Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway.

Background: Withdrawals of drug indications may reveal potential inadequacies in the regulatory approval processes of new drugs. Understanding potential weaknesses of the regulatory approval process is paramount given the increasing use of expedited pathways. In this paper, we focus on three poly-ADP-ribose polymerase inhibitors (olaparib, rucaparib and niraparib) for the treatment of women with heavily pretreated, recurrent ovarian cancer, which were eventually withdrawn. Methods: We use a comparative case study approach to evaluate the regulatory histories of these drug indications in the US and Europe. Results: Two drug indications benefited from the FDA's accelerated approval pathway, which explicitly lowers the bar for evidence of efficacy at the time of approval. Following accelerated approval, manufacturers are mandated to conduct post-marketing studies to confirm clinical benefit. The FDA granted accelerated approval to olaparib and rucaparib based on data on surrogate endpoints and converted the approval to regular approval after the submission of additional data on surrogate endpoints from one of two required confirmatory trials, that is, without data on clinical benefit. Niraparib directly received regular approval based only on data on a surrogate endpoint. By contrast, the EMA granted conditional marketing authorisation to rucaparib and was quicker to restrict usage than the FDA. Conclusion: The regulatory histories of these drug indications highlight the need to reform the accelerated approval pathway by ensuring that post-marketing requirements are followed, and that regular approval is only based on evidence of clinical benefit.

Financial toxicity of withdrawn poly (ADP-ribose) polymerase inhibitor indications for ovarian cancer.

OBJECTIVE: We sought to quantify exposure to and financial impacts of PARPi treatments for eventually withdrawn ovarian cancer indications. METHODS: We identified in Optum's de-identified Clinformatics® Data Mart database 1695 patients with ovarian cancer diagnoses who received olaparib, rucaparib, or niraparib between January 2015 and September 2021. We describe PARPi use and out-of-pocket (OOP), total health care, and PARPi spending among ovarian cancer patients with 3 or more prior lines of therapy (LOT). RESULTS: Of the 1695 patients who received PARPi, 254 were estimated to have been heavily pretreated and exposed to eventually withdrawn indications. Cumulative total medical and pharmacy costs for these patients were $53,392,184; PARPi costs accounted for 34%. Median PARPi cost per patient was $43,347. Cumulative out-of-pockets costs totaled $533,281. CONCLUSIONS: Potential patient harm, including financial toxicity, might have been mitigated through more stringent drug approval requirements.

Association Between Preapproval Confirmatory Trial Initiation and Conversion to Traditional Approval or Withdrawal in the FDA Accelerated Approval Pathway.

This study examines the Food and Drug Administration's accelerated approval pathway and whether preapproval initiation was associated with faster conversion to traditional approval or withdrawal for drugs with nononcology indications.

Changes in use of low-value services during the COVID-19 pandemic.

The COVID-19 pandemic led to a significant disruption, then recovery, of health care services use. Prior research has not examined the relative rates of resumption of high-value and low-value care. We examined the use of 6 common low-value services that received a D grade from the US Preventive Services Task Force compared with clinically comparable high-value services in a large commercially insured population nationwide from before the pandemic to April 1, 2021. We found that, overall, low-value services and high-value services were disrupted similarly. In aggregate, low-value care declined to 56.2% and high-value care to 53.2% in the initial month of the pandemic (April 2020) relative to baseline (number of visits in 2019 normalized by relevant enrolled population), then rebounded to 83.1% of baseline for low-value services and 95.0% of baseline for high-value services by January 2021. Substantial heterogeneity appeared across clinical contexts, such as prostate cancer screening for men 70 years and older rebounding to 111.8% of baseline and asymptomatic chronic obstructive pulmonary disease screening remaining at 38.5% of baseline in January 2021. This suggests that although, on average, resuming lower-value services may have been perceived to be a lesser priority by providers and patients, the pandemic may have had heterogeneous effects on consumer and provider decision-making along the dimension of clinical value. This enhances our understanding of how disruptions affect the relationship between clinical value and usage of different services and suggests the need for more targeted interventions to reduce low-value care.

Accelerated Approval Of Cancer Drugs: No Economic Reward For Drug Makers That Conduct Confirmatory Trials.

The Food and Drug Administration uses expedited approval of drugs to speed the development and assessment of drugs that address unmet needs related to serious or life-threatening conditions. Drugs approved via this route rely on surrogate endpoints or other clinical indicators that are not direct measures of benefits to patients, such as survival or quality of life. Companies are required to conduct a clinical trial confirming that a drug provides long-term benefits that are clinically meaningful, but prompt completion of these trials frequently does not occur. Theory suggests that because confirmatory trials reduce uncertainty, they should provide an economic reward in the form of higher prices for a positive finding. We used a sample of physician-administered cancer drugs and data on average sales price to test this hypothesis. We found no significant relationship between confirmatory trial completion with a positive outcome and elevated prices. This represents a failure of the market to reward reduced uncertainty about a cancer drug's true benefits. This inefficiency would be mitigated if major payers such as Medicare built price schedules that directly rewarded completion of confirmatory trials. More completed trials would ensure that patients are receiving truly effective chemotherapies and not suffering the adverse effects of drugs that are ultimately not effective.

Biosimilar competition: Early learning.

Biologics accounted for roughly $145 billion in spending in 2018. They are also the fastest growing segment of the pharmaceutical industry. The Biological Price Competition and Innovation Act (BPCIA) of 2010 created an abbreviated pathway for biosimilar products to promote price competition in the market for biological drugs. There was great anticipation that the BPCIA would lead to a moderation in drug prices driven by market competition. The observed levels of competition and the accompanying savings have not reached those expected levels. We investigate the early impacts of biosimilar competition on the use and pricing of biological products. We focus especially on the ways in which altered market structures stemming from the implementation of the BPCIA have affected the prices for biological products subject to biosimilar competition. We do so by studying seven products that have recently faced biosimilar competition. We estimate fixed effects and Instrumental Variables models to estimate the impact of market competition on prices. Our results indicate that in the range of one to three entrants each additional marketed product results in a reduction in weighted average market prices of between 5.4% and 7% points. These are the result of a combination of reductions in originator prices and shifting in demand to biosimilar products.