Drug Submissions: Review Process

Agnes V. Klein, MD

Biologics and Genetic Therapies Directorate

February, 2003

www/hc-sc.gc.ca/hpb-dgps/therapeut

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

Introduction The Regulatory Organizations The Regulatory review

What is it? Purpose? Health of the Public Information/Promotion

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?

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….

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 (format and 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…

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

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 happens upon 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

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

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.

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:

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.

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