Draft guidance on human and veterinary drug submissions based on promising evidence and terms and conditions: Submission screening and review
On this page
- Targets for human drug submissions granted advance consideration of promising evidence status
- Targets for veterinary drug submissions
- Advance consideration of a human drug submission supported by promising evidence of efficacy was not pursued or not granted
- Issuance and response to anticipatory terms and conditions letter
- Issuance of the "Terms and conditions letter"
- Figure 1: Process flow for a new drug submission or a supplement to a new drug submission based on promising evidence for human drugs
- Figure 2: Process flow for promising evidence consideration during review of a new drug submission or a supplement to a new drug submission where a request for advance consideration status was not filed or not granted for human drugs
- Figure 3: Process flow for a new drug submission or a supplement to a new drug submission based on promising evidence for veterinary drugs
Targets for human drug submissions granted advance consideration of promising evidence status
If we grant advance consideration promising evidence (ACPE) status for human drugs, reduced targets for the screening and review of the NDS or SNDS are as follows (Figure 1):
- 10 calendar days for administrative processing
- 25 calendar days for screening
- 200 calendar days for submission review (60 additional days will be added to the review target for review and finalization of T&Cs)
Response to notice of deficiency (NOD): The above-noted targets for the submission would also apply to screening and review of a response to a NOD.
Response to a notice of non-compliance (NON): The targets for screening and review of a response to a NON are as follows:
- 10 calendar days for administrative processing
- 25 calendar days for screening
- 90 calendar days for submission review (60 additional days will be added to the review timeline for review and finalization of T&Cs)
Targets for veterinary drug submissions
While every effort to expedite the submission will be made, it will be resource-dependent. As such, the screening and review targets for veterinary drugs are in accordance with the following:
For more information on performance standards refer to:
Advance consideration of a human drug submission supported by promising evidence of efficacy was not pursued or not granted
Manufacturers may have filed a drug submission that was:
- for a proposed indication that was supported by information not based on promising evidence of efficacy or
- denied advance consideration of promising evidence (ACPE)
These drug submissions usually follow the standard 300-day review target. However, during review, if promising efficacy data is found for a specific use but uncertainties remain, T&Cs may be imposed under section C.08.003.2 of the Food and Drug Regulations (regulations). In such cases, we will issue an anticipatory terms and conditions letter to give the manufacturer the opportunity to respond. The 300-day target remains unchanged, and the response is reviewed within that period (Figure 2).
A manufacturer may have requested a priority review for their drug submission and if granted, the submission follows a 180-day review target. "Promising" clinical evidence including the use of non-validated surrogate markers, do not fall within the scope of drug submissions that would be granted priority review.
However, during the priority review, we may find promising efficacy evidence but also significant uncertainties of effectiveness, requiring T&Cs under section C.08.003.2 of the regulations. In such cases, an anticipatory terms and conditions letter will be issued before the 180-day review target ends, extending the target date by 60 calendar days. This will allow the manufacturer an opportunity to be heard and will provide us with time to review the manufacturer's response (Figure 2).
For more information on priority review refer to:
Guidance for Industry - Priority Review of Drug Submissions
Issuance and response to the anticipatory terms and conditions letter
For information on the issuance and response to the anticipatory terms and conditions letter, refer to:
Human drug submissions that have been granted ACPE status will be subject to a 200-calendar day review target. However this review target date will be extended by 60 calendar days when the anticipatory terms and conditions letter is issued to allow time for the manufacturer to respond and for Health Canada to review the response (Figure 1).
Manufacturers should submit a response within 30 calendar days of receiving the Anticipatory Terms and Conditions Letter from Health Canada, outlining how the T&Cs will be fulfilled. If no response is received, we may contact the manufacturer to inform them that we will proceed with imposing the T&Cs based on available information.
The response should include details on the confirmatory trials intended to verify the drug's clinical efficacy, as well as timeframes for their initiation and completion. The nature and scope of the proposed confirmatory trials must be:
- feasible, well-designed and include an assessment of key clinically relevant efficacy and safety endpoints
- carried out in accordance with established scientific standards and
- initiated and completed in a timely fashion
It is recognized that when an authorization with imposed T&Cs is granted, confirmatory trials may already be underway in Canada or other jurisdictions. At our discretion, these trials that are already underway may be acceptable confirmatory trials for a T&C.
Factors for consideration of confirmatory trials that may already be underway include:
- trial design
- clinical endpoints
- safety measures
The manufacturer is responsible for bridging the outcomes from the ongoing trials to the outcomes of the anticipatory T&Cs from the Health Canada-requested confirmatory trials, with appropriate rationale.
If the manufacturer does not agree with the confirmatory trials requested in the anticipatory terms and conditions letter, they must provide a written response. This response should include:
- the reason for their objections
- an alternative proposal to confirm the drug's efficacy
Additionally, the response should include a supporting rationale explaining why the proposed alternative is preferable. For example:
- improved technical feasibility
- a less burdensome way of achieving the objectives
Responses to an anticipatory terms and conditions letter should reference the submission control number and be provided through the common electronic submissions gateway (CESG).
Issuance of the "Terms and conditions letter"
Upon receipt of the manufacturer's response to the anticipatory terms and conditions letter, we will review the response within 30 calendar days. During this review, we may ask for clarification. This will be done in accordance with the following guidance documents:
- For human drugs: Guidance on management of drug submissions and applications
- For veterinary drugs: Management of regulatory submissions guidance
Should the information in the manufacturer's response be considered acceptable, we will finalize the terms and conditions and prepare the T&Cs Letter. The letter will specify the:
- applicable DIN(s) on which the T&Cs will be imposed for confirmatory studies for the target population for which the clinical benefit is to be confirmed
- T&Cs to be fulfilled
- information to be submitted by the market authorization holder and
- required timeframe for fulfilling the imposed T&Cs
The "Terms and conditions letter" will be issued to the manufacturer with the notice of compliance (NOC) at the end of review.
Figure 1 - Text description
If the sponsor wishes to have the submission considered based on promising evidence before filing, a pre-NDS or pre- NDS meeting should be held. The decision to grant or deny advance consideration will be provided within 14 calendar days of finalization of the meeting minutes. If advance consideration is denied, the sponsor may file a revised request within 30 calendar days from the date of the decision letter. If advance consideration is granted, the sponsor is expected to file the submission within 60 calendar days. The submission will enter a 10-calendar day processing period, followed by a 25-calendar day screening period. Possible outcomes include a screening deficiency notice, or, if the submission is acceptable, it will enter review with a review target of 200 calendar days. Possible outcomes of review are a notice of deficiency (NOD), notice of non-compliance (NON) or a notice of compliance (NOC) and assignment of a DIN. If prior to assigning the DIN and issuing the NOC, an anticipatory T&C letter is issued, the review target will be extended to 260 calendar days. The response to anticipatory T&C letter should be filed within 30 calendar days. The response will be reviewed, and one possible outcome is a NON. If the response is acceptable, a DIN may be assigned and a NOC may be issued with T&Cs imposed on the DIN(s) by day 260. The T&Cs will be communicated to the sponsor in a T&C letter along with NOC issuance.
Figure 2 - Text description
Sponsor files the submission. However, a request for advance consideration status is not pursued or denied at the outset. The submission undergoes screening and enters a 10-calendar day processing period, followed by a 45-calendar day screening period. If the sponsor filed for priority review and the submission has been granted priority review, the screening time will be 25 calendar days. Possible outcomes include a screening deficiency notice, or, if the submission is acceptable, it will enter review. Review target is 300 calendar days unless priority review has been granted in which case the review target will be 180 days. Possible outcomes of review are a notice of deficiency (NOD), notice of non-compliance (NON), or a notice of compliance (NOC) and assignment of a DIN. If T&Cs are needed, they will be communicated in an anticipatory terms and conditions (T&Cs) letter issued during review. The review target will remain as 300 calendar days. If the submission has been granted priority review and T&Cs are needed, the review target will be extended to 240 calendar days when the anticipatory T&C letter is issued. The response to anticipatory letter should be filed within 30 calendar days. The response will be reviewed, and one possible outcome is a NON. If the response is acceptable, a DIN may be assigned and a NOC may be issued with T&Cs imposed on the DIN(s) by day 300 for standard submissions and by day 240 for priority review submissions. The T&Cs will be communicated to the sponsor in a T&C letter along with NOC issuance.
Figure 3 - Text description
If the sponsor wishes to have the submission considered based on promising evidence before filing, a pre-NDS or NDS meeting should be held. Notification of suitability will be provided within 14 calendar days of finalization of the meeting minutes. If the submission is suitable, it should be filed within 6 months. The screening time is 45 calendar days. Possible outcomes include a screening deficiency notice, or, if the submission is acceptable, it will enter review with a review target of 300 calendar days for new drug submissions (NDS), and 240 calendar days for supplements to new drug submissions (SNDS). Possible outcomes of review are a notice of deficiency (NOD) or a notice of compliance (NOC) and assignment of a DIN. If T&Cs are needed, they will be communicated in an anticipatory terms and conditions (T&Cs) letter issued during review. The response to anticipatory T&C letter should be filed within 30 calendar days. The timelines associated with the issuance of the anticipatory T&C letter, the sponsor's response to the anticipatory T&C letter and review of the response are all included within the 300-day or 240-day review targets. The response will be reviewed, and one possible outcome is a NOD. If the response is acceptable, a DIN may be assigned and a NOC may be issued with T&Cs imposed on the DIN(s). The T&Cs will be communicated to the sponsor in a T&C letter along with NOC issuance.