Canada Seeks To Make Decentralized Trials More Practical For Sponsors

By formally adopting a modernized definition of a clinical trial site, Health Canada is hoping to provide greater flexibility to sponsors who want to incorporate decentralized elements in their trials.

Source: Alamy

A Patient's Home, Where Trial-Related Activities Are Conducted, Will Qualify As A Clinical Trial Site

As part of ongoing efforts to modernize its clinical trials framework, Health Canada is planning to introduce measures to support the conduct of decentralized studies. Among these are plans to adopt a formal definition of what constitutes a clinical trial site.

The term is currently not defined in Canadian regulations and has resulted in a “lot of questions regarding this topic coming to our offices,” said Alicja Kasina, a senior regulatory advisor for clinical trials compliance program at Health Canada.

“Of course, the concept of a clinical trial site depends on the trial size, type and design,” and it can involve “multiple locations, for both treatment and follow up care,” Kasina noted. But the growing use of decentralized trials – which allow certain activities to be conducted remotely and in, or near, the homes of participants – has prompted the need to clarify the definition of a trial site to “accommodate new technological advances” and address “other implications for possible participants.” 

Kasina was speaking at this month’s virtual 2022 Good Clinical Practice (GCP) symposium, which was organized by the UK Medicines and Healthcare products Regulatory Agency in partnership with regulators from the US and Canada. 

When attempting to define a trial site, Kasina explained that the government department would aim to “accommodate all types of trials” and “cover all locations like hospitals, community labs, participants’ homes and so on.”

It has proposed defining a trial site as: the location(s) where trial-related activities are actually conducted, where “trial related activities” could include recruitment, informed consent, monitoring and visits that are done in a virtual manner.

While the current regulations do not prohibit decentralized trials, the Health Canada official believes that “this new definition is really needed” as it could help drive “greater modernization” of clinical trials by promoting different approaches, such as the use of virtual tools and home visits, and “foster greater agility and flexibility in the regulatory framework.” This, in turn, would make clinical studies more accessible to Canadians, “who may not otherwise consider CTs [clinical trials] as a possibility, for example, due to living in remote areas.”

When finalizing the definition, the department will have to consider its impact on aspects such as provincial and territorial jurisdictions, privacy of data and information, research ethics committee approvals, the role and responsibilities of trial sponsors and investigators, existing trial processes (eg, notifications) and compliance and enforcement activities, said Kasina.

Other changes proposed by Health Canada to support decentralized trials are:

• Using the term “documented informed consent” instead of “written informed consent” in Canadian regulations, where the term "documented" may refer to an “electronic signature, a video or audio recording of the consent process when a verbal confirmation is provided by the participant.”

• Allowing for a witness to attest that informed consent was given, if necessary, under exceptional circumstances. Health Canada has previously issued interim orders permitting the use of this provision for COVID-19-related trials.

• Allowing for greater flexibility in who can be a qualified clinical trial investigator by permitting a wider scope of health professionals to be considered for the role.

The proposed regulatory changes, if implemented, could make decentralized trials more practical for sponsors. Kasina clarified that in Canada the sponsor has the overall responsibility for the conduct of the trial, while the qualified investigator (QI) is responsible for all medical decisions. If a single QI is responsible for different locations, logistical support should be in place “so that the investigator has sufficient time and ability to oversee the sites in all locations,” she added.

UK Definition Sufficiently Flexible

UK and US regulators at the symposium said they were also supportive of decentralized trials. The key message that regulators from the three regions wanted to get across was that they were all “looking at innovative ways of working” and “encourage anybody who is planning such trials, who is doing anything new, to come and talk to the regulators beforehand,” said Andy Fisher of the MHRA. 

The three regulators are also examining whether they need to clarify their existing regulatory provisions relating to clinical trials.

In the UK, the current legislative definition of a trial site is “sufficiently flexible” to facilitate trials where patients can participate from their homes or they have to visit a local site only for specific services, eg blood draws or scans, said Fisher, who is lead senior GCP inspector at the MHRA.

While medically qualified staff should always be present to oversee trial participants as necessary, “there are flexibilities allowed in relation to qualified doctors’/dentists’ specific involvement,” said Fisher. “Some delegation is allowed,” for example, in relation to “consent or investigational medicinal product prescribing, particularly in Type A trials, where health care professionals are acting within their role in normal clinical practice,” he explained.

Also, the investigator may need to have oversight of individuals undertaking study-related activities, depending on what these activities are in relation to normal clinical practice. In the case of nurses conducting trial assessments at the patient’s home, for example, “the investigator needs to be ensuring that these personnel are suitably trained and qualified,” Fisher said. Where the sponsor is involved in contracting these services, a mechanism is required to assure that the investigator can undertake these responsibilities, when necessary.

In cases where local site facilities are used for trial activities, “there may be a need for appropriate contractual arrangements to be in place – either with the sponsor or with the investigator. These situations can be quite complex” and guidance on the website of the Integrated Research Application System (the UK portal for submitting trial applications) should be consulted, Fisher said.

Kirsty Wydenbach, deputy unit manager and expert medical assessor at the MHRA, said: “The UK has always been able to allow some flexibility” and permit the use of “decentralized elements in trials through our guidance.”

A key example of this was during the COVID-19 pandemic, when “we published additional wording on flexibilities” in a guideline that reiterated “what was already noted elsewhere,” Wydenbach said. “We didn't need to implement any sudden legislative changes to allow things like direct-to-patient shipping” of investigational medicinal products.

The UK is also updating its clinical trials legislation and a key element of the proposed changes is about “empowering researchers to take more risk-appropriate approaches to the whole of the trial lifecycle,” said Wydenbach. This should further support the uptake of decentralized trials “with the potential to really have a risk-adaptive approach tailored to each specific trial, which can only be a benefit to patients.” (Also see "UK Kicks Off Landmark Overhaul Of Clinical Trial Framework" - Pink Sheet, 17 Jan, 2022.)

Remote Monitoring Was Always An Option

Remote monitoring of trials by sponsors – whereby appointed representatives get direct access to the electronic health records (EHRs) of trial participants to check source data – has gathered pace during the COVID-19 pandemic.

The practice, which is an example of a decentralized element, was available to sponsors before the COVID-19 pandemic but had been used sparingly, noted the Canadian and US regulators at the symposium.

There is “nothing in our regulations or guidance” that precludes “remote monitoring,” said Health Canada’s Asma Syed. It is “one of those concepts” that was “always there and we encouraged the use of,” but it “just wasn't well understood by our industry or the fact that it was available to them,” said Syed, who is national manager at the government department’s Regulatory Operations and Enforcement Branch (ROEB).

The use of remote monitoring also increased in the US after the COVID-19 pandemic started. Jean Mulinde of the Food and Drug Administration noted that the agency had observed remote monitoring was starting to “creep into sponsors’ oversight practices” even before pandemic “and we were… fine with that.”

In the UK, the MHRA issued two new guidance documents on remote monitoring last year – one looked at data privacy expectations when allowing access to EHRs, while the other dealt with short-term mitigations that sponsors could put in place during the COVID-19 pandemic when fully-compliant EHR systems were not yet in place. (Also see "UK Explains Dos And Don’ts Of Remote Clinical Trial Monitoring" - Pink Sheet, 10 Sep, 2021.)