Draft guidance on human and veterinary drug submissions based on promising evidence and terms and conditions: About terms and conditions

On this page

• Significant uncertainties – Section C.08.003.2 of the Food and Drug Regulations for terms and conditions
• Confirmatory studies and terms and conditions if criteria in section C.08.003.2 of the Food and Drug Regulations is met
• Intent to impose terms and conditions
• Terms and conditions for notification on issues identified by foreign jurisdictions

Significant uncertainties – Section C.08.003.2 of the Food and Drug Regulations for terms and conditions

A drug must demonstrate it is safe, effective and of high quality, even when the efficacy data supporting a drug submission is based on promising evidence. All requirements of the Food and Drugs Act (FDA) and regulations must be met to be considered for authorization.

However, as per section C.08.003.2 of the regulations, if there are significant uncertainties regarding a new drug's effectiveness, the Minister may, in examining the submission or the supplement, consider whether T&Cs under section C.01.014.21 could help provide additional information on these uncertainties when the criteria is met.

The Minister may take this approach if the new drug is intended for:

• patients suffering from serious or severely debilitating diseases or conditions, and no drug has been issued a DIN, or the DIN has not been cancelled or
• a condition where the drug shows a significant increase in efficacy or a significant decrease in risk, compared to an existing drug with a DIN that has not been cancelled

The criteria in the provisions of section C.08.003.2 of the FDR state:

In cases where there are significant uncertainties respecting the evidence of the effectiveness of a new drug that was provided in a new drug submission or supplement to a new drug submission, the Minister may, in examining the submission or supplement, take into account whether terms and conditions that may be imposed or amended under section C.01.014.21 would enable the Minister to obtain additional information respecting the uncertainties, if

1. (a) the new drug is intended to diagnose, treat, mitigate or prevent a disease, disorder or abnormal physical state, or symptom of a disease, disorder or abnormal physical state, that poses or may pose a serious risk of injury to human or animal health and
2. (b) the recommended purpose and conditions of use of the drug either:
   1. (i) do not fall within the recommended purposes and conditions of use of any other drug for which a drug identification number has been assigned and not been cancelled or
   2. (ii) do fall within the recommended purposes and conditions of use of any other drug for which a drug identification number has been assigned and has not been cancelled, but the Minister has reasonable grounds to believe that the new drug is significantly more effective, or poses a significantly lower risk than the other drug

Confirmatory studies and terms and conditions if criteria in section C.08.003.2 of the Food and Drug Regulations is met

Drug submissions that are supported by promising evidence of efficacy may have significant uncertainties with the drug's clinical effectiveness. Therefore, to be considered for market authorization, drugs that are supported by promising evidence of efficacy may have T&Cs imposed on the DIN of the drug to further characterize the benefit of the drug while monitoring the risk so as to ensure a favourable benefit-risk profile is maintained. Confirmatory trials generate statistically conclusive evidence of the drug's efficacy and safety by testing it in larger groups or for longer times. Generally, these confirmatory trials would be conducted in the same population for which an approval with promising evidence was given. There are some circumstances where flexibility may be considered with a strong rationale (for example, confirmatory trial conducted in a different line of therapy). T&Cs may also be imposed that require market authorisation holders (MAHs) to provide results from confirmatory trials submitted to a foreign jurisdiction.

Through the imposition of T&Cs, MAHs will be required to pursue confirmatory trials. MAHs will be required to design, carry out, and report on additional human or animal clinical trials to verify the anticipated benefit for the authorized indication within a specified time frame, when the data may have been limited, or surrogate markers were used in clinical trial studies. T&Cs may also be imposed to require MAHs to provide results from confirmatory trials submitted to a foreign jurisdiction.

During the review period, prior to issuing a notice of compliance (NOC), we will apply section C.08.003.2 of the Food and Drug Regulations (regulations) if the criteria are met, and evaluate the acceptability of the proposed confirmatory studies.

There may be cases where a new drug submission or supplement to a new drug submission was not filed with information based on promising evidence of clinical efficacy but the information supporting the drug submission is insufficient to recommend the issuance of a NOC. However, during the review, we could determine that there is promising evidence of clinical efficacy for an unmet medical need. In such cases, if the drug meets the criteria in the regulations (section C.08.003.2) we may contact the manufacturer to discuss the potential for imposing T&Cs to require confirmatory evidence of effectiveness for a drug to be considered for a NOC since the drug demonstrates there is promising evidence of clinical efficacy.

As per section C.08.003.2, 2 criteria must be met (criterion (a) and (b)) when taking T&Cs into account when examining a submission for a drug that was supported by promising evidence of efficacy. Consideration is given to the following when assessing whether the 2 criteria are met:

For criterion (a), serious or severely debilitating diseases or conditions are generally associated with morbidity that causes a substantial impact on day-to-day functioning. We may accept promising evidence of efficacy for new drugs or new indications proposed to be for:

• use in the treatment, prevention, or diagnosis of reversible, but recurrent serious or severely debilitating diseases or conditions or
• non-serious conditions that, left untreated, could be expected to progress to a serious or severely debilitating condition or mortality

Promising evidence of efficacy would not be acceptable for new drugs or new indications proposed for use in the treatment, prevention, or diagnosis of a condition that is:

• self-limiting
• of short duration
• a non-serious condition in a patient with a serious disease or severely debilitating condition (for example, a minor skin irritation in a patient with cancer)

When considering criterion (b)(i), the proposed recommended purpose and condition of use of the drug should:

• seek to provide treatment, prevention or diagnosis of a disease or condition for which no drug has been assigned a DIN in Canada, for the same recommended purpose and condition of use intended by the new drug
• address a favourable effect on a serious symptom or manifestation of the condition for which no drug has been issued a DIN in Canada, for the same recommended purpose and condition of use intended by the new drug

For criterion (b)(ii), the proposed drug should have promising evidence of clinical efficacy to demonstrate in comparison to a drug that has been assigned a DIN for the same recommended purpose and condition of use that it has achieved at least one of the following:

• treatment has shown improvement in one or more of the serious outcomes of the condition
• treatment has shown a benefit for patients who are unable to tolerate, or are unresponsive to, available therapies
• the proposed drug has greater improvement in one or more of the serious outcomes of the condition when combined with one or more approved drug(s), compared to use of the authorized drug(s) alone
• the proposed drug should have promising evidence to show it has a benefit similar to that provided by currently available therapy(ies) but includes:
  1. a) avoidance of serious toxicity that is associated with currently available therapy(ies) and/or
  2. b) avoidance of toxicity that commonly results in the discontinuation of currently available therapy(ies) for a serious disease or severely debilitating condition and/or
  3. c) the ability to provide similar benefit to existing therapies while demonstrating improvement in some factor, such as compliance or convenience, shown to lead to improved effects on serious outcomes

In assessing criterion (b)(ii), statistically significant and/or clinically relevant benefit is expected to be identified through well-designed clinical trials and veterinary studies.

Intent to impose terms and conditions

T&Cs may be imposed to require MAHs to conduct confirmatory trials or veterinary studies within a specified timeframe, to verify the anticipated benefit of the drug over time for the authorized indication and to ensure that a favourable benefit-risk profile is maintained.

During the review of the drug submission, if the criteria are met, we will inform the manufacturer of our intent to impose T&Cs for confirmatory studies to obtain additional information to address significant uncertainties. We will send an "Anticipatory terms and conditions letter" to allow the manufacturer an opportunity to be heard.

Terms and conditions for notification on issues identified by foreign jurisdictions

If the new drug or indication under review has obtained a market authorization from a foreign regulator, in addition to imposing T&Cs for confirmatory trials, we may also impose T&Cs to require notifying and reporting on specific issues of concern that have been identified by a foreign jurisdiction as part of addressing the significant uncertainties a new drug with promising evidence may have. We may require the MAH to do both of the following actions:

1. a) Notify Health Canada within 15 calendar days of the date on which an expert panel or advisory committee has been struck in a foreign jurisdiction to address an issue regarding the drug as it relates to safety, efficacy or quality. Alternatively, notify Health Canada within 15 calendar days of the date on which there has been significant regulatory action in another jurisdiction. This includes a direction to issue warnings, a health advisory or the removal of a product from the market.
2. b) Prepare and submit a report on the issue that prompted the action in the foreign jurisdiction. The report should be available to Health Canada within 30 calendar days of the notification. This timeframe may be subject to negotiation with Health Canada when the scope of the issue under investigation warrants additional time to gather the necessary information.

Notifications and reports should be directed to the relevant pre-market authorisation directorate, the Marketed Health Products Directorate for human drugs, or to the Veterinary Drugs Directorate for veterinary drugs.