Legal Aspect of Remdesivir and Crisis of Remdesivir in India

Written by Tanya Kukade [i] and Mr Sanjay Kumar [ii]

[i] Final year student, Symbiosis Law School, Pune

[ii] Ex Partner KSK Advocates


Source: Business Standard


Disclaimer: Please note that the views expressed below represent the opinions of the article's author. The following does not necessarily represent the views of Law & Order.


In this article the authors will discuss the origin and development of Remdesivir and analyze its licensing, regulatory approval, price control and applicable laws in view of COVID-19 crisis in India.


Regulatory Approval for Manufacturing & Marketing of Remdesivir


Veklury/Remdesivir has been approved or authorized for temporary use as a COVID-19 treatment in approximately 50 countries worldwide. In the United States, the Food and Drug Administration (FDA) approved Veklury on October 22, 2020 for the treatment of adults and paediatric patients in emergency cases under an Emergency Use Authorization (EUA).


In India, DCGI too granted Gilead marketing authorisation for ‘restricted emergency use’ vide notice dated 1st June 2020 via an accelerated process in light of the emergency situation in our country upon taking an import license from CDSCO. It is to be used as an investigational therapy for COVID 19 patients in accordance with the Clinical Management Protocol issued by MoHFW due to the lack of sufficient data pertaining to its efficacy and reliability.[1] Upon which CDSCO has permitted the manufacture and market of the drug by M/s. Cipla, M/s, Hetro and M/s. Mylan Lab.

Both Remdisivir and Favipiravir formulations are required to be sold under the prescription of medical specialists only.

Further, Remdisivir formulations are required to be supplied for use only to the hospital / institutions to ensure proper use of the drug as recommended. In both the cases, informed consent of the patient or his /her representative in the prescribed form is mandatory before initiating the treatment.

Subsequently, on 2nd July 2020 DCGI issued a notice taking cognizance of sale of Remdesivir above MRP and asked states to keep a vigil in this practise.[2] This drug has still not been approved (market authorization) by the US FDA where like India it continues only under an Emergency Use Authorization.[3] CDSCO has waived off the requirement of local clinical trials for these companies by invoking emergency provisions under the New Drugs and Clinical Trial Rules, 2019.


Price Control by National Pharmaceutical Pricing Authority (NPPA)


NPPA and DCGI are the organisations monitoring prices of the drug and Indian Council of Medical Research (ICMR) has proposed a price cap for remdesivir. Both remdesivir and favipiravir have seen a sharp decline in price since the availability of the first generic in India.[4]


In light of the wide variation in pricing of Remdesivir by various companies, NPPA vide office memorandum dated 17th April 2021 revised and capped the Maximum Retail Prices (MRP) for 7 brands of Remdesivir injections in order to ensure availability and affordability of the injection to the public.[5]

The said action may be justified under Para 19 of DPCO which allows fixing of prices of drugs which are of public interest.


Innovation and Development of Remdesivir


Veklury(“Remdesivir”)(GS-5734), a pre-existing drug candidate developed by Gilead Sciences in collaboration with the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), as part of an antiviral development effort. Remdesivir was innovated by Gilead is an investigational nucleotide analog with broad-spectrum antiviral activity both in vitro and in vivo in animal models against multiple emerging viral pathogens, including Ebola, Marburg, MERS and SARS. The in vitro testing conducted by Gilead demonstrated that Remdesivir was active against the virus that causes COVID-19. The pharmacokinetics of Remdesivir was documented by the European Medicines Agency (EMA) in 2020.


Clinical Trials


Positive and promising data from post Phase 1 and Phase 2 clinical trials. Gilead completed Phase 3 trials in April 2020 on Remdesivir. The specific object of this study was to determine the duration of treatment of patients with the drug was compared in order to achieve efficacy while observing the rates of adverse events that may be reported during the trials. Gilead initiated two randomized, open-label, multi-centre Phase 3 clinical trials for Remdesivir, the SIMPLE studies, in countries with high prevalence of COVID-19 infection.


A large simple trial is a medical trial that involves a very large number of patients, typically over 1,000 participants.It is randomized clinical trial ideally to answer important clinical questions and answers questions in a broader patient population and it has a large sample size and statistical power to detect clinically relevant treatment effects, providing unambiguous results and minimizing the effects of random errors.


The Phase 3 data revealed that, the time for clinical improvement for 50 percent of patients was 10 days in the 5-day treatment group and 11 days in the 10-day treatment group. More than half of patients in both treatment groups were discharged from the hospital by Day 14.

The study is being conducted at 180 trial sites around the world, including sites in the United States, China, France, Germany, Hong Kong, Italy, Japan, Korea, the Netherlands, Singapore, Spain, Sweden, Switzerland, Taiwan and the United Kingdom.


Patent Position


Gilead has filed 5 patent applications in India, 4 molecule patents have been granted by the Patent office while 1 remains under examination.


Voluntary Licensing Agreements for Remdesivir


In light of the growing demand for the drug, and the shortage experienced in countries with rising COVID-19 cases, Gilead has signed non-exclusive voluntary licensing agreements with generic pharmaceutical manufacturers based in Egypt, India and Pakistan to further expand supply of remdesivir. The agreements allow the companies – Cipla Ltd.; Dr. Reddy's Laboratories Ltd.; Eva Pharma; Ferozsons Laboratories; Hetero Labs Ltd.; Jubilant Lifesciences; Mylan; Syngene, a Biocon company; and Zydus Cadila Healthcare Ltd. to manufacture remdesivir for distribution in 127 countries.[6]


Under the licensing agreements, the companies have a right to receive a technology transfer of the Gilead manufacturing process for remdesivir to enable them to scale up production more quickly. The licensees allow the companies to set their own prices for the generic product they produce.

The licenses are royalty-free until the World Health Organization declares the end of the Public Health Emergency of International Concern regarding COVID-19, or until a pharmaceutical product other than remdesivir or a vaccine is approved to treat or prevent COVID-19.

Thus, such agreements are voluntary and bearing no consideration for Gilead in the process.


Current crisis of availability and supply of Remdesivir


It has come to be regulated after more than a year in light of reports of stocking and black marketing of the drug which is commonly resorted to in cases of severe infection of COVID-19. In light of the shortage, it is alleged to have been hoarded and black marketed in our country. Prices of the drug have shot up to Rs.38000 for a vial in the black market as reported. In light of which a need for regulation was felt by the Government.[7]


Action taken by DCGI


Upon receiving a letter from M/s. Local Circles through MoHFW, raising concerns regarding black marketing and over pricing of Remdesivir, DCGI vide notice dated 06.07.2020 instructed enforcement officials to keep strict vigil on the matter and prevent such activities. Followed by the notification dated 07.04.2021 wherein MoHFW reported a shortage in supply of the drug in a few states predicting hoarding and black marketing of the same, asking the States to undertake remedial measures to ensure supply of drug is not hampered.[8]

Subsequently, on 10.04.2021 DCGI notified enforcement activities to stop hoarding/black marketing/ overcharging of the Drug to all states and Union Territories.[9]

High courts (HC) on availability of Remdesivir


Recently, the Bombay HC has suggested the Centre to include Remdesivir in the list of scheduled drugs and to regulate its pricing. While regulation of prices of drugs is covered under the Drugs Price Control Act, (DPCO) for scheduled drugs, Remdesivir failed to fulfil this requirement. The Courts highlighted that the provisions of the Drugs and Cosmetics Act, 1940 as well as the DPCA enable the Central Government to issue a notification to fix rates of essential drugs during a calamity.


The Court lashed out at Maharashtra government for not having a proper mechanism to procure and distribute Remdesivir across the State while directing it to exercise its powers under the Disaster Management Act and Epidemic Diseases Act to centralise the purchase of all COVID- 19 related medications to save time. The delays were caused due to the private purchase of the drug and the same required central allocation and distribution.


Conclusion


All new drugs proposed in India have to undergo trials before getting approval for marketing. The New Drug and Clinical Trial Rules, 2019, provide for certain provisions of waiver of Phase-III clinical trials of the drug if it is approved and marketed in certain countries in light of the pandemic and for public interest.


Efforts are being taken by the regulatory authorities as well as the State governments to scale-up the manufacturing of the drug in addition to ensuring measures for optimum supply of the drug and actions being taken against hoarding and black marketing to prevent deprivation of the public from having access to the life-saving drug by ensuring continuous vigil is maintained on the supply chain and distribution.


Use of Remdesivir is not a conclusive treatment for COVID-19 as also notified by WHO[10] although it is the most promising one. Gilead has notified the users of further studies to be conducted by the company and the other contenders undertaking trials of various drugs in regard to the virus and there still is scope for the introduction of new and effective drugs in our country to sail through this pandemic.


[1] Clinical Management Protocol: Covid-19, issued by Ministry of Health and Family Welfare, https://www.mohfw.gov.in/pdf/UpdatedClinicalManagementProtocolforCOVID19dated03072020.pdf

[2]https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=NjIxMw== [3] Status of Remdesivir, update posted by the Ministry of Health and Family Welfare, dated 14.06.2020, https://pib.gov.in/PressReleasePage.aspx?PRID=1631509 [4] https://www.europeanpharmaceuticalreview.com/news/125380/prices-of-remdesivir-and-favipiravir-being-monitored-in-india-says-report/ [5] File No. 37008/2021/Div.VI/NPPA, Office Memorandum dated 17th April 2021. [6] https://www.gilead.com/purpose/advancing-global-health/covid-19/voluntary-licensing-agreements-for-remdesivir [7] https://www.newindianexpress.com/states/andhra-pradesh/2021/apr/29/remdesivir-priced-at-rs-38k-a-vial-in-black-market-2296288.html [8] Notification 273/2020-3 dated 07.04.2021, https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=NzExMg== [9] Notification dated 10.04.2021, https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=NzExMw== [10] https://www.who.int/news-room/feature-stories/detail/who-recommends-against-the-use-of-remdesivir-in-covid-19-patients

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