Biosimilar Drugs for Multiple Sclerosis: An Unmet International Need or a Regulatory Risk?

摘要

Multiple sclerosis (MS) more than any other neurological disorder has experienced a tremendous progress in available evidence-based innovator disease modifying therapies (DMT). These medications include injectable complex nonbiological drugs (CNBD), the injectable biological products β-interferons-1a and -1b, and the infusible monoclonal antibodies (MAB), as well as oral synthetic therapeutic molecules. The degree of efficacy and adverse effects profile is variable. By the end of 2019, all medications have been approved for relapsing forms of MS, including five with indication for clinically isolated syndrome (CIS), two for active secondary progressive MS, and one for primary progressive MS. With the advent of the first generation or “platform” injectable DMT in the 1990s the cost of MS care increased substantially driven basically by the cost of these therapies. As new drugs licensed by health agencies appeared in the global market, the cost of these agents notably increased augmenting the economic gravamen of disease particularly in North America This industrial phenomenon has been promoted by the remarkable profits obtained by the biopharmaceutical companies producing these medications, costs increasing about seven times per patient per year in the span of two decades. The global MS drug market was valued at US$16.3 billion in 2016, expecting to reach US$27.8 billion by 2025. The societal and economic effect of these costs constitute an international concern for health systems which adjudicate an increasing portion of financial resources to MS care. This effect has had a more notorious impact in emerging countries with economies in development. In the early 2000s the industry producers of biosimilar molecules initiated the concept of manufacturing follow-on biosimilar therapeutic options for MS available at a reduced cost without affecting efficacy and safety. Latin American biotechnological companies from Mexico, Argentina and Uruguay, introduced into the regional markets biosimilar β-interferons. These products were licensed by the local regulatory agencies without challenging pharmacological profile and their claims of similarity with the innovator medications. In the licensing process, biosimilar manufactures have typically utilized published literature and phase III clinical trials data previously acquired by the brand medication (“third approval pathway’’). This has raised concerns among local neurological communities and patient organizations in the area. This situation is compounded by the fact that no discernible health cost savings have resulted since their introduction in Latin American countries. In some European countries where the health care system, public and private systems, regulated by Ministries of Health, negotiate with the pharmaceutical industry drug pricing and payment systems. The business scenario has stimulated local industries to produce follow-on biosimilar medications, theoretically to compete or replace the original brands. Countries such as Iran who have experienced a substantial increase in MS prevalence (101.19 per 100,000 inhabitants) has enabled their national Food and Drug Organization (FDO) to license locally produced biosimilar interferon 1-a and 1-b based on somewhat limited clinical studies. The Ministry of Health of the Russian Federation, approved the first biosimilar β-interferon-1a (44 mcg subcutaneous administration) manufactured in the country and developed in accordance to the guidelines of the European Medicine Agency (EMA) for phase I and phase III studies. The EMA, however, along with other international licensing agencies: United States Food and Drug Agency (FDA), Health Canada, the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the UK Medicines and Healthcare Products Regulatory Agency (MHPRA), and others, have produced strict guidelines regulating registration of biosimilar medicines. Thus far these agencies have not approved any interferon or MAB for MS based on these principles. The main obstacles for the approval of biosimilar medications by international health agencies is their consistent inability to demonstrate therapeutic equivalence through physiochemistry, biology, immunogenicity aspects, molecular behavior and clinical studies, preferably through a controlled phase III study, or ideally, utilizing a comparative head-to-head trial with the innovator. Recommendations proposed by experts from the Latin American region to guarantee production quality of biosimilar products, efficacy and safety, include strict application of current regulations; avoid uncontrolled interchangeability; implement strong pharmacovigilance; educate healthcare professionals and regulatory officials on the different issues involved in the biosimilarity concept and use evidence-based decision for therapy selection. The main priority should always be the protection and well-being of the patient irrespectively of therapy availability or pharmacoeconomic issu