Transforming uncertainties into legitimate regulation? NICE and CONITEC agencies’ decisions on rare diseases

Vicente, Geison; Cunico, Cássia; Leite, Silvana Nair

doi:10.1590/1413-812320212611.34542020

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ARTICLE • Ciênc. saúde coletiva 26 (11) • Nov 2021 • https://doi.org/10.1590/1413-812320212611.34542020 copy

Transforming uncertainties into legitimate regulation? NICE and CONITEC agencies’ decisions on rare diseases

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

As a scientific and technological practice, the evaluation of health technologies (HTA) is, at the same time, a challenge to determine the value of the technologies to be incorporated. This study aimed to explore and compare the results and technical elements of the evaluations issued for rare diseases between the English (NICE) and the Brazilian agency (CONITEC). The first part of the study involved the systematic search for evaluations from 2013 to 2019. In the second stage, the reports were analyzed based on: (i) descriptive narrative review; and (ii) calculation of the absolute and relative frequency according to each domain and component (element) applied in the European HTA network model. Twenty-four medicines were distinctly assessed during the study period. Through 126 questions (elements) distributed among nine domains, the analysis revealed that 67 (53.2%) and 44 (35.0%) were described in the reports, 42 (33.3%) and 59 (47.0 %) were only considered partially, and 17 (13.5%) and 23 (18.0%) were not considered in the NICE and CONITEC reports, respectively. We identified a relatively low agreement between the Brazilian agency with the English agency in the reports issued for rare diseases. It remains to be seen whether the agencies are able to capture the various values of these medicines, as well as manage uncertainties in the evaluations.

Key words:
Health technology assessment; Rare diseases; Government regulation; Uncertainty

Medicine	Indication	NICE	CONITEC
Elosulphase Alpha	Type IV A mucopolysaccharidosis (Morquio syndrome)	Recommended for treatment based on a risk-sharing agreement	Recommend the incorporation of Elosulphase Alpha under conditions *
Brentuximab	Treatment of adult patients with refractory or relapsed Hodgkin’s lymphoma after autologous stem cell transplantation	Recommended as an option for the treatment of CD30 positive. Hodgkin’s lymphoma in adults with relapsed or refractory disease, under certain clinical conditions and based on commercial agreement	Incorporate brentuximab for the treatment of adult patients with refractory or relapsed Hodgkin’s Lymphoma after autologous hematopoietic stem cell transplantation, through price negotiation and CPTG
Canakinumab	Treatment of Systemic Juvenile Idiopathic Arthritis	Does not recommend, as it believes that there are not enough data to propose a robust evaluation of the medicine to be considered in clinical practice in England	Do not incorporate canakinumab for the treatment of systemic juvenile idiopathic arthritis
Eculizumab	Treatment of patients with Atypical Hemolytic Uremic Syndrome (aHUS)	Recommended only if all conditioning criteria are met *	Do not incorporate eculizumab for the treatment of Atypical Hemolytic Uremic Syndrome
Eltrombopag olamine	Chronic Idiopathic Thrombocytopenic Purpura (ITP)	Recommended if refractory to standard treatments and rescue therapies or with severe illness and a high risk of bleeding that requires frequent courses of rescue therapies through a managed patient access scheme	Recommend the incorporation of eltrombopag olamine for the treatment of refractory ITP using CPTG
Evolocumab	Homozygous familial hyperlipidemia (HoFH)	Recommended in certain clinical conditions and good basis for managed patient access scheme	Recommend the non-incorporation of Evolocumab for the treatment of HoFH
Nintedanib	Idiopathic pulmonary fibrosis (IPF)	Recommended under certain clinical features and based on manufacturer-provided discount, patient access scheme	Do not incorporate Nintedanib for IPF treatment
Nusinersen	Spinal Muscle Atrophy (SMA) 5q	Recommended as a treatment option for SMA 1,2,3 through a risk-sharing agreement	Incorporate Nusinersen for spinal muscular atrophy (SMA) 5q type I through a risk-sharing agreement
Pirfenidone	Idiopathic pulmonary fibrosis (IPF)	Recommended under certain clinical features and based on manufacturer-provided discount, patient access scheme	Non-incorporation of Pirfenidone for the treatment of IPF
Romiplostim	Chronic Idiopathic Thrombocytopenic Purpura (ITP) in refractory adults and at high bleeding risk.	Recommended under certain clinical features and based on manufacturer-provided discount, patient access scheme	Non-incorporation of Romiplostim for the treatment of ITP

Medicine	Indication	Recommendation (CONITEC)
Alfa, beta, Agalsidase	Fabry disease	Do not incorporate alpha-agalsidase and beta-agalsidase as enzyme replacement therapy in Fabry disease, within the SUS
Eftrenonacog alfa (Factor XI)	Treatment of patients with Hemophilia B	Recommends the non-incorporation of Eftrenonacog alfa (Fc recombinant coagulation factor XI) into the SUS for the treatment of patients with hemophilia B
Efmoroctocog alfa (Factor VIII)	Induction of immunotolerance in patients with hemophilia A and inhibitors	Do not incorporate Efmoroctocog alfa (recombinant Fc coagulation factor VIII) for induction of immunotolerance in patients with hemophilia A and inhibitors, within the SUS
Taliglucerase alfa	Treatment of Gaucher Disease	Recommends the incorporation of Taliglucerase alfa for pediatric use in Gaucher Disease
Alglucosidase alfa	Pompe disease	Recommends the incorporation Alglucosidase alfa for the treatment of the early form of Pompe’s disease within the SUS, according to PCDT
Eculizumab	Paroxysmal Nocturnal Hemoglobinuria	Incorporate Eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH), within the SUS, under conditions*
Emicizumab	Treatment of individuals with hemophilia A and factor VIII inhibitors refractory to immunotolerance treatment	Incorporate Emicizumab for the treatment of individuals with hemophilia A and factor VIII inhibitors refractory to the treatment of immunotolerance, within the SUS
Galsulfase	Type VI Mucopolysaccharidosis (Maroteaux-Lamy syndrome)	Incorporate Galsulfase for long-term enzyme replacement therapy in patients with a confirmed diagnosis of type VI mucopolysaccharidosis (N-acetylgalactosamine 4-sulfate deficiency), within the SUS, under conditions*
Idursulfase	Type II Mucopolysaccharidosis	Incorporate Idursulfase alfa as enzyme replacement therapy in type II mucopolysaccharidosis under the SUS according to PCDT
Laronidase	Enzyme replacement in type I mucopolysaccharidosis	Recommends the incorporation of Laronidase for enzyme replacement in patients with type I mucopolysaccharidosis according to PCDT
Miglustat	Neurological manifestations of Niemann-Pick type C disease (NPC)	Does not recommend the incorporation of Miglustat for neurological manifestations of Niemann-Pick type C disease (NPC)
Tafamidis meglumine	Treatment of transthyretin-associated amyloidosis in adult patients with early-stage symptomatic polyneuropathy and not undergoing liver transplantation	Incorporate Tafamidis meglumine for adult patients with early-stage symptomatic polyneuropathy and not undergoing liver transplantation, through price negotiation and PCDT in the SUS

Medicine	Indication	Recommendation (NICE)
Asphotase alpha	Perinatal/infant and juvenile hypophosphatasia	Recommended as an option for pediatric treatment in hypophosphatasia only: for people who meet the treatment criteria within the managed access and for the duration of this agreement, and as per the other specified conditions, and when the company supplies Asphotase alpha to confidential business terms under the health system
Brentuximab	Cutaneous CD 30+ T-cell lymphoma	Recommended as an option for the treatment of CD30-positive cutaneous T-cell lymphoma after at least 1 systemic therapy in adults, and only if: they have stage IIB or higher mycosis fungoides, primary cutaneous anaplastic large cell lymphoma or Sézary syndrome and the company provides Brentuximab vedotin under a commercial agreement
Burosumab	Treatment of X-linked hypophosphatemia (XLH)	Recommended to treat X-linked hypophosphatemia (XLH) with radiographic evidence of bone disease in children 1 year of age and older and in young people with growing bones. Recommended only if company provides Burosumab under a commercial agreement
Cerliponase alpha	Type 2 neuronal ceroid lipofuscinosis (NCL2) or Batten’s disease	Recommended as an option for the treatment of type 2 neuronal ceroid lipofuscinosis (NCL2), also known as tripeptidyl peptidase 1 (TPP1) deficiency, only if the conditions of the managed access contract are established
Eliglustat	Type 1 Gaucher Disease	Recommended for treatment of type 1 Gaucher disease, i.e., for long-term treatment in adults who are poor, intermediate or extensive cytochrome P4502D6 metabolizers. Eliglustat is only recommended when the company provides the agreed discount on the patient access scheme
Inotersen	Hereditary transthyretin amyloidosis in adults with stage 1 and 2 polyneuropathies	Recommended as an option for treating polyneuropathy in people with hereditary transthyretin-mediated amyloidosis. Recommended only if the company provides Inotersen under a commercial agreement
Migalastat	Fabry’s disease	Recommended as an option for the treatment of Fabry disease in persons aged 16+ with a mutation based on the discount agreed via the patient access scheme and only if enzyme replacement therapy (ERT) is offered. With the discount provided in the patient access system, Migalastat has a lower total cost than ERT and potentially offers greater health benefits than ERT
Patisaran	Hereditary transthyretin amyloidosis in adults with stage 1 and 2 polyneuropathies	Recommended as an option for treating polyneuropathy in people with hereditary transthyretin-mediated amyloidosis. Recommended only if the company provides Patisaran under a commercial agreement
Strimvelis	Adenosine deaminase deficiency - severe combined immunodeficiency (ADA-SCID)	Recommended as a treatment option when no human leukocyte antigen-compatible cell donor is available
Voretigene neparvovec	Leber’s congenital amaurosis	Recommended as an option for the treatment of RPE65-mediated inherited retinal dystrophies in people with vision loss caused by biallelic-confirmed inherited retinal dystrophy, confirmed mutations in RPE65 and who have sufficient viable retinal cells. Recommended only if the company supplies Voretigene neparvovec under a commercial agreement

Domains	Components (elements)	Eculizumab		Nusinersen		Elosulphase Alpha
Domains	Components (elements)
Health problem and current use of technology (18 questions - elements)	Health problem and target population	✔	✔	✔	✔	✔	✔
	Epidemiology	✔	✔	*	✔	*	*
	Regulatory status	✔	✔	✔	✔	✔	✔
	Alternative to technology	✔	✔	✔	✔	✔	X
Description and technical characteristics of the technology (15 questions - elements)	Technology review	✔	✔	✔	✔	✔	✔
	When was it developed and proposed indication	✔	✔	*	*	✔	*
	Who will use the technology, how and at what level of the health system	✔	✔	✔	✔	✔	*
	Materials, facilities, qualified personnel, equipment	X	*	*	*	X	*
	Training and necessary information	X	*	X	X	X	X
Security (11 questions - elements)	Direct and indirect damage to patients	✔	*	X	*	✔	*
Security (11 questions - elements)	Damage risk reduction	✔	X	*	*	X	X
Clinical Effectiveness (12 questions - elements)	Health and quality of life benefit (QUALY)	✔	*	*	*	✔	*
Clinical Effectiveness (12 questions - elements)	Effectiveness and safety	*	✔	*	*	✔	*
Cost and economic evaluation (11 questions - elements)	Identification and measurement of price, value and comparison of cost and technology outcomes based on value-based price judgment and priority setting across different healthcare technologies	*	*	*	*	*	*
Cost and economic evaluation (11 questions - elements)	Use of resources, unit price, indirect cost, outcomes and consequences, and incremental cost-effectiveness	✔	✔	*	✔	✔	✔
Ethical analysis (20 questions - elements)	Social and moral prevalence, norms and relevant value of technology	✔	✔	*	*	*	*
	Ethical issue of technology and consequences of implementation and non-implementation	✔	*	*	*	X	*
	Identification of ethical and moral problems inherent in technology assessment	✔	*	*	✔	*	✔
Organizational aspects (15 questions - elements)	Technology dispensing model	*	*	*	*	*	*
Organizational aspects (15 questions - elements)	Process, resource, and management analysis	✔	X	✔	X	X	X
Social aspects (7 questions - elements)	Considerations, prior and post-implementation experiences	✔	✔	X	✔	✔	✔
	Where patients will use the technology (hospitals, primary system, and clinics)	*	✔	*	✔	✔	✔
	What are the main goals that people aim with technology	✔	*	✔	*	*	*
Legal aspects (17 questions - elements)	Basic patient rights such as autonomy, informed consent, privacy, and confidentiality	✔	✔	✔	✔	✔	*
Legal aspects (17 questions - elements)	Legal requirements, authorization, guarantee, and market regulation	✔	X	X	X	✔	X

Domains	Elements (n)	Described (%)		Not described (%)		Partially described (%)

I	18	83.3%	83.3%	0.0%	8.3%	16.7%	8.3%
II	15	53.3%	40.0%	33.3%	13.3%	13.3%	46.7%
III	11	50.0%	0.0%	33.3%	33.3%	16.7%	66.7%
IV	12	50.0%	16.7%	0.0%	0.0%	50.0%	83.3%
V	11	33.3%	50.0%	0.0%	0.0%	66.7%	50.0%
VI	20	33.3%	33.3%	11.1%	0.0%	55.6%	66.7%
VII	15	33.3%	0.0%	16.7%	50.0%	50.0%	50.0%
VIII	7	50.0%	50.0%	0.0%	0.0%	50.0%	50.0%
IX	17	83.3%	33.3%	16.7%	50.0%	0.0%	16.7%
Total	126	67/126 (53.2%)	44/126 (35.0%)	18/126 (14.3%)	23/126 (18.0%)	41/126 (32.5%)	59/126 (47.0%)

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[1] Collaborations

We emphasize that G Vicente and SN Leite participated in the paper’s design, planning, discussion, and final review. Furthermore, C Cunico and G Vicente contributed to the analysis of the results, discussion, and review of the writing of the manuscript.