II 

117TH CONGRESS 

1ST SESSION S. 3390 

To increase research, education, and treatment for cerebral cavernous 

malformations. 

IN THE SENATE OF THE UNITED STATES 

DECEMBER 14, 2021 

Mr. LUJA ́N (for himself and Mr. HEINRICH) introduced the following bill; 

which was read twice and referred to the Committee on Health, Education, Labor, and Pensions 

A BILL 

To increase research, education, and treatment for cerebral 

cavernous malformations. 

1 Be it enacted by the Senate and House of Representa2 tives of the United States of America in Congress assembled, 

3 SECTION 1. SHORT TITLE. 

4 This Act may be cited as the ‘‘Cerebral Cavernous 

5 Malformations Clinical Awareness, Research, and Edu6 cation Act of 2021’’ or the ‘‘CCM–CARE Act of 2021’’. 

7 SEC. 2. FINDINGS. 

8 Congress finds as follows: 

9 (1) Cerebral cavernous malformations (referred 

10 to in this section as ‘‘CCM’’), also known as cavVerDate Sep 11 2014 17:26 Dec 17, 2021 Jkt 029200 PO 00000 Frm 00001 Fmt 6652 Sfmt 6201 E:\BILLS\S3390.IS S3390

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1 ernous angioma, or cavernoma, is a devastating 

2 blood vessel disease characterized by vascular lesions 

3 that develop and grow within the brain and spinal 

4 cord. 

5 (2) Detection of CCM lesions is achieved 

6 through costly and specialized medical imaging tech7 niques, often not accessible or convenient to patients 

8 who need them. 

9 (3) While CCM is a common type of vascular 

10 anomaly, many individuals are not aware they have 

11 the disease until the onset of serious clinical symp12 toms. CCM is often inherited unknowingly. 

13 (4) CCM affects an estimated 600,000 people 

14 in the United States. 

15 (5) Individuals diagnosed with CCM may expe16 rience neurological deficits, seizure, stroke, or sud17 den death. 

18 (6) Due to limited research, there is currently 

19 no treatment for CCM other than brain and spinal 

20 surgery, and only for certain patients. 

21 (7) There is also a shortage of trained physi22 cians to provide skilled and timely diagnosis and ap23 propriate treatment for CCM. 

24 (8) While the hereditary form of CCM may 

25 occur among any ethnicity, the presence of a mutaVerDate Sep 11 2014 17:26 Dec 17, 2021 Jkt 029200 PO 00000 Frm 00002 Fmt 6652 Sfmt 6201 E:\BILLS\S3390.IS S3390

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1 tion called the ‘‘common Hispanic mutation’’, has 

2 passed through 14 or more generations of American 

3 descendants from the original Spanish settlers of the 

4 Southwest in the 1590s. New Mexico has the highest 

5 population density of CCM in the world; Texas, Ari6 zona, and Colorado also have high rates of CCM due 

7 to the common Hispanic mutation. 

8 (9) A second mutation (CCM2 Common Dele9 tion) originating in the Southeastern United States 

10 before 1800 has increased rates of the illness in 

11 South Carolina, Georgia, Florida, Alabama, Mis12 sissippi, Louisiana, Texas, Oklahoma, Kentucky, 

13 Kansas, and northern California. 

14 SEC. 3. EXPANSION AND COORDINATION OF ACTIVITIES OF 

15 NATIONAL INSTITUTES OF HEALTH WITH RE16 SPECT TO CEREBRAL CAVERNOUS MAL17 FORMATIONS RESEARCH. 

18 Part B of title IV of the Public Health Service Act 

19 (42 U.S.C. 284 et seq.) is amended by adding at the end 

20 the following: 

21 ‘‘SEC. 409K. CEREBRAL CAVERNOUS MALFORMATIONS RE22 SEARCH ACTIVITIES. 

23 ‘‘(a) EXPANSION AND COORDINATION OF ACTIVI24 TIES.—The Director of NIH, in coordination with the di25 rectors of the National Institute of Neurological Disorders 


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1 and Stroke, the National Center for Advancing 

2 Translational Sciences, the National Heart, Lung, and 

3 Blood Institute, and other national research institutes, as 

4 appropriate, for the purpose of conducting research and 

5 related activities concerning cerebral cavernous malforma6 tions (referred to in this section as ‘CCM’)— 

7 ‘‘(1) shall strengthen and coordinate efforts of 

8 the National Institutes of Health; and 

9 ‘‘(2) may award grants and cooperative agree10 ments to public or nonprofit private entities (includ11 ing State health departments, political subdivisions 

12 of States, universities, and other medical or edu13 cational entities). 

14 ‘‘(b) ACTIVITIES.—The research and related activi15 ties described in subsection (a) shall include the following: 

16 ‘‘(1) CLINICAL, TRANSLATIONAL, AND BASIC

17 RESEARCH.—The Director of NIH shall conduct or 

18 support, through funding opportunity announce19 ments, grants, or cooperative agreements, basic, clin20 ical, and translational research on CCM, including 

21 research on— 

22 ‘‘(A) the identification and development of 

23 affordable biomarkers that fulfill the require24 ment of the Food and Drug Administration for 

25 biomarker qualification as proper measures of 


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1 CCM pathogenic biology, including diagnosis, or 

2 response to clinical intervention; 

3 ‘‘(B) pre-clinical trials of promising CCM 

4 drug treatment candidates; 

5 ‘‘(C) novel biomedical and pharmacological 

6 interventions designed to target existing lesions 

7 to reduce their size and clinical activity; 

8 ‘‘(D) clinical research related to 

9 repurposing currently approved drugs for appli10 cation for CCM treatment; 

11 ‘‘(E) the gut-brain axis and the effects of 

12 microbiome composition on clinical 

13 symptomology; 

14 ‘‘(F) the microbiome as a therapeutic tar15 get for CCM treatment; 

16 ‘‘(G) research related to gene therapy as a 

17 treatment for familial CCM; 

18 ‘‘(H) research related to the mechanistic 

19 overlap between CCM and other disorders, in20 cluding vascular disorders and cancer; 

21 ‘‘(I) research related to improving and 

22 measuring the quality of life for individuals 

23 with CCM and their families; 

24 ‘‘(J) contributions of genetic variation to 

25 clinical presentation as targets for therapy; 


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1 ‘‘(K) clinical training programs aimed at 

2 increasing the number of scientists and clini3 cians who are trained to treat patients and 

4 carry out the research described in this para5 graph; 

6 ‘‘(L) continued development and expansion 

7 of novel animal models for preclinical research 

8 relating to CCM; 

9 ‘‘(M) proteomic, pharmacological, and cell 

10 biological analysis of CCM molecules; 

11 ‘‘(N) biological mechanisms for lesion gen12 esis, development, and maturation; 

13 ‘‘(O) biological mechanisms for lesion 

14 bleeding and symptomology; 

15 ‘‘(P) novel biomedical and pharmacological 

16 interventions designed to inhibit new lesion de17 velopment, lesion growth, and lesion bleeding; 

18 and 

19 ‘‘(Q) continued research related to under20 standing better the natural history and clinical 

21 variation associated with CCM, particularly as 

22 it relates to the development of drug develop23 ment tools and clinical outcome assessments. 

24 ‘‘(2) FACILITATION OF RESEARCH RESOURCES; 

25 CLINICAL TRIAL PREPAREDNESS.— 


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1 ‘‘(A) IN GENERAL.—The Director of NIH 

2 shall award grants and contracts to public or 

3 nonprofit private entities to fund all or part of 

4 the cost of planning, establishing, and providing 

5 basic operating support for a network of CCM 

6 Clinical Research Centers, including Coordi7 nating and Participating centers regarding re8 search on various forms of CCM. 

9 ‘‘(B) CLINICAL AND RESEARCH COORDI10 NATING CENTERS.— 

11 ‘‘(i) IN GENERAL.—The Director of 

12 NIH shall build upon the network created 

13 by the U01 Clinical Trial Readiness Re14 search Project to identify and support the 

15 development of 2 geographically distributed 

16 national clinical and research coordinating 

17 centers with unique clinical expertise and 

18 the potential for coordinating multisite 

19 clinical drug trials with respect to CCM. 

20 ‘‘(ii) DUTIES.—The coordinating cen21 ters identified under clause (i) shall pro22 vide a model for the participation centers 

23 described in paragraph (3), facilitate med24 ical research to develop a cure for CCM, 


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1 and enhance the medical care of individ2 uals with CCM nationwide, including by— 

3 ‘‘(I) maintaining an institutional 

4 infrastructure capable of hosting clin5 ical trials and facilitating translational 

6 research projects and collaborations 

7 for clinical trials; 

8 ‘‘(II) implementing the programs 

9 dedicated to patient education, patient 

10 outreach, and awareness developed by 

11 the Cerebral Cavernous Malformations 

12 Consortium under subsection 

13 (c)(3)(B); 

14 ‘‘(III) developing the capacity to 

15 establish and maintain communication 

16 with other major CCM research and 

17 care institutions internationally for in18 formation sharing and coordination of 

19 research activities; 

20 ‘‘(IV) demonstrating clinical ex21 pertise in the management of CCM 

22 and appointing a director and support 

23 staff, including a trainee and patient 

24 representative, for CCM research pro25 gramming; 


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1 ‘‘(V) treating a sufficient number 

2 of eligible patients for participation 

3 with particular focus on unique sub4 populations, such as patients with the 

5 common Hispanic mutation, Ash6 kenazi Jewish mutation, CCM2 Com7 mon Deletion, or CCM3 gene muta8 tion carriers; and 

9 ‘‘(VI) maintaining a telehealth 

10 infrastructure to support and provide 

11 clinical consultation for remote and 

12 underserved communities. 

13 ‘‘(3) PARTICIPATION CENTERS.— 

14 ‘‘(A) IN GENERAL.—The Director of NIH 

15 shall build upon the network created by the 

16 U01 Clinical Trial Readiness Research Project 

17 to identify and support the development of ap18 proximately 6 to 10 clinical and research par19 ticipation centers to facilitate medical research 

20 to develop a cure for CCM and enhance the 

21 medical care of individuals with CCM, in part22 nership with the coordinating centers under 

23 paragraph (2) and other national and inter24 national entities, as appropriate. 


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1 ‘‘(B) ELIGIBILITY.—To qualify for selec2 tion as a participation center under subpara3 graph (A), an entity shall— 

4 ‘‘(i) at the time of selection— 

5 ‘‘(I) be affiliated with an estab6 lished research network of the Na7 tional Institutes of Health; and 

8 ‘‘(II) have the potential to par9 ticipate in a multisite clinical drug 

10 trial with respect to CCM; 

11 ‘‘(ii) demonstrate— 

12 ‘‘(I) an institutional infrastruc13 ture capable of hosting a clinical trial 

14 site and facilitating translational 

15 projects and collaborations for clinical 

16 trials; 

17 ‘‘(II) the capacity to maintain 

18 communication with other major CCM 

19 research and care institutions inter20 nationally for information sharing and 

21 coordination of research activities, es22 pecially through health information 

23 technology; and 

24 ‘‘(III) clinical expertise in CCM 

25 management or complete the CCM 


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1 clinical training program under sub2 section (c)(4); and 

3 ‘‘(iii) have a sufficient number of eli4 gible patients with CCM. 

5 ‘‘(C) DURATION OF SUPPORT.—The Direc6 tor of NIH may provide support for participa7 tion centers under this section for a period not 

8 to exceed 5 years. The Director of NIH may ex9 tend the period of support for a center for one 

10 or more additional periods, not to exceed an ad11 ditional 5 years, if the operations of such center 

12 have been reviewed by an appropriate technical 

13 and scientific peer review group established by 

14 the Director of NIH and if such group has rec15 ommended to the Director that such period 

16 should be extended. 

17 ‘‘(c) CEREBRAL CAVERNOUS MALFORMATIONS CON18 SORTIUM.— 

19 ‘‘(1) IN GENERAL.—The Director of NIH shall 

20 build upon the network created by the U01 Clinical 

21 Trial Readiness Research Project to convene a Cere22 bral Cavernous Malformations Research Consortium 

23 (referred to in this section as the ‘consortium’). 

24 ‘‘(2) MEMBERSHIP.—The consortium— 

25 ‘‘(A) shall include representatives of— 


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1 ‘‘(i) the institutions that are part of 

2 the U01 Trial Readiness Project of the 

3 National Institutes of Health, or that are 

4 part of other nationally recognized clinical 

5 Centers of Excellence; and 

6 ‘‘(ii) at least 1 national CCM patient 

7 advocacy organization, which may be an 

8 entity that receives a grant or contract 

9 under subsection (b)(2)(A); and 

10 ‘‘(B) may include representatives of the 

11 National Institutes of Health or the Food and 

12 Drug Administration, in an advisory or ex offi13 cio role. 

14 ‘‘(3) RESPONSIBILITIES.—Through a con15 sensus-based decision-making model, the consortium 

16 shall divide assignments and be responsible for— 

17 ‘‘(A) developing and implementing training 

18 programs for clinicians and scientists in accord19 ance with paragraph (4); 

20 ‘‘(B) developing patient education, out21 reach, and awareness programs and materials, 

22 which may be tailored for specific regional or 

23 local needs including— 

24 ‘‘(i) a regional multimedia public 

25 awareness campaign; 


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1 ‘‘(ii) patient education materials for 

2 distribution by regional physician and sur3 geon offices; 

4 ‘‘(iii) an education program for ele5 mentary and secondary school nurses to fa6 cilitate early detection and diagnosis of 

7 CCM in areas in which there is a high den8 sity of cases of CCM; 

9 ‘‘(iv) regular regional patient and 

10 family-oriented educational conferences; 

11 and 

12 ‘‘(v) nationally relevant electronic 

13 health teaching and communication tools 

14 and a network of professional capacity and 

15 patient and family support; and 

16 ‘‘(C) preparing a biannual report to Con17 gress, in accordance with paragraph (5). 

18 ‘‘(4) TRAINING PROGRAM FOR CLINICIANS AND

19 SCIENTISTS.— 

20 ‘‘(A) IN GENERAL.—The consortium shall 

21 establish or expand a physician training pro22 gram, including information and education on 

23 advances in the diagnosis and treatment of 

24 CCM, and training and continuing education 

25 through programs for scientists, physicians, 


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1 medical students, and other health professionals 

2 and care coordinators who provide care for pa3 tients with CCM, telehealth, and research rel4 evant to CCM, for the purpose of supporting 

5 the development of new centers through edu6 cational programming to gain the expertise 

7 needed to become clinical and research centers 

8 with the potential to participate in clinical drug 

9 trials. 

10 ‘‘(B) STIPENDS.—The Director of NIH 

11 may provide stipends for health professionals 

12 who are enrolled in the training programs de13 scribed in subparagraph (A). 

14 ‘‘(C) ELIGIBILITY.—To be eligible to par15 ticipate in the training program, an individual 

16 shall be affiliated with an entity that is in an 

17 existing clinical research network of the Na18 tional Institutes of Health. 

19 ‘‘(5) REPORT TO CONGRESS.—The consortium 

20 shall biennially submit to the Committee on Health, 

21 Education, Labor, and Pensions of the Senate and 

22 the Committee on Energy and Commerce of the 

23 House of Representatives a report that describes the 

24 research, education, and other activities on CCM 

25 conducted or supported through the Department of 


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1 Health and Human Services. Each such report shall 

2 include— 

3 ‘‘(A) a research plan; 

4 ‘‘(B) provisions specifying the amounts ex5 pended by the Department of Health and 

6 Human Services with respect to various forms 

7 of CCM, including those affected by the com8 mon Hispanic Mutation, Ashkenazi Jewish mu9 tation, CCM2 Common Deletion, CCM3 gene 

10 mutations, and other familial and sporadic 

11 forms of cerebral cavernous malformation and 

12 patients who identify as Black or African Amer13 ican; and 

14 ‘‘(C) recommendations for particular 

15 projects or types of projects that the national 

16 research institutes or other entities in the field 

17 of research should conduct on inherited or non18 inherited forms of CCM. 

19 ‘‘(d) PRIORITIZE CCM FUNDING FOR BIOTECH.— 

20 The Director of NIH, in coordination with the directors 

21 of the National Institute of Neurological Disorders and 

22 Stroke, the National Center for Advancing Translational 

23 Sciences, the National Heart, Lung, and Blood Institute, 

24 and other national research institutes, as appropriate, 

25 shall prioritize the provision of grant funding for small 


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1 biotechnology entities that are working to develop treat2 ments for CCM.’’. 

3 SEC. 4. CENTERS FOR DISEASE CONTROL AND PREVEN4 TION CEREBRAL CAVERNOUS MALFORMA5 TIONS SURVEILLANCE AND RESEARCH PRO6 GRAMS. 

7 Part B of title III of the Public Health Service Act 

8 (42 U.S.C. 243 et seq.) is amended by inserting after sec9 tion 317U the following: 

10 ‘‘SEC. 317V. CEREBRAL CAVERNOUS MALFORMATIONS SUR11 VEILLANCE AND RESEARCH PROGRAMS. 

12 ‘‘(a) IN GENERAL.—The Secretary, acting through 

13 the Director of the Centers for Disease Control and Pre14 vention, may award grants in such sums as may be nec15 essary and cooperative agreements to public or nonprofit 

16 private entities (including State health departments, polit17 ical subdivisions of States, universities, and other medical 

18 or educational entities) for the collection, analysis, and re19 porting of data on cerebral cavernous malformations (re20 ferred to in this section as ‘CCM’). 

21 ‘‘(b) NATIONAL CEREBRAL CAVERNOUS MALFORMA22 TIONS EPIDEMIOLOGY PROGRAM.—The Secretary shall 

23 award grants and cooperative agreements, including tech24 nical assistance, to public or nonprofit private entities 

25 for— 


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1 ‘‘(1) the collection, analysis, and reporting of 

2 data on CCM; and 

3 ‘‘(2) epidemiological activities, including encour4 aging consistency in ICD–10 coding, adoption of 

5 ICD–11 coding, collecting, and analyzing informa6 tion on the number, incidence, correlates, and symp7 toms of cases and the clinical utility of specific prac8 tice patterns. 

9 ‘‘(c) NATIONAL SURVEILLANCE PROGRAM.—The 

10 Secretary shall— 

11 ‘‘(1) provide for a national surveillance program 

12 for the purpose of carrying out epidemiological ac13 tivities regarding CCM, including collecting and ana14 lyzing information on the number, incidence, cor15 relates, and symptoms of cases of CCM and the clin16 ical utility (including costs and benefits) of specific 

17 practice patterns; and 

18 ‘‘(2) wherever possible, ensure that the surveil19 lance program is coordinated with the data and sam20 ple collection activities of the National Institutes of 

21 Health under section 409K. 

22 ‘‘(d) TECHNICAL ASSISTANCE.—In making awards 

23 under this section, the Secretary may provide direct tech24 nical assistance, including personnel support. 


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1 ‘‘(e) COORDINATION WITH CLINICAL CENTERS.— 

2 The Secretary shall ensure that epidemiological informa3 tion is made available to clinical centers as supported by 

4 the Director of the National Institutes of Health under 

5 section 409K. 

6 ‘‘(f) AUTHORIZATION OF APPROPRIATIONS.—There 

7 are authorized to be appropriated such sums as may be 

8 necessary to carry out this section.’’. 

9 SEC. 5. FOOD AND DRUG ADMINISTRATION CEREBRAL CAV10 ERNOUS MALFORMATIONS CLINICAL TRIAL 

11 PREPAREDNESS AND SUPPORT PROGRAM. 

12 (a) BIOMARKER QUALIFICATION PROGRAM.—The 

13 Secretary of Health and Human Services, acting through 

14 the Commissioner of Food and Drugs, shall coordinate 

15 with clinical centers, investigators, and advocates to sup16 port the qualification of appropriate surrogate biomarkers 

17 for diagnosis and measuring pathology and treatment effi18 cacy in an effort to expedite clinical trials for cerebral cav19 ernous malformation. 

20 (b) CLINICAL OUTCOME ASSESSMENT QUALIFICA21 TION.—The Secretary of Health and Human Services, act22 ing through the Commissioner of Food and Drugs, shall 

23 coordinate with clinical centers, investigators, and advo24 cates to support the qualification of newly developed pa25 tient reported outcome measures for quality of life as a 


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1 clinical outcome in an effort to hasten the pace of clinical 

2 trials for cerebral cavernous malformation. 

3 (c) INVESTIGATIONAL NEW DRUG APPLICATION.— 

4 The Secretary of Health and Human Services, acting 

5 through the Commissioner of Food and Drugs, shall co6 ordinate with clinical centers, investigators, and advocates 

7 to support appropriate investigational new drug applica8 tions under section 505(i) of the Federal Food, Drug, and 

9 Cosmetic Act (21 U.S.C. 355(i)) in an effort to hasten 

10 the pace of clinical trials for cerebral cavernous malforma11 tion. 

12 (d) ADAPTIVE TRIAL DESIGN AND EXPEDITED RE13 VIEW PATHWAYS.—The Secretary of Health and Human 

14 Services, acting through the Commissioner of Food and 

15 Drugs, shall coordinate with clinical centers, investigators, 

16 and advocates to support appropriate adaptive trial de17 signs for rare disease research and expedited peer review 

18 mechanisms for including orphan drug designation, fast 

19 track, breakthrough therapy designation, and priority re20 view or accelerated review, where appropriate, in an effort 

21 to hasten the pace of clinical trials for cerebral cavernous 

22 malformation. 

Æ 


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