Quality requirements for investigational biologic drugs used in clinical trials: Notice to clinical trial sponsors

In many clinical trial applications and amendments to a clinical trial application, the (quality) chemistry and manufacturing information required for biologics used in clinical trials share common deficiencies. This notice explains the quality requirements of Part C, Division 5 of the Food and Drug Regulations as well as the cross-referencing approach.

On this page

• Background
• Including quality information in new applications or amendments
• Biologics quality guidance
• Contact us

Background

Sponsors often use the same investigational drug for multiple clinical trials. For this reason, they may cross-reference the (quality) chemistry and manufacturing information that was authorized in 1 application with subsequent applications involving the same drug. Third parties may also provide a letter of access to sponsors allowing them to cross-reference this quality information.

The cross-referencing approach thus reduces the regulatory burden for sponsors.

You should assess the differences between the proposed and cross-referenced information for impact on product quality and patient safety. Health Canada may require updated quality information for changes related to:

• dosage
• novel combinations
• changes in route of administration
• phase of clinical trial
• change in patient population

Including quality information in new applications or amendments

When filing a quality package in support of a clinical trial application (CTA) or amendments to an application (CTA-A), sponsors should:

• confirm the quality information is accounted for each investigational drug
• identify new information and proposed changes

When cross-referencing, the sponsor should consider the drug's use in the current protocol or amendment, and how this use may differ from the original protocol for which it was authorized. Sponsors should also:

• ensure the cross-reference is accurate and clearly outlines where the original source information is located
• provide the control number and dossier ID where the latest quality information is found in the application
• indicate which information applies (example specific sections) if only certain information in the cross-referenced submission is applicable
• if further details are required, the sponsor should give a rationale in the 'note to reviewer' section of the application

The sponsor should also confirm that no manufacturing changes have been made since the date of the cross-reference, if this is applicable. The sponsor should provide any updated batch and stability data that may have since become available.

For both CTAs and CTA-As, any changes should be described in detail and supporting information provided. You should provide a:

• summary of the changes to the quality information in Module 2.3 of the application
• tracked change version of the quality overall summary (QOS) or investigational medicinal product dossier (IMPD), if applicable

For CTAs, information that has been reviewed in a previous application should be referenced. The sponsor should provide a summary of changes to the latest authorized information even when the quality information is submitted again.

If the sponsor is not the owner of the information, they should coordinate with the relevant third party before filing the CTA or CTA-A with us. A letter of access should be provided when cross-referencing to third-party information in a submission that Health Canada has already authorized.

For further instructions on cross-referencing, please refer to Table 1, section 3.2 of the following guidance document:

• Guidance document for clinical trial sponsors: Clinical trial applications

Dosage

A new clinical trial may propose a higher maximum dose, compared with the authorized use in the cross-referenced submission. In this case, the sponsor should submit re-calculations for impurities where residual levels are justified per dose (for example, endotoxin, host cell DNA) and viral clearance. The results should demonstrate that the:

• proposed control strategy ensures product quality and patient safety
• exposure to specific impurities or adventitious agents at the higher dose do not impact patient safety

The summary of changes should also highlight any changes to the dosage.

Novel combinations

A new clinical trial may propose co-administration with a different drug other than those assessed in the cross-reference submission.

You should use appropriate data to assess, describe and support the differences in product quality and patient safety. For example, impurity levels (such as endotoxin) should be reassessed given the contributions by the co-administered drugs and any diluents used in compounding. Compatibility and in-use stability data will be required if the drugs are combined in a single container, either during the manufacturing process or just before they are administered together.

Changes in route of administration

If the sponsor changes how the drug is administered, they should provide the relevant quality information. This is required for marketed and non-marketed investigational drugs. For example, if the container closure system is changed to support the new route of administration, information on the container closure and stability of the product may be required.

Note that a comprehensive quality package is required for a change in formulation.

Phase of clinical trial

The sponsor's experience and knowledge of the drug will increase through the development phases (from Phase I to III). The quality information associated with this part of the clinical trial should reflect the stage of development.

For example, quality information provided in support of an earlier trial phase can be cross-referenced in the quality package for a later trial phase. Sponsors should identify which sections in the submission still apply and which have been updated.

Health Canada may ask for additional information, consistent with the trial phase, if the cross-referenced information for the proposed clinical trial was authorized in an earlier clinical trial. Alternatively, you should justify why the cross-referenced information is appropriate.

Change in patient population

If the drug was authorized for use in a different patient population, you should reassess the risk profile of the drug and modify the cross-referenced information accordingly.

For example:

• cross-referenced information in a previous application for an adult patient population should be further assessed for process-related impurities if the new trial is for a pediatric patient population
• sponsors should submit a new calculation if the change in target patient weight affects the original endotoxin calculation

Biologics quality guidance

The regulatory requirements for chemistry and manufacturing information for clinical trial drugs are outlined in sections C.05.005(g) and C.05.008(3)(d) of the Food and Drug Regulations.

Please refer to the following guidance documents when preparing quality (chemistry and manufacturing) information for your CTA or CTA-A:

• Guidance document for clinical trial sponsors: Clinical trial applications
• Guidance for Industry Preparation of the Quality Information for Drug Submissions in the CTD Format: Biotherapeutic and Blood Products
• Harmonized requirements for the licensing of vaccines and guidelines for the preparation of an application
• Preparation of clinical trial applications for use of cell therapy products in humans
• Information and submission requirements for biosimilar biologic drugs
• Regulatory roadmap for biologic (Schedule D) drugs in Canada

Contact us

For questions or information about this notice:

Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate
100 Eglantine Dr
Address Locator: 0601C
Ottawa ON K1A 0K9

Email: brdd.ora@hc-sc.gc.ca