Managed Care Strategies and Considerations

To claim CE credit for this activity, please visit https://www.pharmacytimes.org/courses/coverage-access-and-managed-care-decision-making-evidence-for-exon-skipping-therapies-in-duchenne-muscular-dystrophy

Total Cost of Care

DMD is associated with a substantial and progressively increasing economic burden. Total health care spending is estimated to be 32 times higher in DMD, exceeding $100,000 more per patient per year, compared to controls.⁶⁴ Pharmacy spending alone is approximately $45,000 more per patient per year.⁶⁴ Costs due to increased health care resource utilization, including office visits, inpatient stays, and specialist visits, were significantly higher in patients with DMD compared with healthy controls.⁶⁴ As the disease advances, patients require lifelong multidisciplinary care; increasing medical interventions, including durable medical equipment, assistive technologies, and home modifications; and substantial caregiver support, all of which result in considerable direct and indirect health care expenditures. A recent systematic review demonstrated that the economic burden of DMD rises substantially with disease progression, with annual total costs increasing as patients transition from ambulatory to nonambulatory stages.⁶⁴

Value-Based Care

The rapid expansion of disease-modifying therapies for DMD has fundamentally altered the treatment landscape while introducing considerable financial challenges for health care systems. Novel therapies, including exon-skipping agents, gene therapy, and emerging mutation-agnostic treatments, are associated with uncertainty regarding acquisition costs, long-term durability, and clinical benefit. Consequently, managed care organizations must balance timely patient access to innovative therapies with responsible stewardship of finite health care resources. Achieving this balance requires evidence-based coverage policies that support appropriate treatment selection while considering the total value of therapy across the disease continuum.

Coverage decisions for DMD therapies are further complicated by the FDA’s Accelerated Approval Program, which has enabled earlier access to exon-skipping therapies and, initially, delandistrogene moxeparvovec.^32,65 Under this pathway, approval may be granted for therapies that address serious or life-threatening diseases when they demonstrate an effect on a surrogate end point, such as dystrophin levels in DMD, that is reasonably likely to predict clinical benefit.⁶⁵ Manufacturers are required to conduct postmarketing confirmatory trials to verify anticipated clinical benefit, and the FDA may withdraw approval if these studies do not demonstrate benefit or are not completed with due diligence.⁶⁵ Nevertheless, the interval between accelerated approval and completion of confirmatory studies may span several years.

DMD exemplifies the type of disease for which the Accelerated Approval Program was designed: It affects a relatively small patient population, progresses irreversibly over time, and has substantial unmet therapeutic need, making large or prolonged trials using traditional clinical outcomes challenging. At the same time, the well-characterized relationship between dystrophin deficiency and DMD provides a biologically plausible surrogate end point that can be measured earlier, while confirmatory studies evaluate whether biomarker improvements translate into meaningful clinical benefit.

Despite this, controversy has surrounded the approval of several DMD therapies, namely eteplirsen and delandistrogene moxeparvovec. Some FDA reviewers were uncertain that the modest increases in dystrophin seen with eteplirsen would translate to meaningful clinical benefit.⁶⁶ Still, the therapy was ultimately granted approval in 2016, requiring a 2-year confirmatory study with a projected completion date of 2021.^32,66 No information is available on the status of confirmatory data as of the time of writing in 2026. Additionally, despite concerns raised by FDA reviewers regarding limitations in the data used to demonstrate delandistrogene moxeparvovec’s ability to improve functional outcomes, the therapy was granted full approval for ambulatory patients with DMD and accelerated approval for nonambulatory patients in 2024.⁶⁷ These decisions were unusual, as the director of the Center for Biologics Evaluation and Research within FDA overrode the conclusions of the review team regarding the efficacy of the therapy, stating, “The benefit to risk considerations are favorable, taking into account the existing uncertainties, such as the ultimate duration of response, which is not yet known, as well as the significant unmet need.”⁶⁸ The subsequent removal of the nonambulatory indication due to safety concerns, as previously described, demonstrates the challenge of offering novel products for patients with an unmet need based on the limited data available to guide approval decisions.

These few events may inappropriately cast a negative light on a program that otherwise provides earlier access to promising therapies for patients with few treatment options. In fact, only 15% of therapies granted accelerated approval have been withdrawn since the inception of the program in 1992.⁶⁹ Still, accelerated approval presents challenges for payers. Coverage decisions must often be made before confirmatory trial data capturing functional outcomes, durability of response, or long-term safety data are available.⁷⁰ Reliance on surrogate end points introduces uncertainty regarding the magnitude of meaningful clinical benefit, with 38% of payers reporting a lack of confidence in applying surrogate end points, like dystrophin levels, to formulary decisions.⁷⁰ Additionally, relatively small clinical trials, delayed confirmatory trials, and evolving safety profiles may complicate assessments of comparative effectiveness and long-term value, requiring payers to establish a process to review additional evidence as it becomes available.⁷⁰

To address these challenges, the FDA has released 3 draft guidance documents to reform the accelerated approval process.^71-73 For example, the guidance encourages drug sponsors to provide details as to why the FDA should consider a surrogate end point to be “reasonably likely” to predict a clinical outcome and recommends that confirmatory trials be underway at the time of accelerated approval.⁶⁹ The Institute for Clinical and Economic Review (ICER) suggests 5 areas for continued improvement, including strengthening evidence foundations, improving transparency and accountability, improving the basis for shared decision-making, aligning financial incentives with evidence and value, and waiving cost-sharing, strengthening oversight and enforcement.⁶⁹

Additionally, many payers have adopted evidence-based utilization management strategies that facilitate patient access to therapies approved through accelerated approval while promoting appropriate use. Prior authorization criteria may appropriately include confirmation of a molecular diagnosis of DMD, documentation that the patient’s mutation is amenable to a mutation-specific therapy when applicable, alignment with FDA-approved eligibility criteria, specialist prescribing or consultation, relevant baseline clinical assessments, completion of therapy-specific safety screening and monitoring, and ongoing clinical assessments to justify reauthorization. At the same time, payers are encouraged to avoid requirements that add administrative or clinical burden without meaningfully improving treatment selection, such as repeat genetic testing after a confirmed molecular diagnosis, routine repeat muscle biopsies, mandatory 6-minute walk testing in nonambulatory patients, arbitrary age restrictions extending beyond FDA labeling or the supporting evidence, or other requirements that are not biologically or clinically appropriate. Some payers may adopt criteria narrower than FDA labeling based on their P&T committee’s assessment of the clinical evidence available when the policy was developed, particularly when approval relies on surrogate end points or long-term clinical benefit remains uncertain.

These strategies are intended to ensure that high-cost therapies are used in appropriate patients who are most likely to benefit while supporting ongoing policy evaluation as additional evidence emerges. Payer considerations are summarized in TABLE 4.

Patient Journey

The patient journey is characterized by complex, lifelong care that spans multiple health care settings, specialists, and payer benefits.⁷⁴ As treatment options continue to expand, patients and caregivers must navigate an increasingly fragmented health care system while managing the progressive physical, emotional, logistical, and financial challenges of the disease. From diagnosis through advanced disease, successful care requires coordination among specialists such as neurologists, cardiologists, pulmonologists, and endocrinologists; genetic counselors; physical and occupational therapists; social workers; and primary care providers.⁷⁴ This multidisciplinary approach has become increasingly important as disease-modifying therapies are integrated into routine clinical practice alongside comprehensive supportive care.

The complexity of the patient journey is further compounded by benefit design. Many health plans administer DMD therapies under both the pharmacy and medical benefits, requiring patients with carved-out benefits and their caregivers to coordinate care across separate benefit administrators. Oral therapies, including corticosteroids, vamorolone, and givinostat, are typically covered under the pharmacy benefit, whereas infused therapies such as exon-skipping agents and gene therapies are generally reimbursed through the medical benefit.⁷⁵ These carved-out benefit structures may require separate prior authorization processes, different specialty pharmacies or infusion providers, distinct case management programs, individual site-of-care requirements, and multiple cost-sharing arrangements. As a result, patients and caregivers may face additional administrative burden, delays in treatment initiation, and challenges in coordinating benefits across multiple entities.

Treatment decisions may also have important long-term implications for future therapeutic options. For example, administration of delandistrogene moxeparvovec generally precludes eligibility for future AAV-based gene therapy clinical trials. Further, although exon-skipping therapies may be continued or initiated following gene therapy based on evolving clinical evidence and individual patient circumstances, the optimal sequencing and combination of disease-modifying therapies remain areas of active investigation.⁴⁹ While the evidence is evolving, payer coverage policies may currently restrict coverage of exon-skipping therapies after gene therapy. Consequently, treatment selection requires careful consideration of current clinical status, future therapeutic opportunities, and the rapidly evolving treatment landscape through shared decision-making among patients, caregivers, and the multidisciplinary care team. Still, the absence of evidence, not necessarily the absence of effect, creates a challenge for payers as they attempt to balance the currently available clinical data with the needs of individual patients who may require combination or sequential therapy.

As therapeutic options have expanded, patient experience has become an increasingly important component of both regulatory and payer decision-making. The FDA’s Patient-Focused Drug Development initiative emphasizes the systematic incorporation of patient perspectives into drug development and regulatory evaluation, recognizing that traditional clinical end points may not fully capture outcomes that are meaningful to individuals living with rare diseases.⁷⁶ Similarly, ICER incorporates “Insights Gained From Discussions With Patients and Patient Groups” into its evidence assessments to contextualize clinical trial findings and better understand the lived experience of disease.²

A patient preference study demonstrated that individuals with DMD and their caregivers prioritize different treatment goals depending on ambulatory status.⁷⁷ Ambulatory patients emphasized preservation of existing function, improving muscle strength, and reducing fatigue, while treatment goals for nonambulatory patients included increased upper body strength and greater independence in ADLs.⁷⁷ Incorporating these patient-centered outcomes alongside traditional clinical end points is critical to treatment and coverage frameworks.⁷⁸

Assessing Novel Agents

The expanding therapeutic landscape for DMD presents the challenge of evaluating increasingly complex therapies while ensuring timely access for eligible patients. As mutation-specific therapies, gene therapies, and disease-modifying agents continue to emerge, coverage decisions extend beyond drug acquisition costs to consider long-term clinical value, durability of benefit, and the potential to alter disease progression and reduce health care resource utilization.

Traditional cost-effectiveness analyses based on quality-adjusted life years often face limitations when applied to rare diseases such as DMD because conventional models may not fully capture the broader value of therapies that preserve independence, delay disability, reduce caregiver burden, or improve quality of life.⁷⁹ Economic evaluations of emerging DMD therapies must adopt a lifetime perspective that considers both direct and indirect costs. Although many novel therapies are associated with substantial upfront expenditures, delaying major disease milestones, including loss of ambulation, ventilatory dependence, progressive cardiomyopathy, and institutional care, may reduce downstream health care utilization.^64,80

Emerging therapies with improved tissue targeting or mutation-agnostic mechanisms may further expand treatment algorithms in the coming years. Important questions remain regarding optimal sequencing, combination therapy, and the role of subsequent therapies following gene therapy administration.⁴⁹ In addition, given the rarity of the disease, the relatively small number of eligible patients, and the availability of approved disease-modifying therapies, randomized head-to-head clinical trials comparing novel agents are unlikely to be feasible. Although indirect treatment comparisons and network meta-analyses may be used to inform comparative assessments, these analyses must be interpreted cautiously. Differences in trial design, including ambulatory status requirements, permitted background therapies, and the use of external or historical controls, can substantially influence observed treatment effects. Comparisons between therapies are generally unavailable, limiting the ability of clinicians and payers to determine the relative efficacy and safety of competing treatment options.

Rather than delaying access until mature outcomes and comparative efficacy data become available, managed care organizations are tasked with developing evidence-based coverage policies using the best available data at the time of approval while recognizing that these policies will require ongoing reassessment. Coverage criteria must be sufficiently flexible to evolve alongside the evidence base, allowing incorporation of new clinical findings, expanded indications, or changes in treatment sequencing. At the same time, utilization management strategies are designed to promote appropriate use without creating unnecessary administrative burden.⁸¹ In DMD, “time is muscle”: Because progressive muscle loss is largely irreversible,⁷ administrative delays or coverage criteria requiring patients to reach a predefined level of disease severity before treatment may sacrifice functional muscle that therapy is intended to preserve rather than recover.

Conclusion

DMD remains a devastating, progressive neuromuscular disorder that imposes substantial physical, emotional, and financial burdens on patients, families, caregivers, and the health care system. However, the landscape of FDA-approved therapies for DMD has advanced remarkably over the past decade. What was once limited to supportive care now includes multiple disease-modifying therapies, including 4 FDA-approved exon-skipping therapies and 1 gene therapy available, as well as next-generation exon-skipping agents and other innovative approaches progressing through clinical development. These advances offer renewed optimism that earlier intervention and more effective treatments may further alter the natural history of DMD.

The pace of therapeutic innovation in DMD is unlikely to slow. Payer benefit design strategies that remain static will rapidly become outdated. Future managed care strategies must therefore prioritize flexibility, timely incorporation of emerging evidence, and policies that facilitate appropriate patient access while supporting ongoing reassessment as the therapeutic landscape evolves. Although many recently approved therapies carry cost considerations and uncertainty regarding long-term outcomes, payers have increasingly recognized the high unmet need in DMD and have generally provided broad coverage for eligible individuals. Going forward, coverage policies necessitate reflecting the evolving evidence base, balancing clinical effectiveness, safety, and long-term value while remaining adaptable as additional data become available. Importantly, formulary and coverage decisions should continue to incorporate not only clinical and economic evidence but also the needs, perspectives, priorities, and lived experiences of individual patients and their caregivers, recognizing that preserving function, independence, and quality of life are outcomes that matter most to the DMD community. n

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