Draft guidance on management of rolling reviews for drug submissions: Rolling review process, eligibility

On this page

• The rolling review process
• Eligibility for rolling review status
• Eligibility assessment template

The rolling review process

Health Canada is offering an option for a rolling review of a new drug submission (NDS) or supplement to a new drug submission (SNDS) that meets specific eligibility conditions. Sponsors nearing the end of clinical development of a drug can apply to Health Canada for rolling review status for a forthcoming drug submission. The sponsor’s Rolling Review Application Package (RRAP) must contain an eligibility assessment and a submission plan.

If Health Canada grants rolling review status after assessing the RRAP, we will provide the sponsor with a “notice of rolling review status”. The notice indicates the sponsor may file the drug submission with some, but not all, of the information necessary for us to assess the safety, efficacy and quality of the proposed drug. The sponsor may then provide the missing information over time after filing their drug submission.

The notice outlines how and when to provide the missing information. The sponsor must provide the submission to us within 60 calendar days after Health Canada issues this notice.

Only the recommended purpose and conditions of use (referred to in this guidance document as the proposed indication) outlined in the RRAP are eligible for a rolling review. In the case of an emerging infectious disease, it is possible that both an adult and a pediatric indication could be included in the same RRAP. However, the sponsor may not seek approval for additional indications within the submission beyond the indications put forward in the RRAP.

Once Health Canada processes and screens the submission, we will issue a screening acceptance letter (SAL). The review 1 period will then begin. The submission is immediately placed on “rolling review” until we receive the missing information, as indicated in the notice. Refer to the page on performance targets and standards for more information.

Note that the intent is for Health Canada to begin reviewing any submission information that has been provided during the period the submission is in “rolling review”. We may also issue clarification requests during this period.

Once Health Canada reviews all of the information required to assess the safety, efficacy and quality of the drug, we will issue a decision on whether a notice of compliance (NOC) will be granted.

Eligibility for rolling review status

The regulations outline conditions that an NDS or SNDS must meet in order to be eligible for rolling review. These conditions are outlined as follows.

Eligibility conditions: C.08.002(4) and (5), and C.08.003(5)

Subsections C.08.002(4) and (5) and C.08.003(5) of the regulations set out the conditions that must be met for a drug submission to be eligible for a rolling review. The proposed human or veterinary new drug must meet the conditions of paragraphs C.08.002(5)(a), (b) or (c) to diagnose, treat, mitigate or prevent:

1. an emerging infectious disease that poses, or may pose, a serious risk of injury to human or animal health, and the Minister considers the proposed drug is needed for such a purpose. Within this context, a need is generally considered to include situations where:
   • there is a pressing necessity for other options even if there are 1 or more other drugs with a drug identification number (DIN) that have the same recommended purpose and conditions of use

Within the context of condition a), a serious risk of injury to human or animal health is in relation to an emerging infectious disease, which is defined by the World Health Organization as “one that has appeared in a population for the first time, or that may have existed previously but is rapidly increasing in incidence or geographic range.”

Sponsors of generic and biosimilar drugs may seek to establish eligibility for rolling review status on the basis of a).

2. a disease, disorder or abnormal physical state that poses or may pose a serious risk of injury to human or animal health where:
   • the recommended purpose and conditions of use do not fall within those of any other drug with a DIN that has been assigned and has not been cancelled

The condition in b) is intended for novel drugs to address an unmet medical need. Sponsors of generic and biosimilar drugs are not intended to establish eligibility for rolling review status on the basis of b). Comparison-based submissions are not meant to result in the approval of drugs that have conditions of use that are broader than the drug that they compare themselves to.

3. a disease, disorder or abnormal physical state that poses or may pose a serious risk of injury to human or animal health where:
   • the recommended purpose and conditions of use of the drug falls within the recommended purposes and conditions of use of 1 or more other drugs for which a DIN has been assigned and has not been cancelled, and
   • there are reasonable grounds to believe that the new drug is significantly more effective, or poses a significantly lower risk, than each of the other drugs

Sponsors of generic and biosimilar drugs are not expected to establish eligibility for rolling review status on the basis of c). Comparison-based submissions are not meant to result in the approval of clinically superior drugs.

With regard to b) and c), a serious risk of injury to human or animal health refers to a disease, disorder or abnormal physical state generally associated with clinically meaningful morbidity that causes a substantial impact on day-to-day functioning. In determining whether a disease, disorder or abnormal physical state is serious, Health Canada will consider factors such as:

• survival
• day-to-day functioning
• the likelihood that the untreated disease, disorder or abnormal physical state will progress from a less severe to a more severe state

Diseases, disorders or abnormal physical states where there is a serious risk to health are generally associated with morbidity, which causes a substantial impact on day-to-day functioning.

The regulations do not enable a rolling review under the ANDS/SANDS pathway. Therefore, any submission based on a direct or indirect comparison that meets the eligibility condition in C.08.002(5) must be provided as an NDS/SNDS.

Note that the terms “recommended purpose and conditions of use”, both in the regulations and in this guidance document, should be understood as the proposed indication of the drug.

List of influenza vaccines for which an SNDS can be filed

A sponsor of an influenza vaccine listed in the List of Influenza Vaccines for Which Supplements to New Drug Submissions Can Be Filed specified in C.08.003(2)(b.1) may file an SNDS that does not yet include all of the information and material required under C.08.003 without submitting an RRAP if that submission only seeks to update the strains of the influenza vaccine. This is outlined in sections C.08.003(2)(b.1) and C.08.003(10) of the regulations.

Within this context, an influenza vaccine submission eligible for a rolling review without an RRAP is expected to only include information on:

• changes to the virus strain(s)
• changes to the seed banks that are required to produce vaccine for the upcoming influenza season

All other changes require a separate submission. In this case, all information required to assess the safety, efficacy and quality of the drug must be provided at the time the submission is filed in the normal course.

Please refer to the following for more information and guidance:

List of Influenza Vaccines for Which Supplements to New Drug Submissions Can Be Filed, as amended from time to time
• Guidance document: Annual update of seasonal influenza vaccines

Missing information that can “roll”

If the drug submission meets all eligibility conditions, a sponsor may:

• file an NDS without some of the information required in paragraphs C.08.002 (2)(g) to (i), (m), (n) and (p) of the regulations at the time the submission is filed and, if applicable, corresponding information that is required to be included under section C.08.005.1
• provide to Health Canada the missing information in accordance with the notice of rolling review status after the submission has been filed

Only the information in C.08.002(2)(g) to (i), (m), (n) and (p) is permitted to be provided after the NDS has been filed.

Similarly, a sponsor may file an SNDS without some of the information that is required to be included in a supplement under C.08.003(3) and, if applicable, corresponding information that is required to be included in the supplement under section C.08.005.1. The sponsor may provide the missing information in accordance with the notice of rolling review status after filing the submission if the proposed drug meets any of the conditions in C.08.002(5).

In all cases, the sponsor must provide information on the medicinal ingredient, formulation, dosage form, use and route of administration for which authorization is sought at the time the submission is filed. These elements cannot be part of the missing information and are not expected to significantly change over the course of the review. Any significant changes to the formulation (including strengths), dosage form or use must be sought through a separate supplement rather than as part of the missing information provided after the submission has been filed.

For veterinary drugs, the sponsor must provide the following information when the drug submission is filed:

• the species and sub-type
• if the drug will be used to treat food-producing animals

For human drugs, from the clinical perspective, it is very likely that a pivotal or supportive clinical study may be nearly complete at the time the submission is filed. Depending on the progress of the ongoing clinical trial, the following documents may need updating after the clinical trial is completed:

• product monograph
• risk management plan
• clinical overview and clinical summary
• final version of clinical study report for the ongoing study
• for vaccines, process validation data including a data package that shows comparability of commercial lots to the clinical lots, including drug substance and/or drug product tests, additional characterization data and analytical procedures, with particular attention to potency and safety

For veterinary drugs, note that if an interim analysis is submitted with the submission, the final analysis may affect other aspects of the submission (for example, labelling).

For both human and veterinary drugs, please refer to the eligibility assessment template for more details about information requirements.

Pre-submission meeting

Before submitting an RRAP, the sponsor is encouraged to request a pre-submission meeting to:

• discuss potential eligibility
  • to help sponsors decide if their forthcoming drug submission may be suitable for rolling review
  • Health Canada will not determine the eligibility of the forthcoming drug submission for rolling review status at the pre-submission meeting
• discuss the proposed plan for providing the missing information after the submission has been filed
• provide guidance on the process involved in applying for rolling review status through an RRAP
• outline the evidence describing the benefits, risks and uncertainties of the proposed drug

If a pre-submission meeting is to take place, Health Canada recommends that a relevant Canadian health care professional participate. For example, a practising clinical specialist who has expertise on the disease and available treatments in Canada, particularly in the case of an unmet medical need. The health care professional should disclose any potential conflict of interest before the meeting takes place.

Sponsors should include the pre-submission meeting minutes with their RRAP.

For more information on pre-submission meetings, refer to the following guidance documents:

• Management of drug submissions and applications
• Veterinary drugs - Management of regulatory submissions guidance
• Preparation of regulatory activities in the eCTD format
• Preparation of regulatory activities in non-eCTD format

Eligibility assessment template

The eligibility assessment should be no longer than 25 pages (excluding references) and must include the elements outlined as follows, with headings in bold text. Explanatory text is provided for context and should be removed from the completed document before submitting it to Health Canada.

Date of application for rolling review status:

Sponsor name: Contact information:

Product information: Proposed dosage, formulation and route of administration. Confirm that the same dosage was used in the clinical trial or veterinary pivotal study. Is this a combination product? Drug class: Is this a first-in-class drug? If a comparator (for example, placebo, standard of care therapy) was used in the clinical trial or veterinary clinical study for a new drug, confirm that the recommended dose for the indication was used in the trial. In addition, provide the role of the comparator (for example, Canadian clinical guidelines) in the current Canadian setting.

If the forthcoming drug submission will be made on the basis of a direct or indirect comparison with another drug for which a DIN is assigned: A notice of compliance will be sought on the basis of a direct or indirect comparison to a drug for which a DIN is assigned. Refer to C.08.002(4)(v) or C.08.003(5)(iv): Yes □ No □ If Yes, provide the DIN(s) here: _______________________________________

Proper or common name of product and proposed brand name (if known)

Specific proposed indication Only the proposed recommended purpose and conditions of use (indication) sought for rolling review should be provided

Patient population Describe the patient population for this new drug For veterinary drugs, include: species and subtypes multiple species, if for 1 indication If they are used for the treatment of food-producing animals

Regulator decision or application status in foreign jurisdictions: The sponsor should provide information about the application status in foreign jurisdictions: Is the new drug under review in another jurisdiction and, if so, is this review being conducted by that jurisdiction’s regulatory authority under an accelerated timeline? Was the new drug approved or denied approval in another jurisdiction? If denied approval, include details of the proposed indication and rationale for denial, including date of denial. Is the sponsor now seeking a review of the new drug with new clinical data in Canada? In the case of human drugs, if the drug is authorized in another regulatory jurisdiction based on interim data or phase 1 or 2 study results, provide prescribing information. In the case of veterinary drugs, if the drug is conditionally approved in other regulatory jurisdictions, please provide the conditionally approved labelling. Health Canada requests the sponsor’s authorization to allow Health Canada to discuss all information included and related to the submission with the foreign jurisdiction.

Complete eligibility condition (a) or (b) or (c) [Select 1 only.]

Eligibility condition (a) The new drug is needed to diagnose, treat, mitigate or prevent an emerging infectious disease that poses or may pose a serious risk to human or animal health. Provide an overview of the emerging infectious disease and treatment options, if any Provide the clinical context within which the drug will be used to support the request Eligibility condition (b) The new drug is intended to diagnose, treat, mitigate or prevent a disease, disorder or abnormal physical state that poses or may pose a serious risk of injury to human or animal health, and The recommended purpose and conditions of use of the drug do not fall within the recommended purposes and conditions of use of any other drug for which a DIN has been assigned and has not been cancelled. Provide an overview of the disease, disorder or abnormal physical state and treatment options, if any Provide the clinical context within which the drug will be used to support the request Demonstrate the recommended purposes and conditions of use do not fall within those of any other drug with a DIN that has been assigned and has not been cancelled Eligibility condition (c) The new drug is intended to diagnose, treat, mitigate or prevent a disease, disorder or abnormal physical state that poses or may pose a serious risk of injury to human or animal health, and There are reasonable grounds to believe that the new drug is significantly more effective or poses a significantly lower risk than 1 or more other drugs for which a DIN has been assigned and has not been cancelled. Describe how the new drug is significantly more effective or poses a significantly lower risk relative to available drugs with a DIN in Canada (for example, current standard of care) Provide the clinical context within which the drug will be used to support the request and indicate how the drug will provide additional benefits over the available clinical management of the disease or condition in Canada

Clinical evidence Include the following: Concise information about the study(ies) to be submitted including design, enrolled patient population, inclusion and exclusion criteria, primary and key secondary endpoints, key safety findings (if available) and so on. This information may be presented in point form or in a table. For the study(ies) to be provided at the time the forthcoming drug submission is filed, describe the efficacy results and discuss statistical significance and clinical meaningfulness in support of the efficacy conclusions. If the results are based on an interim analysis, provide anticipated completion dates. For human drugs, provide the data from phase 2 proof of concept trials and the available data from phase 3 trials. For veterinary drugs, provide data from completed dose determination and dose confirmation studies. Provide the status of any relevant ongoing study(ies) and indicate if any of these study(ies) are intended to verify the favourable benefit-risk profile of the drug. For each such study, include a brief outline of the design. The sponsor must indicate the timeframe for the provision of these outstanding studies in the submission plan.

References An appendix can provide all references supporting these data/the indication as cross-referenced in the eligibility assessment. A sponsor can designate up to 12 key references to facilitate the review.