Main

Advances in fundamental knowledge and technological innovation during the last decade have catapulted cell and gene therapies (CGTs) from a boutique research niche to the largest growing segment of the biopharmaceutical industry. Eighteen CGTs have been approved in the United States and/or Europe since 2016 (Table 1), several of which mediate impressive benefits in children. Tisagenlecleucel (Kymriah), an engineered T cell product that expresses a chimeric antigen receptor (CAR) that targets CD19, improves survival in children with recurrent/refractory B cell acute lymphoblastic leukemia (B-ALL) resistant to all other therapies1,2. Voretigene neparvovec-ryzl (Luxturna), a locally administered gene replacement therapy for Leber’s congenital amaurosis, can restore sight in adults and children with congenital blindness3,4. Onasemnogene abeparvovec-xioi (Zolgensma), a gene replacement therapy for spinal muscular atrophy, prevents loss of function in presymptomatic infants and improves overall survival5,6. Two gene-editing therapies that deliver the CRISPR-edited autologous cell product exagamglogene autotemcel (Casgevy)—for the treatment of sickle-cell disease and transfusion-dependent β-thalassemia—lower or eliminate the incidence of vaso-occlusive crises and transfusion requirements, respectively, in adolescents7,8.

Table 1 FDA/EMA approvals for CGTs as of March 2024

The impressive list of CGTs with benefits already demonstrated for children provides the first glimpse of a much larger wave of emerging therapeutics predicted to transform outcomes for children with a wide array of severe diseases. Genetically engineered T cell therapies are showing promise for otherwise untreatable pediatric solid tumors (including brain tumors) where standard therapies have stalled9,10. Gene therapies targeting hematopoietic stem cells (HSCs) are showing impressive efficacy for immunodeficiencies, hemoglobinopathies and cerebral leukodystrophies11,12, and adeno-associated virus (AAV)-based gene therapies are demonstrating benefit for monogenic and complex genetic diseases13,14. New approaches for targeted genome editing using the CRISPR platform continue to emerge15,16,17, and next-generation immune cell therapies for infectious disease, autoimmunity and potentially tissue regeneration, are poised to broaden the array of pediatric diseases amenable to treatment with this therapeutic class18,19.

Despite this progress and opportunity, we are witnessing a market failure for pediatric CGTs. In this Perspective, we discuss the problematic status quo, the major factors contributing to the problem and potential solutions—with an emphasis on automating cell manufacturing, leveraging the intrinsically platform nature of genetic therapies, evolving regulatory paradigms and amending licensing practices. To stimulate discussion and catalyze action, we propose creation of a Pediatric Advanced Medicines Biotech (PAMB), an entity that would conduct registrational trials, sponsor biological license applications and commercialize approved CGTs for children. The PAMB would work closely with the academic ecosystem (pediatric centers of excellence, academic medical centers and research institutes) to identify CGTs ready for late-phase pediatric testing; use academic manufacturing to reduce costs; and achieve regulatory milestones as early as possible to recoup a revenue stream from payors. We focus predominantly on the US context, but note that several models are under development in other countries to address this issue19,20,21,22,23,24,25, some of which are briefly highlighted in Box 1.

The status quo

The expanding potential for impact of CGTs is driving immense capital investment, with the CGT market in the United States projected to expand from ~US$7 billion in 2022 to ~US$39 billion by 2032 (ref. 26). The biopharmaceutical industry, the de facto entity responsible for drug development, views that its requisite fiduciary duty is to provide a risk-adjusted rate of return on investment to shareholders. This model has delivered hundreds of effective therapies and cures but prioritizes development of agents for which there is a large market. While the public health impact of cancer and genetic disease in children is high, these are all ‘rare’ diseases27, for which the traditional biopharmaceutical model will not yield an adequate return on investment. Nevertheless, new therapies that could dramatically benefit children exist and will continue to be developed, yet they cannot achieve a market-based rate of return. This challenge is magnified for CGTs, which are more expensive to develop today than small molecules or biologics.

An additional challenge that must be solved is the need to evolve the regulatory framework for manufacturing CGTs for small populations. As a specific example, under current guidelines, manufacturing requirements for critical reagents and drug substances required to generate an approved CRISPR–Cas9-based medicine for a disease indication with 10,000 patients would be the same as for a disease developed to treat 10 patients. In addition to the financial challenges posed by small pediatric markets, many tasks associated with pediatric drug development are challenging for most biopharmaceutical companies, due to gaps in pediatric-specific expertise—for example, knowledge about pediatric-specific formulations, dosing strategies and clinical trial designs appropriate for children. It is also possible that a risk–benefit analysis might lead biopharmaceutical companies to be concerned that severe toxicity or death of a child on a trial would put the adult drug development program in jeopardy. Together, these circumstances are driving a market failure for pediatric CGTs despite the outsized opportunity for clinical benefit. A representative example of the resulting status quo is that among four leading publicly held biotechnology companies in the gene-editing space, active development is underway for a paltry 5 of ~6,000 known genetic diseases, all with a focus on the adult patient population.

Statutory incentives and requirements have been created to catalyze drug development for children in the United States (Box 2), but CGT development for children continues to stall, even for agents demonstrated to be safe and effective—as illustrated by two vignettes summarized in Box 3. The market failure affects agents for which there is no adult indication (such as gene therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency syndrome (ADA-SCID)), as well as agents with activity in a common adult indication (such as the CD22-targeting CAR, which is active in pediatric B-ALL and adult large B cell lymphoma). Experience demonstrates that pediatric access to agents with demonstrated activity cannot be ensured through perpetual clinical trials because only a very limited number of institutions can deliver any specific investigational agent and highly restricted geographic availability exacerbates disparities in access to novel agents. Furthermore, the high costs of funding clinical trials cannot be sustained in perpetuity, nor is it appropriate to use research funds to support delivery of an agent that has already been demonstrated to be safe and effective.

Recouping development costs by increasing drug prices

CGTs have the dubious honor of being the most expensive therapeutics thus far, with the price of several exceeding US$1 million (Table 1). Increasing the price of CGTs for small markets to offset development costs poses a substantial risk of diminishing access, which we have already witnessed with the withdrawals of betibeglogene autotemcel (for β-thalassemia) and elivaldogene autotemcel (for cerebral adrenoleukodystrophy) from the European market, due to an inability to obtain agreeable reimbursement rates from governmental health care authorities (Table 1). High costs also prevent access in low- and middle-income countries and cause major strain on the health care systems of high-income countries23. In the United States, emerging data demonstrate that African American children comprise a smaller fraction of Kymriah recipients than would be expected on the basis of the rate of high-risk B-ALL in this population28, raising the prospect that high costs, logistical complexities, health care insurance coverage and access inequities, and provider bias may already be limiting access of pediatric CGTs to underserved populations. Thus, continued cost increases to incentivize development of pediatric CGTs within the traditional biopharmaceutical model will not address the overarching goal of enhancing access of CGTs to children in need.

Factors driving market failure and modifiable levers

Just as scientific progress in CGT is rapidly evolving, the field is also witnessing rapid technological innovation poised to lower the costs of manufacturing CGTs, emerging regulatory programs designed to accelerate approval of new therapeutics, and an increased interest in licensing intellectual property (IP) from the academic ecosystem to entities capable of commercializing CGTs. Below, we discuss challenges and opportunities within these evolving arenas to reduce costs and increase pediatric access.

Manufacturing

Reducing high costs through automation

Development costs for CGTs are higher than for small molecules and biologics29, largely due to the need to manufacture individualized products for each patient. All current US Food and Drug Administration (FDA)-approved engineered cell therapies are autologous products using centralized manufacturing, manual cell handling and expensive reagents with limited supply chains, and thereby incur high labor, reagent and logistic costs. Current commercial processes are difficult to scale, as evidenced by the inability of several recent FDA-approved CGTs to meet clinical demand30,31,32. Efforts are underway to develop ‘off-the-shelf’ allogeneic cell therapies, which could diminish cost and increase accessibility, but thus far equivalent potency and durability of allogeneic compared to autologous products has not been demonstrated33.

Automation provides new opportunities to diminish costs, increase scale and enhance access to autologous CGT products. Automated platforms greatly reduce labor costs, as well as the potential for human error and contamination, which can lead to batch failure. By enabling distributed and point-of-care manufacturing, automation can also reduce logistics costs. For example, the CliniMACS Prodigy (Miltenyi), an automated platform used by several academic sponsors to engineer T cells according to current good manufacturing practice (cGMP) specifications for early-phase clinical trials at single or multiple cGMP facilities34,35,36,37, is also being used in centralized cGMP facilities by commercial sponsors to manufacture CGTs. Several additional automated platforms are emerging that show promise for dramatic scaling, integration of automated quality-control monitoring and the potential to modify manufacturing conditions in real time to deliver more consistent products. Increasing availability and sophistication of automated platforms are predicted to substantially reduce costs of manufacturing and improve product quality and consistency in the near term.

Platform standardization for genetic therapies

There is great interest in developing more standardized platforms for delivering gene therapies, to reduce both the cost and the regulatory burden. This approach is most advanced for AAV-based therapies, for which efforts are underway to use one common vector ‘backbone’ across indications—into which a specific gene of interest can be inserted, depending upon the disease targeted. For example, the Bespoke Gene Therapy Consortium, a public–private partnership administered by the Foundation for the National Institutes of Health is a $100 million investment that is seeking to reduce regulatory burden and costs and thereby hasten drug development by providing common platforms, wherever possible. A related effort is the Platform Vector Gene Therapy Pilot Project, launched in 2019 by the National Center for Advancing Translational Sciences. This project seeks to develop four distinct gene therapies for four different monogenic diseases using the same manufacturing process and AAV9 vector backbone but varying the gene replacement insert. There is hope that a standardized AAV platform that enables a ‘plug-and-play’ model to treat many diseases could dramatically lower costs, shorten timelines from bench to clinic and diminish regulatory risk, thereby accelerating development of gene replacement therapies for pediatric disease.

A third related effort is the US National Institutes of Health Somatic Cell Genome Editing program that recently awarded $25 million to each of five disease teams across US academic institutions to advance CRISPR–Cas-based therapeutics for more than one disease indication, explicitly leveraging the platform nature of CRISPR to facilitate flexibility across indications. For example, one team aims to develop a platform approach for liver-targeted in vivo gene editing to treat multiple inborn errors of metabolism, while another team seeks to do the same for inherited genetic disorders of the visual system. The overarching goal is to shift regulatory practice from the status quo, where currently, a small change within an otherwise standardized platform—for instance, replacing only the mutation-correcting guide RNA component with a new, patient-specific one—is regulated as an entirely new product. Ideally, nonclinical and manufacturing data from the previously reviewed regulatory package could be leveraged in a new package that uses a different guide RNA.

Regulation

Given the novelty of CGTs, and the potential that permanent genetic changes could induce unexpected, late and/or permanent toxicities, regulatory agencies have generally taken a cautious approach to the study and approval of this class of therapies. Several early cases of gene therapy-associated toxicity in the 1990s and 2000s accentuated this caution, including leukemias observed in boys treated with gene therapy for X-linked SCID38,39 and fatal liver toxicity in a patient treated with adenoviral-based gene replacement40. Since that time, the scientific community has developed safer approaches to deliver genetic payloads, and gene therapy has amassed an impressive track record of safety41,42, although long-term monitoring for adverse late effects of gene therapy is expected to be required for the foreseeable future to fully assess risk43,44. The nascent field of somatic genome editing has also, thus far, maintained a good safety record, with the first FDA and European Medicines Agency (EMA) approvals for two ex vivo engineered medicines in December 2023 (ref. 45).

Understanding this backdrop, a fundamental challenge of developing CGTs for pediatric diseases is a lack of consensus around the level of certainty that should be required to designate a CGT developed for a rare or ultra-rare disease as safe and effective, within a reasonable time frame. Requiring the same level of statistical certainty for therapeutics developed for large markets is not feasible when developing therapeutics for rare pediatric diseases. The most extreme examples are the so-called ‘n-of-1’ diseases46,47, wherein a therapeutic, such as a gene-editing therapy based on the nimbly malleable CRISPR platform, is developed for a mutation occurring in one individual. An important precedent for this concept is provided by the development of Milasen, an antisense oligonucleotide developed for a disease occurring in one individual48. Fit-for-purpose standards are needed for n-of-1 diseases, ultra-rare diseases (such as ADA-SCID, which affects approximately 10–12 new infants a year in the United States), and rare diseases, which together encompass essentially all pediatric diseases for which CGTs are being developed. The lack of clarity around the standards required to define safety and efficacy for these diseases has stalled progress towards developing curative gene-editing medicines for more than 500 cataloged inborn errors of metabolism (of which ADA-SCID is one), despite the near congruence of the cell product manufacturing path and the technological feasibility of repairing the causative mutations using CRISPR–Cas gene-editing platforms.

An affirmative regulatory decision is facilitated when agents have large effect sizes in populations with high unmet need, which is true of most CGTs approved thus far. Indeed, the overwhelming majority of CGT approvals have resulted from single-arm studies based on large effect sizes and high clinical impact compared to historical control groups (Table 1). One approach the FDA has taken to address the challenge of regulatory uncertainty for agents that show promise for diseases with high unmet need is the ‘accelerated approval pathway’ (Box 2), which provides the opportunity for patients to access lifesaving drugs faster, and diminishes the cost of developing new therapies since payor reimbursement begins earlier in the drug development life cycle. Obtaining accelerated approval as early as possible for safe and effective pediatric CGTs is a critical means to diminish the risks and costs associated with developing these therapies.

IP licensing

The revolution we are witnessing in CGT began in academia with foundational IP resulting from research usually funded, at least in part, by federal dollars. Following passage of the Bayh–Dole Act in 1980, federal grantees across the academic ecosystem were given ownership of IP rights to discoveries made using federal funds. As a result, academic centers have developed increasingly sophisticated processes for filing patents to protect IP, identifying IP licensees and negotiating license terms. This model has proven highly beneficial for patients and the academic ecosystem, as evidenced by the large number of products developed in the last four decades emanating from research conducted at academic centers, and the substantial revenue received by academic centers from licensing fees and royalties. However, current IP licensing norms do not include pediatric development requirements and thus may inadvertently enable the market failure we are witnessing in the pediatric arena. This is ironic because many institutions responsible for foundational discoveries that are enabling pediatric CGT development are also committed to improving outcomes for pediatric conditions. Establishing new IP licensing practices that require or enable pediatric CGT development is essential to address the market failure, and potential models will be discussed further below.

A PAMB to commercialize pediatric CGTs

Academic groups and advocates from several countries have recognized the market failure for pediatric CGTs, and challenges related to accessibility and cost of CGTs for some adult indications, and these concerns are driving the development of new models to deliver CGTs to children, outside traditional biopharmaceutical routes19,20,21,22,24,25,49,50. Because regulatory requirements and pathways, pricing terms and market forces differ greatly between countries, successful models are likely to vary by country, with several emerging models illustrated briefly in Box 1. Thus far, there has been limited organized effort within the United States to commercialize pediatric CGTs outside biopharmaceutical routes.

Here, we propose creation of a PAMB designed to address the market failure for pediatric CGTs in the United States. Just as the biopharmaceutical industry does for CGTs developed for common adult indications, the PAMB would provide the resources, infrastructure and expertise needed to conduct registrational trials of the most promising pediatric CGTs, assemble and file biologic license applications (BLAs) and conduct post-approval manufacturing and marketing. The strategic vision of the PAMB focuses on three major pillars: (1) building strong, productive relationships with the academic ecosystem to access innovation relevant to pediatric disease and diminish costs of manufacturing; (2) maximally leveraging accelerated approval and cost recovery pathways to diminish cost and regulatory risk; and (3) establishing licensing practices that protect IP relevant to pediatric CGTs. In the sections below, we detail the three strategic pillars, describe what the life cycle of a pediatric CGT developed by the PAMB would look like and briefly discuss PAMB funding and sustainability.

Strategic partnering with the academic ecosystem

The academic ecosystem has fueled the explosion of opportunity we are witnessing for pediatric CGTs and will continue to provide foundational knowledge for breakthrough advances. Whereas the biopharmaceutical industry typically spends millions of dollars in research and development for each new commercial product, public monies, foundations and philanthropies provide a sustained source of funding to academic institutions to support basic science, therapeutic platform development and early-phase clinical testing of pediatric CGTs. These investments are yielding an exciting pipeline of emerging CGTs for pediatrics that could be accessed by the PAMB to sustain a robust pipeline of therapeutics while largely avoiding research and development costs to the PAMB itself. Pediatric centers of excellence have deep experience with pediatric clinical trials and access to pediatric patients and clinical expertise, which cannot be reproduced in the private sector. The PAMB would not duplicate nor compete with the academic ecosystem but will complement and support its work by focusing on late-phase development and commercialization—activities that are outside the academic scope. Success of the PAMB will hinge on its ability to forge effective partnerships with the community of researchers and the organizational entities that comprise the academic ecosystem based on the shared goal of delivering curative therapies for children with severe and life-threatening diseases.

Many academic centers have created cGMP facilities capable of manufacturing clinical-grade viral vectors and engineered cell products that the PAMB could leverage for manufacturing for registrational trials and post-approval manufacturing. Most of the current FDA-approved gene therapies originated in academia, and early clinical trials delivered products manufactured in academic cGMP facilities. This is in stark contrast to small molecules and biologics, which are very rarely manufactured in academic facilities. Accreditation of academic GMP facilities in the United States is undertaken by the Foundation for the Accreditation of Cellular Therapy (FACT). FACT was founded in 1996 by the American Society for Transplantation and Cellular Therapy and the International Society for Cell and Gene Therapy, aiming to be the standards-setting and accreditation body that comprehensively oversees clinical practices, cell collection and laboratory services to foster research and development in the field of cell therapy.

Academic cGMP facilities do not routinely manufacture products for registrational trials or conduct commercial manufacturing following drug approval, but the expertise and infrastructure embedded within many of these facilities could potentially support these activities51. Regulatory requirements for post-approval manufacturing specify adherence to the quality assurance and control guidelines provided in the Code of Federal Regulations (21CFR Part 211), which several FACT-accredited academic cGMPs have already instituted. All FACT-accredited cGMP laboratories are harmonized since they each address 15 quality system elements required by FACT, and standard operating procedures could be instituted across participating centers to further align quality systems and ensure Part 211 compliance. Thus, while all FDA-approved CGTs are currently manufactured by for-profit entities, the expertise, platforms and facilities needed to manufacture CGTs according to cGMP specifications are available and/or achievable within many academic cGMP facilities.

Increasing application of automated manufacturing platforms is poised to further enhance the capabilities and scale of academic cGMPs52. Indeed, many academic cGMP facilities already manufacture products on a contractual basis for biopharmaceutical-sponsored clinical trials. Studies have demonstrated that products meeting cGMP standards can be manufactured in academic facilities at a reduced cost compared to list prices of approved products53. Thus, we anticipate that the costs of manufacturing pediatric products in academic facilities will be lower than those available within Contract Development and Manufacturing Organizations. Success of the PAMB will hinge upon its ability to create acceptable terms for contracting with academic cGMP facilities to conduct manufacturing for PAMB-sponsored pivotal trials and for post-approval manufacturing.

Leveraging accelerated approval and cost recovery pathways

The PAMB will prioritize agents for development for which safety and efficacy can be demonstrated with single-arm studies, the approach utilized by nearly all CGTs approved thus far (Table 1). Single-arm studies are well suited for pediatric diseases with high unmet need since considerable effort has been expended to create patient registries and amass contemporaneous historical control groups. Pediatric CGTs could receive full approval from a pivotal single-arm study, or provisional approval via the accelerated approval pathway. Regarding drugs developed for adult indications, those that receive provisional approval must be subsequently studied in a ‘definitive’ trial within a reasonable time frame, to convert to full approval. Definitive trials typically involve randomization and incur sizeable cost to study an additional population with the same disease. For pediatric indications, randomized trials are not likely to be feasible given the challenge of identifying sufficient populations with the same rare disease and ethical concerns of randomizing access to an agent already demonstrated to be safe and efficacious. Alternatively, post-marketing single-arm trials (for example, phase IV trials) could provide the confirmatory evidence necessary to convert provisional approval to full approval. Phase IV trials would be highly feasible in the pediatric arena, especially for CGTs wherein it is standard to follow patients for at least 15 years to comply with FDA guidelines. Given that the PAMB will prioritize development of agents with high signals of activity for areas of unmet need, we anticipate success in obtaining full approval on the basis of single-arm trials, and/or provisional approval that could convert to full approval via phase IV trials—which could be completed with modest costs through close partnership with academic partners.

A distinct but complementary approach to accelerating payor reimbursement during the drug life cycle involves ‘investigational drug cost recovery’ (Box 2), whereby permission to request payor reimbursement before filing a BLA is provided by the FDA to offset manufacturing costs. However, while some health plans provide explicit benefits for cost recovery in line with this, the majority do not, which limits the effectiveness of this approach for recouping the costs of an investigational product. The PAMB would advocate to improve the success rate for obtaining payment from payors through investigational drug cost recovery.

Establishing licensing practices that protect IP

An essential element of successful drug development requires IP licensing to provide the freedom to develop and market the agent under study. As noted above, current licensing practices typically provide exclusive licensing to the biopharmaceutical industry without requiring any pediatric development milestones, which essentially prohibits a pediatric-focused entity from developing agents for pediatric diseases (Fig. 1a). The PAMB will advocate with academic partners to obtain pediatric licensing provisions sufficient to enable CGT development in pediatrics. Alternative licensing arrangements could take many forms, some of which are illustrated in Fig. 1b–e, and we anticipate that the optimal arrangement will vary on the basis of the therapeutic under consideration. Creative licensing arrangements could not only provide the PAMB with freedom to develop pediatric CGTs originating in academia, but also provide a revenue flow to sustain the PAMB. For instance, if an agent is commercialized first for pediatrics, but has the potential for impact in an adult indication, the PAMB could sublicense the IP to the biopharmaceutical industry and thereby collect fees and royalties to sustain the PAMB in the longer term (Fig. 1d).

Fig. 1: Licensing models for pediatric CGTs.
figure 1

a, Schematic represents the status quo, wherein exclusive licenses are provided to the biopharmaceutical industry without any specific milestones or requirements for pediatric development. This model would prevent the PAMB from developing the agent since it would not have access to the IP. b, A modification to the status quo by requiring milestones for pediatric development within a reasonable time frame, but this would require developing approaches to enforce the requirement. c, A novel approach, wherein two exclusive licenses are negotiated, one with the biopharmaceutical industry for adult indications and one with the PAMB for pediatric indications, providing each entity freedom to operate for their intended use. d, Schematic illustrates an option whereby the PAMB receives an exclusive license for the asset and then sublicenses to the biopharmaceutical industry for the adult indication, thus reaping an additional revenue stream. This approach would be appropriate if the PAMB de-risks the agent, develops proprietary know-how or otherwise improves the asset rendering it more attractive for biopharmaceutical development. e, Schematic illustrates an option whereby the PAMB could negotiate a sublicense from the biopharmaceutical industry but would be obligated to meet their terms and potentially pay substantial fees and royalties.

Life cycle of a pediatric CGT developed by the PAMB

The life cycle would begin when academic investigators identify a pediatric CGT with substantial activity and acceptable safety in phase I/II clinical trials and approach the PAMB for possible late-stage development (Fig. 2). PAMB activities in stage 1 would focus on pivotal trial readiness, including conducting licensing negotiations with the academic institution, working with academic colleagues to iterate cGMP manufacturing from a process suitable for early-phase testing to one suitable for registrational and commercial manufacturing. During this phase, the PAMB would also meet with the FDA to discuss plans for assessing comparability between early-phase manufacturing and late-phase manufacturing, and for the design of the registrational trial, leveraging to maximum effect the enhanced access provided to investigators according to the designations described in Box 2.

Fig. 2: Life cycle of a pediatric CGT within the PAMB.
figure 2

Academia would ‘hand-off’ a therapeutic that has shown promising safety and efficacy in phase I studies to the PAMB, which would ensure pivotal trial readiness, then conduct the pivotal trial and file the BLA, then commercialize the agent upon FDA approval. Public monies, philanthropy and investment capital will be needed to launch the PAMB, while payor reimbursement, pediatric priority review vouchers and royalties will be needed to sustain the entity.

Stage 2 activities would focus on pivotal trial execution, beginning with identifying and qualifying manufacturing and treating sites, the number of which would vary based on disease incidence and manufacturing complexity, but the PAMB would seek to maximize geographic diversity to enhance access. The PAMB would sponsor and monitor the pivotal clinical trial, and supervise manufacturing in partnership with academic cGMPs. A critical element would be instituting appropriate quality-control and quality assurance systems across cGMP sites, which meet the standard required for registrational trials. Following completion of the registrational trial, the PAMB would compile and file the BLA and, ideally, receive full approval or provisional approval, on the basis of a single-arm study.

Stage 3 would focus on post-approval manufacturing and marketing. During this period, the PAMB would establish pricing, market the agent and negotiate with payors for reimbursement. Stage 3 activities are well outside the scope of the academic ecosystem and will require the PAMB to develop a commercialization unit, not unlike those found in the biopharmaceutical industry. Additional potential benefits of developing pediatric CGTs via the PAMB pathway could include more effective and comprehensive monitoring for late effects of CGTs (including second malignancies43,44), as well as incentivizing increased public investment in cGMP infrastructure, which could prove valuable beyond the pediatric arena.

Funding

The long-term financial sustainability of the PAMB will require diligent focus on reducing costs of CGT development, obtaining payor reimbursement as early as possible, diminishing regulatory risk and creating multiple sources of revenue. Just as the launch of a biotechnology company requires capital investment, so too would a successful launch of the PAMB. Revenue streams necessary for launch would include public monies, philanthropy and potentially investment from academic medical centers or the private sector. Revenue streams for sustainability would include payor reimbursement, sale of pediatric priority review vouchers (Box 2) and royalty income (Figs. 1 and 2). In addition, the PAMB could generate revenue by partnering with the biopharmaceutical industry to conduct pediatric studies of CGTs required of them to meet their statutory requirements required by the RACE Act (Box 2). Similarly, amending licensing practices to incorporate pediatric milestones within exclusive licenses could incentivize the biopharmaceutical industry to partner with the PAMB for pediatric development and thereby provide a source of revenue. Whether the PAMB is configured exclusively as a non-profit or as a hybrid non-profit/for-profit entity will be determined on the basis of financial considerations and optimization of the business model, taking into account tax liabilities, access to investor monies or lending opportunities, or other factors. While the ultimate goal is to create a self-sustaining entity, it is possible that the PAMB will require subsidies from public monies, gifts from philanthropy or other revenue streams for long-term sustainability to ensure ongoing access to these lifesaving therapies.

Conclusion

The field has witnessed entry of several exciting new pediatric CGTs into the therapeutic armamentarium, but there is broad consensus that the standard model for drug development via the biopharmaceutical industry will not deliver the breadth of new pediatric CGTs that scientific progress is making possible. Here we have outlined major factors responsible for the market failure for pediatric CGTs and propose a new model for late-stage development and commercialization of pediatric CGTs outside the biopharmaceutical industry in the United States. Critical next steps to execute the PAMB vision include partnering with the academic ecosystem to build consensus around the model, raising funds to launch the effort and identifying promising therapeutics that are ready for late-phase testing using this approach.

Modern science and medicine have created unparalleled possibilities for improving the health of children in our world. But these advances are for naught if we are not able to deliver these therapies to children in need. Just as innovation and commitment created these new therapeutic possibilities, so can innovation and commitment create new models for making these therapies accessible to all children in need.