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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.

Covid-19: Will Pharma Deliver What It Can Do The Best, Soon?

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The news of a bright possibility of finding magic bullets to significantly tame, if not totally annihilate Covid-19, is coming almost every passing day. As expected, these are being initiated mostly by drug companies, alongside various academia, located in several countries of the world, including India. It rekindles hope to return to some kind of normalcy in daily life, work and business.

However, the hype created around each of these, either too early or based on some anecdotal reports, apparently driven by the desire for a windfall commercial gain, may be counterproductive. That some remedial measures to tackle the notorious virus will come very soon, could influence a number of decisions of those who are engaged in managing the situation.

The pressing need to restart the economic activity – come what may, even before the first wave of Covid-19 subsides in a developing country like, India, comes along with a strong storm signal. Balancing life with livelihood has never been so difficult ever. In tandem, it poses a great challenge also for the pharma industry to demonstrate what it stands for the society, such as:

  • Bringing scientifically proven, safe and effective drugs and vaccine, in a specified timeframe falling close to the realm of a genuine possibility.
  • Making these drugs and vaccines available, at an affordable price and accessible to all, globally.

In this article, I shall focus on the relevance of these two critical expectations of all, where, incidentally, pharma is expected to do and deliver the very best – particularly against the prevailing and near-chaotic scenario. Let me begin with the first point first.

A great challenge:

Understandably, the above task is not a piece of cake due to many reasons. For example, according to a leading pharma trade association in the United States, ‘On average, it takes at least ten years for a new medicine to complete the journey from initial discovery to the marketplace, with clinical trials alone taking six to seven years on average.’

Thus, logically, a new drug molecule for Covid-19 can’t possibly be expected, by any stretch of imagination, within the next 12 to 18 months. What one can possibly expect for the same is, repurposing older drugs for the same. Quite logically, steps are being taken in this direction. However, even for such drugs, a clinical trial would take ‘six to seven years on average.’ Considering the urgency to combat the Covid-19 pandemic, can a fair clinical trial be completed in the next 12 to 18 months?

Therefore, the challenge in hand for the drug companies, even considering a super fast-track regulatory assessment and approval in 12 to 18 months, appear a pretty tough proposition. The challenge gets more complex, if Covid-19 starts changing.

A new issue is unraveling:  

Recently, a new dimension got added to the mounting challenge of coming out with an effective drug or vaccine to fight Covid-19 pandemic, as evident from the Bloomberg article of May 20, 2020. It carries a headline ‘China’s New Outbreak Shows Signs the Virus Could Be Changing.’

It reported, Chinese doctors are seeing the Coronavirus manifest differently among patients in the new cluster of cases of their northern provinces of Jilin and Heilongjiang, compared to the original outbreak in Wuhan. Apparently, it indicates that the pathogen may be changing in unknown ways, complicating efforts to manage the infection. Although, more details need to be unraveled in this area, this incident could flag a fresh uncertainty over the virus mutation that may hinder current efforts of developing safe and effective drugs and vaccine for Covid-19.

Still no available drugs and vaccine for Covid-19 with proven clinical efficacy:

‘The Lancet’ article of April 02, 2020 – ‘‘Global coalition to accelerate COVID-19 clinical research in resource-limited settings’ has also emphasized the above point. It reiterated, there is still no available vaccine against Covid-19 infections and no drug with proven clinical efficacy, although there are several candidates that might be effective in prevention or treatment.

As of March 24, 2020, there were 332 COVID-19 related clinical trials, 188 of which were open for recruitment and 146 trials are preparing to recruit. These clinical trials were either planned or being carried out, mostly in China, South Korea, Europe and North America. However, not many trials were planned in south and southeast Asia, Africa, and central and South America at that time, the article pointed out. But the hype for the availability of drugs continues to reverberate, generally in the media reports. Nevertheless, the work is still in progress.

Some unproven hype as on date?

Despite so much of publicity on availability of drugs for the treatment and prevention of Covid-10, starting from Chloroquine and Hydroxychloroquine, which the US President Donald Trump called a “game changer” for Coronavirus – right up to Remdesivir, none has demonstrated scientifically proven clinical efficacy, as yet.

For example, the latest clinical trial results for Covid-19 on 15000 people, published in The Lancet on May 22, 2014 found, hydroxychloroquine and chloroquine did not benefit patients with the Coronavirus, either alone or in combination with an antibiotic. Moreover, the drugs caused an increased risk of cardiac arrhythmia. Earlier,  ‘The BMJ’ article of May 14, 2020 also found that the administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard care alone in mild to moderate Covid-19 infections. This study also noted, adverse events with the recipients of hydroxychloroquine were higher than non-recipients.

On the other hand, in India, as reported on May 23, 2020, the Union Health Ministry has issued an advisory expanding the pool of people to be given the anti-malarial drug hydroxychloroquine (HCQ) as a prophylactic to prevent them from contracting the infection.

Similarly, even Gilead had stated in its Press Release of April 29, 2020: ‘Remdesivir is not yet licensed or approved anywhere globally and has not yet been demonstrated to be safe or effective for the treatment of COVID-19,’ besides some  initial success reports. Notably, in India, Union Health Ministry has also recommended the use of anti-HIV drug combinations Lopinavir and Ritonavir for high-risk group patients, although there is no proven clinical evidence for its efficacy and safety in Covid-19 patients, if not against the use of this combination therapy.

Commercial activity progresses even before evidence-based regulatory approval:

Although, a single clinically proven drug is yet to come out, commercial activities for some of these drugs – in a near desperate situation – based apparently on hype created, including by the US President, have progressed or progressing. This had happened for hydroxychloroquine and has now started happening for remdesivir.

Almost every passing day one finds yet another repurposed drug being put on clinical trial by a different company, probably for similar reasons. There is nothing wrong on that, but which drugs work and which do not, must be evaluated in a more cohesive manner and sooner.

The good news is, the World Health Organization (WHO), which is concerned with recommendations for ‘administering unproven treatments to patients with COVID-19 or people self-medicating with them,’ has announced the “Solidarity” clinical trial for the new Coronavirus treatments. This is an international clinical trial, aimed at the scientific assessment of 4 treatment options to slow the disease progression or improve survival rate for COVID-19 patients.

Otherwise, a strong desire for people to survive – ‘somehow’, will prevail in this desperate situation, over what these medicines can actually deliver. Even drug companies never experienced in the past or even could even envisage such a pandemic at this humongous global scale.

A similar scenario is witnessed with some major vaccine development initiatives. For example, stock markets soared with the early signs of viral immune response of the much publicized experimental Covid-19 vaccine being developed by Moderna Inc. However, a few days later, after ‘parsing the data to gauge the company’s chances of success’ by the analysts, it was reported: ‘It’s too soon to assume success for Moderna Inc’s COVID-19 vaccine.’ Curiously, it continues to happen in the early days with almost all such well publicized initiatives. Nonetheless, the pursuit to find out safe, effective and clinically proven drugs and vaccine continues.

Which is why, bringing scientifically proven safe and effective drugs and vaccine sans the early hype, in a specified time, falling close to the realm of a genuine possibility, becomes a key deliverable of pharma players, in this situation. That said, it brings me to the second point where pharma and biotech companies are widely expected to meet the other expectations of all – making these drugs and vaccines available, affordable and accessible to all, globally.

Making Covid-19 drugs and vaccines available, affordable and accessible to all, globally:

Again, this seems to be an equally tough call for most drug players, as has been happening, generally. But Covid-19 drugs and vaccines are just not for saving life, these are also intimately related directly to the livelihood of a very large global population, especially in the developing nations, like India. Therefore, ‘Coronavirus vaccine should be for everyone, not just those who can afford it,’ as articulated in the article, published in the STAT news on March 05, 2020.

This apprehension arises among many in the United States, as well. Mainly because, as reported in the above article, vaccine coming out of the two vaccine development projects funded by the U.S. government, one by Sanofi and another by Johnson & Johnson, may not be affordable to all Americans.

Further, quite a number of countries in the world lack resources, infrastructure, and health care personnel to detect the virus and prevent it from spreading quickly and easily among populations. In which case, without drugs and vaccines, the number of cases is likely to grow exponentially, putting stress on already burdened health care workers and facilities. Consequently, it will make harder to provide timely care for those who are ill. Thus, vaccines will be an important tool for preventing such a catastrophe.

For those with resources – ‘rich countries and rich people,’ a Covid-19 vaccine will certainly be valuable to save lives. However, for most people in all countries, including India, it may be essential for the livelihood, as well. Without it, they will suffer disproportionately and unnecessarily, the article concluded. Thus, in this hour of multiple crisis of global dimension, the drug players are expected to come forward, making these drugs and vaccines available, affordable and accessible to all, globally – a task where they can deliver the best, compared to others.

Conclusion:

Amid ‘Lockdown.4’ in India, as on May 24, 2020 morning, the recorded Coronavirus cases have mounted to 131,920 with 3,869 deaths. By the way, on the same day, the most populated country in the world – China, where Covid-19 struck first in December 2019, records 82,974 cases with 4634 deaths, so far.

That apart, Covid-19 is a very special situation for all countries, probably more than what happened during the 1918 Spanish flu pandemic, for several reasons. Comparing these two pandemics, especially during the lockdown period, has been common. Due to this pandemic, as many as 675,000 people, reportedly died only in America, many of them were previously healthy young adults. Almost similar situation is on the horizon with the Covid-19 pandemic.

Agreed, that the overall healthcare infrastructure and global scientific resources to combat these two pandemics may not be comparable. But even in the context of the 21st century, this is a very critical global situation, for both – saving life and also the livelihood. Thus, for pharma and biotech companies ‘this is not a time to make money’, as the chief executive officer of Serum Institute of India, which is helping produce a vaccine for Covid-19 developed by Oxford, puts it succinctly. Be that as it may, the answer to the two questions that I started with, still remains elusive.

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.