Tissue Agnostic Drug 
Development in 
Oncology 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Steven Lemery 301-796-2276 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 (OCE) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
October 2022 
Clinical/Medical
   
Tissue Agnostic Drug 
Development in 
Oncology 
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 
10001 New 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 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
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 (OCE)  
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
October 2022 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION ...................................................................................................... 1 
II.  BACKGROUND ON TISSUE AGNOSTIC DRUG DEVELOPMENT .................... 2 
III.  DETERMINING WHETHER TISSUE AGNOSTIC DEVELOPMENT MAY BE 
APPROPRIATE ......................................................................................................... 3 
A.  Biology ......................................................................................................................... 3 
B.   Subject Population ........................................................................................................ 4 
C.   Clinical Pharmacology and Clinical Safety and Efficacy .................................................. 4 
1. Clinical pharmacology .................................................................................................... 4 
2. Clinical safety and efficacy .............................................................................................. 4 
IV.  ISSUES TO ADDRESS IN TISSUE AGNOSTIC DRUG DEVELOPMENT            
PROGRAMS .............................................................................................................. 6 
A.  Nonclinical Assessment.................................................................................................. 6 
B.  Clinical Development  Subject Selection........................................................................ 7 
C.  Clinical Development - Study Designs............................................................................. 8 
D.  Statistical Considerations .............................................................................................. 9 
E.  Endpoints ..................................................................................................................... 9 
F.  Pediatrics ....................................................................................................................10 
G.  Diagnostic Considerations ............................................................................................11 
H.  Postapproval Data and Information ..............................................................................13 
I.  Labeling ......................................................................................................................13 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Tissue Agnostic Drug Development in Oncology 
2  Guidance for Industry1 
3   
4   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
7  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
8  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
9  for this guidance as listed on the title page.   
10   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance provides recommendations to sponsors regarding considerations for tissue 
17  agnostic drug2 development in oncology.  For the purpose of this guidance, the term tissue 
18  agnostic oncology drug refers to a drug that targets a specific molecular alteration(s)3 (a kind of 
19  biomarker) across multiple cancer types as defined, for example by organ, tissue, or tumor type.  
20  A tissue agnostic oncology drug can therefore be used to treat multiple types of cancer (e.g., 
21  colorectal, thyroid, and breast cancers) with the targeted molecular alteration (e.g., either the 
22  same targeted molecular alteration or targeted molecular alterations affecting a single pathway).  
23  Although applications for a tissue agnostic oncology drug are reviewed for safety and 
24  effectiveness under the same legal and regulatory standard as drugs indicated for a tissue specific 
25  cancer, the development of a tissue agnostic oncology drug raises issues that generally do not 
26  arise in more traditional development approaches.  This guidance describes the development of 
27  tissue agnostic drugs, scientific considerations in determining when tissue agnostic oncology 
28  drug development may be appropriate, and, if appropriate, issues to be addressed during such 
29  development.  
30   
31  This guidance does not address the development of drugs intended to prevent or decrease the 
32  incidence of cancer and does not address the treatment of cancer in the adjuvant or neoadjuvant 
33  setting.  
34   
35  The contents of this document do not have the force and effect of law and are not meant to bind 
36  the public in any way, unless specifically incorporated into a contract.  This document is 
37  intended only to provide clarity to the public regarding existing requirements under the law.  
 
1 This guidance has been prepared by the Oncology Center of Excellence, Center for Drug Evaluation and Research, 
and Center for Biologics Evaluation and Research in consultation with the Center for Devices and Radiological 
Health. 
2 For purposes of this guidance, references to drugs include drugs approved under section 505 of the Food, Drug, 
and Cosmetic Act (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 For the purpose of this guidance, molecular alteration refers to a broad array of molecular changes in DNA, RNA, 
or proteins, including point mutations, gene fusions, mutational load, antigen or neoantigen burden, epigenetic 
changes, and over-or under-expression.   
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38  FDA guidance documents, including this guidance, should be viewed only as recommendations, 
39  unless specific regulatory or statutory requirements are cited.  The use of the word should in 
40  Agency guidances means that something is suggested or recommended, but not required. 
41   
42   
43  II.  BACKGROUND ON TISSUE AGNOSTIC DRUG DEVELOPMENT 
44   
45  When drugs are developed for disease indications, the disease has been traditionally defined by 
46  pathologic processes, signs or symptoms, or histologic findings in affected organs or specific 
47  sites of the body.  In oncology, drugs are also developed for subtypes of organ- or tissue-specific 
48  cancers defined by molecular alterations (e.g., tumor markers, hormone-receptor status).  Based 
49  on advancements in the knowledge of disease pathways in oncology, it may be possible, and 
50  more efficient, to develop certain oncology drugs for the treatment of cancer for tissue agnostic 
51  indications.  Tissue agnostic drug development represents a change in approach to oncology drug 
52  development in which a drug is developed for an indication defined by a specific molecular 
53  alteration across cancer types. 
54   
55  Tissue agnostic drug development may be possible both for intrinsic alterations (or receptors) 
56  (e.g., neurotrophic receptor tyrosine kinase (NTRK) gene fusions) and for factors extrinsic to the 
57  cancer (e.g., the tumor microenvironment or surrounding immunologic milieu).  
58   
59  A key difference between tissue agnostic oncology drug development and traditional oncology 
60  drug development is the inherent need in tissue agnostic drug development to generalize4 
61  treatment effects based on data observed in some cancer types to other cancer types with the 
62  same targeted molecular alteration, when no subjects (or a limited number of subjects) with the 
63  other cancer types were included in the clinical trial(s).  As described further in this guidance, 
64  such generalization may be justified, in appropriate cases, by a strong scientific rationale and 
65  clinical circumstances, and may expedite or enable the development of new therapies for patients 
66  with rare cancer types when it may not be feasible to test the drug in an adequate number of 
67  subjects for every cancer type. 
68   
69  Generalization of treatment effects in tissue agnostic drug development can introduce some 
70  uncertainty about a drugs effectiveness across all individual cancer types.  In some clinical 
71  circumstances, this uncertainty may be acceptable.  This is consistent with FDAs longstanding 
72  approach to evaluation of data supporting effectiveness.5  Therefore, when justified by strong 
73  scientific rationale, clinical data demonstrating effectiveness across different cancer types with 
74  the same molecular alteration, plus specific clinical circumstances (e.g., unmet medical need), 
75  may support generalization of efficacy across cancer types.  
76   
 
4 Although we use the term generalize here, we acknowledge that the term extrapolate may also have been used in 
other similar contexts.  See, for example, the guidance for industry Developing Targeted Therapies in Low-
Frequency Molecular Subsets of a Disease (October 2018).  FDA updates guidances periodically.  For the most 
recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
5 See section 505 of the FD&C Act; see also the draft guidance for industry Demonstrating Substantial Evidence of 
Effectiveness for Human Drug and Biological Products (December 2019).  When final, this guidance will represent 
the FDAs current thinking on this topic. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
77  FDA has relied on the generalization of efficacy in other settings such as treatment effects across 
78  sex (e.g., in certain circumstances, seeing a response to a drug in female breast cancer and 
79  permitting labeling for use in male breast cancer)6 and across age groups7 when supported by the 
80  biology of the disease and the pharmacology of the drug.  The Agency also notes in the guidance 
81  on developing targeted therapies in low-frequency molecular subsets of a disease that when 
82  sponsors follow the principles for grouping subjects, extrapolation of efficacy findings across 
83  multiple subsets may be possible despite the low frequency or absence of patients in some 
84  subsets.8  As that guidance acknowledges, different types of evidence can support a grouping 
85  strategy, the strongest of which is clinical evidence  i.e., preliminary clinical studies showing 
86  that subjects with the proposed group of specific molecular alterations exhibit similar responses 
87  to the drug.9 
88   
89   
90  III.  DETERMINING WHETHER TISSUE AGNOSTIC DEVELOPMENT MAY BE 
91  APPROPRIATE 
92   
93  Sponsors should consider the following factors when determining whether a tissue agnostic 
94  oncology drug development program may be scientifically and clinically appropriate.   
95    
96  A.  Biology 
97   
98  A robust understanding of the biology (e.g., molecular pathophysiology of the cancer, molecular 
99  alteration(s), drugs mechanism of action, and response to the drug) across cancer types is 
100  essential, because it will form the basis for the scientific rationale for tissue agnostic 
101  development of a specific drug and may provide support for a conclusion that the drugs effect 
102  across cancer types would be expected to be similar.  Nonclinical models and existing scientific 
103  data may provide support for a drugs mechanism of action in different cancer types.10  See 
104  section IV.A, Nonclinical Assessment, for additional information. 
105   
106  Sponsors should have an appropriate understanding of the molecular alteration(s), such as an 
107  understanding of the pathophysiology of the molecular alteration across cancers, including how 
108  the molecular alteration influences the natural history of the underlying cancers.  In some cases, 
109  natural history studies may provide supportive information regarding the prognosis of subjects 
110  with a particular molecular alteration as compared to those with the same cancer who do not 
111  harbor the same alteration.11  The sponsor should also have an appropriate understanding of the 
 
6 See the guidance for industry Male Breast Cancer:  Developing Drugs for Treatment (August 2020).   
7 See the draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies for Drugs 
and Biological Products (December 2014).  When final, this guidance will represent the FDAs current thinking on 
this topic. 
8 See the guidance for industry Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease. 
9 Section II.A of the guidance for industry Developing Targeted Therapies in Low-Frequency Molecular Subsets of 
a Disease. 
10 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible. We 
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency 
to an animal test method. 
11 See the draft guidance for industry Rare Diseases:  Natural History Studies for Drug Development (March 2019).  
When final, this guidance will represent the FDAs current thinking on this topic. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
112  distribution of the molecular alteration(s) across cancer types prior to determining the optimal 
113  drug development approach.  Certain molecular alterations may not be appropriate for inclusion 
114  in a tissue agnostic oncology drug development program.  For example, de novo or acquired 
115  resistance mechanisms within a subset of cancer types with the molecular alteration may result in 
116  heterogeneity of treatment effect (e.g., non-response) across cancer types.  Sponsors should 
117  develop, if possible, an understanding of potential resistance mechanisms within and across 
118  different cancer types.  
119   
120  B.   Subject Population 
121   
122  If a molecular alteration across tumor types is extremely rare (e.g., NTRK fusions), tissue 
123  agnostic oncology drug development may represent a more feasible developmental strategy.  In 
124  some cases, if a particular alteration is more frequently present in a specific, common cancer 
125  type (e.g., RET-positive lung or thyroid cancer), a sponsor should first assess whether a drug 
126  could be developed more efficiently in that cancer type rather than in a tissue agnostic setting.  It 
127  may be acceptable for a sponsor to seek a tissue agnostic indication in a supplemental application 
128  following initial drug approval in one or more specific cancer type(s).  The supplemental 
129  application for a tissue agnostic drug indication should include data in subjects with cancer types 
130  not studied in the initial tissue specific indication(s).  
131   
132  C.   Clinical Pharmacology and Clinical Safety and Efficacy 
133   
134  1.  Clinical pharmacology 
135   
136    Generally, sponsors should collect blood samples to assess pharmacokinetics (PK) 
137  and pharmacodynamics (PD).  Collection of blood for sparse PK assessment in 
138  clinical trials may be sufficient if PK (and PD if appropriate) have been extensively 
139  characterized in other clinical trials.  
140   
141    Sponsors should consider whether there might be meaningful PK or PD differences 
142  across cancer types, for example due to patient factors, tumor burden, or tumor 
143  location.  Exposure-response models should be developed to determine, for example, 
144  if drug clearance varies among cancer types resulting in a wide variation in exposure.  
145  Sponsors should address whether such differences are clinically relevant resulting in 
146  differential safety or effectiveness across cancer types such that a tissue agnostic 
147  indication may not be appropriate.   
148   
149    Sponsors should consider whether the same dose is appropriate across cancer types. 
150  For example, hepatic impairment may increase or decrease exposure of a drug and 
151  may be more common in certain tumor types (e.g., hepatocellular carcinoma).  
152  Sponsors should provide justification for dose selection in subjects across tumor types 
153  and should consider whether certain tumor types should be excluded from a tissue 
154  agnostic development program due to PK factors.  
155   
156  2.  Clinical safety and efficacy 
157   
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
158    Sponsors should consider whether early clinical data show generally similar response 
159  rates across different cancer types.  For example, lack of responses in select cancer 
160  types may not provide the scientific rationale necessary to support tissue agnostic 
161  oncology drug development and therefore, it may be more appropriate and efficient to 
162  focus development on the individual cancer type(s) that met a threshold level of 
163  response.  While it is possible that observed response rates in individual cancer types 
164  as defined by organ, tissue, or tumor type may differ substantively from the mean 
165  overall effect across cancer types due to chance (e.g., due to small sample size for 
166  certain cancer types), true differences in treatment effect among cancer types may 
167  also occur.  
168   
169    The number and types of cancers that should be studied prior to determining whether 
170  a sponsor should pursue a tissue agnostic indication should be justified based on the 
171  biological factors described above and discussed with the appropriate review division. 
172  Sponsors should provide justification for their plan to enroll a representative 
173  population of subjects with the molecular alteration in different cancer types to 
174  support a tissue agnostic indication.  Furthermore, cancer types in which the 
175  prevalence of a molecular alteration is comparatively high (e.g., colon cancers and 
176  endometrial cancers with MSI-H/dMMR) should be studied in adequate numbers 
177  sufficient to describe the treatment effects in these subjects in the development 
178  program.  
179   
180    FDA advises sponsors to seek diversity in clinical trial enrollment, including race, 
181  ethnicity, and other underrepresented populations defined by demographics such as 
182  sex, gender identity12, age, socioeconomic status, disability, pregnancy status, 
183  lactation status, and co-morbidity. FDA encourages sponsors to also submit diversity 
184  plans that help ensure the adequate participation of relevant and underrepresented 
185  populations and analyses of data collected from clinically relevant subpopulations. 13 
186   
187    Sponsors should consider whether any unique safety considerations exist for their drug that 
188  might limit the drugs use in a particular population (e.g., a subject with hepatocellular 
 
12 See National Strategy on Gender Equity and Equality. 
https://www.whitehouse.gov/wpcontent/uploads/2021/10/National-Strategy-on-Gender-Equity-and-Equality.pdf  
13 Adequate participation and analyses of data collected from clinically relevant subpopulations may provide 
important information pertaining to medical product safety and effectiveness for product labeling. Additional patient 
characteristics such as age, sex, gender, geographic location (e.g., rural), emotional, physical, sensory, and cognitive 
capabilities can often be important variables when evaluating medical product safety and efficacy. While these 
additional characteristics are not addressed in this guidance, FDA encourages sponsors to consider broadening their 
diversity plans to include all clinically relevant populations as appropriate. FDA guidance for industry Enhancing 
the Diversity of Clinical Trial Populations: Eligibility Criteria, Enrollment Practices, and Trial Designs 
(November 2020) encourages the inclusion of persons with disabilities in clinical trials including during the study 
design phase. For example, FDA guidance recommends that sponsors consider the recruitment challenges that may 
occur because of the planned visit schedule and difficulties with accessibility. In addition, guidance for industry 
Inclusion of Older Adults in Cancer Clinical Trials (March 2022) provides recommended guidance for this 
demographic. 
 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
189  carcinoma and cirrhosis when the drug under development is hepatotoxic).  In such cases, 
190  tissue agnostic development may still be appropriate but there may be specific labeling 
191  considerations (e.g., limitation of use in patients with hepatic impairment, different dosage 
192  regimen for patients with hepatic impairment, or description of risks in Warnings and 
193  Precautions).   
194   
195    Sponsors should provide justification regarding prior therapies and the intended 
196  patient population prior to initiating studies intending to support a tissue agnostic 
197  indication.  Sponsors should collect information on disease characteristics and prior 
198  therapies in all subjects enrolled intrials supportive of a tissue agnostic indication to 
199  support the new drug application (NDA) / biologics license application (BLA) 
200  review.  Sponsors pursuing accelerated approval should consider whether data will be 
201  collected in subjects for which the tissue agnostic indication will be sought with 
202  respect to unmet medical need.14   
203   
204   
205  IV.  ISSUES TO ADDRESS IN TISSUE AGNOSTIC DRUG DEVELOPMENT 
206  PROGRAMS 
207   
208  Sponsors should have early and frequent discussions with FDA to discuss development 
209  approaches that are critical to tissue agnostic oncology drug development, including the 
210  nonclinical data, justification for the sample sizes for the overall population and for subgroups of 
211  specific cancer types, and approval pathway (traditional or accelerated approval).   
212   
213  Additional considerations to be addressed in a tissue agnostic drug development program 
214  include: 
215   
216  A.  Nonclinical Assessment 
217   
218  In general, the nonclinical development program for drugs seeking tissue agnostic indications 
219  should follow recommendations in the ICH guidance for industry S9 Nonclinical Evaluation for 
220  Anticancer Pharmaceuticals15 (ICH S9) and the ICH guidance for industry S9 Nonclinical 
221  Evaluation for Anticancer Pharmaceuticals Questions and Answers (ICH S9 Questions and 
222  Answers).16  Nonclinical pharmacology studies should include cell lines from multiple cancer 
223  origins, harboring the molecular target(s) of interest.  Nonclinical pharmacology studies 
224  conducted in support of first-in-human trials may also be supplemented with nonclinical or 
225  clinical results from other drugs with the same mechanism of action showing similar effects in 
226  tumor types with the targeted molecular alteration(s).17  Confidence in the relevance of findings 
227  from one drug to another in the same class depends on their similarity in structure, binding sites, 
 
14 For additional information on accelerated approval, see 21 CFR parts 314, subpart H and 601, subpart E; section 
506(c) of the FD&C Act, as amended by section 901 of the Food and Drug Administration Safety and Innovation 
Act of 2012 (FDASIA); and the guidance for industry Expedited Programs for Serious Conditions  Drugs and 
Biologics (May 2014). 
15 March 2010. 
16 June 2018. 
17 See footnote 8. 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
228  and other drug properties.  Although nonclinical data supporting the biological rationale for a 
229  drugs effect across molecular alteration-positive cancer types can provide support for a tissue 
230  agnostic indication, FDA does not expect a sponsor to conduct a nonclinical study in every 
231  potential cancer type where the molecular alteration might exist in humans. 
232   
233  In some cases, clinical data might direct a sponsor to conduct additional nonclinical studies to fill 
234  in gaps to support a tissue agnostic indication.  Ultimately, a sponsor should provide justification 
235  within an NDA or BLA regarding the nonclinical approach used to support development of a 
236  tissue agnostic oncology drug.  
237   
238  For cellular or gene therapy products being developed for tissue agnostic indications, sponsors 
239  should consult the guidance for industry Preclinical Assessment of Investigational Cellular and 
240  Gene Therapy Products,18 and should discuss their nonclinical development program with the 
241  appropriate division within CBER. 
242   
243  B.  Clinical Development  Subject Selection 
244   
245  Tissue agnostic oncology drug development will be informed by the disease, patient population, 
246  presence or absence of unmet medical need, and characteristics of the drug determined from 
247  nonclinical or early clinical information.  For example, it may be appropriate to begin studying 
248  the drug:  (1) in one or a small number of subgroup populations, (2) across a larger number of 
249  subpopulations, or (3) by excluding a certain subgroup population(s).  Information from earlier 
250  clinical testing can inform the approach taken to continue developing the drug in a tissue 
251  agnostic versus tissue specific setting(s). 
252   
253  If a sponsor intends to develop a drug for a tissue agnostic indication targeting a specific 
254  molecular alteration and contemporaneously develop the drug separately in a specific cancer 
255  type(s), sponsors should address how inclusion of molecular alteration-positive subjects in tumor 
256  specific studies would impact the efficacy results.  This may require some understanding of a 
257  drugs effect on cancers without the targeted molecular alteration.  The appropriate study 
258  population and design of a cancer specific study will depend upon a drugs effect in molecular 
259  alteration-positive and -negative populations and the incidence rate of the molecular alteration in 
260  the specific cancer type.  At a minimum, the presence of the alteration should be assessed in any 
261  cancer specific study.  In some cases, FDA may recommend separate analyses in the molecular 
262  alteration-negative subject populations.  
263   
264  Consistent with the statutory standard for safety and effectiveness,19 a tissue agnostic indication 
265  will require an assessment of efficacy of the drug in subjects with an appropriate spectrum of 
266  different cancer types and an adequate assessment of safety.  Furthermore, if the molecular 
267  alteration is complex (e.g., a fusion with multiple partners or a continuous biomarker), sponsors 
268  should provide justification that an appropriate spectrum of specific cancer types and an 
269  appropriate spectrum of biomarker-defined cancers (e.g., based on the different fusion partners) 
270  is included in clinical trials and that the efficacy results are not heavily weighted towards a 
271  specific cancer type or specific biomarker-defined tumor. 
 
18 November 2013. 
19 See section 505(d) of the FD&C Act and section 351 of the PHS Act. 
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Draft  Not for Implementation 
272   
273  Additional information regarding the evidence supporting the appropriateness of grouping 
274  subjects together based on a molecular alteration can be found in the guidance for industry 
275  Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease.  
276   
277  C.  Clinical Development - Study Designs 
278   
279  The choice of the study design depends on multiple factors, including available therapies, unmet 
280  medical need, observed magnitude and duration of benefit, and size of the patient population. 
281  Early in development, sponsors of oncology drugs frequently conduct smaller single arm trials to 
282  assess the activity of a drug in one or more cancer types.  Early trials of a drug agnostic of tumor 
283  type or in multiple cohorts of patients with different tumor types may provide information to 
284  determine whether tissue agnostic development is appropriate.   
285   
286  Single arm trials using response rate and duration as a primary efficacy endpoint to support 
287  further development or where appropriate, to support an approval, may be acceptable if the 
288  investigational drug is intended for patients with refractory, advanced, or metastatic cancers and 
289  the results are clinically meaningful.20  Response rates can be assessed in nonrandomized trials 
290  in oncology because, in general, tumors do not decrease in size in the absence of therapy.  The 
291  acceptability of whether one or more single arm trials will support an approval will depend on 
292  multiple factors including available therapy (e.g., for an accelerated approval), magnitude and 
293  duration of effect, clinical context, and clinical trial and patient population sizes.  Sponsors 
294  should also consider whether the safety profile of the drug can be adequately assessed using a 
295  single arm design.  
296   
297  Randomized controlled trials in rare molecular alteration-positive tumor types with known 
298  unprecedented effects on endpoints such as response may not be feasible or may not be 
299  appropriate in a refractory setting.  Furthermore, because standard of care and prognosis is 
300  different across cancer types, ensuring baseline balance (i.e., comparability) across two or more 
301  treatment arms may be difficult in a clinical trial that allows for the enrollment of subjects with 
302  different cancer types.  Due to the challenges of such trials, sponsors should seek FDAs advice 
303  prior to conducting any randomized trial that intends to enroll subjects across multiple cancer 
304  types selected by a particular molecular alteration.   
305   
306  In some cases, however, a randomized trial of a drug in one or more cancer types might provide 
307  data to inform a separate tissue agnostic program of the drug.  Randomized trials in specific 
308  cancer type(s) may also be necessary if the drug is intended for use in early stages of the disease 
309  or when there is satisfactory available therapy. 
310   
311  Codevelopment of more than one drug for a tissue agnostic indication should be supported by 
312  nonclinical data (see ICH S9 and ICH S9 Questions and Answers), or clinical data, or both, to 
313  demonstrate the contribution of each drug to the overall safety and effectiveness of the 
 
20 See the guidance for industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(December 2018). 
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Draft  Not for Implementation 
314  combination for the tissue agnostic oncology drug indication.21  When a development program 
315  involves codevelopment of more than one drug, randomized trials in one or more cancer types 
316  may be necessary to demonstrate that each drug contributes to effectiveness.  
317   
318  Various types of master protocol designs that use a single infrastructure, trial design, and 
319  protocol to simultaneously evaluate multiple disease populations may facilitate efficient drug 
320  development and may be appropriate for tissue agnostic oncology drug development.  The design 
321  and conduct of clinical trials intended to simultaneously evaluate more than one cancer type are 
322  addressed in the guidance for industry Master Protocols:  Efficient Clinical Trial Design 
323  Strategies to Expedite Development of Oncology Drugs and Biologics.22  The guidance discusses 
324  biomarker development, specific design considerations including adding and stopping treatment 
325  arms, and content of a master protocol.  In some cases, master protocols will investigate the 
326  effects of different drugs that target different molecular alterations.  Sponsors should discuss 
327  with FDA how subjects will be grouped for the purposes of analysis and such plans should be 
328  prespecified prior to conducting any analyses.  The guidance for industry Adaptive Designs for 
329  Clinical Trials of Drugs and Biologics23 includes recommendations that may facilitate tissue 
330  agnostic drug development. 
331   
332  D.  Statistical Considerations 
333   
334  Sponsors should prospectively provide adequate justification for the number of subjects and 
335  cancer types (sample size) in each trial that might provide support for approval of a tissue 
336  agnostic oncology drug as well as for the number of subjects and cancer types across trials (if 
337  applicable).  This is generally accomplished after developing a hypothesis based on a meaningful 
338  treatment effect while controlling for Type I error or to ensure adequate precision of the 
339  treatment effect.  Bayesian approaches can also be considered; however, sponsors should discuss 
340  such approaches with the Agency prior to initiation of clinical studies.  The appropriate number 
341  of subjects and cancer types may differ for each drug development program because the 
342  distribution of the molecular alteration across different cancer types may differ across different 
343  programs.  In some cases, a separate statistical analysis document may be necessary to analyze 
344  information across multiple randomized trials.  
345   
346  Although FDA recommends that sponsors prespecify their statistical analysis plan(s), FDA may 
347  not be able to determine if a tissue agnostic oncology drug indication (versus a more limited 
348  indication) will be appropriate until FDA assesses the data from the clinical trials in the 
349  development program.  For example, although a trial may allow for enrollment of any number of 
350  cancer types, if a sponsor only enrolls subjects with lung cancer, the indication may be limited to 
351  alteration-positive lung cancer.  
352   
353  E.  Endpoints 
354   
 
21 See the guidance for industry Codevelopment of Two or More New Investigational Drugs for Use in Combination 
(June 2013).   
22 March 2022.  
23 November 2019. 
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355  Sponsors considering the development of drugs in the tissue agnostic oncology drug setting 
356  should review the guidance for industry Clinical Trial Endpoints for the Approval of Cancer 
357  Drugs and Biologics.24  Any tumor specific response criteria should be predefined with adequate 
358  justification.   
359   
360  F.  Pediatrics 
361   
362  A tissue agnostic oncology drug indication should address the needs of patients of all ages; 
363  therefore, sponsors should consider in their development plan how they will develop a drug to 
364  address the needs of children with the targeted molecular alteration.25, 26, 27  Consultation with 
365  the Agency regarding pediatric studies is recommended as early as possible in drug development. 
366  In general, FDA recommends enrollment of children as early as safely possible in clinical trials 
367  to support a tissue agnostic oncology drug indication.  Sponsors should consider enrolling 
368  children age 12 years or older in adult trials.28 Sponsors should consider the following factors to 
369  determine the appropriate pediatric development plan for a tissue agnostic oncology drug 
370  indication: 
371   
372    The spectrum of the molecular alteration across pediatric cancers and the expected 
373  distribution of patient ages in the pediatric setting.  
374   
375    The incidence of molecular alteration-positive disease in the pediatric population and 
376  the expected rate of the molecular alteration across different cancer types.  Even if a 
377  disease is rare, it may be easier to identify subjects if most or all of a cancer type is 
378  expected to be molecular alteration-positive (compared to a setting where the 
379  alteration rarely occurs in a more common cancer).  
380   
381    The age groups and any safety considerations arising from the intended use of the 
382  drug.  For example, if patients receiving the drug are anticipated to survive long-term 
 
24 December 2018. 
25 For additional information on oncology drug development in children, see the guidance for industry Cancer 
Clinical Trial Eligibility Criteria:  Minimum Age Considerations for Inclusion of Pediatric Patients (July 2020) and 
the guidance for industry Considerations for the Inclusion of Adolescents in Adult Oncology Trials (March 2019). 
26 Section 505B(a)(1)(B) of the FD&C Act requires that all original new drug applications (NDAs) or biologics 
license applications (BLAs) for a new active ingredient, must submit reports on the molecularly targeted pediatric 
cancer investigation required under section 505B(a)(3) with the application, if the drug or biological product that is 
the subject of the application is (i) intended for the treatment of an adult cancer; and (ii) directed at a molecular 
target that the [FDA] determines to be substantially relevant to the growth or progression of a pediatric cancer, 
unless the requirement is waived or deferred.  Section 505B(a)(1) of the FD&C Act also requires NDAs and BLAs 
(or supplements to applications) for a new active ingredient, new indication, new dosage form, new dosing regimen, 
or new route of administration to contain a pediatric assessment unless the requirement is waived or deferred.  For 
information on marketing applications for certain drugs that are directed at a molecular target FDA determines to be 
substantially relevant to the growth or progression of a pediatric cancer, see the guidance for industry FDARA 
Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs:  Amendments to Sec. 
505B of the FD&C Act (May 2021).  
27 For information regarding an initial pediatric study plan (iPSP) and any amendments to the iPSP, see the guidance 
for industry Pediatric Study Plans:  Content of and Process for Submitting Initial Pediatric Study Plans and 
Amended Initial Pediatric Study Plans (July 2020).    
28 See the guidance for industry Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical 
Trials. 
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Draft  Not for Implementation 
383  and clinical or nonclinical safety signals have been identified during development, 
384  sponsors should assess the impact of late effects (e.g., growth and development, 
385  cognitive functioning, reproductive safety, risk of secondary malignancies). 
386  Additionally, in this setting, sponsors should discuss with FDA the need to conduct 
387  additional nonclinical or human studies or to obtain long-term follow-up information 
388  to further assess drug safety in pediatric patients.  Sponsors should discuss with FDA 
389  any such considerations before exclusion of any pediatric populations from a tissue 
390  agnostic oncology drug indication development program.  
391   
392    Whether a different formulation (e.g., liquid formulation) or dosing regimens are 
393  necessary to address the needs of children.29  Additional data will likely be needed to 
394  support the use of a new formulation.30 
395    Whether information is available to inform a dose in children of all ages based on 
396  safety and PK information from adult studies as well as any data from completed 
397  pediatric dose-finding studies.31  
398   
399    Whether extrapolation (e.g., of data from adult cancers to pediatric cancers) is 
400  appropriate based on similarity of disease and the mechanism of action of the drug.  
401   
402  There are several important ethical considerations specific to including pediatric subjects in 
403  clinical trials outlined in the FDA regulations addressing human subject protection at 21 CFR 
404  part 50, subpart D, Additional Safeguards for Children in Clinical Investigations.32  
405   
406   
407   
408  G.  Diagnostic Considerations 
409   
410  Tissue agnostic indications are identified by a molecular alteration that can range from simple 
411  genetic alterations such as single nucleotide changes, amplifications or fusions, or complex 
412  phenotypic alterations such as microsatellite instability or tumor mutation burden that occur 
413  broadly across cancers but infrequently in many cancer types.  The identification of molecular 
414  alteration-defined populations is dependent on the availability of accurate and reliable diagnostic 
415  tests that can identify patients irrespective of cancer type.  When accurate testing for molecular 
416  alterations is essential for the safe and effective use of the drug, an FDA-cleared or -approved 
417  companion diagnostic for this intended use should be commercially available at the time of drug 
418  approval to identify patients in the health care setting.   
419   
420  There are unique challenges regarding the development of a companion diagnostic in the tissue 
421  agnostic oncology drug setting, for example, variability in specimen collection and handling 
 
29 FD&C Act  505B(a)(1).  
30 See the draft guidance for industry Bioavailability Studies Submitted in NDAs or INDs  General Considerations 
(February 2019).  When final, this guidance will represent the FDAs current thinking on this topic. 
31 See footnote 7. 
32 For additional information regarding these regulations, see section III.A.1 of the guidance for industry Cancer 
Clinical Trial Eligibility Criteria:  Minimum Age Considerations for Inclusion of Pediatric Patients. 
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422  across tumor types and limited tissue for testing multiple biomarkers.33  Platforms such as next-
423  generation sequencing may facilitate testing for the presence of multiple alterations at the same 
424  time and increase the likelihood that a patient may be eligible for clinical studies of targeted 
425  therapies.  Nevertheless, subjects will often be identified (or pre-screened) using a different test 
426  or platform than the test or platform that a device sponsor may be developing.  When subjects are 
427  enrolled based on different tests than the device sponsor is developing, the drug sponsor should 
428  have a robust plan to acquire and save adequate tissue from subjects to perform a bridging 
429  study.34  Information on the performance characteristics of local and central tests used to enroll 
430  the patients in the trial should also be collected.  FDA recommends that device sponsors discuss 
431  with the Agency appropriate pathways for clinical validation of the companion diagnostic.  
432   
433  For some alterations (e.g., fusions), testing sensitivity may vary from platform to platform.  For 
434  example, testing sensitivity may depend on the fusion partners tested in the panel.  There may be 
435  cancer specific factors that influence the sensitivity or specificity of a companion diagnostic that 
436  should be considered when developing a companion diagnostic.  Identification of patients who 
437  will respond to the drug should be ideally achieved by use of a companion diagnostic that has 
438  been approved or cleared by FDA to accurately and reliably detect and measure the relevant 
439  molecular alteration(s). 
440   
441  The challenges for validation of complex biomarkers such as the extent of tumor mutation 
442  burden lie in the uniform definition of the biomarker and the demonstration that a cut off can be 
443  established across cancer types for an individual companion diagnostic, to ensure accurate 
444  identification of the intended patient population.  The companion diagnostic for a tissue agnostic 
445  biomarker should provide sufficient evidence that assures that measured test performance (both 
446  analytical and clinical) is representative across cancer types and accounts for cancer specific 
447  variables that can impact final results.     
448   
449  If FDA determines that an IVD companion diagnostic device is essential to the safe 
450  and effective use of a novel therapeutic product or indication, FDA generally will not 
451  approve the therapeutic product or new therapeutic product indication if the IVD companion 
452  diagnostic device is not approved or cleared for that indication. In deciding whether to approve 
453  in the absence of an approved IVD companion diagnostic device, FDA would consider whether 
454  the  drug treats a serious or life-threatening condition for which no satisfactory alternative 
455  treatment exists and the FDA determines that the benefits from the use of the drug outweigh the 
456  risks from the lack of an approved or cleared companion diagnostic.  Generally, a postmarketing 
457  commitment to develop such a companion diagnostic postapproval will be requested in these 
458  situations.  
459   
 
33 For additional information on companion diagnostics see the guidance for industry Developing and Labeling In 
vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products (April 2020), the 
guidance for industry and FDA staff In Vitro Companion Diagnostic Devices (August 2014), and the guidances for 
stakeholders and Food and Drug Administration staff Considerations for Design, Development, and Analytical 
Validation of Next Generation Sequencing (NGS)  Based In Vitro Diagnostics (IVDs) Intended to Aid in the 
Diagnosis of Suspected Germline Diseases (April 2018) and Use of Public Human Genetic Variant Databases to 
Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics (April 2018). 
34 Li, M, Statistical Methods for Clinical Validation of Follow-On Companion Diagnostic Devices via an External 
Concordance Study, 2016, Statistics in Biopharmaceutical Research, 8(3): 355-363.   
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460  FDA recommends that drug and device sponsors meet with the appropriate Center(s) in the 
461  Agency to determine the requirements for approval of a companion diagnostic as soon as the 
462  decision to initiate a tissue agnostic development program is made.  FDA recommends that 
463  device sponsors describe their plan to analytically validate the companion diagnostic across 
464  cancer types and discuss this prospectively with FDA.  
465   
466  H.  Postapproval Data and Information 
467   
468  Additional information about tissue agnostic oncology drugs is likely to be obtained in the post 
469  approval setting.  In particular, for drugs granted tissue agnostic indications, postmarket 
470  information may provide additional effectiveness data in cancer types not studied or studied only 
471  in a small number of subjects prior to approval.  Postmarketing studies may be required for drugs 
472  granted accelerated approval35 or they may be requested to assess effectiveness issues for certain 
473  cancer types, including any resistance mechanism(s) and whether there is a lack of effect in a 
474  tumor type(s). 
475   
476  Sponsors should discuss with FDA what types of data will be required or should be collected in 
477  the postmarket setting.36  If substantive data emerge postmarket (e.g., indicating a drug lacks 
478  effectiveness in a particular tumor type) FDA would review the emerging data and take action as 
479  appropriate.  
480   
481  I.  Labeling 
482   
483  If an application is approved, efficacy results across cancer types should be described in the 
484  CLINICAL STUDIES section of labeling.  Pooling of overall response rate and duration of 
485  response, if assessed as the primary endpoint, may be included in labeling when adequately 
486  justified by sponsors.  Such justification should include an assessment of effects across studies or 
487  cancers.  Efficacy results may also be described by listing response rates by tumor or histologic 
488  subtype or based on individual studies if adequately justified; however, if the number of subjects 
489  with a specific cancer type is very small, it may be more appropriate to list the response for each 
490  subject rather than describe a specific percent and confidence interval.  
491   
492  In general, studies to support efficacy supplements after initial approval should be based on a 
493  prespecified analysis plan(s).  However, as described in the previous section, FDA may consider 
494  reviewing the status of the indication if there is accumulating data in a sufficient number of 
495  patients related to the lack of effectiveness of a drug in a specific cancer type; sponsors should 
496  discuss with FDA.  
 
35 See for example, 21 CFR part 314, subpart H and 21 CFR part 601, subpart E, for postmarketing requirements for 
accelerated approval. 
36 See for example, 21 CFR part 314, subpart H and 21 CFR part 601, subpart E, for postmarketing requirements for 
accelerated approval; see also FD&C Act 505(o)(3). 
  13