Direct-to-Patient Clinical Trials: Everything You Need to Know

What does DtP stand for in clinical trials?

DTP stands for direct-to-patient, and in clinical trials, it describes a decentralized clinical supply chain management model that sees study drugs delivered straight to patients.[1]

Direct-to-patient clinical trials offer significant benefits to both sponsors and patients, but they come with certain concerns and considerations related to patient privacy, handling of the study drug, and compliance with Good Clinical Practice (GCP).

In this article, we delve deeper into the direct-to-patient (DtP) model and discuss its advantages and some challenges to overcome.

What is the direct-to-patient process?

In traditional clinical trials, the supply chain of study drugs generally includes the following steps:

drug manufacturer → centralized pharmacy or depot → trial site(s)

The patients then visit the trial site for study visits, wherein they will receive their supply of the study drug.[2]

The direct-to-patient model involves a modified distribution chain to get the patients the study drug at their homes, generally using one of the following setups:[3]

• Site-to-patient: the study drug goes from the drug manufacturer or pharmacy to the trial site, and then from the site to the patient. This approach is generally used when drugs do not need to cross borders to reach a patient.
• Depot-to-patient: a depot in the patient’s locality delivers the study drug to them. This model obviates the trial site from the supply chain, which means sponsors can avoid the additional storage and logistic costs. This approach is preferred for cross-border deliveries, and for fully remote/decentralized trials that do not involve sites.
• Hybrid model: DTP study drug distribution is combined with elements of traditional approaches, such that the study drugs are delivered to the participant, but the participant is also required to visit the trial site for certain visits or to receive other interventions.

Drugs that are especially appropriate for delivery directly to patients’ homes via a DTP trial model are those that are easy to self-administer (i.e., oral medicines with simple dosing schedules). In some cases, the route of administration may require assistance from a local healthcare provider (family doctor, local clinic, etc.), such as in the case of drugs for intravenous (iv) injection or infusion. In that case, the patient would bring the study drug to the local healthcare professional, or the study drug could be shipped directly to that provider/clinic, if authorized.

What is a DCT or decentralized clinical trial?

Decentralized clinical trials (DCTs) implement a combination of remote strategies such as DTP and digital tools to make trials more accessible to patients and reduce travel time related to in-person study visits. DCTs and hybrid trials (those with only certain aspects of decentralized trials) often make use of the following:[4]

• Remote data collection and electronic data capture (EDC)
• Real-time monitoring, often linked to connected and wearable devices
• Virtual communication channels (video calls, etc.)
• Healthcare proxies (local laboratories and clinics, mobile health units, at-home doctor visits, etc.)

A key theme of DCTs is enhancing patient-centricity, making trials less burdensome, simpler, and more appealing for patients, aiming to improve accessibility, enrollment, and retention.

The evolution of trials: DCTs and DTP models

Clinical research has been evolving rapidly, shifting from the traditional fully in-person, on-site models to increasingly decentralized and remote models. Much of this has been made possible by technological advances that facilitate secure and streamlined connectivity and communication.[4]

Over the past decade or so, aspects of decentralization were slowly being adopted in clinical research, but were generally concentrated to small-scale settings or geared towards supplementing (rather than replacing) traditional research models. Direct-to-patient trials are also not a new concept; certain clinical trials, particularly those working with patients who were unable to travel to trial sites for health reasons, had study drugs shipped directly to patients.

During the extreme circumstances produced during the COVID-19 pandemic, the clinical research industry had to innovate in order to keep research efforts alive, and it was quickly seen that remote and decentralized trial strategies were, in many cases, feasible.[5] Within the first year of the pandemic, 76% of sponsors and CROs adopted techniques such as telehealth, video conferencing, patient portals, and remote monitoring apps and devices.[6],[7]

The accelerated adoption of DCTs and DTP models at such a large scale not only maintained momentum in research efforts, but also led to the optimization of different trial processes, even for traditional study models. Software tools and technological advances have supported improvements in various aspects of trial operations, from participant engagement to data management and compliance.

Benefits of direct-to-patient trials for sponsors

DTP trials offer a potential way to overcome, at least partially, some of the most challenging aspects of clinical research - namely participant recruitment and retention - in several ways, including: [1],[8],[9]

• Allowing sponsors to expand the geographical scope of the trial and tap into a larger (and thus likely more diverse) patient population
• Improving diversity in trial populations, making them more representative of actual patient demographics
• Reducing or even eliminating costs sponsors may incur from maintaining inventory at various clinical sites
• Improving trial timelines, as drug distribution can be expedited and patients don’t need to travel to study sites at distinct times
• Allowing sponsors to research conditions that would be much harder to study via traditional methods, such as rare diseases, wherein the patient population may be especially disperse
• Making trials more appealing to patients as they don’t have to travel repeatedly to trial sites, which can improve enrolment as well as retention
• Helping patients feel more empowered and involved with their trial participation and their health journey; improved communication and engagement can improve adherence to protocol.

Logistical challenges in the adoption of direct-to-patient trials

While beneficial in many ways, there are relevant concerns that can make direct-to-patient trials challenging and, in some cases, unfavorable to sponsors or even infeasible, as explained below:[1],[8],[10]

1. Drug distribution needs to be tightly controlled, as study drugs could be unstable, temperature sensitive, or have short expiry time frames. Study drugs must be delivered in good condition and within a specific deadline, and participants must store them properly.

If any of these conditions are not fulfilled, the drugs may become unusable or may not arrive on time, which can have costly consequences such as:

• A participant misses a dose and becomes disqualified
• A participant suffers adverse effects from taking a damaged/expired investigational product
• Trial outcomes become compromised
• Additional costs are incurred to replace drugs

2. Tracking study drugs as they make their way to participants is also vital, and even more so when the drugs cross international borders. Furthermore, the custody chain of the drug, i.e., the intermediaries through which the study drug is exchanged, must be appropriately controlled and monitored in order to guarantee compliance with Good Clinical Practice (GCP). The risk of tampering or mishandling increases with each added intermediary, which can raise regulatory concerns and must be explicitly considered.

3. The lack of clear and standardized framework/regulations for direct-to-patient clinical trials makes it more challenging to design protocols that satisfy all regulatory requirements, especially for international trials.

4. The willingness to adopt DTP trials varies greatly between regions, representing another factor that increases the complexity of designing multicenter and international trials.

5. The feasibility of the direct-to-patient model also depends on the dosing method of the study drug and the trial protocol. While patients are often comfortable taking oral medications, they would generally be less willing to give themselves intravenous injections. In such situations, sponsors can consider working with healthcare proxies (local clinics, family physicians, etc.) who can administer the study drug to the patient.

6. Treatment adherence and patient compliance is also more difficult to ensure in DPT models. The absence of direct observation by researchers raises questions such as:

• Is the patient taking the study drug at the right time?
• Is the patient taking the drug at all? How can this be proven?
• Is someone else taking the medication?

Luckily there are simple ways to overcome these concerns should they be particularly relevant, such as quick video calls with the investigator to oversee study drug administration.

Patient data privacy is another concern, as non-specialized logistics service providers are unlikely to be familiar with Good Clinical Practice (GCP) guidelines. The names and addresses of participants may need to be concealed in order to avoid revealing their participation or condition. A potential solution for this is to have the study drug shipped directly to an authorized caregiver or family member. On the other hand, in randomized trials, care must be taken to avoid unblinding the participant by revealing the identity of the investigational product, which can present challenges related to shipping unlabelled medicinal products. Sponsors will have to work with logistics companies to establish clear protocols for the handling of the study drug and personal information. Otherwise, patient confidentiality and/or study integrity may be compromised, which could result in serious compliance issues.

Feasibility: What kind of trials are suited to DTP models?

Generally speaking, direct-to-patient trials are often more suitable for phase II, phase III, and phase IV clinical trials. This is because phase I clinical trials often represent the first use of the medicinal product in humans, and thus close safety monitoring is especially important. As preliminary safety data is collected, there should be a lower risk of adverse reactions in subsequent trials, making it relatively safer for patients to self-administer the study drug at home.

There are many others factors that should be considered to determine whether a direct-to-patient protocol is feasible for a given trial, such as:[1],[3]

• Is the trial fully remote, or will participants need to visit sites or local healthcare facilities?
• What is the general health of trial participants? Are they able to travel?
• Does the DtP model offer tangible advantage(s), economically or otherwise?
• Will a healthcare proxy be involved to support trial participants? How often?
• Is the administration of the study drug on a fixed schedule, or at the discretion of the investigator?
• How stable is the study drug? Can it be stored properly and easily outside of a pharmacy?
• What is the route of administration of the study drug?
• Is specialized training required to handle and administer the study drug safely?
• How will participants be monitored, and compliance ensured?

With these in mind, trials that seem to be best suited for the direct to patient model include:

• Those that run for a minimum of two years, as this allows time for shipping procedures to be stabilized, and can boost patient retention for longer studies wherein patients might get tired of traveling for site visits.
• Those involving stable study drugs with a long shelf life, allowing sponsors to ship more doses per shipment and less frequently, reducing the costs incurred in study drug distribution.
• Those involving study drugs that do not require training or special qualification to dispense or administer. The easier the drug is to handle, the easier it is for trial participants to follow the treatment schedule. The shipment of drugs that are controlled substances can introduce significant risks, or may be prohibited entirely.
• Trials wherein the patient population is particularly disperse or located far away from trial sites. In such cases, travel requirements could be especially burdensome, and DtP trial models can improve the patient experience and even motivate more patients to enroll.
• Trials which are already employing decentralized strategies such as healthcare proxies, remote data collection, or telehealth. DtP distribution is likely to be easier to integrate in such cases, and is a particularly good fit for supporting such remote/decentralized models.

The future of direct-to-patient clinical trials

There is no question that direct-to-patient clinical trials have found their place in clinical research. For studies that are well suited to a DtP model, direct to patient distribution offers tangible benefits in terms of enrollment, engagement and retention, and patient centricity, and can help sponsors diversify their trial populations, streamline logistics, and accelerate timelines.[1],[5]

However, certain studies are not well suited to direct-to-patient models, such as multicenter, international trials involving regions with high barriers to the implementation or regulation of specific aspects of such protocols, or trials on investigational products that are unstable or require specific qualifications or skills to administer. Tracking and ensuring GCP compliance and proper handling throughout the study drug supply chain introduce another level of logistical complexity to direct-to-patient trials.

Given the increasing prevalence and popularity of the direct-to-patient clinical trial model, there is a call for the development of a standardized regulatory framework to help sponsors remain compliant and navigate the specific challenges of DtP trials, particularly in the face of the ever-growing globalization of clinical research efforts.