Virtual and hybrid clinical trials have arrived. Having learnt from pilot projects, pharma companies are systematically incorporating patient-centric services into trials, resulting in a significant minority of today’s studies featuring virtual elements. The surge in interest reflects recognition that running trials without sites, or at least reducing site visits, enables studies to access new patient populations, accelerate enrollment and increase retention.
In their purest form, virtual clinical trials eliminate the need for study sites. A range of technologies and processes cover the tasks normally performed at sites. Participants can enroll and give consent online before receiving shipments of study drugs direct to their homes. In some cases, nurses visit participants to administer drugs and collect data. In other trials, devices including wearables enable the remote collection of data.
These technologies and processes have enabled a number of sponsors, starting with Pfizer in 2011, to design and run site-free trials. Such trials have big benefits. Whereas only patients who live close to sites and have the time to visit them frequently can commit to traditional clinical trials, people all over a country can join virtual studies with minimal effect on their day-to-day lives. This opens up clinical development to new groups of patients and makes it easier for them to join and stay in trials.
Despite these benefits, fully-virtual trials remain an exception. Many studies need to perform MRIs, biopsies and other assessments that cannot take place at a patient’s home, meaning only a subset of protocols are suitable for the fully-virtual model.
Faced with a desire to unlock the benefits of virtual trials and a need to perform some procedures at sites, sponsors have hit upon hybrid designs as the best of both worlds. These studies allow sponsors to significantly reduce the number of sites and the frequency with which patients visit them through the use of the technologies and processes that enable virtual trials, but still have physical locations to perform certain procedures.
The hybrid model has proven to be popular. Sponsors have run hundreds of clinical trials featuring virtual elements across tens of countries in a wide range of indications, most notably CNS, oncology, cardiovascular and rare diseases, in adults and children, alike. The model has specific benefits in some of these populations. Sponsors of rare disease trials easily enroll geographically-dispersed patients, while companies studying pediatric drugs spare parents the burden of taking their children to sites. In some cases, these trials would be impossible to run without the virtual elements.
As sponsors have integrated direct-to-patient (DTP) and direct-from-patient (DFP) services into more protocols, it has become clear that virtual and hybrid trials are not overly complicated and that the designs are applicable to a wide range of studies. That said, there are critical differences between traditional and virtual or hybrid trials that must be considered upfront to ensure success.
Preparing to run virtual and hybrid trials
Sponsors of traditional clinical trials typically start considering the supply chain toward the end of the planning process. The approach works because the supply chain is relatively routine in many trials. That is not the case in virtual and hybrid trials.
In DTP and DFP studies, the supply chain is a vital layer in that must be discussed at the start of the process by all the stakeholders. The sponsor, CRO, supply chain specialist and other vendors need to sit down together before the trial goes live to discuss the protocol design and draw up a very robust distribution plan.
The plan must address how the trial will distribute and track the medication, and, most crucially, how it will ensure the safety of patients treated at home. A robust safety management plan is vital. This plan needs to do far more than just address how patient safety will be guaranteed during normal conditions. It must address innumerable “what if...?” scenarios that could put patients at risk so that contingency plans are in place and everyone knows their role if an incident occurs.
Incidents that affect patient safety are the worst of the “what if...?” scenarios but they are far from the only eventualities the teams designing virtual and hybrid trials need to consider. The distribution plan must consider a range of other routine and unusual situations that teams could encounter when shipping packages to and from patient’s homes. What happens if a person is not home to receive a package? How will patients return unused medications at the end of the trial? What will happen to the drugs?
These questions need to be asked and answered before the trial starts. Teams that start virtual trials without addressing these and other “last mile” topics risk losing the chain of custody for packages whenever there is an unexpected change to the normal supply chain.
Technologies address some of the supply chain challenges but they can only do so much. Packages can be tracked using GPS and rigged up to alert teams to excursions from the optimum temperature range for their contents. It is up to people to quickly act on this information, though. Sponsors and CROs need to adopt processes for dealing with deviations such as temperature excursions and have someone available around the clock to implement them.
Other issues that should be discussed and documented upfront include who can talk to the patients, how data will be kept blinded and how the team will coordinate with nurses for home care. The team also needs to consider what steps will need to be taken at the end of the trial to ensure there is full documentation of the chain of custody for all patients.
Managing the remaining challenges
From trial to trial, many of the questions sponsors, CROs and other stakeholders need to ask during the planning stage will remain the same. The answers will be different, though. The variability in the best way to design and run hybrid and virtual clinical trials stems from regional differences in how the studies are regulated.
To pick one example from many, some countries allow depots or central pharmacies to ship drugs direct to patients. However, this practice is prohibited in other countries, which only allow sites to provide study drugs to patients. A similar patchwork of non-harmonized requirements applies to the return and destruction of drugs. These local laws dictate what can be shipped and how.
The regional variation in laws and regulations is one of the few impediments to hybrid and virtual trials. Sponsors have responded to the impediment by limiting the geographic reach of their studies. To date, the vast majority of trials with DTP and DFP elements have only enrolled people in the US. Limiting enrollment to one country eliminates many of the challenges related to hybrid and virtual clinical trials, but also restricts the impact of the model.
Recognizing that, sponsors, CROs and vendors are working to apply the lessons learnt in the US to trials in Asia, the European Union and Russia with a view to running global, multi-country hybrid and virtual clinical trials. For the industry to enroll patients in multiple countries, it will need to figure out an efficient, compliant way to ship medicines to participants.
Ideally, a sponsor would have one central pharmacy per region to ship drugs across borders to all patients enrolled in the study. For now though, the feasibility of this approach remains largely untested and major questions about who prescribes and dispenses medicines still need to be resolved.
Sponsors need to be aware of these and other limitations and restrictions as they design virtual and hybrid trials. The barriers to adoption of the model are lower and less prevalent than some people realize, though. Many sponsors are designing highly-effective hybrid and virtual clinical trials despite the challenges created by regional regulatory variation.
These sponsors are getting patients into trials faster and keeping them in longer, accelerating the progress of new medicines and facilitating the completion of long-term outcomes studies.