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Pink Sheet – Companion Diagnostics: US FDA Streamlines Risk Determinations In Oncology

Pink Sheet – Companion Diagnostics: US FDA Streamlines Risk Determinations In Oncology

Executive Summary

Information about investigational drug and in vitro diagnostic may be submitted in single IND to agency’s drugs or biologics centers, eliminating need for separate submission to devices center; new process should give greater therapeutic context to decisions of whether the IVD is considered a significant risk.


The US FDA’s new streamlined approach to risk determination requests for oncology drug companion diagnostics should simplify the process for some sponsors who now have to work across product centers while also giving such determinations greater therapeutic context.


However, the program’s limited reach means the new process will not amount to a shortcut for all sponsors who are developing oncology therapeutics with companion diagnostics.


In a draft guidance released April 12, FDA lays out an optional approach for sponsors seeking an agency determination of whether use of investigational in vitro diagnostics (IVDs), including those that incorporate next-generation sequencing (NGS) technology, in oncology drug trials are exempt from, or subject to, investigational device exemption (IDE) regulations.


The streamlined mechanism would allow premarket information related to the investigational drug and IVD to be contained in a single Investigational New Drug Application (IND) submitted to the agency’s drugs or biologics centers, eliminating the need for a separate submission to the devices center.


“The streamlined process is “a step toward our goal of having a common filing for a drug and diagnostic system where the drug is co-developed with a diagnostic test,” FDA Commissioner Scott Gottlieb said in prepared remarks at the 2018 Community Oncology Conference.


Gottlieb used the speech to announce release of the draft document, “Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination,” along with final versions of two guidances aimed at accelerating the development of NGS tests. (See sidebar for story in our sister publication Medtech Insight.)


Collectively, the guidances are aimed at making development of new cancer therapeutics a more efficient and less costly process, Gottlieb said.


“The policy approach outlined in these new guidance documents will provide test developers with a more efficient path to market. These new policies will improve the FDA’s ability to protect public health by ensuring these tests provide accurate and meaningful results, while at the same time speeding patient access to NGS assays by lowering barriers to innovation,” Gottlieb said.

Single Point Of Contact

Currently, separate applications are required for an investigational drug or biologic and an investigational IVD that are being developed together.


Under the streamlined process described in the draft guidance, a sponsor would submit all information about the oncology co-development program, including information about the investigational IVD, to the appropriate center for the IND, which would be either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER).


As part of the IND review, CBER or CDER would coordinate and consult with the Center for Devices and Radiological Health (CDRH) to determine if the investigational IVD is considered a significant risk, nonsignificant risk or exempt from IDE regulation. If found to be a significant risk, the trial may require approval of an IDE in addition to the IND.


“Significant risks can occur if the test would, for example, cause a patient to be assigned to an experimental treatment and forgo highly effective treatments that are already available,” Gottlieb said.


Through the new streamlined process, “NGS test developers and drug sponsors could engage with a single agency lead during the submission of INDs,” Gottlieb said. There will be “a clear line of communication between reviewers and sponsors, and on a single timeline. It will avoid the potential for confusion that could come when NGS and drug sponsors engage separately with different medical product centers.”


The emphasis on a single point of contact goes both ways.


“One sponsor should take the lead in communicating with FDA about the IND,” the guidance states. “FDA intends to communicate all feedback, (including feedback about the investigational IVD) to the same lead sponsor.”

Cross-Center Approach Reflective Of OCE

The new cross-center approach to risk determinations aligns with the Oncology Center of Excellence’s remit.


Created as part of the federal Cancer Moonshot initiative, OCE was established in January 2017 to integrate the agency’s drug, biologic and device experts to evaluate products intended to screen, prevent and treat cancer.


“This cross-center approach to streamlining the process for determining the review requirements for diagnostics used in drug trials is an example of the Oncology Center of Excellence’s ongoing efforts to expedite the availability of safe and effective cancer treatments for patients,” FDA said in a press release.


Jeff Allen, president and CEO of Friends of Cancer Research, told the Pink Sheet the streamlined process will get the drug and biologics product centers’ therapeutic experts more closely involved in device evaluations and bring more clinical context to companion diagnostic risk determinations.


“This is something we looked at in the context of the Oncology Center of Excellence, with the idea being that for many oncology products it would be important to make sure that it is being evaluated in the clinical context of the disease … it is being used to treat,” Allen said in an interview.


Similarly, FDA said that consolidating information about the investigational drug and device into the same application “can enable more efficient review and help better establish the scientific relationship between the drug and the diagnostic used to select patients for treatment.”


The new procedures also should simplify the co-development regulatory process for some sponsors.


Historically, one challenge to developing companion diagnostics has been the difficulty that sponsors have encountered in trying to work with two distinct centers in FDA, Allen said. Over time, as the agency has dealt with more of these co-development programs, it has clarified and improved its coordination across centers. However, the process may still be confusing for some sponsors, particularly those that do not have much experience in drug/diagnostic co-development, Allen said.


“The growth in terms of the use of IVDs in clinical trials for oncology was probably one of the reasons for starting there in terms of looking at ways the process could be streamlined,” Allen said. The draft guidance “is probably a reflection of [FDA] evaluating these best practices that have been determined and looking for processes to increase efficiency there.”


The American Society of Clinical Oncology (ASCO) welcomed the streamlined risk determination process.


“Our ultimate objective is to ensure that the right patients are receiving the right drugs, in an environment of rapidly developing information about diagnostic tests,” ASCO Chief Medical Officer Richard Schilsky said.


“Co-development of in vitro diagnostics and targeted therapeutics presents many challenges, particularly for those tests determined to carry significant risk, such as genomic tests intended to guide treatment selection. The FDA’s proposal of a streamlined process for determination of study risk will accelerate development timelines so that promising targeted drugs co-developed with companion diagnostic tests reach patients in need as quickly as possible.”

Optional Process, But Not For Everybody

The guidance encourages sponsors to use the streamlined process when possible “to reduce administrative burden on sponsors and FDA and to maintain the current level of regulatory review.” However, the process is not available to all-comers.


The new submission mechanism applies only to clinical trials involving co-development of an investigational IVD with an investigational oncology drug. “It does not apply to co-development programs in other disease areas,” the guidance states, also noting that IND-exempt studies are ineligible.


Perhaps most notably, the streamlined mechanism is not available to sponsors when an invasive biopsy that presents a potential for serious risk to the health, safety or the welfare of the subject is required for investigational IVD testing for enrollment.


FOCR’s Allen said this exception would apply to studies where a biopsy of an internal organ, such as the pancreas or liver, is required for investigational IVD testing, but likely would not apply to biopsies of skin lesions.


FDA notes that sponsors who do not qualify for the streamlined process, or who choose not to follow it, should continue to submit risk determination requests to CDRH using what is known as the “Q-submission” program.

What Sponsors Need To Do

Sponsors wishing to use the streamlined submission process should indicate their intent to do so in the IND Form 1571.


The trial protocol should include information about how the results from the IVD will be applied in the study, as well as what is known about the prevalence of the biomarker evaluated by the IVD in the patient population. The protocol also should detail the type of specimen that will be collected for IVD testing and whether any required biopsy could present a potential for serious risk to the health, safety or welfare of the subject.


In addition, informed consent documents reviewed by institutional review boards should address risks associated with the consequence of an incorrect test result from the investigational IVD during the screening phase as well as risks associated with the investigational drug.


CBER or CDER will consult with CDRH and determine if the use of the investigational IVD in the study is significant risk, nonsignificant risk or exempt.


If the investigational IVD is deemed nonsignificant risk (NSR), CBER or CDER will confirm this determination in a letter allowing the study to proceed, but that letter may include a statement similar to the following: “You should ensure that NSR procedures are used in obtaining any biopsies taken for testing with the investigational IVD and submit unanticipated adverse device effect reports to the IND.


If the investigational IVD is considered significant risk, CBER or CDER will confirm the determination in the letter allowing the trial to proceed but may ask the sponsor to submit an IDE to CDRH and to wait to initiate the trial until after the IDE is approved.…