Threshold for oncology drug development is raised: FDA pays attention to clinical trial dose design

In recent years, with the increase of global oncology drug development enthusiasm, domestic and foreign regulatory agencies are interested in cooling down for this: after all, it is now necessary to start to shift from quantity to quality!

Regarding the clinical trials of oncology drugs, on July 2, the Drug Evaluation Center of the National Medical Products Administration issued the "Clinical Value-Oriented Guidelines for Clinical Research and Development of Antitumor Drugs (Draft for Solicitation of Comments)", which was considered to be a "me- Too" the market is cooling down

In the United States, the FDA has also begun to operate on the dose

Recently, the agency is launching the Optimus project of the FDA Oncology Center of Excellence, which will develop new guidelines for cancer drug manufacturers to explore a wider range of doses in early trials

FDA starts action

Mirat Shah, a medical oncologist in the Office of Oncology Diseases of the FDA's Center for Drug Evaluation and Research (CDER), said that the Optimus project, named after dose optimization, is solving difficult problems

The FDA understands that these dosage issues are not limited to a few oncology drugs, but are related to the mode of drug dosage selection used in oncology for decades

The MTD method is unique in the field of cancer

Even in the absence of evidence that MTD is more effective than low doses for the treatment of cancer, we still see drug developers choosing MTD for research in later trials

Dr.

The sponsor should comprehensively consider the interaction between the drug and the target, how it works, and its safety

As cancer treatments become better and more precise, the agency has long been pushing for a more deliberate approach to drug delivery

Two benchmarks in the industry

At least two companies-Amgen and Kura Oncology-have experienced the FDA's new project firsthand

Kura announced in the first quarter that it would conduct a new dose optimization trial for acute myeloid leukemia therapy KO-539, and the FDA also asked Amgen to conduct the same trial on the newly approved KRAS inhibitor Lumakras (sotorasib)

Kura: Take the initiative

At the end of last year, when the available data began to show that the maximum dose was not found, Kura was doing dose escalation to find the best point of MTD: the patient did not experience any level of toxicity, but the drug proved to be effective

Kura CEO Troy Wilson said that Kura preemptively decided to expand the dose considerations in the early clinical trials of its leading project, which he called the "typical" of the Optimus project

Troy Wilson admitted that the extended dose trial may temporarily slow the development of KO-539, but they are also using this opportunity to further adjust the types of patients who may benefit from treatment

In addition, Kura hopes to push the drug-administered patient group directly into the phase II trial, which will help speed up in the future

Amgen: Late request

The case of Amgen shows that the regulatory agency may be late for the dose test request, but the FDA is working hard to ensure that this is no longer an accident
.

According to Greg Friberg, Vice President and Head of Oncology Therapy of Amgen, Lumakras has made rapid progress in the development process.
After the study found the effect of various doses (but low toxicity), Amgen determined the 960 mg dose very early.
Dose
.

The high-dose response rate of Lumakras seems to be higher than the low-dose response rate-now the gap between these numbers is small, and this is the challenge
.

Amgen needs more data and a larger patient population to determine a better possible dose range for Lumakras to treat patients with KRASG12 mutant non-small cell lung cancer
.
Amgen cooperated with the FDA to start a high-dose and low-dose study of Lumakras after its marketing
.

The FDA made this new trial a condition for Lumakras' accelerated approval and required the study to "further describe the characteristics of serious adverse events," such as gastrointestinal reactions
.

Greg Friberg said that the 960 mg dose is no problem, and the once-daily dosing regimen works well for patients, but they plan to continue to explore the efficacy and patient experience of Lumakras in the next few years
.

Industry analysts said that Mirati Therapeutics, Amgen's main competitor in the field of KRAS inhibitors, may also find itself the target of the FDA's late request for more dose optimization studies, even though it has not yet received regulatory requirements
.
Mirati said that they are aware of this regulatory trend and will not be surprised even if they receive a request from the FDA at the last minute
.

summary

In recent years, due to the prolonged survival of cancer patients after receiving new therapies, oncology drugs should also focus on safety and tolerability, because these greatly affect the quality of life of patients, and ultimately affect their treatment of drugs.
Compliance determines the patient’s experience of the overall benefits of medication
.

Therefore, determining the optimal dose of tumor drugs that will benefit patients has undoubtedly become the focus of attention from all walks of life
.

Of course, not all drugs are being developed tumors require dose optimization trials, but studies show the efficacy of treatment with different doses of the drug will be "fully belongs to the category Optimus project"
.