What we heard: Consultations on clinical trials regulatory modernization initiative (spring and summer 2021)

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Executive summary

The current clinical trial regulatory framework has served Canada well by upholding high standards and patient safety. A modernized clinical trials regulatory framework is needed in light of:

By building on the current framework, we are proposing to introduce flexibilities to support innovation and evolving trial complexity.

The modernization of the clinical trials framework is one of 5 pillars under the Regulatory Innovation Agenda for health products. Key aspects of the clinical trial regulatory modernization initiative include:

Clinical trials have been at the forefront during the COVID-19 pandemic. The interim orders adopted as exceptional measures were designed to provide greater flexibility on how to conduct clinical trials during the pandemic. This provided us with the opportunity to pilot some of the elements that we were already considering as part of this modernization initiative. It also demonstrated their value and feasibility long-term.

As part of this regulatory modernization process, we have consulted and gathered feedback from stakeholders to help us refine the policy and develop regulations.* Stakeholders were invited to comment in writing to a consultation paper through an online questionnaire and email submissions and to participate in 8 interactive webinars. We received 122 written submissions and close to 1,000 stakeholders participated in the webinars.

Overall, respondents agreed with the proposals to modernize the clinical trials framework. Respondents highlighted key benefits for patients and stakeholders in Canada. The proposal would, for example:

Respondents also provided suggestions on how to improve the clinical trials framework. These included:

Some respondents also emphasized aspects that need to be taken into consideration while designing the clinical trials framework. These included:

This report summarizes the comments and responses we received during this consultation period, which lasted from May to July 2021.

*Please note that a separate consultation on the proposed regulatory framework for clinical trials on foods for a special dietary purpose (FSDP) was held. Read the "what we heard report related to FSDP".

Introduction

There are 5 key pillars of the Government of Canada's Regulatory Innovation Agenda for health products. One of those pillars is the modernization of clinical trial regulations. This pillar is an important goal for the federal government and will benefit people living in Canada.

Technology is advancing quickly and new types of promising health products and foods for a special dietary purpose are being developed. We are also seeing new clinical trial types and designs. In light of such advances, there's a need to modernize Canada's clinical trials regulatory framework.

A modernized regulatory framework for clinical trials in Canada should support the adoption of promising novel safe and effective health care therapies. It should also support innovations that can improve people's health. With this initiative, we also want to ensure that people have access to the information they need to make informed decisions about their health.

As we stated in the Forward Regulatory Plan for 2021-2023, Health Canada is committed to modernizing the clinical trials framework. We intend to: 

The interim orders for clinical trials during the COVID-19 pandemic

Clinical trials have been at the forefront during the COVID-19 pandemic, both domestically and internationally. This exceptional crisis has highlighted the need for a revised clinical trials regulatory framework.

Canada was quick to respond to the pandemic by issuing temporary interim orders (IO). Specifically, the IOs for clinical trials on medical devices and drugs related to COVID-19 gave greater flexibility on how to conduct clinical trials during the pandemic. The first IO was approved on May 23, 2020, and the second IO on May 3, 2021.

The IOs provided the opportunity to pilot and demonstrate the value and feasibility for some elements that Health Canada was already considering under the clinical trials modernization, including:

The IOs also made it possible to conduct a broader range of clinical trials and how they are conducted through:

While the scope of the IOs is narrower than what is being proposed, lessons learned from the COVID-19 pandemic clinical trials have helped us develop the proposed Clinical Trials Regulatory Modernization Initiative. As well, comments received from stakeholders during the consultations were very positive and emphasized the importance of the new measures we implemented as part of the IOs.

Consulting with stakeholders

As part of the modernization initiative, we consulted stakeholders across Canada. Their feedback is being used to inform the development of the proposed policy and regulatory framework.

We thank all the stakeholders across Canada who took part in the spring and summer 2021 consultation process. They came from various sectors, including academics and research institutes, industries, patient advocacy groups, health care practitioners and health care organizations.

About the consultations and who participated

Health Canada conducted consultations on the proposed Clinical Trials Regulatory Modernization Initiative between May and July 2021 to gather feedback from stakeholders. As part of this process, we published a consultation paper and invited stakeholders to comment in writing. We also consulted key stakeholder groups interactively during webinar sessions.

Written submissions

From May 20 to July 4, 2021, stakeholders were invited to submit their comments and input by filling out an online questionnaire (around 35 questions) or by sending an email. We received 122 written submissions (85 through the online questionnaire). Responses were received as follows:

Webinar sessions

We also held 8 interactive webinar sessions in June 2021 to engage stakeholders on the Clinical Trials Regulatory Modernization Initiative. We received many comments and questions at these sessions, which close to 1,000 stakeholders attended.

Consultation sessions Number of sessions Number of attendees (approximate)
Research institutes, academia and contract research organizations stakeholders 1 350
Medical devices stakeholders 1 205
Pharmaceutical, biologic and over-the-counter medicines industry stakeholders 1 150
Patients and patient groups stakeholders 1 100
Biologic and radiopharmaceutical drugs stakeholders 2 84
National research organizations stakeholders 1 80
Natural Health Products industry stakeholders 1 22

What we heard

Overall, most stakeholders supported the modernization initiative. Approximately 75%* of the respondents said the modernization proposals would facilitate and encourage innovative clinical trials in Canada if certain conditions were met.

These conditions included, for example:

More generally, respondents affirmed that the proposals would improve people's access to health technologies that may help diagnose, prevent, treat or cure physical and mental health conditions.

Most respondents favoured international alignment. Others, however, said it's important to learn from other regulators' challenges.

Respondents also emphasized that safety is paramount to any innovation. As well, consideration should be given to the needs and issues related to high-risk populations (such as children, people living with rare and/or fatal diseases).

Patients and patient groups recommended looking at ways to increase patient involvement and engagement when designing studies (for instance, collaborative research). This would ensure outcomes that matter to patients are included (for example, by setting research priorities and defining research questions).

*Note: We posed the question "Based on your experience and knowledge, would the proposals in the consultation paper meet Health Canada's goal of enabling innovative clinical trials in Canada?". About 75% of the stakeholders who gave an answer said "Yes", 18% "Don't know" and 7% "No".

The agile life cycle approach

Most respondents favoured a more agile life cycle approach to regulating clinical trials (for example, such an approach would create a more favourable environment for conducting master protocols and adaptive trials).

The modernized framework would enable and support novel and innovative types of clinical trials in Canada. It would also:

Patient safety

Respondents agreed that helping participants to access innovative clinical trials is important while ensuring participant safety. Some emphasized that the innovative nature of the trial should not supersede the safety of the trial. Others favoured simplifying the regulation of trials involving multiple products (for example, umbrella trials) as long as the expertise needed to review each component is kept.

International alignment

Industry respondents said that the proposed changes are aligned better with international clinical study practice requirements. Harmonization, collaboration and alignment across global regulators are valued, certainly for complex and innovative clinical trials. Biologic and radiopharmaceutical drugs stakeholders suggested that Health Canada accepts or considers foreign clinical trial authorizations to decrease submission burdens.

Research ethics boards and Health Canada alignment

Industry respondents also said it's important to ensure that research ethics boards and Health Canada are better aligned in their processes. Further clarification of their respective roles would also ensure efficiency.

Sponsors should be able to submit their trials for review to both a research ethics board and Health Canada at the same time. Efficiencies are best realized when processes are consistent and predictable.

Other suggestions and concerns

Other suggestions for Health Canada to consider included the following:

Some industry and patient group respondents were concerned the new regulatory framework may create significant administrative barriers (for example, monitoring safety while the trial is ongoing). They felt these proposed requirements should be further clarified. Others viewed those tools and requirements as beneficial to better ensure the safe conduct of trials in Canada.

Some respondents said the key to efficient clinical research lies with the integration of clinical research within the health care system rather than novel trial designs. They said that the regulatory framework should not only allow Health Canada to better regulate new research designs, but that it should also cover the type of research infrastructure needed to deliver clinical trials. It was suggested that Health Canada contribute to developing certain requirements for a permanent research infrastructures across Canadian sites.

Other suggestions included introducing a clearly defined mechanism for post-trial access to investigational products. This would allow patients who benefit from a treatment to continue to receive it after a clinical trial ends.

Single authorization for multiple products

A modernized regulatory framework would make single authorization possible for clinical trials involving:

Efficiency and reducing burdens

A modernized regulatory framework would significantly increase efficiencies for the application, amendment and authorization processes for clinical trials involving multiple health products. This would further streamline Health Canada's interactions with the sponsor throughout the trial.

Most respondents said the more streamlined approach would reduce the burden on sponsors for trials that involve multiple products. Currently, these fall under different regulations. The proposed approach would facilitate the conduct of more complex trial types in Canada.

Given the potential complexity associated with the single authorization process, some respondents said a guidance document outlining the administrative and technical requirements and the implementation phase would be helpful.

Good clinical practice

To support the single authorization of a clinical trial involving multiple product lines, it's important to align the clinical trial authorization holder's regulatory good clinical practice (GCP) obligations and requirements across product lines. This would protect participants and the integrity of the data throughout the duration of the clinical trial.

Most respondents indicated that they did not anticipate issues adhering to GCP across product lines. Most medical device respondents did not foresee challenges associated with complying with GCP principles in the International Organization for Standardization (ISO) 14155 standard.

However, some respondents from the medical devices industry suggested lighter regulatory requirements for trials involving in vitro diagnostic devices. Others recommended allowing sufficient time to adapt to the proposed changes for organizations conducting trials involving natural health products.

Risk-based approach

The proposed risk-based approach for clinical trials would stratify different levels of regulatory requirements based on the known safety information and relative risk of the product(s) involved in a trial. Health Canada proposes to establish a coherent risk-based approach in the regulations for clinical trials for all product lines, ensuring the regulations align domestically and internationally where possible.

Most respondents said this approach would be more efficient without adversely affecting patient safety. It would also facilitate the conduct of clinical trial research in Canada by reducing the administrative burden for lower-risk trials.

Clearly defining risk categories and process

Industry respondents asked for more clearly defined, detailed and articulated risk categories (for example, in a guidance document). They requested greater evidence as to why certain trials fall under each risk categorization. They also asked for examples of the different trial requirements and criteria used to distinguish between risk categories.

Predictable and consistent regulatory requirements

Industry respondents also said that efficiencies are best realized when regulatory requirements are predictable and consistent.

Patient advocacy groups stressed the importance of ensuring timely and appropriate access to innovative health products for patients.

Other considerations

Health care providers said the approach would have the greatest positive impact on investigator-initiated studies that look at repurposing existing therapies for new indications.

Academic and research institute respondents noted that this approach would be more feasible with experienced and educated research staff. They also suggested that Health Canada consider putting together expert groups to assess risk levels for high-risk populations (for example, clinical trials involving the pediatric population).

Some respondents noted that, for research involving critically ill patients, it would be important to consider the relative risk to these patients and not exclude them from clinical trials. One patient advocacy group suggested having separate trials and regulatory requirements for lethal and non-lethal diseases.

Terms and conditions

The proposed initiative would give Health Canada the ability to apply terms and conditions to a clinical trial at any point of the trial. This makes the regulations more agile and provides options to protect the health and safety of clinical trial participants better.

For the product being tested or the way the trial is being conducted, the intent is to apply terms and conditions on a case-by-case basis to address a significant uncertainty or mitigate a significant risk.

Well-defined parameters

Most respondents supported this approach. Academics and research institutes, industries and patient advocacy groups emphasized the importance of having well-defined parameters for using terms and conditions to ensure they are applied in a predictable manner. They suggested that Health Canada hold planning meetings with sponsors before a clinical trial starts, to work on terms and conditions together.

Research ethics boards and Health Canada alignment

Some industry respondents said the responsibilities of Health Canada and research ethics boards should be clarified. Where possible, they should also be harmonized to avoid redundancies and potential contradictions.

Other concerns

There were also concerns that terms and conditions may put more burden on sponsors (for example, asking for information not required in any other jurisdiction).

Decentralized clinical trials

Most respondents supported the proposed approach to facilitate the use of decentralized clinical trials (DCTs) in Canada. This is an important initiative, as over 30% of the population lives outside medium-sized and large urban areas.

DCTs are conducted with study participants located outside of clinical research centres. For example, some studies could take place remotely, without a physical visit to a trial site, after the necessary technology has been installed and explained to the patient.

DCTs may include the use of videoconferences with investigators, internet-based tools for collecting data, and reporting and mobile technologies such as biosensor devices.

As reported by respondents, COVID-19 will have a lasting, but positive impact on the use of remote technologies and patient-centricity in clinical trial execution. Video visits have been used in several trials because of COVID-19 and results are generally positive.

Facilitating participation in clinical trails

Respondents agreed that DCTs are more equitable. They provide an opportunity for patients and clinicians who are not connected to major health institutions and/or cannot relocate to a clinical site due to disabilities, family, work, social challenges or other factors.

DCTs may be particularly useful for studying rare diseases, where it can be difficult to get a large enough patient pool together to provide statistically significant trial results. Respondents said DCTs would improve a patient's access to novel therapies. As stated by an industry respondent, the additional flexibility provided by DCTs during the COVID-19 pandemic (for example, patients not necessarily needing to go to investigational sites for clinical trial intervention) is a move towards ensuring more patients are able to get treatment faster.

It was noted, however, that only patients who are connected to the internet and can afford the technology are able to take advantage of a virtual trial. Other patients would still be left out.

More information and clarity needed on DCTs

Respondents also said that additional details and clarity are needed to better define DCTs in Canada.

Research institutes, academia and contract research organizations stakeholders said that oversight requirements must be clearly outlined in a guidance document to help with implementation and ensure compliance. They also requested more information on how Health Canada will ensure safety for clinical trial participants through adverse events reporting and expanded inspection efforts.

Academics and research institute respondents feel that the lack of clarity from regulators on how remotely generated data will be accepted leads to hesitancy to adopt novel technologies.

Technologies and DCTs

Industry respondents said that further clarification is needed on the technological requirements for data collection and other types of technologies that may be used to support DCTS (for example, requirements for e-signatures and digital identity). They also said that documented informed consent requires clear interpretation to ensure it incorporates remote and virtual consent formats.

National research organizations also favoured an informed consent process through electronic means (for example, electronic signature, video or audio recording) and better use of current communication technologies to enhance communication between participants and researchers.

Hybrid approach to DCTs

Some industry respondents favoured a hybrid approach for decentralized trials (a combination of site and virtual/remote options). Some assessments could be remote (performed at the patient's home or in their local care community). Or there could be a mix of partial-remote/partial-traditional (performed on site) within the same study.

A hybrid approach would increase options for the participant, which would in turn mean a greater proportion of the population could participate in a trial.

Service provider oversight

Proposed amendments to the regulations would give us direct authority and oversight over service providers (for example, contract research organizations (CROs), site management organizations (SMOs)). This would enable us to address non-compliance or deficiencies in the conduct of clinical trials, which could affect participant safety and data integrity. Essentially, with the proposed amendments, we would have authority over both the sponsor and any service providers to whom the sponsor has outsourced its activities.

Most sponsors of clinical trials reported outsourcing a variety of activities to service providers. Outsourced activities could include core laboratory tests, data transfer portals and statistical analysis. Some sponsors noted that it's already common practice to outline legal responsibilities between the sponsor and the service provider in a contract.

From the sponsors' perspective, respondents supported the proposal, stating it would help clarify expectations between sponsors and service providers involved in a clinical trial. It would also increase the quality of outsourced activities since service providers would be accountable for their actions (for instance, improve adherence to regulatory requirements).

However, some respondents are concerned that it would likely increase the costs of clinical trials, since service providers would accept more legal risks. Research institutes, academia and contract research organizations requested more information on this proposal (for example, the scope of inspections, selection criteria and verifying compliance of international players).

Transparency

Most respondents saw value in a new transparency policy and/or regulations for registering trials and reporting results. Support was strongest from the academic community (73%) compared with industry (54%).

There were general statements of support for an updated policy or new regulation and the potential benefits this would have for people living in Canada. One academic says, "Far too often, the outcomes are not known, shared or easy to find."

Responses cite benefits for patients:

Responses cite benefits for researchers:

About 13% of total respondents did not see value in a new transparency policy. Reasons given included the following:

Some pharmaceutical, biologic and over-the-counter medicines industry stakeholders wanted more information on the reasoning behind this regulatory change given that clinical information is disclosed under Vanessa's Law. Some natural health product sponsors indicated that a lack of intellectual property protection may deter some sponsors from doing research in Canada if results reporting were mandated.

Registration

Most respondents from industry and academic research institutes (86%) register their trials with an international registry.

Almost all who mentioned a registry use ClinicalTrials.gov. It's the standard or the most widely accepted platform. Some use the EU Clinical Trials Register and 1 respondent recommends ISRCTN. Device sponsors note that EUDAMED will also be used in the future when it becomes law.

Challenges to keep registration information up to date

Feedback indicated that more academic researchers have challenges in keeping their international registration up to date compared with industry researchers. Several industry respondents said they have established practices in place for this.

The most common challenge around keeping information up to date in the registries was the burden of being required to use multiple registries in different countries for multinational trials. Other challenges included the dedicated resources needed to maintain up-to-date registry information and registries that are not user-friendly.

Public disclosure of results

Most respondents from industry and academic research institutes (73%) report their results in international registries. Many commented on the value of results reporting.

Well-established practice

Respondents explained that reporting their results is an established part of their good clinical practices when conducting research and/or part of a standard operating procedure. Some explained that reporting is an international or research ethics board requirement, or a requirement for publication.

Challenges with reporting results

Of the 27% of respondents who said they do not report their results in international registries, about half say it's not their role or responsibility. These were contract research organizations (CROs) working with both industry and academic sponsors. Most said this is the sponsor's responsibility.

Of those who do not report their results in international registries, 20% (representing both industry and the academic community) said they publish results (for example, anonymized patient level data or result summaries) on their company website.

Concerns about burden

Burden plays a large role in compliance for reporting. Some respondents who do not support a new policy or regulation said they support transparency in principle or certain aspects of Health Canada's proposals, particularly for higher-risk products. However, many respondents said they are concerned about certain possible requirements (for example, a new Canadian registry, the need to provide clinical study reports), even though these were not proposed in the consultation.

Minimize additional burden by aligning internationally

Since they are already required to register, particularly in ClinicalTrials.gov, some respondents indicated that a new policy or regulation on registration in Canada should rely on existing registries. They said a new registry may add to the burden.

Respondents suggested that Health Canada should align the new policy with international regulations. They discouraged Canadian-specific requirements. Suggestions included:

Clear communication

Some respondents said that Health Canada should clearly communicate its expectations for how to meet a new policy by outlining:

Online information

With enhanced transparency measures, more information about Canadian clinical trials would be available from international registries. Health Canada proposes to play a role in making this information more accessible on the Government of Canada website.

Some respondents indicated that bringing together information about Canadian trials from other sources is useful, including extracting information registered elsewhere or providing links on the Government of Canada website. For example: "Canadians who are interested in clinical trials should be able to access a Health Canada-hosted site to search for clinical trials, find information related to contacting those conducting the clinical trials and learn about the trial results."

Biologic and radiopharmaceutical drugs respondents underlined the importance of the peer-review process undertaken by scientific journals to prevent incorrect information from being communicated to the public. They suggested that Health Canada consider this when developing its public registry policy.

Research institutes, academia and contract research organizations respondents requested more transparency for the following:

Medical devices

With the 2018 Action Plan on Medical Devices, Health Canada committed to reviewing longstanding stakeholder concerns about how the current regulatory framework for medical devices might be unintentionally limiting clinical trials in Canada. Through the Clinical Trials Regulatory Modernization Initiative, we aim to encourage more clinical research in Canada, while continuing to focus on the protection of patient safety. Respondents who identified themselves as medical device stakeholders were asked questions on the following topics.

Off-label use trials of licensed devices

Health Canada is exploring the possibility of reducing the requirements for clinical trials studying off-label use of medical devices licensed in Canada. Patient safety remains a priority.

Most responses supported reduced regulatory requirements for off-label use trials of licensed medical devices, as these products have known safety profiles. However, some stakeholders said there may be cases where a new use could result in significant and/or unexpected new risk that would necessitate proportionate regulatory oversight.

Notifications and amendments

As part of the regulatory modernization initiative, Health Canada is proposing to allow amendments to clinical trial applications to be made without requiring the sponsor to submit a new application.

Most respondents supported the 3 pathways proposed for clinical trial amendments (significant changes, notifiable changes and non-significant changes). Industry stakeholders highlighted the importance of a simple and streamlined online system with predictable timelines that's easy to navigate. They also requested further guidance on the assessment of changes as significant or non-significant.

Investigator-initiated trials

The current Medical Devices Regulations permit only manufacturers and importers of medical devices to apply for clinical trial authorization. The Clinical Trial Modernization framework would expand who can file an application to include independent investigators in addition to manufacturers and importers.

Some stakeholders indicated that these trials may help to generate new clinical data. Others felt that independent researchers may lack the internal resources and experience needed to submit a full application and conduct a clinical study. As well, they may not have adequate access to medical device records from the manufacturer, and thus may not understand fully the risk involved. It was recommended that investigators should coordinate with manufacturers and receive their approval before they apply for an authorization.

In all cases, stakeholders emphasized that patient safety and clinical trial integrity should remain priorities.

Next steps

Health Canada appreciates the comments and input from the various stakeholders involved in clinical trials in Canada.

The feedback received during the consultation process will help us refine the policy and develop regulations to modernize the clinical trials framework.

We will continue to engage stakeholders and subject matter experts as this initiative progresses. Please continue to consult the Forward Regulatory Plan 2021-2023: Modernization of the Regulation of Clinical Trials for updates and future opportunities to provide your feedback on this important initiative.

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