Toward a Proportionate Regulatory Framework for Gene Transfer: A Patient Group-Led Initiative

Background

T he views discussed herein are those of the representatives of patient organizations, academia and clinical committees, regulatory medicines agencies, and funding bodies. Discussions were aimed at identifying key elements of gene therapy medicinal product (GTMP) clinical development that could be supported by patient organizations. Patient organizations would like to ensure that the clinical development process appropriately responds to and addresses the needs and interests of patients with regard to innovative therapies addressing unmet medical needs.

In fact, a workshop initiated by representatives of patient organizations sitting on the international advisory committee of the CliniGene Network of Excellence for the Advancement of Clinical Gene Transfer and Therapy was held at the Abbaye de Royaumont, France on March 6 and 7, 2009. This was a timely initiative because applications for Marketing Authorization by the European Commission have been submitted to the European Medicines Agency. Recent European legislation has established a new expert scientific Committee for Advanced Therapies (CAT) at the agency, whose membership includes representatives from patient groups, clinical and scientific bodies, as well as those from national competent authorities/medicines agencies from each country (Schneider et al., 2010).

The motivation for the workshop arose from the growing confidence of patient organizations in Europe to assert their right to be part of the process of deciding the strategic direction of research into unmet medical needs and its regulation. Patients are partners in this process, not “just subjects” for researchers or recipients of the benefits of others' work. The involvement of patients provides a route toward balancing the hope and the hype associated with research in areas at the forefront of our scientific capability, such as gene and cell therapy. This research is potentially controversial, and patient organizations have a role to play in framing and contextualizing it—balancing the fear that things will not happen with the fear that they will. Informed engagement with patient organizations will create a realistic framework for progress, where the need for novel therapies is balanced with a timeline for delivery that reflects the complexity of the diseases under investigation.

This workshop report is intended as a contribution to the development of common understanding about the parameters of a sustainable framework for the development of gene transfer research and its translation into GTMPs for patients.

Patient Organizations and GTMP Development

Currently available interventions for the treatment of complex diseases often address symptoms rather than targeting the underlying flaw in the patient's biological function that precipitates the development of the disease in question. Noncurative interventions, whether surgical or pharmaceutical, often offer only temporary relief, allowing the disease to resume its progress after a period of time. It is hoped that gene and cell therapy may provide a route to address the underlying causes of disease, preventing the development of symptoms or ensuring substantially symptom-free survival on a long-term basis.

In recent years, patient organizations and advocacy groups have undertaken an active role in seeking the development of new treatments to address unmet needs. To give just a few examples, EURORDIS, Genetic Alliance, the U.S. National Organization for Rare Diseases, and organizations focused on single diseases, such as hemophilia or Tourette syndrome, all promote such research partnerships. This role may be especially important in the development of gene and cell therapies, precisely because patients and families have experiences and insights about the differences between symptomatic and potentially curative treatments that can be of considerable value to scientists and regulators. Although there has been some progress toward taking account of the views of patients, families, and caregivers in ethical and regulatory reviews, in the eyes of patients' representatives, ethical and regulatory committees too often make decisions on behalf of patients without involving or even consulting them (London et al., 2010).

Partnerships between academic, clinical, and commercial groups planning clinical trials and patients and patients' organizations at a range of different levels may open new perspectives. These collaborations can result in more effective trial design, with a shared understanding of the nature and relative value of possible benefits and harms associated with the planned research. Such partnerships may entail a role for patients and patients' organizations at the level of promoting awareness of a promising trial, assisting with subject recruitment, or serving as members of planning and implementation committees, to organize and to monitor the progress of the research. Not all patient organizations have developed to the point at which they can play a role as full partners, but engagement at the appropriate level can bring benefits. These may be practical (such as speeding the recruitment of relevant families to clinical trials), societal (explaining and communicating to the media and the public), scientific (making sure that end points relevant to the patient experience of the disease are selected and helping to ensure compliance with the trial regimen), or ethical (advising on ethical matters from a patient point of view as part of the approval process for the proposed research). When selecting end points, a balance may need to be reached between those deemed important by regulators as appropriate for establishing safety and efficacy, and those identified by affected individuals and families as important to quality of life and dignity.

Of course, taking any medicinal product development program through all the stages from concept to clinical application is complex, expensive and time consuming. Research trajectories for advanced therapy medicinal products (ATMPs) in general, and gene and cell therapy medicinal products (GCTMPs) in particular, are even more demanding. It may involve collaboration across sectorial boundaries, with patient organizations, funders, academics, and industry having a part to play. When gene transfer trials for patients with very rare conditions are proposed, patient organizations may lack the frameworks and mechanisms to collaborate in a meaningful sense with sponsors of clinical trials or clinical investigators, in part because they may lack experience with clinical research. In the case of rare single gene disorders (currently the focus of a number of gene transfer clinical trials) there may be little prospect of commercialization, thus requiring public and/or not-for-profit agencies to develop regulatory expertise fulfilling regulatory requirements that have been more traditionally the responsibility of commercial partners in the drug development process (Arkin et al., 2005). Researchers in academic/clinical contexts unfamiliar with the regulatory approval process may be unaware of existing resources of advice and support (such as access to scientific advice and protocol assistance from the European Medicines Agency for intended products with an orphan designation). Commercial partners may have to be found to continue medicinal product development until marketing authorization. If the program is successful, and the GTMP is granted marketing authorization, the issues of manufacture, pricing, and reimbursement may be difficult to address when organizations lack the infrastructure to deliver the product to patients in a timely, affordable manner. It is therefore important not only that patient organizations be involved in the development of GCTMPs to an extent compatible with their ability to contribute, but also that they be afforded opportunities to develop additional expertise in order to increase their collaborative capacities.

A Patient- and Family-Friendly Regulatory Framework

Patient organizations, regulatory authorities, and bioethics scholars agree that an appropriate regulatory framework takes account of many factors in determining whether and how to proceed with a gene transfer clinical trial, including the nature of the subject population (should it be healthy volunteers, patients with stable disease, terminal patients, children, etc.); the quality and relevance of data from preclinical research; the adequacy of the trial design; and the nature, magnitude, and likelihood of the risks of harm associated with participation. It is also relevant to consider whether or not alternative treatments exist, and the extent to which their existence should affect the justification (if at all) for pursuing the proposed research (King and Cohen-Haguenauer, 2008).

Ethical review of clinical studies should include consideration of the design features of trials, especially in first-in-human and early-phase trials. Relevant design features include the criteria used to determine the selection of subjects. Taking the first step into human use, or progressing toward registration, must be based on robust justification of the need for the next research step, including not only consideration of the anticipated outcome but also the need to minimize possibilities for harm to participants.

Sometimes, patient organizations consider regulatory authorities too cautious in their approach to clinical trials. This difference in viewpoint is particularly common in clinical research involving children, where guidelines concerning the burden of the trial and the need for direct benefit can sometimes appear to patient groups to be too narrowly interpreted. Ethical review committees that fail to approve gene transfer clinical trials enrolling children, because of concern that the risks outweigh the potential benefits to the child subjects, may be seen by patient organizations as failing to take seriously the willingness of affected families to undertake risks in the hope of contributing to future progress.

Although the tendency of review bodies to take a cautious approach can be understood, nevertheless, it often appears to patient organizations that the assessment of risks and potential benefits is too heavily weighted toward risks. Patient organizations fear that, especially when there is media interest in potentially controversial research, the desire to avoid accusations of using patients as “human guinea pigs” can lead ethical review committees to refuse to authorize otherwise valuable clinical trials. Patient organizations would like to be assured that review committees, when assessing clinical trials authorization applications, focus equally on both the risks of experimental interventions and their potential benefits. It should be remembered that not carrying out clinical trials has ethical as well as scientific consequences for the development of specific GCTMPs, as no new knowledge will accumulate.

A well-designed, proportionate, and transparent regulatory framework gives clarity and provides protection for patients and researchers, and helps maintain public confidence in the process of research and development. There are risks inherent in all research using human subjects, for if the outcomes of a clinical trial were known in advance there would be no need to do the experiment. As the TGN 1412 trial showed, these risks of harm can sometimes be very substantial (Goodyear, 2006). An appropriate ethical and regulatory framework helps determine the timing of the step to “first in human” experiments, and aids in the selection of the subject population for the minimization of potential harm and the maximization of possible benefit.

Patient organizations also emphasize that participation in clinical trials may be beneficial to patients, in many instances even when the research itself does not contribute directly to better health outcomes. The psychological benefits of contributing to the development of interventions that may help others in the future can be significant for some participants. In addition, there may be benefits from the additional personal attention that accompanies the researcher–subject relationship (although there may be burdens as well) (King, 2000). Thus, public discussion of research participation and the role of the research subject is important. For example, the recently adopted Constitution for the National Health Service (in the United Kingdom) requires that patients be made aware of research of particular relevance to them—although how this is to be accomplished in practice is yet to be established.

When research subjects are patients with serious conditions for which only symptomatic relief is available, as is the case with most gene transfer research subjects for very rare diseases, it can be difficult to determine where the line between research and treatment is to be drawn. This is particularly true when there is no incentive to commercialize the therapy because the total population potentially able to benefit is tiny. Patients with life-limiting rare diseases may be vulnerable to pressure from researchers anxious to move to human use, and they have a right to be protected from premature application of insufficiently proven interventions (especially if they are minors, for whom permission to participate is given by others).

The fundamental driver for determining the “next step” in the development of GTMPs must be science of the highest quality. It is also essential to develop methods for explaining to participants what is expected of them, what the risks are, and the potential benefits that may be expected—if any—from receipt of the experimental product.

Given the uncertainty inherent in all research, attention should be given to developing criteria for framing thresholds of acceptability for maximal levels of risk (perhaps varied according to subject population) and minimal expectations of benefit (both within each particular trial and as part of the therapy development process), so that uncertainty can be managed within acceptable levels. Requiring clinical researchers to explain how the risks of harm will be minimized and why they cannot be further reduced may help ethical review committees to place the risks of harm in perspective. In this guidance development process, there is a need to share expertise and build on the experience of others, both across projects and across jurisdictions.

Such guidance should also help in framing appropriate processes for securing valid and meaningful consent from potential participants. It is essential to explain the limits and possibilities of the trial compared with the current “gold standard,” and to avoid overselling the opportunity to participate through inadvertent fuelling of the therapeutic misconception commonly encountered in clinical trials—that is, the mistaken belief that research participation is a treatment, or the overestimation of the possibility of benefit to individual patient-subjects from participation (Henderson et al., 2006, 2007).

Overestimation of direct benefit to patient-subjects, by either those research subjects or by clinical researchers, is not unique to gene transfer research. However, there may be an assumed potential for benefit in gene transfer trials because of the general perception that gene transfer interventions are based on a deeper knowledge of the biology of the disease than is the case with conventional pharmaceuticals (Churchill et al., 1998). Explicit discussion can help to dispel this perception. Regulatory authorities should be especially careful to exclude any offering of the possibility of direct benefit from the gene transfer intervention in “first in human” trials (King et al., 2005).

Disclosure and discussion of the uncertainties inherent in research is particularly challenging when different stakeholder groups are willing to set different levels of expectation. As previously noted, investigators and patients may be comfortable with uncertainties and risks that may cause concern for ethical review bodies. Disagreements among stakeholders about issues such as the meaning of the data, and the appropriate balance between the risks of harm and the chance of benefit, may be reasonable, and should not be a barrier to research so long as these differences are clear and information has been effectively and appropriately shared. Dialogue and transparency are essential elements of good governance.

In gene transfer research, success comes from the undertaking of high-quality scientific work, the outcomes of which are widely disseminated and subjected to peer and public scrutiny. Ethical and regulatory bodies have an important role in this process, but they must work in partnership and in parallel with other mechanisms, such as patient engagement and public communication strategies. Regulators can neither work alone, nor stand on the margins as disinterested observers.

A Platform for Progress

There is an urgent need for those operating in unfamiliar contexts to share knowledge, expertise and resources in a precompetitive context in order to create the possibility for efficient and effective progress toward the approval of GCTMPs. Such a shared platform could be open to not-for-profit foundations, public sector bodies, and small- and medium-size enterprises (SMEs) lacking capacity or expertise to promote good science and safe, affordable manufacture and clinical investigation into novel GTMPs.

The European Medicines Agency (EMA) has set forth mechanisms to improve transparency and provide advice and guidance. However, its regulatory role with respect to ATMPs does not readily enable it to fulfill the coordinating role that is necessary to facilitate efficient progress in the development of GCTMPs. For example, a regulatory body like the EMA is able to approve or decline to approve an ATMP, but not necessarily to advise several developers of similar products about collaborations that might be more beneficial to patients than competition. In addition, from the standpoint of both investigators and patient organizations, there is a significant ethical tension between the need to perform clinical trials in order to advance knowledge and the pace at which technology is progressing: should one wait for the best technology to reach the ideal level of sophistication, or should still-imperfect technology be used in clinical trials, so long as the harm–benefit balance is deemed tolerable? This fundamental and critical tension is difficult to address directly through the regulatory process alone. It must be carefully and thoroughly considered by consultative bodies with advisory roles, which are able to operate freely, outside of and upstream from the regulatory context.

A genuinely contributory platform for progress should operate independently from regulatory bodies, ideally at a pan-European level, because accurate expertise can be found at this level only (Table 1).

European Union Regulation and Oversight of GCTMPs

The role of patient organizations, ethical review, and informed decision-making in gene transfer research must be compatible with, and interact appropriately with, the regulatory process for the development of ATMPs in the European Union (EU). The overall aim of the EU regulatory framework for ATMPs is the same as for conventional medicinal products: to develop products that meet agreed-on standards for quality, safety, and efficacy, allowing the determination of a positive balance between benefits and risks that can then be used by clinicians for the treatment of disease after marketing authorization. However, there are important differences in the science of ATMPs that render some of the conventional methods for establishing quality, safety, and efficacy inapplicable. Therefore, the EMA has established the Committee for Advanced Therapies (CAT) to assess the quality, safety, and efficacy of ATMPs, including GCTMPs (Schneider et al., 2010).

Regulatory competence in the area of advanced therapies thus exists at the European Medicines Agency, the EU member state Medicines Agencies, and other competent authorities in charge. Dialogue with other stakeholders will be a key element for long-term follow-up of those receiving gene transfer interventions to facilitate effective monitoring of safety and efficacy, risk management, mechanisms for reporting of adverse events, and responding to future possibilities. In creating this framework it is important to identify and focus on whether, and if so, precisely how GTMPs differ from other classes of biological medicinal products or biomedicines. The CAT has begun this identification process (Schneider et al., 2010, pp. 198–199); it will be the responsibility of the marketing authorization holder or sponsor to establish systems for effective follow-up, and the responsibility of the CAT to assess proposed measures as part of the risk management plan, to ensure the collection of information that is relevant, not just easily collectable.

Systems for regulation of GTMPs have been developed outside of the European Union, in the United States and elsewhere in the world. Regulatory harmonization will be crucial for the successful development of these biomedicines. As scientific and technical possibilities increase, the regulatory framework will need to be able to respond flexibly to take account of developments, balancing the encouragement of desirable outcomes with the deterrence of undesirable ones.

One example of the need for flexible but thorough oversight is provided by examining the scope and utilization of regulatory exemptions. The Advanced Therapy Medicinal Products (ATMP) Regulation (EC) No. 1394/2007, via Article 28, permits EU member states to define by regulation those circumstances under which certain ATMPs may be excluded from the scope of the ATMP regulation. This potential exemption applies to ATMPs prepared on a nonroutine basis according to specific quality standards, and used within the same member state in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient. This exemption, which has a counterpart in the U.S. Food and Drug Administration's regulatory exception for single uses of experimental interventions for patients who do not meet enrollment criteria for a relevant clinical trial (U.S. Food and Drug Administration, 2010), poses the risk of confusing an unproven experimental product with an effective treatment, and thus should be employed only after careful consideration of the ethical implications of such use.

There is no specific provision for ethical review in the ATMP regulations. It is recognized that Article 28 is meant to be used rarely, in a hospital setting where the clinician takes full responsibility (except for product quality considerations, where competent authorities ensure compliance), and it is expected that hospitals' internal clinical governance arrangement will be adequate to address ethical implications. This means that unless individual EU member countries decide to require ethical review in their national implementation of the ATMP regulations, no ethical review of administration of gene transfer products under Article 28 will take place. This is consistent with the intended spirit of the exemption, as being a very rare and exceptional scenario. However, without additional oversight, the exception could grow—either because patient organizations seek to use it although researchers wish to adopt a more cautious approach, or because researchers strongly believe in a product and wish to promote its use despite the reluctance of patient groups to support research.

To avoid Article 28 becoming a loophole through which premature human use occurs, proposals for interventions to be made under its umbrella should be scrutinized by a committee with relevant expertise. In the United Kingdom, the suggestion was made that the Gene Therapy Advisory Committee (GTAC) could be called on, if necessary, to provide ethical advice to medical practitioners on the use of gene transfer interventions and stem cell line-derived materials made and used under the exemption. Harmonization of the application of Article 28 in EU member states' regulations would thus help generate a consistent interpretation of when it is appropriate to move to use in humans, and when a development has passed the point at which the Article 28 exemptions can be allowed to apply. In general, the experience collected on the benefits and risks of GCTMPs is so small that these medicines should be administered only in the framework of controlled and authorized clinical trials.

In areas where novel therapies are emerging there is, ideally, a partnership between manufacturers, regulators, ethics scholars, advisors, and patients who are potential users of the therapies to define limits and possibilities. Although understanding should be based on consensus, the statutory function of bodies like the CAT and the review of clinical trial applications by national ethics committees like the United Kingdom's GTAC and the Dutch Expert Group on ATPs of the Medicines Evaluation Board places important constraints on partnerships at key points in the process. Regulators must maintain their independence in order to give a fair and objective assessment of data and make decisions free from any conflicts of interest. Regulators need to be free of possible conflicts of interest (e.g., between clinical caution and commercial opportunity) and independent of pressures (such as the desire to promote leadership in the field) that may risk pushing research and product development more quickly than is warranted by current scientific understanding.

Central to effective EU regulation is trust among the stakeholders involved. Trust is not blind, but based on the mutual expectation of fulfillment of defined criteria (such as technical capability, resource availability, professional competence, etc.), as well as on an assessment of identifiable risks and effective strategies to respond should these risks materialize. Clear delineation of the scope and limits of the regulatory role, and the promotion of public understanding of that role will also maintain public confidence in the regulatory process.

As far as possible, regulation and data assessment need to occur in an open and transparent context. Of course some information may be clinically or commercially confidential, and this must be respected, but undertaking regulation in a public arena is a valuable way of ensuring probity, rigor, and appropriateness. For example, in the United States, the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health (NIH) provides an open, public forum for the consideration of scientific, safety, and ethical aspects of gene transfer work. This has enabled the creation of a public record of progress in the form of a searchable database (Genetic Modification Clinical Research Information System, GeMCRIS) and a number of public guidance documents and information brochures on topics such as informed consent (Office of Biotechnology Activities, NIH, 2011).

The content and timing of regulatory submission are crucial: key data must have been collected and be available for review, but it must not be too difficult or expensive to amend the protocol if amendment is required. Guidance on the timing and content of submissions, including clinical and preclinical supporting data, is essential. Early advice from national medicines agencies and from the EMA thus has an important role to play in identifying scientific, ethical, legal, and regulatory issues in the development of GTMPs. The EMA provides scientific advice to SMEs at reduced cost, but this advice is not available for academic investigators. Significant progress has recently been reported in academic-led clinical trials based on ATMPs. Given the complexity of gene- and cell-based therapeutic approaches, there will be a significant lead time before GCTMPs are ready for product licensure. This long development time is not attractive for commercial investment, particularly for small companies; as a result, academia is likely to retain an important role in the development and conduct of early-phase clinical trials of GCTMPs. This prioritizes a role for national regulatory bodies, as well as for nonregulatory advisory bodies.

In a rapidly developing field such as gene transfer, a partnership approach between the CAT, external experts, and other stakeholders should provide a positive framework for product development, as well as a means of mitigating undue pressures to approve complex and expensive ATMPs even if they show only a small benefit. Although there is now an EU centralized procedure for market authorizations of ATMPs via the regulations, and there are discussions taking place between EU competent authorities as to the feasibility of regulatory harmonization of clinical trial authorizations (e.g., via a single clinical trial authorization per trial for all EU member countries), there is no parallel process for the ethical approach to trials to be harmonized at the EU level. This leaves ethical approvals at the national level, which perpetuates current practical problems in conducting multinational, multicenter trials, and fails to cultivate opportunities for knowledge-sharing about the ethical implications of the science in development of ATMPs.

Appropriate collaboration between the CAT, patient groups, and nonregulatory advisory entities can play an important role in balancing patient expectations, moving understanding from the emotional to the rational, and contributing to a sustainable environment in public understanding of product development at the budding edge of scientific possibility, while at the same time acknowledging and openly discussing inevitable conflicts of interest, so that they may be managed effectively and fairly.

Last, it is pertinent to examine the policies and practices of the EMA in light of patients' and patient organizations' expectations. Doing this is made possible by a welcome commitment to openness outlined in the EMA's Transparency Policy (European Medicines Agency/232037/2009) published in draft form in June 2009 (European Medicines Agency, 2009a), the aim of which is

To be better able to address the increasing need for information from civil society

The agency has also released in 2009 a useful document pertaining to information on benefit–risk of medicines: patients', consumers', and healthcare professionals' expectations (European Medicines Agency, 2009b).

The EMA has published a series of guidelines, concept papers, and other documents with the intent to allow scrutiny of the decision-making process and to facilitate input to its committees and working parties from external perspectives. Nevertheless, in this complex and cutting-edge field, the multiple guidelines have ended up in a framework that is difficult for users and stakeholders to follow (European Medicines Agency, Committee for Medicinal Products for Human Use, 2005, 2006, 2007a,b, 2008a,b, 2009a,b, 2010a; Commission of the European Communities, 2006a,b; European Medicines Agency, Committee for Human Medicinal Products, 2007; European Commission, Enterprise and Industry Directorate General, 2009a; European Medicines Agency, 2009c,d; European Medicines Agency, Committee for Advanced Therapies, 2010a,b).

Two guidance documents promulgated in December 2009 attempt to correct this complexity. The first is a list of questions and answers on gene therapy (European Medicines Agency, Committee for Medicinal Products for Human Use, 2009c, 2010b), which addressed issues of general concern, clinical, nonclinical, and environmental issues. The second and more important is a concept paper on the revision of the note for guidance on quality, preclinical, and clinical aspects of GTMPs (European Medicines Agency, Committee for Medicinal Products for Human Use, 2009d) designed to take account of scientific advances since the drafting of the original guidelines a decade ago. It is expected that this revised guideline will consolidate information and requirements formulated in all others, so that users need only refer to a single cross-indexed consolidated document.

Last, a public consultation on the assessment of the functioning of “clinical trials directive” 2001/20/EC [ENTR/F/2/SF D(2009) 32674] has been initiated by the Directorate General for Enterprise (DG-Enterprise) of the European Commission, closing on January 8, 2010 with a view to modifying the current clinical trials directive (European Commission, Enterprise and Industry Directorate General, 2009b).

Included in the membership of the CAT are two representatives from European patient organizations and their alternates, with full rights and responsibilities alongside the other members of this committee. This should help ensure that the operating practices developed and implemented reflect the issues discussed in this report. It is also encouraging that the CAT seems to be adopting a more proactive approach to the issue of patient engagement, for example, through the development of a public statement on unauthorized stem cell therapies, which has been posted on the EMA website (www.ema.europa.eu).

However, the CAT is not alone in undertaking engagement with patient interests within the EMA. Other regulatory committees (e.g., the Committee for Orphan Medicinal Products [COMP] and the Paediatric Committee [PDCO]) incorporate patient representatives, and the Patient and Consumer Working Party (PCWP) engages in active dialogue with pan-European patient and consumer organizations in an effort to meet its statutory duties in a way that is perceived to be appropriate by those whose interests are ultimately affected by the regulatory decisions taken on their behalf. Nonetheless, for reasons stated throughout this report, a nonregulatory platform to promote best-quality coordinated science and collaborative advice should supplement the efforts of regulatory bodies to incorporate the needs, interests and concerns of patients, ensure consistent ethical review, and respond rapidly to support innovative science.

A Sustainable Role for the CliniGene Consortium

The CliniGene Network of Excellence (NoE), funded by the European Commission's 6th Framework program, has created both critical mass and momentum toward high-quality gene transfer research at the level of basic science and its translation into well-designed clinical trials. Like all EU-funded NoEs, it is time-limited, and will finish in its present format by mid-2011. However, plans are underway to create a sustainable not-for-profit structure that will preserve the expertise that CliniGene has created and master the momentum underpinning gene transfer research and its safe, effective clinical applications. This would result in the eventual formation of a nonprofit “European Institute for Clinical Gene and Cell Therapy” to promote good practice and develop standards that will define good laboratory practice (GMP) in gene transfer research. This institute could implement and streamline European and international exchange of information and experience; the holding of workshops, seminars, conferences, and other events; as well as the setting up and editing, promotion, and distribution of publications in any form; submission of expert advisory opinions; and cooperation with European and international public and nongovernmental organizations.

The objectives of such an institute should focus on the facilitation, development, and implementation of the full range of professional activity of gene transfer and cell therapy researchers (Table 2).

Such an institute would be well positioned to undertake the role of the platform described previously in a dynamic framework able to respond quickly to the changing demands of a rapidly developing area of science. This would provide the opportunity not only to incorporate novel scientific and technical possibilities, but also to create the appropriate ethical, regulatory, and public communication frameworks necessary to secure public endorsement and legitimization for gene transfer research.

During the past 5 years, research on gene and cell therapy (GCT) has made enormous progress, owing in large part to the integration of research in Europe with EC support. Initiatives such as the CliniGene-NoE have been key catalysts serving this purpose. As a result, several GCT small-scale trials—all investigator-driven and based on new vector technologies matching improved efficacy and safety requirements—are currently in search of the means and sponsors to undertake full-fledged clinical trials. There is currently an urgent need to streamline cooperation and interoperability among GMP facilities. Complex technical challenges require existing production facilities to adapt to emerging technologies in a coordinated manner. A consensus has emerged on the directions and priorities to adopt, applying to advanced technologies with improved efficacy and safety profiles, in particular adeno-associated virus-based, lentivirus-based, and oncolytic vectors. Translating cutting-edge research into first-in-human trials requires that prenormative research be conducted that aims to develop standard assays, processes, and candidate reference materials, in order to help harmonize practices and quality.

There is likewise an urgent need to fund and support the collaborative cultivation of human skills in GCTMP development, in order to promote high-quality innovative GCT science. These investments can dramatically enhance academic-led “first-in-human” gene transfer research. The not-for-profit business framework proposed for the institute would ensure that its efforts are focused on the needs of stakeholders rather than on financial returns. Once proof of efficacy is gathered, technology can be transferred to the private sector, which can then take over further development, taking advantage of the industry knowledge and infrastructure appropriate to later stages of ATMP research.

Essential components of a successful next step are as follows:

First, to acknowledge that research on GCTMPs must be translational—that is, coordinated across the development of assays and materials, and from preclinical through clinical trials, rather than simply focusing on research with human subjects

Last, it must be emphasized that any regulatory framework or platform for progress that is to fulfill its role effectively must be not only accountable and transparent, but also based on sound science and rational decision-making, where priority is given to matching progress in the advances in our understanding of basic biology with ethical imperatives, and with the safety, needs, and interests of patients and families. Frameworks with these characteristics stand a greater chance of supporting desirable developments and preventing undesirable ones without being either too permissive or too draconian. But we have to start from where we are, not where we might wish to be. There is a well of altruism in patients that should continue to support high-quality research that is appropriately valuable and safe, so long as patients who become research subjects recognize the inescapable uncertainty that accompanies new science and are prepared to accept the reasonable risks that come with participation. A proportionate, appropriate regulatory framework and supporting advisory and platform mechanisms will help to realize the potential inherent in gene transfer research and GCTMP development for patients with serious life-limiting diseases as quickly, as safely, and as efficiently as possible.