'Fit-for-Purpose' Considerations for Remote Trials
Q&A with Joachim Lövin explores the challenges and lessons learned in boosting the flexibility of conducting decentralized clinical trials post-COVID.
In the following Q&A, Joachim Lövin, a specialist in the area of decentralized clinical trials (DCTs) at Novo Nordisk, and workstream lead on modernizing clinical trial conduct with the industry consortium TransCelerate BioPharma Inc., shares insights on new learnings and approaches around DCTs coming out of the COVID-19 pandemic and the continuing challenges in implementing and conducting remote clinical trials.
Applied Clinical Trials: What have been some of the biggest post-COVID challenges for DCTs? How are you seeing them be addressed?
Joachim Lövin: There is no single answer. There is certainly concern about the level of difficulty in meeting regulator standards, but there is also hesitation—warranted or not—to design trials that make use of pandemic-era provisional regulations that permitted DCT elements. For both reasons, many stakeholders have returned to more familiar pre-pandemic trial designs.
That said, health authorities are releasing guidance that should give sponsors comfort. For example, the Danish Medicines Agency was the first to establish DCT guidelines.1 The FDA released draft guidance last year.2 Also, the ACT EU initiative3 has released a recommendation paper4 that includes an excellent appendix outlining each European Union country’s position on various DCT elements—such as electronic signatures or remote access to source data.
Still, even with established regulations, changing how we operate poses another critical challenge. I include myself when I say the biopharmaceutical industry tends to be set in its ways. Therefore, sound change management support should be considered to ensure all stakeholders—including internal teams, partners, patients, and sites—understand and are comfortable with DCT processes. In fact, a recent survey of sponsors’ post-COVID DCT experiences suggests how important it is to implement change management practices that uphold decentralized ways of working.5
In addition to assessing all the DCT elements available and the regulatory landscapes around them, we must also carefully consider which elements are truly fit-for-purpose for any given study. So, many industry organizations—such as the Decentralized Trials & Research Alliance,6 the Clinical Trials Transformation Initiative,7 and TransCelerate BioPharma Inc.8—are stepping in.
For example, as a part of its modernizing clinical trial conduct team,9 TransCelerate developed and made freely available seven process frameworks.10 This buffet of freely available tools can help sponsors assess how to adapt to digital data collection, direct-to-patient shipping, electronic informed consent, home health visits, local community-based facilities, remote site monitoring, and telemedicine.
Implementing DCT elements is not necessarily easy. Nevertheless, sponsor organizations must be the first to change and to think about DCT elements differently. Then, we must engage with regulators.
ACT: Why should the design of DCTs be more fit-for-purpose?
Lövin: The short answer is that clinical trials not fit-for-purpose will most likely fail. They won’t be able to measure and report on whatever the trial is studying. At best, they will struggle to recruit and retain the patients and sites on which the trial’s success depends.
That’s because “fit-for-purpose” refers to using those tools, technologies, and methods that best engender answers to the protocol question. Although it’s crucial to consider DCT elements that also reduce patients’ and sites’ participation burdens, easing those burdens is only one layer of a fit-for-purpose study design. To ensure DCT elements are fit-for-purpose, sponsor companies and their partners must always return to the scientific purpose driving the study. In other words, they should ask themselves two questions:
- What scientific question is the protocol trying to answer? (What is the endpoint?)
- Why do we want to deploy each particular DCT element?
The ideal, of course, is to leverage DCT elements that satisfy the protocol question and fit the study’s populations and locations. Sometimes, the data collection technology is not optional, but options are possible in the elements around it—such as telemedicine or direct-to-patient shipments. That’s why our TransCelerate team also built an Operational Complexity Assessment Tool (O-CAT)11 to be used independently or in tandem with the frameworks mentioned earlier. This tool can help organizations better understand how various DCT elements might impact their studies, and challenges them to think in the context of the geography and infrastructure in their clinical trial locations.
When possible, sponsors should also rely on patient advisory boards and key opinion leaders at their sites to better understand patient (and site) burdens. Publicly available tools, such as TransCelerate’s Patient Protocol Engagement Toolkit,12 can also help connect with intended patient populations during protocol development to ensure more fit-for-purpose designs.
ACT: How important is it to engage with health authorities when running a DCT?
Lövin: It varies, actually. Sometimes, it’s essential. Other times, it serves little use. Whether and when to approach health authorities in advance depends on the DCT elements being considered.
Once a trial is designed and its fit-for-purpose DCT elements are identified, it’s time to examine the regulatory landscape of the targeted countries. The need to engage with health authorities diminishes when clear guidance exists for the identified DCT elements. However, engaging with regulators is crucial when there’s no guidance, or it’s unclear whether a particular DCT element can be deployed as intended.
It becomes even more relevant when digital data collection tools are involved, and the intent is to start building novel digital endpoints. The question is then, “Have we used this technology here before?” If the answer is no, it’s important to explain to regulators:
- The purpose/why you want to use the DCT elements.
- What you want to achieve.
We sometimes forget, though, that laws outside of regulators’ purview might prevent deploying a DCT element. In such cases, there’s little point in talking with them. For example, in Sweden, an on-site presence is required to access patient data. Therefore, remote source data verification is prohibited. Swedish health authorities recognize the challenge this presents for DCT elements, but the law constrains them.
Regardless of the elements or countries intended for a trial, study teams should always work closely with their regulatory affairs contacts or their organizations’ policy and intelligence departments to develop a proactive regulatory strategy. These departments usually have valuable insights and may even have opportunities to converse with health authorities in advance.
ACT: What are some risk assessment and monitoring strategies for DCTs?
Lövin: Similar to connecting proactively with internal regulatory departments, clinical trial teams shouldn’t forget their organizations’ risk-based quality management teams. Involve them early. Their jobs become much more difficult, for instance, when they’re unaware that a trial will collect data through newer digital methods instead of traditional ones. Likewise, engaging any available central monitoring units can help determine what is permitted remotely and where pitfalls may arise.
Tools such as the O-CAT, or something equivalent, can also be used to pressure-test whether various DCT elements are feasible and what their implementation might require. Still, having backup measures ready is always a good idea. What if a DCT element fails? What alternatives could be deployed?
Equally critical is leveraging appropriate data management processes. If a DCT element generates data, for example, a well-thought-out plan should be in place to gain control over the data flow, both for internal and external use.
If nothing else, trial teams can get a reality check from their country-based affiliate network once they send the draft protocol. Boots-on-the-ground personnel know what they can or cannot do in their own countries. However, if a trial team gets pushback against a DCT element, they should ask why. Is there a legal or regulatory barrier? Is there a belief that sites won’t like it? Or is it because it hasn’t been done before, so it’s new and uncomfortable? If the answer is the latter, change managers may be able to assist in overcoming the resistance.
Every time a trial uses DCT elements, stakeholders should capture what they have learned and bring it back in-house. DCT elements often represent new ways of working. So, we must be willing to share knowledge within our own organizations and with the broader drug development community for the benefit of all.
References
2. https://www.fda.gov/media/167696/download
7. https://ctti-clinicaltrials.org
8. https://www.transceleratebiopharmainc.com/
9. https://www.transceleratebiopharmainc.com/assets/modernizing-clinical-trial-conduct-solutions/
10. https://www.transceleratebiopharmainc.com/wp-content/uploads/2021/12/MCTC-Process-Frameworks.zip
12. https://www.transceleratebiopharmainc.com/ppet/planning-for-patient-engagement/
