Advanced therapies (ATs) such as cell therapy, gene therapy, and tissue engineering represent a groundbreaking force in medicine and research. Whereas traditional therapies may use small molecule chemical or biologic products to treat disease, ATs use cells with specifically modified DNA or RNA components to systemically control a disease, replace an aberrant gene, or repair defective tissue. These cellular investigational products have the potential to cure a disease. It is this potential of eliminating disease that could make ATs so revolutionary. At their core, ATs are the result of researchers harnessing the building blocks of life to improve the quality of human lives.

Although less than two dozen ATs are approved by FDA so far,¹ the pipeline to develop these therapies is rapidly growing, targeting therapeutic areas such as genetic disorders, cardiovascular disease, and infectious disease. Currently, however, the majority of ATs focus on oncology, as the unmet need remains high in this area and the rates of most cancers are increasing (see Figure 1).

As global head of immuno-oncology at IQVIA Biotech, I am heavily invested in helping our customers navigate the operational complexities that arise when designing and running clinical trials for ATs. Three leading challenges specific to AT trials include identifying and selecting the most capable sites, navigating the additional regulatory requirements, and juggling the logistical demands of manufacturing of the investigational cellular product and also handling complex biospecimens.

Site selection

For most clinical trials, the initial stage of the study is notoriously challenging due to the intense planning, robust site selection, and timely site activation required. But clinical trials for ATs come with additional requirements that make the site selection process even more difficult and more critical to trial success.

Since cell and gene therapy trials require integration and coordination with numerous disciplines within the institution (e.g., any combination of the medical or hematological or treating department; a leukapheresis center to isolate the white blood cells; a cell therapy laboratory; an investigational pharmacy; an in-patient treating facility; and outpatient clinics), the number of contributing departments alone presents a difficulty. To address this complexity, we advise customers to invest additional time during qualification and initiation visits to confirm that the sites are fully capable and prepared to handle adoptive cell or gene therapy studies.

Each of these departments will require a visit and assessment of capabilities, and sometimes contract research organizations (CROs) engaged to conduct the trials need to speak directly with a multidisciplinary investigator team during site selection. This extra time investment during site selection and activation ensures that the sites have the requisite equipment and processes, appropriate handling knowledge, and trained staff and expertise.

To aid site identification and selection activity, biotech companies can start by considering Foundation for the Accreditation of Cellular Therapies (FACT)-accredited institutions. These AT-capable global sites have already established their capabilities and infrastructure and have met recognized accreditation standards. Evaluation of these sites to confirm that they meet all capabilities and possess the appropriate expertise for the specific AT trial is still requisite; however, targeting some of these sites is one component to creating a robust site identification strategy. To supplement this strategy, interrogation of a CRO partner’s site database or evaluation of a subscription database on site and trial performance may yield additional sites to consider. Lastly, investigator relationships, networks, and thought-leader support are paramount to concluding a comprehensive site identification strategy.

Currently, facilities needed to conduct AT trials are highly specialized and are, therefore, restricted to a limited pool of medical and academic institutions. In the future, one goal is to increase the number of locations where patients in need can access these therapies. To achieve this, locations such as privately owned sites or community-based facilities may partner with a larger organization and work together to navigate the various in-patient, out-patient, and specific protocol requirements. Alternatively, as the AT field continues to advance, AT trials may become less complex, thereby reducing some barriers to participation by community centers. Although significant progress is being made, there are still monumental challenges to overcome before this will be commonplace. Before we can expand treatment opportunities and localities, AT manufacturing, standardization, and the time and cost of administration must be optimized to meet patient needs in a variety of settings.

Regulatory requirements

After selecting a suitable site, an AT trial must receive approval of the investigational product and intended clinical trial protocol from country-level regulators and site-level committees and boards before enrolling any patients. In addition to fulfilling global International Conference Harmonization Good Clinical Practice (GCP) guidelines² and receiving standard requisite approvals (e.g., FDA and institutional review board [IRB] clearance), AT trials are often evaluated by specialized committees or local standards. These reviews differ from country to country but are intended to ensure oversight of the scientific property or genetic material used within the AT, to ensure adequate handling of the AT, or to uphold public safety.

Because of the genetic nature of ATs, they are often subject to strict, country-specific guidelines. For example, studies using viral vectors such as lentivirus and adenovirus are subject to genetically modified organism (GMO) directives in the European Union (EU) but not in the U.S.^3,4 Raw materials or local testing performed during development of the AT may be accepted in one region, but not in another (e.g., donor cell testing and documentation or non-GMP reagents), and this represents global variability to the AT technology itself. Biotech companies planning an AT clinical trial should ensure their technology is accepted in all countries in which they plan to operate, otherwise they will risk having to increase the amount of capital they invest to render the technology acceptable for the trial. Therefore, global regulatory planning and landscape understanding is critical to the success of AT development and running an AT trial.

Furthermore, there are regulatory checkpoints in place to ensure adequate handling of the AT material and to protect patient, clinician, and public safety. In the U.S., institutional biosafety committees (IBCs) review most AT studies at an institutional level, while in Europe, studies must meet the standards of the advanced therapy medicinal product (ATMP) directive⁵ and may need to be reviewed by national GMO experts. In lay terms, IBCs are similar to IRBs, though instead of reviewing research ethics, their core objective is to ensure adequate and safe handling of the AT material. IBCs operate under U.S. National Institutes of Health (NIH) Guidelines-and it should be mentioned that many, but not all ATs, must have an IBC review in the U.S.

Similarly, in Europe, GMO requirements are intended to ensure adequate and safe handling of the AT material, but there may be national variability depending on the precise GMO classification and environmental risk determination. Each of these steps can lengthen start-up times as compared to non-AT studies, but are important to ensure that proper handling procedures are implemented, and patient or public safety is protected.

Due to the broad variability of requirements globally for AT studies, as well as the growing comfort with ATs, it is important to evaluate each AT trial based on the specific therapy, scientific construct, and potential manufacturing process against a contemporaneous global and local regulatory landscape to determine what additional expert reviews must be met before enrolling patients. The regulatory landscape has changed for ATs recently with the 2018 NIH Statement and April 2019 Guidelines,^6,7 and it will likely continue to change (e.g., EU CTR 536/2014). Because of this, it is important for biotech companies to understand the current state and anticipate the future state, both of which may impact their AT development goals.

Logistics

AT clinical trials have tremendous logistical complexities, from the manufacturing supply chain of the AT product itself to the frequency of biospecimen collection during the study. Biospecimen collection in AT studies seemingly occurs around-the-clock, to ensure safety, evaluate kinetics, determine function or efficacy, and collect exploratory samples. Biotech companies must have a detailed protocol laid out that dictates the timing, quantity, and type of biospecimens needed for the trial, as well as a plan for how to transport and store and assay them.

Autologous therapies, which are AT therapies manufactured from a patient’s own cells, are manufactured by a web-like supply chain (see Figure 2), and final products must meet specific release requirements. Because these ATs are highly perishable and unique to the specific patient, they require intricate storage, labeling, traceability, custody, packaging, and shipping requirements. The starting cellular material taken from the patient is often stored at ambient temperature, and, therefore, clinicians and couriers have only 24-48 hours to transport it from the patient to the manufacturing facility.

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At the manufacturing facility, biotech companies must manage the nuances of the heterogenous cell populations of each received donor, viral transduction variability for the genetic material going into the cells, and differences in resulting cell viability. With an autologous therapy, each manufacturing run follows the same overall process; however, because the starting material differs patient to patient, the consistency and quality of each patient’s result product must be carefully monitored. Once the manufacturing process is complete, the final product is evaluated per release specifications. Only then can the final product be packaged, often frozen, and shipped to the site, where it may again be stored temporarily.

The site must follow careful preparation instructions prior to administering the patient’s modified cells back to him or her. Due to the personalized nature of these therapies, chain of identify (“what patient it is”) and chain of custody (“who has it”) are imperative to ensure integrity and accountability during the vein-to-vein process.

Being AT therapies made from a single donor, allogeneic therapies follow an important but slightly modified supply chain requirement, starting at “manufacturing” in Figure 2. The overall process, release specifications, and manufacturing considerations still apply; however, the chain of identity may be of lesser importance in the allogeneic setting, unless multiple donors and multiple cell lines are being developed.

Once the AT product is administered to the patient, another web of biospecimen samples must be collected and assayed, or processed and shipped, or stored for batching. The samples required are diverse and range from important safety labs, to immunogenicity tests, to persistence and efficacy, to unique exploratory assays. While there is not universal prescription of lab quantity or quality, each AT trial is certain to have many samples required to both protect patient safety and foster the scientific pursuit of understanding mechanisms and improving outcomes.

To ensure appropriate communication and planning, it is important that each AT trial have a dedicated individual to oversee logistics. Appropriate communication and planning are especially important for handling precious cell materials, to minimize risk at all sample handovers between patient and site and biotech or lab, and to ensure compliance and reconciliation of samples. Such measures can help to make sure a maximum of exploratory samples is obtained. Innovative technology-based solutions can also be leveraged to ensure superior compliance and tracking, as well as risk mitigation, of the logistics chain. Vendor solutions offer cold chain shipping, tracking, and custody solutions to support the specialized shipping requirements of AT studies. Finally, central repositories and/or central labs for biospecimens increase ease for and compliance of clinicians, as well as reduce shipping errors that may result in sample loss or assay integrity issues.

Such steps can ultimately improve the scientific outcomes of AT studies. Taken together, these solutions can help to manage the logistical complexity of biospecimens and materials on an AT trial.

Role of the CRO

CROs can help sponsors navigate the many operational steps involved with site selection and start-up, regulatory requirements, and product and biospecimen complexity. They can also provide data-driven guidance to enhance the probability of regulatory and clinical success.

Throughout AT trials, CROs should rely on data to assist with site identification, as well as protocol validation and optimization. In addition, they should support customers through changes in the AT regulatory landscape. For example, the forthcoming EU Clinical Trial Regulation (EU CTR 536/2014) represents the most significant change to clinical trial regulations in Europe in the 15 years since the implementation of the EU CT Directive. The EU CTR will introduce an overhaul of the procedures for clinical trial applications, amendments, and requirements for notifying authorities and ethics committees during the conduct of all interventional trials. A CRO’s understanding of these regulations positions it to help customers navigate these upcoming developments.

As AT technologies evolve, we anticipate that they will become more universal and less complex. Allogeneic therapies, applicable to multiple patients, may replace autologous therapies manufactured for individuals. We anticipate that the agents in the pipeline now will result in progress and understanding in the field to decrease AT complexity. Further, a major goal is for more sites outside of high-powered medical and academic institutions to offer AT therapies, which will put them in more proximity of the patient populations they serve. Pioneering locations, such as Novartis-Penn Center for Advanced Cellular Therapeutics, a collaboration between the University of Pennsylvania’s Perelman School of Medicine and Novartis, are already laying the groundwork for this. Perhaps other leading public and private institutions will follow suit, given their extensive resources. Currently, it is impractical for privately owned physician practices and dedicated sites to offer ATs, as they would need to have the technology, facilities, and infrastructure required to support specialized AT protocol requirements, support complex patient care needs, and perform bioprocessing on site. Although these are massive challenges to overcome before AT will become more widespread, the clinical trial sector is taking its first steps toward bringing these game-changing therapies to all patients who need them.

References

1. “Approved Cellular and Gene Therapy Products.” U.S. Food and Drug Administration, https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. Accessed Aug. 8, 2019.
2. “ICH HARMONIZED TRIPARTITE GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R1). “International conference on harmonization of technical requirements for registration of pharmaceuticals for human use.” June 6, 1996.
3. “DIRECTIVE 2009/41/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of May 6, 2009, on the contained use of genetically modified micro-organisms.” Official Journal of the European Union. May 21, 2009.
4. “DIRECTIVE 2001/18/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of March 12, 2001, on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC.” Official Journal of the European Union. March 21, 2008.
5. “REGULATION (EC) No 1394/2007 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of Nov. 13, 2007, on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004.” Official Journal of the European Union. Oct. 12, 2007.
6. “Statement on modernizing human gene therapy oversight.” U.S. National Institutes of Health, https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-modernizing-human-gene-therapy-oversight. Accessed Aug. 22, 2019.
7. “NIH GUIDELINES FOR RESEARCH INVOLVING RECOMBINANT OR SYNTHETIC NUCLEIC ACID MOLECULES (NIH GUIDELINES).” Department of Health and Human Services. National Institutes of Health. April 2019.

Erin Finot, MS, MBA, is Global Head of Immuno-Oncology, IQVIA Biotech