The release of FDA’s draft guidance, “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases,” has been greatly anticipated since June 2021, when FDA announced in its accelerated approval of the KRASG12C inhibitor sotorasib that it would require a randomized, controlled trial comparing the efficacy of the labeled dose (960 mg once daily) to a 75% lower dose (240 mg once daily) as a condition of full regulatory approval (The Cancer Letter, June 11, 2021; April 29, 2022).
Nor will a post-marketing requirement of this nature likely be needed again, based on the language of the (albeit non-binding) draft guidance: “Sponsors should note that development of a drug under an FDA expedited program (e.g., breakthrough therapy designation) is not a sufficient justification to avoid identifying an optimal dosage(s) prior to submitting a marketing application.”
The draft guidance is consistent with FDA’s recent publications on the topic of premarket oncology dose optimization, and thus its recommendations are not surprising. Nor is the content of the draft guidance new.
The second sentence of the draft guidance states, “This guidance should be considered along with the International Conference on Harmonisation (ICH) E4 guidance on Dose-Response Information to Support Drug Registration….,” a document published in 1994. (For those readers who do not have a specific memory of 1994, Netscape Navigator was the web browser of choice, and Sweden had not yet joined the European Union).
However, the many oncology investigators and sponsors who either never had familiarity with E4—or willfully forgot its contents—may be in for a rude awakening with this draft guidance.
There are implications for all stakeholders as FDA Project Optimus is fully implemented, potentially impacting not only drugs under investigation, but marketed drugs as well. The most obvious implications relate to sponsors of drugs under development, particularly those who have only focused on maximizing the administered dose (or dose-intensity).
This development decision could result in an otherwise efficacious agent failing to obtain even accelerated approval due to safety concerns at the maximal dose, potentially leading to dire consequences for both the sponsor and its shareholders.
Since money talks, the final push will need to come from those payers who have financial incentives to reduce the cost of oncology drug prescribing.
The September 2022 meeting of the Oncologic Drugs Advisory Committee is instructive, with the Committee voting against new (or continued) approval of three drugs due to concerns that the risks outweighed the benefit at the proposed doses: poziotinib (for HER2 exon 20 insertion-mutated non-small cell lung cancer), melphalan flufenamide (for relapsed/refractory multiple myeloma), and duvelisib (for relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma) (The Cancer Letter, Sept. 23, Sept. 30, 2022).
Furthermore, at least one shareholder lawsuit has been filed in the wake of the poziotinib vote.
Investigators who conduct early-phase clinical trials will also be impacted by the draft guidance. Aside from the obvious implication of necessary changes in study design, there may also be a financial impact for centers whose business models are based on recruiting a diverse group of patients with refractory malignancies.
Whereas historical designs for phase I trials have focused on only the dose-toxicity relationship, modern phase I studies will need to focus on the dose-efficacy relationship, perhaps utilizing blood-based biomarkers, such as circulating tumor DNA, or possibly advanced modeling techniques based on radiological endpoints, aiming to identify a range of doses for phase II trials.
Modern phase I studies may require a different study population than in the past; perhaps less heavily pretreated patients, or a predominance of patients with diseases for which the investigational agent is predicted to be effective.
Furthermore, phase I trials will need to be integrated with disease-specific trials, which may present operational challenges at larger centers, where phase I trials may even be siloed to a separate department. And phase II studies will need to incorporate randomized dose-ranging designs and will be presumably limited to those investigational agents that demonstrate clear signs of efficacy in phase I.
The principles of FDA’s Project Optimus, which was initiated based on the recognition that many oncology drugs require dose adjustment, resulting in excess toxicities, is embodied in the draft guidance (The Cancer Letter, April 29, 2022). This, too, has implications for marketed oncology drugs.
While manufacturers of marketed drugs will not be required to conduct post-marketing dose optimization studies (except those subject to post-marketing requirements), the draft guidance implies that those oncology drugs that came to market prior to Project Optimus have been approved at excessive doses.
This is far from a stretch: It is Project Optimus’s central thesis!
Critically, the absence of a manufacturer requirement to optimize marketed drugs’ doses should not be interpreted as an endorsement of current doses, and it does not imply that such studies are unnecessary. While it is understood that most companies would see no business benefit from demonstrating that a 50-75% dose reduction decreases toxicity but not efficacy, there is no question that other stakeholders would benefit from this information, especially patients—and many payers.
More realistically, post-marketing dose optimization trials are coming down the pike. In fact, the U.S. Senate Appropriations Committee, on page 122 of its explanatory statement accompanying the FY2023 appropriation for FDA, stated:
“The Committee strongly encourages FDA to organize clinical trials, in collaboration with academic medical centers and other Federal agencies, of marketed cancer drugs and biologics to assess whether dosing and frequency adjustments may decrease the cost of care and/or toxicities of treatment without compromising efficacy.”
There are also ongoing efforts in Europe to develop such trials. For example, the British National Institute for Health and Care Research, in collaboration with the National Health Service, has funded one such study, and a revolving research fund has been created for this purpose in the Netherlands.
Post-marketing dose optimization studies differ greatly from pre-marketing dose optimization studies in their cost structure. Whereas pre-marketing studies of investigational agents conducted under an IND are notoriously expensive, post-marketing studies will have fewer data requirements, and generally would not require an IND.
Furthermore, for most post-marketing studies, the experimental arm(s) will use less drug, thereby reducing drug costs. If appropriately designed and targeted at the right drugs, the savings generated by provisioning less drug in the experimental arm(s) will be greater than the study’s costs (i.e., such studies have a negative cost), which is particularly attractive to studies conducted within a single-payer system.
The opportunities for developing post-marketing dose optimization studies in a single-payer system (e.g., the United Kingdom’s National Health Service) cannot be easily replicated in the U.S., given the multitude of U.S. payers. However, U.S. payers can be divided into three categories: 1) federal, 2) self-insured corporations (who may process claims via a private payer), and 3) private.
Both federal and corporate payers could also conduct such post-marketing trials at a negative cost if an infrastructure were available for study conduct. In contrast, private payers may have a decreased incentive, given the pervasive and Byzantine rebate system involving both payers and pharmacy benefit managers.
The most important stakeholders, patients, have the most to gain from the application of the teachings of Project Optimus. Unfortunately, patients undergoing treatment for cancer have come to expect significant adverse events and some patients may be afraid that a lack of side effects implies a lack of benefit—even for precision medicines (e.g., sotorasib) (The Cancer Letter, Sept. 23, 2022).
It is imperative for oncologists, regulators, and drug developers to tackle the harmful psychology of “no gain without pain” head-on, and there needs to be extensive promulgation of the implications of Project Optimus for patients, particularly regarding marketed drugs.
This educational effort will be critical for enrolling patients in post-marketing dose optimization trials, and ideally, patient groups should be involved in the design of such studies. And for those drugs for which there is robust preclinical and/or retrospective evidence that lower doses are near-equivalent to the labeled dose, patients will need to be educated regarding the likely similar benefit of that lower dose.
Finally, there will need to be extensive education of physicians who prescribe oncology drugs. This would include the entire gamut of prescribers, ranging from community physicians to investigators at academic medical centers, with a particular focus on oncology trainees who may be more flexible in their thinking.
The concept that “more is better” has been taught to oncologists for decades, and in many ways has become tantamount to religion.
Many oncologists would rather risk fatal toxicities than reduce the dose, even in the presence of preclinical and/or retrospective data suggesting that the labeled dose is excessive by orders of magnitude. Oncologists may also be hesitant about initiating treatment at a dose substantially below the labeled dose, either within a clinical trial or based on the results of a completed trial. Like the adoption of biosimilars, oncologists may be hesitant to have these somewhat technical conversations with patients. Furthermore, some oncologists have clear financial incentives to prescribe a higher dose.
In conclusion, the draft guidance provides a roadmap for a patient-centered dosing paradigm change in oncology.
But the full benefit of the draft guidance cannot be realized without extensive modifications of the current oncology ecosystem. Since money talks, the final push will need to come from those payers who have financial incentives to reduce the cost of oncology drug prescribing.
Disclaimer: Strohbehn is an employee of the U.S. federal government (Department of Veterans Affairs). The views expressed in this editorial represent his personal views and do not necessarily reflect those of his employer.
