Denise Golgher Ph.D. Attorney Licks Attorneys
R. Rodrigues Licks Attorneys
R. Massafera Licks Attorneys
Looking Ahead after the Approval of the Monoclonal Remsima
Brazil has approximately 200.4 million inhabitants, the fifth largest and one of the fastest aging populations in the world. The country has undergone a fast demographic and epidemiological transition. In 2030, the population will have increased by 10%, the number of elderly people can achieve 40 million. The disease-related mortality rates in the country are caused by chronic degenerative non communicable diseases, which incidence will worsen. The local law establishes an obligation of the government to provide free public health care to its population. The public health care, called the Unified Health System (SUS) is also responsible for the provision of free drugs.
One of the most relevant programs of the government seeking to provide drugs to the population is called PDPs, public-private partnerships geared primarily for the transfer of technology and production of costly medicines.
Imports fulfill many of the medical necessities in Brazil, importation of drugs grew from US$ 1.4 billion in 2002 to US$ 6.5 billion in 2013. While there was a 375% increase in all medication imported, the share of biologics grew by 13.000% during the same period. Biological products represent 51% of the total budget of the Ministry of Health. They comprise 12% of all medication distributed by SUS, but take up 61% of the total budget.
The deficit of the Ministry of Health is already US$ 5.5 billion and according to predictions, Brazil will soon rise from the sixth to the fourth country in pharmaceutical spending, behind only the US, China, and Japan. The government is under great pressure to take action toward reducing this deficit. In this sense, following worldwide trends, the Brazilian food and drug agency (ANVISA) is pushing itself for granting marketing authorizations for biosimilars in the country.
This year, on April 27, ANVISA granted authorization for Celltrion’s Remsima, a copy of Janssen’s Remicade (infliximab). This was the first marketing authorization for a monoclonal-antibody biosimilar in the country.
ANVISA’s Regulatory Framework for Biological Products and the First mab Biosimilar
Anvisa’s regulation for biologics, Rule #55 of 2010, established the requirements for granting marketing authorization to both new biologicals and biosimilars (ANVISA does not officially use the term biosimilars, although this may change). The rule provides three pathways for obtaining marketing authorization for a biological drug (Figure 1).
Remsina was approved via the regulatory comparative pathway, for the same therapeutic uses of Remicade (ANVISA R1 21/05/2015).
The First Approval: Celltrion’s Infliximab
ANVISA’s approval of Remsima followed Celltrion’s launch of the product in several countries of the European Union. Celltrion’s application for marketing authorization of Remsima was filed in Brazil in November 2012 and approved in April, 2015. ANVISA regularly takes between two to three years to grant a marketing authorization, although this timing can be different in PDPs (see below).
ANVISA’s report for authorization of Celltrion’s biosimilar followed EMA’s conclusions about the safety and efficacy of the drug. Celltrion submitted the same data related to manufacturing, quality control, and the therapeutic experimentation report filed before EMA: ANVISA’s analysis was published and indicated that the only differences between the two biologics was in the glycosylation pattern of the antibodies and the consequent difference in affinity of its binding to the Fc receptor (FcyRIIIa). Similarly to EMA, the agency accepted the argument that there would be no clinical impact regarding these differences.
Remsima’s approval in Brazil was obtained by Celltrion Healthcare Distribuidora de Produtos Farmaceuticos do Brasil Ltd., a local subsidiary of Celltrion Inc.
Tech Transfer Partnerships (PDPs) for the Development of Complex Biological Products in Brazil
One of the goals of the PDPs program is to boost the development of the local pharmaceutical industry (private and state-sponsored) that matured primarily for the commercialization of generic drugs, with API imported from countries such as China and India.
Changing from a manufacturer of generics to a manufacturer of complex biologicals is a huge leap forward. Considering the lack of expertise and infrastructure to generate and scale up these molecules, the government created the PDPs program. The program involves the transference of proprietary technology from private companies (foreign or domestic) into the country (guidelines published in 2014). To be considered for a PDP, a product must be in a list published by the Ministry of Health.
Although any institution can submit a request for the inclusion of a new technology to the list, the final decision is a strategic one, which considers the cost/benefit of the new technology. After its publication, which happens on the second semester every year, PDP applicants (state-owned institutions) interested in manufacturing a product can submit a project in partnership with a private company (from the 1st of January to the 30th of April of the following year). For example, the list of strategic products for 2015 was published on the 30th of December of 2014. It included the following biologics: Adalimumab, filgrastim, infliximab, rituximab, somatropin, L-asparaginase. The list of approved PDPs can be found on the Ministry’s of Health website, it was published recently, on the 30th of September.
The results showed that the government approved and rejected many PDPs. For instance, Pfizer had two projects approved for PDPs with the local company Orygen and the governmental laboratory Bahiafarma for the production of infliximab and rituximab. Merck S/A had a project approved with the local company Bionovis and the laboratory FUNED for the production of adalimumab. Other companies, such as Abbvie faced the rejection of a PDP to produce adalimumab. Also, Celltrion’s PDP for infliximab was not approved.
The first mAb biosimilar approval by ANVISA shows that the Brazilian Agency will likely follow EMA’s conclusion regarding the effectiveness and safety of biological products. In this sense, obtaining an authorization before EMA will improve drastically the chances of getting approval of the same product in Brazil.
Despite the positive development concerning the authorization of the first mAb biosimilar, some questions are arising regarding how new biological products and biosimilars will interplay in the public health care system. The pricing of biosimilars is also a pending question to be addressed by the government. The government has not issued any specific guidelines, but the price to be approved to Celltrion’s Remsima will be an important parameter for the next coming biosimilars.
Concerning the PDP scenario, most of the PDPs regarding biologics involve medications for oncologic or immunological applications, areas that have experienced a lot of innovation in the past five years. New treatments will have to be imported into the country, private hospitals are already looking into technology transfer of innovative antibodies, biobetters and cell therapy products. If we consider the realm of immunotherapy and gene therapy technologies that are being developed abroad, it is easy to envision more difficulties for the Brazilian government and many new business opportunities for foreign companies: only in 2015 the government had plans to buy approximately US$3 billion in drugs.
D. Golgher, R. Rodrigues, and R. Massafera are at Licks Attorneys, Rio de Janeiro, Brazil.