Evaluating Cancer 

Drugs in Patients with 

Central Nervous 

System Metastases 

Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit electronic comments to https://www.regulations.gov. Submit written 

comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 

Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the 

docket number listed in the notice of availability that publishes in the Federal Register. 

For questions regarding this draft document, contact (CDER) Shanthi Marur at 240-402-6373 or 

(CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010. 

U.S. Department of Health and Human Services

Food and Drug Administration

Oncology Center of Excellence

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

August 2020

Clinical/Medical
Evaluating Cancer 

Drugs in Patients with 

Central Nervous 

System Metastases 

Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information 

Center for Drug Evaluation and Research

Food and Drug Administration

10001New Hampshire Ave., Hillandale Bldg., 4th Floor 

Silver Spring, MD 20993-0002 

Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353

Email: druginfo@fda.hhs.gov 

https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 

and/or

Office of Communication, Outreach and Development 

Center for Biologics Evaluation and Research

Food and Drug Administration

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Silver Spring, MD 20993-0002

Phone: 800-835-4709 or 240-402-8010

Email: ocod@fda.hhs.gov

https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 

U.S. Department of Health and Human Services

Food and Drug Administration

Oncology Center of Excellence

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

August 2020

Clinical/Medical
Contains Nonbinding Recommendations

Draft — Not for Implementation

TABLE OF CONTENTS 

I. INTRODUCTION...................................................................................................... 1

II. BACKGROUND ........................................................................................................ 1

III. CLINICAL TRIAL DESIGN CONSIDERATIONS .................................................. 2

A. Patient Population ........................................................................................................ 2

B. Available Therapy ........................................................................................................ 2

C. Prior Therapies............................................................................................................ 3

D. Assessment of CNS Metastases....................................................................................... 3

E. Study Endpoints........................................................................................................... 4

F. Leptomeningeal Disease (LMD)..................................................................................... 5
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1

1 Evaluating Cancer Drugs in Patients with Central Nervous System 

2 Metastases 

Guidance for Industry1 3 

 4 

5 

6 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 

7 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 

8 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 

9 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 

10 for this guidance as listed on the title page. 

11

12

13

14

15 I. INTRODUCTION 

16

17 The purpose of this guidance is to describe FDA’s recommendations for clinical trial designs of 

cancer drugs or biological products2 18 regulated by CDER and CBER that are intended to support 

19 product labeling describing the antitumor activity in patients with central nervous system (CNS) 

20 metastases from solid tumors originating outside the CNS. 

21

22 FDA’s current thinking regarding inclusion of patients with brain metastases in clinical trials is 

23 addressed in the guidance for industry Cancer Clinical Trial Eligibility Criteria: Brain 

Metastases.3 24

25

26 In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 

27 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 

28 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 

29 the word should in Agency guidances means that something is suggested or recommended, but 

30 not required. 

31

32

33 II. BACKGROUND

34

35 The solid tumors that most often metastasize to the CNS are small cell and non-small cell lung 

cancers, breast cancer, melanoma, and renal cancers. 36 4 CNS metastatic disease includes 

37 parenchymal metastases to the brain or spinal cord, as well as leptomeningeal disease (LMD) 

 

1 This guidance has been prepared by the Oncology Center of Excellence, the Center for Drug Evaluation and 

Research (CDER), and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug 

Administration. 

2 For purposes of this guidance, references to drugs include drugs approved under section 505 of the FD&C Act (21 

U.S.C. 355) and biological products licensed under section 351 of the Public Health Service Act (42 U.S.C. 262).

3 July 2020. We update guidances periodically.For the most recent version of a guidance, check the FDA guidance 

web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 4 Nayak L, Lee EQ, Wen PY, 2012, Epidemiology of Brain Metastases, Curr Oncol Rep, 14(1): 48-54.
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38 involving the pia, subarachnoid leptomeninges, and cerebrospinal fluid (CSF). LMD may present 

39 with or without concurrent parenchymal disease and represents widespread dissemination of 

40 cancer cells throughout the CNS.

41

42 Metastatic cancer is a systemic disease; therefore, evaluation of the effectiveness of cancer drugs 

43 includes consideration of whether the cancer is controlled at all disease sites. The potential for 

44 benefit of a drug as assessed by tumor shrinkage of CNS lesions is uninterpretable without 

45 information regarding tumor shrinkage at extra-CNS disease sites. Furthermore, evaluation of 

46 anti-tumor activity, particularly durability of tumor response in the CNS may not be attributable 

47 solely to the investigational drug, as treatment would generally be changed at the time of extra48 CNS disease progression in patients with evidence of stable or responding CNS lesions. The 

49 recommendations below reflect the challenges in assessing the potential benefit of systemic 

50 therapies at a single disease site in patients with disease in, or at risk for disease progression in,

51 CNS and extra-CNS sites. 

52

53

54 III. CLINICAL TRIAL DESIGN CONSIDERATIONS

55

56 The recommendations discussed below pertain to clinical trials for systemic anticancer drugs 

57 where patients with CNS metastases are included in the study population and CNS anti-tumor 

58 activity is intended to be described in product labeling. These recommendations are also 

59 applicable to trials conducted exclusively in patients with CNS metastases. 

60

61 A. Patient Population

62

63 FDA recognizes that treatment of CNS metastases presents several challenges and unique 

64 considerations (e.g., circumventing the blood-brain barrier); however, CNS disease should not be 

65 evaluated in isolation from metastatic disease in the rest of the body. FDA will evaluate effects 

66 of systemic drugs on CNS metastases in the context of the entire burden of metastatic disease, 

67 regardless of whether the trial was conducted exclusively in patients with CNS metastases or 

68 where only a subset of patients has CNS metastases. Therefore, efficacy claims based on 

69 endpoints measuring CNS activity alone may not be appropriate. For example, evaluation of the 

70 clinical significance of overall response rates or progression-free survival (PFS) that considers 

71 only CNS disease sites (CNS-ORR or CNS-PFS, respectively) is difficult to interpret as it does 

72 not take into account extra-CNS metastatic disease. Likewise, a labeling indication specifically 

73 for treatment of CNS metastases alone may not be appropriate. Where anti-tumor activity has 

74 been demonstrated in both the CNS and extra-CNS sites of disease, treatment effects on CNS 

75 metastases may be described in Section 14 (“Clinical Studies”) of the product label. 

76

77 B. Available Therapy

78

79 For the purposes of determining whether an expedited program is an appropriate regulatory 

80 pathway for a given drug, an available therapy for a metastatic solid tumor would be an available 

therapy5 81 for CNS metastases of that solid tumor, unless otherwise specified in the labeling for 

 5 For the definition of available therapy, see section III.B of the guidance for industry Expedited Programs for 

Serious Conditions – Drugs and Biologics (May 2014).
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82 that therapy (e.g., the drug is contraindicated for CNS metastases). For example, since alectinib 

83 is approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive 

84 metastatic non-small cell lung cancer (NSCLC), alectinib is considered available therapy for the 

85 treatment of patients with CNS metastases from ALK-positive NSCLC. 

86

87 C. Prior Therapies

88

89 FDA recommends that trial designs incorporate the following elements regarding therapies that 

90 subjects may have received prior to enrolling in the trial:

91

92 • Case report forms should be designed to capture information on all prior CNS-directed 

93 treatments such as surgery, stereotactic radiosurgery (SRS), or whole brain radiation 

94 therapy (WBRT), including the dates of such therapy and response to therapy at baseline.

95

96 • The protocol should specify the interval between completion of CNS radiation therapy 

97 (RT) and study entry as an eligibility criterion. The interval should be of sufficient 

98 duration to allow attribution of treatment effects to the study intervention, and to reduce 

99 the likelihood of enrolling patients with radiographic post-RT pseudoprogression. In most 

100 cases, an interval of at least 12 weeks may suffice, unless there is reasonable certainty of 

101 disease progression supported by additional information (e.g., histologically proven, new 

102 disease outside the RT field) prior to that time. 

103

104 • The protocol should specify appropriate stratification factors for randomization to 

105 minimize bias based on prior therapy(ies) (e.g., treated vs. untreated CNS metastases at 

106 baseline; presence or absence of CNS metastases at baseline).

107

108 D. Assessment of CNS Metastases

109

110 • Magnetic resonance imaging (MRI) with gadolinium contrast is the preferred imaging 

modality for tumor assessment.6 111

112

113 • The protocol should require baseline imaging evaluation of the CNS in all enrolled 

114 patients to identify patients with CNS disease prior to initiation of protocol-specified 

115 therapy. 

116

117 • The protocol should apply accepted standard response criteria for evaluation of CNS 

118 disease (e.g., Response Assessment in Neuro-Oncology – Brain Metastases [RANO119 BM]). Any proposed modifications or adaptations to standard response criteria should be 

120 adequately justified. 

121

122 • The protocol should require on-study imaging assessments for CNS disease at the same 

123 time points as those for extra-CNS disease. Any unscheduled disease assessments (e.g., 

124 due to clinical worsening) should include evaluation of both CNS and extra-CNS disease.

 6 Lin NU, Lee EQ, Aoyama H, et al., 2015, Response assessment criteria for brain metastases: proposal from the 

RANO group, Lancet Oncology, 16(6): e270–e278.
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125

126 • Sponsors should provide a radiology charter describing the imaging modalities, 

127 sequences, and other standardized parameters that should be applied at all trial sites.

128

129 • The protocol and the radiology charter should specify the conditions under which 

130 previously radiated lesions may be included as target lesions (e.g., documentation of 

131 progressive disease).

132

133 • Case report forms should capture data at baseline and during the study on variables that 

134 may impact interpretation of radiographic response, including presence or change in 

135 neurological symptoms, concurrent steroid use/change in steroid use, and concurrent anti136 seizure medications/change in anti-seizure medications.

137

138 E. Study Endpoints

139

140 The selection of the appropriate endpoint to evaluate CNS activity of a systemic drug will 

141 depend in part on the study population, including whether the trial is intended to evaluate only 

patients with CNS metastases. 142 7 The following study endpoints may be considered:

143

144 • Time-to-event endpoints

145

146 o As discussed in the guidance for industry Clinical Trial Endpoints for the Approval of 

147 Cancer Drugs and Biologics, data derived from externally controlled trials are 

148 seldom reliable for time-to-event endpoints and those endpoints should therefore be 

149 evaluated in randomized, internally controlled trials.

150

151 • Overall Survival (OS):

152

153 o OS can generally only be evaluated in randomized controlled trials. 

154

155 o As it is challenging to accurately attribute death to CNS disease, death due to any 

156 cause should be used to determine OS.

157

158 • Endpoints based on tumor assessment:

159

160 o Key efficacy endpoints based on tumor assessments should incorporate evaluation of 

161 both CNS and extra-CNS disease (see III.A). Specifically, the ORR and PFS should 

162 be determined based on evaluation of all metastatic disease, regardless of whether it 

163 occurs in the CNS or extra-CNS.

164

165 o When the primary endpoint is based on tumor assessment, it should be verified by 

166 independent, blinded central review with neuro-radiology expertise. Where necessary 

167 and when supported by adequate justification, a random sample-based blinded central 

 7 For additional information on study endpoints, see the guidance for industry Clinical Trial Endpoints forthe 

Approval of Cancer Drugs and Biologics(December 2018). 
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168 review auditing approach could be used; such an approach should include a pre169 specified auditing plan with a strategy to detect potential assessment bias. 

170

171 o Capture duration of response (DoR). The proportion of patients with durable 

172 responses at specific time points (e.g., 12-month DoR) may also be described.

173

174 o CNS-RR may be uninterpretable in a population with recent CNS-directed therapy 

175 such as RT; therefore, responses should be reported based on time from prior RT 

176 (e.g., < 3 months, < 6 months).

177

178 o Time to CNS progression or CNS-PFS may be uninterpretable due to censoring of 

179 patients at the time of extra-CNS progression or death, resulting in a large number of 

180 censored patients or disproportionate censoring. For solid tumors where the CNS is a 

181 common metastatic site, the incidence of CNS as first site of progression, alone or 

182 with concurrent extra-CNS progression, may be reported. 

183

184 F. Leptomeningeal Disease (LMD)

185

186 • For the purposes of this guidance, FDA considers LMD to be a disease of the entire CNS 

187 compartment. Clinical trials intended to evaluate drug effects on LMD should also 

188 evaluate CNS parenchymal disease and efficacy claims will be based on assessment of 

189 disease in the entire CNS unless there is a biological rationale for why a product may 

190 affect LMD preferentially (e.g., local delivery to the CSF). 

191

192 • LMD can be identified based on imaging or CSF analysis; however, clinical symptoms 

193 should also be evaluated and followed. The presence of at least one site of MRI evaluable 

194 disease amendable to repeat assessment is preferred to establish and evaluate LMD. 

195

196 o Patients with suspected LMD by clinical symptoms only (without imaging findings), 

197 should undergo CSF analysis to substantiate the diagnosis of LMD. 

198

199 o Responses should be confirmed by follow-up imaging or cytology depending on how 

200 the diagnosis was established.