Med Check

Purpose: Programs referred to as Risk Evaluation and Mitigation Strategies (REMS) have been implemented to assess the risk with drug and biologic therapies. Prescriber assessment of risks awareness with a medication can be done through third party web-based surveys in which the resultant data are analyzed in aggregate form to assess if the communication and education surrounding the REMS is meeting its goal. The purpose of this study is to provide prescriber data and outcome of the infliximab (IFX) REMS program at the 18-month assessment time period. Methods: The FDA may now require manufacturers like Centocor Ortho Biotech Inc. to implement a REMS (a strategy to manage a known or potential serious risk associated with a drug or biologic), if they determine that a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks of the medication. The IFX REMS was required with the following goals outlined in the approved REMS: To communicate and mitigate the risks associated with IFX by: 1. Alerting and warning health care providers (HCPs) about cases of unrecognized histoplasmosis (Histo) and other invasive fungal infections associated with Tumor Necrosis Factor (TNF) blockers; and 2. Educating patients about the serious risks associated with IFX therapy. An individual medication's REMS program is unique to the product and may include one or more of the elements listed in the table below. Assessments of the REMS have time tables and at minimum must be submitted to FDA at 18 months, 3 years, and 7 years after approval of the strategy, with additional assessments as required by the FDA. Results: The IFX REMS includes a medication guide, communication plan and a timetable for assessments (18 months, 3 years and 7 years). The implementation of the IFX REMS communication plan consisting of a Dear Health Care Professional Letter (DHCPL) and Serious Infection Guide disseminated to >13,800 adult and pediatric gastroenterologists (GEs) combined and >356,000 other HCPs, including infusion centers has been executed. Medication Guides are included in each dispensed vial of IFX. Data presented will include the prescriber assessment findings for 415 IFX prescribers (gastroenterology subspecialty, n=211). Risk survey data indicate that nearly all prescribers surveyed were aware of re-activation of TB (97% [GEs n=211, 98%]) and of the development of Histo and other invasive fungal infections (91% [GEs n=96, 90%]) when questioned as to possible risks associated with taking IFX. Conclusion: REMS is an important tool that can be used by the FDA, HCPs and the pharmaceutical industry to improve medication safety and access to efficacious treatment options. The IFX 18-month assessment data indicate the IFX REMS is meeting its goals. Disclosure: JR McGowen: Employee, Centocor Ortho Biotech Services; L Brajdic: Employee, Centocor Ortho Biotech Services; B Sarokhan: Employee, Centocor Ortho Biotech Services; S Patel: Employee, Centocor Ortho Biotech Services. This research was supported by an industry grant from This study was sponsored by Centocor Ortho Biotech Services, LLC.Table: Elements of REMS

Risk management of drug products and the U.S. Food and Drug Administration: Evolution and context

Risk evaluation and mitigation strategy (REMS) programs are intended to improve safe use of US Food and Drug Administration-approved drugs. However, controversy exists over whether they consistently accomplish this goal. We aimedto assess how initiation of the erythropoiesis stimulating agents (ESAs) darbepoetin alfa and epoetin alfa changed following implementation and enforcement (following a 1-year post-implementation grace period) of a prominent REMS program warning physicians against use in cancer patients with hemoglobin above 10g/dL. Using claims data from a large US commercial insurance company, we conducted interrupted time-series analyses of darbepoetin alfa and epoetin alfa initiation among adult cancer patients in the 12 months before REMS program implementation, after REMS program implementation, and after REMS program enforcement. We also evaluated differences in inappropriate initiation (hemoglobin tests all above 10g/dL in the prior month) between the periods. In total, we identified 3456 darbepoetin alfa initiators and 2632 epoetin alfa initiators. Over the study period, the monthly number of initiators per 100,000 patients with cancer fell from 119 to 32 for darbepoetin alfa and from 82 to 34 for epoetin alfa. However, non-significant post-REMS program implementation level and slope changes per 100,000 adult patients with cancer were observed for darbepoetin alfa (level0.03 [95% confidence interval (CI) -14.98 to 15.05]; slope 1.94 [95% CI -0.22 to 4.10]) and epoetin alfa (level -4.10 [95% CI -16.85 to 8.65]; slope -0.52 [95% CI -2.35 to 1.32]). Non-significant post-REMS program enforcement level and slope changes were also seen for both drugs (darbepoetin alfa level 1.58 [95% CI -0.58 to 3.74,slope -0.28 [95% CI -15.29 to 14.73]; epoetin alfa level 1.58 (95% CI -0.26 to 3.42],slope 5.74 [95% CI -7.01 to 18.49]). Finally, non-significant changes in inappropriate darbepoetin alfa (60% vs. 53% vs. 57%, p = 0.68) and epoetin alfa (53% vs. 53% vs. 46%, p = 0.41) initiation were observed between the three study periods. REMS program implementation and enforcement were not associated with significant changes in ESA initiation, adding to concerns over the degree to which certain REMS programs enhance patient safety.

Macitentan: Endothelin receptor antagonist

The Food and Drug Administration Amendments Act of 2007 gave the FDA the authority to require drug sponsors to submit a risk evaluation and mitigation strategies (REMS) program for those medicines with serious risks such that failure to effectively manage these risks would tip the benefit-risk balance. As of August 8, 2013, the 34 distinct individual and shared REMS programs that have specific elements to assure safe use (ETASU) were reviewed to ascertain the types of risks managed, the goals of the REMS, and the tools that were employed targeting prescribers, health care facilities, pharmacists, and particular conditions for safe use. Most REMS (65%) have a combination of risk mitigation and educational goals, but 4 REMS programs (12%) have exclusively educational goals. Preventing fetotoxicity (25%) is the most common risk managed by REMS with ETASU. Seventy-nine percent of ETASU REMS employ prescriber-based tools that include performing laboratory testing (eg, pregnancy, hepatic enzymes) or monitoring (eg, ophthalmologic examinations, documenting vaccination). The goals of REMS programs should focus on measurable behaviors that directly reduce risk. The tools that are employed should create the appropriate conditions for safe use. With the number of programs and the plethora of tools applied, serious consideration should be given to better integration of risk management into health care and pharmacy systems that are best equipped to manage such risks.

FDA on April 13 ended the risk evaluation and mitigation strategy (REMS) program for erythropoiesis-stimulating agents (ESAs), a decision that caught some longtime users of the program off-guard. At Ministry Saint Michael’s Hospital, part of Ascension in Stevens Point, Wisconsin, a nurse’s inability to look up a new prescriber’s registration information at the REMS program’s website was the first hint of change. “That’s when we noticed that the REMS program was no longer active,” said Brook DesRivieres, director of pharmacy at the 50-bed hospital. Known officially as the ESA APPRISE Oncology Program, the REMS program was approved in 2010 by FDA for two epoetin alfa products—Amgen’s Epogen and Janssen’s Procrit—and Amgen’s darbepoetin alfa product, Aranesp. The REMS plan was created to ensure that the benefits of the products exceed their risks when used as an alternative to red blood cell transfusion in cancer patients with anemia resulting from myelosuppressive therapy. The specific risks named in the REMS program were shortened overall survival time and an increased likelihood of tumor progression or recurrence in patients with cancer.

Successful Implementation of a Chimeric Antigen Receptor T-Cell Risk Evaluation and Mitigation Strategies (REMS) Program

e18501 Background: Cancer clinical trials based in the United States (US) have lacked adequate representation of racial and ethnic minorities, the elderly, and women. Pivotal clinical trials leading to United States Food and Drug Administration (FDA) approval are often multi-national trials and may also lack generalizability to underrepresented populations in the United States. We determined the racial, ethnic, age, and sex enrollment in pivotal trials relative to the US cancer population. Methods: We reviewed the FDA’s Drug Approvals and Databases for novel and new use drug approvals for breast, colorectal, lung, and prostate cancer indications from 2008 through 2020. Drugs@FDA was searched for drug approval summaries and FDA labels to identify clinical trials used to justify clinical efficacy that led to FDA approval. For eligible trials, enrollment data were obtained from FDA approval summaries, FDA labels, ClinicalTrials.gov, and corresponding journal manuscripts. Enrollment Fraction (EF) was calculated as enrollment in identified clinical trials divided by 2017 SEER cancer prevalence. All data sources were publicly available. Results: From 2008 through 2020, 60 drugs received novel or new use drug approval for breast, colorectal, lung, or prostate cancer indications based on 66 clinical trials with a total enrollment of 36,830. North America accounted for 9,259 (31%) enrollees of the 73% of trials reporting location of enrollment. Racial demographics were reported in 78% of manuscripts, 66% of ClinicalTrials.gov pages, and 98% of FDA labels or approval summaries. Compared with a 0.4% enrollment fraction among White patients, lower enrollment fractions were noted in Hispanic (0.2%, odds ratio [OR] vs White, 0.46; 95% confidence interval [CI], 0.43 to 0.49, P< 0.001) and Black (0.1%, OR 0.29; 95% CI 0.28 to 0.31, P< 0.001) patients. Elderly patients (age ≥ 65 years) were less likely than younger patients to be enrollees (EF 0.3% vs 0.9%, OR 0.27; 95% CI 0.26 to 0.27, P< 0.001) despite accounting for 61.3% of cancer prevalence. For colorectal and lung cancer trials, females were less likely than males (EF 0.7% vs 1.1%, OR 0.66; 95% CI 0.63 to 0.68, P< 0.001) to be enrolled. Conclusions: Black, Hispanic, elderly, and female patients were less likely to enroll in cancer clinical trials leading to FDA approvals from 2008 to 2020. Race and geographic enrollment data were inconsistently reported in journal manuscripts and ClinicalTrials.gov. The lack of appropriate representation of specific patient populations in these key clinical trials limits their generalizability. Future efforts must be made to ensure equitable access, representation, and reporting of enrollees that adequately represent the US population of patients with cancer.

Section Editors: Marc Fisher MD Antoni Davalos MD The Food and Drug Administration (FDA) evaluates applications for new human drugs, biologics, and complex medical devices. Companies must obtain FDA approval to legally market these products. In August, the FDA gave Concentric Medical clearance to market its Merci Retriever system to “remove blood clots from the brain in patients experiencing an ischemic stroke.” Given that the FDA is charged with “protecting the public health by assuring the safety, efficacy, and security of… biological products and medical devices…, ” “advancing public health by helping to speed innovations that make medicines … more effective, safer, and more affordable,” and “helping the public get the accurate, science-based information they need to use medicines … to improve their health,”1 the FDA’s decision to approve the Merci Retriever system is of concern. The pathways to approval are reviewed by Felten et al in the accompanying article and are outlined in Figure 1. Figure 1. Potential pathways for device approval. The decision to approve the Merci Retriever was based on data from the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial; the approval was granted through the 510(k) process. The Merci Retriever system includes a flexible nickel titanium (nitinol) wire that obtains a helical shape once it is passed through the tip of the guidance catheter. In practice, the catheter/wire is passed distal to the thrombus, the catheter is removed, and the helical configuration assumed by the wire; the clot is then trapped in the helix and withdrawn from the vasculature (Figure 2). The 510(k) clearance means that the Merci Retriever was felt to be substantially equivalent to a predicate device. In this case, the predicate device was the Concentric Retriever, which itself received 510(k) clearance by the FDA in May 2001 for “use in …

Among novel pharmaceutical dosage forms of analgesics, whose number and diversity are continuously increasing over the past two decades, of particular importance are transdermal opioid analgesics (fentanyl, buprenorphine) for the treatment of chronic pain, fentanyl iontophoretic transdermal drug delivery system for suppression of acute postoperative pain, as well as compressed lozenges, buccal tablets and film, sublingual tablets and nasal sprays for fentanyl treatment of breakthrough cancer pain. To improve the efficacy of the migraine pain treatment, compared to the solid dosage forms (tablets) of tryptans, pharmaceutical preparations of sumatriptan (solution for subcutaneous injection, nasal spray and nasal powder) and zolmitriptan (orodispersible tablet) are developed and marketed for migraine pain treatment. The benefits of these pharmaceutical preparations are minimal invasiveness and suitability to meet the individual therapeutic needs of patients, including the pediatric population, in terms of onset and duration of action and delivered dose of the drug. In the last few years, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have warned of fatal errors during use or abuse of fentanyl transdermal patches and have indicated the importance educating health workers and patients about potential risks. Also, novel pharmaceutical forms of fentanyl for treatment of acute pain can be prescribed and used exclusively within the framework of the FDA REMS (Risk Evaluation and Mitigation Strategy) program aimed to provide greater benefits from potential risks. There are still no precise attitudes about the importance of recently approved pharmaceutical products of analgesics, and clinical assessments of their relative efficacy and tolerance at the site of application are also needed.

White paper on designing a risk evaluation and mitigation strategies (REMS) system to optimize the balance of patient access, medication safety, and impact on the health care system

The US FDA Amendments Act of 2007 was signed into law on 27 September 2007. A provision of this law granted the FDA new powers to enhance drug safety by requiring the pharmaceutical industry to develop Risk Evaluation and Mitigation Strategies (REMS). REMS are deemed necessary when a question exists as to whether the benefits of a drug outweigh its risks. REMS constitute a safety plan with several potential components, including a medication guide, a communication plan, elements to ensure safe use and an implementation system to help guide the prescribers, pharmacists and patients. This applies to existing drugs on the market, new drug applications (NDAs), abbreviated NDAs (generics) and biologics licence applications. REMS represent an 'upgrade' from previously required risk minimization action plans, based on the strengthening of FDA powers of authority and enforceability to incur monetary penalties against individuals representing the pharmaceutical industry who fail to comply. For illustrative purposes, we chose the drug romiplostim (Nplate®) to present an REMS, as all components were utilized to help assuage risks associated with the drug. Romiplostim is an FDA-approved drug used to treat thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura that has a significant adverse safety profile based on the risk of changes in bone marrow reticulin formation and bone marrow fibroses, and other associated risks. This review of current REMS policy is intended to provide the prescriber with a better understanding of current modalities in FDA-mandated drug safety programmes, which will impact day-to-day healthcare provider practices.

Objective. Opioid abuse is a serious public health concern. In response, the Food and Drug Administration (FDA) determined that a risk evaluation and mitigation strategy (REMS) for extended-release and long-acting (ER/LA) opioids was necessary to ensure that the benefits of these analgesics continue to outweigh the risks. Key components of the REMS are training for prescribers through accredited continuing education (CE), and providing patient educational materials.Methods. The impact of this REMS has been assessed using diverse metrics including evaluation of prescriber and patient understanding of the risks associated with opioids; patient receipt and comprehension of the medication guide and patient counseling document; patient satisfaction with access to opioids; drug utilization and changes in prescribing patterns; and surveillance of ER/LA opioid misuse, abuse, overdose, addiction, and death.Results and Conclusions. The results of these assessments indicate that the increasing rates of opioid abuse, addiction, overdose, and death observed prior to implementation of the REMS have since leveled off or started to decline. However, these benefits cannot be attributed solely to the ER/LA opioid analgesics REMS since many other initiatives to prevent abuse occurred contemporaneously. These improvements occurred while preserving patient access to opioids as a large majority of patients surveyed expressed satisfaction with their access to opioids.

The United States Food and Drug Administration (FDA) is the scientific, regulatory, and public health agency that regulates many products, including food products, drugs, medical devices, radiation emitting devices, and cosmetics for the federal government of the United States. The FDA's mission is to assure that consumer products made and sold in the United States are safe, effective, and pure. The purpose of the package insert (also known as prescription drug product insert or professional labeling) is to provide detailed drug information compiled and distributed by the drug manufacturer, after FDA review and approval. In 2006, the standard format for the package insert was changed in an attempt to make it more user-friendly and a more efficient resource tool for practitioners. According to the Institute of Medicine, in-hospital adverse drug reactions occur at a rate of 400,000 per year and incur $3.5 billion of extra hospital expense. It is expected that the new package insert format will enhance rapid access to important pharmacologic information and improve patient safety by decreasing medication errors.

FDA's role in anesthetic drug development.