Introduction

Rare diseases, as classified by the FDA and EMA, are conditions that affect fewer than 200,00 people in the US¹ or fewer than five in 10,000 people in the EU². Because of these small populations, rare diseases often face unique – and some respects potentially more significant – hurdles in implementing clinical trials, thus delaying development of novel therapies and leaving significant clinical unmet needs. From a patient perspective, this means fewer, if any, available treatment options, that can often only be received at a limited number of specialised research centers.

One patient subgroup that is particularly affected by the challenges faced in rare disease research is paediatric and adolescent patients, especially in conditions that primarily occur in this population. Traditional clinical trials in paediatric populations are difficult to design and execute due to the lack of validated endpoints and biomarkers; poorly understood natural history; and ethical and other special considerations required for children including drug effect, dosage and disease progression, that often vary from adults³.

Consequently, it is imperative that a new outlook and approach is addressed in order to overcome these challenges and progress clinical trials, thus improving outcomes for patients affected by rare diseases. That involves not only assessing and adapting the current clinical and regulatory guidelines to allow flexibility in trials, but also importantly, listening to affected patients and addressing what is actually important to them from both a trial conduct and outcome perspective. Public and patient engagement is rightly a watchword for developers of treatments for rare diseases.

A recent result of this patient advocacy action is the Research to Accelerate Cures and Equity (RACE) for Children Act that, as of 2020, requires pharmaceutical companies developing novel cancer therapies to evaluate them in pediatric as well as adult populations⁴. Another example, the Rare Disease Evidence Principles (RDEP) was introduced by the FDA in 2025 to provide a more streamlined process with faster review and predictability of therapies to treat rare genetic diseases, specifically in extremely small patient populations with significant clinical unmet need⁵. These principles were intended to better align the FDA and rare disease drug developers on a flexible approach to bring safe and effective treatments to patients with most critical need. The current trend relies upon the FDA and drug developers to work together to find alternative methods for meeting the statutory standard that is both viable and rigorous for rare disease populations.

One rare disease facing a particularly long uphill battle with no substantial success in the last three decades of clinical trials is osteosarcoma, an aggressive bone cancer that primarily affects paediatric and young adult populations. Current standards of care for the majority of those diagnosed is heterogeneous,and may include multiple rounds of chemotherapy and resective surgery, and survival rates remain low in patients with metastatic disease. This intense multimodal treatment has long-term adverse effects, particularly on patient quality of life (QOL)⁶. This alone necessitates the need for new and novel therapeutics, and thus demands acceptance of new strategies in innovative clinical trials where data supporting strong efficacy and acceptable safety profiles meet patients’ needs in rare diseases.

Currently acceptable study endpoints and their value

In order to improve chances of success in clinical trials, we must first understand how success is measured. In osteosarcoma, the preferred efficacy endpoint is overall survival (OS) as objective response rate is not always evident by imaging⁷. OS is easy to measure and objective, however it can take years to become meaningful such that there is less access for patients, particularly paediatric patients, not enrolled in the trial and higher costs to the sponsors⁸. As a result, event- (EFS) or progression-free survival (PFS) is used to provide earlier insight in therapeutic-efficacy.

EFS is defined as the time from randomisation to any event including disease progression, discontinuation of treatment for any reason or death⁹. In osteosarcoma, an EFS benchmark of four months in patients with measurable disease and 12 months for completely resected disease has been utilised in recent clinical trials⁷. Unfortunately, per FDA guidance, single arm trials are unable to adequately characterise time-to-event endpoints and therefore cannot utilise these EFS benchmarks to support marketing applications⁷. As a result, there is a greater wait for patients to access these new therapies because single-arm trials need to wait for OS data, or trials have to be randomised and appropriately powered, which results in a greater required trial population and a longer time to recruit.

Alternatively, PFS is the time from initiation of treatment to measurable disease progression such as increased tumour size, new lesions or death¹⁰. Unfortunately, longer PFS often does not correlate with OS or QOL, and both PFS and EFS are subject to various forms of bias including measurement error, which can result in early termination of studies based on false findings of disease progression¹¹. Similarly, PFS cannot be used as a surrogate endpoint to support a marketing application in single-arm trials.

Notably, single arm trials with appropriate regulatory engagement, study design, biostatistical analysis and clear risk benefit profiles can yield regulatory approvals in non-rare disease settings¹². Unfortunately, this is not the case for osteosarcoma or countless rare diseases, highlighting a gap which regulators, drug developers and clinicians should be seeing as an opportunity to improve historically poor patient outcomes. In order to do so, these separate bodies must identify their own individual practices that contribute to the lack of therapeutic progress and address them as necessary.

For example, there is still no consensus among researchers, clinicians and regulators on appropriate endpoints for osteosarcoma at any stage, making comparison between trial results difficult particularly in single-arm trials¹³. Recent reviews of ongoing efforts to progress clinical trials in osteosarcoma have highlighted a lack of data on historic controls, as well as failure to identify crucial biomarkers or mutations that drive disease progression^13,14. Additionally, though it has been possible to conduct randomised, placebo-controlled trials in recurrent osteosarcoma¹⁵, rarity of osteosarcoma as well as ethical concerns regarding the use of placebo in this patient population make patient recruitment and compliance extremely challenging⁷. Finally, due to the largely paediatric population, consent and compliance to clinical trial protocols via patient carers creates is difficult. All of these factors should be carefully considered and addressed by all involved when designing, reviewing and participating in the future clinical trials.

Patient perspectives

Patients are very clear that their ultimate goals for treatment are increased survival whilst maintaining QOL in terms of physical, psychological, social and general health. In young patients, this often relates to self-perceived body image; ability to remain independent with limited to no disability; and vulnerability to further disease. Therefore, whilst it is undeniably the goal of clinical trial sponsors to see treatments under investigation showing clinical efficacy, it is important that clinicians continue to learn and understand what is actually of value to the patients and their families and/or carers. Studies have shown that patients and the general public are unfamiliar with clinical trial endpoints, and have difficulty understanding results described on drug labels or in adverts¹¹. Furthermore, when focusing on patient QOL, this can look different to patients depending on cancer location and patient age⁶. This adds another layer of complexity to how we measure patient-reported outcomes (PROMs), and how they can be utilised to inform and direct clinical trials design.

As mentioned above, there are serious ethical concerns surrounding the inclusion of a placebo group to clinical trials in osteosarcoma in patients of any age. Patients and their advocates and caregivers have openly expressed their unwillingness to participate in a clinical trial if there was a possibility of their child being given a placebo, particularly given the poor prognosis for recurrent disease and the financial and logistical burden of being in a trial⁷. This supports the use of single-arm trial design for therapeutics, meaning historical data would need to be used as a control. However, historical data comes with its own caveats, namely difficulty finding appropriately matched populations as well as variability in the standard of care (SOC). For osteosarcoma, not only does SOC vary between countries, particularly in those carrying out the majority of osteosarcoma clinical trials (USA, China, Europe), but also within countries and states¹⁶. Furthermore, single-arm trials are not acceptable to regulatory bodies for use in marketing applications; highlighting yet another hurdle in the development of novel therapeutics for osteosarcoma.

Regulatory authorities will consider communications from patients and their advocates in a typical filing. One standard method that may be included by the drug developer is a Delphi study, which is a structured method for reaching expert consensus on research questions where direct evidence may be limited or absent. In principle, it works by involving a panel of experts (specifically from the region or country under consideration in the application) – which may include patients and their representatives or carers, as well as clinicians and study personnel – in rating or ranking a series of statements across several rounds of iteration until a consensus is reached. For patients and their carers, participation in such a study presents a meaningful opportunity to have their voices and opinions heard on an equal footing with researchers and healthcare experts, and affords greater weight to the priorities most important to those living with a disease in the design of a clinical trial. In the case of osteosarcoma, where patient numbers are small and treatment options remain limited, patient and carer perspectives are particularly valuable in shaping decisions, ranging from what constitutes an acceptable burden of treatment to how trial eligibility criteria should reflect real-world experience.

The need for regulatory flexibility in consideration of novel clinical trial design

In recent years, modest progress has been made in other rare disease settings by regulatory agencies practicing flexibility for clinical trials. In oncology alone, between 2002 and 2021, 176 new therapies were approved by the FDA based on single-arm trials, 116 of which were granted accelerated approval¹². Less than 10% of these therapies were removed from the market after approval, suggesting single-arm trials and regulatory flexibility in assessing evidence largely improves patient access to effective drugs earlier than would otherwise be possible.

However, despite these displays of flexibility and success, we are arguably no closer to delivering approved therapies that measaurably improve survival or QOL for patients with recurrent osteosarcoma. Clinical trials in rare diseases, particularly with paediatric populations, should not be treated with the same rules and regulations as other trials with large populations and diseases that manifest in adults. As we develop new therapies such as immunotherapies and gene therapies that don’t fit within regulatory bodies’ known traditional criteria for non-rare diseases, the ways in which these drugs are assessed will change, thus demonstrating the agencies’ ability to exercise even greater flexibility such as reliance upon real world data, surrogate endpoints and/or biomarkers for novel gene therapies, and paediatric extrapolation.

In many cancers, potential therapies are tested in animal models to prove initial safety and efficacy, as well as gaining a greater understanding of the molecular mechanisms underlying disease pathogenicity. For osteosarcoma, the best available model is canines, who develop osteosarcoma at a much higher rate than humans along with a similar disease phenotype in a shorter timeframe. This means comparative oncology studies can be completed much faster with a greater number of study subjects, and when utilised alongside human clinical trial data of surrogate endpoints could support quicker regulatory approval. Additionally, canine osteosarcoma could be used to identify novel biomarkers that translate to humans, which the FDA has highlighted as a promising future avenue for accelerated review⁷.

Mechanisms including Accelerated Approval and Conditional Marketing Authorisations (CMAs) – and their regional equivalents – are systems already in place to allow therapeutics showing promise in early clinical trials to be allowed wider distribution whilst post approval confirmatory trials are ongoing, thus allowing clinical unmet needs to be addressed¹⁷.  Unfortunately, legislative initiatives in the US including RACE, Pediatric Research Equity Act (PREA), Best Pharmaceuticals for Children Act (BPCA) and the Rare Pediatric Disease Review have had only modest success. Few cancer drug approvals in paediatric cancers from 2012 to 2021 can be attributable to these legislative initiatives¹⁸. That said, the FDA’s Accelerated Approval Program first established in December 1992 through December 2021 has been shown that over 50% of accelerated approvals converted to traditional approvals within an average of 3.2 years. However, in recurrent osteosarcoma, in which no new therapies have been approved in over 40 years and survival rates remain far too low, the offer of a potential novel therapy with strong preliminary evidence of safety and efficacy remains a priority goal and a critical unmet need which could be a lifeline to many.

As such, there is a misalignment between the drivers of patient need and government policy aspirations, compared to the operational and regulatory reality of clinical development in rare diseases. And perhaps nowhere else is this disappointing status quo more severe than in paediatric osteosarcoma.

Conclusion

In the face of continued challenges of the US regulatory environment, in which the FDA administration leadership and it’s staffing have undergone significant shifts specifically over the last 18 months, drug manufacturers are left facing an uncertain drug approval landscape where innovation is met with ongoing regulatory process and communication inconsistencies. The lack of current treatment options for osteosarcoma leaves patients feeling unheard and unhopeful of a future in which their disease does not define their QOL or their life expectancy. Clearly, the current failing clinical trial landscape in osteosarcoma and other rare diseases warrants discussion and exploration of the ways in which regulatory authorities and clinical trials sponsors can adapt and evolve from long-standing rigid systems to adequately answer patient need. In order to progress from this therapeutic standstill, not only do clinical trial sponsors need to adapt their designs to effectively measure therapeutic efficacy both from a disease and patient outcome standpoint, but regulatory agencies must utilize their ability to exercise flexibility specifically within the rare disease and paediatric population setting. In these cases, ‘perfect’ clinical trial design simply isn’t possible, and population characteristics as well as patient values must be incorporated into the ways in which clinical trials are evaluated. The use of biomarkers and surrogate endpoints, historical control data in single-arm trials and accelerated approval programmes will need to be utilised if we can hope to address even a fraction of the unmet need to patients with osteosarcoma and other rare diseases.

References

1. The Orphan Drug Act of 1983. 97–414. 1983.
2. REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 1999 on orphan medicinal products. 141/2000. 1999.
3. PEDIATRIC RARE DISEASE CLINICAL TRIALS: MEDPACE CLINICAL RESEARCH EXPERTS SHARE STRATEGIES FOR SUCCESS [Article] [Internet]. 2023. Available from: https://www.medpace.com/wp-content/uploads/2023/03/Article-Pediactric-Rare-Disease.pdf
4. Liu ITT, Kesselheim AS. The RACE Act and Pediatric Trials of Adult Cancer Drugs. Pediatrics. 2024 Oct 1;154(4):e2024066920.
5. CDER/CBER Rare Disease Evidence Principles (RDEP) [Internet]. 2025. Available from: https://www.fda.gov/industry/fda-rare-disease-innovation-hub/cdercber-rare-disease-evidence-principles-rdep
6. Sebio A, Berger C, Tabone MD, et al. Quality of Life and Patient-Reported Outcomes in Patients With Osteosarcoma: A Systematic Review. Eur J Cancer Care (Engl). 2025 Jan 1;2025(1):5802523.
7. Wessel KM, Janeway KA, Davis LE, et al. Considerations for Clinical Trial Design in Relapsed and Refractory Osteosarcoma: An FDA Symposium. Clin Cancer Res. 2026 Mar 2;32(5):831–4.
8. Delgado A, Guddati AK. Clinical endpoints in oncology – a primer. Am J Cancer Res. 2021;11(4):1121–31.
9. Gyawali B, Hey SP, Kesselheim AS. Evaluating the evidence behind the surrogate measures included in the FDA’s table of surrogate endpoints as supporting approval of cancer drugs. EClinicalMedicine. 2020 Apr;21:100332.
10. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228–47.
11. Tregear M, Visco F. Outcomes that matter to patients with cancer: living longer and living better. eClinicalMedicine. 2024 Oct;76:102833.
12. Agrawal S, Arora S, Amiri-Kordestani L, et al. Use of Single-Arm Trials for US Food and Drug Administration Drug Approval in Oncology, 2002-2021. JAMA Oncol. 2023 Feb 1;9(2):266.
13. Van Ewijk R, Cleirec M, Herold N, et al. A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design? Cancer Treat Rev. 2023 Nov;120:102625.
14. Gazouli I, Kyriazoglou A, Kotsantis I, et al. Systematic Review of Recurrent Osteosarcoma Systemic Therapy. Cancers. 2021;13(8).
15. Davis LE, Bolejack V, Ryan CW, et al. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol. 2019 Jun 1;37(16):1424–31.
16. Bhattasali O, Vo AT, Roth M, et al. Variability in the reported management of pulmonary metastases in osteosarcoma. Cancer Med. 2015 Apr;4(4):523–31.
17. Cox EM, Edmund AV, Kratz E, et al. Regulatory Affairs 101: Introduction to Expedited Regulatory Pathways. Clin Transl Sci. 2020 May;13(3):451–61.
18. Zettler ME. A decade of FDA approvals for pediatric cancer indications: What have we learned? EJC Paediatr Oncol. 2023;1:100005.

About the author

Biolacuna’s Dr Katy Walsh supported by other Biolacuna team members led the development of this manuscript for and on behalf of OS Therapies, a developer of novel therapeutics for the treatment of osteosarcoma. Biolacuna is a global life sciences advisory firm supporting companies in translating innovations into creative solutions.

The post Novel regulatory science considerations in osteosarcoma: the imperative for regulatory flexibility to meet critical unmet patient and clinical needs appeared first on Drug Discovery World (DDW).