Original Title: Avis: Pénurie d’immunoglobulines – traitements alternatifs aux immunoglobulines humaines non spécifiques

Authors' objectives: During the health crisis due to the coronavirus pandemic (COVID-19), as during other crisis situations that may arise in the future, supply and production problems could lead to a reduction in reserves or a shortage of nonspecific human immunoglobulins (Ig) in Québec. To deal with such situations, the Ministère de la Santé et des Services sociaux (MSSS) has developed a framework for managing Ig shortages. This framework includes specific rules regarding access to Ig that have been validated by the Institut national d'excellence en santé et en services sociaux (INESSS). During its implementation, there will be limited access to intravenous Ig (IVIg) for treating a number of neurological and hematologic disorders, among others. To be able to efficiently treat patients who will have limited access to IVIg during the implementation of the framework for managing nonspecific human immunoglobulin shortages, the MSSS asked INESSS to identify alternative treatments to IVIg for treating the following indications in a context of diminishing reserves or a shortage of IVIg: myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and newly diagnosed persistent or chronic immune thrombocytopenia. In addition, if the treatments so identified are not listed in the formularies or if their coverage conditions do not allow their use in a regular context or in a context of alternative treatments to IVIg, specific work will be carried out and published separately by INESSS’s Direction de l'évaluation des médicaments et des technologies à des fins de remboursement.

Authors' results and conclusions: RESULTS: (1. Myasthenia gravis): Based on a level of evidence considered low, the results of the primary studies and the systematic reviews with meta-analysis indicate that: • Plasma exchange is as effective as IVIg in treating children and adults with myasthenia gravis; • Eculizumab is effective in treating adults with chronic myasthenia gravis. (2. Chronic inflammatory demyelinating polyneuropathy): Based on a level of evidence considered moderate to low, the results of the primary studies and the systematic reviews with meta-analysis indicate that plasma exchange, SCIg and corticosteroids are at least as effective as IVIg in treating children and adults with chronic inflammatory demyelinating polyneuropathy (3. Newly diagnosed persistent or chronic immune thrombocytopenia): Newly diagnosed persistent or chronic immune thrombocytopenia (4. Economic aspects and coverage issues): From an economic standpoint, the temporary nature of an IVIg shortage and the access and availability issues regarding certain alternative therapies make it very difficult to evaluate the cost-effectiveness of a given therapy compared to one or more other options. For the same reasons, it is difficult to estimate the budget impact of replacing IVIg in the specific context of diminishing reserves or a shortage of IVIg. Indeed, certain alternative treatments are currently available without limitation, while others would require additional work in order to make them accessible in the short or long term in the specific context of diminishing reserves or a shortage of IVIg. For drugs already listed under certain conditions, a reevaluation of payment indications may be required. For drugs for which an evaluation has never been requested, the manufacturer will have to submit a listing request so that INESSS can proceed with an evaluation and send a listing recommendation to the Minister of Health and Social Services. The fact that certain treatments do not have a Health Canada notice of compliance for the indications of interest in this report also raises certain evaluation- and recommendation-related issues in light of An Act respecting health services and social services. Thus, eculizumab, rituximab, eltrombopag, romiplostim and fostamatinib all pose an access issue related to their listing in the formularies or to their coverage conditions. CONCLUSION: The assessment of all the scientific and contextual data and of the stakeholders’ perspectives led to the identification of several alternative treatments to IVIg to be used in patients with myasthenia gravis, chronic inflammatory demyelinating polyneuropathy or immune thrombocytopenia in a context of diminishing reserves or a shortage of IVIg. This report will help ensure the safe and effective management of patients who might have limited access to IVIg when the framework for managing nonspecific human immunoglobulin shortages is implemented and will promote the use of IVIg in those patients who need it most and for whom there is no alternative treatment to IVIg for their autoimmune disorder. In the event that the coverage conditions for the identified alternative treatments to IVIg need to be evaluated or reviewed in a regular context or in a specific context of diminishing reserves or a shortage of IVIg, specific work addressing these issues will be carried out and published separately by INESSS’s Direction de l'évaluation des médicaments et des technologies à des fins de remboursement. The advisability of updating this report will be assessed in four years, i.e., in 2026, on the basis of the changes in the health-care system’s needs, the context and scientific knowledge or of the changes in the availability or accessibility of the alternative therapies to IVIg for the indications of interest.

Authors' recommendations: INESSS’s clinical recommendations concerning alternative treatments to IVIg for myasthenia gravis, chronic inflammatory demyelinating polyneuropathy and immune thrombocytopenia in a context of diminishing reserves or a shortage of IVIg are the culmination of systematic and rigorous work that integrated scientific data and the experience of Québec experts in different specialties, namely, neurology and hematology-transfusion medicine. Contextual data were taken into consideration as well. The assessment of these different data sources increased the reliability of the recommendations. It is important to emphasize that the recommendations made in this report take into account the specific context of diminishing reserves or a shortage of IVIg. Consequently, these recommendations should be applied when the framework for managing shortages of nonspecific human immunoglobulin is implemented. The efficacy and safety mentioned below do not imply recognition of therapeutic value as stipulated in the drug review processes for listing purposes. The options proposed by INESSS that are not covered by the RAMQ for certain indications (in the orange boxes in the table of recommendations) must be approved by a pharmacy and therapeutics committee or via the exception patient measure.

Authors' methods: For the purpose of its task, INESSS evaluated the efficacy and safety of alternative treatments to IVIg in children and adults for each of the three indications of interest. Three systematic reviews were conducted in several bibliographic databases, the reviews covering the period from the date of their inception to November 2021, to identify all the primary studies and systematic reviews with meta-analysis published on these topics. To supplement the search regarding the safety of alternative treatments to IVIg, the official monographs for Health Canada-approved treatments and Health Canada advisories were consulted. To round out the search, a systematic literature review was conducted to identify guidance documents, clinical practice guidelines, and other items containing clinical recommendations published between January 2010 and November 2021 for the three disorders in question. Items were selected according to predefined exclusion and inclusion criteria, and the quality of those selected was assessed using the appropriate tools. These steps were carried out independently by two scientific professionals. The data were then extracted by one of them and validated by the other. The main efficacy results reported in the selected studies were summarized, and a statement of scientific evidence was put forth. An overall level of scientific evidence was assigned to each statement of evidence according to a four-level scale (high, moderate, low, insufficient). Contextual data and the perspectives of the different stakeholders were collected to document the accessibility, organizational, administrative, legislative and ethical issues. The analysis and synthesis of the scientific and contextual data, and the stakeholders’ perspectives were used to structure the argument leading to the identification of alternative treatments to IVIg for myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and newly diagnosed persistent or chronic immune thrombocytopenia in a context of diminishing reserves or a shortage of IVIg. Only those alternative treatments to IVIg on which there was a consensus among the experts are presented in this report. Since this task specifically concerns one-off situations involving diminishing reserves or a shortage of IVIg, a comparative cost-effectiveness evaluation of IVIg and the alternative treatments was not done. As for the budget impact analysis, the issues related to estimating the costs or savings that might be generated by using the alternative treatments in place of IVIg were reviewed. Because of several major limitations, the budget impact could not be estimated.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/en/publications/publications/publication/penurie-dimmunoglobulines-traitements-alternatifs-aux-immunoglobulines-humaines-non-specifiques.html

Year Published: 2022

URL for published report: https://www.inesss.qc.ca/en/publications/publications/publication/penurie-dimmunoglobulines-traitements-alternatifs-aux-immunoglobulines-humaines-non-specifiques.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Gouvernement du Québec