Labeling of Disease-Modifying Therapies for Neurodegenerative Disorders

Abstract

Neurodegenerative disorders are characterized by progressive degeneration of nerve cells resulting in functional decline of cognition and/or movement. As the prevalence of many of these disorders increases with the aging global population, there is an urgent need for disease-modifying drugs that will halt or slow the progression of these devastating diseases. A summary of the scientific information needed to guide the safe and effective use of a drug is provided in the product label in which the indication section should clearly state the treatment concept, e.g., distinguish between symptomatic, preventive, and curative treatments. However, a review of the United States (US) and European Union (EU) product labels for disease-modifying multiple sclerosis (MS) drugs reveals that the indications are not aligned with the regulatory guidance on labeling. Indication claims such as "delay of accumulation of disability" and "slowing of disease progression" were previously accepted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, all recently approved MS drugs include no such specification of the treatment concept in the label indication sections despite similar clinical data packages supporting the approvals. Coincidently, the FDA and EMA therapeutic guidelines pertaining to development of drugs for treatment of neurodegenerative disorders have changed from providing recommendations for specific disease modification label claims to a more general focus on the clinical development approach. Our analysis of MS drug labels could imply that the FDA and EMA may be unlikely to accept disease modification-related indication claims for drugs to treat neurodegenerative disorders in general. We envision that a potential disease-modifying effect is more likely to be inferred from the label descriptions of the mechanism of action, clinical efficacy data and trial design, and target patient population. This poses a challenge for communication of the clinical benefit in a language that can be easily understood by patients and prescribers.

Keywords: European Medicines Agency; US Food and Drug Administration; disease modification; indication; label; neurodegenerative disorders; regulatory guidelines.

Figure 1

Historical development in FDA (A) and CHMP (B) Alzheimer's disease (AD) development guidelines with respect to disease modification terminology and reference to actual label claims. Examples of terminology applied in the respective guidelines are shown. The first CHMP guideline for development of drugs to treat AD and other dementias was adopted by the CHMP in 2008 (30). A CHMP discussion paper on AD and other dementias was published in 2014 (31) as part of the revision of the guideline, which was finally adopted by the CHMP in 2018 (3). The FDA released its first draft guidance pertaining to AD (antidementia drugs) in 1990 (32). The FDA draft guidance for industry pertaining to the pre-dementia stages of AD was first published in 2013 (33) and replaced with an updated version in 2018 (7).

Figure 2

Original indications (abbreviated) of medicines approved for treatment of multiple sclerosis in both the US (FDA) and the EU (via the EMA Centralized Procedure). Numbers in oval blue and read shapes signify approval year. Blue/gray shading signifies that the sponsor applied for an indication with disease modification-related terminology in the EU. Daclizumab was withdrawn in the EU in 2018.

Figure 3

Summary overview of the pivotal clinical data (type of control group and clinical outcomes) supporting FDA and EMA approvals of the relapsing MS indication. Relapse measures included one or more of the following efficacy endpoints: annual relapse/exacerbation rate or proportion of patients free from relapses/exacerbation at a given time. Disability progression measures included an evaluation of progression of disability using the Kurtzke's Expanded Disability Status Scale (EDSS). MRI measures included MRI derived parameters used for monitoring CNS lesions. Green, statistically significant positive outcome(s); yellow, ambiguous positive/negative outcomes; red, statistically insignificant outcome(s); P, (co-)primary outcome measure; S, secondary outcome measure. ⁱFDA accelerated approval based on 1-year data, meaning the co-primary endpoint of 2-year disability progression was not included in support of the FDA approval. ⁱⁱOnly the placebo-controlled pivotal trial was positive on the disability progression measure. ⁱⁱⁱOnly one of the two active-controlled pivotal trials was positive on the disability progression measure. ^ivOne of the pivotal studies was clearly positive on all MRI measures, while the second study showed mixed results. ^vThe active-controlled pivotal trial showed mixed disability progression results.

Figure 4

Selected examples of indications of disease-modifying drugs for rheumatoid arthritis (A), amyotrophic lateral sclerosis (B), spinal muscular atrophy (C), and CHMP regulatory guideline use of disease modification-related terminology.