Different initiatives were identified in the pre-launch, peri-launch, and post-launch categories from 2014 to 2020, as described in the text below and in Table 2.
Table 2
3.1 Pre-launch
The establishment of the National Policy for Technological Innovation in Health, regulatory procedures related to research involving human beings, and clinical trials with medicines were identified. Furthermore, the methods by which the industry can offer experimental medicines to patients suffering from diseases hitherto untreated in the country were defined, and the right to post-study access to clinical research protocols was granted to patients with ultra-rare diseases.
Regarding rare disease medicines, the National Repository of Clinical Trials (ReBEC) research showed two clinical trials for new medicines, 14 existing pharmacological treatments, and five on food supplementation, either financed by public, private, or mixed capital and having a national or international scope. Moreover, clinical or pre-clinical research registered in Decit/SCTIE/MS totaled 11 studies involving rare diseases, carried out with public funding, and in most cases, under the responsibility of Brazilian universities.
In 2017 an MS investment enabled the construction of the Pharmacological Innovation Laboratory (Laif) at the Federal University of Alagoas (Ufal) aimed at seeking therapeutic alternatives, in particular for Amyotrophic Lateral Sclerosis (ALS).
In addition to these, in 2019, the National Council for Scientific and Technological Development (CNPq), in a partnership with the Ministry of Health (MS), issued a call for research to obtain epidemiological information on rare diseases in Brazil17.
The promotion and incentives for research in rare diseases are provided in the 2020-2030 Pluriannual Plan guidelines and the work of the Interministerial Committee on Rare Diseases. In addition, 30% of the resources destined to the Health Research Promotion Program for the technological development of medicines, immunobiological, health products, and other therapeutic modalities are now allocated to treat rare or neglected diseases (Table 2).
The horizon scanning is being improved in the country as a result of a partnership between Decit/MS and the Biomedical Engineering Program of the Alberto Luiz Coimbra Institute for Graduate Studies and Research in Engineering (COPPE) of the Federal University of Rio de Janeiro (UFRJ) and the Support Program for Institutional Development of the Brazilian Public Health System (PROADI-SUS). Furthermore, a systematic search in the CONITEC website showed that four alerts (2 in 2016, 1 in 2017, 1 in 2018), three reports (2017, 2019, 2020), and 19 sections in recommendation reports of studied medicines (9 in 2018, 6 in 2019 and 4 in 2020) were published while this study was carried on.
3.2 Peri-launch
In Brazil, the sanitary registration of medicines for rare diseases was standardized in 2017 with the publication of the Collegiate Board Resolution (RDC) 205 and its following updates. The swiftness in regulatory processes for rare diseases medicines and the regulatory bases for registering new cellular therapy products, human gene therapy products were also regulated, according to data described in Table 2.
Considering what is described in item 2.4, the medicines for treating rare diseases in Brazil (under this study exclusion criteria) are listed in Table 3.
Table 3
– Medicines for rare diseases registered aftter RDCa 205/2017, ANVISAb, Brazil, 2017-2020.
Medicines | Dosage | Clinical Indication | Registra-tion Date | Registra-tion Validity | Regulatory Category | Demanded to SUSc / Incorporated into SUS |
Ocrelizumab | 30 mg/mL | Multiple Sclerosis | 26/02/2018 | Feb/28 | Biological | Yes/No |
Nonacog Gamma | 250 UI; 500 UI; 1000 UI; 2000 UI; 3000 UI | Hemophilia B | 26/02/2018 | Aug/29 | Biological | No/No |
Agalsidase Beta | 35 mg/20 mL | Fabry Disease | 30/04/2018 | Apr/20 | Biological | Yes/No |
Cerliponase Alfa | 30 mg/mL | Neuronal Ceroid Lipofuscinosis Type 2 | 16/07/2018 | Jul/28 | Biological | No/No |
Emicizumab | 30 mg/mL; 60 mg/0,4mL; 105 mg/0,7mL; 150 mg/mL | Hemophilia A | 16/07/2018 | Jul /28 | Biological | Yes/Yes |
Ivacaftor+Lumacaftor | 125 mg+100 mg; 125 mg+200 mg | Cystic Fibrosis | 23/07/2018 | Jul /23 | New | Yes/No |
Ivacaftor | 150 mg | Cystic Fibrosis | 03/09/2018 | Sep/23 | New | Yes/Yes |
Albutrepenonacog Alfa | 250 UI; 500 UI; 1000 UI; 2000 UI; | Hemophilia B | 08/10/2018 | Oct/28 | Biological | No/No |
Vestronidase Alfa | 10 mg/5mL | Mucopolysaccharidosis VII | 15/10/2018 | Oct/28 | Biological | Yes/Yes |
Defibrotide | 80 mg/mL | Liver Veno-Occlusive Disease | 11/03/2019 | Mar/29 | Biological | No/No |
Burosumab | 20 mg/mL | X-Linked Hipophosphatemia in adults and children (age >1 years old) | 25/03/2019 | Mar/29 | Biological | Yes/No |
Ataluren | 125 mg; 250 mg; 1000 mg | Duchenne Muscular Dystrophy | 29/04/2019 | Apr /29 | New | No/No |
Selexipag | 0,2 mg; 0,4 mg; 0,6 mg; 0,8 mg; 1 mg; 1,2 mg; 1,6 mg | Pulmonary Arterial Hypertension | 29/04/2019 | Jan/28 | New | Yes/Under review |
Carglumic Acid | 200 mg | Hyperammo-nemia | 10/06/2019 | Jun/29 | New | No/No |
Hemin | 350 mg | Acute Intermittent Porphyria | 19/08/2019 | Aug/29 | Biological | No/No |
Ravulizumab | 10 mg/mL | Paroxistic Nocturnal Hemoglobinuria | 02/09/2019 | Sep/29 | Biological | No/No |
Betaine | 1 g/g | Homocystinuria | 09/09/2019 | Sep/24 | Specific | No/No |
Nitisinone | 2 mg; 5 mg; 10 mg; 20 mg | Hereditary Type 1 Tyrosinemia | 07/10/2019 | Oct/24 | New | No/No |
Inotersen | 200 mg/mL | Polyneuropathy caused by Hereditary Transthyretin-mediated Amyloidosis | 29/10/2019 | Oct/24 | New | No/No |
Migalastat | 123 mg | Fabry Disease | 02/12/2019 | Dec/24 | New | Yes/Under review |
Lonoctocog Alfa | 250 UI; 500 UI; 1000 UI; 2000 UI; 3000 UI | Hemophilia A | 02/12/2019 | Dec/29 | Biological | No/No |
Octocogue Beta | 250 UI; 500 UI; 1000 UI; 2000 UI; 3000 UI | Hemophilia A | 06/01/2020 | Jan/30 | Biological | No/No |
(Tezacaftor/Ivacaftor)+Ivacaftor | (100 mg/150 mg)+ 150 mg | Cystic Fibrosis | 27/01/2020 | Jan/23 | New | No/No |
Damoctocog Alfa Pegol | 500 UI; 1000 UI; 2000 UI; 3000 UI | Hemophilia A | 17/02/2020 | Feb/30 | Biological | Yes/Under review |
Patisiran | 2 mg/mL | Polyneuropathy in Hereditary Transthyretin-mediated Amyloidosis (hATTR amyloidosis) | 26/02/2020 | Feb/23 | New | No/No |
Crizanlizumab | 10 mg/mL | Vaso-occlusive crisis in Sickle Cell Anemia | 02/03/2020 | Mar/23 | Biological | No/No |
Velmanase Alfa | 10 mg | Alpha-mannosidosis | 06/04/2020 | Apr/23 | Biological | Não/Não |
Givosiran | 189 mg/mL | Acute Hepatic Porphyria in adults | 20/07/2020 | Jul/23 | New | No/No |
Voretigene Neparvovec | 5,0 x 1012 gv/mLd | Inherited Retinal Dystrophies | 06/08/2020 | Aug/25 | Advanced Therapy Products | No/No |
Onasemnogene Abeparvovec-xioi | 2,0 x 1013 gv/mL | Spinal Muscular Atrophy (SMA) | 17/08/2020 | Aug/25 | Advanced Therapy Products | No/No |
Rurioctocog Alfa Pegol | 250 UI; 500 UI; 750 UI; 1000 UI; 1500 UI; 2000 UI; 3000 UI | Hemophilia A | 28/09/2020 | Jan/30 | Biological | Yes/Under review |
Teduglutide | 5 mg | Short Bowel Syndrome | 28/09/2020 | Nov/28 | Biological | No/No |
Agalsidase Alfa | 1 mg/mL | Fabry Disease | 28/09/2020 | Jul/29 | Biological | Yes/No |
Lanadelumab | 150 mg/mL | Hereditary Angioedema (HAE) | 28/09/2020 | Oct/29 | Biological | Yes/Under review |
Risdiplam | 0,75 mg/mL | Spinal Muscular Atrophy (SMA) | 13/10/2020 | Oct/23 | New | Yes/Under review |
Lomitapide | 5mg; 10 mg; 20 mg | Homozygous Familial Hypercholesterolemia | 07/12/2020 | Dec/23 | New | No/No |
Satralizumab | 120 mg/mL | Neuromyelitis Optica Spectrum Disorder | 21/12/2020 | Dec/30 | Biological | No/No |
Source: Prepared by the authors based on data from the digital repositories of National Health Surveillance Agency (ANVISA) and National Committee for Health Technology Incorporation (CONITEC). |
a = Collegiate Board Resolution |
b = National Health Surveillance Agency |
c = Unified Health System |
d = viral genome/mL |
Search corresponds to the period 01/12/2017 to 31/12/2020. |
Table 3
Regarding HTA, no specified and validated criteria for the rare disease were identified. The Brazilian Network for Health Technology Assessment (REBRATS) held several events: discussion on Multicriteria Decision Analysis (MCDA) in HTA; workshop in partnership with The National Institute for Health and Care Excellence (NICE) to address methodological aspects of HTA and strategies for the involvement of patients, industry sectors, and other stakeholders; and a congress on patient involvement in the HTA process.
In October 2020, CONITEC launched on its website an area designed for the public and patient involvement called Patient's Perspective (Perspectiva do Paciente), where patients or caregivers can write about their experiences concerning the disease they are facing. In addition, rare diseases were the subject of two public calls for medicines analysis between October and December 2020.
Incorporation requests of medicines for rare diseases were the most frequent (n=64). Requests for amendments in the Brazilian List of Essential Medicines (RENAME), such as expansion, restriction, and withdrawal, were identified (n=16). As to medicines incorporation requests, the external applicants submitted most proposals (pharmaceutical industry: n=40, 62.5% and judicial branch: n=1, 1.6%), whereas the internal applicant (MS) submitted 23 requests (35.9%). There was agreement in the recommendations in 32 decisions; 18 (56.3%) were requests from the external applicant and 14 (43.8%) from the internal applicant. The incorporation or non-incorporation recommendations are described in Table 4.
Table 4
– Recommendations obtained from CONITEC according to the year of publication, Brazil, 2014 - 2020.
Year | Clinical Indication | Medicines | Recommendation |
Rare Genetic Diseases (Axis I)* |
2014 | | | |
| Gaucher Disease | Alfataliglicerace | Incorporation |
2015 | | | |
| Hereditary Angioedema | Icatibant | Non-incorporation |
| Sickle Cell Disease | Erythropoietin | Non-incorporation |
| Congenital Adrenal Hyperplasia | Hydrocortisone 10mg | Incorporation |
| Congenital Adrenal Hyperplasia | Hydrocortisone 20mg | Incorporation |
2016 | | | |
| Cystic Fibrosis | Tobramycin | Incorporation |
2017 | | | |
| Hemophilia B (age < 19 years old) | Nonacog Alfa | Non-incorporation |
| Mucopolysaccharidosis I | Laronidase | Incorporation |
| Mucopolysaccharidosis II | Idursulfase | Incorporation |
2018 | | | |
| Fabry Disease | Agalsidase Alfa | Non-incorporation |
| Fabry Disease | Agalsidase Beta | Non-incorporation |
| Phenylketonuria | Sapropterin | Incorporation |
| Paroxistic Nocturnal Hemoglobinuria | Eculizumab | Incorporation |
| Homozygous Familial Hypercholesterolemia | Evolucumab | Non-incorporation |
| Mucopolysaccharidosis IVa | Elosulfase Alfa | Incorporation |
| Mucopolysaccharidosis VI | Galsulfase | Incorporation |
| Familial Amyloid Polyneuropathy | Tafamidis | Incorporation |
2019 | | | |
| 5q Spinal Muscular Atrophy - type 1* | Nusinersen | Incorporation |
| Pompe Disease | Alglucosidase Alfa | Incorporation |
| Niemann-Pick tipo C Disease | Miglustat | Non-incorporation |
| Paroxistic Nocturnal Hemoglobinuria | Meningococcal Conjugate Vacines ACWY | Incorporation |
| Paroxistic Nocturnal Hemoglobinuria | Meningococcal B Vacines (Recombinant) | Non-incorporation |
| Hemophilia A with factor VIII inhibitor | Emicizumab | Incorporation |
| Hemophilia A | Eftrenonacog Alfa | Non-incorporation |
| Hemophilia B | Eftrenonacog Alfa | Non-incorporation |
| Classical Homocystinuria | Methionine free metabolic formula | Incorporation |
| Atypical Hemolytic Uremic Syndrome | Eculizumabe | Non-incorporation |
2020 | | | |
| Cystic Fibrosis | Ivacaftor | Incorporation |
| Congenital Hypothyroidism | Levothyroxine | Incorporation |
| Mucopolysaccharidosis VII | Vestronidase Alfa | Incorporation |
Rare Non-Genetics Disease (Axis II)* |
2014 | | | |
| Multiple Sclerosis | Fingolimod | Incorporation |
2015 | | | |
| Acromegaly | Pegvisomant | Non-incorporation |
2016 | | | |
| Ankylosing Spondylitis | Golimumab | Incorporation |
| Relapsing-remitting Multiple Sclerosis | Dimethyl Fumarate | Non-incorporation |
2017 | | | |
| Crohn's Disease | Certulizumab | Incorporation |
| Relapsing-remitting Multiple Sclerosis | Fingolimod | Incorporation |
| Relapsing-remitting Multiple Sclerosis | Dimethyl Fumarate | Incorporation |
| Relapsing-remitting Multiple Sclerosis | Teriflunomide | Incorporation |
| Relapsing-remitting Multiple Sclerosis | Aletumzumab | Non-incorporation |
2018 | | | |
| Primary Biliary Cholangitis | Ursodeoxycholic Acid | Incorporation |
| Paget’s Disease | Zoledronic Acid | Incorporation |
| Relapsing-remitting Multiple Sclerosis | Glatiramer 40 mg | Incorporation |
| Ankylosing spondylitis | Secukinumab | Incorporation |
| Idiopathic Thrombocytopenic Purpura | Eltrombopag Olamine | Incorporation |
| Non-infectious Intermediate Uveitis, Posterior Uveitis and Active Panuveitis | Adalimumab | Incorporation |
| Relapsing-remitting Multiple Sclerosis | Alentuzumab | Non-incorporation |
| Idiopathic Pulmonary Fibrosis | Nintedanib | Non-incorporation |
| Idiopathic Pulmonary Fibrosis | Pirfenidone | Non-incorporation |
| Inoperable Chronic Thromboembolic Pulmonary Hypertension | Riociguat | Non-incorporation |
| Systemic Lupus Erythematosus | Belimumab | Non-incorporation |
| Idiopathic Thrombocytopenic Purpura | Romiplostim | Non-incorporation |
| Non-infectious Intermediate Uveitis, Posterior Uveitis and Inactive Panuveitis | Adalimumab | Non-incorporation |
2019 | | | |
| Relapsing-remitting Multiple Sclerosis | Dimethyl Fumarate | Incorporation |
| Juvenile Idiopathic Arthritis | Canakinumab | Non-incorporation |
| Crohn's Disease | Vendolizumab | Non-incorporation |
| Relapsing-remitting Multiple Sclerosis | Ocrelizumab | Non-incorporation |
| Progressive Multiple Sclerosis | Ocrelizumab | Non-incorporation |
| Inoperable Chronic Thromboembolic Pulmonary Hypertension or recurrent after surgery | Riociguat | Non-incorporation |
| Ankylosing Spondylitis | Secukinumab | Non-incorporation |
Source: Prepared by the authors based on data from the digital repositories of National Committee for Health Technology Incorporation (CONITEC). |
* Axis according Ordinance nº 199, 20143. |
Table 4
To obtain the 32 incorporation recommendations, the time elapsed to achieve a result was 233 days (median; n=32; minimum time=49 days; maximum time=607 days), complying with the law18. The maximum time observed referred to the methionine-free metabolic formula for classical homocystinuria.
In Brazil, in 2018, some incorporation recommendations of medicines for rare diseases (nusinersen, eculizumab, galsulfase, elosulfase alfa) started to require patients' follow-up in reference centers to collect evidence of the clinical effectiveness in real-world situations. Then, within three years, a subsequent reassessment by CONITEC should be carried out, which in the reports is called ad experimentum use reports.
An innovative approach to financing the purchase occurred in April 2019, when the MS decided to incorporate nusinersen for spinal muscular atrophy (5q SMA) type 2 and 3 through a risk-sharing agreement. This project was an alternative measure to produce additional evidence about the therapeutic value of this medicines and observe the real impacts on patients' health and quality of life. However, this agreement failed due to the lack of detailed regulations and legal standards for implementation within SUS scope19.
A bill related to the costing and supply of medicines and therapies for treating rare or neglected diseases is in progress in the Chamber of Deputies and awaits conclusive consideration (Table 2).
3.3 Post-launch
It was identified that CONITEC made public and patient involvement possible through a poll (Enquete) to discuss aspects in the initial phase of PCDT drafting. During the period of this study, four polls addressed rare diseases.
Prior to the PNAIPDR, there were 35 PCDT for rare diseases in the SUS scope. The strategy defined for implementing the PNAIPDR was convening an expert panel to establish criteria and priorities for drafting further PCDT5.
Thirty-one PCDT for rare diseases were updated, and 16 new ones were implemented, totaling 51 PCDT (Table 5).
Table 5
– Clinical guidelines for rare diseases, Brazil, 2014-2020.
CLINICAL GUIDELINES |
Before PNAIPDR | Updated | New |
Acromegaly | Ordinance SAS/MSa nº 199 – 25/02/2013 | Joint Ordinance nº 02 – 07/01/2019 | |
Aplastic Anemia, Myelodysplasia and Constitutional Neutropenias | Ordinance SAS/MS nº 212 – 23/04/2010 | Ordinance SAS/MS nº 113 – 04/02/2016 | |
Autoimmune Hemolytic Anemia | | | Joint Ordinance nº 27 – 26/11/2018 |
Hereditary Angioedema | Ordinance SAS/MS nº 109 – 23/05/2010 | Ordinance SAS/MS nº 880 – 12/07/2016 | |
Acquired Chronic Pure Red Cell Aplasia | Ordinance SAS/MS nº 227 – 10/05/2010 | Ordinance SAS/MS nº 449 – 29/04/2016 | |
Juvenile Idiopathic Arthritis | | | Joint Ordinance nº 14 – 31/08/2020 |
Reactive Arthritis - Reiter's Syndrome | Ordinance SAS/MS nº 207 – 23/04/2010 | Ordinance SAS/MS nº 1.150 – 11/11/2015 | |
5q Spinal Muscular Atrophy - type 1* | | | Joint Ordinance SAS/SCTIE nº 15 – 22/10/2019 |
Primary Biliary Cholangitis* | | | Joint Ordinance nº 11 – 09/09/2019 |
Biotinidase Deficiency | | | Joint Ordinance nº 13 – 04/05/2018 |
Hypopituitarism | Ordinance SAS/MS nº 110 – 10/05/2010 | Joint Ordinance nº 28 – 30/11/2018 | |
Dermatomyositis and Polymyositis | Ordinance SAS/MS nº 206 – 23/04/2010 | Ordinance SAS/MS nº 1.692 – 22/11/2016 | |
Diabetes Insipidus | Ordinance SAS/MS nº 710 – 17/12/2010 | Joint Ordinance nº 2 – 10/01/2018 | |
Focal Dystonias and Hemifacial Spasm | Ordinance SAS/MS nº 376 – 10/11/2009 | Joint Ordinance nº 1 – 29/05/2017 | |
Crohn's Disease | Ordinance SAS/MS nº 711 – 17/12/2010 | Joint Ordinance nº 14 – 28/11/2017 | |
Gaucher Disease | Ordinance SAS/MS nº 708 – 25/10/2011 | Joint Ordinance nº 4 – 22/06/2017 | |
Paget’s Disease | Ordinance SAS/MS nº 456 – 21/05/2012 | Joint Ordinance nº 2 – 17/01/2020 | |
Pompe Disease* | | | Joint Ordinance nº 12 – 03/08/2020 |
Wilson Disease | Ordinance SAS/MS nº 848 – 05/12/2011 | Joint Ordinance nº 09 – 27/03/2018 | |
Sickle Cell Disease | Ordinance SAS/MS nº 55 – 29/01/2010 | Joint Ordinance nº 5 – 19/02/2018 | |
Hereditary and Acquired Epidermolysis Bullosa | | | Joint Ordinance nº 11 – 26/06/2020 |
Amyotrophic Lateral Sclerosis | Ordinance SAS/MS n° 496 – 23/12/2009 | Joint Ordinance nº 13 – 13/08/2020 | |
Multiple Sclerosis | Ordinance SAS/MS nº 1505 - 29/12/2014 | Joint Ordinance nº 7 – 03/07/2019 | |
Systemic Sclerosis | | | Joint Ordinance nº 09 – 28/08/2017 |
Ankylosing Spondylitis | Ordinance SAS/MS nº 640 – 24/07/2014 | Joint Ordinance nº 25 – 22/10/2018 | |
Phenylketonuria | Ordinance SAS/MS nº 712 – 17/12/2010 | Joint Ordinance nº 12 – 10/09/2019 | |
Cystic Fibrosis | Ordinance SAS/MS nº 224 – 10/05/2010 | Joint Ordinance nº 8 – 15/08/2017 | |
Paroxistic Nocturnal Hemoglobinuria* | | | Joint Ordinance SAES/SCTIEb nº 18 – 20/11/2019 |
Autoimmune Hepatitis | Ordinance SAS/MS nº 457 – 21/05/2012 | Joint Ordinance nº 14 – 09/05/2018 | |
Congenital Adrenal Hyperplasia | Ordinance SAS/MS nº 16 – 15/01/2010 | | |
Pulmonary Arterial Hypertension | Ordinance SAS/MS no 35 – 16/01/2014 | Ordinance SAS/MS nº 35 – 23/09/2014 | |
Hypoparathyroidism | Ordinance SAS/MS nº 14 – 15/01/2010 | Ordinance SAS/MS nº 450 – 29/04/2016 | |
Congenital Hypothyroidism | Ordinance SAS/MS nº 56 – 23/04/2010 | Ordinance SAS/MS nº 1.161 – 18/11/2015 | |
Classical Homocystinuria* | | | Joint Ordinance SAES/SCTIE nº 3 – 23/01/2020 |
Hereditary Ichthyosis | Ordinance SAS/MS nº 13 – 15/01/2010 | Portaria SAS/MS nº 1.162 – 18/11/2015 | |
Primary Immunodeficiencies with Antibody Deficiency | Ordinance SAS/MS nº 495 – 11/09/2007 | | |
Addison's Disease | Ordinance SAS/MS nº 15 – 15/01/2010 | Joint Ordinance nº 20 – 24/11/2020 | |
Exocrine Pancreatic Insufficiency | Ordinance SAS/MS nº 57 – 29/01/2010 | Ordinance SAS/MS nº 112 – 04/02/2016 | |
Systemic Lupus Erythematosus | Ordinance GM/MSc nº 100 – 07/02/2013 | | |
Myasthenia Gravis | Ordinance SAS/MS nº 229 – 10/05/2010 | Ordinance SAS/MS nº 1.169 – 19/11/2015 | |
Mucopolysaccharidosis I* | | | Joint Ordinance nº 12 – 11/04/2018 |
Mucopolysaccharidosis II* | | | Joint Ordinance nº 16 – 24/05/2018 |
Mucopolysaccharidosis IV A* | | | Joint Ordinance SAS/SCTIE nº 19 – 05/12/2019 |
Mucopolysaccharidosis VI* | | | Joint Ordinance SAS/SCTIE nº 20 – 05/12/2019 |
Osteogenesis Imperfecta | Ordinance SAS/MS nº 1306 – 22 /11/2013 | | |
Familial Amyloid Polyneuropathy* | | | Joint Ordinance nº 22 – 02/10/2018 |
Idiopathic Thrombocytopenic Purpura | Ordinance SAS/MS nº 1316 – 22/11/2013 | Joint Ordinance nº 9 – 31/07/2019 | |
Guillain-Barré Syndrome | Ordinance SAS/MS n° 497 – 22/12/2009 | Joint Ordinance nº 15 – 13/10/2020 | |
Turner Syndrome | Ordinance SAS/MS nº 223 – 10/05/2010 | Joint Ordinance nº 15 – 09/05/2018 | |
Primary Nephrotic Syndrome in Children and Adolescents | Ordinance SAS/MS nº 459 – 21/05/2012 | Joint Ordinance nº 1 – 10/01/2018 | |
Non-infectious Uveitis * | | | Joint Ordinance nº 13 – 11/09/2019 |
TOTAL | 35 | 31 | 16 |
Source: Prepared by the authors based on data from the digital repositories of National Committee for Health Technology Incorporation (CONITEC) and Report on Prioritizing Guidelines for Comprehensive Care for People with Rare Diseases in Brazil5. |
a = Secretariat of Health Care / Ministry of Health |
b= Secretariat of Specialized Care / Secretariat of Science, Technology, and Strategic Inputs |
c= Minister’s Office / Ministry of Health |
* Rare diseases for which drugs were recommended in the study period. |
For the 11 rare diseases for which there was no prior treatment available in the SUS and whose medicines were recommended during the study period (Table 5), it was identified that eight of them did not comply with the period established by law. Thus, the data obtained in this study were 292 days (median; n=11; minimum time=156 days; maximum time=351 days).
From the 32 incorporated medicines, the gathered data concerning the financing responsibility of 30 of them: 1 (3.33%) referring to the Strategic Component of the Pharmaceutical Assistance; 24 (80%) referring to group 1A of Specialized Component of the Pharmaceutical Assistance (CEAF); 3 (10%) to group 1B and 2 (6.66%) to group 2. For the following medicines: methionine-free metabolic formula (incorporated on 23/07/2019) and ivacaftor (incorporated on 31/12/2020), data were not available at the time of this study.
When assessing the period required for the financial agreement, it was observed that in 15 situations, the timeframe did not comply with the law18. The data obtained in this study were 193 days (median; n=24; minimum time=10 days; maximum time=778 days). The maximum time observed was for tobramycin 300mg/5mL indicated for cystic fibrosis.
As for the national public medicines manufacturing, it was observed that, as of 2015, some medicines for treating rare diseases were in the SUS list of strategic products, eligible for the Partnership for Productive Development (PDP) project proposal submissions. The partnerships in force in 2020 included treatments for multiple sclerosis (interferon beta-1a, fingolimod 0.5 mg, teriflunomide 14 mg); juvenile idiopathic arthritis (leflunomide 20 mg); juvenile idiopathic arthritis and ankylosing spondylitis (adalimumab 40 mg/0.8 mL, certolizumab pegol 200 mg/mL, etanercept 25 and 50 mg/mL, golimumab 50 mg, infliximab 10 mg/mL, tocilizumab 20 mg/mL); sickle cell anemia (hydroxyurea 500 mg); Crohn’s disease (infliximab 10 mg/mL); pulmonary arterial hypertension (sildenafil 20 mg, 25 mg, 50 mg); hemophilia (recombinant factor VIII); hypopituitarism and Turner syndrome (somatropin 4 IU and 12 IU); acromegaly (cabergoline 0.5 mg); Gaucher disease (taliglucerase alfa 200 UI); amyotrophic lateral sclerosis (riluzole 50 mg).
Table 5
The service offer was evaluated by identifying qualified reference centers after the promulgation of the PNAIPDR. By 2020, 19 Reference Services for Rare Diseases had been enabled in the country, according to the data described in Table 6.
Table 6
– Reference Services for Rare Diseases, Brazil, 2014-2020.
Geographic Location | State | City | Initial jurisdiction | Axis Ia | Axis IIb |
Midwest | Distrito Federal | Distrito Federal | 12/2016 | 1, 2, 3 | 1,3 |
Midwest | Distrito Federal | Distrito Federal | 12/2019 | 1, 2, 3 | 1,2,3 |
Midwest | Goiás | Anápolis | 10/2016 | 1, 2, 3 | 1 |
Midwest | Minas Gerais | Belo Horizonte | 12/2019 | 1, 2, 3 | |
North East | Pernambuco | Recife | 10/2016 | 1, 3 | 1,2 |
North East | Bahia | Salvador | 07/2018 | 1, 2, 3 | |
North East | Bahia | Salvador | 06/2019 | 1, 2, 3 | 1,2,3 |
North East | Ceará | Fortaleza | 12/2019 | 1, 2, 3 | 1,2,3,4 |
North East | Ceará | Fortaleza | 12/2019 | 1, 2, 3 | 1,2,3,4 |
Southeast | Espírito Santo | Vitória | 12/2019 | 1 | |
Southeast | Rio de Janeiro | Rio de Janeiro | 12/2016 | 1, 2, 3 | |
Southeast | São Paulo | Campinas | 12/2019 | 1, 2, 3 | |
Southeast | São Paulo | Santo André | 12/2016 | 2, 3 | 2,3 |
Southeast | São Paulo | Ribeirão Preto | 12/2019 | 1, 2, 3 | |
Southeast | São Paulo | Ribeirão Preto | 12/2020 | 1,2,3 | 1,2,3 |
South | Paraná | Curitiba | 10/2016 | 1, 2, 3 | 1,2,3 |
South | Paraná | Curitiba | 12/2020 | 1 | |
South | Rio Grande do Sul | Porto Alegre | 12/2016 | 1, 2, 3 | |
South | Santa Catarina | Florianópolis | 12/2019 | 1, 2, 3 | 1,2,3 |
Source: prepared by the authors based on National Register of Health Establishments; Ordinance 3166, of 03/12/2019; Ordinance 3709, of 22/12/2020; Ordinance 3968, of 31/12/2020 (sources and searches performed are described in Table 1). |
Axes according to PNAIDR:
Axis Ia = Rare genetic diseases, with three groups: 1 - Congenital or late-onset anomalies, 2 - Intellectual disability, 3 - Inborn errors of metabolism.
Axis IIb = Rare non-genetic diseases, with the following groups of causes: 1 - Infectious, 2 - Inflammatory, 3 - Autoimmune, 4 - Other rare non-genetic diseases.
Many medicines for treating rare diseases are listed on the Specialized Component of the Pharmaceutical Assistance (CEAF) strategy. In 2020, a change was identified in its execution model, increasing from three to six months the expiry period of the Report for the Request, Evaluation, and Authorization of Medicines from the Specialized Component of Pharmaceutical Assistance (LME).
Due to the Covid 19 pandemic, special criteria in the implementation of CEAF related to the documentation renewal and dispensing anticipation were advocated. Also, patients with Gaucher disease assisted by the MS, through the provision of enzymatic therapy by Bio-Manguinhos/Fiocruz, started to be given the medicines infusion via home care service20.
Searches on the websites of the Legislative Power, social demands were identified in the scope of rare diseases, which were discussed in the Special Subcommittee on Rare Diseases of the Chamber of Deputies and in the Temporary Subcommittee on Rare Diseases of the Senate. Topics such as scientific research carried out in Brazil; incorporation of technologies by SUS considering specificities; expansion of diagnostic methods; defense of rights and social inclusion and improvement of specific legislation.