TWN Info Service on Health Issues (Oct21/14)
19 October 2021
Third World Network

Intellectual Property Monopolies Perpetuate Inequitable Access to COVID-19 Therapeutics

London, 19 October (Sangeeta Shashikant): Shortages and high prices are hindering access to therapeutics in developing countries, say experts participating in a webinar on access barriers to COVID-19 therapeutics and diagnostics organized by the People's Health Movement and Third World Network on 6 October.

They underscored the importance of therapeutics and diagnostics in the fight against COVID-19, for treating the unvaccinated, for breakthrough infections, to counter new variants that are resistant to vaccines, and especially due to the vast inequality in access to vaccines as well as in the context of “test and treat strategy”.

The experts expressed serious concern that mistakes contributing to the staggering inequity in vaccine and diagnostic access are being repeated in therapeutics. Voluntary licenses where granted, are restricted to a few manufacturers, while excluding supply to many developing countries that are suffering from the effects of COVID-19.

Supply constraints can be unlocked, if generic manufacturers in developing countries are engaged, by addressing the legal barrier of intellectual property, argued the experts, stressing the positive role a TRIPS waiver could play in this regard. With more suppliers in the market, affordability would also increase as prices drop with an increase in competition.

The panel of experts included Christa Cepuch, pharmacist coordinator for Médecins Sans Frontières (MSF) Access Campaign, Michelle Childs, the director of policy and advocacy of Drugs for Neglected Diseases initiative (DNDi), and Reshma Ramachandran, a physician and fellow at the Yale University national clinician scholars’ program.

In recent months WHO has recommended several therapeutics for treating patients affected with COVID-19. On 6 July, WHO recommended IL-6 receptor blockers (tocilizumab or sarilumab) for patients with severe or critical COVID-19 infection.

Even before this recommendation, many developing countries such as Kenya, Jamaica, India and South Africa have struggled with affordable access to tocilizumab.  In South Africa despite an expert panel finding that tocilizumab reduced deaths, the recommendation was for the drug to not be used because it is “not affordable at the current offered price”.  At the cost of around $2000 per patient, this life-saving therapy is largely out of reach for African populations, according to WHO’s regional director for Africa, Matshidiso Moeti.

WHO has also issued a non-conditional recommendation for the use of a combination of neutralizing monoclonal antibodies (casirivimab and imdevimab) in non-severe COVID-19 patients at the highest risk of severe disease and in severe and critically ill COVID-19 patients with seronegative status.

In its 24 September statement, WHO also called for equitable access and “urges producing companies and governments to address the high price and limited production of the Regeneron antibody combination”.

Meanwhile, news reports on Merck’s molnupiravir have raised hopes that this medicine will offer an outpatient antiviral therapy for newly diagnosed cases of COVID-19, curtailing its spread. At the same time there is apprehension that Merck’s intellectual property monopolies will affect affordable access globally.

Expert Panel

Christa Cepuch highlighted that MSF had engaged with Roche (manufacturer and patent holder) to try and procure 6000 vials of tocilizumab forecasted to be needed for 3 months in its projects, but have “hit a dead-end”.

“Roche has said from the beginning, that they would never be able to meet the demand that would come with COVID, and they say that they're facing a global stockout, but we don't hear any high-income countries really complaining, so we know where the shortages lie, and that is with countries in, you know, low- and middle-income countries [LMICs] and low resource settings where there's really very little access to tocilizumab”, said Cepuch stressing on the struggle to procure tocilizumab in India. 

“Roche is allocating on a six-week basis to avoid hoarding, but they say that the future allocation framework will be better, but we don't have any visibility on that”.

On the patent landscape, Cepuch explained that primary patents expired in 2017, but secondary patents have been filed. 

Roche has announced that they would not assert their patent rights in LMICs but this leaves out key manufacturing countries such as South Korea. “We have asked them to not assert their patent rights anywhere but they have not responded to that request”, Cepuch said.

[Hetero, an India-based company has obtained approval from India’s drug regulator to launch a biosimilar version of tocilizumab.]

“The price per dose, historically for rheumatoid arthritis indications, is anywhere from USD 600 to over USD 3,000 per dose,” Cepuch said.  For instance, the price of tocilizumab is very high in most countries, ranging from USD 410 in Australia, USD 646 in India to USD 3,625 in the USA per dose of 600mg for COVID-19.

Cepuch however added that “studies have been done on monoclonal antibodies in general, would estimate that with large scale production, you could get cost of production to USD 60 per dose of 600 milligrams”. Manufacturing costs of monoclonal antibodies are often below USD 100 per gram when produced on a large-scale.

Cepuch also shared that Roche had agreed to assist WHO’s ACT-A in countries where tocilizumab is not registered, but “apparently there are only few vials from Roche for these 58 plus countries and island states” (i.e. 4500 vials to be distributed among 58 plus countries). Cepuch added that the “price per vial is still not confirmed or public” and “it's done through bilateral negotiations with Roche and the ACT-A consortium”.

On casirivimab and imdevimab, Cepuch said, “We have poor visibility on the manufacture from Regeneron…there's really no clarity on…procurement channels...or how allocation would be done and…there's not yet any indication of biosimilars under development.”

Cepuch said the “situation is that most doses, three million so far, have been bought up by just a few countries…USA has bought up already three million doses, about USD 2000 per treatment. This is not data specifically from Regeneron but just through media reports, again not in a very transparent process.” 

Cepuch also pointed to access challenges for potential new treatments (yet to be recommended by WHO).

For instance, baricitinib has been granted Emergency Use Approval (EUA) by several jurisdictions. According to an MSF blog, “A recently published trial (COV-BARRIER) showed that baricitinib — even when used without remdesivir — is associated with a 40% decrease in the risk of death among severe cases, meaning that one death can be prevented for every 20 patients treated with baricitinib. These new results led to a July 2021 update in the EUA by the US Food and Drug Administration, now allowing the drug to be used without remdesivir and thus making it simpler to treat patients”.

Eli Lilly holds patent or pending patents which expire in 2029 in many countries that have been hit hard by the pandemic and this could be extended in countries with patent-term extension. It is also patented in India.

Cepuch explained that Eli Lilly has granted a voluntary licence to Indian generic companies to produce the drug locally; this means that generics cannot be exported to other countries where it is also needed if these countries are not included in the licence, which is obviously a big barrier. The generic price is also significantly much lower in India at USD 0.54 per tablet versus Eli Lilly’s price of USD 44 per tablet. Bangladesh is also an important source of generics for baricitinib.

With respect to molnupiravir, Cepuch said it could be interesting for “test and treat strategies, so this is where the importance of the access to diagnostics as well comes in very importantly”.

Merck has granted a non-exclusive voluntary license to eight Indian generic companies for supply to 100 LMICs. However patent applications are pending in many developing countries that are excluded from being supplied under the VL (e.g. Brazil, South Africa). Merck’s patent application is also opposed in India.

[According to Brook Baker, Senior Policy Analyst at Health GAP, “Middle-income countries excluded from the license had 30 million infections in the first half of 2021, and 50% of all infections in LMICs.  Even if the eight Indian generics make it to market and can satisfy this demand in licensed territories, Merck will be unable to meet the remaining 70% of global need”.]

Cepuch pointed to how molnupiravir supply is being snapped up at high prices, a “great example of pandemic profiteering”.  She said that the US FDA has procured three million treatment courses of the Merck product at about USD 700 for a five-day treatment, while studies show that the cost of production is about USD 20 with a 10% profit margin, while Indian generic companies (not part of Merck’s VL) that are planning to launch at risk are expected to price it at USD 13, according to media reports.

Leena Menghaney, also from the MSF Access Campaign contributed to the discussion, arguing that to fight infectious diseases simply by going down the route of prevention is insufficient; treatment also has to be prioritized.  Hence the TRIPS waiver should extend to therapeutics for currently, there are a lot of IP barriers coming to the forefront.

Responding to a glowing New York Times feature on monulpiravir’s VL, Menghaney said it was “a really inferior piece of reporting”, explaining that monulpravir is being developed because Indian companies have started to be reassured that the Indian government is serious about not enforcing intellectual property. She also pointed to the fact that the VL is extended to cover territories where there are no patent barriers, and where there are patent barriers there are no licenses. “So, I think really the voluntary license needs much more shredding apart than we have done”.  

On TRIPS flexibilities, Cepuch argued that with patent opposition “there's always a risk of failure, it takes a long time and a lot of technical and financial resources” (as oppositions have to be done application by application in each country).    

She stressed that VLs “that we have seen now … just continue to feed into the monopoly situation; it excludes producers and other manufacturing countries, where they already have manufacturers that are ready and capable to produce these types of medicines”.

“The TRIPS waiver obviously would allow countries to export and import generics without any fear of state-to-state dispute settlements or infringement claims regarding pending patent applications, new patent applications and other IP,” Cepuch said. She emphasized that while compulsory license is also an option, again though it is country by country and sometimes it is difficult to assess pending applications and what is incoming as well.

Michelle Childs referred to DNDi’s policy report titled “Another Triumph for Science But Defeat for Access” referring to positive lessons from COVID-19’s “big global response and there's been a lot of funding which has enabled major scientific progress, and we have seen the rapid development of vaccines and some diagnostics, and that has the potential to transform just not COVID but also other infectious diseases.”

However, Childs added, “We have accelerated to the status quo, which we're calling in the report the unfinished business in global health of ensuring equitable access. And this is in relation to the vaccine apartheid that we are seeing and also lack of access to diagnostics for a variety of reasons, and we want to see if we can avoid that, in relation to therapeutics”.  

Childs stressed that “we need therapeutics for all stages of COVID, not just because of the lack of access to vaccines, but also for those people who can't, or won't take vaccines, and also for the possibility of vaccine evading mutations.”  She said that “there is a particular need to look at developing therapeutics for people with mild to moderate COVID, particularly in countries or regions which have very limited intensive care units, because you want to try to avoid the disease progression, and therefore having them to be hospitalized”.  

On the hopeful interest in Merck’s monulpiravir, Childs expressed caution that “we don't enter into science by press release, and we need to see the details” adding generally that there still remains “insufficient political and financial attention paid to therapeutic research … research is still fragmented and it's focused primarily on high income countries, and even the Merck drug is really focused on a limited subset of people.”

She further said that “ACT-A has really not yet been able to really focus on some of the  IP barriers and … it's unclear if treatments which are developed will be affordable and more importantly that there will be sufficient supply” adding that “COVID-19 tools should be developed as far as possible as global public goods, because we have seen as DNDi that IP can act as a barrier to development and to access”.

Childs also said that “when you're looking at the treatments, you have to ask yourselves: will they be developed for, and fitted for, remote and resource limited settings. Although the Merck drug is interesting, it is predicated on the fact that you will be able to have rapid diagnostic tests, and get people on treatment within five days. And that may not be possible in a number of resource limited settings, which means that you are going to be looking to need probably a combination of drugs, which may be an antiviral and maybe an immune suppressing drug, and the problem with that is that traditionally, companies have been unwilling to spontaneously collaborate, to share their drugs, to test them in combination, and we've seen that both in HIV and in hepatitis, where combination drugs were needed. So there's a real question about whether IP or other barriers would stop the ability for combinations to be tested and developed.”

“Test and treat is working on the basis that you have access to rapid diagnostic tests, and we are seeing already that there is a huge disparity between the availability and use of rapid diagnostic tests”, she said, adding that the are variety of reasons for that including IP.

She also expressed concerns that VLs “tend to exclude the same countries, particularly middle-income countries, who have the ability also to manufacture and help themselves. So we really need to find a way to ensure that there is access for those countries.”  

Childs highlighted three ways to course-correct to address the challenge of access:

1.      Governments, particularly those that fund R&D, should use their leverage to negotiate clear and transparent terms and conditions that ensure sharing of research data, knowledge, and technology on a non-exclusive basis, enabling adequate production scale-up to ensure sufficient supply, equitable allocation, and affordability.

2.      Governments should support a temporary (TRIPS) waiver on IP for COVID-19 technologies, which would support increased access to such technologies globally by removing any risk of IP infringement for all stakeholders. A waiver must cover all forms of IP (not only patents) and apply not only to vaccines but also to all COVID-19 medical technologies, including therapeutics and diagnostics. 

3.      Companies owning COVID-19 technologies also need to increase their contributions and commit to either not enforcing their existing IP or to sharing relevant know-how, technology, and IP by non-exclusively licensing it to interested entities.

Specifically on the TRIPS waiver, she called on governments to support a waiver not just for vaccines but also therapeutics, diagnostics and all of the health tools adding “it’s not unsurprising that South Africa and India, countries that have had experience of dealing with infectious diseases put forward this proposal, because they recognize that with any infectious disease you need to have all of these tools”.

She further emphasized the importance that the waiver covers “the ability to ensure combinations” and that “depending on the technology, IP waiver may be the thing that is needed.  This is “to ensure that you can have scale-up. Because there are a number of companies which we've seen with antivirals, that may not need technology transfer, but may be actually intimidated about scaling up because of the fear of legal repercussions, because of the monopolies from IP …  it's important that governments have all of the tools that they need in order to be able to lift these barriers”.

Childs also described DNDi’s initiative “Moonshot” a spontaneous international collaboration of open science to develop antivirals for global equitable access. This initiative crowd-sourced ideas for molecular compounds from over 150 scientists globally which are available in the public domain.

She said that “because of necessity, they wanted to move quickly and they wouldn't have time to negotiate all of the agreements and to lift any intellectual property barriers so they agreed to work together in an open science approach but they have now agreed, as a central part of this project, that they want to see if they can develop a new antiviral which is going to be IP free, so that it could be direct to generic from the start, and ensuring that it can be equitably and affordably available as a global public good”.

“This involves a number of institutions from countries that are blocking the waiver and from countries all over the world. And it shows that there is a clear role for research institutes, but also funders, both public and private to support ways in which you can remove IP barriers, and to develop and to ensure treatments that can be global public goods”, Childs added.

In her presentation, Reshma Ramachandran, a physician and fellow at the Yale University national clinician scholars’ programme, reinforced the importance of therapeutics and diagnostics to be a critical part of building an arsenal against COVID-19 from a clinical perspective. She stressed the key role of therapeutics in the US for patients who are unvaccinated, under-vaccinated populations that are immunocompromised as well as for the continued concern with effectiveness of vaccines due to emergence of variants and global inequities in access. 

She emphasized the extensive public investment by the US in diagnostics and therapeutics. In October 2020, nearly USD3 billion was allocated for COVID-19 therapeutics just through Operation Warp Speed. The National Institutes of Health (NIH) have set up the Rapid Acceleration of Diagnostics (RADx) and the Acceleration COVID-19 Therapeutic Interventions and Vaccines (ACTIV), investing personnel, financial and other resources in the R&D of therapeutics and diagnostics. The US FDA has also engaged in the development process by allocating resources and personnel towards hastening the review of these different products, through their own Coronavirus Treatment Acceleration Program (CTAP) program.

Ramachandran showed that across various therapeutics authorized by the US FDA – tocilizumab, sotrovimab, bamlanivimab and etesevimab, casirivimab and imdevimab (REGEN-COV), baricitinib (Olumiant), remdesivir (Veklury), the US government has provided  significant amounts of public funding from Operation Warp Speed, NIH, Biomedical Advanced Research and Development Authority (BARDA) and Defense Advanced Research Projects Agency (DARPA).

She added that molnupiravir was initially discovered at Emory University through significant NIH funding, before being licensed to a non-profit organization within the university called the Drug Innovation Ventures (DRIVE) in 2017 and that these initial grants were again funded through the NIH and another government agency, called the Defense Threat Reduction Agency.

An exclusive licensing agreement was then signed with Ridgeback Biotherapeutics based in Florida which subsequently gave exclusive rights to Merck. The “US government does have claim over a number of the key patents underlying this drug as well”, Ramachandran said.  

In terms of monoclonal antibodies, apart from shortages seen by MSF and in other countries, there are also shortages of different types of monoclonal antibodies announced by the US FDA, she added.

“We have been seeing continued supply shortages, including in high income countries, remdesivir for instance, last summer…and currently we're seeing this with monoclonal antibodies so the idea of the TRIPS waiver is being an effective tool to overcome these supply shortages”, Ramachandran said, and “we do need to make sure that there is going to be an equitable and adequate supply for countries worldwide, and that low income countries in particular, are not pushed into the back of the line as we've seen with vaccines”.

She stressed that the “TRIPS waiver can play a crucial role in terms of not only opening up supply, but also ensuring affordability and accessibility for countries worldwide,” adding that the waiver can help to remove the chilling effect of actually doing comparator trials, and also to overcome procuring a very costly branded comparator.

Ramachandran said that “doses are charity but knowledge is definitely justice, and so we need mechanisms like the TRIPS waiver to ensure equitable access to the doses now but also for enabling adequate supply through expanding global manufacturing in the future as well”.+