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Pink Sheet – Guidance By Guidance, US FDA Is Reshaping The Look Of Cancer Drug Trials

Pink Sheet – Guidance By Guidance, US FDA Is Reshaping The Look Of Cancer Drug Trials

Executive Summary

Recent draft guidance documents address adolescent enrollment in adult cancer trials, use of cohort designs in early-phase studies, and inclusion of placebo controls; more advice is coming soon on master protocols, adaptive designs and novel endpoints, FDA’s Gottlieb says.


The US FDA is using its guidance-writing powers to reshape the look of oncology clinical trials, with the goal of streamlining and modernizing cancer drug development in order to foster a more patient-focused approach.


In the past three months, the agency has issued draft guidance documents aimed at expanding the ages of cancer patients eligible for clinical trials, giving sponsors more flexibility in designing studies, and clarifying when placebo controls should be used.


The agency also can be expected to take a serious look at proposed guidance documents recently submitted by two leading cancer research organizations aimed at further expanding eligibility criteria for clinical trials.


In an Aug. 29 blog post on FDA’s initiative to modernize for innovation, Commissioner Scott Gottlieb pledged that even more advice is on its way in the oncology clinical trial space.


“In the coming weeks, we’ll be issuing additional guidance” on master clinical trial protocols “and efficient trial design strategies to help expedite the development of oncology drugs and devices,” Gottlieb said. “We’ll also be issuing guidance on the use of adaptive trial designs, and innovative endpoints like minimal residual disease in hematologic cancers.”

Limiting Use Of Placebos

In the blog post, Gottlieb highlighted the recently issued draft guidance on use of placebos in randomized oncology trials.


“Advances in care, and trial design, can make it unethical and infeasible in some circumstances to use placebo controls in cancer trials,” he said. “At the same time, the FDA is advancing the development of natural history models for rare diseases. These models may obviate the need for placebo arms in some trials by allowing researchers to replicate the behavior of patients who otherwise are left untreated.”


Use of placebo controls in cancer drug trials can present practical issues, such as toxicity-related unblinding with active treatment, as well as ethical concerns, such as when standard effective therapy is already available, the draft guidance states.


The guidance emphasizes a preference that studies incorporate an active control if one is available rather than a placebo control, or that the investigational agent be compared against placebo when each are added to the standard of care.


“Given the challenges of using a placebo in randomized controlled clinical trials for therapies to treat hematologic malignancy and oncologic disease, FDA recommends that a sponsor use a placebo-controlled design only in selected circumstances (e.g., where surveillance is standard of care), or with certain trial design features (e.g., if the trial uses an add-on design, when the endpoint intended to support a labeling claim has a high degree of subjectivity, such as patient- reported outcomes),” the guidance states.


The guidance also includes considerations for unblinding in cancer trials.


“Unless there are no available appropriate treatment alternatives, FDA recommends unblinding a patient at the time of documented disease recurrence or progression to ensure optimal patient management,” the guidance states.


In addition, the patient and investigator should be unblinded when the former experiences an adverse event suspected to be related to the investigational treatment and for which management with substantially toxic drugs or invasive procedures is being considered. “In such cases of unblinding, the patient should not be removed from the trial,” the guidance states.


When asked why the agency felt it needed to issue the placebo controls guidance, FDA told the Pink Sheet: “This topic has been discussed many times in the community, and we wanted to bring clarity to this issue.”

Placebo-controlled designs should be reserved as an alternative for the “right settings rather than a reflexive approach” for all cancer trials, FDA’s Gottlieb tweeted.

In an Aug. 23 tweet about the guidance, Gottlieb said that as more breakthrough drugs show outsized benefits in carefully selected patients, it allows FDA to “advance new, rigorous ways for testing meds, and makes placebo studies an [alternative] for the right settings rather than a reflexive approach for all [oncology] trials.”


FDA released the placebo controls document close on the heels of another draft guidance on “seamless” clinical trials, part of the agency’s implementation of 21st Century Cures Act provisions on modernizing clinical trial design. (Also see “US FDA’s Gottlieb Touts ‘Seamless’ Clinical Trials, Worries About Second-To-Market Products ” – Pink Sheet, 25 Jul, 2018.)


The draft guidance, “Expansion Cohorts: Use In First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,” includes advice for sponsors on the design and conduct of first-in-human clinical trials intended to efficiently expedite the clinical development of cancer drugs through multiple expansion cohort trial designs. (Also see ““One Continuous Trial” In Oncology: US FDA Offers Guidance And Encouragement” – Pink Sheet, 22 Aug, 2018.)

Adolescents Welcome In Adult Trials

FDA took another step toward modernizing cancer clinical trial design with a June draft guidance, “Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials.”


The guidance notes that adolescents, because of their age, generally are not eligible for enrollment in adult oncology trials, and initial pediatric studies for many drugs often are conducted after a product is approved for adults. “As a result, adolescents may have delayed access to potentially effective therapies,” FDA said. “In addition, accrual of adolescents to pediatric trials evaluating approved drugs may be difficult because of off-label use.”


Adolescents should be eligible for enrollment in adult cancer trials at all stages of drug development “when the histology and biologic behavior of the cancer under investigation is the same in, or the molecular target of the drug is relevant to, cancers in both adult and adolescent patients,” the guidance states.


For first-in-human or dose-escalation trials, adolescents may be enrolled after initial adult pharmacokinetic and toxicity data are obtained. “In general, adolescents enrolled in these early phase trials should have cancers that are relapsed after or refractory to standard therapy with no curative options or for which no standard therapies with curative intent exist,” the guidance states.


Adolescents can be enrolled simultaneously with adults in later-stage trials intended to estimate drug activity or confirm clinical benefit, the agency said.


The guidance also includes ethical considerations and recommendations on safety monitoring and dosing.


For drugs with dosing based on body size, adolescents should receive the same body size-adjusted dose given to adults. For fixed-dose drugs, adolescents weighing at least 40 kg generally can receive the same fixed dose as that given to adults. Adolescents weighing less than 40 kg should receive an adjusted dose based upon either body weight or body surface area, the agency said.

Industry seeks clarification on the timing for discussions with FDA on proposed inclusion of adolescents in adult trials, whether such studies would satisfy Pediatric Research Equity Act requirements, and international regulatory alignment.

In comments filed on the guidance, industry representatives requested clarification on several issues, including the timing for sponsor discussions with FDA on proposed inclusion of adolescents in adult trials and whether such studies would satisfy Pediatric Research Equity Act requirements.


Industry representatives also questioned how FDA’s recommendations would align with those of regulators across the globe.


“Because the draft guidance signals the first time that a health authority memorializes the principles outlined in the guidance (i.e., recommendation to enroll adolescents in adult oncology studies), we ask the FDA to consider reviewing and discussing the draft guidance with other global health authorities at upcoming pediatric cluster calls,” the Biotechnology Innovation Organization’s (BIO) comments state. “Sharing and discussing the principles outlined in the draft guidance with other global health authorities serves as an important mechanism for ensuring global harmonization of the inclusions of adolescent patients in adult oncology clinical trials.”


BIO and the Pharmaceutical Research and Manufacturers of America (PhRMA) also urged FDA to educate institutional review boards (IRBs) about the agency’s view on enrolling adolescents.


“In order to fully realize the benefits of adolescent participation in adult trials, input from the IRB community and acceptance of the draft guidance will be necessary,” PhRMA’s comments state.


PhRMA said the guidance provides an opportunity to increase adolescent participation in trials beyond the cancer space.


“The consideration of adolescent inclusion in adult drug development outlined in this guidance may be relevant beyond oncology products,” PhRMA said. “The recommendations in this draft guidance could help provide a pragmatic solution for numerous other medical conditions across the therapeutic spectrum, particularly where the relevant disease is severe and life-threatening. With appropriate input from interested stakeholders, FDA could consider extending these recommendations beyond oncology.”


However, the public interest group Public Responsibility in Medicine and Research (PRIM&R) urged caution on this point.


“We urge the guidance to emphasize that it is written specifically to address inclusion of adolescents in adult oncology trials; though the guidance may be helpful to sponsors of studies on other diseases, there should be no assumption that the same considerations will hold in all cases,” PRIM&R’s comments state.

ASCO, FOCR Proposals On Trial Eligibility

Lowering the minimum age for trials is the focus of one of five proposed guidance documents aimed at modernizing cancer trial eligibility criteria recently submitted by the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR).


The proposals grew out of an ASCO/FOCR initiative, with input from FDA, to develop consensus-driven recommendations on when it is scientifically and clinically appropriate to expand eligibility criteria for patient groups that traditionally have been excluded from cancer studies due to the existence of brain metastases, age, HIV-positive status, prior malignancies and organ dysfunction. (Also see “Cancer Trials: Broader Eligibility Criteria Could Mean Novel Labeling Claims” – Pink Sheet, 5 Dec, 2016.)


The goal – one strongly endorsed by FDA – is to move away from copying eligibility criteria from older protocols to newer trials and, instead, develop more rational eligibility criteria tailored to the drug, disease, and population under study. (Also see “Cancer Drug Trials Could Benefit From ‘Rational’ Eligibility Criteria” – Pink Sheet, 19 Apr, 2017.)


The recommendations in the proposed draft guidances “aim to maximize the generalizability of clinical trial results while also maintaining the safety of clinical trial participants,” ASCO Senior VP and Chief Medical Officer Richard Schilsky and FOCR Chairperson and Founder Ellen Sigal said in a cover letter to the agency.

“The rationale for excluding patients from eligibility for a cancer clinical trial should be clearly articulated and should be based on the specific therapy under investigation and the study population to help improve trial accrual, ensure optimal patient access, and maximize information learned during the clinical trial.” – ASCO and FOCR

“FDA guidance will assist sponsors in designing more representative trials, and we hope FDA seriously considers adopting the proposed set of guidance documents,” the letter states. “We believe that the rationale for excluding patients from eligibility for a cancer clinical trial should be clearly articulated and should be based on the specific therapy under investigation and the study population to help improve trial accrual, ensure optimal patient access, and maximize information learned during the clinical trial.”


FDA told the Pink Sheet it is reviewing the proposed guidances submitted by ASCO and FOCR, “but it is too early to say what type of response FDA will provide.”


However, the recommendations could help inform draft guidance documents required under the FDA Reauthorization Act aimed at expanding clinical trial eligibility criteria more generally.


The statute requires that FDA issue guidance addressing methodological approaches sponsors may take to broaden eligibility criteria for clinical trials and expanded access trials, especially for serious and life-threatening diseases, and approaches to developing eligibility criteria and increasing recruitment for trials so that enrollment more accurately reflects the patients most likely to receive the drug.…