December 31, 2018
Drug regulators will consider event-free survival and complete response as surrogate endpoints and symptom improvement or relief as a clinical benefit in cancer trials, the FDA says in a new final guidance issued in mid-December.
The agency is also willing to talk about emerging endpoints such as minimal residual disease or metastasis-free survival, the 19-page document states.
The new, final guidance replaces a final guidance issued in May 2007. It reflects, FDA officials say, updated thinking in an industry that has evolved rapidly in the last decade or more.
The revised guidance makes clear that regulators see tumor measurements as the better endpoints than other biomarkers. Its biggest change appears to be the event-free survival discussion, which has been tacked on to the guidance on disease-free survival. Either can be “a surrogate endpoint to support accelerated approval, a surrogate endpoint to support traditional approval, or it can represent direct clinical benefit based on the specific disease, context of use, magnitude of the effect, the disease setting, available therapy, and the risk-benefit relationship,” the FDA says.
The same is true for complete response, the document states.
Decreasing the severity of cancer’s symptoms has already been used to support traditional drug approvals as long as the candidate drug has also been shown to attack tumors. But sponsors should take caution that using symptom relief as a clinical benefit “requires that the population” of the trial “be symptomatic at baseline, which can be problematic in many cancer trials where patients can often be asymptomatic at baseline,” the guidance states.
Symptom relief can also fall victim to open label response bias, “the magnitude of which is not well described,” the FDA says.
Emerging endpoints, such as minimal residual disease have already been used as surrogate endpoints for accelerated approval — in minimal residual disease’s case, in approval for treating acute lymphoblastic leukemia. But the FDA urges sponsors to talk with regulators before designing a trial with emerging endpoints.
If trials are going to measure tumors for their endpoints, the protocol should carefully define an adequate measure for each patient visit. “The analysis plan should outline a comparison of the adequacy of follow-up in each treatment arm,” the guidance states. “Methodology for analyzing incomplete and/or missing follow-up visits and censoring methods should be specified in the protocol. The analysis should specify the primary analysis and one or more sensitivity analyses to evaluate the robustness of the results.”
When possible, an analysis should include the number of deaths of “patients who have been lost to follow-up,” the guidance states.
Read the FDA’s guidance here: https://bit.ly/2UXSG9K
R&D Returns Shrink to Lowest Level in Decade, Analysis Finds
Drug companies’ returns on R&D investments have sunk to their lowest level since 2010 and analysts at Deloitte attribute the decline mostly to the soaring costs of clinical trials.
The 12 largest drug companies were expected to see an average of 1.9 percent return on every dollar invested in R&D in 2018 — the lowest percentage since Deloitte began analyzing the data in 2010. Returns fell for smaller drug companies, too — from 12.5 percent last year to 9.3 percent this year.
R&D returns have fallen steadily over the past decade — the average rate was about 8.2 percent in 2010. Clinical trial costs have nearly doubled since 2010, Deloitte says.
Adding all the failed trials, each new drug costs more than $2.1 billion to bring to market, according to researchers at Tufts University. Trial costs have grown in six of the past eight years.
EMA Seeks Comments on Rare Allergy Trials
The European Medicines Agency is seeking public comments as it prepares new guidelines for rare allergy clinical trials.
Clinical trials work best when disease strains can be isolated, but that’s a tall order for allergies. Individuals who have a rare allergy usually have several other kinds of allergies, making it hard to test the efficacy and safety of a proposed allergy treatment on a big enough patient population, the agency says.
The EMA hopes to clarify clinical endpoints, provocation tests and surrogate markers for allergy trials.
The agency has committed to releasing draft guidance by July2020. The comment deadline is June 30, 2019.
Read the EMA paper here: www.fdanews.com/ema-concept-paper-allergan.pdf
Drug Sponsors Urge FDA to Think Bigger about Master Protocols
Leading drugmakers are urging the FDA to think bigger about its master protocol guidelines for clinical trials and expand beyond cancer trials.
In September, the agency issued a draft guidance on master protocol design, hoping to encourage sponsors to use more adaptive trials and speed life-saving anticancer drugs to market.
In comments on the draft, Pfizer, Novartis and Regeneron urged the agency to look beyond cancer for master protocol designs. Regeneron said the use of master protocols in rare diseases presents a good opportunity to expedite orphan drug development. Novartis suggested that the FDA work with the Oncology Center of Excellence, CDER and CBER to identify areas where more flexible trial designs might be effective.
Most comments on the draft guidance were positive about the FDA’s moves toward more flexible trial design. But some groups urged the agency to flesh out some areas more carefully. The Association of Clinical Research Organizations, for instance, noted that the draft document doesn’t have a robust discussion of clinical endpoints. ACRO urged the agency to make “a clear statement” about whether regulators would accept the use of different endpoints in different sub-studies.
Read the draft guidance here: https://bit.ly/2GLFa6l