Nearly three out of four biopharmaceutical firms modified traditional protocols to adopt a form of decentralized studies – also known as virtual or siteless trials – in an effort to keep drug development programs on course during COVID-19. The strategy proved successful. Now, having gained a foothold in the biopharma industry, decentralized trials are poised to play a major role in drug development post-pandemic.
To execute decentralized research strategies, sponsors are turning to an integrated supply chain solution known as Direct-to-Patient Services. Direct-to-Patient Services allow patients to participate in clinical trials from their homes by providing them with study drugs and care where they live. This eBook focuses on the integral role Direct-to-Patient Services play in the execution of decentralized trials and how sponsors can maximize these benefits to improve drug development.
Decentralized clinical trials were on the rise for years before COVID-19, but it was their success in keeping drug development programs on course during the pandemic that won these studies a new leading role in mainstream clinical research.
Decentralized trials emerged as a remedy when COVID-19 shutdowns plunged the biopharmaceutical industry into emergency mode. Drug makers faced the prospect of watching costly clinical trials grind to a halt as the pandemic prevented study patients from accessing clinical supplies and care – either due to closed investigator sites or patients’ reluctance to visit open sites and risk possible exposure to the virus.
In an effort to keep their drug development programs on course, nearly three out of four biopharma firms modified traditional protocols to adopt a form of decentralized studies, also known as virtual or siteless trials.1
To execute their decentralized strategies, sponsors are turning to an integrated supply chain solution known as Direct-to-Patient Services. Direct-to-Patient Services enable patients to participate in clinical trials from their homes by providing them with study drugs and care where they live.
In addition to the critical role decentralized studies have played during the pandemic, these patient-centric trials are earning praise thanks to the benefits they offer for patients, investigator sites and sponsors alike. Patients favor these studies because they gain access to novel therapies and customized care without leaving their homes. Investigator sites are pleased because decentralized studies make it easier for them to recruit study patients and they no longer have to store clinical and ancillary materials for the duration of trials.
Finally, sponsors benefit from the solutions posed by decentralized trials for longstanding research challenges. By facilitating patient enrollment and improving patient adherence and retention – issues that are central to the success of clinical research – decentralized trials can potentially reduce the length of trials and enable new treatments to reach the market sooner.
So, it isn’t surprising that more than 90 percent of respondents in a mid-2020 industry survey said they expect to see increased adoption of decentralized studies in the long term. Decentralized clinical trials have gained a foothold in the biopharma industry and are poised to play a major role in drug development after COVID-19 is history.1
The focus of this eBook is the integral role Direct-to-Patient Services play in the execution of decentralized trials, including the options available and when and how to deploy these services for maximum impact.
Decentralized clinical trials have gained a foothold in the biopharma industry and are poised to play a major role in drug development after COVID-19 is history.
DIRECT-TO-PATIENT TRIALS DEFINED
Decentralized clinical trials have been an option available to drug makers since the 1990s. These remote trials accounted for a minority of clinical research until biopharma companies embraced decentralized trials this year due to COVID-19. Today, decentralized trials are one of the hottest topics in drug development.
These studies are executed using telemedicine and mobile/local healthcare providers, and with procedures that vary from the traditional clinical trial model, according to the Clinical Trials Transformation Initiative. Decentralized trials are examples of how digital trial capabilities and enablers are shifting the point of care into the patient’s home.
Decentralized studies dominate a clinical research category known as Direct-to-Patient (DtP) trials. The DtP category includes fully decentralized studies and hybrid trials:
Fully decentralized studies are frequently referred to as virtual or site-less trials. These studies bring the clinical trial to a patient’s home using a central, often virtual, coordinating facility. More than 75 percent of current decentralized trials use mobile technologies. These trials may also harness telehealth, in-home devices, sensors and wearables, and digital therapeutics. The use of artificial intelligence (AI) or Machine Learning (ML) is also becoming more routine to facilitate diagnoses, patient stratification and evidence generation.1
Hybrid trials incorporate some virtual elements into a site-based study. These studies often access a combination of mobile clinics and patient-reported outcomes.1
BENEFITS OF DECENTRALIZED CLINICAL TRIALS
Decentralized trials still represent a minority of clinical research, but their numbers are accelerating. While COVID-19 spurred the adoption of decentralized trials, their continued growth stems from the benefits of these trials.
Biopharma companies are seeing improvements in the key cornerstones of clinical research – recruitment and retention – thanks to decentralized trials.
This is good news for the industry, especially given that 85 percent of clinical trials fail to recruit and retain enough patients in order to meet their enrollment timeline, and 19 percent of registered trials are terminated due to a failure to achieve expected enrollment.2
Decentralized trials improve patient enrollment and participation in clinical trials by making it easier and less time consuming for patients to enroll and remain enrolled. In one study of patients with back pain, for example, the dropout rate for the decentralized arm of the study was 29 percent lower than that of the conventional arm.2, 3
Other benefits include shorter trial timelines, more diverse/representative patient populations, reduced cost and real-time data, according to a 2020 global survey of clinical trial professionals.1
For investigator sites
Decentralized clinical trials benefit investigator sites as well, since they make it easier for investigator sites to recruit participants for studies.
Sites are relieved of the need to store space consuming clinical materials for the duration of a study. These materials include both study drug and ancillaries. Centralized storage of clinical materials is a centerpiece of decentralized studies.
Making clinical trials more patient-centric has been a challenge for the biopharma industry for years. Decentralized trials are proving to be a solution.
Nearly 70 percent of patients say they are willing to participate in clinical research studies, but fewer than 10 percent actually do. And about one in three of those who do enroll in trials drop out before the studies conclude, citing the burden of time and travel.2
The location of investigator sites and the time and cost to reach them were cited as major burdens impacting participation in clinical trials, according to a global research study conducted by the Center for Information and Study on Clinical Research Participation (CISCRP). Distance to the clinical site was the main barrier for participation for 60 percent of the 12,450 respondents.2, 5, 6
Patients are the major beneficiary of decentralized trials. By allowing patients to participate in clinical trials from home and requiring few or no site visits, decentralized clinical trials decrease the burden for patients and their caregivers, contributing to higher recruitment and retention rates, and leading to shorter clinical trials.2, 4, 5, 6, 7
WHAT ARE DIRECT-TO-PATIENT SERVICES?
If investigational medicinal product (IMP) is the fuel in a decentralized clinical trial, then Direct-to-Patient Services are surely the engine.
COMPREHENSIVE SCOPE. With a focus on patient convenience and safety, Direct-to-Patient Services are responsible for executing the patient-centric elements of a decentralized trial. These elements include:
Dispensing the study drug/drugs and arranging timely delivery to a patient’s home
Providing clinical ancillary supplies, which are the equipment, instruments and consumables required in clinical trials. Some examples: Glucose meters, consumables such as alcohol swabs, face masks, disposable gloves and test strips, or even dormitory-sized refrigerators for at-home storage of temperature-controlled study drugs
Should self-administration not be possible, arranging for a home nurse to administer investigational medicinal product (IMP) to the patient and monitor clinical results
Scheduling and coordinating delivery of clinical materials and arrival of a home nurse in conjunction with the patient and/or the patient’s caregiver.
Ensuring that everyone who comes in contact with the patient and/or caregiver – including delivery personnel and home nurses – wears personal protective equipment (PPE) as a safety measure against COVID-19.
BY DESIGN OR EXCEPTION. Direct-to-Patient Services are available by design or on an exception basis, depending upon the needs and wishes of the sponsor.
Use of Direct-to-Patient Services by design occurs when a sponsor has decided to conduct a fully decentralized or entirely home-based trial. As the number of decentralized trials skyrockets, use of this option is growing rapidly.
Sponsors may also opt to use Direct-to-Patient Services on an exception basis or as an add-on to an existing traditional study in cases when circumstances unexpectedly prevent a study patient or patients from traveling to a clinical site. There could be any number of causes – a personal emergency, an illness or injury, the obligation to supervise children at home due to COVID-19 school closings, or even the need for clinical resupplies while on holiday or vacation.
ADAPTABLE APPLICATION. The rule of thumb for the use of Direct-to-Patient Services in supporting decentralized trials is simple: If a physician isn’t necessary for a patient visit and the equipment required for the visit is portable, a nurse can support the visit in the patient’s home.
This makes Direct-to-Patient Services appropriate for a wide variety of trials:
Phase I, II, III and IV clinical trials in many therapeutic areas, among them Oncology, Cardiovascular, Immunology and Inflammation, Neurology, Respiratory, Central Nervous System (CNS), Infectious Diseases, Endocrine and others.
Interactive response technology-driven (IRT) and non-IRT-driven studies
Blinded and unblinded trials
Studies evaluating potential treatments for rare diseases or orphan drug designations, for which it is particularly difficult to recruit patients
Trials involving patients who are accustomed to injecting themselves with medication, such as individuals living with type 1 diabetes and rheumatoid arthritis
Studies including a broad range of therapeutics and delivery routes, including:
Ambient and temperature-controlled drugs
Dispensed tablets, capsules, inhalation devices, pre-filled syringes and vials
Commercially available supporting medications and clinical ancillaries
This patient-centric service offering makes it possible for individuals to participate in clinical studies from the comfort and security of their homes.
MAXIMIZING FLEXIBILITY: DIRECT-TO-PATIENT SERVICE OPTIONS
A pharmaceutical manufacturer partnering with Thermo Fisher Scientific on multiple clinical trials requested assistance in addressing an all-too-common clinical development challenge – the occasional inability of study patients to keep their appointments at clinical sites.
Clinical Site-to-Patient Service
The Clinical Site-to-Patient model entails making planned shipments of clinical materials required for a study – including IMP, other study drugs and ancillaries – from a clinical site to a patient’s home.4
The Clinical Site-to-Patient option is typically available as a standard approach for planned clinical trials or as an add-on for ongoing studies, should circumstances prevent a patient or patients from traveling to the clinical site.
The Depot-to-Patient Services option enables sponsors to leverage depot stock to make planned shipments of IMP and ancillaries to the clinical site and/or directly to the patient’s home.
Orders can be automatically triggered out of IRT systems or sent manually, depending on the clinical trial need.4
The Pharmacy-to-Patient Services option allows sponsors to fulfill prescriptions from a central pharmacy for patients participating in clinical trials at home. This includes patient assistance, compassionate use and early-access programs, as well as both IRT- and non-IRT-driven trials.4
CASE STUDY: HOW A SPONSOR USED DIRECT-TO-PATIENT SERVICES TO PREVENT DROPOUTS BY SUPPORTING AND ENGAGING STUDY PATIENTS
The circumstances were many, varied and legitimate. A hurricane prevented one patient from traveling to the clinical site dispensing study medication. Another patient relocated to the southwestern part of the United States and was unable to travel to the nearest investigator site, which was located on the West Coast. A compassionate use case posed another long-distance dilemma; the patient was living in Florida but the medication was in New England.
Patient retention is critical in clinical research and such situations can put the patients involved at risk of dropping out of a study. No sponsor wants to see that happen, as dropouts can negatively impact both an ongoing trial as well as an entire drug development program.
The sponsor opted for the use of Direct-to-Patient Services on an exception basis to address the problem and prevent potential dropouts. Because all the patients in the trial were able to self-medicate, residential delivery of the study medication was the critical need.
Our teams across Thermo Fisher Scientific including distribution project managers, specialty logistics, and the sponsor’s clinical trial drug supply management team joined forces to identify the needs and possible solutions.
Since the IMP involved in the sponsor’s trials required a variety of temperature controls managed through delivery to the patient, the specialty logistics team recommended the use of reusable shippers. The recommended shippers have a 96-hour hold time and can be validated to three temperature settings – those of -20°C, 4°C and 20°C.
The sponsor then established a Quality Assurance-approved (QA) Standard Operating Procedure (SOP) for the exception deliveries:
The patient contacts the Clinical Research Associate (CRA) to advise that he/she cannot keep the scheduled appointment at the investigator site.
The CRA contacts the sponsor to obtain necessary approvals.
The sponsor notifies the Thermo Fisher Scientific project manager, who obtains the patient-specific details from the CRA.
The Thermo Fisher Scientific project manager contacts the specialty logistics team, providing all of the necessary information – including the timeline, pickup and delivery address, contact information, product needed and temperature requirements.
The specialty logistics program manager arranges for transportation, a validated reusable shipper and temperature logger. The manager coordinates communications with the CRA and the patient, establishing a one-hour delivery appointment and maintaining personal contact throughout the process in the event of delays or other difficulties.
Meanwhile, at the investigator site, the CRA staff packs the study drug in the reusable shipper, activating the temperature logger. The CRA staff hand the shipper off to a courier.
Upon arriving at the patient’s home, the courier stops the data logger and puts on PPE before making the delivery. The temperature information is reported to Thermo Fisher Scientific via the specialty logistics program manager.
The courier returns the reusable shipper to the investigator site.
The patient takes the study medication and remains in the study.
At the center of every clinical trial are patients and everyone involved – the sponsor, CRA, Thermo Fisher Scientific and our specialty logistics team – made serving patients the priority. By doing so, both patients and sponsor benefitted.
Patients received an uninterrupted supply of medication critical to their treatment, while avoiding the burden of costly and time-consuming travel to the investigator site. By demonstrating in a tangible way that it put patients first, the sponsor maximized patient engagement in the study and ensured that the affected patients remained enrolled.
Since then, Thermo Fisher Scientific has optimized its processes for Direct-to-Patient needs by implementing a standard approach for regular study set-ups.
At the center of every clinical trial are patients and everyone involved – the sponsor, CRA, Thermo Fisher Scientific and our specialty logistics team – made serving patients the priority.
CONSIDERATIONS IN PLANNING DIRECT-TO-PATIENT TRIALS
Although decentralized trials have been in use for two decades, sponsors’ experience with them was limited until this year. Many sponsors are mounting decentralized trials for the first time. Following are some key issues to consider when planning such trials.
SPECIAL HANDLING. Consider whether the protocol may dictate the need for a custom playbook or client special work instruction – about the packaging, for the pharmacy or to the driver/courier.
One sponsor, for example, wanted drivers to open the outer shipping package upon arriving at a patient’s home and hand only the inner package containing the drug to the patient or caregiver. This requires factoring in driver training and increases the time necessary to make deliveries.
Allowing plenty of time to have up-front discussions about special instructions or needs will ensure smooth project implementation and prevent unnecessary work and frustration later.
ANCILLARY NEEDS. Even patient-facing trials require the equipment, instruments and consumables that are collectively known as ancillaries. Ancillaries are must-haves, as many trials cannot begin unless both the investigational drug and ancillary components are in place.
However, with sponsors understandably focused on supplying IMP, ancillaries often aren’t given the attention they require during the planning stages of a trial. It’s important to source these materials at the same time that study drug is sourced so all components are in hand for a study to begin.
Examples of commonly used ancillaries in patient-decentralized trials include glucose meters, refrigerators, wearable devices, pre-programmed iPads and iPhones, as well as consumables such as syringes, alcohol swabs, test strips, gloves and face masks.
In one decentralized trial, it was the patients and their caregivers who requested an ancillary that the sponsor hadn’t realized was needed – a dormitory-sized refrigerator to store the 10 one-liter bottles of liquid clinical material required for the study each month.
REGULATORY REQUIREMENTS. Determine the difference between regulatory must-haves and nice-to-haves in individual markets.
For example: What kind of handoff does a driver need to make when delivering medication? Must the person receiving it present proof of identity? It is necessary to have someone sign for a package or is a signature merely optional?
It’s important to be sure patients and their caregivers are aware of the requirements in advance, especially given concerns about COVID-19.
TEMPERATURE-CONTROL ISSUES. Special logistics and packaging to maintain the quality of temperature-controlled drugs as they’re shipped from clinical site, pharmacy or depot to patient homes are another area to consider.
For example, if a temperature monitor is included in the package, as they frequently are, is there a means to download the data on site and make fit-for-use calls?
In one study, the sponsor wanted the home nurse to download temperature-control data, but learned after the study was underway that many of the nurses were unable to do so because they did not carry iPads or laptops.
COMMUNICATION. The necessary management of temperature-control data illustrates the need for effective and consistent communication during the study. Will communication take place via mobile, text or both? Will there be alternative delivery destinations? Settling issues such as these early in the planning process avoids confusion and potentially lost data later.
PARTNER SELECTION. The right partners, both with respect to supply chain management and to home nursing services, are critical ingredients in the smooth conduct of a trial. By their nature, DtP trials require close coordination among multiple parties, including patients, caregivers, couriers/drivers, pharmacy, CRAs and others.
COVID-19 PRECAUTIONS. The pandemic accelerated the demand for DtP studies, but some patients and caregivers have expressed concern about permitting home nurses into their homes and accepting drug shipments from couriers. In some cases, these concerns have led to dropouts.
COVID-19 will remain a concern for some time to come, making it critical to identify possible solutions to allay the worries of patients and caregivers.
Some examples: Including a Personal Protective Equipment (PPE) kit containing masks and gloves with the drug to protect those with compromised immune systems; ensuring that drivers/couriers wear masks and gloves and socially distance during deliveries; prearranging contact-free deliveries where permissible.
BEST PRACTICES FOR DIRECT-TO-PATIENT TRIALS
Preparation and planning are key success factors for all clinical trials, but they may be even more important in managing the complexity of decentralized trials. The following best practices are based upon experience with more than 1,500 shipments of clinical supplies directly to patients in 47 countries.
Ensure planning & stakeholder alignment
If clinical supply is in the lead, be sure to include clinical operations from the beginning so both are on the same page.
Engage partners – including the Clinical Research Organization (CRO), IRT and home nursing – early in the planning process. This is crucial.
Work with a provider that has pre-screened the regulations and laws in each country. This will save precious time and ensure compliance.
Determine roles and responsibilities by developing a robust RACI (Responsible, Accountable, Consulted and Informed) chart.
Work with the provider to be sure that the informed consent covers the planned modes of communication, such as text, email and handover data to a third-party provider, such as a courier.
As always, plan for the unexpected.
Conduct testing and training
Allow time for testing all elements, such as email addresses and phone numbers. Conduct an IRT test run, etc.
Train clinical sites and patients, which is key to a successful decentralized trial.
Start planning earlier for decentralized trials – six months is recommended – compared to traditional trials. Earlier planning is necessary because decision making and stakeholder alignment can take longer.
Know the difference between the regulatory must-haves and nice-to-haves.
Hold review meetings and learn from them
Use meetings as opportunities to identify lessons learned after study setup and start.
You don’t know what you don’t know when you start conducting DtP trials. Reducing the number of vendors involved will minimize the intersections and the unknowns.
Start planning earlier for decentralized trials – six months is recommended – compared to traditional trials.
THERMO FISHER SCIENTIFIC: OFFERING AN EXPANDED SUITE OF DIRECT-TO-PATIENT SERVICES
Thermo Fisher Scientific has been providing many elements of decentralized trials for years, having made 1,500 global shipments of clinical materials to patients enrolled in drug trials for more than 25 indications. The company had been in the process of expanding its Direct-to-Patient Services offering when COVID-19 emerged and “expedited our timeline,” as one member of the Thermo Fisher Scientific team explained.
Response to the enhanced service offering has been excellent, evidenced by the fact that many sponsors who engaged Direct-to-Patient Services for a few trials are now expressing interest in expanding the services to other trials.
This service offering includes a suite of three options, each of which has been thoughtfully designed to support patient-centric supply chains with a maximum of efficiency and flexibility:
Clinical Site-to-Patient/Available globally
Our Clinical Site-to-Patient option provides service to 47 countries that have been approved and vetted by our in-house team of regulatory experts. Our team can assess additional countries upon customer request.
This option leverages a global network of approved suppliers and providers, including the vetted best couriers for each region and country, through our Total Transportation Management (TTM) service. TTM manages the supply chain processes that are required to move investigational drug shipments internationally and within destination countries.
TTM includes courier selection and management, customs and regulatory guidance, storage and distribution facilities, oversight of third-party depot shipments and global quality-assurance support. TTM has been shown to reduce overall transportation management costs while increasing on-time performance, visibility, compliance and control.
Depot-to-Patient/Available in the U.S. only
Thermo Fisher Scientific’s data-protection-compliant processes manage the order fulfillment using a Good Manufacturing Practices-compliant (GMP) supply chain system from our depots in Allentown, Pennsylvania and Mount Prospect, Illinois, USA.
This option leverages specialty logistics provider Patheon Logistics, with stock and shipment visibility through Global Gateway.
Pharmacy-to-Patient/Available in the U.S. only
Operating since 1996, our Pharmacy-to-Patient Services is licensed in all 50 states and is certified for interstate shipping. This scalable and flexible Health Insurance Portability and Accountability Act of 1996-compliant (HIPAA) operation can accommodate high- or low-volume projects.
Staff includes a team of experienced registered pharmacists to fulfill prescriptions. Our pharmacists have access to a Drug Enforcement Administration-certified (DEA) Class 2 vault and Class 3-5 drug cage.
This option also leverages specialty logistics provider Patheon Logistics, with stock and shipment visibility through Global Gateway.
Other features of our Direct-to-Patient Services offering include:
Regional Direct-to-Patient Contact Centers services for patients and clinical sites (APAC, EU, U.S.)
Expertise across the entire supply chain, including support for ancillary sourcing, blinding, patient kit production, clinical supply optimization and decentralized study set-ups
A dedicated Direct-to-Patient Services team, including a dedicated project manager for each project
End-to-end solutions that include manufacturing, packaging for ambient and cold-chain products, labeling, storage and distribution – everything from clinical trial support to commercial support, from one provider
Direct-to-Patient Services is a solution that makes it easier for sponsors and investigator sites to conduct decentralized clinical trials and for patients to participate in them. By reducing the length of clinical trials and enabling new treatments to reach the market sooner, Direct-to-Patient Services is helping to improve the lives of thousands of patients worldwide.
Safety protocols for delivery agents who interact with clients/patients
Processes that meet local country regulations, such as contact-free delivery protocols and use of PPE (masks & gloves)
With unwavering commitment to service, science and process engineering, Thermo Fisher Scientific is powered by people with an exceptional commitment to quality, deeply instilled ethics of personal responsibility and unrivaled expertise.
Thermo Fisher Scientific is the world leader in serving science, with revenues of more than $24 billion and approximately 70,000 employees globally. Our mission is to enable our customers to make the world healthier, cleaner and safer. We help our customers accelerate life sciences research, solve complex analytical challenges, improve patient diagnostics, deliver medicines to market and increase laboratory productivity. Through our premier brands—Thermo Scientific, Applied Biosystems, Invitrogen, Fisher Scientific and Unity Lab Services—we offer an unmatched combination of innovative technologies, purchasing convenience and comprehensive services.
As the leading service provider to the cell and gene therapy community, Fisher Clinical ServicesSM, by Thermo Fisher Scientific, is uniquely positioned with the experience, resources, and global expertise to support our customers on their path towards commercialization. Our global infrastructure enables customers to seamlessly conduct clinical trials across multiple geographies while providing patients around the world with access to life changing therapies. Our cryogenic storage and logistics, combined with proven components and validated procedures, allow us to configure and replicate each site to meet the specific requirements of individual clinical trials with minimal variation, regardless of volume or geographic location. This is supported by a global comprehensive and integrated Quality System based on regulatory requirements, industry best practices and highly trained personnel.
Sommer, Carsten; Zuccolin, Diego; Amera, Valdo; Schmitz, Nicole; Adolfsson, Pernilla; Colombo, Nicolleta; Gilg, Raphaelle; and McDowell, Bryan. “Building clinical trials around patients: Evaluation and comparison of decentralized and conventional site models in patients with low back pain.” Contemporary Clinical Trials Communications. Volume 11. September issue (2018): pages 120-126. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072894/