FormalPara Key Points

New drugs for Duchenne muscular dystrophy (DMD) are emerging rapidly. However, we believe these drugs are achieving regulatory approval prematurely.

In DMD, cardiorespiratory outcomes determine survival. Instead, new drugs are approved under an accelerated pathway based on outcomes such as tissue dystrophin levels and small improvements in timed function tests.

This article takes a critical look at the DMD drug development process and proposes ideas for better respiratory outcomes and improved regulatory pathways.

1 Introduction

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease inherited via X-linked recessive transmission that presents in childhood [1]. This ultimately fatal disease has an estimated pooled global birth prevalence of 19.8 per 100,000 live male births, and its life-limiting complications are cardiorespiratory in nature [2]. Contemporary standards include treatment with assisted ventilation, glucocorticoids (GCs), and cardiac medications [1, 3, 4]. These therapies have extended the average lifespan from around 20 years to the fourth decade of life [5, 6]. Overall, the clinical arc of DMD now spans different life stages, but its diagnosis and initial management remains anchored in childhood.

This is an exciting time for DMD stakeholders because new therapeutics are emerging. These include disease modifiers treating inflammation and fibrosis, dystrophin-restoration therapies based on genetic manipulation, such as exon skipping and nonsense read-through, and gene replacement and editing. Novel therapies are becoming available to patients and clinicians at an unprecedented rate [7]. However, although these therapies are theoretically promising, we and others believe that the latest DMD therapies are entering clinical use prematurely [8,9,10,11,12,13,14,15,16]. In this article, we identify potential causes, including issues with the accelerated regulatory approval process, and the suboptimal methodologies that are being used to study the effect of new drugs on respiratory function.

Integral to our topic is the accelerated regulatory approval pathway practiced by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This pathway is intended to foster innovation for rare diseases with an unmet need [17]. Its intent is admirable, but new DMD drugs are approved under the accelerated pathway based primarily on improvements in tissue levels of non-biologic, truncated dystrophin protein—a controversial surrogate outcome of unproven clinical significance—and on small improvements in scales that reflect muscle strength, such as timed tests and the North Star Ambulatory Assessment. These studies do not examine cardiorespiratory outcomes, but it is the cardiorespiratory complications of DMD that determine survival and the disease's major morbidities. Those complications occur in "older" individuals who are in the non-ambulatory stage of the disease. Instead, accelerated drug approvals are based on studies of young, ambulatory individuals—a group that essentially never experiences cardiorespiratory complications.

Another problem with the current drug development landscape relates to the methodology of studies that do obtain respiratory data [18]. Those methodologies are suboptimal, as they include the use of threshold levels of respiratory function as an outcome measure (thresholds that were intended as clinical strategies, not outcomes); the use of historical controls, whose results vary widely and are influenced by uncontrolled variables related to their observational nature; and the use of percent predicted forced vital capacity (FVC %pred) as an outcome measure, whereby a single rate of decline is inaccurately extrapolated across a wide range of age and physical strength, masking the fact that respiratory trajectory in DMD is heterogeneous: it changes with aging, encompassing rising, plateau, and declining stages of pulmonary function.

To a basic scientist, an effective drug for DMD might be one that causes higher dystrophin levels in samples of muscle tissue. To physiatrists and neurologists—the specialists who have historically been in charge of DMD clinical care and have a neuromuscular perspective—an effective drug might be one that causes a small improvement in standardized muscle strength scales and timed function tests, that is, "minimal clinically important differences" in tests such as the North Star Ambulatory Assessment or the time needed to rise from the floor [19].

Although changes in muscle strength and timed function tests in young, ambulatory populations have important merits, we believe they are not the best way to assess whether a drug will be clinically effective. The key point of our paper is that, for a drug to be considered effective, it must demonstrate improvements in cardiorespiratory function. That definition of "effectiveness" drives our recommendation that cardiorespiratory outcome measures should be integral to DMD drug studies. Our respiratory perspective, and our definition of "effectiveness" differs from those currently used to study, assess, and approve new DMD drugs. That difference underlies the critiques and recommendations for improvement that are the basis of this article. Alongside our critiques, we propose a new approach to respiratory methodology, specifically use of the absolute value of FVC (FVC abs) and its pattern with aging (the "Rideau plot") as the preferred respiratory outcome measure, and the prospective acquisition of natural history data, to minimize the effect of variables that can confound the databases currently used as historical controls.

What makes our views potentially controversial (and well-suited to a Current Opinions article) is the fact that a neuromuscular perspective drives the current DMD drug development process. This makes the implications of our contrasting respiratory perspective potentially quite disruptive of the status quo.

2 Search Strategy

For this narrative review of the literature, we identified FDA-approved drugs for DMD and the associated regulatory proceedings using the search term “Duchenne” at the FDA website and reviewed all related information, such as Drug Trials Snapshots, Center for Drug Evaluation and Research reports, approval announcements, prescriber information, the ClinicalTrials.gov website, and related published scientific articles (https://www.fda.gov/)

An example follows: https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots. FDA-approved drugs were cross-checked on the Parent Project Muscular Dystrophy Duchenne Drug Development Pipeline website (https://www.parentprojectmd.org/duchenne-drug-development-pipeline/) and through web searches.

Similar searches were conducted to obtain the EMA-approved drugs list and related proceedings (https://www.ema.europa.eu/en/homepage).

The site ClinicalTrials.gov was queried for all drugs.

References were identified through broad searches of PubMed and Embase (Elsevier) using the search terms “Duchenne” AND “name of FDA-approved drug”. For PubMed searches, the filter “Clinical Trials” was used from publication dates 2010 to 2024. For Embase, study types (“phase 2 clinical trial” OR “phase 3 clinical trial” OR “clinical trial” OR “clinical trial topic” OR “postmarketing surveillance”) and publication type (“Article”) for publication years 2016–2024 were used. Only articles published in English were included.

For this article, studies and data reports identified in the searches and references within those sources, and the authors' personal files, were reviewed for relevance and were selected for their focus on new therapies for DMD, and their representative methodologies, prioritizing a focus on cardiorespiratory outcome measures whenever available.

2.1 Additional Methodology

In Sect. 3.3 of this article, previously published data from the Canadian Neuromuscular Disease Registry (CNDR) were re-analyzed to better understand the idea of variability in historical databases and the effects of statistical smoothing on respiratory data used as controls. Patients are recruited to the CNDR in accordance with local ethics approval processes (see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902956/). Requests for research projects are approved by the CNDR advisory committee. For this analysis, de-identified registry data were shared with permission. Statistical smoothing was done via the locally estimated scatterplot smoothing (LOESS; Fig. 1a) and generalized estimating equation (Fig. 1b) modeling methods.

Fig. 1
figure 1

Trajectory of forced vital capacity (FVC) of individuals in the Canadian Neuromuscular Disease Registry (CNDR), expressed as FVC percent predicted for each age. a Observed data with a superimposed locally estimated scatterplot smoothing (LOESS) smooth curve; b fitted linear model using generalized estimating equations. In each panel, the grey band represents 95% confidence intervals

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3 Accelerated Regulatory Pathways and Respiratory Outcome Measures

DMD can be thought of as a serious condition with unmet need, criteria that qualify new therapies for accelerated regulatory approval [17]. Accelerated pathways aim to foster therapeutic innovation by expediting the availability of new drugs for rare diseases. However, this positive goal has inadvertently fostered pathways that allow new DMD drugs to achieve regulatory approval prematurely. We examine these ideas in the sections that follow.

3.1 SSHY Studies and the Accelerated Regulatory Pathway

The acronym ‘SSHY’ describes characteristics of the studies that allow new DMD drugs to qualify for accelerated regulatory approval: short (duration), small (size of study population), healthy (baseline medical status of subjects), and/or young (subjects’ age). Regarding our definitions, as discussed below, the clinical course of DMD typically extends into the third decade of life and beyond, with the most impactful cardiorespiratory complications occurring in "older," non-ambulatory individuals. In terms of this clinical context, we describe the ambulatory populations in the listed studies as "healthy" and "young," and the time intervals studied as "short."

In Table 1, we show all the new DMD drugs provisionally approved by the US FDA under the accelerated pathway and the SSHY characteristics of the studies on which the approvals are based. (The Table is current through July 1, 2024; additional details on recent approvals of the drug ELEVIDYS appear in Sect. 4.2.) The data used by FDA for each drug’s approval are shown. There is no central repository of this information; the sources are presented in the reference list [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]

Table 1 SSHY characteristics of studies of drugs for Duchenne muscular dystrophy approved under the US Food and Drug Administration (FDA) accelerated regulatory pathway (current to July 1, 2024).
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Of note, Table 1 includes almost all the therapies for DMD currently approved by the FDA under both accelerated and traditional pathways. For a continuously updated list, see https://www.parentprojectmd.org/duchenne-drug-development-pipeline/. The therapies that would complete the list are: deflazacort, one of the GCs that, like prednisone, is a part of DMD standard of care (SOC), and givinostat, a histone deacetylase inhibitor that was recently granted full FDA approval, whose aim is to decrease muscle damage due to inflammation, regeneration, and resulting fibrosis.

SSHY studies are faster and less costly to perform than traditional studies that require recruitment of larger populations and longer periods of follow-up. Their short duration means that study results can be generated quickly. However, SSHY studies have critical limitations. They cannot demonstrate long-term benefits; they focus on young, ambulatory populations; and they primarily assess functional motor strength, with outcomes such as rise and walk tests and the North Star Ambulatory Assessment scale. The clinical implication of these functional outcomes is uncertain—the results can be used, for example, to predict subsequent loss of ambulation (LOA) [51], but their correlation with systemic morbidities and with mortality is unproven. By contrast, cardiorespiratory dysfunction is the unequivocal cause of DMD’s most significant clinical morbidities and is associated with shortened survival. These include acute respiratory events, such as pneumonia and mucus plugging due to ineffective coughing, and chronic complications, such as the need for mechanically assisted ventilation via mask or tracheostomy. From a cardiac point of view, morbidities include acute and chronic presentations of cardiomyopathy—complications that can lead to heart failure and premature death. Cardiorespiratory complications like these essentially never occur in the young, ambulatory individuals comprising the population of current drug studies; instead, they affect older individuals who are in the late, non-ambulatory stage of DMD  [1, 4, 5, 52,53,54]. Moreover, when patients are treated with assisted ventilation to compensate for their chronic respiratory failure, cardiac function is the main determinant of their survival [54], yet a review of Table 1 reveals a complete absence of cardiac data.

Despite these limitations, under the accelerated pathway, results from SSHY studies suffice for provisional regulatory approval of new DMD drugs and their use on patients. Additionally, as shown in Table 1, regulators place a heavy emphasis on surrogate outcomes, especially the ability of a drug to increase tissue levels of non-biologic, truncated dystrophin protein. However, this surrogate outcome measure is controversial, in part because various aspects of its clinical effects—including minimum threshold levels of effectiveness, dose–response, and association with muscle strength scales—are unknown and/or unproven [36, 42, 43].

Although full regulatory approval is predicated on positive results from larger, better-designed confirmatory studies, those studies are often delayed by years, and no confirmatory studies have been completed involving any of the drugs in Table 1. Revocation of provisional approval by FDA is rare, even for drugs that have ultimately been found to be ineffective, have caused severe side effects, or have failed, in real-world experience, to replicate the results of the pilot studies that led to their approval  [10, 55,56,57,58,59].

In the next sections of this article, we focus on the respiratory outcome measures employed in current DMD drug studies. When those outcomes are suboptimal, drug efficacy cannot be accurately assessed.

3.2 The Limitations of Threshold Pulmonary Function Values

The first respiratory methodology that we discuss is the ability of a drug to delay the age at which individuals reach certain levels of pulmonary function. It has become common practice for studies to claim that a drug has respiratory benefits if it delays an individual’s decline to an FVC level of 60% predicted; an FVC of 50%; an FVC of 30% predicted; and/or an FVC of 1 liter[60,61,62,63,64,65,66]. In the case of the percent predicted FVC values listed above, these are the levels at which various respiratory treatments are recommended in the DMD care guidelines, including those published in 2018 [4] (i.e., lung volume recruitment at FVC ≤ 60% predicted; assisted coughing and ventilation at < 50% predicted) and in 2010 (ventilation at FVC < 30% predicted) [67]. These threshold levels were based solely on expert opinion to encourage anticipatory initiation of assisted ventilation. The thresholds are clinical strategies—they were not intended as outcome measures and have never been clinically validated (in one report, FVC < 50% predicted was actually a poor predictor of nocturnal hypoventilation  [68]). For example, no one knows whether initiating assisted ventilation exactly when FVC falls below 50% predicted results in better patient outcomes, such as delaying or preventing pneumonia, atelectasis, and/or hospitalizations, or whether this strategy prolongs lifespan. Similarly, a delay in time to reach FVC < 1 liter is the basis of inaccurate claims that a drug will prolong survival. In a seminal study published in 2001, a fall in FVC to a level < 1 liter was an ominous sign, with subsequent mean survival of 3.1 years, and 5-year survival of just 8%  [69]. However, that was a natural history study, and the patients were not treated with current SOC. With assisted ventilation, patients with DMD can experience prolonged survival at any FVC level, even when their FVC is unmeasurably low and they require continuous ventilatory support [6]. Thus, the claim that delaying FVC decline to < 1 liter prolongs survival is inaccurate and ignores the benefits of assisted ventilation  [4, 6, 54].

3.3 Concerns Regarding the Use of Historical Control Databases

Current studies of new DMD drugs use historical controls as their comparison group. The rationale is that DMD is a rare disease, making randomized trials difficult to perform. Currently, historical controls are derived from the databases of just a few academic consortiums  [70, 71].

However, results from historical databases are quite variable, allowing drug studies to choose the most pessimistic controls for judging a drug’s efficacy. Faster rates of pulmonary function decline in the control group make it easier to show that a new drug is beneficial by lowering the bar that the study drug must exceed to appear effective.

For example, in a recently published study of the monoclonal antibody pamrevlumab for the treatment of DMD [72], three different historical control databases were compared with the study drug. With the drug, FVC %pred declined 4.0% after 1 year of therapy. The databases discussed as potential controls varied in their rate of decline from 5.5 to 8.7% per year. No statistical significance was reported when the drug was compared with the Cooperative International Neuromuscular Research Group (CINRG); however, the drug was reported to have a statistically significant benefit when compared with a more pessimistic database, the phase III DELOS (Study of Idebenone in Duchenne Muscular Dystrophy) [72, 73]. Subjects who received pamrevlumab were also treated with a “stable dose” of GCs, and GCs are known to mitigate decline in pulmonary function in individuals with DMD  [64]. However, GC “dosages and schedules were not available” for one of the historical control groups (CINRG); and the historical control group chosen for the comparator (DELOS) was not receiving GC therapy [72, 73]. This example illustrates how studies of new drugs can pick and choose pessimistic historical control data that make it easier to demonstrate a beneficial drug effect. It also illustrates that comparability in key variables—in this case, GC therapy—can be lacking [72]. In the pamrevlumab study, the better pulmonary function displayed by the treated group could have been due to GC treatment and not the positive effects of the drug. This type of error reflects the observational nature of historical databases. When data are acquired prospectively, the nature and quality of relevant variables are known. Historical databases lack this rigor because of their observational nature  [64]. Their outcome data embody treatment by many different clinicians, pulmonary function testing by different technicians, and variations in institutional treatment protocols. Thus, their results are subject to the influence of numerous uncontrolled variables, with unpredictable effects. Indeed, variability in clinical management is a hallmark of historical databases. Numerous studies have examined real-world enactment of SOC, including GCs [64]. They have found that adherence to the standards is low, implementation varies between centers, and the reasons for poor implementation are complex [74,75,76,77,78]. Consistent with these findings, databases currently used as historical controls fail to report crucial details on variability in GC formulations, doses, and schedules; relevant treatment changes and pauses; and compliance  [79,80,81]. Despite these limitations, use of historical controls is now customary  [81].

A deeper examination reveals that GC treatment is just one example of the uncontrolled variables affecting historical databases. These variables can be categorized by their origins: external variables, including SOC such as GCs, assisted ventilation, assisted coughing, and lung volume recruitment [82]; intrinsic variables, including a patient’s pulmonary phenotype, which can make their respiratory course unexpectedly mild or severe; the presence and severity of scoliosis, if applicable; and technical variables, such as the fact that height measurements can become inaccurate when patients lose ambulation, affecting the calculation of their FVC %pred [83].

All these variables affect pulmonary function; their influence can be substantial, and their nature and impact will vary. For example, one individual in the historical control group may have a detrimental pulmonary phenotype; another individual might be non-compliant with GC therapy. The pulmonary function of each of these individuals will be worsened, but the causes differ, as may the severity. Considering these variables, it is unsurprising that databases used as historical controls report wide variability in their annual rate of decline of FVC %pred, as described above.

To better understand how historical controls may inaccurately mask pulmonary function variability, we examined data from the CNDR, a large multicenter database of more than 400 patients  [84,85,86]. With the support of the CNDR, we re-analyzed their respiratory data and statistically converted individual pulmonary function results into a single annual rate of decline in FVC %pred, as is done by the databases currently used as historical controls. Figure 1a shows the raw data for FVC %pred by age for individuals aged 10–18 years, the age bracket used by control databases, including CINRG. As discussed, there is a high degree of respiratory variability, with a wide span and considerable scatter of the individual values of FVC %pred. Online Resource 1 in the electronic supplementary material shows that changes in FVC %pred are not constant but instead vary widely from year to year within the age bracket. Finally, Fig. 1b shows the same data in the form that is used for controls—a single, constant rate of decline across the entire age bracket. Overall, the statistical analysis employed by historical controls results in a single, constant rate of decline that inaccurately masks the intrinsic variability of the study population (i.e., variability in individual values of FVC %pred and variability in the annual rate of FVC %pred decline). Our analysis illustrates a flaw in existing historical databases, and the findings are not likely due to the unique characteristics of CNDR. Canada has a publicly funded national health system, and individuals with DMD receive care at specialized centers. If anything, this standardized approach to treatment should minimize the effect of uncontrolled variables on pulmonary function  [86].

The CNDR data also illustrate how, when historical databases such as CINRG choose the age bracket of 10–18 years as representative of their population, they are choosing the most pessimistic rate of decline [64]. The annual rate of decline of FVC %pred for the overall CNDR population is −3.19% per year. However, the rate of decline for the group aged 10–18 years is −5.1% per year. The same is true for the CINRG database: the age group 10–18 years displays the fastest rate of decline in the whole population  [64]. When this pessimistic rate of decline is reported as representative of the overall historical control group, it lowers the bar that the treatment group must attain, making it easier to claim efficacy for a study drug. The fact that this age group is the most pessimistic one supports our prior hypothesis about etiology of the variability. In that age group, a number of key events may occur: GC therapy may be discontinued, negatively impacting pulmonary function; LOA can occur, causing inaccuracies of height measurement and calculation of FVC %pred; and pulmonary phenotypes become divergent, with the potential for individuals to express an unexpectedly mild or severe course of respiratory function. Thus, the annual rate of decline in FVC %pred may be most severe in those aged 10–18 years because that is the age range when the largest number of uncontrolled variables are active, variables that confound the ability of historical control data to isolate and assess the effect of a new drug on pulmonary function.

Despite these concerns, a single rate of decline in FVC %pred is the respiratory outcome measure of choice reported by historical databases  [62, 63, 65, 72], and it is almost always used as the control comparator in studies of new drugs. Next, we examine the limitations of FVC %pred as an outcome measure in greater detail.

3.4 FVC % Predicted is a Suboptimal Pulmonary Outcome Measure

In patients with DMD, FVC %pred begins declining in childhood, at or not long after the earliest age that pulmonary function testing can be performed, and the decline continues throughout an individual’s lifespan  [64, 87].

Studies of new drugs have adopted FVC %pred, and its annual rate of decline, as their preferred respiratory outcome measure. First, a single rate of decline is determined statistically among individuals spanning an age range (typically 10–18 years); that rate of decline is assumed to remain constant  [64, 73]. Those are the historical controls, sourced from one of a few historical databases. Their rate of decline is compared with the rate among subjects treated with a study drug. If the rate of decline in the treated subjects is statistically better than the rate in the historical controls, a beneficial effect on pulmonary function is claimed.

However, the effect of DMD on pulmonary function varies over time and is a product of progressive muscle weakness, the hallmark of the disease. It is therefore inaccurate to apply a single, constant rate of respiratory decline to individuals as they age. For example, the age bracket 10–18 years typically spans the ambulatory to late non-ambulatory stages of the disease, reflecting progressive weakness with aging and heterogeneity of muscle strength.

It is helpful to understand pulmonary function in DMD in the context of unaffected individuals. In a healthy population, lung function rises through puberty, plateaus in early adulthood, and then declines from about 30 years of age  [88, 89]. The rate of rise in FVC abs is especially rapid in adolescence, corresponding to linear growth acceleration during puberty (Fig. 2). Overall, in a healthy population, linear growth is the primary driver of the impressive rise in pulmonary function that occurs from childhood into adolescence.

Fig. 2
figure 2

Lung function trajectory by age in healthy individuals

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Individuals with DMD are, of course, different from this healthy population. Their pulmonary function results from the effect of two opposing forces: linear growth, which causes FVC abs to rise, and progressive weakness, which causes FVC abs to fall. The relative influence of these two opposing forces varies with aging, resulting in three sequential stages of FVC abs over the lifespan.

In early childhood, corresponding to the ambulatory stage of the disease, the degree of weakness is mild, and children with DMD are also gaining height. Overall, linear growth predominates and FVC abs rises. Conceptually, this rising stage can be represented by the equation “Growth > Weakness” (Fig. 3). With aging, weakness worsens, and linear growth slows. In the early, non-ambulatory stage of DMD, the rise in FVC abs levels off and reaches a plateau. At this point, the influence of linear growth and progressive weakness are balanced. This plateau level of FVC abs remains constant for several years, and it is represented by the equation “Growth = Weakness” (Fig. 3). Finally, with additional aging, linear growth ceases but weakness is progressive. This corresponds to the late, non-ambulatory stage of the disease. With the influence of weakness unopposed, FVC abs falls until death. This is the declining stage of pulmonary function, and it can be represented by the equation “Weakness > Growth” (Fig. 3).

Fig. 3
figure 3

Lung function modified by Duchenne muscular dystrophy portrayed with a Rideau plot (absolute value of forced vital capacity [FVC] by age), showing three stages of pulmonary function (pulm fx): rising (green), plateau (blue), and declining (red)

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These three stages of pulmonary function—rising, plateauing, and declining—exist in a healthy population, as shown in Fig. 2. When modified by DMD, the pattern changes to the one illustrated in Fig. 3. The stages of pulmonary function specific to individuals with DMD were described by Rideau et al.  [90] over 40 years ago. We call this graphical representation of FVC abs on the y-axis plotted by age in years on the x-axis, a “Rideau plot.”

Referring now to Fig. 4a and b, we compare a Rideau plot of FVC abs to FVC %pred  [64, 84, 87]. In Fig. 4a, a single rate of decline in FVC % pred is ascribed to all individuals aged 10–18 years. When results from the same age bracket are viewed as a Rideau plot, in Fig. 4b, we see that, instead, pulmonary function during this age range is dynamic: it rises, plateaus, and then declines, spanning all three pulmonary function stages. Unlike FVC %pred, with its single, constant annual rate of decline, the Rideau plot has the potential to be a valid outcome measure because it accurately indicates the varying influence of linear growth and progressive weakness across the age span.

Fig. 4
figure 4

Trajectory of forced vital capacity (FVC) among individuals aged 10–18 years expressed as a percent predicted, where the rate of decline is portrayed as constant throughout the age range, and b absolute values, where it can be seen that forced vital capacity changes with age and spans three stages of pulmonary function: rising (green), plateau (blue) and declining (red)

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The Rideau plot also has potential to become the best way to assess the effect of a drug on pulmonary function. This can be seen by considering the effect of GCs, a key component of DMD SOC. That effect is seen in Fig. 5 in the form of two Rideau plots: pulmonary function in individuals with DMD not treated with GCs (the lower curve) and pulmonary function modified by treatment with GCs (the upper curve). The values of FVC abs portrayed in the figure cover ages 10–18 years [64, 73, 87].  Thanks to the Rideau plots, it can be seen that treatment with GCs causes peak FVC abs to reach a higher value, that the peak value is achieved at a later age, and that the subsequent plateau level is maintained slightly longer. Thus, the declining stage starts at a later age, and the decline commences from a higher value of FVC abs. This allows GC-treated individuals to maintain a better level of pulmonary function longer. In the untreated individuals, FVC abs in those aged 10–18 years spans all three stages of pulmonary function: rising, plateauing, and declining. In contrast, with GC therapy, individuals remain in the rising stage of pulmonary function longer and do not reach their peak value of FVC abs until about 18 years of age. The diverging pattern of the two Rideau plots in Fig. 5 strikingly illustrates the beneficial effect of GCs, including the timing, magnitude, and nature of those beneficial effects. That level of detail is crucial to assess clinical relevancy and to apply the findings to clinical practice, for example, to decide whether a patient is a steroid responder. That level of detail can also inform the design of drug studies assessing the effect of different GC formulations and doses as well as the effect of adding a new drug to pre-existing therapy with GCs.

Fig. 5
figure 5

Absolute forced vital capacity (FVC) in individuals aged 10–18 years, with (red) and without (blue) glucocorticoid (GC) therapy

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Regarding assessment of new DMD therapies, FVC abs can also provide conceptual clues to the mechanism of a drug’s benefit. Returning to Fig. 3, recall that, in the rising stage, the opposing forces determining pulmonary function can be understood by the equation Growth > Weakness. This is true from the point of view of untreated natural history. However, when considering the effect of a drug—especially GCs, which are potent linear growth inhibitors  [91]—the drug’s effect on weakness is the main determinant of its beneficial effect. This therapeutic effect is best understood when the equations in Fig. 3 are expressed in a different form: in the rising stage of pulmonary function, Growth/Weakness > 1; in the plateau stage, Growth/Weakness = 1; and in the declining stage, Growth/Weakness < 1. The concept is illustrated by the upper curve in Fig. 5, which shows that, with GC treatment, pulmonary function remains in the rising stage throughout ages 10–18 years. In terms of our equations, this beneficial pattern appears attributable to a GC-induced improvement in muscle strength. That is, with GC therapy, Growth/Weakness remains > 1 and FVC abs rises longer than expected because GCs are causing Weakness to decrease, despite GC inhibition of Growth. The Rideau plot helps us to understand the mechanism of the beneficial effects, at a conceptual level.

Unlike the impressive benefits of GCs illustrated by FVC abs in Fig. 5, when the same data are examined using FVC %pred, annual decline in the GC-treated group is only slightly better than that in the untreated group (e.g., − 5.44% per year GC-treated vs − 6.06% per year GC-untreated in the CINRG database)  [64]. With FVC abs, it is easy to see how GCs change the levels and pattern of pulmonary function in a way that suggests compelling clinical benefit. By contrast, annual change in FVC %pred is portrayed by a single, constant negative value, even in the GC-treated group, suggesting a relentless functional decline. The timing, magnitude, and nature of the benefits are less visible, and the effect of GC therapy looks marginal, that is, a small attenuation in rate of decline that is statistically significant, but whose clinical significance is much less obvious.

Our discussion reveals the potential advantages of using FVC abs instead of FVC %pred to study the effects of a drug on pulmonary function. In the next section, we suggest ways to use FVC abs to improve the design of future studies evaluating the effect of new drugs on individuals with DMD.

4 Recommendations

The following ideas apply to the study of new therapies for DMD. The ideas are conceptual and have not yet been validated. To do so will require collection and analysis of prospectively acquired data in individuals with DMD who have received consistent SOC, including GC therapy.

4.1 In Search of a Better Respiratory Outcome Measure

A good respiratory outcome measure will have the ability to predict an individual's long-term pulmonary function early in the course of their disease, providing accurate natural history control data for therapeutic studies. It will not be influenced by extraneous variables, and thus will accurately isolate and assess the effect of a study drug on pulmonary function. In this section, we discuss how FVC abs and its pattern with aging, the Rideau plot, can potentially fulfill these goals.

As illustrated by Fig. 3, certain key features of the Rideau plot have potential to predict long-term pulmonary function and might even turn out to be early predictors of future pulmonary function. Examples of these components include the duration and slope of the rising stage of pulmonary function, the age of attainment and value of the peak FVC abs, the duration of the subsequent plateau, and the initial age and rate of fall of the declining stage of pulmonary function. Each of these characteristics of the Rideau plot has the potential to be a clinically meaningful outcome measure. For example, perhaps a higher FVC abs, achieved at an older age, predicts a mild respiratory course across the lifespan. Evaluation of this strategy will require prospectively acquired data, from individuals with DMD receiving optimal SOC, including treatment with GCs. Prospectively acquired data are crucial because, as we have discussed, current historical control databases are observational and neither sufficiently detailed nor reliable enough to assess adherence to GC therapy, an uncontrolled variable that can have a profound effect on pulmonary function.

A related concept is to identify patterns of FVC abs, occurring at a young age and over a short period of time, that predict long-term pulmonary function. Such biomarkers would make drug studies easier to accomplish. As a hypothetical example, suppose an unusually rapid rise and an unexpectedly high value of FVC abs over the 3 years spanning ages 7–10 years predicts favorable pulmonary function with aging. With this methodology, the respiratory effect of a new drug could be assessed in young individuals who are treated over relatively short periods of time. We call this approach minimum reliable periods of observation (MRPOs). The idea is theoretical. Prospective studies will be needed to determine the viability of the MRPO approach and whether there are specific pulmonary function parameters and time intervals that have the requisite predictive power.

The strategies discussed above are ways that Rideau plots might be used to identify respiratory phenotypes (i.e., patterns of FVC abs over the lifespan that reflect an individual's severity of respiratory impairment). Among individuals with DMD, respiratory function can vary widely, even among brothers who share an identical dystrophin mutation  [92]. This variability is different from that described in Sect. 3.3, where we discussed the limitations of historical controls. When historical controls are employed, numerous extrinsic, uncontrolled variables, including differing SOC, can cause pulmonary function variability that is confounding. If the data are collected prospectively in individuals treated with verifiable and consistent GC dosing, then variability in FVC abs has the potential to help identify non-overlapping respiratory phenotypes. This intrinsic phenotypic variability may be common, and genetic modifiers are the likely cause [7]. Although certain associations have been reported, these modifiers are still investigational in nature [92]; thus, the ability to profile an individual's modifier genes at a young age and predict their respiratory phenotype is still theoretical. Meanwhile if, as discussed above, key features of the Rideau plot and use of MRPOs can categorize individuals by their respiratory phenotype, then DMD drugs could be studied using phenotypically homogeneous cohorts. That would be an improvement over current methodologies, as it would assure that the observed results are due to the study drug and not the presence of subjects who possess an unusually mild or severe respiratory phenotype. This grouping of individuals into homogeneous phenotypic cohorts could help to translate the use of FVC abs to the study of DMD populations, not just individuals.

Another potential way to identify respiratory phenotypes early in the clinical course is to use age at LOA [93]. Humbertclaude et al. [93] correlated age at LOA with the three respiratory phenotypes described by Rideau et al. [90]. LOA at < 8 years of age predicted the severe respiratory phenotype, LOA between 8 and 11 years of age predicted the typical respiratory phenotype, and LOA at > 11 years of age predicted the mildest phenotype. Subjects with the same respiratory phenotype could be identified by their age at LOA, allowing creation of homogenous study cohorts. To evaluate the viability of this strategy, it will be necessary to replicate the Humbertclaude study in GC-treated individuals, as the Humbertclaude study involved individuals who were steroid naïve, and GCs both improve respiratory function and prolong ambulation [1, 4]. Once again, those studies will need to be done prospectively, as existing historical control datasets are neither sufficiently detailed nor reliable enough to assess adherence to GC treatment.

Our focus on FVC is not meant to detract from future research on alternative respiratory outcome measures. Various tests have been proposed as potential respiratory outcome measures, including the sniff inspiratory pressure maneuver, standard maximal inspiratory and expiratory pressures, peak cough flow, breathing patterns and ventilatory response to carbon dioxide, sleep studies, and various invasive maneuver [4, 68, 94,95,96,97].

That said, FVC embodies a group of benefits that other outcomes cannot claim: it is the best studied respiratory function parameter in individuals with DMD. It is the primary respiratory function test parameter in expert consensus statements and is fundamental to their assessment and management recommendations[4, 94]. The technical standards for FVC test validation can be applied consistently across study centers, improving the reliability of multicenter trials. Those technical criteria make FVC less vulnerable to variable patient effort, a common source of false results in volitional testing. FVC is noninvasive and well-known to respiratory technicians and clinicians, who are comfortable with its technical aspects and interpretation. Lastly, the equipment needed to perform the test (which can be as simple as a portable spirometer) is inexpensive and likely to be available, even in medically challenged settings.

Finally, there is a need to gather cardiac data in this field. Cardiac phenotypes have not been definitively characterized in DMD. In one single-center observational study, there were two phenotypes: severe, with onset of left ventricular dysfunction (LVD) at < 18 years of age, and mild, with onset of LVD at ≥ 18 years of age. Once LVD commenced, cardiac dysfunction was progressive, leading inexorably to congestive heart failure, at which point mean survival was just 8 months [98]. Prospectively collected cardiac data in populations treated with SOC, including GCs and cardiac medications, are urgently needed, since cardiac complications can be life limiting. Indeed, when individuals with DMD are treated with assisted ventilation, cardiac function has been reported to be the main determinant of their survival  [54].

4.2 Case Studies and the Implications of Maintaining the Status Quo

We have presented a critical review of the accelerated regulatory pathway, an in-depth examination of challenges in the methodologies used to study new DMD drugs, and our proposals for better respiratory outcome measures. A related issue is to consider the results of the current drug development process and the potential harms of maintaining the status quo.

An action by the EMA illustrates this concept. The EMA recently revoked approval for the drug ataluren [11]. The drug had been granted conditional marketing authorization in 2014. Subsequently, a series of publications supported by the drug’s developer appeared in the scientific literature touting the safety and effectiveness of the drug, including pulmonary function benefits  [60,61,62]. 

Ultimately, the EMA deemed the drug ineffective based on negative results from a trial they mandated in 2016 and the methodological concerns found in their review of other available study data [11]. The EMA recently confirmed the revocation of ataluren’s approval after an appeal of the original decision [99].  Of note, the EMA’s re-examination again focused on methodological limitations in studies that reported positive results, including the use of historical controls, as described in this article. The EMA's decision shows that, even when presented with multiple studies purporting to show a drug's benefits, regulatory organizations must examine the quality of study methodologies to determine whether a drug is likely to be efficacious.

Indeed, ataluren’s published studies display several of the methodological concerns we have discussed in this article: a young study population; use of pessimistic historical control data for the comparison group; uncertainties regarding SOC in historical control comparison subjects, including potential inconsistencies in GC treatment; and suboptimal outcome measures, including reliance on unvalidated threshold pulmonary function levels as evidence of drug effectiveness  [60,61,62]. 

Overall, the EMA’s fast-track approval process enabled the use of an ineffective drug in patients for almost 10 years. Patients suffered opportunity cost: treatment with a potentially more effective drug was precluded by their use of ataluren. Individuals taking ataluren may have to stop treatment and have a psychological cost: abrupt discontinuation of a therapy they have relied upon [55]. Payors, including national health services, used their finite resources to pay for an ineffective therapy (in the case of ataluren, an estimated $495,000 per year per patient) [100]. Similarly, limited effectiveness and lack of cost–benefit justification have been identified for other DMD drugs receiving fast-track approval, such as eteplirsen  [12,13,14, 36].

Another drug that received accelerated approval for a narrow age range, the adenovirus-associated (AAV) gene therapy delandistrogene moxeparvovec-rokl (ELEVIDYS), failed to achieve its primary outcome measure in a recent randomized study that was intended to “confirm” its accelerated approval. [43, 101,102,103]. Despite this finding, the US FDA fully approved this drug based on modest improvements in secondary outcome measures, such as a 0.64 s improvement in the “time to rise” test  [103]. Patient eligibility was greatly expanded from its current provisional approval for individuals aged 4–5 years only to full approval for all ambulatory individuals aged 4 years and older, and provisional approval for non-ambulatory individuals. The latter was primarily based on surrogate tissue dystrophin levels in eight subjects and on data regarding the performance of upper limb test from just six individuals  [103]. AAV gene therapies as a group have also been associated with adverse effects that can be severe or even fatal (e.g., hepatoxicity, multi-organ angiopathy, myocarditis), and which can limit options for future therapy (adenoviral antibody production) and the duration of therapeutic effect (immune response to and/or dilution and loss of the delivered transgene) [104]. The data from the "confirmatory" study reported 21 serious adverse effects in 63 treated subjects, including one case of hepatotoxicity/liver injury and a case of myocarditis [103]. 

Concerns about accelerated regulatory pathways, and the lack of effectiveness of the drugs they approve, are broadening. All the antisense oligonucleotide exon-skipping therapies have recently come under scrutiny, and their safety, efficacy, and financial cost have all been questioned  [105,106,107]. When drugs that were provisionally approved are found to be ineffective or unsafe and withdrawn from the market, it may appear that the system is working. Instead, the withdrawal of these drugs from patient use is often delayed by years, the treated patients experience opportunity cost when they become ineligible for potentially better therapies, and the financial cost to the healthcare system is often impressive. As discussed in recent publications, accelerated pathways can have far-reaching negative effects [106, 107].

4.3 Conclusions

It is not our intention to disparage the need for innovative DMD therapies or to minimize the power and importance of individuals with DMD, their caregivers, and their advocates as they champion expeditious development of new drugs. However, with this article, we provide support for the view that changes are needed in the way those new drugs are developed [106,107,108]. We hope that the logic of our arguments will compel stakeholders to find consensus on the need for reforms, such as integration of cardiorespiratory outcomes into study methodologies, and improvements in the regulatory process, to facilitate better treatments for individuals with DMD.