FDA Updates Clinical Trial Guidelines to Account for CNS Metastases

The considerations investigators must take into account when designing clinical trials include patient population, previous therapies, assessment of the central nervous system, end points, and leptomeningeal disease, according to the new guidelines.

New guidance from the FDA informs clinical trial sponsors about recommendations to trial designs with an eye towards systemic oncologic drugs and their antitumor activity in patients with central nervous system (CNS) metastases. Additionally, the guidance addresses CNS antitumor activity that is described in product labeling.1

These recommendations can also apply to patient populations exclusively with CNS metastases. The considerations investigators must take into account when designing clinical trials include patient population, previous therapies, assessment of CNS, end points, and leptomeningeal disease (LMD), according to the new guidelines.

The FDA recommends that CNS involvement should not be evaluated wholly separate from the metastatic disease present in other parts of the body. The effects of systemic drugs on CNS involvement should be evaluated in the context of metastatic disease including populations where the entire group has CNS metastases as well as groups where subsets of the population have CNS metastases. Limited efficacy reporting such as overall response rate (ORR), or progression-free survival (PFS) supported by findings from CNS metastatic groups alone are inappropriate as they do not account for any extra-CNS disease.

When evaluating prior therapies, the guidance recommends case reports of all CNS-directed treatments such as surgery, stereotactic radiosurgery, and whole brain radiation therapy. Therapy dates and response to therapy at baseline dates should be noted in the reports. The FDA also recommends including the intervals between completion of CNS radiation therapy and trial entry. A typical interval would be 12 weeks unless there is reasonable certainty backed by evidence of disease progression to support an abbreviated interval. Trial designs should include at least 1 stratification factor for randomization to reduce bias based on prior therapy.

Tumor assessment is best evaluated through magnetic resonance imaging (MRI) with gadolinium contrast.2 CNS baseline imaging should be required in all patients to identify CNS disease prior to protocol therapy. CNS imaging should follow the modified RECIST v1.1, Response Assessment in Neuro-Oncology—Brain Metastases (RANO-BM), standard response criteria. The FDA notes that any modification of standard response criteria should be justified. Further, trials completing on-study imaging assessments for CNS are required to occur at the same time for those patients with extra-CNS disease. Sponsors of the study must provide a radiology charter describing imaging modalities, sequences, and other standard parameters applied at all trial sites. Investigators should specify the conditions with which prior radiated lesions may be included as target lesions within the radiology charter. Also, case reports should capture baseline data and data during the study on variables that can impact radiologic response interpretation such as presence or change in neurologic symptoms, current steroid use or change in steroid use, and current antiseizure medication or change in antiseizure medication.

Trial end point selection depends on trial population and whether the study population includes patients with CNS only. The FDA recommends referring to the industry guidance Clinical Trial End Points for the Approval of Cancer Drugs and Biologics for more information.3 The FDA comments that data derived from externally controlled trials are seldom reliable for time-to-event endpoints. Time-to-event end points should be evaluated in randomized, internally controlled trials. Overall survival (OS) can be evaluated in randomized trials, but because it is difficult to attribute death to CNS disease, death from any cause should be used for OS.

Efficacy end points based off tumor assessment should incorporate patients with both CNS disease and extra-CNS disease, specifically the ORR and PFS. Further, if the primary end point is based on tumor assessment, it should be confirmed by an independent, blinded central review with neuro-radiology expertise. Tumor assessment end points should include duration of response (DOR) in addition to systemic DOR. If investigators aim to record CNS-ORR, this may be unreliable in a patient population with recent CNS-directed therapy. Responses should be based on time from prior CNS-directed therapy. CNS-PFS may also be uninterpretable because of censoring patients at the time of extra-CNS progression or death. In cases where solid tumors appear often in the CNS, as it is a frequent metastatic site, PFS in patients with brain metastases at the first site of progression, alone or with concurrent extra-CNS progression, may be reported.

The CNS Guide for Industry makes special highlight of LMD. The FDA recognizes LMD as disease of the entire CNS. With this designation, clinical trials whose intention is to evaluate drug effects on LMD should also evaluate CMS parenchymal disease. And unless there is a rationale for a product to affect LMD favorably, efficacy will be based on the assessment of disease in the entire CNS compartment. Cerebrospinal fluid (CFS) analysis and imaging can identify LMD; however, clinical symptoms should be followed and evaluated. The FDA prefers to establish LMD through the presence of at least 1 site of MRI-evaluable disease amendable to repeat. Further, patients who are suspected of LMD by clinical symptoms, without imaging findings, should undergo CFS analysis to support an LMD diagnosis.


1. U.S. Department of Health and Human Services Food and Drug Administration. Evaluating cancer drugs in patients with central nervous system metastases guidance for industry. July 2021. Accessed December 6, 2021. https://www.fda.gov/media/141507/download

2. Lin NU, Lee EQ, Aoyama H, et al., 2015, Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 16(6): e270–e278. doi: 10.1016/S1470-2045(15)70057-4

3. US Food and Drug Administration. Clinical trial end points for the approval of cancer drugs and biologics guidance for industry. December 2018. Accessed December 7, 2021. https://www.fda.gov/media/71195/download