The fact of the matter
We read a recent opinion article titled, “An opaque model of drug approval”, in The Telegraph with interest. We respectfully disagree with the author, and appreciate the opportunity to correct the factual inaccuracies with evidence.
Itolizumab was first approved by the Drugs Controller General of India for the treatment of patients with active moderate to severe chronic plaque Psoriasis in 2013 based on “double-blind, randomized, placebo-controlled, Phase III study”. The safety and efficacy of the drug was published in globally reputed, peer-reviewed journals and in proceedings (Journal of the American Academy of Dermatology, and the 6th annual European Antibody Congress, respectively).
Global regulatory bodies such as the US-FDA, EMA and WHO each has procedures that allow for the emergency use of medicines. FDA’s emergency use authorization allows for previously approved and unapproved products to be used in situations where “there are no adequate, approved, and available alternatives”. Similarly, EMA allows for the conditional approval of products based on limited data in emergency situations. India’s equivalent for Emergency Restricted Use is as per Sec. 26B of the Drugs and Cosmetics Act, 1940 (23 of 1940). The DCGI has approved other drugs to treat Covid-19-related illness under the same process, such as Remdesivir and Favipiravir.
The approval under this category comes with restrictions, including the requirement of written informed consent of each patient before the use of this drug, and the requirement of an additional larger prospective clinical trial, thereby putting patient safety first. Contrary to the author’s claim that “waiver of Phase III clinical trials is unheard of even during public health emergencies”, in 2018 “the US-FDA granted one out of eight approvals with only Phase 1 or Phase 2 alone.” Those that have experience in the global regulatory process know that the regulators always put patient safety first followed by prioritizing saving life by making risk-benefit estimates in the drug approval decision process. The DCGI also adopted the global process by considering the overall safety of the drug, observing the safety and efficacy in a controlled trial, and on the basis of the recommendation of the Subject Expert Committee.
Among the causes of death in patients with Covid-19 is Acute Respiratory Distress Syndrome. ARDS occurs due to an acute systemic inflammatory response, or hyper-activation of T-cells causing massive release of cytokines. Itolizumab, an anti-CD6 humanized IgG1mAb, acts upstream on target cells, resulting in potent anti-inflammatory effect, and reducing the production of cytokines. By effectively controlling hyper-activation of the immune system, Itolizumab prevents morbidity and mortality related to a cytokine storm. Its mechanism of action is identical between Psoriasis (approved based on Phase III trials) and Cytokine Release Syndrome in Covid-19. Therefore, an additional Phase III trial in Covid-19 is redundant. We intended to add further clinical evidence of safety and efficacy for the treatment of CRS in Covid-19 patients under a prospective clinical trial.
In addition to the initial clinical trial, we intended to generate additional evidence of efficacy and safety under a prospective clinical trial (not an observation study, as claimed by the author). Additionally, we intend to publish Real World Evidence in peer-reviewed journals. We have always claimed that Itolizumab is for the right patient at the right time, and is not for all patients with Covid-19.
The DCGI has been proactive, responsible and transparent with the entire process. On March 13, the DCGI issued a public notice on requirement of Chemistry Manufacturing and Controls documents for approval of additional indication of an already approved drug product. On March 19, it issued a public notice to encourage research and development of drug or vaccine for prevention or treatment of Covid-19. On April 8, SEC evaluated Biocon’s pivotal Phase II trial proposal for additional indication to an approved product. On June 18, the SEC recommended protocol amendments. On July 10, the SEC reviewed clinical trial data and recommended an additional indication. Biocon announced that DCGI had granted approval for Restricted Emergency Use in the country for the treatment of CRS in moderate to severe ARDS patients due to Covid-19 on July 11. On July 21, Biocon submitted Phase IV clinical trial protocol to the DCGI.
In light of the facts provided, we can confidently state that the claims made by the author are factually inaccurate. Claims without evidence constitute a great disservice to the public. The drug regulator acted in public interest to serve an unmet medical need based on science and evidence in a transparent manner.
The author is Global Head of Regulatory Affairs at Biocon Biologics