Access To Affordable Biologics In The Context Of COVID-19: Will WHO Step Up To Its Responsibility? Inside View 14/04/2020 • Chetali Rao & K M Gopakumar Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to print (Opens in new window) A common cause of death from COVID-19 is through a cytokine storm. Cytokines are chemical messengers released by the immune system. New Delhi, India – COVID-19 has posed unique challenges for healthcare providers across the globe, as the world has been grappling with the pandemic with no approved treatments or vaccines for the disease. Researchers are searching everywhere for drugs that may help treat or prevent the spread of the deadly virus. This has led to the assessment of a large number of already commercialized antiviral drugs, as well as new small molecule compounds currently in research and development. And as R&D advances, ensuring wide, equitable access to such drugs has also been thrust to the forefront of health policy debates, including frequent references to this pressing need by WHO’s Director-General Dr Tedros Adhanom Ghebreyesus, and his senior management. Yet the robust biologic pipeline of candidates to treat COVID-19 or its symptoms – and the special role these drugs could play in the COVID-19 battle, has received far less attention. And should these prove effective, stiff barriers exist for the development of COVID-19 biosimilar compounds – beginning with WHO’s own guideline policies. In fact, access to potentially life-saving biosimilar products at an affordable price will remain a distant dream, unless WHO updates its Guidelines for the Evaluation of Similar Biotherapeutic Products (SBPs). Biologics with Potential to Treat COVID-19 So far, the drugs with the greatest potential include those aimed at host targets, such as interleukin-6 (IL-6) receptor inhibitors. Apart from this, many researchers and pharmaceutical companies are working to develop monoclonal antibody-based treatments. In terms of IL-6, recent preliminary data on COVID-19 patients from China reported high plasma levels of cytokines, including IL-6, that are related to the severity and the prognosis of the disease with a clear implication for the occurrence of the deadly “cytokine storm” or Cytokine Release Syndrome (CRS). Anti-IL-1 and anti-IL-6 drugs may therefore interfere with this cytokine storm, thus helping to reduce lung inflammation and improve lung function in severe cases of COVID-19 patients. Roche’s biotherapeutic Actemra, commonly known as tocilizumab, is an anti-IL-6 receptor antibody that has been used clinically to treat rheumatoid arthritis and other autoimmune diseases. Since its approval a decade ago, it has become the go-to drug against inflammatory conditions, including cytokine storms in cancer patients receiving cell therapies, and it has also been approved for the treatment of a variety of clinical conditions that include CRS. A small cohort study in China has suggested that tocilizumab effectively improved clinical symptoms and repressed the deterioration of severe COVID-19 patients. According to reports, a 3-month clinical trial with tocilizumab has been registered in China, that has recruited 188 coronavirus patients, and will take place from February 10 to May 10, 2020. Malaysia will begin a 6-month clinical trial involving about 300 COVID-19 patients starting in mid-April. Furthermore, Roche has also confirmed that it will expedite the trials of the drug to determine its effectiveness in COVID-19 patients. Another biologics drug, Kevzara (Sarilumab) jointly developed by Regeneron and Sanofi, also inhibits the IL-6 pathway and clinical trials have been initiated for the treatment of patients with COVID-19. This U.S.-based trial will begin at medical centres in New York, one of the epicenters of the U.S. COVID-19 outbreak. The multi-centre, double-blind, Phase 2/3 trial has an adaptive design with two parts and is anticipated to enrol up to 400 patients. Even though these biologic medicines hold promising avenues for the treatment of severe diseases, offering new hope for patients, the real question is how many people will really be able to access this class of drugs. With an estimated cost of infusions per patient per year between US$ 20,000 and US$ 30,000 for rheumatoid arthritis (RA) treatment, the U.S. was the drug’s biggest market, and Americans spent about US$ 620 million on tocilizumab prescriptions. This high price of tocilizumab already excludes it as a viable option for RA treatment in many low and middle-income countries. Introducing non-originator versions is the best way to reduce the price and enhance the supply. Unfortunately, this is not possible due to the high regulatory barriers to introduce the non-originator versions of biotherapeutics (biosimilars), which are in fact established by the WHO. IL-6 inhibitors like Tocilizumab can dampen cytokine storm in patients with severe COVID-19. WHO Guidelines On Biosimilar Approvals – Requiring New Phase 3 Comparative Trials According to WHO’s own guidelines on biosimilar drug development, which date to 2009, regulatory approval for biosimilars requires developers to launch comparative Phase 3 Comparative Clinical Trials (CCTs) – a costly and time-consuming requirement that does not exist for generic versions of small molecules. Nearly 50% of the development cost of a biosimilar is to purchase the originator version for the comparative clinical trials. This regulatory barrier virtually eliminates the competition even in the absence of patent protection. WHO is the main influential agency that has created these entry barriers; its own SBP guidelines make Phase 3 clinical trials a rule of thumb for biosimilar approval. Against these guidelines, the discretionary powers of national and regional regulatory authorities to approve biosimilars without Phase 3 trials remains very limited. For instance, one of the conditions set down by the WHO guidelines for waiving Phase 3 trials of biosimilars is that the drug under review possess at least one identical pharmacodynamic (PD) marker, which is a marker linked to efficacy (e.g. an accepted surrogate marker for efficacy). In many cases, PD markers for efficacy do not exist, and hence biosimilar manufacturers are forced to carry out CCTs. Thus, WHO’s SBP Guidelines from 2009 have even delegitimised the diverse regulatory pathways that previously existed in many countries for approval of biosimilars. Looking at the progress of scientific knowledge, technical advancements, accumulation of experience in the field and fast-expanding national regulatory needs and capacities, voices have been repeatedly raised, including those from the scientific field, to increase access and affordability of biosimilar products across the globe. Life-saving biologics need to be affordable to the burgeoning population of people who can be successfully treated with these drugs. Last year a group of scientists wrote to WHO demanding a review of its SBP Guidelines, and elimination of Phase III Comparative Clinical Trials. The letter noted that advancement in analytical techniques enables the biosimilar developer to capture the molecule structure of the originator drug very accurately, and the structural similarity of the biosimilar is thus reflected in its therapeutic efficacy. Requirements for CCTs should be replaced by requirements for detailed structural characterisation as part of the WHO guidelines, the scientists stated. The demonstration of similarity in quality is sufficient to assure the safety and efficacy of most products. Emphasis on further testing should focus on quality-assurance, e.g. drug impurity profiles and potency. Further, the safety concerns should be addressed through in vitro studies. According to the scientists, carrying out Phase 3 trials in around 300 to 500 clinical subjects does not reveal any difference between similar products. As Francois-Xavier Frapaise, one scientist in the field, stated in his paper: “Clinical trials are not powered to detect meaningful differences in the safety profiles of biosimilars, and when numerical imbalances in adverse events are observed during clinical development of a biosimilar, the interpretation of limited differences is very difficult; only large cohort studies may detect differences, if there are any, in safety parameters.” Even so, WHO has consistently opposed changes to its SBP Guidelines. Already in 2014, a World Health Assembly Resolution asked then-WHO Director-General Margaret Chan “to convene the WHO Expert Committee on Biological Standardization to update the 2009 Guidelines”. But the Expert Committee in its subsequent meeting, refrained from any revisions, rejecting the decision of its highest decision-making body without citing any reason. Once again, in October 2019, WHO’s Expert Committee on Biological Standardisation (ECBS) declined a request to revise the SBP Guidelines without citing any reason. The Chair summary simply states: “Chair of the Committee communicated the conclusions of the Committee to the WHO Assistant Director-General MVP (Access to Medicines, Vaccines and Pharmaceuticals) who said that WHO will evaluate current scientific evidence to support the updating of the 2009 Guidelines”. The summary failed to provide any scientific rationale for its decision. And since then, there has been absolute silence from WHO regarding the promised science review. This stonewalling also generates doubts about whether such a review, whenever it is finally carried out, will be undertaken in a transparent manner and free of conflict of interest. WHO’s reluctance to update its SBP Guidelines has effectually created a wall blocking access to generic versions of many important and expensive biologics medicines such as tocilizumab, and has inadvertently nudged COVID-19 patients to face the deadly cytokine storms without such drug treatments. Will the organisation with a mandate to safeguard public health show greater accountability and transparency about biologics in this moment of a global pandemic? _______________________________________ Chetali Rao is a lawyer specializing in patent, access to medicines and health issues. K M Gopakumar works as Legal Advisor for the Third World Network (TWN). Both authors are based in New Delhi. Image Credits: Scientific Animations, University of Science and Technology of China, Chetali Rao, K.M Gopalkumar. 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