Strengthening the Food and Drug Administration Office of Clinical Pharmacology's Labeling Authority

ABSTRACT

Optimal prescribing of drug products requires accurate informative drug labels. One critical aspect of a label is the recommended dosage. We suggest that the final authority for this portion of the label should reside in FDA's Office of Clinical Pharmacology (OCP), rather than in the Office of New Drugs, given that most FDA clinicians do not have sufficient expertise to interpret pharmacometric analyses of dose‐exposure, and dose/exposure‐efficacy/safety relationships.

1.

The availability of a drug product without appropriate instructions for use has little utility. Prescription drug labeling is required to provide the essential scientific information needed for safe and effective use and must also be updated when current labeling is inaccurate, false, or misleading. Given the narrow therapeutic index of many drugs, particularly those for serious medical illnesses (e.g., cancer, HIV), information regarding the dosage is of particular importance.

Optimizing dosing of drugs prior to approval has been global regulatory policy since 1994, with the publication of a guideline by the International Conference on Harmonization entitled “Dose‐Response Information to Support Drug Registration.” [1] While FDA senior leadership has previously expressed concerns about “getting the dose right” [2], it is our opinion that recent leadership may have prioritized rapid approval decisions over dosage optimization, resulting in suboptimal excessive dosages for some newly approved therapies that needlessly raise risks but not necessarily the benefits. FDA's dosage expertise resides in the Office of Clinical Pharmacology (OCP), usually directed by a pharmaceutical scientist or clinical pharmacist. OCP conducts a formal Clinical Pharmacology review of New Drug Applications and original Biologic License Applications, utilizing a question‐based review template [3]. One of the key questions is, “Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought?” The previous review template (dated 23 September 2016) provided reviewers an opportunity to offer “Detailed Labeling Recommendations”, but that privilege was removed in the 30 January 2023 revision. Instead, the current template instructs reviewers to “Describe labeling recommendations at a high level, including areas of concurrence/disagreement. The information should be captured in a narrative description of the labeling issues.” (authors' emphasis added) [3].

FDA's organizational chart indicates that the Director of OCP reports to the Office of Translational Sciences, which then reports to the Center for Drug Evaluation and Research (CDER). However, all reviews are under the purview of the Office of New Drugs, which integrates information across multiple disciplines and makes a final determination of approvability and labeling. Thus, OCP appears to lack organizational authority to require labeling changes to address a suboptimal (or even unacceptable) labeled dosage.

This is particularly problematic for drugs with Breakthrough designation, for which there may be great enthusiasm for approval, often receiving accelerated approval based on a single‐arm phase 2 trial (i.e., without any rigorous studies of dose–response). How should providers be instructed to prescribe this drug? Should they be advised to err on the high side or the low side? Who has final say over the recommended dose ultimately carries a great deal of weight in the clinic.

In our experience, few clinicians (including those at FDA) can be relied upon to interpret pharmacometric data, given their limited training in clinical pharmacology. Provided that the goal of regulators determining the recommended dosage (or dosages) of a new drug is to maximize its benefits and minimize its risks, the authority for dose determination should be vested in the entity best suited to interpret the relevant data—in this case, OCP.

Oncology has been an area of particular concern, given the historical dogma in oncology regarding the importance of maximizing dosage. FDA's Oncology Center of Excellence implicitly acknowledged that it had not been focused on the teachings of ICH E4 through its announcement of Project Optimus in 2021 [4], which putatively requires sponsors to optimize the dose of oncology drugs prior to approval (if not prior to initiation of a registration trial). Both the Project Optimus announcement and the subsequent Draft Guidance included OCP authorship, supporting the notion that this effort would be multi‐disciplinary and that OCP would have a pivotal role.

Project Optimus appears to have been inspired, at least in part, by the development of sotorasib, the first covalent inhibitor of mutant KRAS G12C to enter clinical trials. Based on two responses at the starting dose of 180 mg, sotorasib received Breakthrough designation. However, the sponsor continued escalation, ultimately seeking accelerated approval at a dosage of 960 mg once daily for KRAS G12C‐mutated non‐small cell lung cancer. Despite lacking evidence for a dose‐exposure relationship, let alone a dose–response relationship, the application for accelerated approval was approved. OCP's review at the time was scathing [5], noting that the dosage was “not considered optimal” and that there was “saturable absorption with similar systemic exposures at steady state across all dose levels ranging from 180 to 960 mg.” Consequently, sotorasib's accelerated approval came with a postmarketing requirement (PMR) to evaluate a 75% dose reduction in a comparative efficacy trial “that may provide comparable efficacy with improved safety (especially local GI tolerability) as compared to the 960 mg dose,” in addition to the usual requirement that the phase 3 trial (which was already underway at the 960 mg dose) confirm efficacy benefit.

The randomized dose‐ranging trial demonstrated similar sotorasib exposure despite the fourfold dose difference, and no difference in progression‐free survival [6]. Yet, FDA's medical oncologists determined that there was insufficient evidence to conclude that the lower dose would not be less effective, and thus did not require a change in the dosage from 960 to 240 mg [5]. Notably, the paper published by FDA justifying this decision did not include OCP coauthors or discuss the relevant pharmacometric data [7]. Instead, the paper focused on statistically unsubstantiated relationships between dose and efficacy that could not be explained pharmacologically, given the absence of a dose‐exposure relationship. Consequently, sotorasib remains on the market at a dosage four times higher than necessary to achieve saturation of its target (and maximal clinical benefit)—a dose that doubles the probability of severe and life‐threatening treatment‐related adverse events [6].

Beyond the recommended starting dose, the sotorasib package insert is not only inconsistent with the overarching goal of Project Optimus to shepherd oncology away from its historical “more is more” bias but is internally inconsistent. The package insert recommends dose reduction for severe (albeit not moderate and/or chronic) toxicities; a tactic that successfully reduces gastrointestinal toxicity caused by unabsorbed drug. At the same time, the package insert states that similar exposure is achieved by all doses, which was confirmed by the randomized dose‐ranging trial's failure to find a statistically greater area under the concentration‐time curve (AUC) for the 960 mg dose. FDA's conclusion appears more consistent with a “more is more, even when the data demonstrate otherwise” bias than with the patient‐centered, multidisciplinary effort that Project Optimus promised.

It is hard to envision OCP supporting this decision, and the review of these data is not publicly available. While it is logically flawed to conclude the presence of a general problem from a specific example, we worry that OCP's place in FDA's reporting structure contributes to this problem—and risks more examples like sotorasib in the future.

For all the challenges faced by those regulators that remain at FDA, there are opportunities to build back better. New FDA Commissioner Dr. Marty Makary published a paper in 2017 entitled “Overtreatment in the United States,” the first sentence of which reads, “Waste in health care is increasingly being recognized as a cause of patient harm and excess costs [8].” The sotorasib example—labeled at an excessive dose, causing patients harm, and lacking evidence of benefit attributable to the incremental unabsorbed drug—therefore seems a poster child for overtreatment. Furthermore, requiring a change in the recommended dosage to 240 mg daily may over the short term reduce or eliminate excess costs, since the daily cost of the drug would be reduced by 75%, and payers could limit coverage accordingly. Second‐order effects of such a decision may include shifting market share toward competitors, over whom payers and regulators could exert comparatively greater leverage to achieve safe, efficacious care. Sotorasib is far from the only example like this, reflecting a systems‐level issue that requires a systems‐level fix.

Oncology is not the only therapeutic area where the originally approved dosages have been demonstrated to be excessive, although these issues are often resolved during the approval process and/or through post‐marketing requirements. In a recent analysis for the period from 2018 to 2022, drugs receiving accelerated approval were nearly six times more likely to eventually require dose modification [9]. The most common therapeutic areas for downward dose modifications were oncology (9/68) and neurological diseases (6/38). Notably, there were no such downward modifications in infectious diseases (0/26).

Thus, to ensure consistency in dosage optimization across therapeutic areas, we propose that FDA elevate the Director of OCP to report directly to the Director of CDER and, perhaps more importantly, to vest OCP with the authority to provide final approval of all dosage recommendations in drug labels, in collaboration with the Office of New Drugs. Since this major organizational change could have unanticipated consequences, we recommend further discussion within FDA and external stakeholders, including potentially lawmakers, as there has also been Congressional interest in post‐marketing dosage optimization, as detailed in the report language accompanying FDA's 2023 appropriation [10].

Many countries across the world, particularly in North America and Europe, invest a substantial portion of their resources conducting science to aid the discovery of new drugs and, when those drugs reach market, purchasing them. In other words, the focus is on the tools, not the instructions. We owe it to patients and the funders of the foundational science—chiefly taxpayers, via their governments—to ensure that the prescribing instructions are worthy of the active pharmaceutical ingredients.

Disclosure

G.W.S. is an employee of the US Federal Government; this work does not represent official US Federal Government policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Ratain M. J. and Strohbehn G. W., “Strengthening the Food and Drug Administration Office of Clinical Pharmacology's Labeling Authority,” Clinical and Translational Science 18, no. 9 (2025): e70337, 10.1111/cts.70337.