Draft guidance on terms and conditions for human and veterinary drugs: About terms and conditions

On this page

• Regulatory provision in section C.01.014.21 of the Food and Drug Regulations
• Why we impose terms and conditions
• Significant uncertainties
• Promising evidence of efficacy and significant uncertainties
• Examples of why we may impose terms and conditions
• Examples of terms and conditions that may be imposed
• Subsequent-entry drugs

Regulatory provision in section C.01.014.21 of the Food and Drug Regulations

We may impose terms and conditions (T&Cs) when necessary to manage risks or address significant uncertainties. We may also impose T&Cs when new or additional information is received that may affect the drug's benefit-risk profile.

As per section C.01.014.21, the provision states:

1. The Minister may, at any time, impose terms and conditions on a drug identification number assigned for a drug or amend such terms and conditions after considering
   1. whether there are significant uncertainties relating to the benefits or risks associated with the drug
   2. whether the requirements under the Act are sufficient for the following objectives to be met:
      1. optimizing the benefits and managing the risks associated with the drug
      2. managing the uncertainties relating to the benefits and risks and
      3. collecting information to enable the continuous assessment of the benefits and risks, the identification of any changes to them and the management of the uncertainties
   3. whether the proposed terms and conditions may contribute to those objectives being met
   4. whether compliance with the proposed terms and conditions is technically feasible and
   5. whether there are less burdensome ways for those objectives to be met
2. The Minister shall notify, in writing, the manufacturer who was issued a document under subsection C.01.014.21(1) that sets out the drug identification number of any terms and conditions imposed on the drug identification number and of any amendment to those terms and conditions.

Why we impose terms and conditions

We will review drug submissions and applications as per existing guidance and policy documents and apply the appropriate requirements of each submission or application type or class.

For information on drug submissions and applications, refer to:

• For human drugs: Guidance on management of drug submissions and applications
• For veterinary drugs: Management of regulatory submissions guidance

In order for a drug identification number (DIN) to be assigned to a drug, the information supporting the drug submission or application must demonstrate that:

• the drug has a favourable benefit-risk profile and
• the information complies with the Food and Drugs Act (FDA) and the Food and Drug Regulations (FDR)

To be assigned a DIN, manufacturers must submit information to satisfy the requirements of section C.01.014.1 of the FDR. The DIN permits the drug to be marketed in Canada.

T&Cs may be imposed on the DIN of a drug to:

• optimize the benefits and manage any risks or significant uncertainties that could cause harm
• collect information to:
  • continuously assess the benefits and risks
  • identify changes (such as increased frequency of an adverse drug reaction)
  • reduce uncertainties related to the drug's safety, efficacy or quality
• manage significant uncertainties, including for:
  • compliance monitoring and enforcement of pharmacovigilance or
  • risk minimization activities, including those in a human drug's risk management plan (RMP)

For information on risk management plans, refer to:

• Submitting risk management plans guidance document

We may also impose or amend T&Cs if new risks or significant uncertainties are identified about the drug's safety, efficacy or quality. New risks or significant uncertainties could be identified, for example, through:

• post-market safety assessments
• assessments of real-world evidence
• new information from foreign regulators
• review of information submitted for post-authorization changes
• new evidence from studies or reports, including from information filed to fulfill T&Cs

Prior to imposing T&Cs on the DIN, we will consider the factors listed in the proposed section C.01.014.21 of the FDR. That is, we will consider if:

• the proposed T&Cs are technically feasible
• there is a less burdensome way of meeting the objectives of the proposed T&Cs and
• another regulatory mechanism could address the issues identified

Significant uncertainties

All drug submissions must have the necessary information to enable the Minister to assess the safety, efficacy and quality of the drug. Data from clinical trials can be limited in providing information about how the drug will perform in the real world once it is on the Canadian market.

Limitations in the methodologies of clinical trials may lead to uncertainties in the benefits and risks of a drug. Therefore, limitations of the information obtained from clinical trials may, for example, include:

• effects of the drug when used with other drugs
• unknown long-term safety and effectiveness of the drug
• inclusion or exclusion criteria that limits the use of the drug in the real world (such as effects of the drug on populations not identified in the trial)

As a result of these limitations, our review of the information in a drug submission may identify significant uncertainties. Examples include uncertainties related to the:

• clinical trial methodology
• risks when the drug is used in real-world conditions

To address these significant uncertainties we may impose T&Cs on the DIN to monitor the safety of the drug and mitigate risks that occur in the real world. T&Cs allow us to verify that a market authorized drug maintains a favourable benefit-risk profile over time.

Promising evidence of efficacy and significant uncertainties

A new drug submission (NDS) or supplement to a new drug submission (SNDS) for human and veterinary drugs, shall contain sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug. In accordance with sections C.08.002 and C.08.003 of the FDR, sufficient evidence must be provided to support the safety and effectiveness of the drug for its indicated use and conditions of use.

New drugs under development for serious or severely debilitating conditions may have promising evidence of clinical efficacy, but the available data is limited. We recognize that efficacy data may be limited due to various important considerations such as:

• the availability of only preliminary or interim data on relevant endpoints
• the long duration of time required to collect data on conventional endpoints or
• a small number of patients who participated in clinical trials due to limited availability of patients, such as in cases of rare diseases or conditions

While the available data may be limited, it may provide promising evidence that a drug could help reduce or prevent serious signs, symptoms, or adverse clinical outcomes of a disease or condition. This evidence may demonstrate a clinical benefit and that the benefits outweigh the known risks associated with the drug's use.

New drugs supported by promising evidence of clinical efficacy should be made available to individuals with serious or severely debilitating conditions where there is an unmet medical need. If the supporting information shows that the benefits outweigh the known risks and meets the requirements of the FDA and the regulations, a notice of compliance (NOC) may be issued to allow market authorization of the drug.

However, when a drug is supported by promising evidence, significant uncertainties about its effectiveness may remain. In such cases, the available evidence may still meet regulatory requirements if additional confirmatory studies are performed to further verify the new drug's effectiveness. T&Cs can be imposed to support a market authorization by applying section C.08.003.2 of the FDR. This allows us to take into account whether T&Cs could provide more information about any significant uncertainties on a new drug's effectiveness.

For more information on drug submissions based on promising evidence of efficacy, refer to:

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

Examples of why we may impose terms and conditions

We may impose T&Cs to manage risks and uncertainties related to:

• long-term use of a drug
• safety risks in veterinary drugs
• the impact of certain marketed veterinary drugs on food safety
• compliance monitoring and enforcing elements of an RMP for human drugs
• limited safety or efficacy information in a specific population using the drug
• outcomes of studies or pharmacovigilance activities which may impact the benefit-risk profile
• new information from markets outside Canada or from published evidence in scientific journals

Examples of terms and conditions that may be imposed

We may impose T&Cs to:

• conduct additional studies
• verify impurities identified in a drug
• require implementation of an ongoing quality, risk mitigation or monitoring program
• increase the frequency of preparing summary reports and submitting them as stated in the T&C letter (more frequently than annually as required by the FDR)

Drugs authorized by a foreign regulator may already have conditions imposed on them that oblige the MAH to pursue further studies. On a case-by-case basis, we may consider conditions imposed by a foreign regulator when imposing T&Cs on the Canadian DIN.

Subsequent-entry drugs

Subsequent-entry drugs (generic and biosimilar submissions) can use a Canadian reference product (CRP) or Canadian reference biologic drug (CRBD) with T&Cs as a comparator. In such cases, T&Cs imposed on the DIN of the subsequent-entry drug may be the same or similar to those imposed on the CRP or CRBD as described below.

Sometimes the comparator has a T&C to conduct a confirmatory trial, because the authorization of the CRP or CRBD was based on promising evidence of clinical effectiveness. In this case, the MAH of a subsequent-entry drug will not necessarily have to complete the same study. For human drugs, generic or biosimilar products that compare to a CRP or CRBD that has T&Cs to confirm clinical benefit may need to reflect the promising nature of efficacy in their Product Monograph and include a copy of the Package Insert within the product packaging materials. For specific wording for subsequent entry products, refer to:

• Guidance document - Product monograph

There may be instances, however, where MAHs of subsequent-entry drugs may be required to conduct trials to address significant uncertainties related to the effectiveness of the drug.

An example of this could be when the MAH of a CRP or CRBD cancels their DIN before completing and submitting the confirmatory trials. A T&C may require the MAH of the subsequent-entry drug to provide data verifying the clinical benefit. When we consider imposing a T&C to conduct a trial, we will take into account the feasibility of the trial. This will include such factors as the:

• ethical considerations for requesting a duplicative trial
• status of the original trials imposed upon the CRP or CRBD
• potential to affect subject recruitment in both the original and subsequent trials
• potential competition for the same and possibly limited human, animal and material resources to conduct the trial

Health Canada will determine, on a case-by-case basis, which T&Cs will be imposed on the DIN of a generic or biosimilar drug. Our goal in these considerations is to avoid:

• unnecessary delay of confirmatory trials
• possibly undermining the objective of the use of T&Cs to verify the clinical benefit of a drug