Real-world evidence used in four CDER approvals

FDA Use of Real-World Evidence in Regulatory Decision Making

Abbreviations

510(k) - 510(k) premarket notification

ACE - Angiotensin-converting enzyme

AEMS – Adverse Event Monitoring System

ARB - Angiotensin receptor blocker

BLA - Biologics License Application

CBER - Center for Biologics Evaluation and Research

CDER - Center for Drug Evaluation and Research

CDRH - Center for Devices and Radiological Health

CMS - Center for Medicare and Medicaid Services

DSC - Drug Safety Communication

EHR- Electronic health records

EMR - Electronic medical records

ESA - Erythropoietin stimulating agent

GBCA - Gadolinium-based contrast agent

GLP-1 RA - Glucagon-like peptide-1 receptor agonists

HCTZ - Hydrochlorothiazide

HDE - Humanitarian device exemption

IAA - Inter-Agency Agreement

IDE - Investigational Device Exemption

MACE - Major adverse cardiac event

NDA - New Drug Application

OSE - Office of Surveillance and Epidemiology

OUS - Outside the U.S.

PLLR - Pregnancy and Lactation Labeling Rule

PMA - Premarket approval application

PPI - Proton pump inhibitor

REMS - Risk Evaluation and Mitigation Strategy

RWD - Real-World Data

RWE - Real-World Evidence

SEE – Substantial Evidence of Effectiveness

U.S. - United States

VHA - Veterans Health Administration

VTE - Venous thromboembolism

Product Name & Number Sponsor/Applicant Data Source(s) Data Source Description(s) Study Design(s) Summary of RWE use and/or Regulatory Action Type / Date of Regulatory Action(s) and/or Other Action(s)

Acetadote (acetylcysteine) NDA 021539 Cumberland Medical Records Three clinical centers in Denmark Cohort RWE contributed to SEE.

A retrospective cohort study using medical chart review (DIVAS) was conducted in clinical centers in Denmark and used to support a dosing regimen change for Acetadote when randomized controlled trials were deemed unethical and impractical. This study compared the efficacy and safety of a two-bag dosing regimen to a three-bag dosing regimen.

The study was positioned as one part of a comprehensive evidence package that also included RWE from other observational studies reported in medical literature. The package as a whole demonstrated similar effectiveness and fewer non-allergic anaphylactoid reactions in patients treated with a modern two-bag regimen instead of a historical three-bag regimen.

Labeling Approval of an efficacy supplement to change dosing regimen: 11/26/2024

Onapgo (apomorphine) NDA 214056 MDD US Operations Medical Records Multiple including: UK Pathfinder database, French neurology clinic, Spanish hospital, and Dutch pharmacy database Descriptive Study RWE contributed additional safety data.

A study using medical record and pharmacy data from four European sources (UK Pathfinder database, a French neurology clinic, a Spanish hospital, and a Dutch pharmacy database) described safety outcomes in patients with advanced Parkinson's disease treated chronically (≥365 days) with high-dose continuous subcutaneous apomorphine infusion (≥6mg/hr or ≥100 mg/day).

This data was intended to supplement the clinical development program's limited high-dose, long-term safety database by providing patient-level data from approximately 50 subjects treated at or above the maximum recommended dose for at least 12 months.

The data showed no serious adverse events were documented in an analyzed population that included 63 patients from the RWD sources in addition to 11 patients from clinical trials.It was deemed safety data necessary for NDA approval and was considered along with other evidence to support proposed dosing. Nevertheless, FDA determined that significant limitations in the adverse event data made it unsuitable for inclusion in product labeling.

Labeling Additional safety data to support approval of a new formulation: 2/3/2025

Isturisa (osilodrostat) NDA 212801 Recordati Medical Records Participating clinical centers in France Cohort RWE contributed to confirmatory evidence.

The LINC7 study was a retrospective cohort study conducted in France to evaluate the safety and effectiveness of Osilodrostat for the Treatment of Non-Cushing's Disease Cushing's Syndrome. As its primary outcome, the study assessed the proportion of patients achieving mean urinary free cortisol ≤ upper limit of normal (ULN) at Week 12.

FDA approved the expanded indication from Cushing's disease (pituitary driven) to all Cushing's syndrome subtypes (regardless of etiology) based on substantial evidence from the original adequate and well-controlled trial (C2301). LINC7 contributed to the evidence package as confirmatory evidence.

FDA accepted as confirmatory evidence (a) shared disease pathophysiology across all Cushing's syndrome subtypes, (b) mechanistic reasoning that osilodrostat's cortisol synthesis inhibition should be effective regardless of the underlying cause of hypercortisolism, (c) real-world evidence from LINC7, and (d) evidence from a small single-arm trial in Japanese patients with Cushing's syndrome not due to pituitary adenoma.

Labeling Approval of an efficacy supplement for a new indication: 4/15/2025

Gamifant (emapalumab-lzsg) BLA 761107 Swedish Orphan Biovitrum Medical Records Medical chart data from nine centers in North America and Europe Externally Controlled Trial RWE contributed to SEE.

In two single-arm open-label studies designed to assess efficacy of Gamifant, the primary analysis achieved marginal statistical significance (p=0.056) with the pre-specified efficacy threshold of 40% complete response rate. FDA, therefore, recommended the Applicant identify a control to interpret the treatment effect of emapalumab in subjects with macrophage activation syndrome (MAS)/ hemophagocytic lymphohistiocytosis (HLH) who had an inadequate response or intolerance to glucocorticoids.

To address this, the sponsor conducted a retrospective cohort study (AMETHYST) utilizing data obtained entirely from medical chart abstraction from nine centers in North America and Europe, between January 2012 and September 2022. The study evaluated treatment patterns and outcomes of MAS episodes in adult and pediatric patients with Still's disease refractory to high dose glucocorticoids.

A Joint Analysis compared an external control group of patients from AMETHYST with pooled data from 39 patients in the two single-arm studies treated with emapalumab.

Despite some limitations, FDA considered the populations sufficiently comparable and found the external control informative as the response rates aligned with the expected natural history of the disease in which patients, refractory to corticosteroids, would be unlikely to achieve a complete response. The results from the joint analysis compared to the interventional studies were relevant and sufficient to conclude that emapalumab will have the intended treatment effect in this population thereby providing substantial evidence of effectiveness along with confirmatory evidence from a closely related indication, primary hemophagocytic lymphohistiocytosis (pHLH).

Labeling Approval of an efficacy supplement for a new Indication: 6/27/2025

Kygevvi (doxecitine and doxribtimine) NDA 219792 UCB, Inc Multiple Medical Records and expanded access data - Clinical sites in the US and Europe Multiple RWE contributed to SEE.

A single adequate and well-conrolled clinical investigation (AWCI) and confirmatory evidence were used to demonstrate SEE for doxecitine and doxribtimine in patients with thymidine kinase 2 deficiency (TK2d).

The single AWCI was an integrated effectiveness assessment using pooled data on treated patients from a single arm trial, two retrospective medical chart review studies and an expanded access program. Information on untreated subjects came from medical literature and one retrospective chart review study. Matching was based on age of symptom onset group (≤2, >2 to ≤12, or >12 in years)

To evaluate the effectiveness of doxecitine and doxribtimine, overall survival was assessed in 78 treated subjects with TK2d symptom onset ≤12 years of age who received either to be marketed doxecitine and doxribtimine or chemical grade combination of doxecitine and doxribtimine. Their survival data were compared with survival data of 78 matched untreated subjects.

Approval package NME Approval: 11/3/2025

Aurlumyn® (Iloprost) NDA 217933 Eicos Sciences Medical Records Medical records Cohort A multicenter retrospective cohort study of frostbite patients with a historical control that used data from medical records and that was published in the literature in July 2022 was used as confirmatory evidence.

Labeling (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217933s000lbl.pdf) 02/13/2024

Vimpat® (Lacosamide) NDA 022253 UCB Medical Records Medical Records Cohort The agency was able to extrapolate efficacy for the treatment of partial onset seizures (in patients aged ≥ 1 month < 17 years) and primary generalized tonic–clonic seizures (in patients aged ≥ 4 years to < 17 years) from existing data, but additional safety data were needed to support the new proposed loading dose regimen.

Labeling 04/28/2023

Actemra (Tocilizumab) BLA 125276 Genentech Registry Registry Randomized Controlled Trial The approval was based, in part, on a randomized controlled clinical trial that leveraged RWD collected from national death records to evaluate 28-day mortality, the trial's primary endpoint.

Labeling 12/21/2022

Vijoice® (Alpelisib) NDA 215039 Novartis Registry Medical Records Cohort The approval was based on a single-arm study of data from patients who were treated through an expanded access program. Medical record data were derived from seven sites across five countries.

Labeling 04/05/2022

Orencia® (Abatacept) BLA 125118 Bristol Meyers Squibb Registry Registry Cohort The approval was based on a traditional randomized clinical trial in patients with a matched unrelated donor and a non-interventional study in patients with a one allele-mismatched unrelated donor.

Labeling 12/15/2021

Voxzogo® (Vosoritide) NDA 214938 Biomarin Registry Achondroplasia Natural History (AchNH) study, a multicenter registry in the United States Externally Controlled Trial The approval was based on one randomized clinical trial and RWE generated through two single-arm trials with external control groups from RWD comprised of patient-level anthropometric data.

Labeling 11/19/2021

Prograf® (Tacrolimus) NDA 050708 Astellas Pharma INC Registry Disease Registry-Scientific Registry of Transplant Recipients Cohort The approval was in part based on a non-interventional study that evaluated graft failure and death up to one year post transplant in recipients of single-or double-lung transplants enrolled in the Scientific Registry of Transplant Recipients registry (SRTR).

Labeling 07/16/2021

Nulibry® (Fosdenopterin) NDA 214018 Sentynl Therapeutics Medical Records Medical Records Externally Controlled Trial The study that led to the approval included RWD in both the treatment and control arms. Specifically, the treatment arm pooled data from participants in two single-arm trials with data from patients enrolled in an expanded access program.

Labeling 02/26/2021