On a small hill in Geneva, adjacent to the Palace of Nations—the original seat of the League of Nations and the current home to several United Nations offices—and not very distant from the World Health Organization headquarters, on avenue de la paix, sits an eclectic late 19th century mansion. Designed with elements of neo-baroque and neo-classical architecture, the Musée Ariana houses the Swiss museum of ceramics and glass. This small but superbly well-kept institution has an exquisite collection of porcelain and pottery from East and West, spanning millennia and depicting the history and development of this unique and indispensable craft, art, and industry. It makes one wonder how objects that started as a luxury have eventually become commonplace and accessible to most people around the world.
In 2015, many colleagues and I participated in the process which updated WHO’s Essential Medicines List (EML), accepting 16 new drugs and bringing its total number of anticancer agents to 46. Importantly, two newer and more expensive medications, the monoclonal antibodies trastuzumab and rituximab, were included. The addition of these medicines brings an important challenge to low- and middle-income countries, as they increase the cost of regimens for breast cancer and lymphoma from a few hundred to tens of thousands of dollars.
For regular medications, international agreements and regulations have created a path for the development of generics once a pharmaceutical patent expires, and physicians, health systems, and patients have made generics a way to increase access to essential medicines around the world. We are, however, just starting to learn about biosimilars, how they compare to innovative biologic products, and how they should be brought to market.
In a 2016 ASCO Daily News editorial (from which this post is adapted), Sergei Tjulandin, Monica Malik, and I introduced the basic concepts and pathways for approval and report on the availability of follow-on biologics, with a focus on emerging markets using India and Russia as examples. (In the near future, we hope to add case experiences from Brazil, China, and South Africa, completing a tour of “Biosimilars in the BRICS Countries”).
Abbreviated pathway for biosimilars
In the United States, the Biologics Price Competition and Innovation Act, signed into law as part of the Patient Protection and Affordable Care Act in 2010, created a pathway for the approval of biologic products that are similar to or interchangeable with a U.S. Food and Drug Administration (FDA)–approved complex molecule, such as a monoclonal antibody. Drawing from the European Medicines Agency experience and guidance from WHO, the FDA and agencies around the world now use an abbreviated pathway for the approval of biosimilars. Several growth factors and rheumatologic agents, and a few emerging cancer medicines, are available as follow-on biologics around the world.
The abbreviated pathway is, nonetheless, more complex than the pathway for approval of small-molecule generics, and it includes several types of studies a company needs to submit for consideration. Analytical studies should demonstrate that the product is “highly similar” to the reference biologic agent, animal studies must show safety and efficacy, and clinical studies (including assessment of immunogenicity, pharmacokinetics, and pharmacodynamics) must prove the purity, safety, and efficacy of a biosimilar candidate. Comparative phase III studies must be done in a sensitive, representative indication (usually, for cancer agents, with surrogate or intermediate outcomes rather than overall survival) and do not have to be repeated for other specific clinical indications once a drug is approved.
Although the FDA and many other agencies around the world use this abbreviated pathway, many countries, such as India and Russia, follow different guidelines regarding the approval of biosimilars.
Biosimilars in India
India, with its established track record of growth in the generic pharmaceutical industry, can potentially emerge as a strong global player in the biosimilar segment. The Indian biosimilar industry is expected to grow from $4 billion in 2015 to more than $70 billion by 2025. Currently, more than 50 biotherapeutics are approved in the country, and over half are biosimilars. Although India does not have stringent regulations, it has a big potential for biosimilars. Most innovator biotherapeutics are unaffordable to the average patient in India, even though the price in the local market is usually lower than that in Western countries. In 2015, India updated its Essential Medicines List in line with the WHO model. A few Indian pharmaceutical companies are substantially investing resources toward expanding their biosimilar portfolios.
For example, Dr. Reddy’s Laboratories, an Indian multinational pharmaceutical company, is one of the key players in the forefront of the biosimilar segment and has developed Reditux™, the world’s first biosimilar antibody. Reditux was launched as a biosimilar version of rituximab (marketed as Rituxan® and MabThera®) in 2007 at almost half the price of the innovator molecule. A retrospective review of 223 patients with diffuse large B-cell lymphoma treated with Reditux versus MabThera showed no significant differences in disease control, overall survival, or toxicity rates. Intas Pharmaceuticals launched its own biosimilar version of rituximab in 2013 under the name Mabtas™. Neither of these products, however, have been developed in accordance with global biosimilar guidelines, which were put in place in India in 2012, but they have, nonetheless, led to competitive pricing and greater affordability for these agents.
Another company, Hetero Drugs, launched its version of rituximab in 2015, and a few more biosimilars of rituximab are expected to be launched this year by various other pharmaceutical companies. At least 13 versions of filgrastim and four versions of pegfilgrastim are currently marketed in India.
The “Guideline on Similar Biologics: Regulatory Requirements Marketing Authorization in India for Biosimilar Drugs” was released by the Department of Biotechnology and the Central Drugs Standard Control Organization to streamline the approval process and ensure high-quality biologics. These guidelines were developed with reference to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines so that products developed in and imported to India will be on par with global regulatory standards. However, these guidelines are yet to be fully implemented.
Meanwhile, Indian pharmaceutical companies are increasingly partnering with their Western counterparts to launch a greater number of biotherapeutics in both local and international markets. At the same time, innovator companies are gearing up to defend their patents and market share. Biocon, an Indian company, has partnered with Mylan and is in the process of conducting phase III trials for a number of biologics, including trastuzumab, bevacizumab, and adalimumab, among others. The partnership led to the launch of the biosimilar version of trastuzumab early in 2014, following approval from the Drug Controller General of India.
Interestingly, trastuzumab was the first candidate drug to be considered for compulsory license under Section 92 of the 1970 Indian Patent Act, which authorizes the manufacture and marketing of a low-cost version of a patented drug without the patent owner’s consent. Compulsory licensing can reduce the drug price manifold and is in practice in a few low- and middle-income countries to make lifesaving medicines (usually to treat HIV) more affordable. The first drug to be issued a compulsory license in India was sorafenib tosylate (marketed as Nexavar®), and it is now being marketed at less than one-tenth of the price of the original drug.
In order to preempt this move, Roche allowed its patent on Herceptin® in India to expire in 2013, while simultaneously teaming up with Emcure Pharmaceuticals to manufacture and sell the drug at a reduced price in India under a different name with the intent of maintaining its strong market share and discouraging competitor biosimilars. At the same time, Roche is questioning the similarity and quality claimed by the competitors in legal battles. Currently, a few Indian pharmaceutical companies, including Biocon and Zydus Cadila, are already marketing their biosimilar versions of trastuzumab at less than half the original price of Herceptin.
There is a strong potential for India to emerge a key player in the manufacture and marketing of biosimilars. At the same time, it is also a large consumer of these drugs because of their lower price. Currently, both manufactures and regulators are gearing up to meet the challenges of this growing segment and offer a larger number of high-quality products.
Biosimilars in Russia
In the beginning of this century, the first biosimilars of octreotide, filgrastim and erythropoietin appeared in the Russian pharmaceutical market. At that time, the established Russian legislation on the registration of medicinal products did not recognize biologic products and biosimilars. Today, Russian law also provides an accelerated marketing approval procedure to biosimilars akin to the one for generic products. As a result of the low registration barriers, a substantial number of biosimilars have been approved for clinical application. Before October 2015, 14 biosimilars of filgrastim (of these, seven are produced locally) and 15 biosimilars of erythropoietins alfa, beta, and theta (eight of which are produced locally) were registered in Russia. We had limited information on efficacy and safety for many of them at the time of approval, particularly for biosimilars from Russia and India.
For medical oncologists and hematologists, particularly for those who are working with high-dose chemotherapy and bone marrow transplantation, the information on the clinical efficacy and safety profile of filgrastim is essential. Two of the most popular biosimilars of filgrastim in the Russian market, Neupomax® (produced by Pharmstandard) and Leucostim Neupomax® (produced by BIOCAD) received marketing approval based on limited clinical experience. Neupomax was approved in 2007 based on two small studies totaling 51 patients. The comparison of Neupomax and lenograstim was made in 11 pediatric patients, and 40 patients with breast cancer received standard chemotherapy with Neupomax for prophylaxis of neutropenia. Leucostim received registration in 2010. For Leucostim registration approval, 56 patients with solid tumors and lymphomas received standard chemotherapy and Leucostim without comparison with filgrastim. Leucostim was also used in 42 patients for bone marrow stimulation and collection of the bone marrow stem cells.
Both Neupomax and Leucostim entered the Russian market and hospitals with limited clinical data. Since marketing approval, further data have been obtained on their safety and efficacy, and, currently, physicians in Russia do not have a particular concern with these drugs. Importantly, since the appearance of Neupomax, the price of filgrastim has decreased substantially. Based on the contract price for the Blokhin Russian Cancer Research Center in the beginning of 2015, a 300 mcg vial of Neupomax, Leucostim, and Neupogen® is R 785 (US $13), R 3,318 (US $63), and R 5,305 (US $102), respectively.
In Russia, state cancer hospitals, which treat almost all patients with cancer in the nation, are able to buy all drugs, including anticancer agents, through electronic auctions. Hospitals submit a bid for procurement indicating only the generic name. The winner is an anonymous contractor who offers the lowest price in the exercise. That is why mostly generic anticancer drugs are available in the Russian health care system.
In the last few years, the medical community, in cooperation with patient advocacy groups and the Russian Ministry of Health, worked together to change the existing federal law On Circulation of Medicines. We proposed to include the definition of “biologic product” and “biosimilar,” and to specify which preclinical and clinical studies are needed for registration.
The Russian Society of Clinical Oncology proposed to consider biosimilars as similar but not identical versions of their originator biological product. We proposed to join the existing and most developed regulatory standards and pathway, produced by the European Medicines Agency.
Opponents of the proposal included the Russian Ministry of Industry and Trade and some Russian pharmaceutical companies that argued for an accelerated pathway for biosimilar registration. The final document was approved in June 2014 and included the definition of biologic products and biosimilars, as well as the differences between biosimilars and generic products and the requirement of preclinical and clinical studies to prove similarity of the biosimilar and originator. However, the Russian government has yet to enact these changes.
Biosimilar cancer agents have also been studied and produced in Russia. A follow-on rituximab (marketed as AcellBia™, produced by BIOCAD), which is widely used to treat hematologic malignancies, received marketing approval in 2014. As part of its dossier, BIOCAD supplied data from a randomized multicenter clinical study comparing the pharmacokinetics, pharmacodynamics, safety, and efficacy of AcellBia and MabThera (rituximab, produced by F. Hoffmann-La Roche). The study included 92 patients with stage II to IV CD20-positive follicular lymphoma, who received either AcellBia or MabThera as monotherapy. The authors concluded that AcellBia was noninferior to MabThera in terms of efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity. AcellBia was well tolerated, with a safety profile comparable to MabThera. The average retail price in Moscow for 500 mg AcellBia and MabThera is R 66,000 (US $1,000) and R 77,000 (US $1,200), respectively. Currently, Russian biosimilars for trastuzumab and bevacizumab, produced by BIOCAD and R-Pharm, are under clinical development.
The future of biosimilars
As we have seen in the examples here, given their complexity, there are more requirements for the approval of biosimilars than there are for generics, including the need for clinical trials. These clinical trials, however, have significantly fewer patients than the studies conducted with the original reference biologic product. Post-approval research and vigilance on the safety and effectiveness of biosimilars compared with their innovator predecessors will be clearly needed to promote confidence in these new products. It should be self-evident, however, that follow-on biologics are here to stay. We truly hope that biosimilars will improve access to cancer medications in low- and middle-income settings in the near future. We just can’t wait the centuries it took for ceramics to become affordable…