The terms real-world data (RWD) and real-world evidence (RWE) are often used inconsistently or interchangeably, including in submissions to the US Food and Drug Administration (FDA) involving RWE to evaluate the effectiveness of drugs and biologic products. Although a misconception sometimes exists that only non-interventional studies utilize RWD to generate RWE, the spectrum of study designs involves various combinations of data sources and design architectures which determine whether RWE is generated or not. Attempts by various stakeholders to identify the role of RWE in regulatory decision-making often do not focus on the contribution of RWD in specifically evaluating drug-outcome associations. Prior examples of FDA approvals demonstrate how RWD can be utilized to generate RWE as part of a marketing application for regulatory decision-making. In accordance with the 21st Century Cures Act of 2016 (Cures Act),1 the Food and Drug Administration (FDA or the Agency) launched a program for evaluating the use of real-world evidence (RWE) to support regulatory decision-making. The Agency's 2018 Framework for FDA's Real-World Evidence Program defines real-world data (RWD) as "data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources" and RWE as "clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD."2 Since passage of the Cures Act, the Center for Drug Evaluation and Research (CDER), in cooperation with the Center for Biologics Evaluation and Research (CBER) and the Oncology Center of Excellence, published a series of guidance documents related to RWD and RWE.3 (Although beyond the scope of this commentary, FDA's Center for Devices and Radiological Health (CDRH) published a guidance4 describing expectations for the use of RWD and RWE for regulatory decision-making for medical devices and also published examples5 of "RWE-based" CDRH approvals.) Despite the focus of the Cures Act on promoting research using RWD, types of data and study designs have not fundamentally changed since passage of the Cures Act. For example, the randomized controlled trial (RCT) is the archetype of study designs for assessing the safety and efficacy of a medical product. Other study design types can be used, however, including when randomization has feasibility challenges or ethical concerns. Although methodological challenges exist with nonrandomized research, such studies can contribute to drug development and support regulatory decision-making regarding effectiveness when adequately meeting evidentiary standards.6, 7 For example, data sources with well-characterized covariates and clinical endpoints are now more available for exploration using existing study design approaches and statistical methods in lieu of randomization. Nonrandomized studies also offer opportunities to study diverse patient populations and better understand long-term outcomes among patients receiving medical products. Although FDA has been using what is now called RWE for years to assess the safety of medical products, since passage of the Cures Act, we have observed increased submissions involving RWE to evaluate effectiveness of drugs and biological products that analyze data collected during routine clinical care. At the same time, and given varying operational definitions of RWD and RWE in the stakeholder community, these terms have often been used inconsistently and sometimes interchangeably. As a result, confusion can arise when similar data sources and study designs are characterized differently in different settings.6 This commentary addresses RWD/RWE terminology for drugs and biological products, specifically related to studies of effectiveness submitted to FDA and whether they are classified as RWE by the agency. We have encountered a misconception8 that only non-interventional (observational) research7 utilizes RWD to generate RWE—in other words, a dichotomy of randomized controlled trials versus real-world evidence is said to exist.6 In reality, the spectrum of study design involves various combinations of data sources and design architectures; see Table 1. For example, externally controlled trials that utilize RWD in the comparator arm generate RWE, despite the treatment arm generating data according to a study protocol in a clinical trial environment. As another example, a randomized trial generates RWE if the primary outcome is based on an assessment of RWD (often referred to as a point-of-care trial). Conversely, although RWD can be utilized to identify potential participants or trial sites in a traditional RCT (along with the ability to promote diversity of study populations), such data are not generating RWE to evaluate the drug-outcome association. In another scenario, a non-interventional study can use RWD to generate RWE even if a prespecified protocol exists to collect additional data, as in a patient registry, as long as the treatment is administered as part of routine clinical care (i.e., per a clinician's judgment).7 Additional considerations arise when characterizing data from various RWD sources. A specific consideration is how to characterize data generated from digital health technologies (DHTs), such as software applications and sensors. If a DHT is used in a clinical trial according to protocol-driven procedures, the data are not considered RWD. In contrast, if data are obtained from personal use of DHTs outside of research setting, the data are considered RWD. When such data are determined to be reliable and relevant, they can be used to generate RWE for regulatory purposes. Another consideration is how to characterize summary-level aggregated data from the medical literature. Although stakeholders sometimes classify non-patient-level data as RWD generating RWE, such information from the literature is not central to the goal of using RWE for regulatory approvals. For example, literature citations that report on disease prevalence or drug utilization are included in most regulatory submissions and may not be viewed as RWE for regulatory purposes. Two FDA approvals help illustrate how RWD can be utilized to generate RWE as part of a marketing application for regulatory decision making. In 2021, the FDA approved Prograf® (tacrolimus) in combination with other immunosuppressant drugs to prevent organ rejection in adult and pediatric patients receiving lung transplantation.9 The evidence in support of approval of this new indication included a non-interventional study using RWD from a US-based registry, compared to historical controls. The FDA considered the RWD fit-for-use and the non-interventional study using these data to be the adequate and well-controlled clinical investigation necessary for establishing substantial evidence of effectiveness for approval. RCTs of Prograf® in other (liver, kidney, and heart) transplant settings provided confirmatory evidence. Another scenario, wherein the RWE played a lesser role, was the approval in 2019 of Ibrance® (palbociclib) for male patients with metastatic breast cancer (MBC) in combination with letrozole, an aromatase inhibitor. The sponsor submitted a supplemental new drug application including data from prior RCTs (PALOMA-1, PALOMA-2, and PALOMA-3) including only women, along with descriptive analyses of electronic health record and medical claims data for men with MBC.10, 11 Substantial evidence of effectiveness relied on the previous RCT data in women, based on the knowledge that the natural history of the disease, response to therapy, and safety would be expected to be similar in men and women. The data from electronic health records on men provided information on safety, indicating the safety profile for the use of palbociclib in combination with hormonal therapies in men was consistent with the known adverse event profile. More generally, external attempts to identify the role of RWD and RWE in regulatory decision-making can lead to different characterizations than those made by the FDA.12-16 For example, an article14 examined the role of RWE in FDA-approved new drug and biologics license applications from 2019 to 2021 and identified studies as RWE when "used to support the application's therapeutic context (e.g., prevalence and incidence of a disease)." Another article15 tracking submissions to the European Medicines Agency from 2018 to 2019 considered the use of RWD "to assess the representativeness of the control arm [of a traditional randomized trial]" as constituting RWE for label expansion and marketing authorization. By not focusing directly on the evaluation of drug-outcome associations, these examples indicate how different applications of real-world terminology can create inconsistency when tracking approvals based on RWE across regulatory agencies. As part of the FDA RWE Program, published guidance17 includes recommendations for sponsors to accurately describe data sources and design attributes in their submission cover letter to the Agency. In that guidance,17 FDA recommends providing specific information describing the regulatory purpose, types of study design, and RWD source; see Table 2. More recently, FDA announced an Advancing RWE Program18 to fulfill a commitment under the Prescription Drug User Fee Act (PDUFA) VII for fiscal years 2023 through 2027. The program includes a new mechanism for identifying approaches to generate RWE that meet regulatory requirements in support of labeling for effectiveness; it also includes a commitment to publicly report on RWE submissions to CDER and CBER starting in 2024. Use of consistent terminology can help FDA classify and quantify RWE and promote better understanding of reports by external entities regarding the use of RWE for regulatory purposes. The FDA Real-World Evidence Program seeks to address current challenges in using RWE for regulatory decision-making, along a spectrum from supportive to pivotal contributions. Inconsistent use of the terms RWD and RWE complicates efforts among regulators to track such data and evidence, causing potential confusion during communications among regulatory agencies, sponsors, and other stakeholders. Although the distinction between studies that generate RWE and those that do not may at times seem confusing to some in the stakeholder community, careful consideration of data and design elements can help sponsors and regulators better describe and characterize RWE. There is no funding information to report. The authors declare no conflict of interest.

An Appropriate Use of Accelerated Approval The FDA decision to grant accelerated approval to aducanumab for Alzheimer’s disease fits squarely in the accelerated approval pathway, which was created ...

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Breakthrough Therapy designation is one tool that the US Food and Drug Administration (FDA) uses to expedite the development and review of drugs to treat a serious condition with an unmet need. The designation brings with it, among other benefits, increased opportunities for the sponsor to obtain FDA guidance on trial design and other aspects of the program. Although trial designs may be influenced by many factors, the true measure of success is bringing promising medications to patients earlier.

In response to a rapid increase in drug development activity during the past two decades, the Food and Drug Administration’s Center for Drug Evaluation and Research launched a multi-year effort in 2017 to modernize the program by which new drug products are regulated, known as the New Drugs Regulatory Program. Following a detailed analysis of FDA activities in new drug development, premarket review, and postmarket monitoring, the Office of New Drugs was restructured to therapeutically align its clinical offices and to add new cross-functional offices for regulatory support. An interdisciplinary review process for new drug and biologics applications was rolled out to reduce redundancy and produce review documents that effectively communicate the scientific basis for the regulatory decision. The investigational new drug (IND) review process was also streamlined. During the next 2 years, the modernization initiative will seek to attract and retain new scientific and regulatory staff, improve postmarket safety monitoring, increase efficiency of drug review via technology-enabled workflows, and standardize the capture and use of scientific data to inform future regulatory decisions. The modernization effort will position the New Drugs Regulatory Program to continually improve and adapt to innovations in science, technology, and drug development.

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New Drug Applications and Biologics Licensing Applications submitted to the US Food and Drug Administration (FDA) are reviewed by an interdisciplinary team of regulatory scientists that includes medical officers, clinical pharmacologists, toxicologists, statisticians, and drug labeling experts. Upon review of an applicant's submitted evidence from nonclinical studies, clinical trials, and manufacturing capabilities, the review team evaluates the benefits and risks of the drug and makes a scientifically-informed decision. As part of a multi-year, multi-phase New Drugs Regulatory Program Modernization effort, the FDA has recently redesigned how it reviews and documents its decisions with regard to marketing applications. This article describes the origins and rationale of the new Integrated Assessment process and Integrated Review document, summarizes how these differ from the FDA's traditional review of marketing applications, and discusses what industry can expect from a modernized drug review.

Epidemiologic study designs are the focus of renewed interest in the current era of real-world evidence (RWE). Described with terms including case-control or cohort studies, observational designs were developed mainly to assess causes and correlates of human disease, but in recent decades, such methods have been used more frequently to evaluate the effects of medical products when used in routine clinical care (ie, not assigned by a research protocol), often with a focus on drug safety. Over the same time period, randomized controlled trials (RCTs) have become the archetype for experimental approaches (ie, protocol-assigned interventions). A dichotomy of randomized trials vs observational studies arose and was subsequently emphasized, related especially to the emergence of evidence-based medicine, with RCTs considered the benchmark of study designs—including for regulatory decisions that require adequate and well-controlled studies as the basis for substantial evidence in support of the effectiveness of new drugs. From a legislative perspective, the 21st Century Cures Act of 2016 provided specific milestones (see 21 U.S. Code § 355 g) for the Food and Drug Administration (FDA) to achieve in evaluating potential uses of RWE to support regulatory decision-making. FDA has defined RWE as “clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of real-world data” and real-world data (RWD) as “data relating to patient health status and/or the delivery of healthcare routinely collected from a variety of sources.” (Of note, RWD differs from data collected in healthcare settings explicitly for research purposes.) Contemporary discourse often invokes a choice between “randomized versus observational” and fails to articulate the spectrum of data and designs that can generate RWE. Without advocating a regulatory policy, this report considers terminology regarding RWE commonly used in the scientific community and seeks to reduce confusion when describing study designs.

To the Editor: With great concern, we read the editorial entitled, “FDA Jeopardizes the Lives of Lung Transplant Recipients and in the Process Severely Increases the Cost to Develop New Immunosuppression” by Drs. Klintmalm, Kaplan, and Kirk.1Klintmalm GB Kaplan B Kirk AD. FDA jeopardizes the lives of lung transplant recipients and in the process severely increases the cost to develop new immunosuppression.Am J Transplant. 2019; 19: 971-972Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar The editorial reflects a misunderstanding of FDA’s role and authority, as well as of the feasibility of randomized controlled clinical trials (RCTs) in lung transplantation. While the FDA focuses on evaluating the safety and effectiveness of new drugs, we are aware of the many challenges transplant patients face and have engaged extensively with the transplant community through public meetings and public–private partnerships with the goal of facilitating new drug development for transplant patients.2Albrecht R, Papadopoulos E, Campbell M, et al. Public private partnerships in transplant drug development [published online ahead of print September 25, 2019]. https://doi.org/10.1111/AJT.15604Google Scholar, 3FDA Center for Drug Evaluation and Research. Evidence-Based Treatment Decisions in Transplantation: The Right Dose & Regimen for the Right Patient/Individualized Treatment. 2018. https://www.fda.gov/Drugs/NewsEvents/ucm605761.htm. Accessed October 1, 2019.Google Scholar, 4FDA Center for Drug Evaluation and Research. The Voice of the Patient: Patients Who Have Received an Organ Transplant. April 2017. https://www.fda.gov/media/105219/download. Accessed October 1, 2019.Google Scholar There are a number of FDA-approved immunosuppressive drugs with indications for prevention of rejection in recipients of organ transplants. However, none of these approved drugs are specifically labeled with an indication for prevention of rejection in recipients of lung transplants. Indications in FDA labeling are based on data from adequate and well-controlled clinical trials submitted by the sponsor, usually a pharmaceutical company, as part of a marketing application. Transplanted organs share common alloimmune mechanisms and can provide supportive data; however, benefit/risk balance cannot be extrapolated, because of differences in organ involvement in product metabolism or drug toxicity. Thus, evidence from RCTs in lung transplantation is needed. Clinical trials in lung transplantation are challenging to conduct because lung transplants are less common than other solid organ transplants; however, the authors’ statement that randomized trials have never been done in lung transplants is incorrect. Numerous clinical trials of immunosuppressants, including randomized trials, have been conducted in lung transplantation. Although many have been small and single center, some have been international and multicenter trials enrolling more than 300 patients.5Hachem RR. Immunosuppression: have we learnt anything?.Semin Respir Crit Care Med. 2018; 39: 171-180Google Scholar It is not the size of the study that is critical, but rather the persuasiveness of the results. There are no barriers to expanding a drug’s indication into rare diseases; of the new molecular entities approved by FDA in 2018, 58% were for rare diseases. Finally, FDA does not regulate the practice of medicine. Healthcare professionals generally may choose to prescribe legally marketed drug for an unapproved use when they judge the unapproved use is medically appropriate for an individual patient. The authors’ statement that there are FDA rules that prohibit the use of mycophenolate or azathioprine in lung transplant patients is factually incorrect. In addition, FDA does not have the authority to determine what products or services are eligible for coverage or what claims are reimbursed by private insurance companies or the Centers for Medicare and Medicaid Services. It is important that transplant experts discuss with payers the evidence supporting clinical care guidelines, and participate in registries and other efforts to gather data to inform practice. The transplant community can also discuss with pharmaceutical sponsors and ultimately the Agency what available evidence could be used to meet FDA regulatory requirements for a change in drug labeling. FDA looks forward to continued engagement with the transplant community on approaches to address these and other challenges. The authors of this manuscript have no conflicts of interest to disclose as described by The American Journal of Transplantation. The views expressed are those of the authors alone and do not reflect the views of the US Food and Drug Administration.

Advances in our understanding of the molecular underpinnings of disease have spurred the development of targeted therapies and the use of precision medicine approaches in patient care. While targeted therapies have improved our capability to provide effective treatments to patients, they also present additional challenges to drug development and benefit–risk assessment such as identifying the subset(s) of patients likely to respond to the drug, assessing heterogeneity in response across molecular subsets of a disease, and developing diagnostic tests to identify patients for treatment. These challenges are particularly difficult to address when targeted therapies are developed to treat diseases with multiple molecular subtypes that occur at low frequencies. To help address these challenges, the US Food and Drug Administration recently published a draft guidance entitled “Developing Targeted Therapies in Low‐Frequency Molecular Subsets of a Disease.” Here we provide additional information on specific aspects of targeted therapy development in diseases with low‐frequency molecular subsets.

Breakthrough-Therapy Designation The authors provide a perspective on the rationale and goals of the designation of “breakthrough therapy” by the Food and Drug Administration.

Breakthrough-Therapy Designation The authors provide a perspective on the rationale and goals of the designation of “breakthrough therapy” by the Food and Drug Administration.

The FDA aims to ensure the timely dissemination of information from postmarketing studies of drugs. The authors argue that an analysis of the effect of the FDA Amendments Act would evaluate the timeliness of FDAAA postmarketing requirements separately from that of other types of requirements.