FDA use of Real-World Evidence in Regulatory Decision Making
The Food and Drug Administration (FDA) has a long history of using real-world data (RWD) and real-world evidence (RWE) to monitor and evaluate the postmarket safety of medical products and is committed to realizing the full potential of fit-for-use RWD to generate RWE that can advance the development of medical products and strengthen their oversight. The studies presented in the accompanying tables exemplify instances in which the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) applied RWE in regulatory decision-making processes since 2011. These include, but are not limited to, product approvals, labeling changes, and assessments that determined no regulatory action was warranted. This compilation forms part of a comprehensive landscape analysis to assess the scope and frequency of RWE use in regulatory determinations across the Agency.
| Drugs and identifiers | Sponsor | Data Source | Study Design | Summary of RWE use or Regulatory Action | Date of Regulatory Action and Labeling |
|---|---|---|---|---|---|
Aurlumyn® (Iloprost) NDA 217933 | Eicos Sciences | Medical records | Retrospective cohort study | Role of study: Confirmatory evidence 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. | February 13,2024 Labeling |
Vimpat® (Lacosamide) NDA 022253 | UCB | Medical records from the PEDSnet data network. | Retrospective cohort study | Role of the study: Safety 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. The applicant was able to leverage safety data from existing clinical use of the new regimen through a cohort study that used medical record data collated by the PEDSnet data network. | April 28, 2023 Labeling |
Actemra (Tocilizumab) BLA 125276 | Genentech | RWD source for primary efficacy endpoint: national death records | Randomized controlled trial | Role of the study: Adequate and well-controlled (AWC) study that generated substantial evidence of effectiveness. 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. | December 21, 2022 Labeling |
Vijoice® (Alpelisib) NDA 215039 | Novartis | Medical Records | Non-interventional study (single arm) | Role of the study: Adequate and well-controlled study that generated substantial evidence of effectiveness. 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. As noted in the review, “since lesions would not be expected to regress in the absence of active therapy, the review team considered the endpoint of radiologic response rate at Week 24 as reasonably likely to predict clinical benefit.” | April 5, 2022 Labeling |
Orencia® (Abatacept) BLA 125118 | Bristol Meyers Squibb | Center for International Blood and Marrow Transplant Research (CIBMTR) registry | Non-interventional study | Role of the study: Pivotal evidence. 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. The outcome assessed in the non-interventional study was overall survival post-transplantation among patients administered treatment with abatacept compared with patients treated without abatacept. The study used data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, an international registry of patients receiving cellular therapies. | December 15, 2021 Labeling |
Voxzogo® (Vosoritide) NDA 214938 | Biomarin | Achondroplasia Natural History (AchNH) study, a multicenter registry in the United States. | Externally controlled trials | Role of Study: Confirmatory evidence. 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 obtained from the Achondroplasia Natural History (AchNH) study, a multicenter registry in the United States. | November 19, 2021 Labeling |
Prograf® (Tacrolimus) NDA 050708 | Astellas Pharma INC | Disease Registry-Scientific Registry of Transplant Recipients | Non-interventional study | Role of the study: AWC study that generated substantial evidence of effectiveness. 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), a source of RWD on organ transplant outcomes in the United States. Clinical outcomes in the treatment arm were compared with the well-documented natural history of lung transplant with no or minimal immunosuppression. Randomized controlled clinical trials in the setting of other solid organ transplants provided confirmatory evidence to support the approval. | July 16, 2021 Labeling |
Nulibry® (Fosdenopterin) NDA 214018 | Sentynl Therapeutics | Medical Records | Single-arm trial with additional treatment data derived from RWD and comparator data derived from RWD. | Role of the study: Adequate and well-controlled (AWC) study that generated substantial evidence of effectiveness. 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. The external control arm included data from a natural history study of patients with confirmed MoCD Type A. Real-world data (RWD) evaluating overall survival, the primary endpoint of the study, was obtained from medical records across 15 countries for both the expanded access population included in the treatment arm and the natural history control arm population. | February 26, 2021 Labeling |
| Drugs and identifiers | Sponsor | Data Source | Study Design | Summary of RWE Use or Regulatory Action | Date of Regulatory Action, Communication or Publication and Links |
|---|---|---|---|---|---|
CLOZARIL (clozapine) NDA 019758 | Heritage Life Sciences (Barbados) c/o Heritage Life Sciences Therapeutics (USA) | Veterans Health Administration (VHA) medical and pharmacy records | Descriptive study | In FDA’s review of the effectiveness of the clozapine REMS, FDA conducted several analyses of clozapine registry patients, describing adherence to absolute neutrophil count monitoring, as specified by the clozapine REMS, and estimating the cumulative risk of severe neutropenia. The study results were included in the November 19 Joint Meeting of the Drug Safety and Risk Management and Psychopharmacologic Drugs Advisory Committee briefing package, where the committee voted to remove the clozapine REMS. Based on the advice from the Advisory Committee and the Agency’s re-evaluation, the Agency removed the clozapine REMS and issued a DSC. | DSC August 27,2025 FDA Drug Safety Communication: FDA removes risk evaluation and mitigation strategy (REMS) program for the antipsychotic drug Clozapine (REMS release, labeling changes) |
Toprol-XL and Lopressor (Metoprolol), Inderal LA (propranolol), [beta blockers] Multiple NDAs | Multiple sponsors | Sentinel System | Retrospective cohort study | The results from a retrospective cohort study in Sentinel indicated an association between beta blocker use and hypoglycemia in pediatric populations. FDA approved safety labeling changes to describe the risk for hypoglycemia in pediatrics or individuals unable to communicate signs of hypoglycemia. This resulted in a labeling change. | Beta Blockers Safety Communications & Labeling Changes (Sentinel Initiative), July. 25, 2025. FDA Labeling Change: Additional Language to Mitigate the Risk of Hypoglycemia Associated with Beta Blockers in Children Beta blockers | Sentinel Initiative |
Entyvio (vedolizumab) BLA 761359 | Takeda Pharmaceuticals | Sentinel System | Descriptive study | The results from a descriptive Sentinel study did not indicate an increased risk for Interstitial lung disease (ILD) in patients treated with vedolizumab or natalizumab for inflammatory bowel disease. However, there were other data from case reports from the medical literature and FDA FAERS. This resulted in FDA adding “interstitial lung disease, pneumonitis” to the Postmarketing Experience subsection of labeling. | Entyvio Safety Communications & Labeling Changes (Sentinel Initiative), April 18, 2024. FDA Labeling Change: Vedolizumab & Interstitial Lung Disease (ILD) |
Prolia (Denosumab) BLA 125320 | Amgen | Medicare claims data | Retrospective cohort study | In FDA’s review of denosumab, an FDA retrospective cohort study in Medicare found an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking this medication. This resulted in a DSC and addition of a Boxed Warning for an increased risk of severe hypocalcemia in patients with advanced chronic kidney disease. | FDA added a boxed warning. DSC, January 19, 2024 (severe hypocalcemia). FDA Drug Safety Communication: FDA adds Boxed Warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine Prolia (denosumab) Prolia label change, November 22, 2022. FDA Drug Safety Communication: FDA investigating risk of severe hypocalcemia in patients on dialysis receiving osteoporosis medicine Prolia |
Anticoagulant, oral Multiple NDAs | Multiple sponsors | Sentinel System | Retrospective cohort study | FDA conducted a retrospective cohort study in the Sentinel System to examine severe uterine bleeding events requiring medical intervention in women treated with oral anticoagulants. The study found a risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions. This finding contributed to a class-wide label change for this risk with oral anticoagulants and that this should be assessed in females of reproductive potential and those with abnormal uterine bleeding. There was also a communication via the Sentinel initiative website. | Oral Anticoagulants Safety Communications & Labeling Changes (Sentinel Initiative), January. 28, 2021. FDA Labeling Change: Oral Anticoagulants and Clinically Significant Uterine Bleeding |
Methotrexate, oral Multiple NDAs | Multiple sponsors | Sentinel System | A chart confirmed analysis was conducted in one Sentinel Data Partner | An FDA medical chart review analysis conducted in a Sentinel Data Partner, found the incidence of low-dose oral methotrexate wrong frequency dosing errors to be 0.4%. This resulted in adding the risk of improper dosing to Section 5 (Warnings and Precautions), removing an option for doses given every 12 hours for 3 days each week from Section 2 (Dosage and Administration). | Oral Methotrexate (Sentinel Initiative), December. 17, 2021. FDA Labeling Change: Oral Methotrexate and Wrong Frequency Dosing Errors |
Singulair (montelukast) NDA 021409 | Organon | Sentinel System | Retrospective cohort study | Retrospective cohort studies conducted in the Sentinel system informed the re-evaluation of the benefits and risks of montelukast use. Considering the totality of evidence, including the negative Sentinel studies resulted in FDA strengthening existing warnings about serious behavior and mood-related changes with montelukast (Singulair and generics). There was also a communication via the Sentinel initiative website. | Singulair Safety Communications & Labeling Changes (Sentinel Initiative), March. 3, 2020. FDA Requires Boxed Warning about Serious Mental Health Side Effects for Asthma and Allergy Drug Montelukast (Singulair); Advises Restricting Use for Allergic Rhinitis |
Hydrochlorothiazide (HCTZ)-containing products Multiple NDAs | Multiple sponsors | Sentinel System | Retrospective cohort study | An FDA conducted retrospective cohort study in the Sentinel System assessed the risk of non-melanoma skin cancer for patients treated with HCTZ-containing products. The study identified an association with an increased risk of non-melanoma skin cancer, predominantly for squamous cell carcinoma and in white patients taking large cumulative doses. These findings informed additions to adverse reactions and patient information sections of the labeling, and a communication via the Sentinel initiative website. | HCTZ Safety Communications & Labeling Changes (Sentinel Initiative), August. 20, 2020. FDA Labeling Change: Hydrochlorothiazide and Non-Melanoma Skin Cancer |
Feraheme, infed, injectafer, monoferric, venofer (Parenteral Iron Products) Multiple NDAs | Multiple sponsors | Sentinel System | Descriptive study | An FDA Sentinel analysis characterized the frequency of IV iron utilization relative to live birth and stillbirth deliveries. The finding contributed to a class-wide labeling update for parenteral iron products to add new safety information to Section 8 (Use in Specific Populations, Pregnancy) of the label. This update describes the risk of severe adverse reactions to pregnant women and their fetus. There was also a communication via the Sentinel initiative website. | Parenteral Iron Safety Communications & Labeling Changes (Sentinel Initiative) The class-wide labeling update regarding risks to pregnant women and their fetus was approved on September. 11, 2020. FDA Labeling Change: Parenteral Iron Products and Risk of Severe Adverse Reactions to Pregnant Women and their Fetuses |
Comtan, Stalevo (Entacapone) NDA 021485/ 20796 | Orion Corporation | VHA claims, medical records, and cancer registry | Retrospective cohort study | In FDA’s review of entacapone, an FDA conducted retrospective cohort study in the VA found no clear evidence of an increased risk of prostate cancer in patients treated with entacapone versus add-on dopamine agonist or monoamine oxidase inhibitor. This resulted in a DSC. | Entacapone DSC, August 13, 2019 (no increase in prostate cancer risk). FDA Drug Safety Communication: FDA review finds no increased risk of prostate cancer with Parkinson's disease medicines containing entacapone (Comtan, Stalevo) |
Pradaxa (dabigatran) NDA 022512 | Boehringer Ingelheim Pharmaceuticals, Inc | Medicare claims data | Retrospective cohort study | In FDA’s review of dabigatran, an FDA conducted retrospective cohort study among Medicare patients, showed lower risks stroke and death but higher risk for gastrointestinal bleeding with PRADAXA compared to warfarin. FDA still considered Pradaxa to have a favorable benefit/risk profile and made no changes to the labeling. This resulted in a DSC. | Dabigatran Drug Safety Communication, May 13, 2014 FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin |
Enbrel (etanercept) BLA 103795 | Amgen Inc. | Sentinel System | Descriptive study | FDA conducted a drug utilization analysis of TNF alpha inhibitors in pregnant women in the Sentinel System. The study found that among pregnant women with a chronic inflammatory condition, there was a preference to use etanercept compared to other TNF alpha inhibitors. This assessment was one source of evidence considered for the Pregnancy and Lactation Labeling Rule (PLLR) Conversion Safety Labeling Change. There was also a communication via the Sentinel initiative website. | ENBREL Safety Communications & Labeling Changes (Sentinel Initiative), July. 11, 2017. FDA Labeling Change: Etanercept (Enbrel) and Use in Pregnancy |
Gadolinium-based contrast agents (GBCA) Multiple NDAs | Multiple sponsors | Sentinel System | Descriptive study | Analyses on gadolinium retention were done with FDA Sentinel data and other data streams. These analyses, in part, resulted in class-wide updates to Section 5 (Warnings and Precautions) to include the risk of gadolinium retention in tissues, including the brain, for months to years, a medication guide, required manufacturers to conduct additional safety assessments. There was also a communication via the Sentinel initiative website. | GBCAs Safety Communications & Labeling Changes (Sentinel Initiative), December. 19, 2017. FDA Warns that Gadolinium-Based Contrast Agents (GBCAs) are Retained in the Body; Requires New Class Warnings |
Comtan, Stalevo (entacapone) NDA 021485/ 20796 | Orion Corporation | Medicare claims data | Retrospective cohort study | FDA conducted a retrospective cohort study in Medicare to assess cardiovascular risk associated with entacapone use. FDA found no clear evidence of increased cardiovascular risk with entacapone. The study resulted in a publication and DSC. | Entacapone DSC, October 26, 2015. FDA Drug Safety Communication: FDA review found no increased cardiovascular risks with Parkinson’s disease drug entacapone Movement Disorder Society Publication, 2013. |
Benicar (olmesartan) NDA 021286 | Daiichi Sankyo | Medicare claims data | Retrospective cohort study | In FDA’s review of Olmesartan, an FDA conducted retrospective cohort study in Medicare found no clear evidence of increased cardiovascular risks associated with high dose use in diabetic patients. As a result, FDA’s recommendations for use of olmesartan (BENICAR, BENICAR HCT, AZOR, TRIBENZOR, and generics) in patients with diabetes remained the same. This resulted in a DSC and the addition of the study information in the labeling. | Olmesartan DSC, June 24, 2014 (Medicare study results added to labeling). FDA Drug Safety Communication: FDA review of cardiovascular risks for diabetics taking hypertension drug olmesartan not conclusive; label updates required |
Benicar, Benicar hct (Olmesartan), Azor, Tribenzor (medoxomil) Multiple NDAs | Daiichi Sankyo Inc. | Mini-Sentinel and Medicare | Retrospective cohort study | In FDA’s review of Olmesartan, an FDA evaluation of the FDA Adverse Event Reporting System (FAERS) and the published literature found evidence of an association between olmesartan and sprue-like enteropathy. To evaluate an ARB class association FDA conducted a retrospective cohort study in Mini-Sentinel and Medicare. These study results did not support a class effect. This resulted in an FDA safety communication that Olmesartan-containing products can cause intestinal problems known as sprue-like enteropathy. | Olmesartan Safety Communications & Labeling Changes (Sentinel Initiative), July. 3, 2013. FDA Approves Labeling Changes to Include Intestinal Problems (Sprue-Like Enteropathy) Linked to Blood Pressure Medicine Olmesartan Medoxomil |
Pradaxa (dabigatran) NDA 022512 | Boehringer Ingelheim Pharmaceuticals, Inc | Mini-Sentinel | Retrospective cohort study | In 2012, an FDA conducted retrospective cohort study in Mini-Sentinel evaluated new information about the risk of serious bleeding associated with use of dabigatran (PRADAXA) and warfarin (COUMADIN, JANTOVEN, and generics). The results indicated that bleeding rates associated with new use of Pradaxa did not appear to be higher than bleeding rates associated with new use of warfarin, which was consistent with observations from the large clinical trial used to approve Pradaxa. FDA issued a DSC to communicate the findings and a communication via the Sentinel initiative website. | DSC November, 02,2012 FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) Sentinel Initiative, October. 31, 2012. Update on the Risk for Serious Bleeding Events with the Anticoagulant Pradaxa (Dabigatran) |
Epogen, Procrit, Aranesp (Erythropoietin stimulating agents (ESA)) BLA 103234 and BLA 103951 | Amgen | Medicare claims data | Retrospective cohort study | In FDA’s review of the effects of a labeling change recommending lower doses of ESAs in dialysis patients, an FDA retrospective cohort study in Medicare which assessed the effects of the changes in reimbursement policy in addition to changes in the ESA’s drug labeling found that the risk of MACE and mortality was unchanged, and risk of stroke was reduced following the labeling change. In Black patients, there was a substantial reduction in MACE and mortality after the labeling change. A bundled comprehensive payment system for dialysis that includes the costs of ESAs, and a revised drug label that recommends more conservative dosing had no adverse effects on older dialysis patients covered by fee-for-service Medicare. This resulted in a publication. | The labeling change regarding use in patients with chronic kidney disease (CKD) was approved on June 24,2011 JAMA Publication, 2016. |
Avandia (rosiglitazone) NDA 021071 | GlaxoSmithKline | Medicare claims data | Retrospective cohort study | FDA conducted a retrospective cohort study in Medicare that evaluated the risk of heart attacks in patients taking rosiglitazone. The study resulted in labeling changes and an update to the Risk Evaluation and Mitigation Strategy (REMS) to include a restricted access and distribution program for all three rosiglitazone products. This also resulted in two Drug Safety Communications (DSC). | Rosiglitazone DSC, May 18, 2011 (imposition of REMS for rosiglitazone use). FDA Drug Safety Communication: Updated Risk Evaluation and Mitigation Strategy (REMS) to Restrict Access to Rosiglitazone-containing Medicines including Avandia, Avandamet, and Avandaryl Rosiglitazone DSC and labeling change, February 3, 2011 (Medicare results added to label). FDA Drug Safety Communication: Avandia (rosiglitazone) labeling now contains updated information about cardiovascular risks and use in certain patients |
Imitrex (sumatriptan), Treximet® (sumatriptan and naproxen sodium) NDA 020626/ 020080/ 020132/ 021926/ | GSK | Pregnancy registry | Prospective registry study | The Sumatriptan/Naratriptan/Treximet Pregnancy Registry collected data on fetal malformations and birth defects from in-utero exposure to sumatriptan (January 1996 to September 2012). A prospective study conducted by the Sponsor identified too few exposed pregnancy outcomes to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Section 8 of the label was updated to reflect that data from the prospective pregnancy exposure registry and other epidemiological studies of pregnant women did not show an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population. | Completed Pregnancy Registry Study (ClinicalTrials.gov ID NCT01059604) Sumatriptan and Naratriptan Pregnancy Registry Study IMITREX labeling update December 14, 2017: See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy TREXIMET labeling update April 28,2021: TREXIMET labeling update April 28, 2021: See Section: 8 USE INSPECIFIC POPULATIONS, 8.1 Pregnancy |
Amerge (naratriptan) NDA 020763 | GSK | Pregnancy registry | Prospective registry study | The Sumatriptan/Naratriptan/Treximet Pregnancy Registry collected data on adverse fetal outcomes from in utero exposure to naratriptan. Section 8 of the AMERGE labeling was updated to reflect that no definitive conclusions could be drawn from the registry and epidemiological studies regarding the risk of birth defects following exposure to naratriptan. | AMERGE label update November 29, 2016 See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy |
Proton pump inhibitors (PPI) Multiple NDAs | Multiple sponsors | Medicare claims data | Case-control study | In FDA’s review of drugs repurposed for treating patients with COVID-19 or drugs being taken by patients with COVID-19, there was concern that PPI use might increase the risk of developing severe COVID-19. An FDA conducted case control study in Medicare compared new users of PPIs versus new users of histamine-2 receptor antagonists and found that PPIs were not associated with increased risk uncomplicated or complicated (ICU, mechanical ventilation, death) COVID-19 hospitalizations. This provided reassurance to FDA that regulatory action was not needed. This resulted in a publication. | Pharmacotherapy publication, 2024. |
Angiotensin-converting enzyme (ACE) Inhibitors (multiple) and angiotensin receptor blockers (ARB) (multiple) Multiple NDAs | Multiple sponsors | Medicare claims data | Case-control study | In FDA’s review of ACE inhibitors or ARBs, an FDA conducted case-control study in Medicare evaluated the effect of ACE inhibitors or ARBs on the risk of developing severe COVID-19 and found that use of these drugs was not associated with increased risk of hospitalized COVID-19 or COVID-19-related mortality. No labeling changes were warranted. This resulted in a publication. | Journal of General Internal Medicine publication, 2021. |
EPOGEN, PROCRIT, ARANESP (Erythropoietin stimulating agents (ESA)) BLA 103234 and 103951 | Amgen | Medicare | Retrospective cohort study | FDA reviewed the effect of the REMS for ESA use for chemotherapy-induced anemia, during and after the discontinuation of the REMS, and conducted a restrospective cohort study in Medicare that showed that the REMS had minimal impact on ESA use or transfusion rates and that the removal of the REMS did not affect subsequent ESA use or blood transfusions. Study results provided reassurance that FDA's removal of the REMS had not led to increased ESA use or transfusions. This resulted in a publication. | Pharmacoepidemiology Drug Safety publication, 2021. |
LYBREL (ethinyl estradiol; levonorgestrel) NDA 021864 | Pfizer | Sentinel System | Retrospective cohort study | An FDA conducted retrospective cohort study evaluated the risk of venous thromboembolism (VTE) for extended cycle contraceptives to determine whether these posed a greater risk of VTE due to increased hormone exposure, compared to 28-day products. The study provided reassurance that VTE risk was not substantially different between traditional and extended use oral contraceptives. | JAMA Publication 2018 |
Januvia (sitagliptin) NDA 021995 | Merck | Pregnancy registry | Prospective registry study | A prospective study conducted by the Sponsor in a pregnancy registry identified too few exposed pregnancy outcomes to support definitive conclusions about overall malformation risk or for making comparisons of the frequencies of specific birth defects. Section 8 of the labeling was updated to reflect that the data available for pregnant women exposed to sitagliptin were not sufficient to inform a drug- associated risk for major birth defects and miscarriage. | JANUVIA label update February 9, 2018. See Section: 8 USE IN SPECIFIC POPULATIONS, 8.1 Pregnancy - Risk Summary |
| Drugs and identifiers | Sponsor | Data Source | Study Design | PMR/PMC Description | Summary of RWE use or Regulatory Action | Date of regulatory action and updated labeling |
|---|---|---|---|---|---|---|
Fragmin (Dalteparin Sodium) NDA 20287 | Pfizer Inc. | Medical records Supportive safety evidence from published literature and two prospective clinical trials | Retrospective chart review study | PMC 3629-1: To characterize safety of dalteparin treatment in neonates (defined as 0 to 28 days of age; gestational age at least 35 weeks) with venous thromboembolism (VTE), conduct a non-interventional, retrospective medical record review study to describe the safety, dosing, pharmacodynamics, and efficacy using real-world evidence in at least 12 neonates receiving dalteparin. Submit the final report, case report forms, and datasets. | Labeling updated in the following sections to extend the indication for the “treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence of VTE in pediatric patients” from 1 month down to birth (gestational age at least 35 weeks): Indications and Usage (1.4), Dosage and Administration (2.4), Clinical Trial Experience (6.1), Use in Specific Populations, Pediatrics (8.4), Clinical Studies (14) | October 15, 2024 Labeling |
Mircera (Methoxy Polyethylene Glycol-Epoetin Beta) BLA 125164 | Vifor (International) Inc. | Registry | Prospective registry study | PMR 3385-2: Submit a summary report and registry data that describes the dosing, aggregate level safety data and hemoglobin concentrations in a cohort of pediatric patients with anemia associated with chronic kidney disease treated with US-licensed Mircera. The cohort will include pediatric patients from 3 months to less than 18 years of age, on peritoneal dialysis or hemodialysis, and subcutaneous or intravenous route of administration. The sample size for the cohort will be a minimum of 125 patients. | Labeling updated in the following sections to extend the indication for the treatment of anemia associated with chronic kidney disease (CKD) in pediatric patients 3 months to 17 years of age on dialysis and not on dialysis who are converting from another erythropoiesis-stimulating agent (ESA) after their hemoglobin level was stabilized with an ESA: Indications and Usage (1), Dosage and Administration (2.2), Adverse Reactions (6), Use in Specific Populations (8), Clinical Pharmacology (12), Clinical Studies (14) | April 30, 2024 Labeling |
Entyvio (Vedolizumab) BLA 125476 | Takeda Pharmaceuticals U.S.A., Inc. | Pregnancy registry | Prospective registry study | PMC 2719-7: Conduct a prospective, observational pregnancy exposure registry study in the United States that compares the pregnancy and fetal outcomes of women exposed to Entyvio (vedolizumab) during pregnancy to an unexposed control population or collect Entyvio (vedolizumab) pregnancy exposure data by collaborating with an existing disease-based pregnancy registry. | Labeling updated with pregnancy registry outcomes in the Pregnancy sub-section (8.1) | February 23, 2024 Labeling |
Zithromax (Azithromycin) NDA 50784; NDA 50670; NDA 50693; NDA 50710; NDA 50711; NDA 50730; NDA 50733; NDA 50797 | Pfizer Inc. | Electronic medical records linked to a death registry | Retrospective cohort study | PMR 2130-1: An observational study of the association of azithromycin use with cardiovascular death, compared to amoxicillin or other antibacterial drugs, in one or more study population(s) with sufficient representation of cardiovascular disease and cardiovascular risk factors. The goal is to replicate the analysis conducted in the Ray et al. study published in 2012 in a different population, and to elucidate the risk and potential risk factors for azithromycin-associated cardiovascular death. | Labeling updated to include the risk of cardiovascular death in the following sub-sections: Warnings and Precautions (5.5), Postmarketing Experience (6.2)) and Patient Information. | November 22, 2021 Labeling |
Mirena (Levonorgestrel-Releasing Intrauterine System) NDA 21225 | Bayer Healthcare Pharmaceuticals Inc. | Electronic medical records | Retrospective cohort study | PMR 3129-1: Observational study of incidence and risk factors for uterine perforation among users and particularly when related to breastfeeding and timing of postpartum levonorgestrel intrauterine contraceptive system (IUS) [Mirena] insertion in US women. | Labeling updated to include the risks of perforation and expulsion, and information on timing of insertion to the following sub-sections: Dosage and Administration (2.2), Warnings and Precautions (5.6,5.7), Postmarketing Experience (6.2), and Patient Information. | June 8, 2021 Labeling |
OxyContin (Oxycodone Hydrochloride) NDA 22272 | Purdue Pharma L.P. | Claims data and electronic medical records | Retrospective cohort drug utilization studies | PMR 2923-2: Conduct a nationally representative drug utilization study of sufficient detail to characterize use of OxyContin in children aged 17 years and younger. The data from this study will provide a denominator for the risks assessed in PMR #2923-1 and any future safety studies and clinical trials used to assess those risks. The following analyses should be conducted with the data collected: 1) Total number of prescriptions dispensed across all settings of care a. stratify by age group (0-1, 2-5, 6-10, 11-17), indication, setting of care, and prescriber specialty, and geographic location b. provide characteristics of dose dispensed (mean, median, range) 2) Total number of unique patients receiving dispensed prescriptions across all settings of care a. stratify by age group (0-1, 2-5, 6-10, 11-17), indication, setting of care, and prescriber specialty i. provide unique incident users every quarter-year b. patient demographics of users of the product c. clinical characteristics of users of the product (including what percentage of patients are opioid tolerant at the time they get the OxyContin prescription) 3) Duration of therapy (include definitions of allowable gaps in drug therapy in calculating duration of therapy) a. total and stratified by indication b. exploration of possible ‘intermittent’ use c. percentage of patients switching from immediate-release opioids to OxyContin d. percentage of patients switching from other extended-release opioids to OxyContin dose adjustments over time. | New PMR established. PMR 2923-3: Conduct a retrospective cohort study in pediatric patients aged 17 years and younger (including patients younger than the approved age of 11 years) to examine the association between opioid nontolerance at initiation of OxyContin therapy and serious risks such as respiratory depression as well as non-fatal and fatal overdose. The sample size must be sufficient to detect any clinically relevant difference in risk from that of an appropriate comparator group(s), and information must be sufficiently granular to assess all relevant demographic, clinical, prescription covariates and outcomes (in a multivariate model). Investigators must be able to ascertain all exposures and deaths regardless of location (i.e., in-hospital or out of-hospital). | April 8, 2021 |
Truvada (Emtricitabine and Tenofovir Disoproxil Fumarate) NDA 21752 | Gilead Sciences Inc. | Antiretroviral Pregnancy Registry | Prospective registry study | PMR 1906-1: Through collaboration with the Antiretroviral Pregnancy Registry, conduct a prospective observational study to collect and analyze data on maternal and fetal outcomes in 200 women who become pregnant while taking Truvada® for a pre-exposure prophylaxis (PrEP) indication and choose to continue Truvada during their pregnancies and in 200 women who become pregnant while taking Truvada for PrEP and choose to discontinue it. Collect and analyze data from at least a similarly sized comparator group of pregnant HIV-infected women taking antivirals other than emtricitabine/tenofovir disoproxil fumarate. Data collected on pregnancy outcomes should include but not be limited to: timing of initiation and duration of Truvada or other antiretrovirals, HIV seroconversions in mothers and infants, spontaneous and elective abortions, spontaneous and scheduled pre-term deliveries, stillbirths, infant weight (normal or low) and infant outcomes, including the presence or absence of congenital malformations. | Labeling updated with pregnancy registry outcomes in the Pregnancy sub-section (8.1) | May 15, 2018 Labeling |
Jadenu (Deferasirox) NDA 206910 | Novartis Pharmaceuticals Corp. | Registry | Prospective registry study | PMR 2888-1: Establish a registry for children aged 2 to < 6 years to enroll approximately 200 patients receiving deferasirox and follow them for 5 years. Collect data at least monthly for renal function and blood pressure and yearly for growth and development and analyze the data for adverse renal reactions and delayed growth and development. | Labeling updated; Conversion to traditional approval for the treatment of chronic iron overload due to blood transfusion in patients 2 year of age and older | May 11, 2018 Labeling |
Jadenu Sprinkle (Deferasirox) NDA 207968 | Novartis Pharmaceuticals Corp. | Registry | Prospective registry study | PMR 3342-1: Establish a registry for children aged 2 to < 6 years to enroll approximately 200 patients receiving deferasirox and follow them for 5 years. Collect data at least monthly for renal function and blood pressure and yearly for growth and development and analyze the data for adverse renal reactions and delayed growth and development. | Labeling updated; Conversion to traditional approval for the treatment of chronic iron overload due to blood transfusion in patients 2 year of age and older | May 11, 2018 Labeling |
| Biologics and identifiers | Sponsor | Data Source | Study Design | Summary of RWE use | Date of regulatory action and links |
|---|---|---|---|---|---|
| Atidarsagene Autotemcel BLA 125758 | Orchard Therapeutics (Europe) Limited | Medical records (European Union) | Externally controlled trial with untreated arm from a natural history study, plus untreated siblings not in the natural history study | Role of Study: substantial evidence of effectiveness Premarketing: RWE from an externally controlled trial with an untreated arm from a natural history study (plus untreated siblings not in the natural history study) was a primary source of clinical evidence of effectiveness from an adequate and well-controlled investigation to support approval for treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD) | March 18, 2024 LENMELDY |
Tdap Vaccine for use during pregnancy sBLA 125111/904 | Sanofi Pasteur Limited | Surveillance network: Emerging Infections Program Network (medical records, immunization registry, surveillance case reports, patient and physician interviews, birth certificate records) (U.S.) | Matched case-control study | Role of Study: Supportive evidence of effectiveness. Premarketing: RWE from a matched case control study provided supportive clinical evidence of effectiveness for the indication for immunization during the third trimester of pregnancy to prevent pertussis in infants younger than 2 months of age. | January 9, 2023 ADACEL |
Elivaldogene Autotemcel BLA 125755 | Bluebird Bio, Inc. | Medical records from a natural history study (Global) | Externally controlled trial with untreated arm from a natural history study and allo-HSCT treated arm from a non-interventional study | Role of Study: Substantial evidence of effectiveness -single study accelerated approval. Premarketing: RWE from an externally controlled trial with an untreated arm from a natural history study and allo-HSCT treated arm from a non-interventional study, was a primary source of clinical evidence of effectiveness from a single adequate and well-controlled investigation to support accelerated approval for indication of slowing the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrohy (CALD) | September 16, 2022 SKYSONA |
Tdap Vaccine for use during pregnancy sBLA 125106/1469 | Glaxosmithkline | Surveillance network: Emerging Infections Program Network (medical records, immunization registry, surveillance case reports, patient and physician interviews, birth certificate records) (U.S.) | Matched case-control study | Role of Study: supportive evidence of effectiveness. Premarketing: RWE from a case control study was used as supportive clinical evidence of effectiveness supporting the indication for immunization during the third trimester of pregnancy to prevent pertussis in infants younger than 2 months of age | October 7, 2022 BOOSTRIX |
| Biologics and identifiers | Sponsor | Data Source | Study Design | Summary of RWE use | Date of action and links |
|---|---|---|---|---|---|
mRNA COVID-19 Vaccines (Comirnaty and Spikevax BLA 125742 | Pfizer-BioNTech and Moderna Tx, Inc | CBER BEST medical and pharmacy claims | Retrospective cohort studies | Two FDA funded postmarket retrospective cohort studies using medical claims and the MACiV (Myocarditis After COVID-19 Vaccination) study contributed to updates to the Prescribing Information for COVID-19 vaccines to include new safety information about the risks of myocarditis and pericarditis following administration. | June 25, 2025 FDA Safety Communication FDA Approves Required Updated Warning in Labeling of mRNA COVID-19 Vaccines Regarding Myocarditis and Pericarditis Following Vaccination |
RSV Vaccines (Abrysvo and Arexvy) BLA 125769 & BLA 125768 | Pfizer Inc and GlaxoSmithKline Biologicals | CBER BEST medical and pharmacy claims | Self-controlled case series analyses | An FDA funded postmarketing study using a self-controlled case series analysis in the CBER Best System contributed to safety labeling changes to the Prescribing Information for. Respiratory Syncytial Virus (RSV) vaccines on a suggested increased risk of Guillain-Barré syndrome (GBS) during the 42 days following vaccination. | January 7, 2025 FDA Safety Communication FDA Requires Guillain-Barré Syndrome (GBS) Warning in the Prescribing Information for RSV Vaccines Abrysvo and Arexvy |
BCMA- or CD19-directed autologous CAR T cell immunotherapies (various products) Multiple BLAs | Various | FAERS | Descriptive study | A postmarket FAERS study, combined with evidence from clinical trial reports on T cell malignancies in patients who received treatment with BCMA- or CD19-directed autologous CAR T cell immunotherapies led to a boxed warning. | April 18, 2024 FDA Safety Communication FDA Requires Boxed Warning for T cell Malignancies Following Treatment with BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies |
Manufacturers of allergenic extracts for diagnosis of food allergy Multiple BLAs | Alk-Abello,Inc Greer Laboratories, Inc
| FAERS | Descriptive study | Safety monitoring using the FDA Adverse Event Reporting System (FAERS) data led to safety labeling changes to the Prescribing Information for all allergenic extracts for the diagnosis of food allergy.
False negative skin test results associated with anaphylaxis from subsequent exposure to the allergen were reported during postmarketing diagnostic use of some food allergenic extracts. | March 3, 2023 FDA Safety Communication FDA Requires Warning about Anaphylaxis Following False Negative Food Allergen Skin Test Results in the Prescribing Information for All Allergenic Extracts for Diagnosis of Food Allergy |
Hydroxyethyl starch (HES) products (various products) Multiple BLAs | Various
| Multiple | Multiple observational study designs | Postmarketing observational studies (non-FDA funded), combined with evidence from a RCT and a meta-analysis led to labeling changes. | July 7, 2021 FDA Safety Communication Labeling Changes on mortality, kidney injury, and excess bleeding with hydroxyethyl starch products |
Herpes Zoster Vaccine SHINGRIX BLA 125614 | GlaxoSmithKline Biologicals | CBER BEST medical and pharmacy claims | Cohort study with self-controlled case series analyses | An FDA funded postmarket cohort study with self-controlled case series analyses using medical claims contributed to safety labeling changes to the Prescribing Information for Shingrix to include a new warning about the risk for Guillain-Barré Syndrome (GBS) following administration. | March 24, 2021
|
Influenza Vaccine BLA 103914 | Sanofi Pasteur | Mini-Sentinel PRISM | Self-controlled risk interval (SCRI) design | During the 2010-2011 influenza season, an increased number of reports of febrile seizures following vaccination with Fluzone were received into the Vaccine Adverse Event Reporting System (VAERS). A Sentinel assessment using a self-controlled risk interval design found no statistically significant association with febrile seizures and provided reassurance of safety. There was also a communication via the Sentinel initiative website. | May 16, 2014. FDA Safety Communication FDA Postlicensure Rapid Immunization Safety Monitoring (PRISM) Study Demonstrates No Statistically Significant Association between Trivalent Inactivated Influenza Vaccine and Febrile Seizures in Children during the 2010-2011 Influenza Season |
Rotavirus Vaccine (RotaTeq) BLA 125122 | Merck Sharp & Dohme Corp | Mini-Sentinel PRISM- commercial claims data | Retrospective cohort study with multiple analysis methods including Self-controlled risk interval (SCRI) | An FDA funded post market cohort study in the Mini-Sentinel PRISM initiative led to revisions to the Prescribing Information and Patient Information for RotaTeq as a result of the new safety data. New information was added to the label Highlights, the existing intussusception subsection of Section 5 (Warnings and Precautions), Section 6 (Post-Marketing Experience), and Section 17 (Patient Counseling Information). There was also a communication via the Sentinel initiative website. | June 13, 2013 FDA Safety Communication FDA Releases Final Study Results of a Mini-Sentinel Postlicensure Observational Study of Rotavirus Vaccines and Intussusception |
Human immune globulin products (various products, Immune Globulins) Multiple BLAs | Various sponsors | Medicare medical and pharmacy claims data, and FAERS data | Retrospective Cohort study | An FDA funded postmarket retrospective cohort study using medical claims as well as adverse event reports contributed to the decision to add information on thrombosis to the boxed warning in the labels of all intravenous human immune globulin products and to add a boxed warning to the labels of all subcutaneous and intramuscular human immune globulin products to highlight the risk of thrombosis and to add information on its mitigation. | November 14, 2013
|
Rotavirus Vaccine (Rotarix) BLA 125265 | GlaxoSmithKline Biologicals | Inpatient medical records from hospitals/medical facilities in Mexico | Self-controlled case series analysis | A postmarket safety study (hospital-based active surveillance study) using self-controlled case series analysis was conducted by the sponsor in Mexico. The study examined intussusception following Rotarix administration. Study findings led to safety labeling changes stating that cases of intussusception were observed in temporal association within 31 days following the first dose of ROTARIX, with a clustering of cases in the first 7 days. | September 17, 2010 FDA Approval Letter (Safety Communication) Approved Products > September 17, 2010 Approval Letter - Rotarix |
Abbreviations
ACE - Angiotensin-converting enzyme
ARB - Angiotensin receptor blocker
CBER - Center for Biologics Evaluation and Research
CDER - Center for Drug Evaluation and Research
CDRH - Center for Devices and Radiological Health
CMS - Center for Medicaid and Medicare Services
DSC - Drug Safety Communication
ESA - Erythropoietin stimulating agent
FAERS - FDA Adverse Event Reporting System
GBCA - Gadolinium-based contrast agent
GLP-1 RA - Glucagon-like peptide-1 receptor agonists
HCTZ - Hydrochlorothiazide
IAA - Inter-Agency Agreement
MACE - Major adverse cardiac event
NDA - New Drug Application
BLA - Biologics License Application
OSE - Office of Surveillance and Epidemiology
OUS - Outside the US
PLLR - Pregnancy and Lactation Labeling Rule
PPI - Proton pump inhibitor
RWD - Real World Data
RWE - Real-World Evidence
REMS - Risk Evaluation and Mitigation Strategy
VHA - Veterans Health Administration
VTE - Venous thromboembolism