BioEntrepreneurship: Navigating the Global Regulatory Pathway


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Speaker: Anne Tomalin, BA, BSc, RAC (US, CAN & EU), President of CanReg Inc.

Topics Addressed

* Planning ahead to add credibility and value with your partners, investors and outside experts
* What is the landscape of various filings for a drug, a medical device or a diagnostic device?
* Developing a multi-disciplinary project team to manage your regulatory strategy:
o Different strategies for different products
o How to formulate a sound path to drug development decision-making
* What is needed for approval of a medical device
* The preclinical studies required for an IND filing
* The multiple components of the actual IND submission
* Management and communication between the teams assembling the IND
o When to outsource and bring in consultants
* Interacting with the regulatory authority

Download an audio file of this presentation at:

Published in: Business

BioEntrepreneurship: Navigating the Global Regulatory Pathway

  1. 1. MaRS BioEntrepeneurship Lecture Series: Navigating the Global Regulatory Pathway Anne Tomalin President, CanReg Inc. January 15, 2007
  2. 2. CanReg Inc. Dedicated exclusively to global regulatory affairs ! ! Founded in 1996; based in Dundas, Ontario ! Approximately 100 in-house employees
  3. 3. Agenda Drug Development Overview ! ! Conducting Clinical Trials • United States • Canada • Europe Marketing Applications ! • United States • Canada • Europe Q&A !
  4. 4. Drug Development Phases of Drug Development ! Exploratory research and Preclinical (animal) Pharmacology Studies • Preclinical Toxicology Studies • Phase I Clinical trials • Phase II Clinical trials • Phase III Clinical trials •
  5. 5. Drug Development Exploratory Research ! • Identification of drug molecules, characterization of their biological and pharmacological activity • May include preliminary toxicology screens • Decision on candidate drugs for further development • NOT subject to Regulatory approval, no requirements to tell the Regulatory Authorities what you are doing EXCEPT: – studies that will eventually used in support of a New Drug Application/Submission/Marketing Authorization may need to follow Good Laboratory Practice (GLP) guidelines
  6. 6. Drug Development Animal Pharmacology ! • Studies are usually conducted in animal models in support of the efficacy of a product for a given indication (i.e. pharmacology tests). • Many of these studies will ultimately fall under the requirements for GLP.
  7. 7. Drug Development Pre-clinical Toxicology Testing ! • Must be conducted under GLP if you are planning to use the study in support of an IND/CTA or NDA/NDS/MA submission OR, provide some justification for why GLP was not followed • Once you reach a point where an IND/CTA is being submitted, the Regulatory Agency expects to see this data • No need to inform the Regulatory Agency of toxicology studies or results prior to this stage HOWEVER, it may be a good strategy to ask the FDA in particular about design of preclinical testing, particularly if your product is unique e.g. recombinant proteins
  8. 8. Drug Development Pre-clinical Toxicology Testing ! CASE STUDY: You are developing three candidate new chemical entities (NCEs) for treatment of type II diabetes, and have conducted preliminary toxicology tests as part of your screening process. Drug Candidate 1 shows major toxicity problems in an animal toxicology study. The other two candidates do not show these problems. Do you need to inform the FDA of Candidate 1’s toxicity profile?
  9. 9. Drug Development Good Laboratory Practices (GLP) for Nonclinical ! Laboratory Studies • 21 CFR 58 • Describes how animal studies should be conducted and documented. • Covers such items as organization and personnel, facilities, equipment, test and control articles, protocols, records and reports including sample and record retention. • Final study reports contain a certification where the laboratory supervisor signs off that the study was conducted under GLP. • Facilities that carry out animal toxicology studies can be inspected by the FDA. • Preliminary pharmacological screening, preliminary metabolism studies, pilot studies (e.g. dose-ranging) do not have to follow GLP.
  10. 10. Drug Development Phase I studies ! First in man • Healthy volunteers • Cannot be done until an IND/CTA is in place • This is the first point at which there is a legal requirement for the • Regulatory Agency’s involvement in the drug development process
  11. 11. Drug Development Phase I studies ! • Protocols for Phase I studies, with the supporting animal data, will be reviewed by the Regulatory Agency for safety aspects. • The Regulatory Agency will decide if there is sufficient information to ensure the there is a reasonably low risk to human subjects. • There is a recognition of the need for flexibility in study design at these early stages of development.
  12. 12. Drug Development Do all animal toxicology studies need to be completed prior ! to starting Phase I trials? CASE STUDY: You plan to initiate the first Phase I trial for a NCE in 24 healthy male volunteers, age 18 to 35. You will be using a single dose of 100 mg and collecting blood sample for out to 24 hours to measure pharmacokinetic parameters. What animal toxicology studies do you need to complete in order to support this trial?
  13. 13. Drug Development ICH Guideline that relates to timing of nonclinical studies in ! preparation for clinical trials: • M3 Nonclinical safety studies for the conduct of human clinical trials for pharmaceuticals. • Amount of information needed is decided on a case by case basis.
  14. 14. Drug Development Phase II and III Clinical Studies ! • Studies in patients • Involves efficacy as well as safety evaluation • Increasing numbers of patients as drug development progresses NOTE: The different “Phases” of development are used by Industry and the Regulatory Agency as convenient terms to describe clinical trials. There is considerable flexibility in the definitions of these Phases within the regulations.
  15. 15. Drug Development Phase II and III studies ! • During review, Phase II and III studies are scrutinized for efficacy as well as safety aspects. • These studies can be put on clinical hold if it is felt the study design is flawed. • By the time you reach Phase III, the clinical endpoints of your trial will be used to determine the indication for your product. These are often major points of discussion between the Agency and the sponsor.
  16. 16. Drug Development Do the different phases of drug development need to be ! conducted in order? CASE STUDY: Your company has just completed two large-scale Phase III studies in support the safety and efficacy of a NCE for the treatment of asthma. Your clinical team then comes to you to submit a Phase I Protocol for this NCE. – Is this allowed under the regulations? – What kind of study might they be planning to do?
  17. 17. Drug Development Regulatory requirements for the conduct of clinical trials: ! • Covered in Good Clinical Practice (GCP) Guidelines • Also covered in US Regulations (21 CFR 312 Subpart D), Canadian Regulations and European Regulations – describes the responsibilities of those conducting clinical trials
  18. 18. INDs & Drug Development Details and documentation about how a Sponsor conforms to ! requirements for Good Clinical Practice (GCP), IRB approval, and informed consent are not required to be submitted with an IND. For example, copies of signed informed consent forms, ! monitoring reports from study sites, etc. What is required is a certification on the part of the Sponsor and ! the Investigator that they agreed to comply with all relevant regulations. Clinical sites can be inspected by the FDA, and documentation ! would need to be provided at that time.
  19. 19. Conducting Clinical Trials
  20. 20. Clinical Trials in the United States
  21. 21. INDs & Drug Development ! Regulations and Guidelines that Relate to INDs ! 21 CFR: ! CFR 312 Investigational New Drug Application ! CFR 58 Good Laboratory Practices ! CFR 50 Institutional Review Boards (IRBs) ! CFR 56 Informed Consent ! CFR 320.31 Bioequivalence ! ICH Guidelines on Good Clinical Practice ! Guidelines on Clinical Trial Design and Nonclinical Testing (FDA and ICH)
  22. 22. INDs & Drug Development ! IND Application ! The IND is essentially an exemption from the FD&C Act that allows an unapproved drug to be shipped in interstate commerce ! In practice, you are submitting technical information on your product to the FDA to allow them to assess the risks to human subjects ! Once an IND is submitted, trials cannot begin until 30 days have passed ! INDs are not approved ! If after 30 days the IND has not been put on “clinical hold”, the IND “becomes effective” and the trial can begin.
  23. 23. INDs & Drug Development ! Exemptions: ! Off label use of approved drugs by physicians (within the practice of medicine) ! Clinical investigations of approved drugs, provided that ! The information is not intended to support significant changes in labeling or advertising ! The trial does not involve a change in the patient population, the route of administration, or a change in the dosage level which might increase risk ! Certain bioavailability studies (generic drugs)
  24. 24. INDs & Drug Development ! CLINICAL HOLDS (21 CFR 312.42 ) ! A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation, or to suspend an on-going investigation ! The Agency can impose a clinical hold for a Phase I study if There is unreasonable risk to human subjects ! The Investigators are not qualified ! The Investigator Brochure is erroneous, misleading or materially ! incomplete The IND does not contain sufficient information to assess risks ! ! The Agency can impose a clinical hold for a Phase II or III study if Any of the above conditions for Phase I Clinical holds applies ! If the study protocol or plan is clearly deficient in design to meet its ! stated objectives
  25. 25. INDs & Drug Development ! In the US, the IND is a dynamic document, and is as much a process as a submission ! Associated with a drug development program rather than a specific protocol ! For example, once an IND is open for a particular drug and indication, multiple protocols can be submitted to the same IND ! There is no “wait time” associated with protocols sent in to an already existing IND
  26. 26. INDs & Drug Development ! Reflects the dynamic nature of drug development ! Non-clinical investigation continues in parallel with clinical development ! Chemistry and Manufacturing changes from small scale to commercial scale ! IND requirements increase with increased clinical development ! The FDA expects to be informed of clinical progress and new information
  27. 27. INDs & Drug Development ! Common issues/questions that arise for US INDs ! What kind of supporting data do we need to submit a US IND for a Phase I study? ! First in man ! Healthy volunteers
  28. 28. INDs & Drug Development Treatment INDs ! Emergency Use INDs !
  29. 29. INDs & Drug Development ! How to put together an IND submission ! Relevant Sections of the CFR: ! CFR 312 Investigational New Drug Applications 312.23 (original submission), 312.30, 312.31, 312.32, 312.33 ! Relevant Guidelines: ! Content and format of INDs for Phase I studies for drugs, including well-characterized, therapeutic, biotechnology-derived products INDs for Phase 2 and 3 studies of drugs, including specified therapeutic ! biotechnology-derived products. Chemistry, manufacturing and controls content and format [DRAFT GUIDANCE]
  30. 30. INDs & Drug Development ! The IND Submission ! The key components are the Pharmacology and Toxicology background information, the Study Protocol, and the Chemistry and Manufacturing information
  31. 31. INDs & Drug Development ! The Submission Process ! Submission is placed in color-coded accupress binders; these are available from the FDA for a fee ! The first submission is given a serial number 000; volumes are labeled 1.1, 1.2, 1.3 etc. ! Pages should be numbered sequentially starting with 001 ! A typical submission for a Phase I study with supporting Pharm/Tox data might be 5 to 10 volumes in length (versus 1 or 2 volumes for a Canadian CTA). ! The application is sent to the FDA in triplicate.
  32. 32. INDs & Drug Development ! Once the IND arrives at the FDA: ! It will be assigned a 5-digit number such as 64,295. This number opens up a file or docket for that product and indication. ! You will receive a letter that the IND has been received, with the date of receipt.
  33. 33. INDs & Drug Development ! Once the IND arrives at the FDA: ! A review team will be assigned to the project Project Manager - non-reviewer, acts as a regulatory coordinator, your ! main contact for the IND Medical Reviewer - usually acts as team leader ! Pharmacology/Toxicology ! CMC ! Biopharmaceutics - only if needed !
  34. 34. INDs & Drug Development ! Once the IND arrives at the FDA: ! The team will review the package, and a consensus will be reached on the acceptability of the IND ! Any comments/advice received are usually from individual review teams ! Example, comments from CMC reviewers
  35. 35. INDs & Drug Development ! The IND is a dynamic process ! Any further correspondence related to the IND goes in under that number, and should be labeled as sequential serial numbers e.g. Serial 001, Serial 002 ! There are four main kinds of updates, or Amendments, which are submitted to INDs
  36. 36. INDs & Drug Development !Types of Amendments ! Protocol Amendments ! Information Amendments ! Safety Reports ! Annual Reports
  37. 37. INDs & Drug Development ! Meetings with the FDA during drug development ! The FDA is obligated to provide an opportunity for meeting with Sponsors on request at specific stages during development Pre-IND meeting ! End-of Phase II Meeting ! Pre-NDA Meeting !
  38. 38. INDs & Drug Development ! By the time a product has reached the NDA stage, it is well-known by the review team ! In most cases, the same individuals will review your NDA ! An advantage for the FDA, since they are mandated to review NDA applications within fixed timelines (target times 6-10 months)
  39. 39. INDs & Drug Development ! THINKING AHEAD ! How to position your product for an NDA ! Pose questions on requirements for certain animal and Phase I studies ! Agree ahead of time with the FDA on clinical endpoints and their relationship to the intended indication ! Be aware of how formulation changes will impact on the acceptability of your animal and early phase human data - will bridging studies be needed?
  40. 40. INDs & Drug Development ! THINKING AHEAD ! Maintain needed clinical trial documents (e.g. financial disclosure forms) for filing and for review of NDA ! Develop labeling (i.e. package insert) as early in the process as possible
  41. 41. INDs & Drug Development ! The US versus the rest of the world- What is harmonized and what is not? ! Harmonized: ! GCP ! Informed consent ! ADR reporting ! Many clinical trial and animal study guidelines ! Not harmonized: ! Actual IND application packages ! Concept of multiple protocols in one IND versus one application per Protocol ! Requirements for INDs at early stages of development (different for different countries)
  42. 42. Clinical Trials and Canada
  43. 43. Clinical Trial Applications When required ! • For clinical trials in Phases 1 through 3 • Includes trials involving marketed products where the proposed use is outside of the NOC or DIN application • Applies to companies and researchers/physicians When not required ! • Phase IV • Practice of Medicine
  44. 44. How Are Clinical Trials Approved? A Clinical Trial Application (CTA) must be filed. ! Approved or rejected within 30 days. ! Each study is its own CTA. !
  45. 45. Phase I Studies Target: review comparative bioavailability trials ! and Phase I trials in healthy adult volunteers within 7 days. • Except: Somatic cell therapies, xenografts, gene therapies, prophylactic vaccines or reproductive and genetic technologies. Trial must have a No Objection Letter (NOL) to ! start.
  46. 46. Pre-CTA Consultation Can be requested at any time ! ! Particularly useful for NCEs or complex studies ! Also useful if you have not filed a study before ! Sponsor can present data and get input from HPFB
  47. 47. TPD - CTAs Received + Outcome (1999-2005) 2000 1500 1000 500 0 1999 2000 2001 2002 2003 2004 2005 # CTAs No Objection Not Satisfactory Withdrawn
  48. 48. BGTD - CTAs Received + Outcome (1999-2005) 300 250 200 150 100 50 0 1999 2000 2001 2002 2003 2004 2005 # CTAs No Objection Not Satisfactory Withdrawn
  49. 49. Bioequivalence Studies - TPD 1200 1000 800 600 400 200 0 2002 2003 2004 2005 Bioequivalence
  50. 50. Phases of Other Studies - TPD 350 300 250 200 150 100 50 0 2002 2003 2004 2005 Phase 1 - 7 Phase 1 - 30 Phase 2 Phase 3
  51. 51. Phases of Other Studies - BGTD 140 120 100 80 60 40 20 0 2002 2003 2004 2005 Phase 1 - 30 Phase 2 Phase 3
  52. 52. Filing a CTA (cont’d) Module 1 ! • 1.1 Table of Contents • 1.2 Application Information – 1.2.1 Drug Submission Application Form & Appendices – 1.2.2 Information on Prior-related Applications – 1.2.3 Investigator’s Brochure* – 1.2.4 ! For Pharmaceuticals, Protocol Synopsis (PCERT) ! For Biologicals, Submission Rationale/Brief Summary
  53. 53. Filing a CTA (cont’d) Module 1 ! • 1.2Application Information (con’t) – 1.2.5 Study Protocol(s)* – 1.2.6 Informed Consent Document(s) – 1.2.7 Clinical Trial Site Information – 1.2.8 Canadian Research Ethics Board(s) Refusals – 1.2.9 Foreign Refusals – 1.2.10 Letters of Access – 1.2.11 Other Application-related Information
  54. 54. Filing a CTA (cont’d) Module 2 ! • For a CTA, this module reflects Quality (Chemistry & Manufacturing) Information only. • 2.1 CTD Table of Contents • 2.2 CTD Introduction – N/A • 2.3 Quality Overall Summary*
  55. 55. Filing a CTA (cont’d) Module 3 ! • 3.1 Table of Contents • 3.2 Body of Data – Any additional Quality information should be provided here. ! 3.2.R.1 Production Documentation ! 3.2.R.1.1 Executed Batch Records ! These should be provided if possible. • 3.3 Literature References – for Biologicals and Radiopharmaceuticals only.
  56. 56. CTA Amendments/Notifications Sponsor proposes information to support changes ! to a previously approved application. ! May involve • Clinical trial supplies • Changes to protocol • Both Amendments require a 30 day review ! ! Notifications can be made immediately and notify Health Canada within a 30 day period.
  57. 57. Labelling Requirements Investigational Drug. To be used by Qualified ! Investigator Only. Drogue de recherche. Reservée uniquement à l’usage de chercheurs competents. Name, number or identifying mark of drug ! Expiry date ! Storage conditions ! Lot number ! Name and address of sponsor ! Protocol Number ! Radiopharm requirement !
  58. 58. Premature Discontinuation If trial is discontinued, must notify Directorate ! in 15 days. ! Notification must include: Rationale • Impact on proposed trials in Canada • Confirmation that distribution stopped • Confirmation that unused drug returned • Confirmation that investigators notified •
  59. 59. Records Must be kept for 25 years. !
  60. 60. Research Ethics Board Men and women ! At least 5 members ! Majority Canadians or Canadian residents ! 2 Scientific – 1 MD • 1 Ethics • 1 Canadian law • 1 Community • 1 Lay Person •
  61. 61. Who Will Be Inspected? Sponsors ! ! Contract Research Organizations ! Site Management Organizations ! Up to 2% of all Canadian trial sites will be inspected each year • 80 inspections per year (approx 4000 trials)
  62. 62. How Will Compliance Be Assessed? Measured against GCP in Division 5 and ICH. ! ! Average time of one week per inspection. ! Most inspections will be announced. ! Unannounced inspections will be conducted at discretion of Health Canada.
  63. 63. Clinical Trials in Europe
  64. 64. Clinical Trial Submissions In Europe Like Canada, you submit your protocol, Investigator’s ! Brochure, and summaries of the rest of the data. • Full toxicology or clinical reports are not required, nor is full Quality data.
  65. 65. Process for Ethics Committee SPONSOR ETHICS COMMITTEE Obtains Eudra CT number Response to Request Valid Application Max + Application 60 days Single Request for additional information
  66. 66. Timelines for Ethics Committee Maximum of 60 days Standard Products Gene therapy +30 days Somatic cell therapy Genetically Modified Organisms +90 days External consultations No time limit Xenogenic cell therapy
  67. 67. Process for Competent Authority Authorisation SPONSOR COMPETENT AUTHORITY Obtains EudraCT number Amended Application Max Valid Application 60 Days Application Grounds for non-acceptance No amendment application rejected
  68. 68. Process for Competent Authority Authorisation Max 60 days Standard Products “tell and do” Products defined in Max 60 days, Part A, 2309/93, or with but written authorisation special characteristics Gene therapy +30 days Somatic cell therapy Genetically modified organisms +90 days Committee Consultation No time limit Xenogenic Cell Therapy
  69. 69. Process for Clinical Trial Applications in EU Notification totoCA Notification toCACA Notification toCA Notification to CA Notification to CA Notification to CA Notification to CA CA Notification Authorisation from Non acceptance Proceed if ethics committee has given positive Positive opinion and if no Apply for Sponsor grounds for EUDRACT non-acceptance Number Application from competent Application Ethics Application to to ApplicationApplication to authority to Application Committees Ethics Ethics Ethics Application to Application to CommitteesEthics Committees to Application Ethics Application to Application to CommitteesEthics Committees to Application Ethics Ethics Application to Application to Committees Ethics Committees to Application Ethics Ethics Application to Committees to Committees Ethics Committees Application to Application Application to to Application Ethics Application to Committees to Committees Ethics Committees Application to ApplicationApplication to Ethics Ethics Ethics Single request for Committees to Committees Ethics Committees Application to Application to ApplicationApplication to Application Ethics Ethics Ethics Committees to Committees Ethics Committees Application to Committees Application Application toApplication to to Ethics Ethics Ethics Application Committees to Committees Ethics Committees Ethics Committees Application Application Ethics toApplication to to Ethics Information (clock stopped Ethics Committees Ethics Committees Application Committees Ethics Committees Ethics Committees to Ethics Committees Committees to Ethics Ethics Committees Committees to Ethics until receipt of info.) Committees Committees Committees Committees Committees Maximum 60 days
  70. 70. Process for Clinical Trial Applications in EU Fees are payable at national level Procedures to get favorable opinion from Ethics Committee and authorisation from Competent Authority can be run in parallel Fees are not excessive but substantial costs due to general increase in bureaucracy and the need for Investigational Medicinal Products to comply with GMP requirements
  71. 71. Implications for Clinical Trials Approval of all phases (incl. phase 1 and 4) of studies necessary Request for Authorisation NOT Notification Specific timescales for ethics review IMPs (investigational medicinal products) to comply with GMP requirements
  72. 72. Implications for Clinical Trials Substantial protocol amendments require a positive opinion from Ethics Committee and CA Specific guidance on monitoring and reporting of ADRs
  73. 73. Implications for Clinical Trials Information on content, commencement and termination of trial to be made available to Member State (MS) For multicentre trials carried out in more than one MS simultaneously, a single opinion from each MS required Inspections to assess compliance with GMP and GCP at sites Sets out requirements for consent processes-focus on children and incapacitated adults
  74. 74. Implications for Clinical Trials GMP and IMPs Includes test products, placebos and active comparator products • Authorisation is required for each manufacturing or importation site • by MS where manufacture or importation occurs Appointment of QP required •
  75. 75. Implications for Clinical Trials QP ensures that each batch of IMP is manufactured and checked in • accordance with - Principles and guidelines of GMP as derived from Dir 91/356/EEC - Product Specification file - The clinical trial submission filed with CA (information notified pursuant to Article 9(2) of the Directive)
  76. 76. Implications for Clinical Trials GMP and IMPs • IMPs manufactured in EU or third country require certification from QP • Comparator product from third country require certification from QP • Once product meets requirements, importation into another MS can be done without further checks • Labelling in at least national language (full details in GMP guidelines on investigational products)
  77. 77. Directive 2001/83/EC Section A- General Requirements ! ! Section B - Conduct of Clinical Trials ! Section C- Presentation of Results ! Section D- Clinical Pharmacology ! Section E- Bioavailability/ Bioequivalence
  78. 78. Directive 2001/83/EC Section F - Clinical Efficacy and Safety ! ! Section G - Documentation for applications in exceptional circumstance ! Section H - Post-marketing Experience ! Section I - Well-established Use
  79. 79. Marketing Applications
  80. 80. Marketing Applications Common Technical Document ! – Use of the Common Technical Document is mandatory in Europe and Canada, and highly recommended in the US. ! Module 1: Administrative and prescribing information (region specific) ! Module 2: Summaries and overview ! Module 3: Information on Product Quality ! Module 4: Nonclinical study reports ! Module 5: Clinical study reports
  81. 81. New Drug Applications (NDAs) in the United States
  82. 82. New Drug Applications Types of Applications ! • Biologic Licence Application (BLE) • New Drug Application – Three main types of applications are described in the FD&C Act under Section 505 1. An application that contains full reports of investigations of safety and effectiveness 505 (b) 1 ! ! Most new chemical entities would fall under this category
  83. 83. New Drug Applications Types of Applications ! • New Drug Applications 2. An application that contains full reports of investigations of safety and effectiveness, but where at least some of the information required for approval comes from studies not conducted for or by the applicant and for which the applicant does not have right of reference 505 (b) 2 ! Use of published scientific studies or previous submissions in ! support of an application Can be a modification such as different salt, different formulation, ! different strength
  84. 84. New Drug Applications Types of Applications ! • New Drug Applications 3. An application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics and intended use to a previously approved product ! 505 (j) ! Abbreviated NDAs for generic drugs (ANDAs)
  85. 85. New Drug Applications PDUFA ! – Prescription Drug User Fees Act 1992 – Renewed in the FDAMA of 1997, and is currently up for a further 5-year renewal – Provides a mechanism for the FDA to collect fees to defray the costs of review – Tied to performance goals for review times by the Agency (“PDUFA clock”) ! 10 months for standard review, 6 months for priority reviews, 4 months for manufacturing supplements
  86. 86. New Drug Applications PDUFA ! • User fees required for review of – NDAs – Supplemental NDAs • User fees not required for review of – INDs – ANDAs – Medical Devices
  87. 87. New Drug Applications PDUFA ! • Current fee structure (2001): – Applications requiring clinical data: ~$700,000 – Applications not requiring clinical data: ~$300,000 – US dollars
  88. 88. New Drug Applications PDUFA ! • NDAs that can be exempted from user fees – Some 505 (b) 2 applications – Orphan Drugs – Small business waivers (less than 500 employees including affiliates) - first application only
  89. 89. New Drug Applications Content - Do you have what you need? ! – Many content issues are dealt with during drug development Some common gaps ! – CMC Stability data – Carcinogenicity studies – Long-term clinical studies conducted as follow-ups for safety – Number or adequacy of clinical studies in support of efficacy
  90. 90. New Drug Applications Adequacy of clinical trials ! • The FD&C Act requires that substantial evidence of effectiveness be provided for approval of a new drug: “evidence consisting of adequate and well-controlled ! investigations by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could be fairly stated and responsibly concluded that the drug will have the effect if purports or is represented to have under the conditions of use prescribed, recommended or suggested by the proposed labeling.” (505 (d))
  91. 91. New Drug Applications Adequate and well-controlled investigations ! • Described in 21 CFR 314.126 • An adequate and well-controlled study has the following characteristics: – Clear statement of objectives – Design allows for a valid comparison with a control to provide a quantitative assessment of drug effect ! Placebo concurrent control ! Dose-comparison concurrent control ! No treatment concurrent control ! Active treatment concurrent control ! Historical control
  92. 92. New Drug Applications Adequate and well-controlled investigations ! • Method of selection of patients ensures they have the disease being studied • Method of assigning patients to treatment and control groups minimizes bias and is intended to assure comparability of groups (randomization) • Adequate measures are taken to minimize bias on the part of subjects and investigators(blinding) • Methods of assessing subject’s response are well-defined and reliable • Analysis methods are adequate
  93. 93. New Drug Applications How many adequate and well-controlled clinical trials are ! needed? • Historically, the term “investigations” has been interpreted to mean more than one, and “adequate” has been interpreted to mean reproducible, which also implies more than one • FDA’s “Gold Standard” has been two adequate and well-controlled trials (pivotal trials) for approval of new drugs
  94. 94. New Drug Applications FORMAT - how to put together your application ! • Described in 21 CFR 314.50 • Several guidance documents available: – Formatting, assembling and submitting new drug and antibiotic applications – Format and content of the summary for new drug and antibiotic applications – Format and content of the nonclinical pharmacology/toxicology section of new drug and antibiotic applications; also for Human PK and BA, Clinical Microbiology, Clinical and statistical sections, CMC • CTD is the recommended format at this time.
  95. 95. New Drug Applications Application and Review Process ! • Before sending in your application: – Request an NDA number Unlike IND numbers that are assigned to the submission after it is sent ! in, the NDA number is assigned ahead of time, and you can use this number as an identifier throughout the application Request user fee number ! – Send in User fee cheque to Mellon Bank, Pittsburgh
  96. 96. New Drug Applications Application and Review Process ! • Once submission arrives, it will be screened for completeness (60 days) – FDA can refuse to file for reasons of incompleteness • If accepted for review, you will receive a letter stating that the application has been accepted for review. • The log-in date is the reference date used for the “PDUFA clock”.
  97. 97. New Drug Applications Application and Review Process ! • Transition from the IND – If an IND is in place, usually the same review team will be involved, including the project manager – Already have a contact in place to ask about the status of the submission – Can inform them that the NDA is being submitted, and when.
  98. 98. New Drug Applications Application and Review Process ! • QUESTIONS FROM REVIEWERS – During the review, the FDA will communicate with applicants about scientific, medical and procedural issues. This communication can take the form of letter, telephone calls or meetings – It is the intent of the Agency to provide notification of easily correctable deficiencies during the course of review – Not as formalized in response time as the Canadian clarifaxes.
  99. 99. New Drug Applications Application and Review Process ! • AMENDMENTS – If a revision, addition or change is sent to the NDA prior to approval, it is referred to as an Amendment – Amendments can be in response to requests from reviewers for more information – If any amendment is substantial, the FDA can stop the PDUFA clock. For example, there may be situations where additional studies may be agreed to, which would add time to the review.
  100. 100. New Drug Applications Application and Review Process ! • Advisory Committee Meetings – Sometimes, the Agency will make use of non-FDA employees to help in the review process – These are usually experts in the field (i.e. medical or scientific specialists) – Usually, the involvement of an Advisory committee is decided at some point in the drug development phase
  101. 101. New Drug Applications Application and Review Process ! • Advisory Committee Meetings – These meetings are open forums, open to the public Including competitors and stockholders ! – An Advisory Committee only has recommending power – However, in practice, 98% of the time if a Committee recommends a course of action, the FDA follows their recommendation – Transcripts and tapes of these meetings are available (public information)
  102. 102. New Drug Applications Application and Review Process ! • Approval letter – Can contain agreements for further work • Approvable letter – An indication that the NDA is basically approvable, providing that certain issues are resolved – Changes to labeling (package insert) a common requested change – 10 days to respond Notify an intent to file an amendment to address the issues ! Withdraw application ! Request a hearing !
  103. 103. New Drug Applications Application and Review Process ! • Not-approvable letter – This letter will describe deficiencies in the application – Can respond as for approvable letter: Notify an intent to file an amendment to address the issues ! Withdraw application ! Request a hearing !
  104. 104. New Drug Applications Application and Review Process ! • Post approval commitments – There are defined requirements that are required after approval of a drug. These include safety updates and annual reports, and apply to all applications – There can also be specific agreements made between the FDA and sponsor to conduct additional studies or follow-up as a Phase IV commitment; these commitments are specific to a given NDA – For example, to comply with pediatric rule, if studies have not already been conducted in pediatrics, it is not uncommon for there to be an agreement to carry out these studies post-approval – These agreements are spelled out in the approval or approvable letter
  105. 105. New Drug Submissions (NDSs) in Canada
  106. 106. The Review Process Log in ! • Takes 10 days. • Everything received; No. given Screening ! • The submission is screened to ensure the quality of the submission is sufficient for review. • Generally takes 45 days.
  107. 107. The Review Process Documents Issued at Screening ! • Clarifax – This is a document that clarifies minor questions. – Generally 10-15 days to respond. • Screening Deficiency – This means that there is a major discrepancy in the data. – Company has 45 days to respond. – Submission then undergoes a further 45 day screen. • Acceptance for Review • Submission Withdrawal
  108. 108. Name Review Health Canada will review the Brand and Generic name ! of your drug for “look alike / sound alike” problems. ! This will occur within 90 days of acceptance of your submission. ! Another review of the names will occur within 90 days of approval of your submission.
  109. 109. Legibility From slides by Dr. Lesar, NY Unasyn or Vancomycin? Protonix or Protamine? Capoten or Cozaar?
  110. 110. The Review Process Both the CMC and the Clinical portions of the ! submission are reviewed by a primary reviewer. ! A second reviewer usually reviews the submission to provide a second opinion.
  111. 111. The Review Process Documents Issued During Review ! • Clarifaxes – These faxes are intended to deal with minor questions. – Usually have 15 days to respond. • Notice of Deficiency – Intended to identify major missing data. – Company has 90 days to respond. – Clock stops and restarts when data is submitted.
  112. 112. The Review Process Documents issued at the end of review ! • Notice of Compliance – This indicates that the submission is approved and sale of the product can commence. • Notice of Non-Compliance – Company has 90 days to address major questions – Submission goes back through screening and review. – If issues not addressed at this stage, submission is withdrawn.
  113. 113. Priority Submissions / Conditional NOCs Applies to serious, life-threatening or severely ! debilitating disease for which no drug is available or which is not currently adequately managed. ! Manufacturer submits a written request to Director of Bureau (Pharmaceutical Assessment or Biologics/Radiopharmaceuticals). ! Priority = all data available ! Conditional = promising data available • Company commits to developing full data
  114. 114. NOC-c’s Approved to Date Year HIV/AIDS Cancer Orphan CV Other 1998 2 1999 1 1 1 1 2000 1 2001 1 1 2002 3 2003 1 2 2004 1 1 2005 1 1 Total 5 8 3 1 2
  115. 115. NOC-c’s Withdrawn 3 were withdrawn ! • 2 were for cancer – Casodex – for safety reasons – Iressa – surrogate marker was not related to prolonged survival. Product was not withdrawn. A subpopulation did respond • 1 Cox II – Celebrex for prevention of recurrence of colorectal polyps – DSMB stopped study – Indication was withdrawn
  116. 116. NDS Targeted Time Frames Class Screen 1 Review 1 Screen 2 Review 2 Priority 25 180 25 90 NOC/c 25 200 25 90 NAS 45 300 45 150 Clin/C&M 45 300 45 150 Comp/C&M 45 180 45 150 C&M/Label 45 180 45 150 Label 7 60 0 0 Admin 45 0 0 0
  117. 117. Average Approval Time - Drugs - NDSs 1000 800 600 400 200 0 2001 2002 2003 2004 2005 Priority NAS NAS
  118. 118. Average Approval Time - Biologics - NDSs 1800 1600 1400 1200 1000 800 600 400 200 0 2001 2002 2003 2004 2005 Priority NAS NAS
  119. 119. Average Approval Time - ANDSs 700 600 500 400 300 200 100 0 2001 2002 2003 2004 2005 ANDS
  120. 120. Biologic and Genetic Therapies Directorate How are biologic submissions different? ! Still NDS. • Require a pre-approval inspection. • Require information on manufacturing facility. • Require samples. • Will require some degree of post-approval release. • Reviewed by the BGTD • Sometimes require toxicity in primates (immune) issue • Require an annual report •
  121. 121. NDSs Abbreviated New Drug Submission Applies to products that are ! Pharmaceutical equivalent • Bioequivalent • Given same route of administration • Sold for the same conditions of use to Canadian Reference Product •
  122. 122. ANDSs Canadian Reference Product A drug which has an NOC and is marketed in ! Canada by innovator. ! Another drug acceptable to the Minister where the Canadian drug is no longer marketed. ! Another drug acceptable to the Minister, where it can be proven that it is the same as the Canadian drug.
  123. 123. ANDSs Declaration of Equivalence NOC for an ANDS states the Canadian reference ! product and constitutes a “declaration of equivalence” for the new product. This is very important from a provincial perspective. ! Provinces are moving to stop bioequivalence reviews at a provincial level.
  124. 124. ANDS Comprehensive Summary Physicochemical Characteristics ! Pharmacology ! Pharmacokinetics ! Drug Product Classification (conventional, etc.) ! Summary of Bioequivalence Studies !
  125. 125. Subsequent Entry Biologics SEB means a biologic product that would be similar to ! and would enter the market subsequent to an approved innovator product. ! BGTD is working to develop a comprehensive regulatory framework for SEBs.
  126. 126. Subsequent Entry Biologics SEBs are subject to all requirements for biologics ! • File NDS • Extent of the clinical data required may be different. • Key factors – Choice of the innovator product – Design of comparability studies – Details of the clinical data provided • Less clinical data may be required for products that are shown clearly to be very similar to the innovator
  127. 127. Subsequent Entry Biologics Data Requirements ! • Complete CMC • Rational for choice of the innovator biologic • Sufficient characterization information to demonstrate both chemical and biological comparability • Sufficient comparative animal toxicity data, where appropriate • Pharmacodynamic data to demonstrate comparable bioactivity • Pharmacokinetic data to demonstrate comparable bioavailability • Immunogenic profile of the SEB in humans • Clinical package
  128. 128. Exclusivity As of October 5, 2006, new drugs will have a minimum ! period of market exclusivity of 8 years. • Includes a 6 year no filing provision for generic submissions. An additional 6 months of data protection is available as a ! pediatric exclusivity. These regulations were published in draft form on June 17, ! 2006 Effective date is June 17, 2006. !
  129. 129. Basic Exclusivity Only applies to “innovative drugs”, i.e., new molecular ! entities Combinations of previously approved medicinal ingredients ! are not eligible for an additional data protection period. Biologic drugs are included within the scope of innovative ! drugs. Protection only applies if drug is marketed in Canada. ! Registry of innovative drugs, similar to the Orange book, will ! be established.
  130. 130. Pediatric Exclusivity Additional 6 months for drug submissions filed within ! the first 5 years of the 8 year protection period, if • Clinical trials were designed and conducted with the purpose of increasing knowledge about the use of the drug in pediatric populations.
  131. 131. NDSs Cost For Review Preclinical/Clinical Fee ! Preclinical & Clinical data: $117,000 • Clinical only: $52,900 • Clinical with supplementary preclinical: $52,900 • Comparative clinical, PD or PK: $17,200 • Published clinical references: $2,200 • Additional ! • Additional route, dosage form or indication – Supported by additional clinical: $52,900 – Supported by comparative clinical, PD or PK: $17,200
  132. 132. NDSs Cost For Review CMC for drug substance: $11,500 ! CMC for dosage form: $15,300 for each dosage form !
  133. 133. Marketing Authorizations in Europe
  134. 134. Types of Marketing Applications Centralized Procedure ! Decentralized Procedure ! National Procedure* !
  135. 135. EMEA & Centralized Procedure EMEA = European Medicines Agency ! • CHMP – Committee for Medicinal Products for Human Use – One member per member state • Committee for Orphan Medicinal Products
  136. 136. Centralized Procedure Obligatory for ! • Biotech products • Orphan medicinal products • New Active Substances for – AIDS – Cancer – Neurodegenerative disorders – Diabetes – Auto-immune diseases & other immune dysfunctions (as of May 20/08) – Viral diseases (as of May 20/08)
  137. 137. Centralized Procedure Optional ! • If the medicinal product is a significant therapeutic, scientific or technical innovation • If the granting of a centralized Marketing Application is of interest at the Community level to patients health (e.g., completely new OTC product) • Other New Active Substances
  138. 138. Timelines in the Centralized Procedure Opinion issued 210 days from receipt of valid ! application to CHMP. ! Timeline can be extended, if justified. ! Accelerated Assessment: time limit reduced to 150 days. • Decision making process shortened from 3-4 months to around 2 months.
  139. 139. Transparency in Centralized Procedure Publication of withdrawal ! ! Publication of refusal ! Publication of Assessment Report, reasons for its opinion in favour of granting authorization
  140. 140. Decentralized Procedure European Phase ! • Report is issued within 90 days of receipt of valid application. • Report, Summary of Product Characteristics (SmPC), labelling and package leaflet sent to Concerned Member States (CMSs) and the applicant. • CMSs have 90 days to approve the assessment report, SmPC, etc. The national decision has to be adopted within 30 days ! after the “European Phase” has ended.
  141. 141. Decentralized Procedure Covers all medicinal products not authorized in the EU ! for which the Centralized Procedure does not apply. Applicant can select the Reference Member State ! (RMS) and lists CMSs. • The RMS is the state that will be the primary reviewer of the submission. Once selected, withdrawal from selected countries is ! not possible.
  142. 142. Timetable in Decentralized Procedure Discussion with RMS Before Day -14 ! ! Submission to RMS & CMSs, validation Day -14 ! ! of dossier RMS starts procedure Day 0 ! ! RMS forwards Preliminary Assessment Day 70 ! ! Report (PAR) & draft SmPC, package leaflet and labelling to CMSs. CMSs send their comments ! Until Day 100 ! Consultation between RMS, CMSs & ! Until Day 105 ! applicant. If consensus, procedure ends. Otherwise clock stop.
  143. 143. Timetable in Decentralized Procedure Restart of clock after receipt of final Day 106 ! ! responses. RMS sends Draft Assessment Report, Before Day 120 ! ! SmPC, package leaflet and labelling to CMSs. End of procedure if consensus reached. ! Day 120 ! National decision to be adopted. ! Day 150 !
  144. 144. Timetable in Decentralized Procedure Start of Assessment Step II. Day 120 ! ! CMSs send final comments to RMS Day 145 ! ! Close of procedure if consensus Day 150 ! ! reached. National approval within 30 days. Day 180 ! If no consensus reached, RMS ! communicates outstanding issues to applicant and prepares report for discussion at Coordinating Group. Until Day 205 Break out group of involved member ! ! states reach consensus. If consensus, closure of the procedure. Until Day 210 ! ! National approvals within 30 days.
  145. 145. Disagreement Between RMP and CMPs In case member state cannot agree on grounds of a ! potential serious risk to human health • Detailed statement of the reasons shall be provided to RMS, other CMSs and applicant. • Points of disagreement shall be referred without delay to the Coordination Group.
  146. 146. Coordination Group Responsible for the examination of any question ! relating to the marketing authorization of a medicinal product in two or more member states. ! Secretariat provided by EMEA ! One representative per member state ! Renewable period of 3 years.
  147. 147. Procedure in Case of Disagreement Until Day 210 ! • Referral to Coordination Group Until Day 270 ! • If consensus reached, procedure will be closed. National approvals within 30 days. If no consensus reached, referral to CHMP for arbitration. CHMP will provide opinion usually within 60 days, but ! can extend period by up to 90 days. ! Member states that have approved the assessment report and labelling of the RMS may, on request of the applicant, grant an MA without waiting for the outcome of the procedure.