Exploring Indicators of Hepatotoxicity-Related Post-Marketing Regulatory Actions: A Retrospective Analysis of Drug Approval Data

<b><i>Background:</i></b> Hepatotoxicity is a major reason for medication withdrawal from the markets. Unfortunately, serious adverse hepatic effects can occur after marketing with limited indicators during clinical development. Therefore, finding possible predictors for hepatotoxicity might guide the monitoring program of various stakeholders such as drug regulatory authorities. <b><i>Objective:</i></b> To explore the potential of drugs, pre-approval regulatory factors as predictors for the occurrence of hepatotoxicity-related post-marketing regulatory actions. Pre-approval factors were specified as: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. <b><i>Methods:</i></b> Using publicly accessible FDA data, we examined clinical review documents for drugs approved in the USA during the period from 2011 to 2016 to evaluate their hepatic safety profile, identifying the 3 specified indicators for analysis. <b><i>Predictors (Covariates):</i></b> We assessed whether these medications meet: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. <b><i>Outcome (Dependent Variable):</i></b> Post-marketing regulatory action related to hepatotoxicity including products withdrawal and updates to either warning, precaution or adverse effects sections. <b><i>Statistical Analysis:</i></b> Drugs that were approved between 2011 and 2016 were included in the analysis with follow-up time from the date of approval until end of December 2019 or the date of first post-marketing regulatory action related to hepatotoxicity, whichever occurred first. The hazard ratio (HR) was estimated using Cox-regression analysis. <b><i>Results:</i></b> A total of 192 medications were included in the study. We classified 48 drugs with grade ≥3 hepatotoxicity, 43 with accelerated approval status, and 74 with labeled information about hepatotoxicity prior to marketing. The adjusted HRs for post-marketing regulatory action for products with grade ≥3 hepatotoxicity was 0.61 (95% confidence interval [CI], 0.17–2.23), 0.92 (95% CI, 0.29–2.93) for drug approved via accelerated approval program, and 0.91 (95% CI, 0.33–2.56) for drugs with labeled hepatotoxicity information at approval time. <b><i>Conclusion:</i></b> Hy’s Law with hepatotoxicity grade ≥3, accelerated approval, and label information on hepatotoxicity were not identified as predictors for post-marketing additional regulatory actions concerning liver adverse effects. However, the evidence is inconclusive due to small sample size and potential channeling bias.

Practical Considerations in the Administration of Aducanumab for the Neurologist

Aducanumab (Aduhelm®), developed by the biotechnology firm Biogen in Cambridge, Massachusetts, was approved using the less common accelerated approval pathway by the Federal Drug Administration (FDA) reserved for treatments that fill a significant unmet need.1 Its approval on June 7, 2021 has been met with an outpouring of opinions from prescribers, insurers, advocacy groups and hospital systems regarding its risk benefit profile.2-4 Originally approved for all forms of Alzheimer’s disease (AD), the FDA updated aducanumab’s labeling on July 8th, 2021 for “treatment in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.5 With six million people nationally in the United States who suffer from AD and an anticipated one third of those who may now fulfill the criteria under the revised labeling, the implications of aducanumab’s approval continue to generate national interest.6

Time to inclusion in clinical guidance documents for non-oncological orphan drugs and biologics with expedited FDA designations: a retrospective survival analysis

ObjectivesDrug and biological products that treat rare, serious or life-threatening conditions can receive US Food and Drug Administration (FDA) orphan designation and expedited programme designations (accelerated approval, breakthrough therapy, fast track or priority review) meant to incentivise development. Timely recommendations from guidance documents may encourage more rapid and appropriate use and access to these medicines for serious conditions. We sought to determine time between FDA approval and inclusion in guidance documents for non-oncological orphan products overall and by number and type of expedited programme designations.Design and settingRetrospective survival analysis of non-oncological orphan products with ≥1 expedited designation approved since 1992. In June 2020, PubMed, Turning Research into Practice and Guideline Central databases were searched to identify guidance documents influencing US practice that included each product.Main outcomes and measuresThe primary outcome was time to guidance inclusion, defined as any recommendation on use provided within the recommendation framework used by the guidance document.ResultsAmong 135 included non-oncological orphan products, 97.0% (n=131) were designated with priority review, 49.6% (n=67) fast track, 16.3% (n=22) breakthrough therapy and 14.1% (n=19) accelerated approval. Sixty per cent of products (n=81) received ≥2 designations. Overall, 74.1% (n=100) were included in a guidance document. The median time to inclusion was 2.87 years (IQR 2.21–4.18) for the entire cohort. In survival analyses, guidance inclusion was more likely to occur earlier for products with ≥2 designations (HR, 1.84; 95% CI 1.21 to 2.79) and for those with fast-track designation compared with priority review (HR 1.40; 95% CI 1.02 to 2.0). Of 35 products not included in a guidance document, 54.3% (n=19) were approved in 2018 or later.ConclusionsAmong non-oncological orphan products with priority designations, nearly 3 years had passed between FDA approval and inclusion in any guidance document. These findings suggest that despite efforts to expedite availability, appropriate access to these treatments may be delayed because of the lack of timely guidance on their use in clinical practice.

Computational Approaches for Supporting Combination Therapy in the Post-Aducanumab Era in Alzheimer’s Disease

With the approval of aducanumab on the “Accelerated Approval Pathway” and the recognition of amyloid load as a surrogate marker, new successful therapeutic approaches will be driven by combination therapy as was the case in oncology after the launch of immune checkpoint inhibitors. However, the sheer number of therapeutic combinations substantially complicates the search for optimal combinations. Data-driven approaches based on large databases or electronic health records can identify optimal combinations and often using artificial intelligence or machine learning to crunch through many possible combinations but are limited to the pharmacology of existing marketed drugs and are highly dependent upon the quality of the training sets. Knowledge-driven in silico modeling approaches use multi-scale biophysically realistic models of neuroanatomy, physiology, and pathology and can be personalized with individual patient comedications, disease state, and genotypes to create ‘virtual twin patients’. Such models simulate effects on action potential dynamics of anatomically informed neuronal circuits driving functional clinical readouts. Informed by data-driven approaches this knowledge-driven modeling could systematically and quantitatively simulate all possible target combinations for a maximal synergistic effect on a clinically relevant functional outcomer. This approach seamlessly integrates pharmacokinetic modeling of different therapeutic modalities. A crucial requirement to constrain the parameters is the access to preferably anonymized individual patient data from completed clinical trials with various selective compounds. We believe that the combination of data- and knowledge driven modeling could be a game changer to find a cure for this devastating disease that affects the most complex organ of the universe.

A comparison of the Food and Drug Administration’s and Health Canada’s regulatory decisions about failed confirmatory trials for oncology drugs: an observational study

Background Oncology drugs are frequently approved on the basis of surrogate outcomes that require further trials to confirm the benefits, but at times these trials fail and regulators need to decide whether to withdraw approval for the indication and/or to remove the drug from the market. This study compares decisions by the Food and Drug Administration and Health Canada about oncology drugs that were approved using either Accelerated Approval (FDA) or Notice of Compliance with conditions (NOC/c, Health Canada) and that failed confirmatory trials. Methods Drug/indications approved by the FDA through its Accelerated Approval Pathway and that later failed confirmatory studies were identified from a published study and additional information on these drugs was collected from Drugs@FDA. Health Canada websites were searched on September 11, 2021 for the same group of drugs to determine if they were approved in Canada under the NOC/c pathway for the same indication as in the US. Information from both the FDA and Health Canada about these products was entered into an Excel spreadsheet. Decisions about whether to withdraw the drugs or remove the failed indication for the drug and requirements for confirmatory studies were compared. In addition, the dates of decisions by the two agencies were compared. Results Ten drug/indications were available for comparison. Regulatory decisions were similar in 4 cases, different in 1 case and could not be determined in the remaining 5, in 1 case because decisions were pending in both countries and in the other 4, because the NOC/c had not been fulfilled in Canada. The requirements for the confirmatory studies were similar in both countries. Decisions were made earlier in the United States. Conclusions This study shows that decisions made by Health Canada and the FDA about whether to withdraw a drug or remove a failed indication when drug/indications fail a confirmatory trial are usually similar, although the sample size on which this conclusion is made is small. The clinical implications of these similarities and differences should be explored.