEARCH ASSOCIATE DIRECTOR FOR REVIEW MANAGEMENT SENIOR ADVISOR FOR COUNTERTERRORISM/MEDICAL COUNTERMEASURES SENIOR ADVISOR FOR INTERNATIONAL AFFAIRS SENIOR SCIENTIST FOR EMERGING & PANDEMIC THREAT PREPAREDNESS EXECUTIVE OPERATIONS STAFF Offices: OFFICE OF MANAGEMENT OFFICE OF COMPLIANCE AND BIOLOGICS QUALITY OFFICE OF BLOOD RESEARCH AND REVIEW OFFICE OF CELLULAR, TISSUE, AND GENE THERAPIES OFFICE OF VACCINES RESEARCH AND REVIEW OFFICE OF COMMUNICATION, OUTREACH AND DEVELOPMENT OFFICE OF BIOSTATISTICS AND EPIDEMIOLOGY 12

13 Center for Devices and Radiological Health (CDRH) Devices: primary intended purposes notthrough chemical action within or on the body Classification 510K PMAs Radioactive products Diagnostics Companion diagnostics Combination products Drug-device combination products Biologics-device combination products 13

14 Food Product Categories Food Foods for Special Dietary Uses Infant formulas, weight loss products Medical Foods Specific dietary management of a disease Nutritionally complete products, oral rehydration formulas Dietary Supplements Vitamins, minerals, botanicals Nutraceuticals* Functional Foods* *These terms are widely used in the marketplace. Such foods are regulated by FDA under the authority of the FD&C Act, even though they are not specifically defined by law.

15 FDA Regulations & Guidances Food, Drug, and Cosmetic (FD&C) Act Federal Law; sets broad legal requirements Regulations (21 CFR) Prescribes specific legal requirements; codified in Code of Federal Regulations. The CFR presents the official and complete text of the Agency s regulations into an organized publication Guidances IND (Title 21 CFR 312) NDA/BLA (Title 21 CFR 314/601) ANDA (Title 21 CFR 320) 505(b)(2) (Title 21 CFR ) PMA (Title 21 CFR 814) Represent FDA s current thinking on a given subject 15

16 Code of Federal Regulations (CFR) Organization and Content Title Broad subject area of an Agency» Title 21 (Food and Drugs) Part Rules on a single program or function» Part 312 (Investigational New Drug Application) Section Basic unit of the CFR» (IND Safety Reports) Paragraph Specific Requirements» (c)(2) (Telephone and facsimile transmission safety reports) 16

17 TACTICAL CONSIDERATIONS 17

18 IND Clinical Trial/Program Initiation Investigational New Drug (IND) Application An IND to test the diagnostic or therapeutic potential of an investigational new drug/biological in a clinical investigation New Chemical Entity (NCE) Approved Drug New indication Unapproved doses New dosage form Change in route of administration Change in dose regimen Pre-IND Meeting: Opportunity to have early discussion with FDA on your product, the preliminary development plan and any issues you would like to obtain guidance/advice Nonclin, CMC, Clin, Reg IND: Described in 21 CFR Part 312 (Investigational New Drug Application) 18

19 What is an IND? Document through which the drug sponsor alerts the FDA of its intention to conduct clinical studies with an investigational drug. Summation of data to support clinical exposure for drug not previously authorized for marketing in the U.S. Promise of compliance and to do no harm In legal terms, the IND is a request for an exemption from the federal statue that prohibits an unapproved drug from being shipped in interstate commerce

20 When is an IND NOT required? The clinical investigation of a marketed drug or biologic does not require submission of an IND provided all six of the following conditions are met: It is not intended to support a new indication for user or to support any other significant change in the labeling It is not intended to support a significant change in the advertising for the product It does not involve a route of administration or dosage level, use in the subject population, or other factor that significantly increases the risk associated with the use of the drug product It is conducted in compliance with the requirements for IRB review and informed consent It is conducted in compliance with the requirements concerning the promotion and sale of drugs It does not intent to invoke 21 CFR (exceptions from informed consent requirement for emergency research) 20

21 IND Clinical Trial/Program Initiation Types of INDs Sponsor (Company/Corporate) IND Investigator (Research) IND (named investigator is Sponsor) Emergency Use IND (named patient/compassionate use, bypasses IRB) Treatment IND (multiple patients for an indication being studied under regular IND) Exploratory IND (micro-dosing in Phase 0) Initiation of Clinical Trials Sponsor (company) may begin trials 30 days after filing IND, unless otherwise notified by FDA During development, maintain ongoing communication with FDA to help guide the program (e.g., EOP 1/2 meetings) 21

22 IND Application IND Content Paper or electronic CTD or 21 CFR 312 format Form FDA 1571 Contains the signature of the Sponsor or the Sponsor s authorized representative 22

23 IND: Scientific Technical Sections Pharmacology & Toxicology Chemistry, Manufacturing & Controls Microbiology Clinical Typical IND for a NCE: ~ 2,800 3,200 pages Drug Regulatory Application Statistics Human Pharmacokinetics and Bioavailability

24 ectdstructure Overview

25 Sponsor Obligations Sponsor Person who takes responsibility for an IND to initiate a clinical investigation Signed off on Form FDA 1571 General Sponsor Responsibilities: Select qualified investigators; provide them with information they need to conduct investigation properly Ensure proper monitoring of the investigation(s) Ensure that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND Maintain an effective IND Comply with safety reporting requirements 25

26 Implications for Non US Company If you do not have your place of business in the USA, you will need to appoint a US Agent The US Agent can be an individual, firm or company physically located in the United States. The Agent is legally responsible for the IND The Sponsor must inform FDA in writing of the name and address of the US Agent The US Agent acts as the company representative and signs all the IND application forms (1571s) and is the contact point of FDA 26

27 IND Review Process Summary FDA does not approve INDs IND is in effect after 30 days (unless placed on clinical hold) Based on calendar no holidays allowed! Clock begins when submission is logged into FDA Document Control Room Clinical hold may occur at any point in the life of the IND and may affect a single study or the entire IND FDA Communication May occur at any time during the course of the IND review Clarifications are usually sought during the review process with the goal of avoiding clinical hold Comments are advisory unless accompanied by a clinical hold order

28 Possible Outcomes of IND Review No Action Passive Approval Deficiency Letter Identifies problems that might, if not resolved, potentially justify the use of clinical hold Due to short review time, rarely used during 30 day review clock Information Request Letter Clarification request for more information whose absence would not justify a clinical hold Advice Letter Recommendations for ongoing or proposed clinical studies or protocols for which no response is necessary Clinical Hold

29 IND Status Active Development program is being actively pursued Clinical investigations are ongoing Inactive Development program is not active Sponsor request FDA Action No subjects entered in to clinical study for a period of 2 years; or All investigations under IND are on Clinical Hold for 1 or greater Clinical Hold FDA order to delay suspend clinical investigations under IND Withdrawn Sponsor Action All clinical investigations under IND must be discontinued Terminated FDA Action IND deficiencies can not be resolved

30 Maintaining the IND Must be updated continually Safety Information Ongoing clinical trials Types of modifications to IND Protocol Amendments Change in previously submitted protocol Add new protocol to original IND IRB approval required prior to implementation

31 Maintaining the IND (2) Types of modifications to IND - continued Information Amendments IB updates New information about study drug CMC information, nonclinical studies, final clinical study report Report new information not ordinarily included in protocol or IND safety report submissions Changes/updates to contact information FDA Form 1572s Letter of cross reference IND Safety Reports Serious and unexpected Adverse Events (AEs) Inform FDA and all participating investigators Annual Reports Yearly submission Within 60 days of effective IND anniversary date Includes enrollment, demographic and conduct status information for each study AE summaries (safety reports, deaths, dropouts) Preclinical study status

32 Marketing Applications New Drug Application (NDA) Biologics Licensing Application (BLA) Premarket Approval Application (PMA)

33 Marketing Application -FDA Review When to file NDA: File at completion of all 3 phases (with exception of accelerated approval) 21 CFR Part 314 (Application for FDA Approval to Market a New Drug) 21 CFR Part 601 (Licensing) FDA has 60 days to accept or refuse to file FDA assembles the Review Team with review schedule shared with sponsor Role of an Advisory Committee To provide Independent advice that will contribute to the quality of the agency s regulatory decision-making and lend credibility to the product review process 33

34 Marketing Application -FDA Review 34

35 NDA/BLA Review Actions Refusal to File <60 days after submission Not Approvable letter List deficiencies in application why product can not be approved based on current submission Approvable letter Signals that product ultimately can be approved. Lists minor outstanding deficiencies (i.e., label, Phase 4 commitments) Approval letter 35

36 NDA/BLA Action Timelines NDA/BLA Action Timeline Priority Review (6 mo) Standard Review (10 mo) PDUFA -Prescription Drug User Fee Act Fee to be paid upon marketing application submission Shortened review timelines 36

37 STRATEGIC CONSIDERATIONS 37

38 Approval/Review Pathways Type of approval Regular Approval Accelerated Approval Filing/review type Fast Track Designation Priority Review Standard Review 38

39 Regular Approval On completion of Phase 3 clinical studies Full data package Application with sufficient data to demonstrate» Safety and Efficacy» Clinical Benefit 39

40 Accelerated Approval Intended to make promising products for life threatening diseases available on the basis of preliminary evidence prior to formal demonstration of patient benefit Under Subpart H (21CFR ) & 21CFR Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity A measurement that is considered likely to predict patient benefit Considered provisional approval with a written commitment to complete clinical studies that formally demonstrate patient benefit If studies don t confirm the initial results, the FDA can withdraw approval Post-marketing studies should be underway. Sponsor needs to show diligence in completing studies in a timely manner. Status update may be requested to report at Advisory meeting If confirmatory study shows clinical benefit, FDA will grant regular approval 40

41 Fast Track Fast Track is a process designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life threatening conditions fill an unmet medical need Applies to the product and the indication May be requested at any time during development. An applicant must submit a request ( 60 days review) Emphasizes the close and early communication between the FDA and sponsor to improve the efficiency of product development Benefits include Rolling submission" for a marketing application More frequent meetings with FDA to discuss development plans and ensure collection of appropriate data needed to support approval The option of requesting evaluation of studies using surrogate endpoints (Accelerated Approval) 41

42 Priority Review Priority Review designation is given to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists The goal for completing a priority review is 6 months (versus standard review period of 10 months) A request for priority review is made by the Sponsor at the time of the NDA filing, and the FDA will determine within 60 days whether a priority or standard review designation will be assigned 42

43 Other considerations: Orphan Drugs To treat a rare disease or condition which affects fewer than 200,000 people nationwide (e.g., cystic fibrosis, Lou Gehrig s, Tourette s syndrome, certain cancers) Congress passed the Orphan Drug Act (ODA) in 1983 Applies to drugs and biologics Provides financial incentives, including tax credits for cost of clinical research Seven years exclusivity if approved first (from approval of NDA/BLA) FDA Assistance with Protocol Development Application for Orphan Drug Designation can be filed at anytime during the drug development process (60 days review) May receive Priority Review 43

44 Other Considerations: Animal Rule Human clinical trials are not ethical or feasible, approval based on nonclinical evidence of efficacy Biodefense Poisoning antidotes A type of surrogate endpoint Requires postmarketingstudies to confirm efficacy observed in animals

45 Other Considerations: Pediatrics Drugs marketed in US are used in patients who are less than 18 years old however, less than 25% have an indication for use in children Best Pharmaceuticals for Children Act 2002 Reauthorized the pediatric exclusivity provisions of FDAMA (+ 6 months) All pediatric supplements to receive Priority review Pediatric Research Equity Act 2003 Reinstates the main provisions of the Pediatric Rule Requires pediatric studies of certain drugs and biological products unless waived or deferred Establishes pediatric advisory committee Exemption for Orphan Drugs (c.f. EU where a PIP is required for orphan product) 45

46 General Strategic Considerations Specific wording for the indication: Claims MUST be derived from well controlled studies and supported by primary endpoints Generally required to have conducted at least two (2) adequate and well-controlled studies to support proposed indication, each convincing on its own, to establish effectiveness. Single study is a review issue; the study must be well designed, well conducted, internally consistent and provide persuasive efficacy findings Studies do not have to be identical in design ICH Guidelines versus FDA Guidances Standards of medical practice (e.g. US versus RoW) Placebo versus active comparators Ethnicity (US population versus others) Timing and use of FDA meetings/interactions to optimize drug development and successful reviews (Pre-IND, EOP 1 / 2, SPA) 46

47 WORKING WITH THE FDA 47

48 FDA Project Manager Contact the Head Project Manager in therapeutic area / Division to determine Project Manager for your company/product Main contact at FDA important to establish an open communication and a good working relationship with your key contact at the Agency ( , telephone) FDA Project Managers assigned for IND -by class of drug or based on project workload Role: Logs submissions and distributes for review; coordinates formal FDA meetings; generates FDA official minutes Handles Compassionate Use IND, Research IND Addresses questions/queries from sponsors 48

49 Where to submit IND? CDER Office of New Drugs - Office of Antimicrobial Products (OAP) - Office of Drug Evaluation I Division of Cardiovascular and Renal Products (DCaRP) Division of Neurology Products (DNP) Division of Psychiatry Products (DPP) - Office of Drug Evaluation II Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) Division of Metabolism and Endocrinology Products (DMEP) Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) - Office of Drug Evaluation III Division of Dermatology and Dental Products Division of Gastroenterology and Inborn Errors Products Division of Reproductive and Urologic Products - Office of Drug Evaluation IV Division of Medical Imaging Products Radioactive Drug Research Committee (RDRC) Program - Office of Hematology and Oncology Drug Products

50 Where to submit IND? CDER Office of New Drugs - Office of Antimicrobial Products (OAP) - Office of Drug Evaluation I Division of Cardiovascular and Renal Products (DCaRP) Division of Neurology Products (DNP) Division of Psychiatry Products (DPP) - Office of Drug Evaluation II Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) Division of Metabolism and Endocrinology Products (DMEP) Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) - Office of Drug Evaluation III Division of Dermatology and Dental Products Division of Gastroenterology and Inborn Errors Products Division of Reproductive and Urologic Products - Office of Drug Evaluation IV Division of Medical Imaging Products Radioactive Drug Research Committee (RDRC) Program - Office of Hematology and Oncology Drug Products

51 Types of FDA Meetings Type A: A critical path meeting (eg. Clinical Hold issue) Scheduled to occur within 30 days of FDA s receipt of request Type B: Pre-IND meetings, certain End of Phase 1, meetings, End of Phase 2 / pre-phase 3 meetings, and pre-nda / BLA meetings. Should be scheduled to occur within 60 days of FDA s receipt of request Type C: Any meetings other than a Type A or Type B meeting. Scheduled to occur within 75 days of FDA s receipt of request Note: no charge to FDA 51

52 FDA Meeting Process Give careful consideration to your selection of the proposed date(s) to optimize your choice Consider the merits of Face-to-Face meeting versus Teleconference Attendees from company/advisors/experts/kols Meetings are allocated 1 to 1.5 hours maximum Use allocated time effectively with careful preparations/rehearsals Summarize clearly the agreements and actions to avoid misunderstanding later FDA s minutes are official and binding version Sponsor may submit minutes 52

53 Special Protocol Assessment (SPA) Upon request, FDA will evaluate certain protocol and issues relating to the protocols to assess whether they are adequate to meet scientific and regulatory requirements identified by the sponsor Three types of protocol eligible: Carcinogenicity protocols Final product stability protocols. Clinical protocols for phase 3 trials 53

54 Special Protocol Assessment (2) For clinical study requests, request for SPA to be submitted at least 90 days prior to the anticipated start of the study Additional documents (e.g., Statistical Analysis Plan [SAO],Charters, CRFs) Process: FDA review = 45 days FDA could request for outside consultation with an advisor committee member or an advisory committee meeting Sponsor can request a Type A meeting after receiving FDA feedback If agreement is not reached, need to submit new SPA 54

55 Advisory Committees Public meetings to review: New NDAs, BLAs, new indications for approved products New guidelines relating to therapeutic areas Development issues during INDs (closed session if proprietary information discussed) Non-FDA Members generally academic, mainly MDs plus statisticians and consumer representatives 55

56 FDA: General Principles -1 FDA is very data driven Pre-plan interaction(s) to increase efficiency. Be specific / clear in requests or issues Advice from FDA is only as good as the background information provided Work with FDA in partnership Early discussions to guide the development program Company drug experts FDA s extended knowledge (i.e., access to a lot of data on a large number of drugs) FDA Terminology advise, recommend, suggest, should = must Document interactions with FDA to ensure understanding and for appropriate follow-up, as needed 56

57 FDA: General Principles -2 Start discussions with FDA early in development program. Effective use of FDA meetings, e.g. Pre-IND, EOP 1 and EOP 2 Use various FDA review process to obtain guidance (e.g., Request for SPA) Regulatory advice normally given in a structured way, in a structured process and generally, within a definitive timeframe FDA has a large number of opinion leaders; seek expert advice to refine your program (particularly important at AdCom) US is an important market impact of global climate 57

58 FDA/EMEA Interactions The relationship between the FDA and EMEA has become closer since the end of the 1980s September 2003, confidentiality agreement announced (allowed Agencies to share non-public information, including pre-decision information, early policy documents etc.) Integrated approach taken for clusters of products e.g. oncology, pharmacogenomics, vaccines, veterinary medicines and advanced therapies. Reciprocal staff placement program Aim for the Agencies to not simply receive but to rely on shared information e.g., GCP inspections Increased activity in Risk Management and Pediatrics 58

59 FDA International Interactions Relationships and communications between FDA and other International Agencies are improving/increasing Confidentiality agreements in place between FDA and Health Canada, Mexico, Japanese Ministry of Health Labor and Welfare, Australian TGA, New Zealand, Singapore and several EU MS (e.g. Ireland, UK, France, Belgium, NL, Germany, Austria, Denmark and Sweden. Introduction of overseas posts e.g. Offices in China and India with regional inspectors 59

60 Working with Alliances/Partners/CRO There can be only one Sponsor of a US application Need to clearly define and establish responsibilities of the respective parties and any transfer of Sponsor obligations Contract Research Organization: A person/entity that assumes, as an independent contractor to the sponsor, one or more of the obligations of a Sponsor e.g., monitoring investigations Any transfer of obligations must be described in writing and indicated in the application The Sponsor holds the final/ultimate responsibility Timely sharing of safety data is essential if clinical studies are ongoing in other countries / regions managed by the Partner 60

61 Thank You Questions: Marga Oortgiesen 61

62 FDA WEBSITES/REFERENCES FDA Homepage About the FDA Overview of the FDA: Choose Short Course- A Tour of the FDA 62

63 FDA Internet Address CDER Home Page CBER Home Page CDRH Home Page Code of Federal Regulations Federal Register Notices CDER Guidelines 63

64 FDA Internet Addresses (contd) CBER Guidelines Freedom of Information Enforcement Reports Guide to Inspections Investigators Operations Manual Regulatory Procedure Manual Warning Letters, etc Advisory Committee Meeting Transcripts 64