An impressive number of public actors are sponsoring and collaborate on Phase II/III trials and observational studies for the development of shorter, more effective regimens for Drug Resistant Tuberculosis (DR-TB), including the new chemical entity bedaquiline. The evidence accrued from these studies is being used by WHO to develop treatment guidelines. It will likely be used by stringent regulatory agencies to grant full registration status to bedaquiline. Despite important public investments, the accessibility of bedaquiline is a major concern for the implementation of the new WHO guidelines for DR-TB treatment and for public health strategies to tackle tuberculosis. Can public actors claim rights over their investments in and contribution to innovation?
Independent Consultant, Pharmaceuticals and Public Health – Programme & Policy Specialist
The Inability of the Patent System to Reward Innovation by Public Actors: the Bedaquiline Example
With WHO recommending bedaquiline as a priority medicine for the treatment of Drug Resistant Tuberculosis (DR-TB) in August 2018, a renovated call for access has mobilized patients, the global health community and civil society to gain access to this life-saving medicine. (1,2)
The bedaquiline story adds a new dimension to the debate of the past 20 years on the patent system and its inability to foster innovation to meet public health needs. Several commissions, working groups and processes have been established within the United Nations umbrella, yet with no tangible reform of the governance system for Research and Development. The last attempts are represented by the WHO Consultative Expert Working Group on Research and Development (CEWG) and by the UN Secretary-General’s High-Level Panel on Access to Medicines.
Bedaquiline was developed by Janssen Pharmaceuticals for the treatment of DR-TB in a stand-alone mode only up to Phase II trial level. The development of the innovator company has allowed for its ‘conditional registration’ in the USA and Europe as an add-on medicine to the toxic cocktail of old medicines in a 24-months DR-TB regimen with an efficacy of around 50%. The ‘conditional registrations’ were provided by the US FDA and the EMA based on Janssen’s Phase IIb results. Subsequently, the US FDA requested Janssen to proceed to a Phase III trial of bedaquiline as part of a new shorter less toxic regimen for DR-TB in order to proceed to a full registration of the medicine. (3) At this point in the story, an impressive amount of public actors and hence public investments come into play to trial bedaquiline as part of new shorter and more effective DR-TB regimens.
Bedaquiline is being studied in at least 8 Phase II and III trials by over 10 public actors as main sponsors (scientific organizations, state research institutions, NGOs, not-for-profit organizations, academic institutions) in over 25 countries. An uncountable number of public institutions are collaborators of the main sponsors of these trials. South Africa presents more than 12 clinical trial sites in public hospitals and TB clinics studying bedaquiline in different regimens. (4) Public actors are also conducting several observational studies in different countries, which contribute to produce evidence on the use and safety of the medicine as part of new regimens for DR-TB. The WHO recommendations on the use of bedaquiline as a priority medicine for new DR-TB regimens are based on evidence produced through the impressive mobilisation and investment by public actors. (5,6)
Janssen Pharmaceuticals holds on to its patents to maintain exclusive price control on bedaquiline as in the usual schemes of private product development and market control. (5, 7) Bedaquiline is widely patented in several middle and low income countries. The filed and granted patents include process patents, patents on the compound family, on the salt of the medicine, on the use of the medicines to treat DR TB and latent TB. Patent expiry for bedaquiline is due some time between 2023 and 2028, thereby providing Janssen with exclusive price control until patent expiry in countries. (8) The company has applied tiered pricing to bedaquiline for public health programmes since the medicine’s conditional registration. The lowest tiered price now applied by Janssen is 400 USD for six months of treatment. This is still a significantly high price for the new WHO-recommended DR-TB regimens. The medicine is available at much higher prices in the Russian Federation and in other middle income countries, making it virtually impossible for countries to implement the new WHO recommendations. (5,6) Civil society organizations and TB activists have filed a patent opposition in India to facilitate generic competition and reduced prices. (9)
There is an additional element that the global health community should consider beyond playing by the patent system. The current governance system for new health technologies largely based on the patent system fails to reward the investments made by public actors as well as to balance public financial incentives for product development. (5)
The US FDA has requested Phase II and III trials in order to proceed to the full registration of bedaquiline. The public entities involved in these trials, including the hosting countries, should request for a reward on their invested resources to the company. Hence, legal actions should not only target the shortfalls of the patent system to provide access to this life-saving medicine, but should also address in other venues a recognition of the public investments to reach full registration for an improved indication of bedaquiline.
The late involvement of public actors in the development of bedaquiline has not been framed within appropriate Public Private Partnerships (PPPs)/Product Development partnerships (PDPs), where ideally the entities taking part in product development obtain an upfront agreement on the future availability and accessibility of the medicine. Several examples show that PPPs/PDPs can be established on very weak terms in relation to pricing and access to the resulting product, hence with little reward to public investment. This approach would have additional limitations in the case of multiple public actors involved in different trials with the purpose of defining a shorter and more effective regimen, as for bedaquiline. Only one agreement is reported between Janssen and one of the trial sponsors. (3,7) The pull incentives granted by the US government for development of bedaquiline as an orphan and neglected tropical disease medicine and eventual agreements with trial sponsors did not have any impact beyond the tiered pricing applied by the company. (5) A recent systematic review intended to assess the functioning and impact of PPPs/PDPs for new health technologies for neglected tropical medicines revealed a clear lack of empirical assessment of PPPs/PDPs (10). Public funded incentives and late stage public investments for the development of shorter more effective regimens for DR-TB are failing to ensure availability and accessibility of this life-saving medicine.
The bedaquiline story once again raises the question: who rewards public investments on product development? Do public actors have the means to legally claim rights over their investment and contribution to innovation? Under which existing governance system and jurisdiction?
- Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB), World Health Organization, Geneva, August 2018. http://www.who.int/tb/publications/2018/WHO_RapidCommunicationMDRTB.pdf?ua=1
- WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update, World Health Organization, Geneva, December 2018. https://www.who.int/tb/publications/2018/WHO.2018.MDR-TB.Rx.Guidelines.prefinal.text.pdf
- Milani B, A pipeline analysis of new products for malaria, tuberculosis and neglected tropical diseases: A Working Paper, United Nations Development Programme, August 2016. http://adphealth.org/upload/resource/ADP_Pipeline_Analysis_Report.pdf
- Clinical trials data on bedaquiline Phase II and III trials were collected through: https://clinicaltrials.gov
- The price of bedaquiline, Treatment Action Group, October 2018. http://www.treatmentactiongroup.org/sites/default/files/reality_check_bedaquiline_10_16_18.pdf
- Open Letter to J&J: Calling for affordable access to critical TB drug bedaquiline, MSF Access Campaign, September 2018. https://msfaccess.org/open-letter-jj-calling-affordable-access-critical-tb-drug-bedaquiline
- A review of the bedaquiline patent landscape, Unitaid, 2014. http://unitaid.org/assets/TMC_207_Patent_Landscape.pdf
- Updated patent landscape for bedaquiline available MedsPaL: https://www.medspal.org/?product_standardized_name%5B%5D=Bedaquiline+100+mg&page=1
- TB activists for first time challenge TB drug patent in India, in bid to prevent J&J from extending monopoly, Press release, MSF, February 2019 https://msfaccess.org/tb-activists-first-time-challenge-tb-drug-patent-india
- Aerts C, Sunyoto T, Tediosi F, Sicuri E. Are public-private partnerships the solution to tackle neglected tropical diseases? A systematic review of the literature. Health Policy. 2017 Jul;121(7):745-754. doi: 10.1016/j.healthpol.2017.05.005. Epub 2017 May 19.