Drug Submissions: Review Process

1. Drug Submissions: Review Process Agnes V. Klein, MD Biologics and Genetic Therapies Directorate February, 2003 www/hc-sc.gc.ca/hpb-dgps/therapeut

2. Items for Consideration • Introduction • Screening • In-depth evaluation • Assessment of Benefits and Risks • International Harmonization • Continuous Assessment

3. Introduction • The Regulatory Organizations • The Regulatory review • What is it? • Purpose? • Health of the Public • Information/Promotion

4. Processes • Role of law, science and medicine • Role of Guidelines, Policies, Practices… • Applies to: drugs, biologics, radiopharmaceuticals, medical devices… • Drugs are developed in a more or less linear fashion • International linkages?

5. What is it we actually do…(Demistifying the process) • We ensure the safety, efficacy and quality of ‘drug products’ and the adequacy of their labeling • Why do we do it? For the benefit of Canadians… • We regulate only manufacturers of products (sponsors); we do not regulate the practice of health professions; however we use the guidelines drafted by the medical profession in particular, to help us arrive at decisions….

6. The Review of Submissions • Is the core function of the Regulatory Organizations • What is Submission: types as noted • Can we measure quality? By the completeness and comprehensiveness of format and content. • Format: ensures that data are organized in a manner that will allow, quickly, to ensure that all necessary parts of a submission are present. • Tools: Guidelines, Policies (Mgmt of Submissions Policy) • Structure currently governed by C.08,005.1 (formatand content acceptable to the Minister) • Administrative Screening: ensures accuracy of forms, submissions, certification, legibility, pagination, general usability, completeness of data, appropriate cross-referencing, presence of pivotal trials, presence and completeness of Chem and Mfr. Information, templates, etc…

7. The Review: • New Drug Submissions and compliance with regulations: • A Drug may not be sold unless: • A NDS has been filed, with sufficient information to assess safety, effectiveness and quality…. ,a Notice of Compliance (NOC) has been issued; the “Minister” must notify the manufacturer is the material is insufficient…,additional information may be requested… • A NOC may be suspended for a many reasons of safety, efficacy or quality, of if the information provided turns out to be untrue • Time-frames • Types of submissions

8. In-depth Evaluation of a Submission • Substance of a submission: special review paper • Who reviews submissions? How are they reviewed? • What are the possible outcomes? • What happensupon completion? Depends on the type of submission • Aims of Review/Evaluation • Establish whether data support claim(s) • Define necessary safety measures reflected in the appropriate sections of the PM • Do not assume the new product is effective and safe, just because it belongs to an already established class of drugs

9. Aims of Review/Evaluation • Establish whether data support claim(s) • Define necessary safety measures reflected in the appropriate sections of the PM • Do not assume the new product is effective and safe, just because it belongs to an already established class of drugs

10. In-depth Evaluation • Substance of the clinical portion of a Submission: • Original information generated by a sponsor for purposes of demonstrating the properties (safety and efficacy or profile) of a product and defining the instructions for its use. It can be conceived as a “review paper” of a very specific nature • What is done? • An assessment (validation) of the sponsor’s summary. This is compared against the original database, ensuing summaries and comment; based on rules of evidence, policies, guidances, precedents, etc. • Applies to pre-clinical as well clinical data. • Expectations • Product Monograph/Package Insert/Instructions to Patients.

11. In-depth Evaluation • The review process as a validation exercise that seeks to prove consistency of conclusions from trials conducted and that needs to place the new therapeutic entity within the context of existant therapies for a disease. • Benefit-risk assessment: a standard for the quality of the information provided: This is where science and medicine meet with statistics, where conclusions can be strengthened or weakened; where reality and perception meet; where policy and risk must be concordant; where ethics and regulation come to forefront, where the Therapeutic Index and the Therapeutic Window encounter patient outcomes, where clinical relevance meets statistical significance, where the place of the ‘new product’ within extant therapies may be defined. • Outcomes:

12. Other comments: • International collaborations: • Regulatory agencies: FDA, EMEA, TGA, • Other: ICH, CIOMS, etc. • ICH: Purpose and Objective; accomplishments to date • The Product Monograph: • Priority Reviews and NOC/Cs • Purpose, scope, status • Other collaborations • Post marketing issues: Adverse Reaction Monitoring: voluntary with multiple limitations; Signal Generation: ( WHO, Cdn ADR program, other Regulatory Agencies, publications, media;) • Purpose:To have an up to date risk-benefit profile of a product, up to date information in the Product Monographs; up to date information to be provided to Health Professionals and Public.

13. Conclusions: • We consider that, in general, we serve the public well • Issues: • Timeliness of Review • Occasional disagreements with Industry • Reality of Risks vs Perceptions of Risk • How to best communicate with public in general and dispel misperceptions