Table 3 FDA feedback on submissions and RWD reported in FDA labels
Therapy– Generic (US Brand name) | Approved Indication | NDA/BLAs’ Primary Clinical Studiesa | RWD Study Design | FDA Feedback on RWD | RWD reported in FDA Label Claim (Y/N) |
|---|---|---|---|---|---|
Elivaldogene autotemcel (Skysona) [20] | Early cerebral adrenoleukodystrophy (CALD) | 1 nonrandomized, open label, single arm study | Natural History | - Overall population not comparable to trial population - Potential selection bias and missing data - Potentially subjective elements of definitions | ✓ |
Vutrisiran (Amvuttra) [21] | Polyneuropathy (PN) of hereditary transthyretin mediated (hATTR) amyloidosis in adults | 1 open label RCT with external placebo control (RWD) | External Placebo Control | - Notable differences in baseline pt. characteristics and disease severity compared to trial - Large effect size was sufficient to overcome potential biases and support efficacy outcomes | ✓ |
Vosoritide (Voxzogo) [22] | Increase in linear growth in children with achondroplasia ages 5 and older with open epiphyses | 3 clinical studies: 1 RCT; 1 open label, single arm; 1 long-term efficacy/safety | Natural History | - Limited data on genetic diagnosis, medical history, medications; but unlikely to skew results in favor of vosoritide - Measurement errors were not expected to have a significant impact on analyses | ✗ |
Allogeneic processed thymus tissue- agdc (Rethymic) [23] | Immune reconstitution in pediatric patients with congenital athymia | Efficacy data derived from 7 open label, non-randomized studies | Natural History | - Missing information on phenotypes, underlying genetic defects, co-morbidities, supportive care - Consistent large survival effects, with a favorable benefit risk profile in patients | ✓ |
Fosdenopterin (Nulibry) [24] | Molybdenum cofactor deficiency (MoCD) type A | 2 open label, single arm studies | Natural History | - Potential for selection bias was adequately overcome; Detection bias didn’t impact observed survival benefit | ✓ |
Lonafarnib (Zokinvy) [26] | Hutchinson-Gilford progeria syndrome (HGPS) and processing deficient progeroid laminopathies (PL) | 2 open label, single arm studies | Registry-based natural history | - Differences in number of patients among cohorts; Treated cohort had a substantially higher censoring rate over time than the matched untreated cohorts - Missing data on concomitant cardiovascular medications in control arm | ✓ |
Viltolarsen (Viltepso) [27] | Duchenne muscular dystrophy | 1 double blind, placebo and NH controlled study | Natural History | - Heterogeneity of the disease, patient characteristics, care - Imprecision of population matching due to lack of control of all known and unknown biases | ✗ |
Risdiplam (Evrysdi) [28] | Spinal muscular atrophy | 2 studies: 1 RCT, 1 open label, single arm study | Natural History | - Considers the external natural history control as sufficient - NH of spinal muscular atrophy is well understood | ✓ |
Triheptanoin (Dojolvi) [29] | A source of calories and fatty acids in the treatment of long-chain fatty acid oxidation disorders (LC-FAOD) | 3 studies: 1 randomized parallel design; 2 open label, single arm studies | Medical Chart Review | - Heterogeneity in disease severity, dietary management, data collection of lab and major clinical events, - Dietary details missing for many patients, prior treatment history not properly collected or accounted for in analysis | ✗ |
Pretomanid Tablet (Pretomanid) [30] | Pulmonary extensively drug-resistant (XDR) and treatment-intolerant/nonresponsive (TI/NR) multidrug-resistant (MDR) tuberculosis in adults | 1 single arm study | Historical Control | - Trial patients had much greater rates of treatment success and lower mortality rates compared to historical control | ✓b |
Onasemnogene abeparvovec-xioi (Zolgensma) [32] | Spinal muscular atrophy (SMA) | 1 open label, single arm study | Natural History | - NH results indicated that the expected treatment effect is large, readily ascertained, and shows close temporal association with the intervention | ✓ |
Triclabendazole (Egaten) [33] | Fascioliasis | 2 open label, randomized studies | Historical Control | - Large treatment effect was observed comparing with the historical control | ✗ |
Stiripentol (Diacomit) [34] | Dravet syndrome | 2 placebo-controlled RCTs | Medical Chart Review | - Methods are not powered to detect significant effects | ✗ |
Fish oil triglycerides inj. Emulsion (Omegaven) [36] | Parenteral nutrition-associated cholestasis (PNAC) | 2 open label studies | Natural History | - Covariate measurement errors, unmet model assumptions, biases in endpoint estimates | ✓ |
Burosumab (Crysvita) [37] | X-linked hypophosphatemia (XLH) | 2 open label studies | Natural History | - NH study and trial results provide support for the effectiveness of burosumab therapy | ✗ |
Voretigene neparvovec (Luxturna) [38] | Biallelic RPE65 mutation-associated retinal dystrophy | 1 open label RCT with cross over design | Medical Chart Review | - Chart review contextualized natural history of retinal dystrophy including many mutations and a variety of clinical diagnoses | ✗ |
Emicizumab-kxwh (Hemlibra) [40] | Hemophilia A (congenital factor VIII deficiency) | 2 studies: 1 randomized, open label with 2 non- randomized arms; 1 open label, single arm study | External Control | - Superiority over other products has not been proven, and results should be interpreted with caution - Note: RWD was used only for contextualization | ✗ |
Vestronidase alfa-vjbk (Mepsevii) [41] | Mucopolysaccharidosis type 7 (MPS VII) | 1 placebo controlled RCT | Medical Chart Review | - No clinical examinations were completed, and degree of cognitive disability appeared to be underestimated in non-interventional studies, which could impact endpoint selection, completion, and interpretation | ✗ |
Cerliponase alfa (Brineura) [42] | Neuronal ceroid lipofuscinosis type 2 (CLN2) | 1 open label, single arm study | Registry-based natural history | - Differences in patient characteristics and clinician-reported outcomes used to compare disease progression in both arms | ✓ |
Thiotepa (Tepadina) [43] | Class 3 β-thalassemia | 1 retrospective, observational, study for efficacy assessment | Historical Control | - Patient demographics were generally similar at baseline, except for history of splenectomy - Justifiable study design as an RCT could not be blinded and enrolment would be impractical due to rareness of the disease | ✓ |