From the desk of Henry Leng
We all know that the registration of biosimilars in any jurisdiction with a competent regulatory agency is not an easy undertaking. This is because the requirements for biosimilar registration are very stringent compared to, for example, generics. Apart from submitting an extensive report on the physicochemical comparability of the candidate biosimilar against the innovator biologic, comparative nonclinical and clinical study reports are also required. This is in addition to the standard requirements of Modules 1, 2 and 3 of the Common Technical Document (CTD). In previous blogs I have argued that nonclinical and clinical studies for biosimilar registrations should not be mandatory as their only utility is to confirm biosimilarity, not safety and efficacy. Biosimilarity, as we are all aware, is demonstrated and proven at the physicochemical and biological (in vitro) levels with state-of-the-art and highly sensitive analytical and biological methods using multiple batches of both the innovator product and candidate biosimilar over the development period of the latter (usually five years). However, navigating the regulatory landscape successfully is not the only barrier that biosimilar manufacturers face to get their products to patients. A much more daunting task, particularly for biosimilars of blockbuster biologics, is overcoming the patent thickets that innovator companies create to protect their products from biosimilar competition, which is to the detriment of patients, not only in developing countries like South Africa, but even to those in the developed world.
A very recent article, published in Nature Biotechnology 1, describes how innovator companies use the US patent system to block biosimilar competition. The authors examined biosimilar-related patent infringement cases filed between 2010 and 2020 involving nine originator biologics facing biosimilar competition. They found that only 6% of patent infringement cases covered the active ingredient. This primary patent was usually filed before FDA approval of the drug. The vast majority of litigations involved secondary patents, such as for manufacturing processes (42%), methods of use (35%) and formulations (24%). Most of these patents were filed ten years after FDA approval of the originator biologic. Clearly the intention of the companies was to extend the patent life of these originator products beyond the 20 year maximum allowed for the primary patents on these products.
Another report2,published in 2018, illustrates the lengths innovator companies would go to in order to defend their products from competition. After analysing the twelve best-selling drugs in the US, the authors found that on average 125 patents are filed and 71 are granted per drug. For example, Humira®, which has been on the US market since 2002, had been issued with 132 patents that would effectively block competition from biosimilars for 39 years; Rituxin®, marketed since 1997, had 94 patents at the time, which would block competition for 47 years; and Avastin®, marketed in the US since 2004, had 86 patents, blocking competition for another 43 years. These patent thickets, as they are referred to, serve as a moat around the main patent of each drug, protecting it from competition.
The question though is whether these studies have any relevance for South Africa. In the US, as well as in Europe, all patent applications are examined for validity (novelty, utility and inventiveness). In South Africa, however, this is not the case, even though the Minister of Trade and Industry, through the release of a draft National Policy on Intellectual Property in 2013, committed to reform the patent law by fully adopting TRIPS health safeguards3, 4. By not substantively examining patents, the patent office of South Africa has granted secondary patents to pharmaceutical companies, which were refused in several other countries3, 5.
It is clear that our local patent office need to be capacitated with knowledge and skills to assess patent applications for fulfilment of patentability criteria. Furthermore, there should be collaboration with the South African Health Products Regulatory Authority (SAHPRA) as the latter can assist in determining whether manufacturing, quality control and formulation information submitted to the patent office in support of secondary patent applications, are indeed novel.
References
1. Van de Wiele VL, Beall RF, Kesselheim AS, Sarpatwari A. The characteristics of patents impacting availability of biosimilars. Nat Biotechnol. (2022); 40(1):22-25. doi:10.1038/s41587-021-01170-5
2. Overpatented, Overpriced: How Excessive Pharmaceutical Patenting is Extending Monopolies and Driving up Drug Prices (IMAK, 2018); https://www.i-mak.org/wp-content/uploads/2018/08/I-MAK-Overpatented-Overpriced-Report.pdf (downloaded 21 February 2022).
3. Patent barriers to medicine access in South Africa: A case for patent law reform. Published by Fix the Patent Laws (2016); www.fixthepatentlaws.org
4. The time to fix South Africa’s patent laws is now. https://www.fixthepatentlaws.org/the-time-to-fix-south-africas-patent-laws-is-now/ (visited on 21 February 2022).
5. Webster PC. South Africa ground zero for reforming drug patents. CMAJ. (2014);186(8):E227-E228. doi:10.1503/cmaj.109-4752