Leveraging Health Canada s Regulatory Framework to Accommodate Accelerated Product Development for Biologic Drugs

Transcription

1 Leveraging Health Canada s Regulatory Framework to Accommodate Accelerated Product Development for Biologic Drugs Nancy Green, Ph.D. Chief, Hormones and Enzymes Division Biologics and Genetic Therapies Directorate Health Canada

2 Presentation Outline What is Health Canada s Regulatory Framework? How does BGTD use our Regulatory Framework? How does BGTD use our Organizational Model? Examples of Accommodations Future: Orphan Drug Regulations and Guidance in Canada

3 What is Health Canada s Regulatory Framework? Food and Drug Act and Regulations Part C Division 1 Administration Division 2 GMP Division 4 Biologics Division 5 Clinical Trials Division 8 New Drugs There is flexibility in the Regulations regarding the evidence satisfactory to the Minister. Approach must be scientifically justified.

4 Clinical Trial Application Review From Division 5 C g) if the drug has not been assigned a drug identification number under subsection C (1) or, in the case of a new drug, a notice of compliance has not been issued under section C or C , the chemistry and manufacturing information in respect of the drug, including its site of manufacture;

5 A Multi-faceted NDS Quality Review Biologics Quality review is based on 3 pillars Dossier review In-house laboratory testing (the lot release laboratories are housed in our review divisions, they are not separate) On-Site Evaluation (conducted by biologics review staff typically those reviewing the file) These 3 elements of Quality review are leveraged to make rational, science-based risk assessments and develop risk management strategies.

6 Division 8 From C Leveraging Health Canada s Regulatory Framework New Drug Submission Review Dossier (2) A new drug submission shall contain sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug, including the following: (a) a description of the new drug and a statement of its proper name or its common name if there is no proper name; (b) a statement of the brand name of the new drug or the identifying name or code proposed for the new drug; (c) a list of the ingredients of the new drug, stated quantitatively, and the specifications for each of those ingredients; (d) a description of the plant and equipment to be used in the manufacture, preparation and packaging of the new drug; (e) details of the method of manufacture and the controls to be used in the manufacture, preparation and packaging of the new drug; (f) details of the tests to be applied to control the potency, purity, stability and safety of the new drug;

7 New Drug Submission Review Dossier Division 8 From C (continued) (g) detailed reports of the tests made to establish the safety of the new drug for the purpose and under the conditions of use recommended; (h) substantial evidence of the clinical effectiveness of the new drug for the purpose and under the conditions of use recommended; (i) a statement of the names and qualifications of all the investigators to whom the new drug has been sold; (j) a draft of every label to be used in conjunction with the new drug; (k) a statement of all the representations to be made for the promotion of the new drug respecting (i) the recommended route of administration of the new drug, (ii) the proposed dosage of the new drug, (iii) the claims to be made for the new drug, and (iv) the contra-indications and side effects of the new drug; (l) a description of the dosage form in which it is proposed that the new drug be sold; (m) evidence that all test batches of the new drug used in any studies conducted in connection with the submission were manufactured and controlled in a manner that is representative of market production; and

8 Division 8 From C Leveraging Health Canada s Regulatory Framework New Drug Submission Review BGTD Laboratory Testing (3) The manufacturer of a new drug shall, at the request of the Minister, provide the Minister, where for the purposes of a new drug submission the Minister considers it necessary to assess the safety and effectiveness of the new drug, with the following information and material: (a) the names and addresses of the manufacturers of each of the ingredients of the new drug and the names and addresses of the manufacturers of the new drug in the dosage form in which it is proposed that the new drug be sold; (b) samples of the ingredients of the new drug; (c) samples of the new drug in the dosage form in which it is proposed that the new drug be sold; and (d) any additional information or material respecting the safety and effectiveness of the new drug.

9 New Drug Submission Review On-Site Evaluation From Part A Administration A An inspector shall perform the functions and duties and carry out the responsibilities in respect of foods and drugs prescribed by the Act, and these Regulations. From Division 2 GMP C Personnel Every lot or batch of a drug shall be fabricated, packaged/labelled, tested and stored under the supervision of personnel who, having regard to the duties and responsibilities involved, have had such technical, academic, and other training as the Director considers satisfactory in the interests of the health of the consumer or purchaser. Rationale: People are the most important element in any pharmaceutical operation, without the proper personnel with the appropriate attitude and sufficient training, it is almost impossible to fabricate, package/label, test, or store good quality drugs

10 New Drug AND Post-Market Review Biologics Lot release Program For Schedule D (biologic) Drugs C On written request from the Director, every fabricator, packager/labeller, tester, distributor referred to in paragraph C.01A.003(b) and importer of a drug shall submit protocols of tests together with samples of any lot of the drug before it is sold, and no person shall sell any lot of that drug if the protocol or sample fails to meet the requirements of these Regulations.

11 Guidances and Policies to support interpretation of the Regulations Management of Drug Submissions Guidance Priority Review Guidance NOC/c policy Lot Release Program for Schedule D (Biologic) Drugs SEB guidance Leveraging Health Canada s Regulatory Framework ICH Quality Guidances

12 How does BGTD use our Regulatory framework? Type of review granted is based on clinical need NDS (300 calendar day review target) performance standard 90% of cost recovered submissions meet the review targets Priority NDS (review 180 vs. 300 day review target) NDS with NOC/c (Notice of Compliance with conditions) requested in advance based on promising clinical evidence

13 An Experienced, Integrated Quality Review Group

14 Lifecycle Management of Products The Quality review group reviews from CTA to NDS and beyond Allows discussions and advice regarding the strengths and weaknesses of the product and the data supporting the submission to be provided During Pre-submission meetings During Review Post review We are always available to discuss your product.

15 A Multi-faceted Quality Review Biologics Quality review is based on 3 pillars Dossier review In-house laboratory testing (the lot release laboratories are housed in our review divisions, they are not separate) On-Site Evaluation (conducted by biologics review staff typically those reviewing the file) These 3 elements of Quality review are leveraged to make rational, science-based risk assessments and develop risk management strategies.

16 Lot Release: Risk-Based Oversight Activities conducted are rationalized based on the available evidence (product history, use, evidence for consistent manufacture & testing) and documented under our Quality system. Activities are reviewed on an ongoing basis, and the level of product oversight changed as appropriate based on review of consistency of product quality or in response to emerging issues Products which changed release groups in 2013: Group 2 3 (15 products) Group 3 4 (4 products) Group 4 3 (2 products)

17 On-Site Evaluation A Pre-Approval Inspection carried out by BGTD review staff during the submission review (team of 2 or 3). Generally conducted when the product under review is in production Drug Substance Sites are prioritized over Drug Product sites Submissions with novel products/processes, sites and new companies are prioritized Agenda is driven by the production schedule and review issues Generally 40-60% of time in production observing activities, remainder, review of documents and discussion of issues

18 Incomplete Commercial Scale Drug Product Process Validation Issue: Use of active/placebo fills to validate the filling and lyophilization process rather than 100% active due to limited quantity of Drug Substance. Considerations: Clinical trial scale lots available with full stability Lyophilizer validation was considered complete due to placement of active vials in known worst case sites Validations well planned and executed Lab testing results acceptable OSE shows personnel are engaged and understand their challenges Allowed a relevant commercial scale to be approved at the NDS stage.

19 Issue: Wide Specification Ranges High potency (enzyme) assay variability, small number of lots Considerations: Dossier and OSE Increased number of replicates to decrease variability Commitments to re-evaluate substrate, enhance assay controls, and to re-evaluate specifications after 30 lots (file NC) BGTD Lot Release Program Consistency testing gave good results Group 3 lot release to monitor lot-by-lot Allowed first cycle approval with path forward to improve assay

20 Issue from Dossier review: Proposed expiration date not supported by stability data Different rates of change for potency; expiration dating based on pooled data Considerations: OSE Open discussion of the issue with SMEs and decision makers. Briefly, half of all lots on stability, method was improved over time, all lots manufactured predicted to meet shelf life using worst case degradation, suggestions for additional control accepted. Requested Expiration date granted, possible periodic product shortages in Canada avoided

21 Problematic Drug Substance Process Validation Issue from Dossier Review: Process validation reports are missing information, have contradictory information, some process parameters not supported by data, etc. Considerations: OSE Extensive discussion with SMEs. Corrections, changes and additional validation data were provided. Data from all batches produced reviewed and discussed. Clear evidence of commitment to continuous improvement BGTD Lot Release program Consistency testing gave good results Group 3 lot release to monitor lot-by-lot Approval of current manufacturing process and specifications (not those submitted

22 Challenges to Using our Flexibility Clinical Trials not conducted in Canada Pre-NDS meeting held too close to NDS filing to effect meaningful change or not prepared to discuss the Quality information Dossier contains bare bones content for novel or unusual approaches or results Response to Review questions is limited rather than a well reasoned argument regarding the issue On-Site Evaluation not possible (opportunity lost) or poorly supported (SME not available)

23 Challenges to Using our Flexibility If accelerated product development is anticipated, early and ongoing meaningful discussions with sponsors regarding the strengths and weaknesses of their approach and the data is critical for success

24 BGTD is happy to discuss your plans throughout the product lifecycle

25 Current work in Health Canada Orphan Drug Regulations and Guidance document are being written Guidance will address both Clinical and Quality elements

26 Thanks to you for your attention Thanks to current colleagues Jeffrey Skene, Wallace Lauzon and Will Stevens and past colleague Chantal Cazeault for productive discussions over the years Thanks to Jeff for his help with this presentation

27 Questions?