Optimizing Study Execution for Advanced Therapies

By: Angi Robinson - Senior Vice President, Specialty Areas - Premier Research

Advanced therapies - including gene-, cell-, and tissue-based products - offer groundbreaking new opportunities for the treatment of disease. As of the end of 2020, there were 1,085 active developers of these therapies and 152 ongoing Phase 3 trials worldwide. According to the Alliance for Regenerative Medicine, regulatory decisions are expected on a record eight new advanced therapy products in 2021.1

As advanced therapy research develops across modalities and therapeutic areas, developers are tasked with designing and executing trials in a competitive landscape where regulations are evolving rapidly. In this article, we explore critical factors for the successful execution of advanced therapy studies.

Engaging Critical Stakeholders 

When designing and conducting advanced therapy trials, a keen understanding of the roles and priorities of diverse stakeholders is key to study success. Developers should consider early engagement with patient advocacy groups, physicians, and regulators in the context of a thorough assessment of the competitive landscape.

Patients and Families 

As a result of the 21st Century Cures Act, the U.S. Food and Drug Administration (FDA) has made patient experience data a requirement in regulatory submissions. Submissions must incorporate experience with the specific disease or condition, data on the impact of the disease or therapy, and even information on patient preference regarding treatment. Consequently, it is crucial to understand at the outset of the clinical development plan what data exists already and how additional data will be collected, either in the context of a clinical trial or through external channels such as advisory meetings with patients and their families.

Interactions with patients and their families are useful for collecting feedback on study design and feasibility, on the meaningfulness of outcomes within specific indications, and on strategies to minimize the patient burden. These conversations also serve as opportunities for advancing study awareness and identifying patients who ultimately may be able to participate in either interventional or natural history studies, depending on the development plan.

Key Opinion Leaders and Physicians 

Engaging with key opinion leaders and physicians is critical to understanding the standard of care and getting feedback on study design and related assessments, particularly in less-well-studied rare diseases. As competition increases within specific indications or treatment options, identifying early collaborators and spokespeople for an investigational medicinal product (IMP) is critical for success. Investing in these early collaborations also creates the opportunity to build an expert advisory board, which can be beneficial along the development pathway. 

Regulators 

In response to the need for meaningful guidance and the expected increase in investigational new drug applications in this sector, the FDA has issued nine guidance documents for advanced therapy programs since January 2020.

The Regenerative Medicine Advanced Therapy (RMAT) designation offers an accelerated path to market for advanced therapies targeted at serious or life-threatening conditions with significant unmet needs. There are also multiple opportunities for early engagement with regulators, such as applying for orphan drug designation or seeking accelerated approval, which supports the use of a surrogate endpoint in pivotal studies. Many elements need to be introduced in early regulatory discussions, including the need for the inclusion of biomarkers as outcome measures, the requirement for long-term follow-up, and key considerations for data needed to support regulatory approval. 

Developers need to consider the possibility of accelerated approval and the downstream impact on chemistry, manufacturing, and controls and IMP readiness. As product demand and the number of patients treated will typically increase as a product progresses through development, the ability to scale processes while maintaining critical quality attributes is essential. In our work, we have found that thinking about these factors, even before the start of the earliest trials, helps ensure contingency plans for any scenarios that may arise throughout development.

In the European Union, the landscape is more complex. The EMA classifies advanced therapies as gene therapy medicinal products, somatic cell therapy medicinal products, tissue-engineered medicinal products, or combinations thereof. This classification is significant because, at the EMA level, advanced therapy and genetically modified organism (GMO) legislation differs. At the member state level, however, this distinction may not exist, and non-GMO advanced therapies may still be subject to GMO legislation, which may require additional approvals and impact the study start-up process.

Sponsors 

With increasing competition in the space, sponsors need to understand the competitive landscape and incorporate that understanding into study timelines. Competition may necessitate an aggressive timeline to get to submission as quickly as possible. In some cases, however, competition for the same small pool of eligible patients has led to a doubling of enrollment timelines. This underscores the need to initiate discussions with patients, patient advocacy groups, and physicians as early in the development program as possible.

Payers and Insurers 

Given the high cost associated with developing and administering advanced therapies, reimbursement is another key consideration.

Advanced therapies are often expensive one-time treatments, and this model introduces new uncertainties for payers as the value of their investment accrues over a long period of time. Moreover, the performance durability of cell and gene therapies remains unproven, further clouding the issue of reimbursement. 

Whether the goal is to sell after early-phase data is available or bring the product to market and commercialization, having value statements appropriate for payers will create a data set that is a tangible asset for success. These include natural history data, quality-of-life data, and health economics data. Considering innovative business models for advanced therapies, such as value-based contracts or alternative financing mechanisms, is also critical for increasing access to these novel medicines.

Considering Study Logistics 

Successfully executing an advanced therapy trial means ensuring everything from certifications and permits for the IMP to, in some cases, assembling the infrastructure required for the manufacture, storage, preparation, transport, administration, and disposal of the product. Advanced therapies are highly customized products that require precise material sourcing, manufacturing, and chain of custody, all of which require close integration of the supply chain with study and site operations. For products classified as GMOs, the logistics of study execution are even more complex.

Thinking About Manufacturing

Particularly in light of the pandemic, there has been a significant strain on production capabilities globally. This has had a considerable impact on developers and their development timelines, so much so that many developers have pivoted to investing in their own manufacturing capabilities. In the absence of an internal manufacturing competency, developers must turn to contract development and manufacturing organizations (CDMOs) and wait in line for a production time slot. Currently, more than 65 percent of cell and gene therapy manufacturing is outsourced to CDMOs, and developers may need to wait up to 24 months to access production capacity.2

Deciding whether to build internal infrastructure or rely on external partners can be daunting. Factors that influence this decision may include the nature of the therapy, the incidence or prevalence of the disease state, and the availability of external capacity and expertise. For early-stage companies, financial constraints may prohibit capital investment into internal manufacturing capabilities. Partnering with a CDMO, however, often means relinquishing control of the manufacturing process. Hybrid models have begun to emerge, with companies making upfront investments for process development and early-phase trials before switching to CDMO partnerships for later-phase trials.

Whether manufacturing is internal or external, it is crucial to be forward- thinking about manufacturing-related risks such as raw material lead times, low yield, product stability, and lot failure. We have seen that engaging cross-functional teams early in development helps ensure a successful transition from R&D and process development to clinical and, ultimately, commercial-scale manufacturing.

Managing Vendor

Beyond the IMP, other devices or drug supplies may be needed to conduct an advanced therapy clinical trial, such as pre-dose immunosuppressants or post-dose steroids. Logistics are crucial for ensuring the right product reaches the right patient within a specific time frame with advanced therapies. Errors along any pointof the supply chain can be devastating for patients and costly for trial sponsors. Developers should consider the complex logistics framework inherent in the delivery and administration of advanced therapy products and develop risk mitigation plans to shore up the clinical trial supply chain.

Selecting Sites

Administration of advanced therapies is a complex, highly choreographed process. Consequently, site selection is a linchpin of study success. Experience with handling and administering advanced therapies is an essential consideration, as is familiarity with the disease under investigation. Developers also should evaluate:

• Site reputation and past performance in advanced therapy studies
• Experience with the target patient population
• Relationships with providers who can refer patients and provide post-treatment care
• Existence of and adherence to standard operating procedures and best practices specific to advanced therapies, including processes for recognizing and managing adverse events
• Experience with the mode of administration, particularly important in studies that require specialized procedures - for example, intracranial administration of vector or cells in in-vivo gene therapy trials
• Impact of competing trials at the site

To maximize engagement, developers may consider aligning study protocol requirements with existing institutional policies. Fitting into existing site workflows rather than reinventing care pathways can help to minimize site burden. Reducing operational complexity also can have a positive impact on post-approval product adoption. To optimize site performance, developers should consider rigorous site training and site-specific execution mapping.

Depending on the IMP, additional site certifications or approvals may be required. Accreditation from the Foundation for the Accreditation of Cellular Therapy or the Joint Accreditation Committee ISCT-Europe & EBMT demonstrates adherence to established standards for the collection, processing, and clinical use of cellular therapy products. For human gene transfer products being studied in the U.S., approval from an institutional biosafety committee is needed to show that the site has the necessary standard operating procedures and processes in place to handle the product under investigation. In the EU, study start-up activities for gene therapy products may be even more complicated depending on the product's regulatory pathway, either contained use or deliberate release, and member state-specific GMO regulations and related authorities.

Recruiting and Retaining Patients

To ensure successful recruitment and retention, sponsors should focus on minimizing patient burden and facilitating - or even enabling - participation under extraordinary circumstances. In a recent lentiviral study, Premier Research helped relocate three families from overseas to the U.S., including a family of four from India that will stay in the U.S. for nine months to be near the site for the extended period of time required for study participation.

Depending on the mode of administration, developers may opt for a hub-and-spoke model where the advanced therapy product is administered at centralized surgical sites, and extended follow-up is performed at local sites. In either scenario, it is critical to consider the costs associated with operationalizing a study, whether it is travel, lodging, off-site visits, or other costs associated with maximizing convenience and minimizing out-of-pocket expenses for patients and their families. 

If extended long-term follow-up periods are required, retention presents an even bigger challenge. Throughout long-term follow-up, patients may relocate and may switch from being followed by a pediatrician to being seen by an adult physician. Consequently, developers may need to initiate new sites with investigators who are not connected with the initial study. Managing these nuances and maintaining engagement as study participants and sites evolve requires persistence and creativity.

Conclusion

Bringing life-changing advanced therapies to market can be challenging. Yet, with more than 1,200 clinical trials underway, enthusiasm for cell, gene, and tissue-based therapeutics is high. To achieve clinical success, developers need to incorporate the priorities of diverse stakeholders into their development plan and execute safe, ethical studies that balance patient preferences with evolving regulatory requirements in an increasingly competitive clinical trial environment.

References

1. Alliance for Regenerative Medicine. Alliance for Regenerative Medicine Annual Report Highlights Record Sector Growth and Resilience in 2020, March 26, 2021. https://alliancerm.org/press-release/alliance-for-regenerative-medicine-annual-report-highlights-record-sector-growth-and-resilience-in-2020/. Accessed May 22, 2021.
2. Maingi, S. Visualizing the Future of Contract Development and Manufacturing for Cell and Gene Therapies, March 19, 2020. https://www.pharmasalmanac.com/articles/visualizing-the-future-of-contract-development-and-manufacturing-for-cell-and-gene-therapies#. Accessed May 22, 2021.

Angi Robinson has been conducting pediatric and rare disease studies for more than 19 years. She has provided oversight and full management support for rare disease studies at Premier Research for over 10 years, including global programs in ultra-rare indications. Robinson has supported FDA pre-IND meetings, IND submissions, and NDA project directorship. Robinson’s experience includes multiple study designs including PK/PD, adaptive design, and she has worked with products granted expedited designations by the agencies including FDA fast track, breakthrough therapy, and PRIME designations, including gene therapy and other advanced medicines. Specifically in orphan drugs Robinson has supported five orphan drug products resulting in agency approval and global access.

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