Advanced Therapies: Strategies for Success in Clinical Development

Clinical Researcher—November 2021 (Volume 35, Issue 8)


Jessica Merryfield


Advanced therapy medicinal product (ATMP) development is on the rise. According to the American Society of Gene + Cell Therapy, there were 1,745 gene therapies in development in May 2021, 70% of which were in preclinical studies, and more than 1,300 of these candidates were in development for oncology, the most active therapeutic area.{1}

Given that ATMPs—and the patient journeys associated with them—are fundamentally different from traditional biopharmaceuticals, designing and conducting trials of these novel therapeutics involves unique regulatory and clinical considerations. In this article, we explore strategies for successful start-up and execution of ATMP studies.

Engaging with Regulators

As the regulatory framework for ATMP development can be complicated, early and proactive engagement with regulators is essential. Requesting feedback on data and biomarker requirements, the need for long-term follow-up (LTFU), and opportunities for expedited review and approval will help sponsors shape their clinical development programs. In the U.S., for example, the regenerative medicine advanced therapy (RMAT) designation offers a streamlined approval pathway for ATMPs that address unmet medical needs for serious or life-threatening conditions.

The European Union (EU) regulatory landscape is a patchwork of European Medicines Agency (EMA) and individual member-state legislation. While the EMA has separate legislation for ATMPs and genetically modified organisms (GMOs), this distinction may not exist at the member-state level, and non-GMO ATMPs may still be subject to GMO legislation that requires additional approvals.

Understanding Stakeholder Priorities

ATMPs are typically costly and complex treatments. Understanding the needs of patients and families, providers, and payers is critical for clinical and commercial success. Involving patients and families in protocol design is useful because their preferences may influence study feasibility, and regulators may require patient experience data. Additionally, early engagement with patients, families, and advocacy groups can help to create enthusiasm and increase awareness about the study.

Conversing with healthcare providers and key opinion leaders can help sponsors understand standard of care and validate proposed assessments and outcome measures. It also can be valuable for identifying clinical champions and collaborators who have access to the target patient population.

From a payer perspective, the long-term value of ATMPs is not yet known, as their durability is still unproven. The high upfront costs of what can often be one-time treatments may require new payment models to increase payer acceptance and patient access. Understanding payer priorities and limitations can help sponsors define their target product profiles and the data needed to support reimbursement for their ATMPs.

Evaluating Sites

Selecting qualified study sites is essential to the development program’s success. Sites should be familiar with the therapeutic area and have experience handling and administering the ATMP under investigation. Key criteria for qualifying sites include:

  • Past performance in similar studies
  • Proven access to the target patient population
  • Existence of GMO-specific standard operating processes and best practices, if the ATMP is a GMO
  • Experience with the mode of administration, especially if the study involves intracranial delivery or other specialized procedures

To limit site burden, it may be useful to try to align study protocol requirements with standard institutional policies and workflows. Developing a rigorous training program and site-specific execution map can help reduce operational complexity and enhance site performance.

Certain types of ATMPs may require additional site certifications or approval. In the U.S., human gene transfer products require approval from an institutional biosafety committee. In the EU, the regulatory environment may be less straightforward. Study start-up activities for gene therapy products may vary depending on the regulatory pathway and the requirements of individual member states.

Considering Lesser-Known Sites

Established sites with proven track records in ATMP studies are highly sought after and may have long wait lists. In an increasingly crowded space, sponsors seeking sites will compete against both investigator-initiated projects and other ATMP programs for attention at these go-to centers. Sponsors may find it useful to widen their search to include other leading, but lesser-known, academic medical centers and community-based hospital systems that have the necessary accreditations and facilities to administer ATMPs.

As of September 15, 2021, 295 U.S. centers have been accredited by the Foundation for Accreditation of Cellular Therapy.{2} In the EU, 284 centers have been accredited by the Joint Accreditation Committee ISCT-Europe & EBMT, with an additional 138 centers in process as of August 31, 2021.{3} Working with lesser-known sites also may broaden access to patients who might otherwise not be interested in—or eligible for—clinical trial participation due to travel limitations.

Enhancing Study Participation

As the number of ATMP clinical trials increases, so does the challenge of recruitment. Sponsors are tasked with making study participation as easy as possible—not just for patients and families, but also for sites and study staff. For rare diseases trials with small and geographically dispersed study populations, sponsors may need to take extraordinary measures—such as relocating families for prolonged periods—to enable study participation. For some ATMPs, it may be feasible to centralize therapeutic administration and then coordinate local follow-up. Sponsors should consider the costs of travel, lodging, and other study amenities that maximize convenience and minimize burden for participants and their families.

Enabling Cross-Border Enrollment

Cross-border enrollment, in combination with remote data collection for studies that require LTFU, offers the potential to increase patient access to investigational ATMPs. With cross-border enrollment, patients enroll in clinical trials at sites outside their countries of residence. Depending on the ATMP, the patients may return to their home countries or be required to remain in proximity to the sites for some period of time.

Cross-border enrollment may be suitable for studies of ATMPs targeting rare and ultra-rare diseases, due to low prevalence and the need for specialized site facilities. Cross-border trials do, however, come with additional regulatory and operational considerations. For example, all patient-facing documents need to be translated into the language of the patient and submitted to the ethics committee (EC) or institutional review board (IRB) in the host country. If screening or pre-screening activities will be conducted in the patient’s country of residence, additional regulatory authority and EC/IRB notifications or approvals may be required. Moreover, in most countries, sharing of medical records is governed by data protection legislation, so any records provided by local healthcare providers need to be anonymized prior to translation.

Sponsors considering cross-border enrollment for ATMP studies will also need to plan for:

  • Travel arrangements, including special accommodations that may be needed to ensure the safety and comfort of the patient
  • Contingencies if disease progression affects travel capability and protocol-specific assessment timings
  • Maintenance of standard of care, including shipping of country-specific drugs to avoid discontinuation of treatment
  • Cultural or social connectivity opportunities, especially for extended stays

Supporting Site Success

ATMP administration generally requires tight coordination among sites, laboratories, hospitals, and sponsors. To support site success, sponsors should consider developing a site onboarding and training program that includes detailed product manuals and checklists to help ensure that all study procedures are performed on time and according to the protocol for every patient. It also may be helpful to provide sites with coding and billing guides, adverse-event management sheets, and other product-specific resources. Performing practice runs of the entire protocol is useful for identifying and mitigating potential risks and increasing confidence among site staff.

Planning for Long-Term Follow-Up

Historically, the 15-year LTFU period has been reserved for lentiviral vectors. With the increasing use of gene editing technology, however, it is likely that the number of investigative therapies subject to the LTFU requirement will increase. When LTFU is required, retention becomes even more challenging. Patients may relocate or transition from pediatric to adult care, and sponsors may need to add new sites using investigators or local healthcare providers who were not affiliated with the initial study.

mHealth and offsite or home nursing visits can be helpful options for reducing patient burden and cost during the follow-up period. These options allow certain clinical trial obligations or study-related assessments and data collection to be completed in the comfort of the home and at the convenience of patients and their caregivers. By bringing the trial to the patients, sponsors also may benefit from increased study engagement.

Technologies such as eSource and eConsent also may be useful tools for facilitating LTFU due to the following considerations:

  • eSource enables flexible direct data capture and instant data validation, with an audit trail for each datapoint containing the full lifecycle of the data.
  • eConsent helps simplify the consenting process, particularly for complex, highly technical studies, by converting paper forms into an electronic format that may include multimedia components to facilitate patient understanding and education. There are also teleconsent options that can be completed from any remote location, eliminating the need to travel to the site.

Sponsors also may consider the use of satellite or community sites, which enable local follow-up during the LTFU period.


With their life-changing potential, ATMPs are a harbinger of hope for patients with unmet medical needs and their families. Research in this field is robust, and the clinical trial landscape is growing increasingly competitive. To succeed, sponsors must stay abreast of evolving regulations, involve patients and families in the process, and focus on optimizing study operations and execution at the outset of clinical trial development planning.



Jessica Merryfield is Senior Director for Program Delivery with Premier Research. She has more than 20 years of pharmaceutical industry experience at overseeing activities for early regulatory authority engagement through approvals.