Draft guidance on management of rolling reviews for drug submissions: Applying for rolling review status

On this page

• The Rolling Review Application Package
• Eligibility assessment
• Submission plan for rolling review
• Notice from the Minister of rolling review status

The Rolling Review Application Package

Sponsors who wish to apply for rolling review status for a forthcoming drug submission must do so before they file their submission.

To apply for rolling review status for a forthcoming new drug submission (NDS) or supplement to a new drug submission (SNDS), sponsors must provide a Rolling Review Application Package (RRAP). The RRAP is forwarded to the appropriate directorate and assessed within 45 calendar days.

The RRAP has 2 components:

1. an eligibility assessment
2. a submission plan

Both components must meet the requirements set out in the regulations. If a pre-submission meeting has taken place, the RRAP should also include the minutes of the pre-submission meeting.

For relevant contact information, refer to the following guidance documents:

• Management of drug submissions and applications
• Veterinary drugs - Management of regulatory submissions guidance

Eligibility assessment

The eligibility assessment must include information for clinical review that demonstrates the proposed drug meets the eligibility conditions for a rolling review. The eligibility assessment should be no longer than 25 pages (excluding references). Refer to the eligibility assessment template.

During the process of demonstrating that a forthcoming NDS meets the eligibility conditions, sponsors must also demonstrate that they possess a significant amount of the evidence to establish the safety and efficacy of the proposed drug. This is in line with the requirements under C.08.002(4)(a) (iii) and (iv) of the regulations.

For an SNDS, sponsors must demonstrate that they possess a significant amount of the information and material required under C.08.003(3). This is in line with the requirement under C.08.003(5)(a)(iii).

The eligibility assessment for submissions for veterinary drugs should also include:

• a summary of dose determination studies, target animal safety studies and laboratory animal studies conducted
• a summary of completed dose confirmation studies and interim analyses or study outlines of any pivotal efficacy studies

Sponsors who wish to seek an NOC for a drug on the basis of a direct or indirect comparison to a drug that has a drug identification number (DIN) must provide the DIN of the drug to which the comparison will be made (C.08.002(4)(a)(v) and C.08.003(5)(a)(iv) in the regulations). Failure to accurately identify the DIN will result in the submission being considered cancelled by the sponsor after it has been filed.

Conditions to be met

The sponsor must be able to demonstrate that the proposed drug meets the eligibility conditions outlined in C.08.002(4)(a)(iii) and (iv) or C.08.003(5)(a)(iii) and C.08.002(5) based on the available information that they have.

For human drug submissions, sponsors should be nearing the end of clinical development. They should have collected significant evidence to establish the safety and clinical effectiveness of the proposed drug for the recommended purpose and conditions of use.

For veterinary drug submissions, these would be final studies conducted to demonstrate efficacy and safety under the proposed conditions of use of the drug in the target population.

To meet the condition of C.08.002(5)(a), the sponsor must provide:

• an overview of the emerging infectious disease that poses or may pose a serious risk of injury to human or animal health
• a description of the treatment options, if available
• the clinical context within which the drug is proposed to be used

To meet the condition of C.08.002(5)(b), the sponsor must provide:

• an overview of the serious disease, disorder or abnormal physical state and treatment options, if any
• information establishing that the disease, disorder or abnormal physical state poses or may pose a serious risk of injury to human or animal health
• the clinical context within which the drug is proposed to be used

The sponsor must be able to demonstrate that the recommended purposes and conditions of use of the proposed drug do not fall within the recommended purposes and conditions of use of any other drug with an assigned DIN that has not been cancelled. Note that the market status of all drugs assigned a DIN can be found in the Drug Product Database.

To meet the condition of C.08.002(5)(c), the sponsor must provide:

• an overview of the serious disease, disorder or abnormal physical state and treatment options, if any
• information establishing that the disease, disorder or abnormal physical state poses or may pose a serious risk of injury to human or animal health
• the clinical context within which the drug is proposed to be used
• information to show that the proposed drug falls within the recommended purpose and conditions of use of any other drug with an assigned DIN that has not been cancelled and that the proposed new drug is
  • significantly more effective or
  • poses a significantly lower risk

The sponsor must be able to show that the drug provides a clinically meaningful improvement in effectiveness and/or safety compared to available therapies in Canada. Health Canada would accept a comparison to the current standard of care. If multiple therapies are available in Canada, consider what constitutes the best available treatment for comparison (for example, current standard of care).

In demonstrating that a drug meets condition C.08.002(5)(c), the eligibility assessment should address the following aspects where relevant:

• a clinically meaningful improvement in 1 or more of the serious outcomes, symptoms or manifestations of the disease, disorder or abnormal physical state on which the effect is claimed, while maintaining an acceptable safety profile
• a clinically meaningful benefit for individuals unable to tolerate or who are unresponsive to available therapies
• a demonstration that the drug provides clinically meaningful benefit that is consistent with available therapies while also demonstrating a more favourable safety profile than existing therapies by:
  • avoiding serious toxicity present in existing therapies and/or
  • avoiding less serious toxicity, common to the therapy, which results in the discontinuation of treatment of a serious disease, disorder or abnormal physical state

Clarification requests related to an eligibility assessment

If Health Canada requests clarification on information provided in the eligibility assessment, the sponsor must respond within 2 business days. If we do not receive supplementary information within this time, we will make a decision on the request for rolling review status based on the information provided at the time we received the RRAP.

Submission plan for rolling review

A sponsor applying for rolling review status for a forthcoming NDS or SNDS must provide a submission plan. This plan is part of the RRAP. It must outline what information the sponsor proposes to provide to Health Canada after the drug submission has been filed and when this information will be provided. (Refer to C.08.002(4)(a)(ii) or C.08.003(5)(a)(ii) of the regulations.)

Submission plan

When developing a submission plan, sponsors should keep in mind that:

• the plan outlines what missing information the sponsor expects to provide Health Canada after it has filed its forthcoming drug submission and when it expects to provide this missing information
• the missing information should be provided to the Minister through a small number of regulatory transactions (up to 3) after the submission has been filed
• the timeline and milestones outlined in the plan should be realistic and credible
• missing information should only be provided after a screening acceptance letter (SAL) has been issued for the submission
• new data/information provided in each transaction should be clearly identified to help Health Canada reviewers easily distinguish new information to be evaluated
• the data/information provided in each transaction should be substantial so that the reviewers can reach a conclusion from the information provided

As outlined in the regulations, the submission plan must provide details on how all required information supporting the safety, efficacy and quality assessment of the drug submission will be provided to Health Canada by the 155th day after the submission has been filed. In some circumstances, we will expect sponsors to provide the remainder of the missing information in less than 155 days. This 155-day period reflects a standard administrative processing period of 10 days, a screening period of 25 days and the first 120 days of the review 1 period. The plan should be in calendar days.

Preparing the submission plan

The sponsor should aim to provide the forthcoming drug submission’s missing information in an efficient and complete manner and consider the following:

• Only information and studies that are not final at the time the submission is filed may be provided after the filing date. All finalized data or information and any available interim data related to the missing information is expected to be provided when the submission is filed.
• The sponsor must provide draft summary documents at the time the submission is filed (for example, module 2 for human drugs). The sponsor should provide an annotated update later, if there are additions to the summary in subsequent transactions.

The submission plan for human drugs should follow the common technical document (CTD) structure and have the following fields:

• CTD module and section/subsections
• description
• content type
• anticipated transaction date(s)

The plan for veterinary drugs should follow the structure outlined in Appendix V: “Master Index” of the Guidance for industry: Preparation of veterinary new drug submissions. It should also have the following fields:

• prescribed structure parts and subparts
• description
• content type
• anticipated transaction date(s)

The plan should be in either MS Word, MS Excel or PDF format. Refer to the relevant eCTD or non-eCTD guidance document:

• Preparation of regulatory activities in the eCTD format
• Preparation of regulatory activities in non-eCTD format

Clarification requests related to a submission plan

Health Canada may request clarification on information provided in the submission plan. The sponsor must respond within 2 business days. If we do not receive supplementary information within the noted time, we will make a decision on the request for the rolling review status based on the information provided at the time we received the RRAP.

During the assessment process, Health Canada may contact the sponsor to discuss and negotiate:

• the nature and extent of the missing information to be provided after the drug submission has been filed
• the date(s) by which the missing information will be provided
• any changes proposed by us in this regard

A request for rolling review status can be rejected on the basis of an unrealistic plan.

Notice from the Minister of rolling review status

If Health Canada finds that the forthcoming drug submission meets the eligibility conditions for a rolling review, we will issue a notice of rolling review status. The notice will confirm this status. It will also state the manner and the dates by which the sponsor must provide the missing information (C.08.002(4)(b) and C.08.003(5)(b) of the regulations). The sponsor is responsible for providing the missing information.

Health Canada will indicate in the notice if the forthcoming drug submission will seek a notice of compliance (NOC) on the basis of a direct or indirect comparison to another drug, as well as the other drug’s DIN. The Minister will rely on the sponsor’s obligation in C.08.002(4)(a)(v) and C.08.003 (5)(a)(iv) to support the determination of whether the forthcoming drug submission will be sought on the basis of a direct or indirect comparison to a drug for which a DIN has been assigned.

If the forthcoming drug submission does not meet the eligibility conditions for a rolling review, Health Canada will inform the sponsor in writing that the RRAP has been rejected. In this case, the sponsor may refer to other guidance documents and file a submission when all of the information is ready:

• Management of drug submissions and applications (MDSA)
• Veterinary drugs - Management of regulatory submissions guidance
• Guidance for industry – Priority review of drug submissions