FDA drafts recommendations for studying cancer drugs in patients with CNS metastases

Regulatory NewsRegulatory News
| 26 August 2020 | By Michael Mezher 

The US Food and Drug Administration (FDA) on Wednesday issued draft guidance providing recommendations to drugmakers on evaluating cancer drugs in patients with central nervous system (CNS) metastases.
FDA says the guidance is meant to inform clinical trial designs to support product labeling that describes antitumor activity of drugs or biologics in patients with CNS metastases from solid tumors originating in other parts of the body.
"There are few effective treatments for patients with central nervous system (CNS) metastases – a type of cancer that has spread from the original tumor to the CNS and is associated with a higher risk of death. In addition, there are also few clinical trials testing therapies for CNS metastases. More attention is warranted to address this unmet medical need,” said Richard Pazdur, director of FDA’s Oncology Center of Excellence.
When looking to enroll patients with brain metastases in clinical trials, FDA directs sponsors to its recently finalized guidance, Cancer Clinical Trial Eligibility Criteria: Brain Metastases. (RELATED: FDA finalizes guidance on broader cancer trial eligibility, Regulatory Focus 10 July 2020; FDA unveils 5 guidances on broadening cancer clinical trial eligibility, Regulatory Focus 12 March 2019).
In the guidance, FDA explains some of the challenges present in evaluating treatments for CNS metastatic disease. “The potential for benefit of a drug as assessed by tumor shrinkage of CNS lesions is uninterpretable without information regarding tumor shrinkage at extra-CNS disease sites. Furthermore, evaluation of anti-tumor activity, particularly durability of tumor response in the CNS may not be attributable solely to the investigational drug, as treatment would generally be changed at the time of extra CNS disease progression in patients with evidence of stable or responding CNS lesions,” FDA writes.
FDA also notes that CNS disease should not be evaluated in isolation from metastatic disease in the rest of the body. As such, FDA says that “efficacy claims based on endpoints measuring CNS activity alone may not be appropriate.”
To determine whether an expedited program for therapies without available therapeutic alternatives, FDA says it considers, “an available therapy for a metastatic solid tumor [to] be an available therapy for CNS metastases of that solid tumor, unless otherwise specified in the labeling for that therapy.”
When it comes to designing clinical trials, FDA says sponsors should take consideration of prior therapies subjects may have received. FDA notes that sponsors should capture information on all prior CNS-directed treatments and that protocols should specify an interval, typically of at least 12 weeks, between completion of CNS radiation therapy and study entry, “to allow attribution of treatment effects to the study intervention.”
Additionally, protocols, “Should specify appropriate stratification factors for randomization to minimize bias based on prior therapy(ies).”
FDA also provides guidance on assessing CNS metastases, noting that magnetic resonance imaging (MRI) with gadolinium contrast is preferred and that protocols should require baseline imaging evaluation of the CNS in all enrolled patients with CNS disease. Other recommendations include applying accepted standard response criteria for evaluating CNS disease and requiring on-study imaging assessments for CNS disease at the same time points as those for extra-CNS disease.
As for endpoints, FDA says the selection of an appropriate endpoint will depend on the study population and whether the study is evaluating only patients with CNS metastases. Some of the endpoints FDA says may be considered include time-to-event endpoints in randomized controlled trials, overall survival or endpoints based on tumor assessment such as overall response rate or progression-free survival.


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