Registry Contributions to Strengthen Cell and Gene Therapeutic Evidence

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After decades of research and technology refinements and a couple of unfortunate setbacks, the recent trend of positive clinical results in the field of cell and gene therapy has been hailed as a triumph for this class of therapeutic. However, the lack of strong evidence for therapeutic effectiveness at market launch and high costs remain major hurdles to their routine clinical deployment, rendering these therapies possibly unaffordable for payers and inaccessible to society. This is already reality, given the withdrawal of several advanced therapies from the EU market due primarily to commercial failures.¹ The same scenario could arise for the reimbursement and commercial viability of chimeric antigen receptor (CAR)-T cell therapy, which employs a genetically engineered cell product to treat cancer. With two approved CAR-T cell products launching in the US market with price tags of $475,000 for Kymriah (tisagenlecleucel, Novartis) and $373,000 for Yescarta (axicabtagene ciloleucel, Gilead/Kite Pharma), it remains unclear whether healthcare systems will be able to bear such cost burdens. Recent findings from the UK’s National Institute for Health and Care Excellence (NICE) show that conventional assessments performed for pricing policies and reimbursement may be insufficient for gene therapies.² Although results from randomized controlled trials (RCTs) are accepted evidence for regulatory and health technology assessments (HTAs), cell and gene therapies generally have small, single-arm, short-term trials likely yielding biased, imprecise clinical results. This trial under-powering, however, is more a consequence of targeting patients suffering from rare, severe, or advanced disease; their recruitment to large controlled trials is challenging.³

A potential and oft-proposed solution to this issue is the use of real-world evidence generated from therapeutic products post-approval. Real-world data (RWD) are defined as observational data collected not under clinical trial conditions (RCTs), but rather from post-approval clinical use, and are usually recorded in registries, electronic health records, and insurance and home-use data. The US Food and Drug Administration (FDA) has already issued a 2017 guidance on using RWD for regulatory decision-making for medical devices.⁴ The EU Commission Expert Group on Safe and Timely Access to Medicines for Patients (STAMP) has made the topic a top priority. Aggregation of clinical data collected through patient outcome registries as one RWD source increases the robustness of data meta-analysis gleaned from clinical trials or post-marketing surveillance to provide sufficient therapeutic evidence. A recent study has concluded that, for innovative and orphan drug development, registries are necessary to collect additional data on drug safety concerns.⁵ In 2015, recognizing the importance that registries play in monitoring therapeutics safety and efficacy, a European Medicines Agency (EMA) initiative sought to encourage better use of existing registries and establish new, high-quality registries where no existing source is available.⁶ As part of the initiative, EMA offers guidance for common data elements, standard methods, and governance principles. Moreover, the April 2017 report by The Bipartisan Policy Center recommended creation of a federally funded US national registry for regenerative cell therapies to strengthen the evidence base regarding treatment effectiveness and safety profiles and to improve clinical practices.⁷ Use of such evidence can also be beneficial in performing comparative effectiveness research and heath technology assessment (HTA) required for reimbursement decisions.⁸ Early product entry in niche indications, such as gene therapies for rare diseases, in particular, can benefit the most from registries collecting RWD on effectiveness and safety.⁹ This article provides a comprehensive analysis of the current global status of registries for cell and gene therapies, registry requirements, and characteristics and highlights the challenges and opportunities for contributing to cell and gene therapeutic evidence collection to better position these products in the market.

Current Cell and Gene Therapy Registries

We first examined the current landscape for cell and gene therapy registries in order to understand their characteristics and potential contributions to evidence synthesis when developing advanced therapeutics. A literature search (November 2017) was performed for English-language based registries for cell and gene therapies. The search yielded 14 registries that were then divided equally into two categories: patient outcomes registries and clinical trials registries (Table 1). These two types of registry have distinct goals. Patient outcome registries aim to collect data on the safety and efficacy of a therapeutic product or intervention administered to patients (including product-based or disease-based registries), while clinical trial registries aim to be a source of publically available clinical trial listings. While the latter provide valuable information on clinical translation of therapeutics, particularly given increasing requirements for clinical trials results reporting, we focused primarily on outcome registries employed for collation of safety and effectiveness evidence in real-world settings. Table 1 shows the full registry list and their information content.

Table 1.

List of Currently Available Registries for Cell and Gene Therapies

Resource Name	Primary Scope	Funding	Accessibility	Website
Patient Outcomes Registries
The European Society for Blood and Marrow Transplantation (EBMT) cell therapy registry	cell and cell-based gene therapies used for treating conditions other than hematopoietic stem cell transplantation (HSCT)	private (membership fees and corporate sponsorships)	member centers of the EBMT or upon request	https://www.ebmt.org/; updated regularly
The Center for International Blood and Marrow Transplantation Research (CIBMTR) cellular therapy registry	cell and cell-based gene therapies used for treating conditions other than hematopoietic stem cell transplantation (HSCT)	public (NIH, USA) and corporate sponsorships	member centers of the CIBMTR or upon request	https://www.cibmtr.org/Pages/index.aspx; under further development & expansion
Registry of Cell Therapy in Non-Ischemic Dilated Cardiomyopathy (RECORD)	evaluation of cell therapy in patients with non-ischemic dilated cardiomyopathy	public (University Medical Centre Ljubljana, Slovenia)	currently recruiting patients (ClinicalTrials.gov Identifier: NCT02445534)	N/A
Registry of Biological Cell Therapy for the Treatment of Patients with Thoracic & Cardiovascular Disease (ClinicalCellRegistry.com)	cell therapy evaluation for the treatment of thoracic and cardiovascular diseases	private (Amit N. Patel, University of Utah)	researchers who provide an IRB approval to the coordinating site at the University of Utah	http://clinicalcellregistry.com/; non- functioning link
Long-Term Follow-Up of Recipient of Gene Transfer Research	evaluation of safety in gene transfer therapy	M.D. Anderson Cancer Center, USA	currently recruiting patients (ClinicalTrials.gov Identifier: NCT01492036)	N/A
GENIALL Lipoprotein Lipase Deficiency (LPLD) Disease Registry (GENIALL)	long-term follow up of alipogene tiparvovec and registration of any genetically confirmed LPLD patients	private (uniQure biopharma and Chiesi Farmaceutici)	restricted	https://www.geniallregistry.com/login.jsp; updated regularly
Strimvelis Clinical Study Registry	evaluation of the long-term safety and effectiveness outcomes of subjects receiving Strimvelis	private (GlaxoSmithKline)	restricted	https://www.gsk-clinicalstudyregister.com/study/200195?search=study&#ps; updated regularly
Clinical Trials Registries
NIH Genetic Modification Clinical Research Information System (GeMCRIS)	information about human gene transfer trials registered with the NIH	NIH	publicly accessible	https://www.gemcris.od.nih.gov/Contents/GC_HOME.asp?id=8434; last available data December 2016
Gene Therapy Clinical Trials Worldwide	searchable information about approved, ongoing, or completed gene therapy clinical trials available on the internet	Journal of Gene Medicine	publicly accessible	http://www.abedia.com/wiley/; updated regularly
Gene Therapy Net	web-based information repository acting as a gene therapy trials portal (recruiting or not recruiting yet) by using the clinicaltrials.gov database	private	publicly accessible	http://www.genetherapynet.com; updated regularly
The European Network for the Advancement of Clinical Gene Transfer and Therapy (CLINIGENE)	gene therapy trials library	European Commission	publicly accessible	http://www.clinigene.org; last available data Dec 2010
Cell and Gene Therapy Catapult	database for preclinical and clinical cell and gene therapy trials that take place in the UK	Department for Business, Energy and Industrial Strategy, U.K. government	publicly accessible	https://ct.catapult.org.uk; updated annually
DeReG: German Registry for Somatic Gene-Transfer Trials	somatic gene transfer trials	public (German Federal Ministry of Education and Research)	N/A	http://ww38.dereg.de/; non-functioning link
Belgian Biosafety Server	gene therapy trials in Belgium	public (Belgian federal web sites)	publicly accessible	http://www.biosafety.be/; updated regularly

PubMed, clinicaltrials.gov, the Registry of Patient Registries (RoPR), the Patient Registry of Europe (PARENT), the WHO international clinical trials registry platform, as well as Google search engine were searched using several keyword combinations, including “cell therapy”, “gene therapy”, “regenerative therapies”, or “advanced therapy medicinal products (ATMPs)” combined with “registry,” “clinical trials registry,” “database,” “observational study”, or “long-term follow-up”. Five publications were identified as related to two cell and gene therapy registries (n = 2). A ClinicalTrials.gov search yielded 41 trials, of which four were identified as patient outcomes registries (n = 4). The AHRQ registry of patient registry (RoPR) search yielded 81 registries, of which one was identified as a relevant registry (n = 1). The search of the patient registry of Europe (PARENT) yielded one registry (n = 1). The WHO international clinical trials registry platform search identified one registry (n = 1). The web-based search identified 9 relevant registries. After removal of duplicates (n = 2) and the exclusion of registries with no clear information about their purpose retrievable through literature and/or their website (n = 1) or language other than English (n = 1), the final relevant registries numbered fourteen (n = 14). These registries were then split into two categories: patient outcomes registries and clinical trials registries. This table summarizes these search results with specific details on each registry characteristics.

Patient registries rely mainly on observational study methodologies. These registries have diverse objectives, which include the description of the natural history of a disease, determination of clinical effectiveness and/or cost-effectiveness of an intervention, assessment of safety or harm of new therapeutics, evaluation of quality of care, and utility in public health surveillance and disease control.¹⁰ Several patient outcome registries exist that actively collect outcomes data obtained from cell and gene therapy trials or interventions. One major effort is the European Society for Blood and Marrow Transplantation (EBMT)’s Cell Therapy Registry (CTR), established in 2016 as a part of their hematopoietic stem cell transplantation (HSCT) registry. It aims to collect data on cell and gene therapies other than HSCT, such as CAR-T cells, as well as clinical characteristics and long-term outcomes of treated patients (Table 1). The Center for International Blood and Marrow Transplantation Research (CIBMTR) registry is considered the US counterpart of the EBMT, with identical scope. Other disease-specific registries targeting rare diseases also exist, most notably the GENIALL (gene therapy in the management of lipoprotein lipase deficiency [LPLD]) (Table 1). In 2014, GENIALL was launched as a part of the EMA regulatory risk management plan required for alipogene tiparvovec (Glybera), the first European Union (EU)-approved gene therapy. GENIALL has since been expanded to not only assess Glybera’s long-term safety and clinical response, but also to determine both epidemiology and demographics of LPLD patients, including quality-of-life (QoL) and dietary adherence. Similarly, a registry has been established for patients treated with Strimvelis (or GSK2696273) gene therapy, the first approved ex vivo gene therapy that targets adenosine deaminase severe combined immunodeficiency disease (ADA-SCID). The registry functions as a long-term prospective, non-interventional follow-up study of Strimvelis safety and effectiveness in accordance with the established EMA risk management plan. The registry plans to collect and follow at least the first 50 patients treated with Strimvelis until the last patient is followed for 15 years. In line with EMA guidance, this registry may also be expanded into a disease registry, similar to the Glybera case.

Registry Data for Evidence Synthesis

Standardized, authorized, and properly enabled registries can provide valuable information on treatment safety and therapeutic efficacy and efficiency not readily available elsewhere.¹¹ Support for data sharing and proper reporting that both improve medical evidence quality and reinforce evidence-based practices continues to grow.¹⁰ For most therapies, RWD does not replace the RCT “gold standard” data; however, RWD can support drug regulatory and HTA decision-making by providing critical information on a therapy’s use, effectiveness, and safety in real-world patient scenarios.¹² For cell and gene therapies in particular, where new products might be approved for use with immature evidence, payors will challenge the limited clinical data as HTA bodies/payors increasingly scrutinize the incremental impacts of innovative “first-in-human” therapies expected to carry high prices.⁸

Increased data availability and evidence diversification (i.e., through advances in medical informatics) drive the need for effective evidence synthesis to enable data-driven HTA. Utilizing registry data analytics for information systems research is becoming an important tool for evidence-based clinical decision-making. Advanced tools, including machine learning, can facilitate data mining, synthesis, and outcome prediction, but data preprocessing and interpretation must be performed competently for appropriate validation. Registries should be exploited as one more resource in the spectrum of clinical data repositories currently available to support evidence-informed translational research, especially when RCT data are scant or difficult to procure. In this regard, registries can also facilitate access to data necessary to reach properly informed regulatory decisions.

Challenges in Using Registry Data

Despite recognized benefits, relying on registry data has important limitations. Usually data quality control is difficult mainly due to the lack of resources required to enable high-quality data collection and curation. As a result, data reporting reliability depends primarily on the efforts or motivation of the developers and/or investigators involved in the clinical product studies. Furthermore, many clinically relevant outcome measures (e.g., patient satisfaction, treatment adherence, costs) are generally not included in a registry, as these can be difficult to obtain. Two other major issues also hinder registries from reaching their full potential in evidence synthesis.

Interoperability and Patient Privacy

Sharing clinical data collected in patient outcome registries uniquely addresses the challenges of insufficient human clinical data threatening an already extremely difficult research field. Possibilities for de-identifying personal data through cross-referencing genetic information from multiple clinical data sources makes patient privacy a crucial issue affecting data-sharing capabilities of these registries. To improve sharing without jeopardizing patient rights, registries should be deliberately designed with interoperability and data-sharing properties, while protecting patient identity, as well as avoiding data duplication during data collation across multiple databases.¹¹ The NIH’s Office of Rare Disease Research has proposed using global unique identifiers (GUID) in a pilot project to create the Global Rare Disease Patient Registry and Data Repository (GRDR).¹³ The GUID system uses and links de-identified patient data between different data sources, collecting new information, preventing data duplication, and limiting identification risks. Another problem facing the interoperability between registries, with a major influence on data usability for evidence synthesis, is the current lack of standards for terminology, data elements, and informed consent. Standardization of these criteria internationally can facilitate the needed merging of different established registries.⁹ Therefore, interoperability issues should be consistently addressed to ensure ongoing value and functionality of such registries to benefit the variety of users, contributors, and stakeholders.

Access to Complete Datasets

Another central issue facing projects targeting improved collation of clinical study results is the lack of enthusiasm of clinical researchers and pharma industries to share relevant human data.¹³ For registry cases, several solutions are offered, including implementation of staged embargo periods to protect clinical result exclusivity temporarily until commercial advantages of these data might be appropriately secured as well as micro-attributions and nano-publications (novel forms of data citation) to encourage, incentivize, and reward data-sharing. The current regulatory situation in both the EU and USA is in transition to allow trial data to be publicly shared for products receiving marketing approval.13, 14 Sharing such trial data provides improved opportunities for secondary data use for data mining and further meta-analyses and also facilitates data organization in specific standardized formats that improve data accessibility and value for more robust analytical power. Until these regulations are routine actions, the clinical research community should work to improve the robustness of reporting clinical trial outcomes, especially for cell and gene therapies targeting rare diseases. Researchers and regulators could both have access to more compelling uniform data to support and possibly advance cell and gene therapy research as more reliable safety profiles are established from diverse patient-specific experiences.¹⁴

Registries collecting clinical data from cell and gene therapies represent an important clinical activity that requires proper design, maintenance, and regulation. Particularly in rare diseases and cancer research, they offer a valuable source of information on the natural history of disease, clinical phenotype, genomic data, therapeutic profiles, and research/trial datasets. The full registry potential may not be realized given both the scarcity and scattered nature of patients. Linking patient outcome registries back to identifiers within clinical trial registries to track the results of interventional human trials, whenever applicable, is also advocated as an essential step. A similar approach is discerned in the RD-connect project funded by the EU in 2012 under the International Rare Diseases Research Consortium (IRDiRC) to link genomic data with registries, biobanks, and clinical bioinformatics tools. This intends to produce a central research resource for rare diseases.¹⁵ Expanding these initiatives into a common, adaptable management platform that collects outcomes data from patients treated with advanced therapeutics globally and works collaboratively with other registries using standardized de-identified patient data would provide a valuable and versatile new global resource with capabilities to improve evidence synthesis for emerging therapeutic categories. We also propose other measures to maximize registry use in drug and therapeutic development (1) call for regulatory agencies to commit to registries as a validated data collection method, (2) issuing regulatory guidance regarding registry technical requirements useful for approval, (3) call for companies to collaborate more effectively with clinical centers to develop user-friendly registries, and (4) call for industry to develop registries more easily used by patients.

Conflicts of Interest

S.K. is an employee of GSK, UK.