Company: APM
Filing Date: 2025-07-15
Form Type: DRS
Source: 0001213900-25-063899
Chunk: 225

Company: Aptorum Group Ltd
Filing Date: 2025-07-15
Form: DRS
Chunk 225
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. In Canada, NDSs are subject to user
fees and these fees are typically increased annually to reflect inflation.

Even if Health Canada approves
a product candidate, the relevant authority may limit the approved indications for use of the product candidate, require that contraindications,
warnings or precautions be included in the product labeling, including a black box warning, require that post-approval studies, including
Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs
to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management
mechanisms.

Health Canada may prevent
or limit further marketing of a product based on the results of post-marketing studies or surveillance programs. After approval, some
types of changes to the approved product, such as adding new indications, manufacturing changes, and additional labeling claims, are subject
to further testing requirements, notification, and regulatory authority review and approval. Further, should new safety information arise,
additional testing, product labeling or regulatory notification may be required.

European Union Regulation

Regulation in the European Union

The process governing approval
of medicinal products in the EU generally follows the same lines as in the United States. It entails satisfactory completion of pharmaceutical
development, non-clinical studies and adequate and well-controlled clinical trials to establish the safety and efficacy of the medicinal
product for each proposed indication. It also requires the submission to relevant competent authorities for clinical trials authorization
and to the European Medicines Authority, or EMA, for a marketing authorization application, or MAA, and granting of a marketing authorization
by these authorities before the product can be marketed and sold in the EU.

Clinical Trial Approval

Pursuant to the currently
applicable Clinical Trials Directive 2001/20/EC and the Directive 2005/28/EC on cGCP, a system for the approval of clinical trials in
the EU (the equivalent of the IND process in the United States) has been implemented through national legislation of the EU member states.
Under this system, an applicant must obtain approval from the competent national authority of an EU member state in which the clinical
trial is to be conducted or in multiple EU member states if the clinical trial is to be conducted in a number of EU member states. Furthermore,
the applicant may only start a clinical trial at a specific study site after the independent ethics committee has issued a favorable opinion.
The clinical trial application, or CTA, must be accompanied by