Study: FDA using postmarketing requirements for oncology drugs more often to assess dose optimization

Over the last decade, more than half of postmarketing requirements (PMRs) issued by the US Food and Drug Administration (FDA) for novel oncology drug approvals were used to determine optimal dosing for those drugs, according to a recent study published in the journal Clinical Cancer Research.

This method for analyzing an optimal dosing method for oncology drugs opens up a possibility to collect data on dose optimization before a drug is brought to market, Grace Collins, a regulatory policy analyst at Friends of Cancer Research in Washington, DC, and colleagues said.

“The push for dose optimization of oncology drugs in the premarket setting is not a new concept; however, this analysis provides timely insights on the types of dosing activities FDA has requested in the postmarketing setting over the last decade which could identify areas where additional dosing information could be collected in the premarket setting,” they wrote.

In their study, Collins and colleagues analyzed 132 novel oncology drugs approved between January 2012 and December 2022, with data for 376 PMRs available for 112 of 132 drugs evaluated. They then determined the percentage of PMRs that included descriptions of dosing, grouping PMR activities into categories based on extrinsic factors, intrinsic factors, dose variation and miscellaneous activities. The researchers also compared PMR type by approval pathway, application type and type of cancer as well as the median time for a PMR to be completed.

The results of the analysis showed 165 of 376 PMRs (43.9%) contained dosing information for 78 of 132 drugs (59.1%). Intrinsic factors (46.7%) and extrinsic factors (29.1%) were the most common type of information provided in dosing PMRs followed by dosing variation (17.6%) and miscellaneous factors (6.7%) like long-term follow-up and QT/QTc assessment. The percentage of PMRs with dosing information that contained extrinsic factors increased from 31.3% between 2012-2015 to 52.1% between 2022.

The time to PMR completion varied by type, with PMRs containing intrinsic factors having a median of 2.1 years to completion, extrinsic factors a median of 1.9 years to completion, dose variation factors a median of 4.5 years to completion, dose modifications and monitoring a median of 6.2 years to completion and dose lowering a median of 5.0 years to completion.

When analyzed by approval path, a higher percentage of drugs submitted through a new drug application (NDA) had dosing PMRs overall compared with those submitted through a biologic license application (BLA) (80.5% vs. 24.0%). Dosing PMRs were increasingly used in BLAs between 2020-2022 compared to 2012-2015 (45.5% vs. 7.7%) while use in NDAs decreased from 2020-2022 compared to 2012-2015 (86.2% vs. 79.2%).

“Across most drug classes, the percentage of approvals with a dosing PMR increased or remained consistent over the last 10 years,” the researchers said.

Most commonly, dosing PMRs were attached to radiopharmaceuticals, chemotherapies and molecular target inhibitors, while monoclonal antibodies and antibody-drug conjugates were the least likely to have a dosing PMR.

Collins and colleagues noted that while manufacturers aim to find a maximum tolerated dose in early oncology trials, the advent of targeted therapies has created scenarios where the efficacy of a treatment could plateau before a maximum tolerated dose Is reached. “[F]or these therapies a lower dose can provide the same efficacy with improved safety and tolerability profiles for patients,” they said.

In addition, longer times to completion with certain PMR types that assessed dose lowering or alternative doses raise the possibility that patients are potentially being exposed to a suboptimal dose, the researchers explained.

“As more of these targeted therapies are introduced, there will be a need to develop tailored dose optimization strategies that account for the nuances that exist between drugs and drug classes. As such, opportunities to adapt dosing strategies and identify appropriate flexibilities that enable timely identification of the optimal dose will be important,” they said.

Clin Cancer Res Collins et al

Study: FDA using postmarketing requirements for oncology drugs more often to assess dose optimization

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