One of the most powerful and significant developments in medical therapies in the past decade has been the maturing of cell and gene therapy (CGT) treatments. Cell therapies such as CAR-T and TCR-T offer transformative outcomes for challenging diseases. Recent cell therapy approvals and the growing number of clinical trials are accelerating the process from discovery through clinical trials to commercial manufacturing and delivery.

Gene therapies can provide significant—and possibly curative—benefits to patients who have genetic or acquired diseases. Through the direct expression of a therapeutic protein or by restoring the expression of an under expressed protein, gene therapy uses vectors to deliver gene-based drugs and therapeutic loads to patients.

While the approvals for treatments for rare diseases are certainly early wins, the impact of gene therapies will significantly expand as approved treatments are administered to larger patient groups and studies expand to address diseases that are broader reaching—for example, with treatments for multiple myeloma, leukemia, and other forms of cancer.

Compared to more standard biopharmaceutical clinical trials, there are unique challenges associated with managing biospecimen samples during trials of CGTs. One of the most critical challenges is properly and safely managing the specimens taken from each patient, since those specimens can actually be used to create the therapy and must be returned with absolute safety to the patient for treatment.

CGT trials, while following their own specific workflows, are generally carried out in similar stages. Cell therapy can be allogenic when produced from cells that are collected from a healthy donor and shipped to a clinical site to treat a patient. Alternatively, there can be autologous therapy, where the biological material is from the patient and is transferred to a biomanufacturing site for genetic modification, and then returned and administered to the patient the sample was taken from.

Although each trial is unique, the major workflow steps are relatively similar. First, genetic or cell-based disease states and potential therapeutic pathways are identified by researchers and the trial design begins to be developed.

Once a trial is designed, trial participants need to be identified. Unlike other biopharmaceutical trials, CGT trials tend to have much smaller patient populations. Biospecimen cells are collected from these patients and need to be transported under the most stringent safety and cryopreservation conditions in coordination with regulatory requirements.

 This includes having well-established cold chain logistics that manage and document each specimen’s condition to ensure that no temperature-related degradation occurs.

Each specimen is then used to biomanufacture the therapeutic cells—either through modification of the cell genome (for cell therapy) or through creation of the viral vectors to deliver gene-based drugs and therapeutic loads to the patients. These temperature-sensitive therapies must then be carefully thawed, with minimum impact on viability and functionality, to be delivered to the patient by the clinical trial team at the investigative sites.

In addition, as part of the clinical trial, portions of the specimens need to be set aside, before and after biomanufacturing, for various testing requirements. Tests like qPCR, ELISA, flow cytometry, and others are critical to conducting the analysis of the therapeutic steps being studied, so proper storage (short-term and long-term) needs to be fully managed.

Proper management of aliquoting biological samples is also a critical element in biospecimen management for these trials in order to mitigate risk of cell deterioration from freeze-thaw cycles. Many research centers require aliquoting to generate sub-samples for distribution to third-party laboratories and clinical partners. Since the source biospecimens from each patient are so much smaller in actual quantity, extraordinary care is needed at every step of biospecimen management not to lose any biological material.

Finally, biospecimen management for CGT trials must include support for stable, multiyear storage. With the administration of gene therapy products into a patient, there is a possibility of delayed biological events that demand the collection of data for a longer period. The therapeutic changes that patients experience due to genomic modification often need to be tracked for 10 to 15 years, so long-term cryogenic storage of the modified cells is a critical element for supporting the trial.

As CGT trials expand, it is important for the industry to investigate and fully understand the best practices researchers should follow for managing living/active samples during CGT clinical trials, especially given some of the unique processes described earlier.

Along with management during the active trial, it is also crucial to long-term biorepository and sample management to ensure your biospecimens are secure and safely stored. These best practices include having a thorough appreciation of the regulatory factors to consider when managing the type of data generated by these trials.

Due to the sensitive nature of this personalized kind of medicine, researchers need to work very closely with regulatory agencies to fully understand and plan the trials according to established protocols. Gene therapy developers have access to expedited approval pathways such as Regenerative Medicine Advanced Therapy (RMAT) designation in the US, PRIority MEdicines (PRIME) designation in the EU, and SAKIGAKE designation in Japan.

Biorepositories address management obstacles

Leading biorepository providers across the globe are responding to the heightened complexities and risks of biospecimen management in CGT trials. They are building on established sample logistics, storage, and management tools to address these unique challenges more fully. Concerns include:

Preserving the specimens from collecting the cells from patients through cell therapy manufacturing and delivery to them. Unlike other treatment regimens, the specimen is also the therapeutic pathway—its safe preservation, management and storage is critical to the progress of the clinical trial and ultimate demonstration that the therapy can be successfully applied.

Rigorous cold chain transport logistics to ensure cryopreservation at multiple stages. This requires detailed, multifactor tracking of each sample so that it is clearly and permanently associated with a specific patient at every point of exchange and every process step, including ancillary steps associated with clinical testing and long-term storage.

Detailed familiarity with requirements and compliance: All clinical practitioners and personnel from biorepository logistics and storage organizations need to be thoroughly grounded in the strict protocols established for each trial and demonstrate how their procedures comply; since CGT therapies are so new, and patient risk is elevated, biorepository operations have a special duty to manage any biospecimen management safety concerns.

The relative newness of CGT programs at major life sciences research institutions has led, in some instances, to a preference for keeping all aspects of clinical trials within a single research organization or network of researchers.

Because the relatively small size of the target patient in a given geographical region is as small as one-tenth the number of patients participating in traditional clinical trials, it has created the need for multiple locations worldwide for conducting clinical trials or having the patients travel for getting the clinical treatment. As a result, researchers tend to set up their own biorepositories, biospecimen management systems, and model industry best practices to maintain sample integrity and traceability across the sample management ecosystem.

While the desire for comprehensive control would seem to make sense, there are distinct advantages to working with expert biorepository operations to manage all key aspects of biospecimen capture, transport and storage. GxP or “good practice” quality guidelines and regulations with leading service providers assures proper storage for the viral vectors and cells so they have the traceability and consistency.

These include creating rigorous chain-of-custody procedures with advanced biospecimen digital documentation and tracking tools that tightly associate each specimen with its source patient throughout every exchange. They have established meticulous biospecimen collection and registration procedures that are flexible enough to adapt to specific clinical trial procedures, patient populations, manufacturing locations and regulatory protocols.

Biorepositories are also customizing their cold-storage logistics and transport procedures to support CGT biospecimens. This includes tracking shipments in real time using automated tracing software and GPS-based tools, as well as working with clinical researchers to minimize transport times from the site of specimen collection to therapeutic manufacturing and specimen storage locations.

Leading biorepositories have also made extensive investments in large-scale, custom-built cryogenic storage facilities. These plants offer storage temperatures ranging from cryogenic -196 °C and ultralow -80 °C to refrigerated and controlled room temperature storage, offering researchers much greater flexibility. These specialized systems are continuously monitored and typically include multiple backup systems to prevent accidental specimen loss due to outside events or local power failures. Some of the leading biorepository providers have sited these state-of-the-art facilities in multiple locations worldwide to enable CGT trials with global footprints and patient populations to work with a single biospecimen management provider.

There are biorepository and biospecimen logistics providers who are actively investing in more robust, expert biospecimen data management systems. Just like their operational procedures, these tools have been developed and continually improved through hands-on experience managing millions of samples for a wide range of research applications.

These material management systems give instant digital access to comprehensive data of biospecimens that have been transported and stored, allowing researchers to efficiently manage biospecimen inventory, submit work requests, and generate standard or custom reports.

In addition, they are further developing these systems to satisfy evolving regulatory requirements for CGT clinical trial data management, since the conditions of the biospecimens at all stages of transport, biomanufacture, and storage need to be exhaustively documented.

Working with expert biorepository organizations and outsourcing biospecimen collection, cold transport logistics and both short- and long-term storage provide CGT researchers with a proven resource that can help prevent error, protect patient safety, and help make CGT trials more efficient.

An effective path forward would include increased collaboration between professional biorepository operations and clinical trial researchers. By fostering true working partnerships, these experts can educate researchers on the risks associated with imperfect or poorly planned biospecimen logistics; especially with multisite trials, they can work to refine standardized procedures and tools used to collect, secure, document, and transport specimens to reduce the risk of error or inefficiencies.

Streamlining and standardizing biospecimen management can ultimately help reduce costs, minimize rework and simplify many clinical trial management tasks often carried out by researchers. The advanced data management capabilities also provide a powerful foundation for conducting advanced data mining and analysis of trial and biospecimen data to augment other research results.

Most importantly, working with biorepository experts to handle these critical tasks will free researchers to focus their valuable time and efforts on advancing the science CGTs.

, Global Director, Biorepository Operations and Strategy; both with Avantor

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Guidance for Industry: Long Term Follow-Up After Administration of Human Gene Therapy Products, January 2020. 

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King, D., Schwartz, C., Pincus, S., & Forsberg, N. (2018). Viral Vector Characterization: A Look at Analytical Tools. Cell Culture Dish. Accessed Dec. 8, 2021. 

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Gene therapy needs a long-term approach. (2021). 

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Pursuing new tools and capabilities in sample logistics, storage, and data analysis.

Managing Biospecimens in Cell and Gene Therapy Trials

A rapidly growing portion of clinical trials involve cell and gene therapy (CGT), or human gene transfer. These studies involve administration of living cells and/or genetically modified DNA or RNA to clinical trial participants. In 2022 to date, the Alliance for Regenerative Medicine has identified 2,093 active clinical trials in this category, testing products from 1,369 cell, gene, and tissue-engineering therapeutic developers.

 Examples include: regenerative medicine products derived from pluripotent stem cells, immune effector cells engineered to express chimeric antigen receptors (e.g., CAR-T cells), genetically engineered oncolytic viruses, and viral vectors expressing therapeutic transgenes to treat inherited or acquired disease. Importantly, within the CGT category, certain operational considerations apply only to cellular therapies or only to gene transfer therapies, and some apply to both.

When research involves potentially infectious or transmissible agents, genetically modified DNA or RNA, or biological toxins, it should be evaluated for potential risk to research staff, the general public, and the environment. Biosafety is the field of practice dedicated to assessing and mitigating these risks, and biosafety oversight at many research centers is provided by an institutional biosafety committee (IBC). 

The NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules

 are
issued by the National Institutes of Health (NIH) and mandate IBC approval for certain clinical trials prior to initiation. For research subject to the NIH guidelines, the approving IBC must be registered with the NIH, and each such IBC registration pertains to a unique institution or clinical trial site.

Historically, each NIH-registered IBC was administered by the respective research institution, usually the university or academic medical center, and the bulk of research under review by these committees was basic science or preclinical studies. More recently, biosafety oversight for many clinical trials has been provided by central commercial IBC service providers, who can manage the IBC registration for multiple sites selected for a multicenter trial, for example.

Whether or not IBC review is mandatory for a particular study, certain biosafety considerations are recommended in the interest of responsible conduct of research. In the sections ahead, we will summarize these considerations in terms of NIH requirements and best practice recommendations.

Study-level biosafety considerations for sponsors

The NIH guidelines require that IBC approvals be issued for each clinical trial site or institution. This means that there are no study-level approvals under the guidelines; nevertheless, there are many ways that clinical trial sponsors can facilitate best practices and efficient IBC approvals. If biosafety considerations are addressed in an investigational new drug (IND) application, they can inform preparation of study documents that are distributed to investigators and review committees. These documents may include the protocol, investigator’s brochure (IB), pharmacy manual (or administration manual/product handling instructions), and draft informed consent form (ICF).

Under the current version of the guidelines, IBCs are not required to review the ICF; however, institutional review boards (IRBs) and IBCs may collaborate to identify and address third-party risks to participants and close contacts or family members, and these considerations may affect IRB approval. Review and consultation with a biosafety professional during the drafting stage of these documents can enhance their utility and facilitate efficient site-level approvals. For example, where appropriate, protocols should include plans for shedding assessments in the schedule of events. Also, the IRB should realistically address potential third-party risks and summarize existing preclinical or clinical shedding data.

A key document for biosafety review in multicenter clinical trials is the sponsor pharmacy manual, or equivalent product handling instructions. The pharmacy manual provides an opportunity for the sponsor to instruct sites and investigators on the safe handling of study agents. The pharmacy manual can also help to inform the site selection and study start-up processes whenever special equipment, such as a biological safety cabinet (BSC) is required. Clinical trials of non-biohazardous drug products often involve the use of laminar flow hoods for drug preparation. However, laminar flow hoods are generally not approvable for preparation of biohazardous products. BSCs (e.g., Class II A2 BSCs) are designed to protect the sterility of the drug product and the safety of the clinical staff and are required for some but not all CGT research. IBCs consider biosafety requirements under both the NIH guidelines

 and the Biosafety in Microbiological and Biomedical Laboratories 

 Depending on the study, drug preparation at a site may also be subject to rules relating to current good manufacturing practices (cGMP), US Pharmacopeia (USP) 797, or USP 800 requirements. Collaborative review by pharmacists and biosafety professionals during the drafting stage of the pharmacy manual can harmonize operating expectations and facilitate site regulatory submissions and clinical trial initiation.

When it comes to site selection, there are a variety of considerations that specifically apply to CGT research. As mentioned, for gene transfer research, sites should either have an IBC registration with the NIH or be willing to become registered. Facilities and equipment required for a protocol should be specified in the respective pharmacy manual or equivalent, and prospective sites should be evaluated to see whether that equipment is available on site, or if purchasing, installation, and certification are required (all of which require time to complete). For cellular therapies, sites with demonstrable expertise in clinical operations may undergo a rigorous evaluation to become certified by the Foundation for Accreditation of Cellular Therapy (FACT).

 On the other hand, for many CGT products, it is possible with expert assistance to enable naïve sites to undertake advanced therapies research—an important consideration as sponsors seek to engage with underserved communities and diverse patient populations.

Biosafety considerations at the site level

For a site with limited experience in gene transfer clinical trials, preparing to conduct research with advanced therapy or gene transfer products may seem like a daunting challenge. IBC review ensures that proposed research activities are compliant with federal biosafety requirements. Clinical staff often report that working with an experienced biosafety professional helps them feel confident about their approach to CGT study start-up and execution.

For any site, the first step in securing IBC approval is to ensure that there is an IBC registered with the NIH for that site. For sites using a commercial IBC service, the registration is generally administered by the commercial service provider on behalf of the site. Once registered with NIH, the IBC may be maintained indefinitely, so a new registration for each new study is not required.

Once the NIH registration is filed, then site staff can begin working with the IBC to secure approval for the first protocol. In general, each clinical trial protocol requires separate IBC approval. In contrast to IRB reviews, which are focused on protecting clinical trial participants, IBC reviews are focused on protecting clinical staff, visitors, the public, and the environment. When reviewing a clinical trial, an IBC will consider numerous factors, including the proposed biosafety level (i.e., BSL-1 or BSL-2) for the research and the equipment, training, and procedures to be used in safe conduct of the research.

As mentioned, a key item of equipment for many (but not all) gene transfer procedures is a BSC, and the most used type is Class II A2. Many research pharmacies are already equipped with this type of cabinet for general use, even without gene transfer research experience. Class II A2 cabinets draw clean air from the surrounding environment via a HEPA filter and then blow clean, HEPA-filtered exhaust air back into the workspace. When properly used, this design will both protect the investigational product (IP) from contamination, and protect clinic staff from unintentional exposure to the gene transfer product. BSCs require certification by an expert inspector prior to initial use and at regular intervals after installation.

In general, IP preparation at clinical trial sites does not require rooms with special airflow or negative pressure to comply with biosafety requirements. However, in certain cases, sponsors or sites may determine that ducted evacuation of exhaust air is needed, in response to special requirements relating to cGMP standards or the use of volatile compounds. These designs may involve Class II B2 or Class III BSCs, which channel air into exhaust ducts. Designing facilities to maintain balanced airflow in the presence of ducted BSCs requires a very significant increase in expense and setup time compared to regular Class II A2 operations. Any such facility should be carefully designed in consultation with architects, HVAC engineers, and biosafety professionals to minimize expense and delays.

Sites preparing for IBC approval should ensure that there is a biosafety standard operating procedure (SOP) appropriate for each protocol under review. The SOP should clearly delineate how the IP is received, stored, transported, prepared, administered, and disposed of, in addition to describing planned response to spills, exposures, and other unexpected events. Spill response for an IP that may contain viral vectors, infectious agents, or bloodborne pathogens requires careful planning. It is important that staff trained on the SOP response are available to respond at any time that spills may occur.

It is also important to ensure that risk to patients and visitors not enrolled in the study is minimized, especially in clinical contexts such as cancer centers where many patients are likely to be immunocompromised. Depending on the study agent, it may be advisable to segregate enrolled participants from other patients, especially during dosing and infusion, when spills or accidental release of IP is most likely. Sites can benefit from planning ahead to identify infusion areas where participants can be kept separate during dosing.

Clinical research with products containing genetically modified DNA and RNA is a rapidly growing area, and includes some of the most promising new advanced therapies. Most sites, even those with little or no experience in this area, can conduct these studies safely when they partner with experienced biosafety professionals. In many cases, the sites will be required to seek IBC approval, which not only ensures compliance with federal guidelines, but also helps ensure that investigators and staff understand best practices and expectations for safe and responsible conduct of gene transfer research.

, PhD, RAC, Senior Scientific Advisor, WCG

Regenerative Medicine: The Pipeline Momentum Builds; September 2022. 

https://alliancerm.org/sector-report/h1-2022-report/. Accessed 08SEP2022

https://osp.od.nih.gov/wp-content/uploads/2019_NIH_Guidelines.htm

The benefits of working with an institutional biosafety committee in CGT research.

A Biosafety Perspective on Operational Challenges in Cell and Gene Therapy Studies

Oncology accounts for 27% of all clinical trials conducted since 2017. Compared to other therapeutic areas, oncology trials are more resource-intensive and less efficient, requiring an average of 16 clinical sites to enroll a median of just 31 patients per study. In fact, average enrollment duration for oncology trials is two times longer than for all diseases combined (22 months vs. 11 months).

Yet research interest remains high, with oncology accounting for 45% of all planned studies from Q4 2021 to Q4 2024. Nearly half of these are Phase II studies and almost 40% include countries in North America, while 35% are being conducted in Asia.

 As of July 2022, among the 19,700 new drugs in the pipeline, 6,731 (34%) are for cancer. This robust development activity spans over 20,000 organizations across 116 countries. Interestingly, 72% of these oncology trials are sponsored by companies outside of the top 50 pharmaceutical organizations and 67% are for rare and orphan disease indications.

Among the more than 1,500 potential oncology biomarkers that have been identified in the preclinical setting, approximately 700 are involved in the active or planned clinical trials in oncology. Over 60% of these studies are for immuno-oncology drugs, with the remainder for targeted therapies.

The rise of personalized medicine has been driven by biomarkers, which have enabled researchers to understand the science behind mechanism of action and have been used to target recruitment. More than one-third of all drugs approved by FDA since 2000 have been personalized medicines, demonstrating that biomarker-driven approaches help optimize treatment impact and improve patient outcomes.

 In fact, a recent analysis of 9,704 development programs from 2011 to 2020 found that trials employing preselection biomarkers have a two-fold higher likelihood of approval, driven by a nearly 50% Phase II success rate.

The value of biomarkers is not limited to the clinical trial setting. Rather, biomarkers play a critical role throughout drug discovery and development, bridging preclinical and clinical studies. Incorporating biomarkers into programs requires careful choreography—from collecting biological samples and analyzing them in decentralized or specialty labs to generating data that will be integrated with other clinical information to support decision-making. It may also require a broad spectrum of logistics and laboratory management capabilities for handling a range of sample types.

Challenges of biomarker-driven development

Table 1 below provides a sampling of FDA-approved biomarker-driven therapies. A key challenge of integrating biomarkers into development programs is selecting the right biomarker. Often, the frequency of the biomarker of interest is very low. The same or similar biomarker may be present in multiple tumor types at varying frequencies, as is the case with HER2 amplifications in breast and gastric cancer. Biomarker frequency may also differ among races and ethnicities—it may also change as the disease progresses. For example, EGFR exon 20 T790M alterations increase in frequency in patients with non-small cell lung cancer who have become resistant to previous lines of therapy. Consequently, selecting the right biomarker is akin to finding a needle in a haystack.

Precision for Medicine was involved in an oncology cell therapy study, where eligibility was based on the expression of two biomarkers. The first biomarker was expression of human leukocyte antigen (HLA)-A*02:01 and the second was a tumor type expressing a certain cell receptor on at least 80% of cancer cells. Precision for Medicine performed an analysis and found that the prevalence of HLA-A*02:01 varied among geographic regions, with a prevalence of 38.5% to 53.8% in Europe and 16.8% to 47.5% in North America (see Figure 1 below). Based on this finding, we recommended conducting this clinical trial in Europe.

Analysis of the expression of the cell receptor of interest showed that expression levels varied not only by tumor type, but even by subtype or demographic (see Table 2 below).

We used these findings to project the number of patients and samples that would need to be screened in order to enroll 36-40 study participants. Our assumptions were that 30% of patients screened would have HLA-A*02:01 expression and 10% of those patients would have ≥80% biomarker expression, and 50% of those would meet all the inclusion criteria for the study.

Based on these assumptions, it was determined that HLA analysis would need to be performed on approximately 2,500 blood samples and immunohistochemistry would need to be performed on about 750 tumor tissue samples to reach the enrollment target.

To increase the efficiency of this study, the Precision for Medicine team implemented various strategies for streamlining the recruitment process:

Identifying where potential patients are located. 

In addition to evaluating epidemiology data, we searched the databases of not only our global clinical site network but also our biospecimen repository, for patients who might be eligible for this study. We partnered with organizations, including commercial next-generation sequencing (NGS) laboratories, that have access to site networks and examined ICD-10 claims data. We also leveraged strategies such as advertising to proactively attract potential patients.

Identifying the best sites for enrolling patients. 

To identify and qualify sites, we leveraged our global clinical site network and key opinion leaders and evaluated sites based on various criteria, including previous experience and competing studies in a similar patient population that might interfere with recruitment. We also assessed the regulatory landscape to understand the nuances involved in conducting the study in different regions or countries with regard to compliance with advanced therapy medicine product guidelines or data protection regulations and access to health data.

 Performing a pre-screening study that is separate from the core clinical trial can help to increase efficiency and enrich the patient funnel. One option for this study was to perform a pre-screening study to analyze blood samples for HLA-A*02:01 expression. Sites were also provided access to EHR Connect, Precision for Medicine’s proprietary data mining tool, to assist in the identification of potentially eligible patients. Concierge services were also offered to help ease the burden of study participation, and other decentralized trial strategies were deployed to enhance enrollment.

As oncology clinical research evolves toward personalized treatment of patients in niche populations, a biomarker-driven approach to drug discovery and development is required. With new biological targets frequently having a low level of prevalence, it is important for researchers and developers to look for more innovative approaches to patient identification.

, Vice President, Operational Strategy and Feasibility, Precision for Medicine

Citeline Search. Precision for Medicine. Data on file.

Ethridge W, Lara, R (2021). Opportunity Trends Analysis for 2022, Precision for Medicine.

BIO, Informa Pharma Intelligence, QLS Advisors. Clinical Development Success Rates and Contributing Factors 2011-2020, Feb. 2021. Available at 

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Personalized Medicine Coalition. Personalized Medicine at FDA – The Scope & Significance of Progress in 2021. Available at 

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Integrated approaches can help enhance recruitment plans.

Enhancing Enrollment in Biomarker-Driven Oncology and Rare Disease Trials

Delivering successful outcomes in rare disease clinical trials requires special attention to study planning, patient recruitment and retention, collaboration, and management. The R&D track record in one disease setting in particular, Duchenne muscular dystrophy (DMD), has shown this to be true. DMD is an x-linked genetic disorder affecting an estimated six in 100,000 individuals.

 It is characterized by mutations in the dystrophin gene that cause progressive weakness due to muscle cell damage as a result of routine physical activity. Over the last 10 years, drug developers have completed multiple successful clinical trials in DMD, leading to regulatory approvals of mutation-specific drugs in the US and Europe.

With a long history of active engagement and interest in clinical trials, DMD clinical care, sites, and communities are uniquely positioned to support clinical study success. Patient groups have brought together clinicians, regulators, and nonprofit organizations to collaborate on various research, clinical, and funding initiatives. As a result, standard clinical care guidelines for DMD are being implemented around the world and have continued to evolve since initial publications on respiratory care in 2004.

 In 2018, FDA published industry guidelines for DMD drug development,

 and, today, the landscape is crowded with multiple sponsors conducting competing clinical trials in global multicenter networks. While each new trial has its own specific needs, past success of DMD clinical studies can offer valuable strategies sponsors, CROs, and researchers can draw upon today.

As DMD illustrates, it is important to consider all available resources when planning a rare disease clinical trial. First, consider if there is regulatory guidance specific for the disease space, as such guidance can inform key trial design decisions about the patient population and outcome measures. When planning international rare disease trials, regulatory agencies may have conflicting preferences and requirements to be addressed—and clinical care for rare diseases can be vastly different, particularly if there is no established standard of care. Even within the same country, sponsors cannot assume a patient in one location is receiving the same type of care as one in another; patient priorities and available support options can vary greatly across communities.

Sponsors and CROs should, therefore, seek to develop relationships with existing academic and medical networks as well as patient organizations during the trial-planning stages. This will allow them to connect with potential investigators and better understand patient perspectives on clinical trial participation. In addition, these relationships can be particularly valuable for understanding the variable regional landscapes. For example, in the case of DMD, the Duchenne Natural History Study

 was conducted by the Cooperative International Neuromuscular Research Group (CINRG), and its datasets have been a key part of the success of many DMD trials.

 Natural history data for rare diseases can be used to inform sample size estimation and outcome measure selection, and, in some cases, serve as a comparator group for investigational trials.

Nevertheless, despite these tools, sponsors of trials targeting rare diseases inherently face operational challenges—the first being practical decisions around whether even investing in clinical development is reasonable, given the landscape of known competitors with late-stage or approved products. As DMD has shown, if the development space is crowded, there is more competition for a limited participant pool. And, fundamentally, healthcare providers, patients, and families need to perceive a new investigational therapy as worthwhile relative to other experimental or approved treatments. Clinical sites can become overburdened with operating too many studies for too few patients. Sample sizes in rare disease trials are typically smaller than those for more chronic, widespread conditions; optimizing data collection and minimizing missing data are even more critical with a small study population. To that end, sites may need additional resources to adequately manage participant follow up and trial assessments. Patients, for example, may need assistance with transportation and accommodations if they live far from a site.

Sponsors should also consider engaging specialized CROs with experience in conducting rare disease trials. These organizations may have connections with sites and patient groups to potentially help bolster recruitment. And their experienced data managers can design case report forms appropriate for the patient population, particularly when standard values in healthy populations are not in alignment with those found in the patient setting. It is important as well for sponsors, when determining outcome measures for rare disease trials, to engage with subject matter experts who have experience standardizing outcome measures across the patient population. Primary outcomes in rare disease studies should be ones that are likely to change and have clinical meaningfulness tied directly to the investigational drug; rather than outcomes that represent disease progression.

Patient recruitment and retention is, of course, critical to the chances of a successful rare disease trial. Recruitment planning begins with understanding the clinical and social contexts of eligible participants. Given the inclusion and exclusion criteria of the study protocol, sponsors and CROs should define what an eligible participant’s symptoms are and how they impact daily life, where the person lives and receives care, and the knowledge level of the individual in regards to research and interventions concerning their condition. This portrait can guide site selection and recruitment strategy, and aid in the development of educational tools. At the patient level, investigators can be better prepared for participants’ expected levels of science and health literacy during recruitment and the informed consent process. In turn, at the study level, sites and CROs may be more apt to set aggressive recruitment goals, use proactive recruitment tactics, and work compassionately with participants.

Regardless of interaction point, patient advocate organizations, such as CureDuchenne in DMD, are playing ever-expanding and critical roles in helping prepare patients for clinical trial readiness through education and outreach. CureDuchenne collaborates directly with sponsors and researchers to fund, advise, and help accelerate the drug development process. Further, its centralized data hub, CureDuchenne Link, has been built to support researchers by combining clinical data, biological samples, and patient-reported data for individuals with DMD and Becker muscular dystrophy, factoring in female carriers, which are very rare in both, as well. The platform facilitates data sharing, which is important to advancing a deeper understanding of the disease and accelerating research closer to a cure.

CureDuchenne also conducts regular workshops and webinars to keep the community informed on the latest scientific developments in DMD research, including status and participation in clinical trials. The group also educates on best practices to extend ambulation, and offers guidance on disease management and care. While DMD may be better positioned for drug development than other rare diseases, there are several approaches sponsors, CROs, and investigators can take from the DMD experience and apply into any rare disease clinical trial.

 Select endpoints and outcome measures based on the natural history data. Leverage natural history study protocols to develop methods for outcome measure collection. If natural history data is not available, investment in this area is critical and will support multiple future clinical trials.

 Clinical trials will struggle to meet endpoints if the clinical care is variable. Design protocols to align with published clinical care guidelines for consistency across sites. Development and publication of guidelines increases the chances for success.

 Select sites with the experience and capacity to successfully conduct the trial. Choose sites to provide adequate geographic coverage with the provided travel support. Prioritize sites that can provide excellent customer service to participants throughout the study.

 Engage with patient advocacy groups early. Once oriented to the study, they will be invaluable partners to help educate families, find eligible participants, and resolve unexpected problems.

 Most rare disease clinical trials will need a global network to succeed. Engage with regional partners to better understand the clinical context in their geography.

Finally, build in recruitment and retention up front

Set aggressive recruitment goals and motivate sites to actively find participants and engage with them about the protocol. Work with advocacy groups and clinical networks to drive referrals and meet recruitment goals.

 Sponsors and CROs may need to educate each other about the intricacies of conducting a smaller clinical trial in a rare disease. Stakeholders may need to reset expectations of what a “large” clinical trial might be in a given disease or therapeutic area. Building internal consensus supports setting effective strategies.

, PhD, Project Manager in Clinical Operations, TRiNDS, 

, MPH, Director of Strategic Solutions, TRiNDS, 

, PhD, Chief Scientific Officer, CureDuchenne, and 

, MS, CGC, Chief Executive Officer, TRiNDS

Crisafulli S, Sultana J, Fontana A, Salvo F, Messina S, Trifirò G. Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis. 

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Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. 

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Guiraud S, Davies KE. Pharmacological advances for treatment in Duchenne muscular dystrophy. 

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Finder JD, Birnkrant D, Carl J, Farber HJ, Gozal D, Iannaccone ST, Kovesi T, Kravitz RM, Panitch H, Schramm C, Schroth M, Sharma G, Sievers L, Silvestri JM, Sterni L; American Thoracic Society. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. 

. 2004 Aug 15;170(4):456-65. doi: 10.1164/rccm.200307-885ST.

Sejerson T, Bushby K; TREAT-NMD EU Network of Excellence. Standards of care for Duchenne muscular dystrophy: brief TREAT-NMD recommendations. 

. 2009;652:13-21. doi: 10.1007/978-90-481-2813-6_2.

Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. 

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Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Colvin MK, Cripe L, Herron AR, Kennedy A, Kinnett K, Naprawa J, Noritz G, Poysky J, Street N, Trout CJ, Weber DR, Ward LM; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. 

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Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment 

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Henricson EK, Abresch RT, Cnaan A, Hu F, Duong T, Arrieta A, Han J, Escolar DM, Florence JM, Clemens PR, Hoffman EP, McDonald CM; CINRG Investigators. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. 

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Approaches sponsors, CROs, and investigators can take from the DMD experience.

Rare Disease Clinical Trials: Strategies Learned from Duchenne Muscular Dystrophy

Cell and gene therapy (CGT)—its risks and promises—are succinctly summarized in this description of clinical trial number NCT01129544, a Phase I/II study in children born with X-linked severe combined immunodeficiency (SCID-X1), an inherited, rare, and life-threatening disease. The eight-person trial, which began in May 2010, continues today. The following paragraph has been edited.

Gene transfer is still research for two reasons. One, not enough children have been studied to tell if the procedure is consistently successful…. [And] we are still learning about its side effects and doing gene transfer safely. In previous trials, five children developed gene transfer-related leukemia; four are in remission; one died.

If the above information has stifled the research community’s scientific curiosity about CGT, it is not evident. Evidence from numerous sources—ClinicalTrials.gov, the Alliance for Regenerative Medicine (ARM), FDA—are chock-a-block with studies, trials, and figures showing these therapies’ popularity. In the second quarter of 2022, 3,633 such treatments were in development, up from 1,745 in May 2021. The vast majority are in the preclinical stage.

Most indicate that academics now have a remarkable presence in the CGT development space, including sponsorship. Last year, for the first time, ARM included sponsorship figures in its twice-annual industry report.

 Academic- and government-sponsored trials far exceeded industry for sponsored trials in CGT. Stephen Majors, senior director for public affairs, ARM, says the alliance knew of academia’s presence for the past few years, but only was able to get data this year from its partner, Global Data.

Less reliable, but still noteworthy, are data from ClinicalTrials.gov: for active Phase I trials, industry has 89; “others,” which covers academia and government, have 50. Industry enrollment for Phase I is 172; others, 116. Phase III is one for others, eight for industry.

A little disruption in pharma’s corner of the world? It seems that way. While basic bench to preclinical to clinical trial has long been the traditional route to FDA approval—and no one interviewed for this article suggested a reroute—what it does imply is that pharma members have some competition from the spin-offs and academic biotechs that historically they have absorbed.

“There are suspected trends that we are watching,” says Majors. As to whether academia’s presence in this spot can be called a trend depends on one’s definition of what a trend is. The Centers for Disease Control and Prevention (CDC) considers changes over a number years to determine a trend; financial investment firms typically evaluate over a two-year period. Considering that CGT companies raised $23.1 billion in 2021, 16% more than 2020,

 the answer to the above question could be, maybe.

The CGT space is still immature, according to Mike Rea, founder of Protodigm, a self-described exploratory research organization that partners with biopharma clients on alternative development and commercial solutions. Physicians need time to be comfortable with these therapies, notes Rea, so they may not be used on a regular basis.

For example, physicians have to understand how to deliver the gene, agrees cardiologist Arthur M. Feldman, MD, PhD, whose lab worked on a heart failure-related mutation in BAG3 for decades.

Last month, the company he founded, Renovacor, agreed to be acquired by Rocket Pharmaceuticals.

 “We are asking physicians to do something they never did before and to understand a very different set of information, including risk/benefit discussions that they didn’t learn about in medical school,” he says. Feldman is a Laura H. Carnell Professor of Medicine, Division of Cardiology, and a member of the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine at Temple University.

Chris Learn, Parexel’s vice president of cell and gene therapy, is unequivocal regarding academia’s increased presence in the drug development space focused around these treatments. He cites MD Anderson and Moffitt Cancer Center as two institutions that are sponsoring their own trials. “The lines are really blurring here,” he tells

The following is a look at how academia is showing up in various reports.

, ARM separated sponsorship, type of therapy—gene, cell-based, and tissue engineering—and trial phase. What these data show are industry far exceeding academic and government sponsored trials for gene therapy, while for cell therapy alone, the reverse is true: 656 cell therapy trials for academic and government, and 424 for industry. For gene therapy, there are 84 for the academics and government, and 222 for industry. In a later report, ARM found non-industry trials dropped.

Pharma Intelligence’s Pharma R&D Annual Review does not break down trials by their sponsors. It does, however, break down what’s in the pipeline in various categories, including by the number of therapies per company, and by disease type.

 In numbers captured prior to March 2020, the analysis reported 1,849 companies with a single drug in its pipeline, up from 1,633 in 2019, comprising more than half of all drug companies. As for types of therapies, gene therapy was in third place, the same spot it occupied in 2019. (Cancer-related therapies occupy the top spots.) Overall, biotech therapies in the pipeline increased by 13.2% in 2020 over 2019—6,135 vs. 5,422. Cellular therapy, the field in which academia is dominating, rose to 14th place, up from 33.

In 1982, Feldman was a resident in the cardiac care unit at the Johns Hopkins Hospital in Baltimore when he took care of a 22-year-old woman, a native Pennsylvanian, who was dying of heart failure. “Sadly, we didn’t have drugs with which to treat her,” he recalls. Feldman’s involvement with the case and the woman’s family led to his career as a cardiologist, he says. Twenty years later in Philadelphia, he was asked to see a heart-failure patient in consult, who turned out to be the aunt of the younger woman. It would take almost another 10 years until the technology became available to identify the genomic anomaly in this family. Here, a genetic variant that is produced by one of two alleles causes the protein product to be unstable. The result: the cell removes it, so the person with the variant has just half the amount of required protein.

BAG3 is an interesting protein that is found in the heart, the skeletal muscles, and the nervous system, including the brain. Its function is to help remove degraded and misfolded proteins, stop apoptosis or programmed cell death, and maintain the structure of the skeletal muscles. A missing allele isn’t the only genetic cause for heart failure, Feldman said. Other patients, while having the correct amount of DNA, have a point mutation–a single amino acid–in half of the produced DNA. That single letter is the wrong amino acid in the specific site in the protein.

Around this time, Kamel Khalili, PhD, Laura H. Carnell Professor, and chair of the department of microbiology, immunology, and inflammation; director of the Center for Neurovirology and Gene Editing; and director of the Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine, Temple University, had created a method by which he could excise the HIV virus from patients using the new technique of CRISPR-Cas9.

Khalili believes that BAG3 may be involved in the pathogenesis of HIV-1 in brain diseases and protein quality control caused by viral infection as well as several other disorders, including Alzheimer’s disease and dementia. BAG3 changes the homeostasis of the cell, he says. “The only solution is to fix the cell.” Khalili has used CRISPR technology to excise the viral genome in both small and large investigational animals and has recently started a Phase I trial to test the safety of the new gene-editing treatment. Khalili, too, started a company, but Temple holds the license. In the case of Renovacor, it was granted the license by Temple.

“As a scientist, when you are doing something in biomed research, [the] goal is to translate bench work to the clinic for [the] wellness of people. We are doing long hours and long days because we want to help. We are trying to see if discovery can help people,” says Khalili. “I know my limit, I stop at business aspects. My interest is to discover research which can help populations.”

Was Feldman happy with his business experience? “As a company gets bigger, others join the team who fulfill other roles, like acquiring funding or developing the actual product,” he says. “Releasing the control reins are difficult.” But if it speeds up the timeline to get an approved product into the clinic, “then it’s all worth it,” he adds.

Researchers such as Feldman and Khalili, says Kaspar Mossman, PhD, director of communications and marketing at QB3, a University of California biotech accelerator, are normally not deeply interested in business. He notes the new flagship space in UC Berkeley called Bakar Lab. So far, it has 25 companies, one-third from university labs. “They collaborate, they share equipment, [at times] they merge,” Mossman tells 

And, he adds, “Academics tend to be very smart individuals. The more time they spend in business, they learn stuff and become serial founders,” says Mossman. “They are honest about not wanting to be a CEO.”

In terms of business, the academics’ employers are also pretty smart. The huge bugaboo with CGT commercialization is the manufacturing process—the need for an apheresis unit, ultra-cold storage, and regulated cell processing facilities.

Some institutions are building their own manufacturing facilities to more easily meet the increasingly complicated standards pertaining to regenerative medicine production. Harvard, MD Anderson, Moffitt, the University of Pennsylvania, and the University Hospital of Liege in Belgium8 all have or are planning to build their own facilities.

As for how academia’s presence impacts the traditional pharma space, those interviewed cited pros and cons. More research is better, more companies vying for venture capital funding is not. But more trials mean more competition among similar therapies, which, says Majors, is a good thing.

“We need experimentation,” adds Rea. If left to pharma, he says, the research wouldn’t happen. “Smaller biotechs are taking the risk.” Over the last 10 years, Rea believes pharma has been slow in the risk-taking department. Once upon a time, pharma didn’t have many competitors. Now, with many numerous smaller companies with viable assets, willing to accept a smaller net profit, the competition is creating some angst. “Pharma can’t project everyone’s movement,” says Rea. “The gene/cell therapy landscape [for products] is huge.”

Likely adding to the angst: Those smaller biotechs are getting financial help. Between April 4, 2021, and June 24, 2021, of 23 start-up financing deals, 19 involved academics.

Learn’s viewpoint is different. He says there are too many players out there, and while large pharma may be averse to risk, “I really do believe what we are witnessing are simply market forces that have played into this.” There is so much cash coming in, he continues, that “people can be blinded by the pitfalls.” The CGT area, he adds, is “bloated” and he says the industry needs an overall strategy.

Learn doesn’t think that academia’s presence in the CGT space is a flash in the proverbial pan. The enthusiasm to find cures is real, and some research institutions have the endowments to see the trials through. “I think it is just the beginning,” says Learn. “Academia will put their futures in front of them. Why put all your sweat equity into it … and not have any fiduciary benefit of the approved product?”

In Pharma Intelligence’s 2020 Pharma R&D Review, its author questioned the wisdom of so many drugs, overall, in the pipeline—4,001 added in 2018 and 4,730 added in 2019, for a total of 17,737 drug candidates. “[A]re the industry’s eyes getting too big for its belly? Unless it can continue to provide [approved therapies] then a certain degree of control in the pipeline might be advisable,” the report stated.

And now to costs. While no one doubts these cures change lives, the question of access persists. FDA’s approval of Bluebird Bio’s second therapy this year, branded as Skysona, for early but active cerebral adrenoleukodystrophy, is expected to cost $3 million. Learn doubts that payers are jumping up and down to get Skysona on their formularies.

It’s still a “fairly dicey business proposition” for companies to invest in this field, Steven Pearson, MD, president of the Institute for Clinical and Economic Review (ICER), said recently.

 There’s “still a risk” that next-generation therapies will not flourish “even in developed countries’ health systems,” he added.

One positive development in the US, however, occurred late last month when Congress reauthorized the Prescription Drug User Fee Act (PDUFA) for the next five years, 2023-2027. The action maintained FDA’s authority to collect fees from manufacturers and keep and recruit agency staff to review the increased number of CGT applications. Majors says most of FDA’s review of CGT products involves scalability and consistent reproducibility in the manufacturing process, which, of course, means traveling.

, FDA is seeking to hire at least 320 new staff members. In a statement, Pharmaceutical Research and Manufacturers of America (PhRMA) said a “modern regulatory framework supported by PDUFA helps ensure patients have timely access to lifesaving medicines.”

PDUFA reauthorization aside, there is little argument that the field of CGT, from research and drug discovery through commercialization, is advancing rapidly. In turn, so are the unique operational and manufacturing challenges that these therapies present. This reality may thin the currently crowded playing field in CGT going forward, with those sponsors and partners best prepared to deliver on the numerous touchpoints required separating from the pack.

, Freelance Writer for Medical, Clinical Trials, and Pharma Information

Clinicaltrials.gov Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector. 

As activity in this space grows, so do the hurdles in moving these products forward.

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