FDA concludes work on guidance on trial participation for those with incurable cancers

The FDA has sent the White House’s Office of Management and Budget a finalized version of an oncology guidance document that would further broaden criteria for who can participate in cancer clinical trials. Once reviewed and returned, the guidance document may make it easier for patients with incurable cancers to participate in clinical trials.

Regulatory Background

• When a drug sponsor initiates a clinical trial, it is typically concerned with two things: Demonstrating that the drug is effective and keeping study subjects safe from unreasonable or unforeseen side effects.
• To accomplish both aims, sponsors will often establish exclusion criteria that define who may not participate in a clinical trial. These exclusion criteria serve two primary aims. First, they may exclude persons who are deemed to be too sick to potentially benefit from treatment, and for which a treatment might be harmful. Second, they generally try to avoid the enrollment of patients who may have other conditions that could complicate the analysis of the drug’s safety or efficacy.
• However, the FDA has traditionally required the exclusion of cancer trial patients who have not exhausted the use of existing FDA-approved treatments for their condition. Those eligibility criteria “generally require that patients have received available therapy(ies) that offer the potential for cure in a substantial proportion of patients … in clinical trials evaluating investigational cancer drugs,” according to the FDA.
• In addition to making sure that patients have received standard-of-care treatment that gives them the best chance for a cure, this approach can also help ensure that all patients enrolled in the trial have similar histories of exposure (i.e., prior use of a particular drug with specific effects).
• There are, however, exceptions to this requirement, such as when the investigational product is intended to be used as an adjunctive therapy (i.e., at the same time as the available therapy). In such cases, one trial arm might receive the available therapy, while the second arm might receive the available therapy and the investigational therapy.

Then, in 2021, FDA issued draft guidance that would change this scenario

• The FDA now believes that in some cases, cancer patients should still be permitted to receive the investigational therapy without first receiving the available therapy. Specifically, for patients in a non-curative setting (i.e., “when there is no potential for cure or for prolonged/near normal survival”), the FDA believes that patients should be allowed to receive the investigational drug as long as they have been “provided adequate information to make an informed decision on trial participation.” The informed consent should include disclosure of “appropriate alternative procedures” that are available to the patient and their respective risks and benefits, FDA wrote in the guidance.
• Sponsors should be prepared to discuss their drug development plans with the FDA “early in development” and to justify their “approach to available therapy when developing eligibility criteria,” according to the FDA’s draft guidance document.
• If sponsors do choose to make investigational therapies available to patients who have not yet received an available therapy, those patients should be enrolled in “separate cohorts, particularly if interpretation of efficacy results requires a homogenous patient population,” according to the FDA’s guidance. “Alternatively, analyses of efficacy may be performed in pre-specified subgroup analyses, defined by prior receipt of available therapy(ies).”
• “The FDA believes patients with incurable cancers, if provided adequate information to make an informed decision, should be eligible to participate in oncology clinical trials,” Richard Pazdur, the Director of the FDA’s Oncology Center of Excellence, said in an emailed statement. “If there is no scientific rationale for excluding these patients, then clinical trial eligibility criteria should be broadened to include these patients, with appropriate informed consent.”

Context for the draft guidance

• FDA’s new guidance is one of almost a dozen released by the FDA in the last two years focused on the issue of exclusion criteria. The basic argument made by the FDA is that companies have been using too many exclusion criteria, which in turn has left clinical trials enrolling patients who aren’t always reflective of real-world populations.
• For example, in March 2020 the FDA released a guidance document on the inclusion of older adults in clinical trials for cancer drugs. In July 2020, the FDA released four additional guidance documents on the inclusion of patients with existing health issues, including HIV and other types of cancer.
• Similar guidance documents have been released focused on pediatric cancer trial eligibility, the inclusion of pregnant women and adolescent patients in trials, and the inclusion of male breast cancer patients and premenopausal women in breast cancer trials.
• The FDA’s latest guidance document might put pressure on companies to allow patients to enroll in studies more quickly than they would traditionally have been permitted to. While the FDA’s guidance isn’t a requirement that companies automatically enroll patients that haven’t yet received available therapy, it does put the onus on companies to be more thoughtful about why such patients would have reason to be excluded.

<h2″>Comments on the draft focused on potential gaps and further expansion of inclusion criteria

• Only six comments were received on the draft guidance, with just two coming from industry. AgencyIQ previously reported on these comments; below is a deeper dive into some of the thinking behind suggested changes to the draft guidance.
• Bristol-Myers Squibb (BMS) weighed in with one recommendation, suggesting that in some cases, patients who have received prior therapies and those who have not may be evaluated together. Wrote the firm, “we propose that it may that it may often be appropriate for the assessment of safety, such as in a Phase 1 dose escalation study, to evaluate patients with heterogeneous prior therapy history together.” This strategy would let sponsors bring expanded eligibility criteria to earlier phases of drug development, wrote BMS.
• The contract research organization Syneos Health observed that the guidance document really doesn’t address the population of individuals for whom ongoing treatment is needed, but who are not being treated with curative intent. Giving the examples of metastatic breast and ovarian cancer and chronic myeloid leukemia, Syneos pointed out that “malignant conditions that were previously terminal with a short prognosis are transforming into chronic conditions which patients can live with for years,” adding that “most oncology drugs approved are not administered to patients with curative intent yet confer a significant survival benefit.” The firm recommended that the background section of the draft guidance document should “explicitly reference the requirement that patients have received all available therapy,” to include therapy that may confer a “significant survival benefit.”
• Syneos also commented on a perceived gap between the content in the background section of the draft guidance document and the recommendations in the document. The firm recommends that the recommendations section address “the requirements of prior therapy in the non-curative setting.” The goal with this suggestion is to require that patients have already received a therapy or therapies “potentially associated with significant survival benefit,” if they are eligible for such a therapy. “Whilst physician discretion and patient informed decision making are factors in determining appropriate therapy, conducting trials including a substantial cohort of patients that have not received already established efficacious and safe therapy – can bias the efficacy and safety of the investigational agent,” wrote the firm.
• ASCO and the Friends of Cancer Research (FOCR) also submitted comments that offered some suggestions on the guidance. However, the jointly submitted comments also focused on recommendations developed by a joint ASCO-FOCR Prior Therapies Work Group that go beyond the strict scope of the draft guidance document.
• These broader recommendations center around “thoughtfully reexamining the use of prior therapy exposure as selection criteria to maximize clinical trial participation,” according to the comment. Including patients in clinical trials whose cancer is not curable is “essential,” and can be achieved, given appropriate informed consent, wrote the organizations. But the two groups made a similar point to that made by Syneos: Patients are not dichotomized into those seeking a cure and those who have abandoned hope for improvement with treatment. Improved quality of life and delaying the progression of cancer may both be important treatment goals for patients, so ASCO and FOCR suggested that the FDA add these additional factors to “add clarity.”
• Separately, the ASCO-FOCR comment also suggested that the FDA issue another guidance document addressing the use of prior therapies as a criterion to screen for patient participation in clinical trials in the curative setting. “ASCO and Friends recommend that patients be eligible for clinical trials regardless of the number and type of prior therapies and without a requirement to have received a specific therapy prior to enrollment unless a scientific or clinical rationale is provided as justification,” wrote the groups in their comment.
• The broad-scope suggestions come out of the work of the ASCO-Friends of Cancer Research Prior Therapies Work Group, which in 2021 published a Clinical Cancer Research article summarizing their recommendations. The paper sets out the recommendations echoed in the comment on the draft guidance, and also delineates when prior therapy could be used to determine clinical trial eligibility. Additionally, as the Syneos comment echoes, the work group recommends that clinical trialists consider “conducting evaluation separately from the primary endpoint analysis for participants who have received prior therapies.”
• In terms of specific recommendations, ASCO and FOCR concur with the agency that patients being treated in a non-curative setting and contemplating trial participation should receive “a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject,” so they can achieve the “full comprehension” necessary for informed decision-making. Unlike BMS’ viewpoint that heterogeneous patients could be pooled for Phase 1 safety assessments, ASCO and FOCR’s comment concurs with the FDA that patients who have and have not previously received available therapies be evaluated separately in “sufficiently powered separate cohorts.”
• The groups also recommend separate analyses of these disparate patient cohorts, although they note that “further elucidation of acceptable analyses to evaluate safety and efficacy in parallel cohorts of those who have and have not received available therapies may also be considered.” The final specific recommendation from ASCO and FOCR is that the agency recommend that sponsors could, in some cases, consider running a parallel cohort of patients who might not meet eligibility criteria related to prior receipt of therapy, since examining this population “would still provide descriptive safety and efficacy information, even if those patients are not included in the intent-to-treat population.”
• The Shepherd Foundation – a nonprofit focused on rare cancers, the American Society of Hematology, and the Oncology Nursing Society all submitted comments in support of the draft guidance without suggestions for substantive change.

The FDA has now sent the final version of the document to the White House for review.

• Today, the Office of Information and Regulatory Affairs (OIRA) received the FDA’s finalized version of the guidance for review, a process that typically takes weeks to months. OIRA is a subdivision of the White House’s Office of Management and Budget (OMB) and acts as a sort of regulator of regulators. It is charged with reviewing all major regulatory actions prior to their release by an Agency, often to ensure that they are consistent with the President’s vision and preferences for the Executive Branch of the U.S. government.
• In recent years, the FDA has begun to send certain guidance documents to OIRA for review – typically those documents that would have a significant economic impact on a particular sector or require the implementation of specific systems (such as those to facilitate the collection of electronic information).
• It’s not yet known whether the FDA took any of the comments into consideration when finalizing the draft version of the guidance document. The draft was notably thin, with just two pages of content. There’s room to fill in some of the detail recommended by oncology professional societies and nonprofits, as well as industry, if the agency chose to do so. AgencyIQ will have an analysis of the finalized guidance document once OIRA has returned it to the FDA and the agency releases it.

Featuring previous research by Alec Gaffney and Kedest Tadesse.
To contact the author of this analysis, please email Kari Oakes ( [email protected]).
To contact the author of this analysis, please email Alec Gaffney ( [email protected]).

Key Documents and Dates

• Cancer Clinical Trial Eligibility Criteria: Available Therapy in Non-Curative Settings