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Covid Vaccine Challenges – Abidance To Defined Health Norms Stays As Lifeguard

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There isn’t even a shade of doubt today that Covid-vaccines are coming. However, some critical questions in this area continue to hang in the air, and are expected to remain so for some more time. Thus, every news on the development of Covid vaccines, particularly in their late stages of clinical trials, fuels billions of hopes and excitement, across the world.

The same thing happened, when Pfizer and BioNTech announced on November 09, 2020, some key details on their vaccine candidate. These include, ‘vaccine candidate was found to be more than 90% effective in preventing COVID-19 in participants without evidence of prior SARS-CoV-2 infection in the first interim efficacy analysis’ from Phase 3 studies. The release also highlighted, ‘Submission for Emergency Use Authorization (EUA) to the U.S. Food and Drug Administration (FDA) planned for soon after the required safety milestone is achieved, which is currently expected to occur in the third week of November.’

Amid these new developments, it is also now beyond doubt that the pandemic will be brought under control, eventually. Interestingly, none possibly knows when it will happen. There doesn’t seem to be any clearly charted – time-bound pathway in place for the same, either – not just yet. That said, from the overall developments in this area for the past 10 months, especially in India, – two other crucial questions also remain elusive, as follows:

  • Has the country started preparing itself against any Covid-like future biological threats? If so, in what manner?
  • As India conducts the world’s largest  Universal Immunization Program (UIP), how robust is the country’s vaccine supply chain to effectively inoculate every Indian with Covid-vaccine?

I have already deliberated on several aspects of the former question in one of my previous articles, in this write-up. Therefore, this write-up will focus on the second query, with a specific reference to the continued relevance of abidance of the defined health norms for some more time, especially for my pharma industry readers. Accordingly, all astute pharma professionals in India, need to accept this new reality, and rewrite their brand demand generation strategies for the new normal. Let me start with how the cold-chain logistics for vaccines, in general, work in the country.

The cold-chain logistics for vaccines:

A paper published by the BBC News, on November 11, 2020, captured how the cold-chain logistics for vaccines, in general, work almost in all countries, including India. The article is titled, ‘Coronavirus: How soon can we expect a working vaccine?’ The steps involved in this exercise are as follows:

  1. Vaccines transported to destination countries (imported varieties).
  2. Refrigerated trucks for transportation to designated cold rooms.
  3. Distribution in portable and appropriate ice boxes to regional centers.
  4. Stored in electric fridges between 2 degree to 10 degree Celsius (for most of the existing vaccines.)
  5. Carried in portable and appropriate ice boxes to local venues for vaccination to individuals.

Associated challenges:

As the above paper highlighted, some important associated challenges in this space, which are mostly faced by the developing countries, like India, are as follows:

  • Adding a new vaccine to the existing mix could pose huge logistical problems for those already facing a difficult environment.
  • According to prescribed norms, all Vaccines in India requires a storage temperature in the range of +2 degree to +8 degree Celsius, except for Oral Polio Vaccine which need to be stored in the frozen state (-25 degree – 15 degree Celsius) at all stores except PHC/ CHC/Health post. The new vaccine ROTAVAC (116E rotavirus) by Bharat Biotech is being recommended to be stored at (-15 to -25 degree Celsius) till the intermediate stores and to be stored in the range of +2 degree to +8 degree Celsius at the last storage points like PHC/ CHC/Health posts. This has not posed much of a challenge. However, expanding it to cover the entire population of the country can be an “immense task.”
  • It is worth noting, although, AstraZeneca vaccine would need the regular cold chain between 2C and 8C, the Pfizer and BioNTech vaccine would need ultra-cold chain – storage at around minus 70C to 80C.
  • ‘Maintaining vaccines under cold chain is already one of the biggest challenges’ that countries face, and this will be exacerbated with the introduction of a new Covid vaccine.
  • Thus, more cold chain equipment will require to be added, making sure that fuel is always available (to run the freezer and refrigerators in absence of electricity) and repair/replace them when they break and transport them wherever you need them.

Curiously, India’s cold-chain logistics that cater to one of the world’s largest immunization programs for children and mothers, may not be enough for Covid-19 vaccination of the country’s 1.3 billion population.

Why India’s cold-chain logistics may not be enough for Covid vaccination:

Before coming to the above question, it is important to note that India is not just the pharmacy of the world, contributing over 20 per cent by value to the global generics market, and over 40 per cent (by volume) of US drugs. According to a recent report of Bernstein Research, Indian vaccine producers, such as, Serum Institute of India supply the bulk – over 40% of the global capacity of 5.7 billion doses annually. Home to some of the world’s biggest vaccine makers, India produces 2.3 billion doses of vaccines yearly, with 74% for export, said the report.

Regardless of this fact, India’s cold-chain logistics may not be enough for Covid vaccination of its entire population, primarily because it is currently geared for children. ‘India Spend’ report of October 13, 2020 titled, ‘India’s COVID-19 Dilemma: Adults Need Vaccines, Supply Chains Geared For Children,’ presents several such interesting facts to ponder over the following points:

  • Being the world’s largest in the Universal Immunization Program (UIP), India targets 26.7 million newborns and 29 million pregnant women every year (55 million people in total, or 4% of the total population). This requires 390 million doses of vaccines, over nine million sessions. But, can this infrastructure effectively handle Covid vaccination of 1.3 billion people?
  • The above question arises, because India has planned to administer 400 to 500 million doses of a COVID-19 vaccine, mostly to its adult population by the first two quarters of 2021. For this effort, the country will have to nearly double the total number of vaccinations given in the public sector program. Thus, one can well imagine, what a humongous task, it will be for vaccination of 1.3 billion population, at the shortest possible time.

Which is why – although, over the last decades, India has created a primary vaccination infrastructure, and gained enough experience in this area, these may not be enough for Covid mass vaccination program, as stated above.

What it would it entail:

As the above ‘India Spend’ report indicates, this effort will entail:

  • Ramping up capacity to administer vaccines,
  • Expanding and further strengthening cold-chain infrastructure and process of storing and transporting vaccines safely, besides logistics,
  • Ensuring adequate availability of ancillary items, such as syringes, glass vials, and intensive training of healthcare workers.

Without these, even if there is a life-saving vaccine available for COVID-19, people will not have access to effective vaccines, the report reiterates. From this perspective, let’s now have a glance to India’s current vaccine cold-chain logistics and infrastructure.

India’s current vaccine cold-chain logistics:

Currently, most vaccines in India are distributed by the Governments UIP mechanism. Accordingly, for the child immunization program, almost the entire vaccine cold chain is publicly funded and managed.

Going by the official statistics, at present there are in total – about 7,645 cold storages in the countrywith 68 per cent of the capacity being used for potato, while 30 per cent is a multi-commodity cold storage. ‘Most of these cater to farm produce in rural areas with ambient temperature storage and therefore are not pharmaceutical ready.’ As the industry sources indicate, ‘only a small part of the remaining 10 per cent of the industry is organized and capable of playing a key role in the distribution of the Covid vaccine.’

The comprehensive multi-year UIP plan for 2018-22 of India also specifies, while India’s UIP is currently supported by more than 27,000 functional cold chain points, only 750 (3 per cent) are located at or above the district level. The rest is located below the district level.

Nevertheless, the ongoing pandemic prompts India to administer Covid vaccines to its entire population of 1.3 billion population, over the shortest possible period of time. To achieve this goal, the cold chain industry of the country is warming up to handle this vaccine distribution challenge, maintaining the integrity of the cold chain.

The only organized pan-India cold chain player with 31 facilities is, reportedly, Snowman Logistics. Other companies, who are mostly the regional operators in this business, include Coldex, ColdStar, Western Refrigeration and JWL. Yet another report indicates, Maersk, is also poised inking a global logistics deal with US-based COVID-19 vaccine candidate COVAXX, including India. Be that as it may, the bottom-line remains, effective Covid vaccination program would not possibly commence until this gap is successfully bridged.

Conclusion:

Meantime, as on November 15, 2020 morning, India recorded a staggering figure of 8,814,902 of Coronavirus cases with 129,674 deaths. The average number of daily new cases appeared to have slowed down in the last few weeks, except Delhi. But, the threat of further spread of Covid infection, in waves, remains as it was before.

Robust and high-quality vaccine cold chain logistics in India assumes so much of importance, because of one critical factor – to preserve its effectiveness till administered to an individual. This is regardless of whether a person is located in cities, small towns or in the remote hinterlands of the country. The successful accomplishment of this task is crucial to combat Covid pandemic, until scientists find any predictable long-term solution.

The good news is, according to a new report: ‘Amid cold chain blues, Pfizer looks to powder vaccine formula in 2021.’ BBC News also reported: ‘A group of Indian scientists are working on such a vaccine. The “warm” or a heat-stable vaccine, they claim, can be stored at 100C for 90 minutes, at 70C for about 16 hours, and at 37C for more than a month and more.’

While the world awaits to witness this happening, we all should recognize a current reality. Tough challenges are still looming large on the way of effective Covid mass vaccination programs, especially for all adult population in India. Thus, the gravity for abidance to basic infection avoidance norms – wearing masks, social distancing and avoiding crowded places, stay unchanged. Accordingly, all astute pharma professionals in India, I reckon, need to accept the prevailing reality, and rewrite their brand demand generation strategies for the new normal.

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.

 

New ‘Patient Compensation’ Norms on Clinical Trials in India: Overdue Action, Sharp Reaction and Ethical Issues

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Responding to the damning stricture made by the Supreme Court on January 3, 2013, the Ministry of Health, as expected, by a gazette notification of January 30, 2013 has made the norms of compensation to patients participating in Clinical Trials (CT) more stringent.

‘Patient Compensation’ will now include injury or death, even if those are not related to the drugs being tested in the CT.

It is worth mentioning that these guidelines have been reportedly worked out after due consideration of around 300 comments received from the stakeholders on the draft proposal circulated by the Ministry of Health in July 2011, couple of rounds of discussion with the members of the civil society, expert groups and against reported ‘stiff opposition from the drug companies’.

Just a day after, on February 1, 2013, the Ministry of Health also notified final regulations on the conditions under which CT sites will be authorized by the local licensing and the inspection authorities of the Central Drugs Standard Control Organization (CDSCO).

Key features of the new Government ‘Action’ on patient compensation:

Following are the key features in the new norms for patient compensation:

1. The sponsors of CTs will now be liable for injuries or deaths, which will take place during the course of a clinical trial and will be required to pay compensation to the patients or their families.

2. The investigator of the CT must inform the concerned pharmaceutical company, the Clinical Research Organization (CRO) and the Ethics Committee regarding injury or death during CT within 24 hours.

3. It will be mandatory for all CT Ethics Committees to be pre-registered with the Drug Controller General of India (DCGI), unlike the old system where this was not required and trial sponsors reportedly could staff the committee.

4. The pharmaceutical companies and the CROs will get 10 days time to submit a detailed report on related serious adverse event to the Ethics Committee, which in turn will get another 10 to 11 days to convey its evaluation on compensation to be paid to the independent expert committee. The Expert Panel will then advise the DCGI of an appropriate financial compensation within 30 days from the date of receiving the above report.

5. It will no longer require inclusion of specific amount of compensation for injury or death in the informed consent form and does not refer to insurance coverage for potential liability.

6. It requires the sponsors of CTs to provide the trial subject with free “medical management” for as long as it will require.

Will make CT more expensive in India:

Clinical Trials (CT), as we know, are of critical importance for obtaining marketing approval of any new drug and at the same time forms a major cost component in the new drug development process, across the world.

Any savings in this area, both in terms of time and money, will add significantly to the profit margin of the product. In that context the above notification will now make CT more expensive in India.

Sharp ‘reaction’ of CT related industry:

Understandably, reacting to this notification, some Clinical Research Organizations have expressed concerns in areas like:

  1. Lack of distinction between study-related injuries and non-study related injuries
  2. The use of placebos in placebo-controlled trials,
  3. Lack of any arbitration mechanism in case of disagreement on causality/quantum of compensation and the lack of clarity on who constitutes the Expert Committee and its composition.

Some other Experts related CT industry do highlight a few more troubling issues in the notification, as follows:

1. Compensation to be paid for ‘failure of an investigational product to provide intended therapeutic effect.’ This, they expressed, is intriguing as the very nature of a CT is to ascertain whether the investigational drug is efficacious or not.

2. If compensation is not paid as required, a sponsor or CRO may be banned from conducting any further trials in the country. This, they feel, provision could make India a challenging place to conduct CT.

3. There should also be clarity on the formula to determine compensation, the process for determining a compensation amount, and how an appeal process would work.

The bottom-line is, due to this new policy on ‘Patient Compensation’ CT expenses may go up considerably in India.

Other expert views:

On the other hand, some other experts opined to the International Weekly Journal on Science – ‘nature’ as follows:

“These reforms should go further to restore public confidence and the Indian government should establish special courts to deal quickly with allegations of medical misconduct, such as not fully disclosing to participants the risks involved in a clinical trial”.

Global concern on ethical issues with ‘Placebo Controlled’ studies:

In this context, though issues related to ‘Placebo Controlled’ trials have been raised by the CT related industry in India, very interestingly a paper of Research Administration of the University of California on the ethical issues with ‘Placebo Controlled’ studies’ clearly articulates that the use of a placebo in clinical research has remained a contentious issue in the medical community since long.

Some strongly argue that use of placebos is often unethical because alternative study designs would produce similar results with less risk to individual research participants. Others argue that the use of placebos is essential to protect society from the harm that could result from the widespread use of ineffective medical treatment.

However, as per the Office for Human Research Protections (OHRP) guidebook, “Placebos may be used in clinical trials where there is no known or available (i.e. US-FDA-approved) alternative therapy that can be tolerated by subjects.”

This issue also needs to be deliberated and effectively addressed by the Indian drug regulator in the debate of patient compensation for ‘placebo controlled trials’.

A perspective on CT in India:

Interestingly, in this critical area India is fast evolving as a major hub. This is vindicated by a study conducted by Ernst & Young and the Federation of Indian Chambers of Commerce and Industry of India (FICCI), which states that India now participates in over 7 per cent of all global phase III and 3.2 per cent of all global phase II trials. The key points of attraction of the global players, so far as India is concerned, were reported as follows:

1. Cost of Clinical Trial (CL) is significantly less in India than most other countries of the world

2. Huge patient pool with different disease pattern and demographic profile

3. Easy to enroll volunteers, as it is easy to persuade poor and less educated people as ‘willing’ participants.

Such opportunities, experts believe, should have ideally made the clinical research industry to demonstrate greater responsibility to ensure that patients’ safety needs are adequately taken care of. Unfortunately, despite such expectations, some important areas like ‘patient compensation’ have still remained blatantly neglected.

It has now come to light with the help of ‘Right To Information (RTI)’ query that more than 2,000 people in India died as a result of Serious Adverse Events (SAEs) caused during drug trials from 2008-2011 and only 22 of such cases, which is just around 1 percent, received any compensation. That too was with a meager average sum of around US$ 4,800 per family.

It has been widely reported that pharmaceutical companies often blame deaths that occur during trials on a person’s pre-existing medical condition and not related to CT.

DCGI had hauled-up 9 companies for blatant negligence:

According to another report quoting the Drug Controller General of India (DCGI), 25 people died in clinical trials conducted by nine pharmaceutical companies, in 2010. Unfortunately, families of just five of these victims received” compensation for trial related death, which ranged from Rs 1.5 lakh (US$ 3000) to Rs 3 lakh (US$ 6000).

This report also highlighted that arising out of this critical negligence, for the first time ever, the then DCGI was compelled to summon these nine pharmaceutical companies on June 6, 2011 to question them on this issue and with a clear directive to pay up the mandatory compensation for deaths related to clinical trial by June 20, 2011, or else all other CTs of these nine companies, which were ongoing at that time or yet to start, will not be allowed.

The report also indicates that after this ultimatum all the nine companies as mentioned therein had paid the compensation to the families of the patients who had died related to the CT.

Long exploitation of the fragile CT regulations in India:

For all these reasons, the subject of CT in India has created a huge ruckus, mainly for wide spread alleged malpractices, abuse and misuse of fragile CT regulations of the country by some players in this field. The issue is not just of GCP or other CT related standards but more of ethical mind-set and reported rampant exploitation of uninformed patients, especially in case of trial related injuries or even death.

The Bulletin of the World Health Organization (WHO) in an article titled, “Clinical trials in India: ethical concerns” reported as follows:

“Drug companies are drawn to India for several reasons, including a technically competent workforce, patient availability, low costs and a friendly drug-control system. While good news for India’s economy, the booming clinical trial industry is raising concerns because of a lack of regulation of private trials and the uneven application of requirements for informed consent and proper ethics review.”

“Pharmaceutical industry seeks to run studies in countries with lower costs”:

There seems to be nothing basically wrong in this approach per se. However, a recent report does highlight as follows:

“Clinical trials conducted by global drug makers and their proxies have generated increased scrutiny in recent years as the pharmaceutical industry seeks to run studies in countries with lower costs and populations where patients are not exposed to as many medications that can confound results. India has been a prime example”.

A lesson to learn by the Indian Drug Regulator:

It is worth noting that US-FDA in a communication meant for the consumers has stated as follows:

“The Food and Drug Administration’s job is to make sure medical treatments are safe and effective for people to use. FDA staff members meet with researchers, and perform inspections of clinical trial study sites to protect the rights of participants and to verify the quality and integrity of the data.”

The above approach seems to be drastically missing with the drug regulator in India as on date.

Conclusion:

Over a long period of time, a blatant negligence on reasonable care and financial compensation was allowed to continue by the Drug Regulator and the sponsors alike on the CTs conducted in India. A perceptible intent of justice to the patients, with the enforcement of stricter compensation laws and regulations for CT though belated, could dramatically change the CT scenario in India for the better in the years ahead.

In the fine balance of national priority for this area, patients’ safety and interest, I reckon, should always weigh more than the possibility of increase in the costs of CT in India. Thus,  the new norms of Patient Compensation indeed bring with it a breath of fresh air for the concerned stakeholders.

That said, the lose knots in some areas of the new norms, as discussed above, must be properly addressed and adequately tightened for greater clarity of the CT process, for all concerned.

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.