Template for the Submission of Comments
Draft guidance on Ministerial Reliance Order concerning decisions or documents on certain drugs by foreign regulatory authorities:
| Section/line numbers | Comment and Rationale | Proposed Revised Text |
|---|---|---|
| General | The guidance document does not specify the consequences on future submissions once reliance is used. Are there consequences if reliance is only used at certain points of a products lifecycle? Ex: if reliance is used for an NDS, do subsequence S/NDSs for that product need to use Reliance as well? | Include a clarifying statement, such as: “The sponsor’s decision to request deeming for certain information in a submission is made in the context of a specific submission. Subsequent decisions on whether to utilize reliance or standard review for future lifecycle submissions are independent decisions and unaffected by previous leverage of the Order. |
| 244 | Guidance document lacks clarity on what the additional information requested may be. | For clarity, include a cross reference here to the section entitled “Evidence Required for Deeming” i.e. to Line 444. Regarding the second bullet, please provide additional context . |
| Lines 257-258 | “For supplements, the deeming request should refer to information that is significantly different from that previously evaluated by Health Canada”. Since supplements are by definition submissions of significantly important difference from previously approved information, the meaning of this statement is confusing. The statement should be revised to more explicitly clarify the intended meaning. An example may be useful here. | For supplements, the deeming request should |
| Lines 285-287 | “a prior submission or supplement filed by the manufacturer for the proposed Canadian drug has not previously been withdrawn after receiving a notice of deficiency or refusal by Health Canada”. There may be instances where a foreign approval to be relied on has fully addressed and resolved the reason for prior withdrawal or deficiency in an earlier Canadian submission. This appears to be too broadly scoped. A submission should remain eligible for deeming if the sponsor can clearly demonstrate that the previous issues have been fully addressed in the foreign submission eg revised indication, addition of new data to overcome uncertainty. | Revise text as follows: “a prior submission or supplement filed by the manufacturer for the proposed Canadian drug has not previously been withdrawn after receiving a notice of deficiency or non-compliance or refusal by Health Canada, unless the sponsor demonstrates to Health Canada’s satisfaction that the subsequent foreign authorization being relied upon fully overcomes the issues raised by Health Canada previously eg by narrowing the indication, or addition of new pivotal data not previously available to Health Canada.” |
| 308-312 | As currently written, this section could be read to imply that a subsequent decision post deeming to revoke an entry on the IbR lists could impact a prior Health Canada decision based on deeming. Will there be retroactive consequences if a drug class or FRA is removed from the IbR list? Could approval be revoked if a product was reviewed under Reliance and the drug class or FRA was later removed from the IbR list? | Propose to add additional text: Amendments to the IbR lists would only impact future submissions. |
| Line 308 – 317 | This section appears misplaced, and substantially overlaps with the information in lines 349-386. | For clarity and comprehension, move lines 308-317 in the section entitled: “Adding or removing classes of drugs and foreign regulatory authorities” and present each distinct concept only once. |
| 348-349 | The interpretation of the qualifiers in the IbR list is not straightforward, as demonstrated by the need for the document Interpretation of the Incorporated by Reference (IbR) List for pediatric-focused drug classes – Canada.ca. Additional information from the interpretation document should be included directly in the Ministerial Reliance Order guidance document | Include the content under “How qualifiers operate under the IbR List” from the interpretation document directly in the guidance to ensure all relevant information is available in a single source. |
| 394 | ||
| 395 | Who is allowed to submit a proposal for amendments to the IbR list and what is the process for this? BIOTECanada suggests that Health Canada should develop an official process such as through the ongoing Pipeline reporting that industry completes, to propose future submissions that would warrant in IbR list consideration. | |
| 421 | What is the rationale for a 6 month delayed implementation period? It is our understanding that Health Canada has some flexibility to reduce this duration. | |
| 421 | “the date the list will be amended, usually following a 6-month delayed implementation period”. BIOTECanada is in support of a transparent, criteria based approach to maintain and update the IbR lists. Following consultation though, it is not clear that a prolonged period is necessary to complete any mandatory notifications to other jurisdications or to allow Industry time to prepare to comply. | “the date the list will be amended, in line with Health Canada’s IbR policy, and typically within 30-60 days of the notice of intent |
| 476-480 | The guidance states: “Under the Order, manufacturers must state which deeming option they are seeking, if seeking general deeming, they must indicate which set of information they are seeking to have deemed for their drug submission….this information is to be included in the cover letter and submitted with a complete, dated and signed Ministeral Reliance Order Sponsor’s Request and Attestation Form for Human Drugs… To streamline the process, it would be less duplicative if all details required for scoping the request deeming under the Order were captured fully and exclusively within the form. | “Under the Order, manufacturers must state which deeming option they are seeking. |
| 554-561 | Proposed revisions to clarify the wording. | The Order allows manufacturers to request deeming even if there are certain differences between the foreign drug and the proposed Canadian drug. Manufacturers must |
| 515-517 | The guidance indicates that “For joint reviews, manufacturers must clearly state those sets of information examined by an FRA that they are seeking to be deemed and meets the applicable requirement in section C.08.004 of the regulations.” As noted in lines 537 to 538, the scope of the deemed aspect of the submission will depend on how Health Canada and the FRAs have divided the evaluation of the drug. Since the division of responsibilities in the context of an Access Consortium review is determined by the participating Regulatory Authorities, rather than by the applicant, it would be more efficient to allow manufacturers simply to consent to those sections of the submission not allocated to Health Canada to review to be automatically deemed. This could be accomplished through a suitable statement with a check box in the attestation form, to be checked by the sponsor if applicable. | |
| 540-541 | “The Minister must receive a copy of the document produced by the FRA for the joint review”. It should be clarified that Health Canada will obtain the document produced by the FRA directly from the FRA, not the sponsor, | The Minister must receive a copy of the document produced by the FRA for the joint review, which Health Canada will be obtain directly from the FRA. |
| 580 | Why are the Modules that can be included in deeming requests different for new drug submissions versus supplement to new drug submissions? As currently written, Module 2 is only included as information that can be deemed for supplement to new drug submissions. This appears to be due to a typographical difference in how the equivalent modules for each type of information in the Order are expressed for NDS, SNDS and ANDS submissions. | Propose to align the information that can be deemed for new drug submissions and supplement to new drug submissions. i.e. for each type of submission, the bullet points should read as: Non-clinical: • For human drugs, roughly equivalent to Modules 2 and 4 in eCTD submission format Clinical: • For human drugs, roughly equivalent to Modules 2 and 5 in eCTD submission format Chemistry and Manufacturing: • For human drugs, roughly equivalent to Modules 2 and 3 in eCTD submission format |
| 624 | Please confirm if for 120-day filings all the clinical, non-clinical, and chemistry and manufacturing information must be included in the deeming request, and what is the rationale for not being able to only request certain section for deeming? | |
| 650-653 | Lacks clarity on how sponsors should demonstrate this and what qualifies as immediate access. It would be clearer to state up front that the key requirement in practice is to demonstrate that there is a legal relationship between the manufacturer filing a submission in Canada and the foreign manufacturer who filed the submission to the FRA, such that there is readily available access to information that was submitted to the FRA and regarding any post-market measures. | Sponsors should clearly describe the relationship between the legal entity filing in Canada and the legal entity who filed the submission with the FRA (e.g. local affiliates of the same global parent company). Demonstration of the existence of a relationship between these legal entities is intended to provide assurance that the applicant in Canada has access to information filed to the FRA to obtain authorization or for any post-market measures and can produce it in a reasonable time frame if requested by Health Canada. |
| 647-648 | It is unclear in the draft guidance if the sponsor will have the opportunity to update the file to reflect any additional information submitted during review to the FRA, but presumably this will be required by Health Canada to ensure the same data considered by the FRA is part of the complete Canadian submission, under 120 day deeming. | “Manufacturers are to provide this information to Health Canada within 30 calendar days of the foreign drug authorization, and can update the Canadian submission with additional data provided to the FRA during the course of the review of the reference submission.” |
| 722-724 | Highlighting difference should be managed through the attestation process, and not in the CPID. Highlighting differences in the CPID, which is ultimately a document capturing what is registered and authorized in Canada, would seem to create unnecessary duplication and likely confusion. | Delete the end of the sentence in lines 722-724 i.e. |
| 726-733 | Acceptable difference for safety and efficacy information lacks clarity. Sponsor would also not delay filing safety information to wait for an FRA to approve it. This section also implies that if a new/subsequent indication is currently under review by the FRA but is out of scope of the Canadian submission, it would render deeming ineligible as it is equivalent to a level 1 category in Canada. This will significantly hamper the implementation of the Order in Canada, and undermine the goal of bringing needed medicines to Canada in a more timely fashion. This section should be rethought, to avoid rendering deeming impossible when inevitable life cycle safety updates or new, unrelated indications will be under review by FRAs simultaneously with Canadian submissions being requested for deeming under the Order. | Lines 726-728 “Health Canada will generally consider differences that would be characterized as level 2 supplement(safety) changes for human drugs (or level 2, notifiable changes (safety) for veterinary drugs) to be acceptable for the purposes of deeming eligibility” Lines 732-733: “Safety related changes falling within the level 1 categories that are under review and not yet approved by the FRA |
| 742-744 | Requiring sponsors to submit only the information supporting the Canadian indication(s) may inadvertently create a barrier to uptake of the reliance pathway. Consider permitting submission of the complete FRA-authorized dossier, accompanied by a sponsor-prepared reference key (for example, a Note to Reviewer) that identifies the specific studies, modules, sections, and labelling relevant to the Canadian indication(s). This would maintain reviewer efficiency while avoiding extensive dossier re-authoring | a sponsor-prepared reference key (for example, a Note to Reviewer) that identifies the specific studies, modules, sections, and labelling relevant to the Canadian indication(s). This would maintain reviewer efficiency while avoiding extensive dossier re-authoring |
| 879/889 | The guidance states that, “Certain Canadian-specific requirements can’t be deemed, including, for example, : • other Canadian-specific information that’s usually provided in Module 1 of the human drug submission” Could Health Canada confirm whether a CSBE would still be required if Module 5 is being deemed? We expect that a CSBE should not be required. | |
| 893-901 | The draft guidance conflates information requirements to (1) ensure a full record of information relevant to the FRA’s decision, with (2) use of this information to make a case-by-case decision on whether an otherwise eligible submission under the order will ultimately be accepted for a deemed review. This appears at odds with the purpose and objectives stated in the RIAS, and appears to be a different approach to similar comparable mechanisms in other jurisdictions eg MHRA IRP, where foreign assessment reports are required, but do not create a protracted review and decision making process on whether reliance can be followed, post validation. | Suggest clarifying the intent of the requirement for foreign reviews/assessment reports. Recommend deleting this stand alone section (lines 893-901) and incorporating this into the information to be included in this submission via the attestation process to ensure a complete submission during screening i.e. section starting on line 827. |
| 895 | Will assessment reports only be used to assess eligibility for reliance, or will they be reviewed? | |
| 899-900 | This wording is very broad, and difficult to action/implement. If the intent is to ensure new safety signals being formally addressed through regulated actions by the FRA are disclosed to Health Canada, this should be explicitly stated. | |
| 930 | Can FRAs that have fully implemented Q12 be relied on? | |
| 981-983 | “If we determine that certain requirements under the Order are not met, we will notify manufacturers and their submissions will undergo a standard Health Canada evaluation as per the regulations.” Would Health Canada consider options to determine eligibility earlier on (before submission), or at minimum, during screening to reduce uncertainty? If one of the goals of the Order is to make foreign reliance an attractive pathway for manufacturers to file submissions that they would not otherwise file in Canada, there should be a mechanism to confirm eligibility before committing a significant amount of work to the submission. In the current proposal, sponsors must prepare a complete submission along with documentation to demonstrate that deeming is appropriate. However, the submission may ultimately be screened into a standard pathway. The MHRA IRP eligibility tracker could be emulated to provide an easy online tool for assessing eligibility under the Canadian Order: https://irpeligibilitychecker.mhra.gov.uk/ | |
| 989 | There should be a set performance standard by when sponsor will be notified if deeming request is accepted. It is recommended that the assessment of eligibility of a request for deeming be completed simultaneously with the current screening process. | Propose to add: Sponsor will be formally notified of acceptability of deeming request within 60 days of submission beingupon completion of screening, when the submission is accepted into review. |
| 989 | If a deeming request is rejected, will the review default to proceed for a normal submission or does the submission need to be withdrawn and resubmitted? To avoid unnecessary delay, it is recommended that if the submission is otherwise acceptable, rejection of a deeming request should not preclude the submission proceeding directly into standard review. | |
| 1011-1018 | There are significant differences between templates across difference Health Authorities. Identifying all differences would be extremely administratively burdensome for both the sponsor and challenging for Health Canada to review. Only differences corresponding to proposed content changes should be identified. | |
| 1033-1035 | Minor revision for clarity | As mentioned earlier in this guidance document, the Order allows manufacturers to request deeming even if there are certain differences between the foreign drug and the proposed Canadian drug. |
| 1041-1043 | Comment: suggest removing the statement. Rationale: The second sentence is a direct restatement of the eligibility criterion expressed immediately above. As it does not introduce a new condition, exception, or clarification, its inclusion may create unnecessary redundancy. | |
| 1060-1062 | Comment: Correction of typo. Rationale: If deeming is to occur following negative feedback from the FRA, the outcome under C.08.004(1)(b) would be an NON/NOD, rather than an NOC. This is also consistent with the following paragraph, which states that manufacturers may amend their submission and file a response to the NON or NOD under subsection C.08.004(2) to address the issues raised by the Minister. | This could lead to the issuance of |
Do you have any other general suggestions or questions for Health Canada to consider? For example (but not limited to) relating to:
- the Sponsor’s Request and Attestation form for Human Drugs, or
- Interpretation of the Incorporated by Reference (IbR) List for pediatric-focused drug classes (https://www.canada.ca/en/health-canada/services/drugs-health-products/ministerial-reliance-order/eligible-drugs/interpretive-incorporated-reference-list-pediatric-focused.html)
| Topic | Comment and Rationale | Proposed Revised Text |
|---|---|---|
| Attestation form | -Attestation is requested to be signed and submitted in Word. However, if form is to be signed it should be submitted in PDF format. -The guidance document states that deeming is possible for M2 for supplemental submissions but this is not included on the attestation form. -Attestation 7: Recommend the removal of the word “immediate”. This is challenging for multinational corporations as different countries will have access to such information upon request, but do not always have direct access to documents maintained by another country. It is also unclear if attestation for post-market measures applies to any potential future communications. | |
| Interpretation of the IbR List | Health Canada is encouraged to provide a mechanism for IbR amendment requests from both sponsors and the public. As in line with Task Force recommendations, to maximize the impact of the Order for patients, the IbR lists should be rapidly expanded to include oncology, HIV, and antimicrobial drugs, vaccines, and drugs that treat rare diseases, and those meeting the criteria for HC Priority Review or NOC(c). BIOTECanada remains of the view that Health Canada should directly address current and future backlog, via expansion of the IbR list of classes for general deeming to include a wider array of innovative medicine submissions needed by Canadians. | |
| Other – please specify | If participation in reliance could lead to a shortened target review period due to documentation efficiencies for Health Canada, this may serve as a meaningful incentive for industry sponsors. Would Health Canada be willing to consider implementing such an approach? | N/A |
| Other – please specify | Many drugs, including most of the drugs on the National Pediatric Drug Priority list, are older drug formulations that have not been introduced to Canada. These drugs may potentially have lengthy regulatory histories and complicated dossiers (e.g., multiple supplements and hundreds of sequences). To be eligible for general deeming, are sponsors expected to create a “clean” dossier reflecting all current information (which may render such a submission unfeasible) or would it be sufficient to clone a copy of the cumulative dossier, representing the current, up to date authorization by the FRA? | |
| Incentivization | Health Canada should appropriately incentivize industry to request deeming where applicable, by: • Establishing predictable service standards by announcing reduced timelines for review under the Order, and committing to a decision on eligibility for deeming during screening • announcing a tangible plan and timeline for assessing the impact on resource requirements of a deemed review and for right-sizing the cost recovery framework according to the revised resource requirement • amending the draft guidance to reduce the uncertainty on whether a final decision to accept a request for deeming will be successful • streamlining the guidance to ensure that the decision to accept a request for deeming is made during the screening period | |
| Timelines | To help sponsors understand the full process and plan submissions with greater confidence, Health Canada is encouraged to consider developing a visual timeline or infographic outlining the key steps, milestones, and expected timelines associated with participation in the reliance pathway. Such a resource could illustrate when sponsors should consider requesting a pre-submission meeting, the recommended interval between a pre-submission meeting and filing, the timing of the attestation form, the anticipated duration of screening and review activities, and when sponsors can expect eligibility and deeming determinations to be confirmed. In addition, a visual roadmap outlining the anticipated timing of subsequent phases of the rollout would be a valuable reference for stakeholders and would support planning, transparency, and uptake of the pathway as it evolves. Additional details of the next phase of implementation, specifically the timeline for opening the 120-day filing scenario are of particular interest to sponsors. |