II 

118TH CONGRESS 

1ST SESSION S. 543 

To increase research, education, and treatment for cerebral cavernous 

malformations. 

IN THE SENATE OF THE UNITED STATES 

FEBRUARY 28, 2023 

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 2023’’ or the ‘‘CCM–CARE Act of 2023’’. 

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 01:12 Mar 08, 2023 Jkt 039200 PO 00000 Frm 00001 Fmt 6652 Sfmt 6201 E:\BILLS\S543.IS S543

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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, although fewer than 200,000 

15 are accurately diagnosed. 

16 (5) Individuals diagnosed with CCM may expe17 rience neurological deficits, seizure, stroke, or sud18 den death. 

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

20 no treatment for CCM other than brain and spinal 

21 surgery, and only for certain patients. 

22 (7) There is also a shortage of trained physi23 cians to provide skilled and timely diagnosis and ap24 propriate treatment for CCM. 


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1 (8) While the hereditary form of CCM may 

2 occur among any ethnicity, the presence of a muta3 tion called the ‘‘common Hispanic mutation’’, has 

4 passed through 14 or more generations of American 

5 descendants from the original Spanish settlers of the 

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

7 population density of CCM in the world; Texas, Ari8 zona, and Colorado also have high rates of CCM due 

9 to the common Hispanic mutation. 

10 (9) A second mutation (CCM2 Common Dele11 tion) originating in the Southeastern United States 

12 before 1800 has increased rates of the illness in 

13 South Carolina, Georgia, Florida, Alabama, Mis14 sissippi, Louisiana, Texas, Oklahoma, Kentucky, 

15 Kansas, and northern California. 

16 SEC. 3. EXPANSION AND COORDINATION OF ACTIVITIES OF 

17 NATIONAL INSTITUTES OF HEALTH WITH RE18 SPECT TO CEREBRAL CAVERNOUS MAL19 FORMATIONS RESEARCH. 

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

21 (42 U.S.C. 284 et seq.) is amended by adding at the end 

22 the following: 


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1 ‘‘SEC. 409K. CEREBRAL CAVERNOUS MALFORMATIONS RE2 SEARCH ACTIVITIES. 

3 ‘‘(a) EXPANSION AND COORDINATION OF ACTIVI4 TIES.—The Director of NIH, in coordination with the di5 rectors of the National Institute of Neurological Disorders 

6 and Stroke, the National Center for Advancing 

7 Translational Sciences, the National Heart, Lung, and 

8 Blood Institute, and other national research institutes, as 

9 appropriate, for the purpose of conducting research and 

10 related activities concerning cerebral cavernous malforma11 tions (referred to in this section as ‘CCM’)— 

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

13 the National Institutes of Health; and 

14 ‘‘(2) may award grants and cooperative agree15 ments to public or nonprofit private entities (includ16 ing State health departments, political subdivisions 

17 of States, universities, and other medical or edu18 cational entities). 

19 ‘‘(b) ACTIVITIES.—The research and related activi20 ties described in subsection (a) shall include the following: 

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

22 RESEARCH.—The Director of NIH shall conduct or 

23 support, through funding opportunity announce24 ments, grants, or cooperative agreements, basic, clin25 ical, and translational research on CCM, including 

26 research on— 


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1 ‘‘(A) the identification and development of 

2 affordable imaging, plasma, and urine biomark3 ers that fulfill the requirement of the Food and 

4 Drug Administration for biomarker qualifica5 tion as proper measures of CCM pathogenic bi6 ology, including diagnosis, response to clinical 

7 intervention, or prediction of adverse clinical 

8 events; 

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

10 drug treatment candidates; 

11 ‘‘(C) novel biomedical and pharmacological 

12 interventions designed to target existing lesions 

13 to reduce their size and clinical activity; 

14 ‘‘(D) clinical research related to 

15 repurposing currently approved drugs for appli16 cation for CCM treatment; 

17 ‘‘(E) development of new non-pharma18 cological treatment approaches, such as focused 

19 ultrasound, and targeted treatment delivery 

20 technology; 

21 ‘‘(F) the gut-brain axis and the effects of 

22 microbiome composition on clinical 

23 symptomology; 

24 ‘‘(G) the microbiome as a therapeutic tar25 get for CCM treatment; 


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1 ‘‘(H) research related to gene therapy as a 

2 treatment for familial CCM; 

3 ‘‘(I) research related to RNA-based thera4 pies; 

5 ‘‘(J) research related to the mechanistic 

6 overlap between CCM and other disorders, in7 cluding vascular disorders and cancer; 

8 ‘‘(K) research related to improving and 

9 measuring the quality of life for individuals 

10 with CCM and their families; 

11 ‘‘(L) contributions of genetic variation to 

12 clinical presentation as precision medicine tar13 gets for therapy; 

14 ‘‘(M) clinical training programs aimed at 

15 increasing the number of scientists and clini16 cians who are trained to treat patients and 

17 carry out the research described in this para18 graph; 

19 ‘‘(N) proteomic, pharmacological, and cell 

20 biological analysis of CCM molecules; 

21 ‘‘(O) biological mechanisms for lesion gen22 esis, development, and maturation; 

23 ‘‘(P) biological mechanisms for lesion 

24 bleeding and symptomology; 


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1 ‘‘(Q) novel biomedical and pharmacological 

2 interventions designed to inhibit new lesion de3 velopment, lesion growth, and lesion bleeding; 

4 and 

5 ‘‘(R) continued research related to under6 standing better the natural history and clinical 

7 variation associated with CCM, particularly as 

8 it relates to the development of drug develop9 ment tools and clinical outcome assessments. 

10 ‘‘(2) FACILITATION OF RESEARCH RESOURCES; 

11 CLINICAL TRIAL PREPAREDNESS.— 

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

13 shall award grants and contracts to public or 

14 nonprofit private entities to fund all or part of 

15 the cost of planning, establishing, and providing 

16 basic operating support for a network of CCM 

17 Clinical Research Centers, including Coordi18 nating and Participating centers regarding re19 search on various forms of CCM. 

20 ‘‘(B) CLINICAL AND RESEARCH COORDI21 NATING CENTERS.— 

22 ‘‘(i) IN GENERAL.—The Director of 

23 NIH shall build upon the network created 

24 by the U01 Clinical Trial Readiness Re25 search Project to identify and support the 


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1 development of 2 geographically distributed 

2 national clinical and research coordinating 

3 centers with unique clinical expertise and 

4 the potential for coordinating multisite 

5 clinical drug trials with respect to CCM, 

6 including serving as United States sites in 

7 international adaptive trials. 

8 ‘‘(ii) DUTIES.—The coordinating cen9 ters identified under clause (i) shall pro10 vide a model for the participation centers 

11 described in paragraph (3), facilitate med12 ical research to develop a cure for CCM, 

13 and enhance the medical care of individ14 uals with CCM nationwide, including by— 

15 ‘‘(I) maintaining an institutional 

16 infrastructure capable of hosting clin17 ical trials, facilitating translational re18 search projects, and domestic and 

19 international collaborations for clinical 

20 trials; 

21 ‘‘(II) implementing the programs 

22 dedicated to patient education, patient 

23 outreach, and awareness developed by 

24 the Cerebral Cavernous Malformations 


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1 Consortium under subsection 

2 (c)(3)(B); 

3 ‘‘(III) developing the capacity to 

4 establish and maintain communication 

5 with other major CCM research and 

6 care institutions internationally for in7 formation sharing and coordination of 

8 research activities; 

9 ‘‘(IV) demonstrating clinical ex10 pertise in the management of CCM 

11 and appointing a director and support 

12 staff, including a trainee and patient 

13 representative, for CCM research pro14 gramming; 

15 ‘‘(V) treating a sufficient number 

16 of eligible patients for participation 

17 with particular focus on unique sub18 populations, such as patients with the 

19 common Hispanic mutation, Ash20 kenazi Jewish mutation, CCM2 Com21 mon Deletion, CCM3 gene mutation 

22 carriers, or Black and under23 resourced patients; and 

24 ‘‘(VI) maintaining a telehealth 

25 infrastructure to support and provide 


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1 clinical consultation for remote and 

2 underserved communities. 

3 ‘‘(3) PARTICIPATION CENTERS.— 

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

5 shall build upon the network created by the 

6 U01 Clinical Trial Readiness Research Project 

7 to identify and support the development of ap8 proximately 6 to 10 clinical and research par9 ticipation centers to facilitate medical research 

10 to develop a cure for CCM and enhance the 

11 medical care of individuals with CCM, in part12 nership with the coordinating centers under 

13 paragraph (2) and other national and inter14 national entities, as appropriate. 

15 ‘‘(B) ELIGIBILITY.—To qualify for selec16 tion as a participation center under subpara17 graph (A), an entity shall— 

18 ‘‘(i) at the time of selection— 

19 ‘‘(I) be affiliated with an estab20 lished research network of the Na21 tional Institutes of Health; and 

22 ‘‘(II) have the potential to par23 ticipate in a multisite clinical drug 

24 trial with respect to CCM; 

25 ‘‘(ii) demonstrate— 


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1 ‘‘(I) the capacity to maintain 

2 communication with other major CCM 

3 research and care institutions inter4 nationally for information sharing and 

5 coordination of research activities, es6 pecially through health information 

7 technology; and 

8 ‘‘(II) clinical expertise in CCM 

9 management or complete the CCM 

10 clinical training program under sub11 section (c)(4); and 

12 ‘‘(iii) have a sufficient number of eli13 gible patients with CCM. 

14 ‘‘(C) DURATION OF SUPPORT.—The Direc15 tor of NIH may provide support for participa16 tion centers under this section for a period not 

17 to exceed 5 years. The Director of NIH may ex18 tend the period of support for a center for one 

19 or more additional periods, not to exceed an ad20 ditional 5 years, if the operations of such center 

21 have been reviewed by an appropriate technical 

22 and scientific peer review group established by 

23 the Director of NIH and if such group has rec24 ommended to the Director that such period 

25 should be extended. 


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1 ‘‘(c) CEREBRAL CAVERNOUS MALFORMATIONS CON2 SORTIUM.— 

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

4 build upon the network created by the U01 Clinical 

5 Trial Readiness Research Project to convene a Cere6 bral Cavernous Malformations Research Consortium 

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

8 ‘‘(2) MEMBERSHIP.—The consortium— 

9 ‘‘(A) shall include representatives of— 

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

11 the U01 Trial Readiness Project of the 

12 National Institutes of Health, or that are 

13 part of other nationally recognized clinical 

14 Centers of Excellence; and 

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

16 advocacy organization, which may be an 

17 entity that receives a grant or contract 

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

19 ‘‘(B) may include representatives of the 

20 National Institutes of Health or the Food and 

21 Drug Administration, in an advisory or ex offi22 cio role. 

23 ‘‘(3) RESPONSIBILITIES.—Through a con24 sensus-based decision-making model, the consortium 

25 shall divide assignments and be responsible for— 


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1 ‘‘(A) developing and implementing training 

2 programs for clinicians and scientists in accord3 ance with paragraph (4); 

4 ‘‘(B) developing patient education, out5 reach, and awareness programs and materials, 

6 which may be tailored for specific regional or 

7 local needs including— 

8 ‘‘(i) a regional multimedia public 

9 awareness campaign; 

10 ‘‘(ii) patient education materials for 

11 distribution by regional physician and sur12 geon offices; 

13 ‘‘(iii) an education program for ele14 mentary and secondary school nurses and 

15 community health workers to facilitate 

16 early detection and diagnosis of CCM in 

17 areas in which there is a high density of 

18 cases of CCM; 

19 ‘‘(iv) regular regional patient and 

20 family-oriented educational conferences; 

21 and 

22 ‘‘(v) nationally relevant electronic 

23 health teaching and communication tools 

24 and a network of professional capacity and 

25 patient and family support; and 


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1 ‘‘(C) preparing a biannual report to Con2 gress, in accordance with paragraph (5). 

3 ‘‘(4) TRAINING PROGRAM FOR CLINICIANS AND

4 SCIENTISTS.— 

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

6 establish or expand a physician training pro7 gram, including information and education on 

8 advances in the diagnosis and treatment of 

9 CCM, and training and continuing education 

10 through programs for scientists, physicians, 

11 medical students, and other health professionals 

12 and care coordinators who provide care for pa13 tients with CCM, telehealth, and research rel14 evant to CCM, for the purpose of supporting 

15 the development of new centers through edu16 cational programming to gain the expertise 

17 needed to become clinical and research centers 

18 with the potential to participate in clinical drug 

19 trials. 

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

21 may provide stipends for health professionals 

22 who are enrolled in the training programs de23 scribed in subparagraph (A). 

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

25 shall biennially submit to the Committee on Health, 


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1 Education, Labor, and Pensions of the Senate and 

2 the Committee on Energy and Commerce of the 

3 House of Representatives a report that describes the 

4 research, education, and other activities on CCM 

5 conducted or supported through the Department of 

6 Health and Human Services. Each such report shall 

7 include— 

8 ‘‘(A) a research plan; 

9 ‘‘(B) provisions specifying the amounts ex10 pended by the Department of Health and 

11 Human Services with respect to various forms 

12 of CCM, including those affected by the com13 mon Hispanic Mutation, Ashkenazi Jewish mu14 tation, CCM2 Common Deletion, CCM3 gene 

15 mutations, and other familial and sporadic 

16 forms of cerebral cavernous malformation and 

17 patients who identify as Black or African Amer18 ican; and 

19 ‘‘(C) recommendations for particular 

20 projects or types of projects that the national 

21 research institutes or other entities in the field 

22 of research should conduct on inherited or non23 inherited forms of CCM based on patient-identi24 fied priorities. 


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

2 The Director of NIH, in coordination with the directors 

3 of the National Institute of Neurological Disorders and 

4 Stroke, the National Center for Advancing Translational 

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

6 and other national research institutes, as appropriate, 

7 shall prioritize the provision of grant funding for small 

8 biotechnology entities that are working to develop treat9 ments for CCM.’’. 

10 SEC. 4. CENTERS FOR DISEASE CONTROL AND PREVEN11 TION CEREBRAL CAVERNOUS MALFORMA12 TIONS SURVEILLANCE AND RESEARCH PRO13 GRAMS. 

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

15 (42 U.S.C. 243 et seq.) is amended by inserting after sec16 tion 317U the following: 

17 ‘‘SEC. 317V. CEREBRAL CAVERNOUS MALFORMATIONS SUR18 VEILLANCE AND RESEARCH PROGRAMS. 

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

20 the Director of the Centers for Disease Control and Pre21 vention, may award grants in such sums as may be nec22 essary and cooperative agreements to public or nonprofit 

23 private entities (including State health departments, polit24 ical subdivisions of States, universities, and other medical 

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1 porting of data on cerebral cavernous malformations (re2 ferred to in this section as ‘CCM’). 

3 ‘‘(b) NATIONAL CEREBRAL CAVERNOUS MALFORMA4 TIONS EPIDEMIOLOGY PROGRAM.—The Secretary shall 

5 award grants and cooperative agreements, including tech6 nical assistance, to public or nonprofit private entities 

7 for— 

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

9 data on CCM; and 

10 ‘‘(2) epidemiological activities, including encour11 aging consistency in ICD–10 coding, adoption of 

12 ICD–11 coding, collecting, and analyzing informa13 tion on the number, incidence, correlates, and symp14 toms of cases and the clinical utility of specific prac15 tice patterns. 

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

17 Secretary shall— 

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

19 for the purpose of carrying out epidemiological ac20 tivities regarding CCM, including collecting and ana21 lyzing information on the number, incidence, cor22 relates, and symptoms of cases of CCM and the clin23 ical utility (including costs and benefits) of specific 

24 practice patterns; and 


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1 ‘‘(2) wherever possible, ensure that the surveil2 lance program is coordinated with the data and sam3 ple collection activities of the National Institutes of 

4 Health under section 409K. 

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

6 under this section, the Secretary may provide direct tech7 nical assistance, including personnel support. 

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

9 The Secretary shall ensure that epidemiological informa10 tion is made available to clinical centers as supported by 

11 the Director of the National Institutes of Health under 

12 section 409K. 

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

14 are authorized to be appropriated such sums as may be 

15 necessary to carry out this section.’’. 

16 SEC. 5. FOOD AND DRUG ADMINISTRATION CEREBRAL CAV17 ERNOUS MALFORMATIONS CLINICAL TRIAL 

18 PREPAREDNESS AND SUPPORT PROGRAM. 

19 (a) BIOMARKER QUALIFICATION PROGRAM.—The 

20 Secretary of Health and Human Services, acting through 

21 the Commissioner of Food and Drugs, shall coordinate 

22 with clinical centers, investigators, and advocates to sup23 port the qualification of appropriate imaging, plasma, and 

24 urine biomarkers for diagnosis and measuring pathology 


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1 and treatment efficacy in an effort to expedite clinical 

2 trials for cerebral cavernous malformation. 

3 (b) CLINICAL OUTCOME ASSESSMENT QUALIFICA4 TION.—The Secretary of Health and Human Services, act5 ing through the Commissioner of Food and Drugs, shall 

6 coordinate with clinical centers, investigators, and advo7 cates to support the qualification of newly developed pa8 tient reported outcome measures for quality of life as a 

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

10 trials for cerebral cavernous malformation. 

11 (c) INVESTIGATIONAL NEW DRUG APPLICATION.— 

12 The Secretary of Health and Human Services, acting 

13 through the Commissioner of Food and Drugs, shall co14 ordinate with clinical centers, investigators, and advocates 

15 to support appropriate investigational new drug applica16 tions under section 505(i) of the Federal Food, Drug, and 

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

18 the pace of clinical trials for cerebral cavernous malforma19 tion. 

20 (d) ADAPTIVE TRIAL DESIGN AND EXPEDITED RE21 VIEW PATHWAYS.—The Secretary of Health and Human 

22 Services, acting through the Commissioner of Food and 

23 Drugs, shall coordinate with clinical centers, investigators, 

24 and advocates to support domestic and international 

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1 dited peer review mechanisms for including orphan drug 

2 designation, fast track, breakthrough therapy designation, 

3 and priority review or accelerated review, where appro4 priate, in an effort to hasten the pace of clinical trials for 

5 cerebral cavernous malformation. 

Æ 


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