Comment from Taizo Nakano

To Whom It May Concern: I am writing in support of the Haystack Project’s Petition for Rulemaking regarding FDA’s framework for evaluating whether clinical investigations in rare and ultra-rare diseases constitute adequate and well-controlled studies. I submit this comment as a clinician and researcher specializing in vascular anomalies, a field that illustrates many of the scientific and practical challenges described in the petition. Vascular anomalies comprise a heterogeneous group of rare disorders involving abnormal development of blood vessels, lymphatic vessels, and associated tissues, including venous malformations, lymphatic malformations, arteriovenous malformations, and complex overgrowth syndromes. Although individually rare, these conditions collectively impose substantial morbidity across pediatric and adult populations. Patients with vascular anomalies frequently experience chronic pain, bleeding, thrombosis, swelling, disfigurement, recurrent infection, functional impairment, and progressive organ dysfunction. For many patients, disease progression results in irreversible morbidity, repeated procedures, and substantial psychosocial burden. Despite significant advances in disease biology and targeted therapeutics, there remains a substantial unmet need for effective medical therapies. Drug development in vascular anomalies presents challenges that are not well addressed by conventional development paradigms designed for common diseases. Patient populations are small and highly fragmented across phenotype, genotype, lesion location, disease severity, and progression rate. Even within a single diagnostic category, patients may differ substantially in clinical course and treatment response. This heterogeneity creates challenges not only for patient recruitment but also for endpoint selection and interpretation of treatment effect. In vascular anomalies, meaningful clinical benefit is often multidimensional and specific to each individual patient. Reduction in lesion size or imaging changes may be informative but may not fully reflect treatment outcomes that matter most to patients and clinicians. Clinically meaningful benefit may instead be reflected by reduced pain, fewer bleeding episodes, improved mobility, improved function, reduced need for invasive procedures, or improved quality of life, depending on how the disease presents and manifests for each patient. Importantly, in many vascular anomalies, treatment benefit may be best reflected not by measurable lesion regression but by stabilization of disease or prevention of further progression. For patients with infiltrative or progressive lesions, halting growth, reducing symptom worsening, or preventing irreversible complications may represent substantial clinical benefit even in the absence of radiographic improvement. Thus, there remains a need to identify and adopt an alternative approach to capturing meaningful outcomes in a patient population for whom a one-size-fits-all approach may not be appropriate. These disease characteristics complicate the application of conventional randomized controlled trial designs and traditional endpoint expectations. Randomized controlled trials remain highly valuable where feasible and scientifically appropriate. However, in certain vascular anomaly populations, alternative study designs (including externally controlled studies, intra-patient comparisons, adaptive designs, or analyses informed by robust natural history data) may be warranted to produce a sufficient degree of meaningful evidence of treatment effect. I write to you do convey my support for the Haystack Project’s central position that the determination of whether an investigation is adequate and well-controlled should be grounded in disease-specific scientific context rather than default methodological assumptions and frameworks. I do not interpret the petition as advocating for reduced evidentiary standards or diminished scientific rigor. Rather, I understand the petition to request greater clarity regarding how FDA applies existing statutory and regulatory flexibility in settings where conventional trial paradigms may not be feasible or scientifically optimal. For these reasons, I respectfully support the Haystack Project’s petition and urge FDA to consider rulemaking that provides a clearer, more transparent framework for evaluating substantial evidence in rare and ultra-rare diseases. Sincerely, Taizo A. Nakano, MD | Professor of Pediatrics Taru Hays, MD, Endowed Chair in Pediatric Hematology | Medical Director, Vascular Anomalies Center Clinical Lead, Bone Marrow Failure Program | Program Director, Hays Clinical Hematology Fellowship Center for Cancer and Blood Disorders | Children’s Hospital Colorado | University of Colorado School of Medicine