Value of Clinical Evidence and Health Economics and Outcomes Research (HEOR) Studies

ABSTRACT

Randomized controlled trials (RCTs) remain the gold standard for establishing the efficacy and safety of new treatments. However, clinical evidence derived from the systematic analysis of real‐world data generated through routine clinical practice can complement RCT data by offering insights into treatment performance in broader, more heterogeneous patient populations and clinical care settings. The integration of high‐quality clinical evidence into health economics and outcomes research (HEOR) is increasingly important, as it supports healthcare decision‐making across multiple stakeholders, including regulatory agencies, payers, clinicians, and patients. Multiple study designs, such as pragmatic trials, hybrid RCTs, external control arms, and observational studies, can provide valuable clinical evidence beyond the controlled trial setting. These data can enhance understanding of comparative effectiveness, patient‐reported outcomes, treatment safety, and healthcare utilization and costs. The field of amyotrophic lateral sclerosis offers a compelling example of how clinical evidence derived from global registries and clinical studies has advanced understanding of disease epidemiology, treatment patterns, and the effectiveness of therapies, including riluzole and edaravone. Consequently, this review and the associated supplementary articles are meant to serve as a primer to inform clinicians of the potential contribution of clinical evidence to HEOR studies.

Abbreviations

ALS

amyotrophic lateral sclerosis

CNDR

Canadian Neuromuscular Disease Registry

CReATe

Clinical Research in ALS and Related Disorders for Therapeutic Development

EMA

European Medicines Agency

ENCALS

European Network to Cure ALS

EURALS

European ALS Consortium

FDA

Food and Drug Administration

GTAC

Genomic Translation for ALS Care

HEOR

health economics and outcomes research

ICMRA

International Coalition of Medicines Regulatory Authorities

ISPE

International Society for Pharmacoepidemiology

ISPOR

International Society for Pharmacoeconomics and Outcomes Research

IV

intravenous

JaCALS

Japanese Consortium for ALS Research

LAENALS

Latin American Epidemiology Network for ALS

MDA

Muscular Dystrophy Association

MND

motor neuron disease

NEALS

Northeast ALS Consortium

PRO

patient‐reported outcome

RCT

randomized controlled trials

RWD

real‐world data

RWE

real‐world evidence

TRICALS

Treatment Research Initiative to Cure ALS

1. Introduction

Randomized controlled trials (RCTs) are the gold standard for establishing the efficacy and safety of medications [1]. Clinical evidence (sometimes referred to as real‐world evidence [RWE]), obtained by rigorous analysis of fit‐for‐purpose data from clinical practice (sometimes referred to as real‐world data [RWD]), can complement findings from RCTs [2] and is an accepted part of health economics and outcomes research (HEOR) [3, 4]. Accordingly, this review and the accompanying articles in this supplement are intended to serve as a primer to help clinicians understand the potential contribution of clinical evidence to HEOR studies.

2. What Is Clinical Data and How Is It Obtained?

The United States Food and Drug Administration (FDA) defines data from clinical practice (here, specifically referring to “RWD”) as, “data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources” [5]. However, other stakeholders have proposed multiple alternate definitions and there is no consensus on precisely what constitutes RWD [6, 7].

In contrast to clinical trials whereby data is collected in structured protocols, clinical data is collected from multiple alternate sources such as: [2, 7]

• Administrative claims databases

• Electronic health/medical records

• Clinical registries

• Contract/academic research organizations

• Patient‐powered research or social media networks

• Data from mobile devices

In aggregate, these sources represent an enormous reservoir of patient‐level data that can be applied to HEOR. Thus, while disparities in RWD definition, collection, and quality have led to some skepticism as to its value, many others—clinicians, researchers, and regulators—acknowledge its potential [8]. Importantly, the need for international agreement on best practices has been recognized by several professional organizations. The International Coalition of Medicines Regulatory Authorities (ICMRA) identified 4 focus areas critical to integrating clinical evidence (RWE) into regulatory decision‐making: [9]

• Harmonization of terminologies, with the goal of generating operational definitions of RWD and RWE

• Regulatory convergence on RWD and RWE guidance and best practices

• Readiness to address public health challenges and emerging health threats

• Transparency in study registration and publication

A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) has published a series of recommendations addressing several of these challenges [10, 11, 12].

3. What Are Studies From Clinical Practice?

Traditional RCTs generally enroll highly selective patient populations and are conducted according to protocols that ensure high‐quality, comprehensive data, but which do not necessarily reflect routine clinical practice [4, 13]. Consequently, the FDA and European Medicines Agency (EMA) acknowledge that such trials cannot generate RWD given their inherent selection biases [5, 14]. But randomization per se does not preclude RWD. Study designs that can generate RWD include the following:

3.1. Pragmatic Trials

These studies are designed to resemble clinical practice closely with regard to factors such as patient and investigator recruitment and routine healthcare visits (i.e., via electronic health records, medical claims data, or pharmacy databases) [10, 15]. They are generally not randomized or blinded [16].

3.2. Hybrid RCTs

A hybrid trial includes both traditional and pragmatic clinical trial elements [16]. Participants are generally randomized to different arms, and the data collected are often derived from a combination of protocol‐defined procedures and routine healthcare visits.

3.3. External Control Arm

In a single‐arm trial, data from clinical practice can be the basis of an external control arm, a strategy that may be useful when randomization to control is either unfeasible (e.g., in the case of a rare disease) or unethical [17, 18].

3.4. Observational Studies

Postmarketing pharmacovigilance and other observational studies are, by definition, based on data from clinical practice and can generate clinical evidence. Traditionally, such studies were used for descriptive analyses (e.g., disease epidemiology, treatment patterns, and burden of illness) and to assess adverse events. However, these studies provide limited to no reliable data regarding efficacy, given inherent selection biases and confounding [19].

4. Integrating Clinical Evidence Into HEOR Studies

Understanding the utility and limitations of data from clinical practice is critical to the proper application of insights from the data. Limitations of studies using data from clinical practice arise from a lack of randomization (particularly in pragmatic [15] and observational studies [5]), unknown or unmeasured confounding variables, and the use of complex statistical analysis techniques [10]. With that in mind, we suggest that clinical studies have the potential to inform and guide debate in the HEOR space as follows (Figure 1).

FIGURE 1.

Potential value of clinical studies for coverage and reimbursement decisions. PROs, patient‐reported outcomes.

4.1. Comparative Effectiveness

Clinical evidence can provide insights into multiple alternative treatments or clinical strategies compared to the current standard of care across a variety of typical practice settings [4, 13]. The hypothetical efficacy would then require confirmation in a controlled trial.

4.2. Broader Range of Outcomes

HEOR encompasses multiple stakeholders, including regulatory agencies, drug and device companies, patients and caregivers, payers, hospitals, and researchers [4]. Each of these stakeholders may have a different perspective on the value of a specific outcome. Clinical studies can compile both patient‐reported and clinician‐reported outcomes in larger and more diverse study populations than those enrolled in RCTs, providing broader generalizability [4].

4.3. Safety Surveillance

Regulatory agencies frequently require post‐marketing pharmacovigilance studies as a condition of approval [2]. Since these clinical studies play a key role in estimating the evolving risk–benefit profile and value of an intervention, they may also influence other stakeholders listed above.

4.4. Healthcare System Metrics

Clinical studies can describe healthcare utilization, services, prescription patterns, and costs to inform quality improvement [4, 13].

5. Selected Clinical Studies in ALS

RCTs in patients with amyotrophic lateral sclerosis (ALS) may have limited generalizability given disease heterogeneity and the need for selective eligibility criteria [20, 21]. Table 1 lists registries of patients with ALS across North and South America, Europe, and Asia [22]. Selected reports from these registries have provided data from clinical practice on differences in diagnosis and care of ALS across Canadian provinces [23], the frequency of comorbid ALS and chronic traumatic encephalopathy [24], identification of novel ALS genes [25], and trauma as a risk factor for ALS [26].

TABLE 1.

Global ALS registries.

Name	Enrolled patients with ALS (N)
North American population‐based
National ALS Registry	12,000
National ALS Registry Biorepository	330
Canadian Neuromuscular Disease Registry (CNDR)	1085
North American clinic‐based
Veterans Affairs Biorepository Brain Bank	287
Muscular Dystrophy Association (MDA) US Neuromuscular Disease Registry	1500
North American consortia/collaborative platforms
Target ALS	Not available
Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS)	28 163 non‐neurologic controls 151 neurologic (non‐ALS) controls
Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium	750
Genomic Translation for ALS Care (GTAC)	1500
Answer ALS	1000
European population‐based
European ALS Consortium (EURALS)	575 1150 age‐matched controls
European Network to Cure ALS (ENCALS)	1028
Treatment Research Initiative to Cure ALS (TRICALS)	3800
US‐European collaborative platform
ALS/Motor Neuron Disease (MND) Natural History Consortium	2100
Latin and South American consortia
Latin American Epidemiology Network for ALS (LAENALS)	Not available
Asian consortia/clinic‐based
Japanese Consortium for ALS Research (JaCALS)	1245
West China Hospital of Sichuan	1201

Note: Adapted from Cook [22].

Clinical studies have helped assess the efficacy of drugs for ALS. Riluzole was approved for treatment of ALS on the basis of two placebo‐controlled RCTs [27, 28]. While these RCTs demonstrated a modest survival benefit, they enrolled highly selected patient populations under tightly controlled trial conditions. An analysis of studies that provided clinical evidence for riluzole found additional supportive evidence for its efficacy [29]. Importantly, this analysis demonstrated that HEOR studies and RWE can complement RCT findings by evaluating treatment effectiveness across broader patient populations that are more representative of those seen in clinical practice. Andrews et al. used data from peer‐reviewed, retrospective, and prospective studies that assessed survival in riluzole‐treated vs. riluzole‐free patients with ALS in clinical practice [29]. These analyses incorporated a wider range of patients, including those with varying disease severity and comorbidities, than those typically eligible for RCTs. The resulting data suggested that the survival benefit of riluzole observed from clinical evidence may be greater than that estimated in RCTs. This review illustrates how HEOR and RWE can provide valuable insights that complement RCT data, validating efficacy across broader clinical populations and potentially uncovering the true magnitude of treatment benefit in clinical settings.

Building on the insights gained from clinical studies of riluzole, similar approaches have been applied to assess the efficacy and safety of edaravone. The following studies investigating edaravone (Radicava IV and Radicava ORS, Tanabe Pharma America, Inc., Jersey City, NJ, denoted “IV edaravone” and “edaravone oral suspension,” respectively, throughout the supplement) are summarized elsewhere in this supplement:

• A retrospective, administrative claims analysis found that patients prescribed IV edaravone over at least 12 months survived longer than those not prescribed the drug [30]

• Published post hoc analyses of IV edaravone efficacy in Study 19 [31, 32, 33, 34]

• Postmarketing pharmacovigilance safety data for IV edaravone were reported in separate published studies at 1‐ and 3‐years post launch [35, 36]

Clinical evidence derived from routine clinical practice is an increasingly valuable complement to RCTs in the generation of meaningful insights for HEOR. While methodological rigor and awareness of limitations are essential when applying clinical evidence, RWD offers important perspectives on the effectiveness of clinical treatment, patient experiences, safety, and healthcare resource utilization. In ALS, global registries and postmarketing studies have demonstrated how clinical data can extend knowledge beyond what is achievable through traditional trials alone. Ultimately, integrating high‐quality clinical evidence into HEOR can foster more informed healthcare decision‐making and improve outcomes for patients, clinicians, and healthcare systems alike.

Author Contributions

Agessandro Abrahao: participated in the conceptualization, study investigation, writing of the original draft, and writing review and editing throughout. Malgorzata Ciepielewska: participated in the conceptualization, writing of the original draft, and writing review and editing throughout. Lorne Zinman: participated in the conceptualization, study investigation, writing of the original draft, and writing review and editing throughout.

Ethics Statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflicts of Interest

A.A. received honoraria as a speaker for Tanabe Pharma America, Inc. and Amylyx. M.C. is an employee of Tanabe Pharma America, Inc. L.Z. received honoraria for consulting with Tanabe Pharma America, Inc., Biogen, Amylyx, and Cytokinetics.

Abrahao A., Ciepielewska M., and Zinman L., “Value of Clinical Evidence and Health Economics and Outcomes Research (HEOR) Studies,” Muscle & Nerve 73, no. S1 (2026): S7–S12, 10.1002/mus.70037.

Data Availability Statement

All relevant data are contained within the manuscript.