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Covid-19: Perils Of Haste In Scientific Decision-Making Process

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Multifaceted threats posed by Coronavirus to the humanity, are getting increasingly complex, every day. Currently, Covid-19 cases in India are ‘the highest that any country has ever recorded on a single day since the start of the outbreak.’ Alongside, the hopes of billions of people – for its predictable and dependable remedies are also soaring sky high. But, despite full throttle global endeavor of scientists, the world continues waiting for scientific-evidence-based, well-proven, safe, and effective Covid-19 drugs, vaccines and other treatments.

It is expected, each of these cures and antidotes should be duly authorized by drug regulators, according to global norms – without any outside non-scientific interference – not even from the very top. Nevertheless, the reality is, as on date, besides some ‘emergency use authorizations’, all scientific pursuits in this area are Works in Progress (WIP) – some are with great potential, though.

The catastrophic impact of Covid-19 pandemic is all pervasive. So is the competition between media publications to attract maximum eyeballs, with details on many aspects of the disease and related scientific development. These include reports on intense, non-scientific pressure on scientists and regulators to make drugs, vaccines or other Covid-19 treatments immediately available for use. In this article, I shall dwell on the perils of haste in the scientific decision-making processes, while combating Covid-19.

A quick research outcome is important – based on ‘rational’ – but not ‘rash’ decisions: 

In pursuit of a quick disease treatment outcome, a rational and ethical approach in any scientific discovery process, is non-negotiable. It has always been so – while dealing with many different health crises, and should remain that way for Covid-19, as well. In my view, for achieving a prompt and desirable treatment outcome – a quick, but rational decision should always be favored – over highly influenced, contentious, non-scientific and rash decisions.

Many wise men believe, a quick decision is one, made quickly supported by irrefutable inputs of an accepted quality and scale. Whereas, a rash decision is one, made with limited, questionable or even no inputs – just based on gut feel, as it were. This broad concept is applicable to Covid-19 drugs, vaccines and other treatments, including -plasma therapy.

In the space of Covid-19 pandemic, there are several such examples, starting from hydroxychloroquine to the most recent plasma therapy – both in India, and also beyond its shores. Without being judgmental, this article will try to join some critical dots, for the readers draw their own conclusions on this issue. Let me start with two examples of this drug regulatory quagmire – the very first, and the most recent ones.

Perils of haste in the Hydroxychloroquine saga:

As I wrote in this blog that the US President Donald Trump, on March 21, 2020,  proclaimed Chloroquine and Hydroxychloroquine as potential game changers against Covid-19 global pandemic, despite doubts from the US-FDA. Interestingly, on March 28, 2020, the US drug regulator granted the emergency use authorization of these two drugs for treating Covid-19. However, it was subsequently revoked on June 15, 2020. The agency justified this action by saying:

“Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that chloroquine and hydroxychloroquine are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other potential serious side effects, the known and potential benefits of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use.”

The World Health Organization (W.H.O) also announced: “Studies show Hydroxychloroquine does not have clinical benefits in treating COVID-19.” However, as published by JAMA on May 28, 2020,following President Trump’s naming these drugs at a press conference, Hydroxychloroquine prescriptions shot up by over 200 percent, over the previous year. Nonetheless, the prescriptions returned to normal as news highlighting the lack of enough evidence to support its use started spreading, across the globe.

Soon, India followed the same… a strange coincidence?

As stated above, on March 21, 2020, the US President Trump proclaimed Chloroquine and Hydroxychloroquine as potential game changers against Covid-19 global pandemic, despite doubts from the US-FDA. Curiously, on March 23, 2020, Indian media also reported:

‘Amid rising Coronavirus cases in the country, the national task force for COVID-19 constituted by Indian Council for Medical Research (ICMR) has recommended hydroxy-chloroquine as a preventive medication for high-risk population. According to the advisory, it should be given to high risk population — asymptomatic healthcare workers involved in the care of suspected or confirmed cases of COVID-19 and asymptomatic household contacts of laboratory confirmed cases.’

The above protocol, recommended by the National Task Force, has been approved by the Drug Controller General of India (DGCI) for restricted use in emergency situations. This seems to have happened even before the US-FDA granted similar authorization. Intriguingly, US-FDA subsequently revoked it on June 15, 2020, for lack of enough scientific evidence, unlike the Indian drug regulator.

Another report of April 09, 2020 summed it up well. It wrote, the hype of Hydroxychloroquine – pushed by the US President Trump as a COVID-19 treatment, has now been joined by many other countries, despite inconclusive medical evidence on the efficacy and safety of the drug. Is this just a strange coincidence?

Be that as it may, India’s decision on the emergency use of Hydroxychloroquine had its rub-off financial impact in the country, in terms of increase in its export demand, which may not be an intended one, though.

Its rub-off financial impact in India:

As the world’s largest manufacturers of Hydroxychloroquine are located in India, many of these companies reaped a rich harvest in the April-June quarter, mostly, based on media reports on its use in treating Covid-19. For example, Ipca Laboratories Ltd, reportedly, garnered ₹259 Crore in additional sales, with consolidated net profit for the quarter soar threefold to ₹454 Crore, from the drug in that period.

Notably, Ipca also acknowledged, ‘HCQ sales were a one-time boost for the company. With the hype waning, after various clinical trials showed the drug did not provide any significant benefit, the company now expects sales to ease to earlier levels,’ as the report goes. Let me now move over to the most recent example.

Perils of haste in the plasma therapy saga:

Since, the third week of this month, a series of incidents related to plasma therapy highlighted the ongoing perils of haste in the scientific decision-making process. These were generally prompted by powerful non-scientific external influences, as reported below:

  • On August 23, 2020, the US President announced that the US-FDA has granted emergency approval of blood plasma from recovered Coronavirus patients as a treatment for those battling the disease. President Trump called the development “a historic breakthrough.”
  • According to Reuters, the US-FDA had authorized its use after President Donald Trump blamed the drug agency for impeding the rollout of vaccines and therapeutics for political reasons.
  • The very next day of President Trump’s announcement, on August 24, 2020, the World Health Organization advised caution about endorsing the use of recovered COVID-19 patients’ plasma to treat those who are ill, saying evidence it works remains “low quality.”
  • American scientists, including researchers at the Mayo Clinic also challenged a key statistic cited by U.S. officials as grounds for emergency approval of the treatment.
  • On August 25, 2020, US-FDA Commissioner Stephen Hahn, publicly apologized ‘for overstating the benefits of plasma for treating Covid-19 patients.’ 
  • “The US-FDA’s emergency use authorization for plasma for Covid-19 looks questionable. If this presages an early vaccine nod, we should be very afraid,” reported another article.

Similar controversy was also witnessed in India. Just days after the Drug Controller General of India (DCGI) gave its go-ahead to a proposal of ICMR for the clinical trial of convalescent plasma therapy in COVID-19 patients, the Ministry of Health said, ‘there is not enough evidence to claim plasma therapy can be used for treatment of COVID-19. Interestingly, several states, such as, Delhi, Gujarat, Maharashtra and Uttar Pradesh, have already started clinical trials for plasma-based treatment. Meanwhile, media reports, such as, ‘India sees black market boom for plasma from recovered Covid-19 patients,’ started pouring in.

Conclusion:

As recorded in the morning of August 30, 2020, total Coronavirus cases in India have reached a staggering figure of 3,542,733 with 63,657 deaths, despite all measures taken by the country. No signs of flattening of the curve are visible, just yet. In this situation, many experts believe, the way prescriptions are written for Covid-19 patients, based on anything but robust considerations, needs to be re-looked. The headline of an article, written by Richard L. Kravitz, Professor of Health Policy and Internal Medicine, University of California, Davis on July 09, 2020, vindicates this point. It said:‘When Trump pushed Hydroxychloroquine to treat COVID-19, hundreds of thousands of prescriptions followed, despite little evidence that it worked.’

Another interesting article, tried to ferret out the truth behind such haste. It voiced, ‘the truth is that researchers, academic institutions, medical journals and the media all face powerful incentives to portray the latest research findings as more earthshaking than they actually are’. The authors spotlighted, under normal circumstances, numerous mechanisms exist to blunt some of the worst over-hyping and many sources of medical information do their best to be accurate in what they report.

It is possible that in the midst of a pandemic, the urgency of the moment may overwhelm these good intentions. The above paper also cautioned, ‘Bad science can be spread far and wide by normally credible sources.” However, the bottom-line is, the scientific research community, under no circumstances, be made to comply with the thoughts and beliefs of non-scientific, but powerful decision makers. It happened in the oldest democracy in the world, as it also happened in the largest democracy on the planet earth.

The above two instances are just illustrations to highlight an important point – without becoming judgmental. The discussion spotlights the perils of haste in the scientific decision-making processes, while combating Covid-19. As many experts believe, it could be counterproductive for non-scientific power sources to influence the robust medical value creators for a quick remedy. Mainly because, patients will continue to be at the receiving end for the net outcome, of such unproven, and scientifically fragile hypes.

By: Tapan J. Ray  

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.

Infections may cause NCDs like, diabetes and cancer: Ongoing scientific quest to decipher the mystery

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To create a positive health impact on the lives of billions of people, the United Nations (UN) on September 19, 2011 unanimously adopted a ‘Political Declaration’ on ‘Non Communicable Diseases (NCDs)’.  In the years ahead, this path-breaking initiative on NCDs, with global commitment, is expected to make a huge difference in the lives of many, across the world.

NCDs have now been identified as a key healthcare challenge of this century and include ailments like, cardiovascular, chronic pulmonary diseases, diabetes, arthritis and cancer. In the developing countries, over 80% of all deaths are related to NCDs.

There are times when NCDs raise issues related to social justice and human rights. For example, in a country like India where out of pocket expenses towards healthcare is around 80%, a major illness like cancer even in a middle income group family, can drive the entire household to huge socioeconomic hardship.

NCDs are preventable:

According to the World Health Organization (WHO), adequate physical activity, healthy diet/nutrition and tobacco avoidance can prevent:

  • 80% of premature heart disease
  • 80% of type II diabetes
  • 40% of cancers

Currently, as we shall see below, immunization is also being considered as a preventive therapy for certain types of NCDs.

NCDs may be of infectious origin:

Dr. Bennett Lorber in his article titled, ‘Are All Diseases Infectious?’, published in the ‘Annals of Internal medicine’ wrote that many common NCDs like, cardiovascular, diabetes, peptic ulcer, arthritis and even certain types of cancer originate from infections by micro-organisms.

Mainly because of this reason and its consequent adverse socioeconomic impact, the low and middle income countries of the world will require controlling many types of infections, possibly through immunization, before they ultimately develop into NCDs.  Such measures, in turn, will help them reducing the risk factors of morbidity and mortality related to NCDs.

Infections and NCDs:

As indicated above by Dr. Bennett Lorber, following are some examples of reported relationship between infection and NCDs:

Reactive Arthritis:

Reactive arthritis or spondyloarthropathy has been known to follow intestinal infection with Salmonella typhimurium and Yersinia enterocolitica or urethral infection with Chlamydia trachomatis.

Scientists from the United Kingdom have already announced that they will soon begin human trial of an experimental rheumatoid arthritis vaccine.

Peptic Ulcer and Gastric Carcinoma:

Helicobacter pylori is known to cause of gastritis and peptic ulcer disease and is an important risk factor for gastric carcinoma.

Researchers at Rhode Island Hospital in collaboration with the University of Rhode Island and EpiVax Inc, have identified a potential vaccine to reduce colonization of Helicobacter pylori, which is known to cause peptic ulcer and gastric carcinoma.

Acute Renal Failure:

It was reported that about 10% of infected persons younger than 10 years of age develop hemolytic uremic syndrome, and as many as 75% of cases of the syndrome in the United States are complications of intestinal infection with E. coli.

Vasculitis:

The most common cause of vascular damage in secondary vasculitis is now considered to be related to different types of microorganisms. Patients were reported to have developed polyarteritis nodosa a few months after having hepatitis B infection.

It is widely reported that in the developed countries most common vasculitis is related to hepatitis B and C. However, in the developing world HIV related vasculitis appears to be  common.

Inflammatory Bowel Disease (IBS)/ Crohn’s Disease:

The precise etiology of Crohn’s Disease though remains to be conclusively deciphered, it is  believed by many researchers that the disease develops due to a reaction to a persistent intestinal infection in vascular endothelial cells.

Diabetes:

A good number of experts support a link between infection with enteroviruses in the pancreata and insulin-dependent diabetes mellitus.

To arrest or slow the autoimmune response that destroys insulin-producing cells in diabetes, it has been reported that the Diamyd vaccine, now in Phase III clinical trial in both USA and Europe, has shown very promising results.

Coronary Artery Disease:

A study published in the journal of ‘Clinical Infectious Disease’, Volume 40, Issue 8 ‘demonstrates a significant association between high titers to C. pneumoniae IgG and IgA and acute Myocardial Infarction (MI) in a cohort of young men and suggests that recent or chronic active infections could be associated with an increased risk for MI.’

In other studies also, patients with acute myocardial infarction were found to have elevated serum antibody levels to Chlamydia pneumoniae. This opens up possibility of preventing heart attacks with a vaccine.

Cancer:

The US FDA has already approved two types of vaccines for cancer prevention:

  • Vaccines against the hepatitis B virus, which can cause liver cancer.
  • Vaccines against human papillomavirus, which are responsible for about 70% of cervical cancers.

In addition, US FDA has also approved another cancer vaccine for metastatic prostate cancer.

A type of cancer known as Kaposi sarcoma is linked to an infectious agent found in patients with  acquired immune-deficiency syndrome. Scientists are in the process of developing treatment vaccines against many types of cancer.

Conclusions:

In the field of NCD, a not so widely publicized scientific revolution is in the making. Many well researched findings have, to a great extent, established that infectious agents could be the causative/precipitative or risk factors for NCDs like, chronic pulmonary and cardiovascular diseases, diabetes and cancer.

The moot question raised by Dr. Bennett Lorber earlier:  ‘Are all diseases infectious?’, is gradually getting answered through intensive scientific research. Otherwise, who would have thought, until recently, that vaccines could be developed for diabetes, certain types of cancer or even peptic ulcer?

Such path breaking scientific research findings are, in turn, creating a hope and opportunity for disease prevention through immunization for many NCDs, especially for the developing nations of the world.

It is very heartening to know that United Nations (UN) have taken note of these revolutionary developments in the ‘Non Communicable Disease’ space and are deliberating on the effective ways to combat NCDs caused by infections with the development and use of appropriate vaccines.

The entire world eagerly awaits more actionable outcome of the ongoing scientific quest to decipher the mystery related to many more NCDs to ensure better health of mankind of the Planet Earth.

By: Tapan J Ray

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.

Biosimilar Drugs -A raging scientific debate with mounting global commercial interest

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On December 11, 2008, Reuters reported that two days after Merck & Co. announced a major push into generic versions of biotechnology medicines, Eli Lilly & Co. signaled similar aspirations. This report raised many eyebrows in the global pharmaceutical industry, in the midst of a raging scientific debate on this issue. Be that as it may, many felt that this announcement ushered in the beginning of a new era. An era of intense future competition with Biosimilar drugs in the world market with immense commercial interest.Globally, the scenario for generic versions of biotechnology medicines, which are called Biosimilars, Biogenerics or follow-on Biologics, started heating up when Merck announced that the company expects to have atleast 5 follow-on biologics in the late stage development by 2012. The announcement of both Merck and Eli Lilly surprised many, as the largest pharmaceutical market of the world – the U.S.A is yet to approve the regulatory pathway for generic biologic medicines. In the developed world, European Union (EU) has taken a lead towards this direction by already having a system in place for regulatory approval of Biosimilar drugs in 2003.What then prompts the research based global pharmaceutical companies like Merck and Eli Lilly to step into the arena of Biosimilar medicines? Is it gradual drying up research pipeline together with skyrocketing cost of global R&D initiatives?

The future business potential of Biosimilar medicines:

Currently, over 150 different biologic medicines are available in the Global Pharmaceutical market. However, the low cost Biosimilar drugs are available in just around 11 countries of the world, India being one of them. Supporters of Biosimilar medicines are indeed swelling as time passes by. At present, the key global players are Sandoz (Novartis), Teva, BioPartners, BioGenerix (Ratiopharm) and Bioceuticals (Stada). This market is expected to develop slowly because of regulatory hurdles in the major countries of the world.

Very recently, the EU has approved Sandoz’s (Novartis) Filgrastim (Neupogen brand of Amgen), which is prescribed for the treatment of Neutropenia. With Filgrastim, Sandoz will now have 3 Biosimilar products in its portfolio.

Raging debate on Biosimilar Drugs still continues:

The debate is centered on the argument that like small chemical molecules is it possible to replicate large biological molecule of the innovator? It is widely believed that a protein cannot be absolutely replicated. How could possibly then Biosimilar drugs be considered equivalent to the original product by a regulator and marketing approval be granted to them without full scale clinical trials ignoring safety concerns of the patients? In favor of this argument some refer to the problem of red cell aplasia that affected many patients administering Johnson & Johnson’s Exprex (Epoetin) after only a minor change made in its manufacturing procedure.

Hurdles to cross for future Market entry of Biosimilar Drugs:

Emergence of second generation branded biosimilar products such as PEGylated products Pegasys and PegIntron (peginterferon alpha) and Neulasta (pegfilgrastim), and insulin analogs etc. have the potential to reduce the market size for first generation Biosimilar drugs creating significant entry barrier.

Even otherwise, the barriers to market entry of Biosimilar drugs are much higher than any small molecule generic drug. In the markets within EU, many companies face the challenge of higher development costs for biosimilar drugs because of stringent regulatory requirements and greater lead time for product development. Navigating through such a tough regulatory environment will demand a different type of skill sets from the generic companies not only in areas of clinical trials and pharmacovigilance, but also in areas of manufacturing and marketing. Consequently, the investment needed to take Biosimilar drugs from clinical trials to launch in the developed markets, will indeed be quite significant.

Current Scenario in the U.S:

Recently in the U.S.A, the new, widely reported, biotechnology policy of President Barak Obama has become one of the most closely watched healthcare policy initiatives of the country. It is expected that such a policy will help facilitate regulatory approval process of Biosimilar drugs in the USA by end 2009. This new policy initiative could have a major impact on many biotech companies who will face new generic competition, rather quickly. On the other hand, it will prove to be a boon to the new entrants in this market like, Merck and Eli Lilly, besides the existing ones.

Global Market Potential of Biosimilar Drugs:

The biosimilar drug market in the world is estimated to be around U.S. $ 16 billion by 2011. Currently, off-patent biologic blockbusters including Erythropoietin offer an excellent commercial opportunity in this category of drugs. By 2013, about 10 branded biologics with a total turnover of around U.S. $ 15 billion will go off-patent.

Biosimilar Drugs in India:

Sales of biosimilar drugs in India are estimated to be around U.S. $ 4 billion by 2011.

Biosimilar drugs fall under high growth segment within Indian pharmaceutical Industry. Recombinant vaccines, erythropoietin, recombinant insulin, monoclonal antibody, interferon alpha, granulocyte cell stimulating factor like products are manufactured by a number of domestic biotech companies like Biocon, Panacea Biotech, Wockhardt, Emcure, Shantha Biotech, Bharat Biotech, Serum Institute of India, Dr. Reddy’s, Ranbaxy, etc. The ultimate objective of all these Indian companies, I am sure, will be to get regulatory approval of such products in the EU and then in the U.S. when the time comes.

It is worth mentioning here that to give a fillip to the Biotech Industry in India, the National Biotechnology Board was set up by the Government of India under the Ministry of Science and Technology in 1982 and the Department of Biotechnology (DBT) came into existence in 1986. The DBT now spends around US$ 200 million annually to develop biotech resources in the country and have been making reasonably good progress. The DBT is reported to have undertaken an initiative to prepare regulatory guidelines for Biosimilar Drugs, which is expected to conform to international quality and patients’ safety requirements.

The points to ponder with the Biosimilar Drugs in India:

It is, indeed, quite surprising that in India there is still no separate transparent and published guidelines for regulatory approval of Biosimilar drugs, although the Drug Controller General of India (DCGI) seems to have a different view in this matter. The Drugs and Cosmetics Acts of India have no separate provisions either, for Biosimilar Drugs. In a situation like this, we find that many Biosimilar Drugs are still getting regulatory approval in India.

Currently India supplies 30% by volume of the global requirements of generic drugs both in regulated and non-regulated markets. In the regulated markets like North America and EU, for small molecule generic products, Indian manufacturers conform to the global safety and efficacy standards by getting these products approved by the most stringent regulators of the world like, U.S. FDA, MHRA (Medicines and Healthcare products Regulatory Agency) etc. The very fact that none of the Biosimilar drugs developed in India could get approval in the EU as yet, may well suggest that the stringent regulatory requirements for both efficacy and patients’ safety followed in the EU for Biosimilar drugs, could not be met by the Indian manufacturers, as yet. The question, therefore, comes to my mind whether the Biosimilar drugs manufactured in India conform to international quality and safety standards? If not, who will address the safety concerns of the patients who are or will be administering these medicines?

Such a concern gets vindicated by widely reported serious quality problems, detected by the drug regulatory authorities, at some large and well known Biosimilar drugs manufacturing units in India and also from the condition of some vaccine manufacturing units in our country.

India needs to manufacture the world class Biosimilar drugs conforming to the highest efficacy and patients’ safety standards, just the way Indian pharmaceutical manufacturers have demonstrated with ‘made in India’ generic drugs, the world over. The Indian drug regulatory authority should now take some important initiative with the publication of world class Biosimilar drugs regulatory approval guidelines, may be following the similar process as what we see in the EU.

Currently, experts from India are participating towards preparation of ‘WHO Guidelines’ for Biosimilar Drugs. The progress made towards this direction is yet to be ascertained. Simultaneously, the DBT is reported to have under taken an independent initiative to prepare similar guidelines, the progress of which is also yet to be known.

Before other developed markets open up for Biosimilar drugs, if India can align itself with its own world class regulatory standards for the same, yet another significant export opportunity could be created for the country, competing with the best performers of the world in this category.

Meanwhile, it will only be good to know that like many other initiatives, India has taken one more important initiative to address this important issue, for the sake of humanity. As the existing process of granting regulatory approval for Biosimilar drugs continues in India, the lurking fear towards patients’ safety with such drugs will remain unabated with a large majority of experts in this field.

By Tapan Ray

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.