The global COVID-19 pandemic has had a significant impact on all our lives, forcing us to adapt and find creative ways to continue our day-to-day lives. Clinical trials are no exception and have had to face many new challenges. Due to local lockdowns, patient and site staff safety, and personal choice, some patients have been unable or unwilling to travel to their clinical site and in some cases, clinical sites have had to close completely. Clinical sites and sponsors have had to quickly implement solutions. This new way of life provides an opportunity for the further decentralization of clinical trials, with Direct to Patient (DTP) reducing or eliminating the need for patients to travel to clinical sites and potentially expose themselves and others to a risk of infection.
Even before COVID-19, decentralized trials offered many potential benefits to clinical sponsors and sites, including: broader patient access and demographics; opening trial participation to patients in remote areas and reducing the geographic barriers; assisting with recruitment and patient retention; and increasing access to patients with rare diseases. They may also help to decrease overall trial costs by reducing the need for investigator and site staff to dispense investigational medicinal products, and the need for storage at clinical sites.
Although they are only now receiving more attention, decentralized trials have been carried out successfully since the 1980s. Whereas traditional centralized clinical trials are conducted at designated study sites, and all procedures are generally performed by investigators and their delegated personnel, technology has opened the way for decentralized models, in which some or all study-related procedures take place away from the investigator site, either via telemedicine or through local healthcare providers, such as primary care physicians, pharmacists, clinics, home-based care or even a regional hospital. Smartphones, tablets, web browsers, access to tele-visits and electronic medical records are making it easier for patients and study staff to communicate and stay in touch in real time. With these advances in technology, the potential benefits are significant.
In a decentralized trial, clinical investigators remain the lead medical professionals conducting the trial, and it is under their authority that the drug is dispensed and administered to a patient. Even if no patient ever visits it, there is still a physical clinical site where the investigator conducts, receives or coordinates all trial-related activities.
Different Approaches
The industry refers to direct-to-patient as all inclusive, and encompassing Site-to-Patient (STP) supply, where the clinical site arranges and ships the product to the patient's home or chosen location from inventory held at the clinical site. True direct-to-patient bypasses the clinical site and the product is dispensed directly to the patient’s chosen location, usually their home or workplace, via a pharmacy. Ideally, the solution will take a hybrid approach allowing the patient and investigators to make the best decision for their unique situation. A best practice, flexible solution would allow for STP and DTP to apply to either all shipments for all patients, some shipments for all patients, some shipments for some patients, or in emergency situations only, depending upon how the approved study protocol is structured. If such flexibility is desired, sponsors must carefully evaluate potential DTP partners with this possibility in mind as not all have the necessary capabilities or infrastructure required to support this type of approach.
Studies can be set up to meet the needs of the patient population and the protocol. If possible, and if the trial design allows for it, patients should be given the choice of telemedicine visits or in-person site visits. Older patients generally express a preference for site visits, while younger patients prefer a telemedicine experience. Flexibility in the protocol design is key: the more options available, the better the experience will be for the patient.
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Direct-to-Patient Studies
Direct-to-patient distribution is a very patient-centric approach that takes into account each patient's quality of life and can remove some of the complexity and burdens of participating in a clinical trial, particularly if traveling to a clinical site would involve a long and difficult journey. In a 2014 study by ISPE (International Society for Pharmaceutical Engineering), approximately 78% of patients indicated it would be very helpful to have their medication delivered to their home rather than traveling to a clinical site.1
There are also numerous benefits of a decentralized trial to sponsors. First, it broadens patient access and the demographics available to the trial by allowing greater participation for patients in remote areas. This is particularly important when the trial involves a rare disease, where the target patient population is sparse, and it would ease some of the difficulties associated with recruiting patients from all over the country or all over the world.
Logistically, a decentralized trial that uses a true direct-to-patient versus STP model reduces the need for many physical site locations, as well as reducing the storage burden on the clinical site, as the investigator's staff are no longer responsible for receiving, storing and physically dispensing the product.
While managing drug supply is a critical component for decentralized studies, it is not the only important consideration that sponsors must address. For example, the structure of these studies must also ensure they adequately support patient compliance and adherence, often using e-technology. The use of technology such as smartphones and access to tele-visits in conjunction with home health care providers, nurses, mobile phlebotomists and other local healthcare providers, are all part of the decentralized trial solution.
Another benefit is that DTP might alleviate product stability concerns resulting from patients transporting the drug from the clinical site to their home. Direct delivery ensures that the drug is kept at the appropriate temperature conditions and fully monitored throughout the supply chain. When all these advantages are considered, it is possible that the improved efficiencies introduced into decentralized trials using DTP distribution could reduce the overall cost of the trial by reducing drug waste and supporting patient recruitment and retention efforts to help studies stay on budget and progress according to plan.
However, DTP distribution of clinical supplies is a complex endeavor that goes far beyond just changing the shipping destination of the patient kits, and there are several important aspects related to the packaging and delivery that need to be addressed before a DTP study can be implemented.
Perhaps the most important components of a successful decentralized study are the patients themselves and their ability to store and take their medication as instructed and complete any necessary self-reporting or other data-generating activities. Prior to offering a DTP option, sponsors must gauge whether patients will have an appropriate level of support to ensure successful administration and reporting in an at-home setting. Patients will need to be given clear instructions on when to start taking the medication, and on when and how to contact their doctor or clinical site for any questions related to their treatment or to report an adverse event. A virtual visit or check-in with the patient on the scheduled date of delivery is best practice, while understanding of procedures can be assessed by a questionnaire or checklist.
The stability of the drug is a critical consideration, and a plan must be put in place to determine how temperature excursions will be detected and handled. For example, if a patient receives a shipment that has been subject to an excursion, the sponsor will need to decide during study set up, whether the product should be left with the patient or automatically returned to the clinical site or pharmacy that dispensed it and a new shipment expedited to ensure that the patient's treatment plan is not disrupted.
Sponsors must put clear guidance in place regarding how the clinical site will document the receipt of the product by the patient, that it was the correct product, that it arrived in good condition and that the patient is clear on protocol instructions. Again, a possible solution would be a virtual tele-visit on the scheduled day of delivery to review the receipt with the patient and to ensure the product was received in good order. Provisions must also be made for the reverse logistics needed to ensure that unused study drug is returned, reconciled and eventually destroyed.
Data Management
Data management considerations are another crucial factor, and the choice of the interactive voice response (IVR) system can have a direct impact on a sponsor’s ability to offer direct-to-patient distribution of clinical supplies. Unlike exclusively clinic-based studies, where certain personal patient information is not needed in the IVR, decentralized studies using DTP distribution may require additional data to be held, such as a patient ID number and/or a patient’s city, state and zip code. Not all IVR systems can be configured to capture this information.
Furthermore, while some IVR systems are designed to be flexible, others are less so. A lack of flexibility within a system may make it difficult or impossible to switch patients during a study between receiving their treatments in a clinical setting and receiving them at home. This may require manual workarounds and extra work for the clinical sites and it is recommended that the study is set up to be flexible from the beginning. For sponsors who already have an IVR in place, understanding potential system limitations is necessary to determine if a current study set-up can accommodate a DTP option.
Sponsors should also consider how the IVR will be updated. For instance, the dispense date is the date the patient receives the medication, and not the shipment date. The IVR will need to be updated when the patient receives the medication, to ensure that the correct dispense date is logged. A decision will need to be made as to who updates the IVR and how this will be done.
Packaging
The packaging configuration for clinical supplies for use by patients in a home setting is another important consideration for sponsors, especially if the patient will not have support from a visiting nurse or other home healthcare provider. For example, the patient must be able to understand and manipulate the packaging and access the drug, so special packaging characteristics may be needed for use in an at home-setting, such as senior-friendly or child-resistant packaging, that would not be necessary in a clinical setting. Additional visual cues may be needed to provide reinforcement that a dose was taken, such as an empty blister cavity or a time-of-day/day number indicator.
The packaging should be of a size, shape and volume that will enable the patient to store it as directed. And if additional components designed for use by patients are required for at-home use, such as an instruction sheet or checklist, these materials will need to either fit into the drug packaging or shipping container or be sent separately. Sponsors should plan their clinical supplies with this in mind.
The Future of Decentralized Clinical Trials
Most clinical studies outside the United States have been site-to-patient. In Europe, direct-to-patient distribution is possible and has been done, but it is dependent on sponsor protocol and patient population and requires approval in each country. Local laws also need to be considered, and a separate supply plan should be put in place for each country to maintain flexibility; these supply plans can then be amended as needed rather than having to redo the entire protocol.
COVID-19 has significantly changed the landscape for clinical trials. Regulations and approval processes have changed rapidly over the past few months, with some countries relaxing their regulations to maintain patient access to critical medications. It remains to be seen if these changes are temporary or will eventually become permanent, but it is likely to open up more possibilities for future studies.
Now, more than ever, STP and DTP services have benefits for patients, sponsors and clinical sites. The COVID-19 pandemic and the consequences it has had on people’s lives and trial logistics has caused many more sponsors to now plan for inclusion of some form of DTP in their future and ongoing protocols. The US FDA has stated that it supports decentralized trials and the expansion of patient access through digital health technology,2 and has produced a lot of guidance to date.
References
- https://ispe.org/pharmaceutical-engineering/may-june-2016/patient-perceptions-impssurvey
- https://www.fda.gov/news-events/press-announcements/statement-fda-commissionerscott-gottlieb-md-new-strategies-modernize-clinical-trials-advance