Summary of findings

This study provides an overview of orphan drug safety through the first, most comprehensive longitudinal analysis of the FDA database on orphan drugs. Our analysis includes all FDA-approved orphan drugs since 1998 with up to 20 years of postmarketing surveillance. Of the 214 FDA-approved orphan drugs, 69.2% had labelling changes related to PMSE since designation and approval. In combination with available evidence from the drug regulatory agency and academic literature, this study reconfirms that timely regulatory action has been in place for orphan drugs with frequent safety-related labelling updates to inform prescription practice.

In our study, one of the approval factors associated with the frequency of PMSEs at 5-years after approval is ‘approved for long-term use’. This suggests a potential cumulative dose effect from the long-term use of a drug. However, this result could potentially be prone to survival bias, given that patient factors and disease trajectories commonly associated with chronic rare diseases differ from more rapidly progressive rare diseases. Patients with rapidly progressive rare diseases may not survive long enough to experience PMSE induced by the drug, and thus less safety reports may be generated. As such, when given sufficient sample sizes, longitudinal studies using electronic medical records may provide further insight regarding the safety of orphan drugs for short- and long-term use, where patient factors can be taken into consideration.

When studying orphan drugs safety, SPSE is a more pertinent consideration than PMSE due to the limited or even absent treatment options for life-threatening rare safety events. In our study, over 15% of FDA-approved orphan drugs had labelling changes related to SPSE, mostly as the reinforcement of initial boxed warnings issued on approval. Newly added boxed warnings only accounted for a small proportion overall. Drugs approved with boxed warnings had earlier labelling updates related to SPSE in multivariable analysis. This is further indication of enhanced label updates for drugs approved with boxed warnings, the evident interaction between pre- and postmarketing regulation and the importance of long-term safety surveillance.

Comparison with other studies

As mentioned previously, few studies had focused on postmarketing safety specific to orphan drugs. Onakpoya et al. assessed the safety of 74 orphan drugs approved by the European Medicines Agency (EMA) between 2002 and 2014 [17]. The study reported that 86.5% of identified orphan drugs had evidence of serious adverse events, a much higher proportion than our study. As with our study, orphan drugs approved for treating cancerous conditions had a higher proportion of adverse events. However, the definition of adverse events was unclear, and the study employed academic databases for evidence regarding orphan drug safety, where reporting and publication biases may exist. Meanwhile, the association between regulatory approval factors and postmarketing safety remain unexplored.

In a broader literature review, several studies that evaluated postmarketing drug safety potentially included a subgroup of orphan drugs, such as new molecular entities, new therapeutic biologics, and drugs that lack safety and efficacy data [14, 18,19,20,21,22,23,24,25,26,27,28]. One study on postmarketing safety of FDA-approved novel therapeutics showed that orphan status was not significantly associated with PMSE [14]. Studies using FDA and EMA databases found that novel therapeutics or biologics with accelerated approval or shorter time to obtain approval, respectively, experienced a higher rate of PMSE [14, 18, 19]. This finding was consistent with our multivariable analysis which focused only/?solely on orphan drugs. Furthermore, these studies focused predominantly on PMSE rather than SPSE.

Caution must be exercised when contextualising these findings from non-orphan drug specific studies as drugs with orphan drug designation might experience different review, surveillance and reporting procedures. Moreover, approval factors are not necessarily comparable among different drug approval agencies. Orphan drugs with identified risk factors for SPSE, namely ‘for long-term use’ and ‘approved with boxed warnings’, should be further examined using real-world data and multiple drug regulatory databases to inform safety monitoring processes.

Implications and future research directions

Findings from this study will inform multiple stakeholders about the frequency of safety-related labelling changes in orphan drugs detected by the FDA. This reinforces the role of postmarketing safety surveillance—to allow health professionals to be updated on any safety-related events for new orphan drugs alongside the predominant benefits to patients with rare diseases. Despite poor prognoses and limited treatment options, patients with rare diseases may be open towards drugs with more uncertainties than traditionally accepted. Decision-makers are therefore challenged to make trade-offs between conclusive safety evidence and timely life-saving treatment to address unmet patient needs. Quality safety data from structured surveillance programmes will assist regulators and payers to better mitigate uncertainties and balance the risks and benefits without further exposing patients to treatments with unproven benefits. Establishing orphan drugs or rare disease registries is imperative for extensive and continuous safety (and effectiveness) monitoring.

Future research should consider aggregating data from various drug surveillance databases to achieve power for more nuanced orphan drug safety assessment. Suggested databases include the safety and approval databases from the EMA, and drugs approved by the Center for Biologics Evaluation and Research of FDA. Other adverse event reporting systems such as the Yellow Card scheme in the United Kingdom, and the Canada Vigilance Program in the Canadian jurisdiction that collect and assess spontaneous reports of adverse drug reactions from patients and health professionals are also viable options for expanding the data [25].


The study findings should be interpreted cautiously with the following caveats. Limited numbers of drugs were assessed in the study given the finite number of FDA-CDER-approved orphan drugs. Uncertainty remains regarding the association between postmarketing safety events and other approval factors that yielded insignificant findings in the current analysis. Underestimating long-term PMSE is likely, given that the reported safety events of orphan drugs are often based on a small population. This, along with the inherent differences between rare disease and orphan drug definitions employed by various drug regulatory authorities, could discount the generalisability of our findings. Furthermore, since the estimation of safety events is based on reports from the drug surveillance system, no comparison between placebo and intervention arms could be made and interpreting the results of our study should be taken cautiously.

It should also be noted that the study only examined newly approved chemical or biological agents with an orphan drug designation. Drugs initially approved for common disease conditions and later repurposed as orphan drugs were not considered. At the same time, drugs with orphan drug designation could be extended to indications of common diseases when adequate and high-quality clinical evidence becomes available, highlighting the importance of safety surveillance when drugs are used on a broader population. For drug developers and regulators there is an inherent trade-off between the demand for life-saving drugs with early treatment access and the need to gather conclusive evidence about the real-world effectiveness and long-term safety. As such, additional safety information discovered after a drug has been approved is both expected and appropriate.

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