Regulatory Failures Are Still Risking Patient Lives

Posted on October 6, 2024 by Tapan Ray

India’s pharmaceutical industry faces renewed scrutiny as the Drug Controller General of India (DCGI) flagged numerous substandard drugs in September 2024. At the same time, an October 02, 2024, Business Standard report highlights an ongoing crackdown on such drugs by regulators. This article explores these contrasting developments, beginning with the September findings.

On September 22, 2024, multiple reports revealed that the DCGI, through the Central Drugs Standard Control Organization (CDSCO), identified 195 instances of substandard drugs, devices, and vaccines over three months. Popular brands like Shelcal 500, NICIP MR, and Pantocid were among the flagged drugs, affecting treatments for common ailments like hypertension and acid reflux. Major companies like Alkem, Sun Pharma, and Hetero Labs were implicated. The DCGI ordered the withdrawal of these drugs and called for stricter vigilance, highlighting ongoing issues despite regulatory frameworks being in place, which is known to all drug manufacturers, but still happening all over the county.

Industry Response:

After the DCGI’s September 2024 report on substandard drugs, responses from pharmaceutical companies were mixed. Many large firms cooperated, taking corrective steps to comply with Good Manufacturing Practices (GMP) and tightening quality control. Some acknowledged the need for stricter oversight and preventive measures.

As happens mostly, there has been notable pushback from a portion of the industry, particularly smaller and mid-sized manufacturers. These companies argue that the stringent audits and frequent shutdowns due to non-compliance are creating significant financial and operational pressures.

Interestingly, some large manufacturers claimed that the faulty products were counterfeit or spurious. This makes the scenario even more complex. Although, both endanger patient lives.

Decades of regulatory failures persist, but at what cost?

Back in June 2015, I highlighted that “Fake Drugs Kill More People Each Year Than Terrorism Over the Last 40 Years.” Shockingly, little has improved since then.

The problem is deeply rooted in nations with weak enforcement - India being a prime example. Alarmingly, the Ministry of Health has long downplayed this threat, as it appears now.

For example, even prior to that, in 2009, their “Report on Countrywide Survey for Spurious Drugs” grossly underestimated the issue, claiming only 0.046% of spurious and 0.1% substandard branded drugs. This underreporting reflects a dangerous “Ostrich Syndrome” among regulators, who continue ignoring this life-threatening crisis, leaving millions at risk.

The question I raised in this blog on October 12, 2015 2015 still haunts me today: “Does India produce ‘world-class’ medicines for all?” Effective checks and accountability are crucial to address this crisis.

To tackle counterfeit drugs, India needs a comprehensive strategy, such as:

Strengthen Regulation: Stricter inspections, penalties, and GMP adherence.
Leverage Technology: Implement digital tracking systems.
Improve Coordination: Better agency collaboration and audits.
Foster Industry Self-Regulation: Internal audits and regulatory partnerships.
Raise Public Awareness: Educate consumers, protect whistleblowers.
Adopt Global Standards: Align with international benchmarks.

Only with strong accountability can India safeguard drug safety.

While there have been reports of some progress, concerns remain:

A Business Standard report from October 02, 2024, highlights a regulatory crackdown on substandard drugs. However, this raises critical questions about the true effectiveness of these efforts. Upon closer inspection, the report reveals limitations that warrant deeper scrutiny. These include gaps in data coverage, inconsistent inspections, and doubts about the sustainability of the actions taken, which cast doubt on how far-reaching and impactful this so-called crackdown really is.

Some of the notable flaws that I find in the report include:

Lack of Comprehensive Data: The report focuses on inspected units, which represents only a small fraction of India’s vast pharmaceutical manufacturing sector, especially considering that 80% of India’s pharma units are micro, small, and medium enterprises that often escape the regulatory radar.
Limited sample size could misrepresent the true scale of substandard drug production.
Inconsistent Inspection Coverage: While the CDSCO has ramped up its audits, the inspection coverage appears uneven. Many smaller manufacturers, particularly those operating in less regulated states, may not face the same scrutiny as larger companies. This could skew the perception of improvement.
Global Discrepancies: Despite claims of reduced international complaints, the report doesn’t fully address concerns like the recent ban on Indian-made antibiotics by Nepal, signaling that quality issues persist in exports.. This suggests a gap between domestic inspections and international quality standards.
Sustainability Questioned: The report emphasizes short-term regulatory actions, but long-term sustainability is unclear. Temporary shutdowns and corrective actions might not be enough to ensure lasting quality improvements, especially in an industry facing systemic issues like weak documentation and quality control in smaller firms

In summary, while the report provides some optimistic updates, its credibility is limited by incomplete data, uneven enforcement, and questions about long-term impact.

Is entity-centric accountability grossly missing in this area?

Absolutely. The accountability of both regulators and pharmaceutical companies regarding substandard and counterfeit drugs in India has been alarmingly deficient for years. Despite recurring reports of poor drug quality, weak enforcement, and ineffective oversight persist.

Regulatory bodies have failed to consistently hold companies accountable, allowing dangerous drugs to flood the market and endanger public health. This systemic neglect, coupled with inconsistent audits and lax penalties, has led to a crisis that remains unresolved even today. Thus, the following two areas, I reckon, need to attract greater focus:

Regulatory Gaps: The Central Drugs Standard Control Organization (CDSCO) has faced criticism for being reactive rather than proactive, with irregular inspections and delays in addressing violations. The weak enforcement of Good Manufacturing Practices (GMP) and insufficient penalties for violators have allowed substandard drugs to continue circulating.

Pharma Companies’ Compliance: Many pharmaceutical companies have either ignored or downplayed the issue, sometimes blaming counterfeiters rather than addressing quality control lapses. While larger companies might cooperate after being caught, the lack of strict and consistent regulatory pressure has allowed many manufacturers to evade full accountability.

This lax accountability, both in the regulatory framework and among drug companies, has created an environment where the production and distribution of substandard and fake drugs continue to pose serious risks to public health in India. The need for stricter enforcement and transparent accountability is crucial for restoring trust in the system.

Conclusion:

Despite years of scrutiny, regulatory lapses in India’s drug industry continue to jeopardize patient safety. Weak oversight and inconsistent enforcement allow substandard and counterfeit drugs to flood the market, with deadly consequences.

Regulatory bodies have failed to take firm action, and pharmaceutical companies are often not held accountable. As a result, millions remain at risk, and trust in the healthcare system is eroding. The cost of these failures is measured in lives, and without immediate reforms, the crisis will only deepen.

This underscores the point that the time for complacency has passed – India’s healthcare system and public trust demand swift, decisive action against counterfeit and low-quality drugs, with clear accountability and stringent punitive measures for violators.

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.

Pharma’s Dual Challenge – To Save Lives And Livelihood

Posted on June 29, 2020 by Tapan Ray

“Jaan hai to jahan hai” (If you have life, you have the world). Prime Minister Modi - with a skillful tweak, used the couplet of the 18^th century poet - Mir Taqi Mir, while announcing the criticality of 21-day national lockdown from March 24, 2020 due to Covid-19 global pandemic. Many Indians lapped up this concept, considering it as a short haul sacrifice to save lives. Possibly, because the Prime Minister had said at that time, ‘Mahabharata battle won in 18 days, war against Coronavirus will take 21 days.’

As the Covid-19 went on a rampage despite the national lockdown, the Prime Minister, on April 11, 2020, changed it to ‘jaan bhi and jahan bhi’ (life also, the world also). This slogan seems to be more relevant in the emerging scenario.

After over a couple of months stringent national lockdown, the necessity and urgency of restarting active life started assuming a priority status for all concerned. But, the restarting process won’t be a piece of cake either – for anybody. As it would not only involve saving lives, but also – ensuring proper means of livelihood, making the industries gradually return to normal, and thereby revival of the country’s economy.

Dr. Ashish Jha, Director of the Harvard Global Health Institute, has summarized the nature of this challenge concisely, as quoted by the article – ‘Five key questions about India’s rising Covid-19 infections.’ This was published by BBC News on June 15, 2020. Acknowledging that India is in a very difficult situation, Dr. Jha said, “We are still early in the pandemic and we have a good year or so to go before we turn the corner. The question is what is the plan to get India through the next 12 to 16 months?”

Like many other industries, this is an arduous task to accomplish even for the drug industry, and for that matter – by any country. From the pharma industry perspective, I reckon, the commencement of the ‘restarting’ process, would pose a tough and dual challenge for many players – for different reasons. The current expectations require them going much beyond developing and delivering effective drugs and vaccine to win the Covid-19 war, and include the following, as well:

The population needs to develop either a vaccine-induced or a herd immunity, for a long-term protection against Covid-19. Pharma companies can facilitate the former one.
The entire population should have access to scientific evidence-based Coronavirus drugs and vaccine – at a price that most people can afford, to achieve the goal of vaccine-induced immunity.

In this article, I shall explore the ground issues in this area while confronting this dual challenge by the pharmaceutical industry, in general.

Developing herd immunity not an option for India:

As it is known to many, even without an effective vaccine, it is possible for the population to develop a herd immunity. However, in this situation, a very large population will need to get infected, with its consequent impact on healthcare infrastructure and people’s lives. But, it will possibly be foolhardy to even think about this option, particularly for any country, such as India.

Dr. Ashish Jha in the above article on the BBC News, has also captured this challenge, aptly. He articulated, ‘India cannot wait for 60% of its people to get infected to achieve herd immunity and stop the virus. ‘That would mean millions of people dead. And that is not an acceptable outcome.’ Moreover, India’s Covid-19 infection curve has not started flattening – there is no consistent and steady decline, just yet. Thus, a vaccine-induced immunity seems to be the only prudent choice for the country.

Other reasons why an early intervention is necessary:

A national lockdown in India was certainly necessary to save lives. However, its prolonged duration of over 3 months, has caused a widespread confusion, anxiety, and fear among the public regarding the disease. Consequently, it has created several unintended social consequences, such as disease related stigma, discrimination, besides triggering several serious health hazards. The World Health Organization (W.H.O) also recognizes this problem.

Instances of stigma and discrimination against medical personnel – doctors and health care workers are common and have already been reported. Similarly, those working in aviation, especially on flights that were sent to bring the Indians back from COVID-19 affected foreign land, also met the same fate. Interestingly, such instances are not uncommon even within various housing societies for high income groups and communities. The stigma associated with COVID-19 is real and here to stay, at least for some time.

Serious health hazards like, panic, depression and anxiety have also gone viral as the nation was observing lockdown. Experts, reportedly, have opined that the fear of contracting viruses, compulsorily going to institutional quarantine centers and rising number of deaths, among others, are big triggers for all. Many believe, various communications – formal and informal – to keep people indoors, have given rise to such unintended consequences involving average Indians.

These developments further reinforce the critical need for an early therapeutic intervention in the disease treatment and prevention areas, such as an effective vaccine, where pharma can deliver what it does the best, and sooner.

Green shoots of overcoming the first challenge are visible:

Although, the world has not reached there, just yet, some green shoots of overcoming the first challenge with scientific-evidence-based drugs and vaccine, are now in sight. Treating Covid-19 effectively with the old warhorse – dexamethasone at a very affordable price, is almost a reality today. W.H.O has also called to ramp up dexamethasone production for Covid-19 patients.

Meanwhile, a few other drugs, such as remdesivir and favipiravir have also received marketing authorization of DCGI for treatment of Coronavirus in India. Similarly, Oxford University and AstraZeneca’s experimental Covid-19 vaccine have, reportedly, entered the final stages of clinical trials. Scientists are now in the final assessment of how well the vaccine works in protecting people from becoming infected by the virus.

A shift in the most vulnerable population poses another tough challenge:

As the need to restart the economy of the country becomes paramount, alongside the urgency of saving lives and livelihood, a shift in the most vulnerable population for Covid-19 infection is clearly visible.

As many would know, Coronavirus pandemic started with the more affluent class of the society who mainly travel abroad for work or studies. However, it is now spreading fast in the lesser privileged social strata, including poor migrant labors and other marginalized population. The spread now spans across from affluent communities, right through densely populated slum areas. The trend keeps going north, as each day passes, as of now.

In such a situation, to contain the disease effectively, Covid-19 drugs and vaccine must be accessible and affordable to all. Making this requirement another tough challenge for the pharma industry – as and when the therapies receive marketing approval of drug regulators.

Recently available drugs are expensive, even in India:

From the recent trend it appears, unlike hydroxychloroquine or dexamethasone, most of these emergency use Covid-19 drugs, such as remdesivir or favipiravir may not be accessible and affordable to a vast majority of the population, as discussed below.

Like remdesivir, favipiravir is also, reportedly, the subject of at least 18 clinical trials involving more than 3,000 patients across India, USA, Canada, Italy, China, France, UK and other countries. Encouragingly, for the Oxford University developed Coronavirus vaccine, Serum Institute is expected to price it at Rs.1,000 per vaccine. Thus, for a family of 4 persons, it would cost around Rs. 4000. Be that as it may, lets have a look at the comparative clinical efficacy of cheaper and relatively expensive repurposed older drugs, against their respective costs.

Comparative efficacy and cost of a cheaper and expensive repurposed drugs:

While comparing the relative clinical efficacy of cheaper and relatively expensive repurposed drugs – against their respective costs, some interesting facts surface, as follows:

According to the reported results, published by FiercePharma in an article on June 24, 2020, dexamethasone treatment led to a 35 percent reduction in death rate among patients on invasive mechanical ventilation and 20 percent for those receiving oxygen without invasive ventilation. The dose used was, 6 mg of dexamethasone in a single dose per day – either orally or via intravenous injection – for ten days at a stretch. Whereas, the cost of Dexamethasone (0.5mg) in India, for a strip of 30 Tablets, is around Rs.6.00.

Similarly, the same article reported, remdesivir has been found to reduce the death rate among severe patients to 7.7 percent from 13 percent for placebo, a difference that was not statistically significant.Whereas, remdesivir in India, will cost around Rs 5,000-6,000/dose. And its recommended dose for adults and pediatric patients weighing 40 kg and higher, is a single loading dose of 200 mg on Day 1 followed by once daily maintenance doses of 100 mg from day 2 up to 5 to 10 days.

Similarly, favipiravir will be available in India as a 200 mg tablet at a Maximum Retail Price (MRP) of Rs 3,500 for a strip of 34 tablets. Whereas, its recommended dose is 1,800 mg twice daily on day one, followed by 800 mg twice daily up to day 14, according to its manufacturer.

An interesting fallout of Dexamethasone study:

An interesting fallout of the dexamethasone study on arriving at a fair price for remdesivir for treating Covid-19 patients, is worth noting. The Institute for Clinical and Economic Review (ICER) had earlier highlighted the “cost-effectiveness” benchmark price of remdesivir ranges from $4,580 to $5,080. However, ‘a new scenario analysis assuming the likely incorporation of dexamethasone as standard of care, produces a lower benchmark price range for remdesivir of $2,520 to $2,800.’

Conclusion:

As on June 28, 2020 morning, crossing half a million mark, the recorded Coronavirus cases in the country have reached 529,577 with 16,103 deaths. And the climb continues. In the context of the same disease, a publication of the London School of Economics and Political Science (LSE) had recently articulated: ‘In less than 3 months, COVID-19 has become a global pandemic of proportions we have not experienced this century. This has led to some of the largest economies in the world racing to develop a vaccine to combat the disease. However, in this time of urgency, patent laws may conflict with the equal provision of these future medicines worldwide.’

In sync with this sentiment, apprehensions of profiteering on drugs, tests, or vaccines used for the COVID-19 pandemic are mounting in almost all countries. Governments are now being encouraged to suspend and override patents and take other measures, such as price controls, to ensure availability, reduce prices and save more lives.

According to reports, Canada, Chile, Ecuador and Germany have already taken steps to make it easier to override patents by issuing ‘compulsory licenses’ for COVID-19 medicines, vaccines and other medical tools. Similarly, the government of Israel issued a compulsory license for patents on a medicine they were investigating for use for COVID-19.

From the industry, a strong demand for fiscal stimulus, such as the removal of the Health Cess and Customs Duty, to support patient access to critical medical products, is also gaining momentum, alongside the early release of Government payment to providers.

Thus, while exploring the dual challenge lying ahead for many pharma companies – to save both lives and livelihood – delivering effective drugs and vaccine may probably be an easier task than improving access to those – for all, in a meaningful way.

By: Tapan J. Ray

For Improving Drug Quality in India – A Bizarre Intent

Posted on January 29, 2018 by Tapan Ray

On January 16, 2017, quoting a Government source, a media report revealed, “India’s drug regulator is looking to inspect US pharmaceutical facilities, making critical medicines so that only high-quality products are imported from them.”

This intent follows a similar decision of the apex regulatory body – the Central Drugs Standard Control Organization (CDSCO), against some Chinese manufacturers on drug quality concern. The latest proposal to this effect was sent to the health ministry the previous week – the above report adds.

In this article, I shall explore the fundamental basis of this specific initiative. If it has any, I shall try to fathom whether it’s yet another case of misplaced priority of the decision makers, if not a bizarre one.

The current perspective:

About a couple of years ago, an article published in the global financial daily – the Financial Times, on September 9, 2015 titled, ‘Indian drugs: not what the doctor ordered’, articulated that the Indian pharma industry ‘now face a serious credibility crisis, as they battle to allay western regulators’ concerns about their manufacturing practices — especially the reliability of data from trials of their medicines.’

The report also pointed out: ‘Overseas regulators have been scrutinizing and banning products from some of India’s biggest and most reputable groups — including Sun Pharmaceuticals, IPCA, and Wockhardt – many of which have ongoing relationships with large multinational drug companies.’

Has anything changed now?

Nothing perceptibly seems to have changed in this area since then, to set our ‘own house in order’. Not even after witnessing a barrage of drug quality related ‘import bans’ by the US-FDA that involves Indian manufacturers of all sizes and scale. Instead, CDSCO turns its focus on setting-right ‘others’ manufacturing houses with its reportedly meagre manpower resources. Curiously, these initiatives include even those countries, which are globally acclaimed for having stringent regulatory frameworks well in place, such as the United States (US) and the European Union (EU).

Where a justifiable reason exists:

On Chinese API import by different countries, the article titled “Imports To Fuel India’s Active Pharmaceutical Ingredients’ Requirements,” published by Bloomberg | Quint on November 15, 2017 brings out a nice comparison. It says: ‘Among the top emerging and developing economies, India is a major importer of bulk drugs from China at 54 percent, followed by Indonesia at 24 percent, Brazil at 12 percent and South Africa at 8 percent.’ It also writes, in comparison, most of the developed markets of the world import in the range of just 2-3 percent from China.’

Going by this fact, Indian drug regulator’s inspection of some of the Chinese API plants is, by all means, understandable – mainly for two reasons. One, India is largely dependent on Chinese bulk drugs for formulations manufacturing and consumption in the country, besides exports. And the second, some incidents of compromised Chinese drug ingredients have already been reported. For example, citing quality issues, the Drug Controller General of India (DCGI) has recently, reportedly banned import of such questionable drug constituents from six major Chinese pharma companies. This is not a solitary instance. Similar incidents involving Chinese drugs were reported in the past, as well.

An irony:

When international media agencies flash headlines, such as “U.S. and EU regulators urge Indian drug companies to step up standards,” Indian drug regulators decide to inspect overseas manufacturing plants, as well. Such a decision becomes intriguing, especially when it includes those countries, where from imports are meager, besides their stringent drug quality standards being globally acclaimed.

This is an irony, as the recent local media headlines like, “India among countries where 10% of drugs are substandard: WHO” or “… 27 medicines sold by top firms ‘fail’ quality tests in seven states”, unfold the veracity of drug regulatory laxity within the country.

The basis of the recent proposal becomes more incomprehensible, when the DCGI himself reportedly admits, even today that: “Substandard medicines are a major issue in India and we are looking out for ways to tackle the problem. As quality regulator, we are developing proper mechanisms to stop manufacturing and sale of counterfeit drugs so that they don’t reach the patients.”

The reasons cited for overseas plant inspection:

According to media reports, the reasons cited in the CDSCO proposal for Indian Drug Inspectors’ (DI) inspecting other overseas manufacturers, including those in the US and Europe, are broadly as follows:

Most of over 28 manufacturing sites registered in India from the US, manufacture critical formulations or critical new therapies, which are not available in other countries, as they fall into high-risk categories.

Inspections will not only result in compliance to the Drugs and Cosmetics Act and Rules, but also give exposure to Indian drugs inspectors to new technology adopted in the manufacturing and state-of-the-art facilities.

The sites will be inspected if they have made substandard drugs, received quality complaints, or faced action by other regulatory authorities.

Companies shortlisted for the proposed inspections include those making biologic and anti-cancer medicines.

Let me hasten to add, there is nothing wrong with this intent as such, but the moot point is: what’s the core issue that we are talking about? While addressing this point, let’s first have a quick look at India’s import of pharmaceutical product around the last two decades.

India’s import of pharmaceutical products – 1996 – 2018:

According to ‘Trading Economics’ (last updated in January of 2018), India’s import of pharmaceutical products decreased to USD 254.57 Million in 2016 from USD 795.34 Million in 2015. Average drug imports are shown as USD 645.06 USD Million from 1996 until 2016, reaching an all-time high of USD 1747.65 Million in 2012, and a record low of USD 64.32 Million in 1996.

Nonetheless, the micro- picture of India’s bulk drugs or API import isn’t quite the same. On December 19, 2017 in a written reply to the Lok Sabha, the Minister of State, Chemicals and Fertilizers gave details of India’s bulk drug imports from top five countries, as follows:

Country	Import value Rs Crore	Import value $ Million (Approx.)
China	12,254.97	1915 (66%)
United States	820.18	128 (4.5%)
Italy	701.85	110 (3.8%)
Germany	485.11	76 (2.6%)
Singapore	422.01	66 (2.3%)
Total	18,372.54	2871

It’s worth noting, although the overall value of API import has declined, including from China, its volume share still remains too high in India. More importantly, Indian drug import from the United States and the European countries, are not only very small, there doesn’t seem to be enough instances of substandard drugs imported from these countries to India, either.

The core issue:

Taking a serious note of the reported incidences of widespread substandard drugs by various reports, including the WHO, the core issue becomes rather obvious. What else could possibly be the core issue other than taking effective remedial regulatory measures to contain the menace of substandard drugs circulating within the country?

An article titled, “Correcting India’s Chronic Shortage of Drug Inspectors to Ensure the Production and Distribution of Safe, High-Quality of Medicines,” published by the International Journal of Health Policy and Management (IJHPM) on April 27, 2017, made an important observation in this regard.

It reiterated: Good drug regulation requires an effective system for monitoring and inspection of manufacturing and sales units. In India, despite widespread agreement on this principle, ongoing shortages of drug inspectors have been identified as a major hindrance to this effort by the national committees, since 1975. Rapid growth of India’s pharmaceutical industry and its large export market makes the problem more acute.

Thus, the major remedial measure that CDSCO needs to take on priority to effectively address this core issue, is the chronic shortage of competent drug inspectors in the country.

An assessment of the current situation:

On the ground, the above situation continues to prevail almost in every state of the country, with a varying degree, though. However, at this point, I shall quote just three such instances – only to illustrate the gravity of the situation.

Example 1 – Delhi:

The article titled, “Delhi’s pharmacy woes: Only 21 inspectors for city’s 25,000 chemists,” published by ‘India Today’ on November 25, 2017, well-captured the latest scenario in this regard, of India’s national capital – New Delhi.

It wrote, there’s no guarantee that the medicine you are buying from a pharmacy is safe. The drug regulatory body does not have enough manpower to conduct regular inspections of the city’s mushrooming chemist shops and wholesale units.

Against the sanctioned posts of 31 drug inspectors, the department has only 21 DI for keeping an eye on Delhi’s 25,000 medical stores, and blood banks. Quoting Government officials the report reiterated, while the number of DI has declined – or at best remained constant – over the past 40 years, the number of pharmacies has increased from 5,000 to 25,000.

Whereas, going by the Centre’s recommendation, Dr. Mashelkar Committee report and the Task Force Committee’s observation, there should be one drug inspector for every 50 manufacturing units. Considering the magnitude of the problem, the Drugs Technical Advisory Board (DTAB), in a recent meeting, reportedly suggested, there should be one official for every 200 sales outlets, and one official for every 50 manufacturing units.

Example 2 – Kerala:

Another report of July 08, 2017, with a similar headline – “Remedial action needed in medicine market”, focused on one more important state – Kerala. It wrote that the Kerala has just 47 drug inspectors to monitor the entire State drug market that has over 20,000 drug stores, excluding those located in the hospitals. “In Kerala – the consumer of about 15 to 20 percent of drugs manufactured in the country, there are no quality checks taking place owing to the manpower shortage” – the article cautioned.

Example 3 – Maharashtra:

Yet another national media report of March 16, 2017 carried a headline ‘FDA faces staff shortage again.’ It discussed the same issue for a major State where the financial capital of India is located – Maharashtra. Giving details, the article pointed out that out of 160 posts of drug inspectors across Maharashtra, only 90 have been filled so far and of the 250 food safety officer posts, just 180 have been filled. More than 50,000 pharmacies, 15,000 wholesalers and over 8,000 manufacturing units, are supposed to be properly governed as per the regulatory rules and godliness, to ensure high quality drug safety standards, by this meager DI staff strength of the State.

Conclusion:

Against the above backdrop, it appears absolutely minimum to expect that CDSCO would make the public know, how does it plan to make the drugs manufactured for domestic consumption of high quality standards, as a safeguard to patients’ health and safety.

This calls for strict quality audits by the DIs of the individual states, at pre-determined periodicity, just as what US-FDA does to ensure exactly the same, for patients in their own country. With dwindling resources of DI, CDSCO seems to be continually failing in achieving this critical goal. There doesn’t seem to be any specific and transparent accountability criteria in place, for the CDSCO to comply with.

In this situation, the plan to audit the overseas manufacturing plants located in the US and EU for drug quality assessment, carving out a slice from the existing DI manpower strength, appears rather foolhardy. Moreover, the safety-risk for those imported medicines is apparently low, not just due to meager quantity of drug import, but also for stringent regulatory environment prevailing in those countries.

In view of all this, the media report on CDSCO’s plan to inspect US and EU pharma facilities, making ‘critical’ drugs to ensure high product-quality, is interesting. If it holds any water, the initiative may be construed by many not merely a case of misplaced priority, but a bizarre one, to say the least.

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.

Generic Drug Quality: Cacophony Masks An Important Note, Creates A Pariah

Posted on May 8, 2017 by Tapan Ray

In the ongoing debate between branded-generics and generic drugs without brand names, the concern about drug quality is occupying the center stage, with the former generally being painted in white, and the later in black – with no shades of gray in-between. Interestingly, many large domestic companies manufacture and sell both these genres of generic medicines, and the marketing approval process of both is no different, in a relative yardstick. The degree of difficulty in testing their quality standards, across the country, is no different, either.

On February 25, 2017, even the USFDA, reportedly, raised concerns, for the first time, on the quality and efficacy of medicines, in general, being sold within India. The news report further highlighted: ‘Over the past two years, many domestic majors, including Sun Pharma, Dr. Reddy’s, Cipla and Zydus Cadila have faced regulatory ire over quality of medicines exported from here and sold in the US and other overseas markets’.

It is undeniable, if prescriptions in generic names are made mandatory, there could be direct job losses within the industry, just as loss of significant business clientele of many professional service providers for branded generic business, directly or indirectly. Its net impact needs to be factored-in too, while taking a final decision on this subject.

Lack of enough credible scientific data establishing superiority of branded-generics over their non-branded equivalents are also striking, so are few instances of doctors filing Pharmacovigilance reports with the DCGI on the inferior quality of non-branded generic drugs. Neither is the most competent body in this area – the Central Drugs Standard Control Organization (CDSCO), has concurred with any such claims, so far. Without these, the whole debate based on seemingly over the top claims of superiority of branded generics as a class, is based no more than a matter of conjecture.

I discussed most of these points in one of my earlier articles published in this blog on April 24, 2017. Thus, in this article, I shall focus mostly on an important generic-drug-quality related amendment, very recently made in the Drugs and Cosmetics Act of India, which hasn’t received as much attention as it deserves. This finer note in the drug regulatory playbook, in fact, got nearly masked in the high-decibel cacophony of arguments and counterarguments on Prime Minister Modi’s recent hint on making prescriptions in generic drug names mandatory.

The core issue remains the same, both for non-branded and branded generics:

In the marketing approval process of any branded generic or a non-branded generic drug, Bioequivalence (BE) studies hold immense scientific importance. It ascertains whether the generic equivalent possesses similar efficacy and safety profile as the original molecule for interchangeability. Which is why, in most countries, including Europe and the United States, BE testing is mandatory for approval of any generic drug. Even the large buyers of these drugs, such as the World Health Organization, buy only those generics with proven BE.

Nonetheless, like many other nations, in India, as well, the marketing approval standards for all generic drugs, with or without a brand name, are exactly the same. However, this approval process gets alarmingly relaxed, for both these generic types, with the passage of time, which is the core issue.

New drug definition in India:

According to section 122-E of Drugs and Cosmetics Rules, 1945 (D&C Rules) new drugs will include unapproved drugs, modified or new claims, such as, indications, dosage forms (including sustained release dosage form) and route of administration of already approved drugs and combination of two or more drugs. A new drug shall continue to be considered as new for a period of four years from the date of its first approval or its inclusion in the Indian Pharmacopoeia, whichever is earlier.

BE studies necessary only for ‘New Drugs’:

For all such new drugs and their Fixed Dose Combinations (FDC), including those which are not covered by a patent, if introduced for the first time in India, would necessarily require its applicant to submit the marketing approval documents well-supported by phase III clinical trial data, which includes BE studies against the original molecules. BE of a drug product is achieved if its extent and rate of absorption do not show statistically significant differences from those of the reference product when administered at the same molar dose.

After the 4-year period BE tests not necessary:

Interestingly, after the 4-year period, D&C rules allow subsequent manufacturers of similar drugs to generally rely on the data generated by other pharma companies to obtain marketing approvals for their drugs. In other words, after this 4-year period, manufacturers of branded or non-branded generic drugs are not required to establish comparable safety and efficacy of their formulations with the original molecule through BE and other studies. It is worth noting here, unlike India, BE tests are mandatory for approval of all generic drugs at any time, in most countries across the world.

How would a doctor select only those branded-generics with BE studies?

As there isn’t any easy way to know and identify, both by the doctors and also the patients, which branded or non-branded generics were introduced without BE studies, both these categories pose equal risks to patients – not just the cheaper generic drugs sans brand names.

Changes recommended:

This laxity in the regulatory framework in India did create a lot of uneasiness about the quality of branded and non-branded generic medicines approved by the drug regulators and sold in the country. Responding to this issue, Professor Ranjit Roy Chowdhury Committee Report recommended in July 2013 to make BE and bioavailability studies mandatory for all types of generic drugs, even after the 4-year period.

Cacophony masks an important note:

The good news is, on April 3, 2017, by a Gazette Notification, Indian Government enacted amendments to the Drug and Cosmetics Act (1940) requiring mandatory BE studies for marketing approval of all generic drugs even beyond the 4-year period of the ‘new drug’ definition. It says, “The applicant shall submit the result of bioequivalence study referred to in Schedule Y, along with the application for the grant of a license of the oral dosage form of drugs specified under category II and category IV of the biopharmaceutical classification system.”

Biopharmaceutics Classification System:

The Biopharmaceutics Classification System (BCS) is a scientific framework to differentiate the drug formulations based on their aqueous solubility and intestinal permeability, and mainly depends on two factors:

How well the drug dissolves in the stomach and intestinal fluids (drug solubility)
How readily the drug passes through the intestinal wall into the blood flow (drug permeability)

The BCS was introduced by Gordon L. Amidon in 1995 to classify drugs into the four categories based on these parameters, as follows:

Class I: High Solubility – High Permeability
Class II: Low Solubility – High Permeability
Class III: High Solubility – Low Permeability
Class IV: Low Solubility – Low Permeability

CDSCO still needs to find the right answer to a key question:

Interestingly, this so important note in the regulatory playbook of India got masked in the high-voltage cacophony on branded and non-branded-generics. However, CDSCO would still require finding out the right answer to a key question: how would a doctor or a patient possibly know on which branded and non-branded generic drugs BE tests were not carried out, before the above amendment came into force.

Reported data on substandard drugs in India:

Quoting CDSCO data, the September-October 2015 issue of the ‘Indian Journal of Endocrinology and Metabolism’ summarized that ‘during the years 2011-2014, the regional laboratories tested samples at 91 percent of the installed capacity, but their overall detection rate of sub-standard drugs were only 3.6 percent’. Many have expressed doubts about these numbers though, nevertheless, these are Government data, and don’t fall in the realm of any conjecture.

In any case, the Union Ministry of Health doesn’t seem to concur that the issue of substandard drugs in India, that includes both the branded and non-branded generics, has assumed a public health menace in India or even alarming.

No qualms on value added branding of generic drugs, but fix the loophole for all:

It is understandable, when generic drugs are branded for tangible value-added product differentiation even within the identical or the same drug molecules. There are no qualms on such branding per se, though it comes at a high cost.

Marketing approval requirements being the same for all branded and non-branded generic drugs with the same pitfalls of no mandatory BE-testing requirement after the 4-year period, branding should add commensurate tangible value. Otherwise, why should most patients pay a significantly extra amount for heavily promoted branded-generics? Is it to help the pharma companies fighting with each other to increase their respective pies of revenue and profit on an essential commodity? Instead, stakeholders should now focus on easy detection of all those branded and non-branded generic drug formulations that avoided mandatory BE studies, prior to April 3, 2017.

In conclusion:

Despite CDSCO’s statistical data on substandard drugs, the general concern regarding the efficacy and safety of medicines manufactured in India is often raised both inside the country, as well as by some well-respected overseas drug regulators. Curiously, when raising the same concern CDSCO banned hundreds of branded FDCs, as these drugs came to the market without carrying out required scientific tests due to some major lacunae in the regulatory system, there was a huge protest in the country raised by almost the same people, as business interests prevailed over patients’ health interest.

Interestingly, displaying a sharp contradiction in today’s cacophony, patients’ health interest has been put in the forefront to protect business interests, especially when the CDSCO has raised no such concern, whatsoever.

The reverberating claims on superior drug quality for branded-generics as a class, over their cheaper non-branded equivalents, with the former generally being painted in white, and the later in black – with no shades of gray in-between, as I said before, is based mostly on conjecture rather than enough hard facts. Thus, the question comes up, who is responsible for ensuring drug efficacy and safety for the patients in India – CDSCO or non-fact based claims being raised mostly by those who have a direct or indirect financial interest in branded-generic business?

Keeping this in perspective, it is indeed intriguing, why such an important regulatory step of April 3, 2017 requiring mandatory BE studies for marketing approval of all generic drugs, even after the 4-year period, is getting masked in the cacophony, mostly favoring the branded-generics as a category. However, it’s no-brainer to understand that this din would continue, projecting all generic drugs sans brand names – a pariah!

By: Tapan J. Ray

In a Quandary of Drug Quality, Price Control, Innovation and Patient Interest in India

Posted on March 6, 2017 by Tapan Ray

The patients in India have every reason to apprehend, whether the prescription drugs that they consume are efficacious, safe and conform to the government approved prices, alongside another important question: Do they affordable access to the fruits of innovation?

The regulator responsible for drug quality in India is responsible for ensuring the first two, and the drug price regulator of the country ensures the remaining two.

Apparently, both these esteemed government bodies, are sure that they are doing the best jobs in their respective areas. Moreover, in these days of social media blitzkrieg, it won’t be uncommon to witness some of them, creating hype on some issues that many feel is better avoided, and at times even contradictory in nature.

Amid this seemingly chaotic continuity of the same or a bit deteriorating scenario, patients are often caught in an unenviable footing.

In this article, I shall discuss on these concerns afresh, quoting a few recent examples. My objective is to encourage all concerned to move away from incessant hype creation by accepting the reality, as the patients feel. This is necessary, because anyone, including the regulators can fall victim of such unfettered developments, at any point of time.

Thus, it may be appropriate for all to jettison any residual arrogance or a faint shade of narcissism, before putting the nose to the grindstone to resolve these pressing issues decisively, for patients’ sake.

Are we consuming effective and safe medicines?

I raised this question first in an article titled, “Are We Taking Safe and Effective Medicines?” published in this blog on November 13, 2013. That deliberation was primarily based on US-FDA ‘import bans’ from various drug manufacturing facilities in India, involving even the top Indian pharma players. Based on their own quality and safety audits, the US regulator had concluded that drugs produced in those factories are not safe for consumption by the patients in America.

This apprehension has now almost reached its crescendo, when on February 24, 2017, probably for the first time ever, US-FDA publicly voiced its apprehension about the efficacy of medicines being sold and consumed by patients in India. The observation came from the India director of the US-FDA in an annual conference of a large pharma trade association of some of the top domestic pharma companies. While commenting, “I do not think any one of us wants to take such drugs which lack efficacy”, the official reportedly revealed, he occasionally gets samples sent from the US embassy health unit in Delhi, and complaints are usually about the medicines not giving the desired results.

It is noteworthy, as earlier, rubbishing claims levelled by media expressing growing concern among overseas regulators over the quality of Indian made drugs, the Drug Controller General of India (DCGI) had reportedly strongly reiterated that there have been no lapse or compromise on quality parameters of the drugs manufactured throughout the country, as the efficacy of the drugs and safety of the patients have always remained the top priority of DCGI.

Yet another news article of August 22, 2016 reported that after a year-long survey involving Government, civil society and pharmacy professionals, and testing nearly 50,000 drug samples across the country during this period, the Ministry of health of India found that medicines produced in India are safe and effective. This study was kicked off in the wake of rising concerns that several medicines made in the country posed risks to patients, the report highlighted.

Should ‘Self-certification’ by industry prevail?

Intriguingly, when questions on drug quality manufactured in India, are regularly being raised by other equally responsible drug authorities, we find ‘self-certification’, in this regard, coming from all those who are expected to resolve this issue beyond an iota of doubt, always prevails.

Apparently, not just the drug regulator and the Union Ministry of Health are in a sustained denial mode, many large pharma companies also seem to be in the same mode. On March 01, 2017, the media reported, “Close on the heels of US FDA India office raising concerns over the quality of medicines marketed in India, pharma leaders came together to defend the quality of their products. There is no question of compromising quality of Indian products meant for domestic market and export, they pointed out.” This rebuttal was expected. Nevertheless, the apprehension lingers: Should such self-certification by pharma players prevail?

That said, one may try to justify this quandary by saying that effectively regulating over 20,000 domestic pharmaceutical companies, including third party and loan license manufacturers, poses a serious challenge to the DCGI and the State Drug Controllers. However, the moot point is, who has been encouraging such over-proliferation of drug manufacturing facilities over a long period of time, in any case? In that sense, whose prime responsibility is it to ensure that drugs consumed by patients in India are efficacious and safe?

The answer to these vexing questions continues to remain unanswered.

Did patients benefit from drug price control orders?

Let me first draw a brief sketch on the global perspective of price increases in generic drugs. It appears that in all those countries where there is no drug price control in place, the entire pharma industry is being adversely impacted by huge generic drug price inflation. This finding has been well captured in a study by Elsevier. It shows, between November 2013 and November 2014, out of its research sample of 4421 generic drug groups, there were price increases in 222 drug groups by 100 percent or more. In 17 drug groups price increases were taken even over 1000 percent, which include even tetracycline. With this trend sharply moving north, many patients, across the world, are struggling hard to find ways to survive in this situation. With this backdrop, I now get back to its India perspective.

I have read some media editorials questioning, just as the pharma industry, whether it is the right approach to make essential medicines affordable through drug price control in India? Nevertheless, there isn’t an iota of doubt in my mind that yes, it is, in the prevailing health care scenario of the country sans universal health care, with out of pocket expenses on medicines being the highest in the world and when market competition doesn’t bring down the price of medicines, for obvious reasons. My questions, on the contrary, will be, is drug price control being enforced in India the way it should? Are the patients getting commensurate benefits out of it? If not, why?

However, on the face of it, the answer to the question above “Did patients benefit from drug price control orders”, may appear to be an affirmative one. This is mainly because, on July 28, 2017, no less than the Union minister for Chemicals and Fertilizers, in a written reply to the Rajya Sabha reportedly conveyed that the Indian consumers have saved nearly Rs 5,000 crore due to the Government fixing the prices of essential medicines under the Drugs Price Control Order (DPCO) 2013.

The ground reality of drug price control:

Let me try to explore a bit in this area with some recent examples.

According to the data from India’s drug pricing watchdog – the National Pharmaceutical Pricing Authority (NPPA), compliance to various Drug Price Control Orders (DPCO) is far from satisfactory. Outstanding dues for non-compliance to notified ceiling prices, including penalty, from scores of pharma companies, have now reportedly piled up over the past two decades exceeding Rs. 4,551 crore (around USD 700 million). Thus, the same question haunts: Has drug price control benefitted the patients in India, as was intended to?

The situation is no different, even with DPCO 2013. On February 23, 2017, NPPA notified the ‘Suspected cases of Noncompliance of Ceiling Price by Pharmaceutical Companies,’ of 634 drugs, along with a ‘Public Notice’ for the same. This listed included the products marketed by some leading pharma companies in India, such as, Cipla, Abbott India, Alkem Labs, AstraZeneca, Dr Reddys Lab and Cadila, among many others.

Yet another fresh allegation related to drug pricing has just come to light. Interestingly, it relates to an anti-diabetic drug that falls outside DPCO 2013. On March 01, 2017, a news articled reported, “India’s drug regulator will look into allegations that four leading pharmaceutical companies are colluding to set the price of anti-diabetic drug Vildagliptin, a move that may rattle the almost Rs. 10,000 Crore (around USD 1540 million) market in the country.” Vildagliptin is a proprietary drug of Novartis, which has licensed it to three other companies. All of them sell Vildagliptin in India under their own brand names. Abbott sells it as Zomelis, USV as Jalra and Emcure as Vysov. The combined sales of these brands stood at Rs. 822 Crore (around USD 125 million) last year, the report states.

Be that as it may, the bottom line, as many believe, continues to remain unchanged, as it has always been – the patients don’t derive intended benefits due to lackluster and apparently ineffective enforcement of the drug price control in India.

Another crucial player:

Besides the two important and powerful Government authorities – DCGI and NPPA, there is another very critical player in this game – the Indian drug industry. Without whole-hearted cooperation and result-oriented action by all the three players, in tandem, nothing can possibly change this agonizing status quo, in this area.

The industry too is in a denial mode:

Quite like the other two critical constituents, who always deny any serious allegation on their actions, not being good enough to fetch the intended benefits for the patients, the drug industry too doesn’t seem to be any different. It always appears to be in a pre-programmed denial mode against all such allegations, irrespective of whether these are on drug quality, price, or on frequent misuse of the term innovation. They always try to justify their action, playing the victim card, as it were, and expecting other stakeholders to believe that they are doing right, always.

Let me now explore each of these areas separately, basically from the pharma industry perspective:

Drug quality: Pharma players, just as the Indian drug regulator, do not seem to accept that many drugs in India do not provide desirable benefits to patients, as alleged even by the US-FDA after studying some test results, following complaints from their local establishments. Many of us, at an individual level, may also have experienced just the same, and nurture the same doubt on the efficacy and safety profile of some branded generics that we consume, but have no wherewithal to prove the same. Doctors just change the brands, when any patient comes with such complaints, as Pharmacovigilance has not taken-off in the country with full steam, just yet. Thus, both the government regulators and the industry are in sync with each other, on this issue.

Drug price control: In this specific area, unlike the issue of drug quality, the respective stands of the government and the industry are poles apart. The former believes that it is working well, and the latter says, it isn’t.

The industry, as I see it, wants to project an impression that drug price control is the root cause of all evils, including compromises on drug quality, and some drugs going out of the market. The industry further highlights that drug price control offers a crippling blow to innovation, as they can’t garner enough financial resources through increased drug prices. It is another matter that they can’t possibly claim, drug price control offers a telling blow on their profit, as despite price control pharma is one of the highest profit making industry in India and globally too.

What innovation means to patients:

Interestingly, both the domestic and multinational pharma players often use the term of innovation, mostly construed as a façade, as it were, in their different advocacy initiatives, and during media outreach, as well. For global players, it primarily means innovation of new products, which offers monopolistic marketing and pricing advantage. Whereas, for generic players, it is generally process innovation, and different generic or biosimilar product development.

This is fine, but why should patients pay high drug prices, only because pharma players want to spend more on innovation, either for a new drug or a new process? I reckon, almost none will be willing to pay just for the heck of it.

Commensurate incremental price for incremental value:

Many patients, on the other hand, will be willing to pay more for any commensurate incremental value that a drug or a process will offer for a speedy recovery from illness, or to live a better quality of life, or for a lesser net treatment cost. Thus, the price of any brand is considered by stakeholders as a function of the value that it promises to offer. Consequently, brand marketing is deemed a value delivery system. For medicines, this value must be easily perceptible, quantifiable and scientific research based. Accordingly, the outcome of any such innovation should convince the regulators, doctors, hospitals and ultimately the patients – what value delivery – path breaking or incremental, for which patients need to pay commensurate incremental prices.

Various ways of ensuring it:

There are several different ways of addressing it, even for branded generics in India. For example, when branded generics of the same drug or similar FDCs of different drugs, are marketed by different companies with a huge price difference, the pharma players should necessarily submit before appropriate authorities, prior to marketing approval, all data regarding incremental and quantifiable value offerings, especially for those branded generics falling at the top of the price band. This is necessary, as an increasing number of brands in the market of the same generic molecules or the same FDCs, may not necessarily lead to greater competition with any significant impact on price. I shall argue on this point below.

What happens, generally:

For any drug falling outside price control in India, branded generic drug makers, usually set prices based on whatever each of them considers the market will accept. This consideration is highly elastic in nature, varying from a very low to a very high price, for any specific molecule and its FDCs. As I said before, it has been well-established by now that competition doesn’t play any significant role to bring down the branded generic drug prices, unlike many other consumables in different industries.

Why market competition doesn’t work for medicines?

This is primarily because, the purchasing decision for medicines does not depend on individual patients, unlike many other consumables. This decision is taken by the doctors while writing prescriptions for them. It is widely alleged, all over the world, that many important doctors are heavily influenced by the drug companies, often through dubious and highly cost intensive means, to prescribe their respective brands or branded generics in the process of treatment of a wide variety of medical conditions. In this rat race of generation of more and more prescriptions, pharma companies require to have a deep pocket to achieve their financial goals. Thus, many brands attract high prices to generate more profit and keep moving this vicious circle. Value based brand differentiation for many leading branded generics or even me-too patented products, aren’t mostly robust enough to stand any scientific or peer scrutiny. Consequently, the prescription demand of a most branded generics or me-too patented products do not have any linear relationship with the nature of market completion, and therefore, on their prices. In this perspective, setting a price for a pharma brand doesn’t depend on quantifiable value offerings for patients, as someone said before, “It is not a science. It is a feel.”

In conclusion:

The overall concern spans across several important public health and safety related issues, which also involve general quality standards of medicines, the effectiveness of drug price control, the core intent of so frequent use of the term ‘innovation’ in various pharma advocacy initiatives, including media outreach.

In this scenario, is the pharma industry, together with the drug quality and pricing watchdogs, failing to fathom the grave residual impact of continuity of this situation? In my view, this specific assumption appears too simplistic, naïve, and unrealistic. Or else, could it be that they are actually in a quandary, not being able to decide what would be the most effective actionable blueprint to resolve these issues?

I reckon, this is high time now for all concerned to accept the reality, seriously introspect on these critical issues, opt for a dip-stick expert analysis to assess the real status, and then work out a time-bound action plan with assigned accountability on the ground.

Together they may wish to address the following queries, among several others:

Why are they still running on a treadmill, as it were, over the last four decades, to come nearer these issues for better understanding, without moving an inch on the ground, despite public outcry?
Are they really in a quandary?
Are these concerns not an outcome of basically governance related failures?
Why hypes are being created all around on significant savings over out of pocket expenses on medicines because of ‘good enforcement’ of DPCOs, when it doesn’t seem so?
What prompts all the key players to be in a consistent denial mode on dubious drug quality standards in India, when foreign drug regulators are pointing it out in public?
Isn’t the term ‘innovation’ being rampantly misused, more as a major tool for advocacy to gain free pricing advantage?
Shouldn’t ‘Que Sera, Sera’ days change now?

By: Tapan J. Ray

Stem Cell Therapy in India: A Potential Game Changer in Disease Treatment

Posted on February 27, 2017 by Tapan Ray

Stem Cells (SC) offer an incredible potential to instill a new lease of life virtually to any organ of the human body, bringing them back to the pre-disease state through its own biological repair mechanism. Intensive research initiatives are on across the world to harness this unique possibility that will be able to successfully address a plethora of serious and chronic ailments for mankind. The good news is, the global scientific community is taking rapid strides in understanding the complex stem cell biology to give shape to a game changing medical treatment blue print for tomorrow.

Capturing one such pursuit, on February 21, 2017, well-reputed British news daily – ‘The Telegraph’, reported the outcome of a path-breaking medical study for freezing the progression of yet another complex and crippling ailment – Multiple Sclerosis (MS). This research followed a unique SC transplantation process. Intriguingly, both such diseases and the treatment are not generally much talked about, particularly in India. If done, it would increase public awareness and help many patients fetch greater benefits from the available and approved SC therapy in the country. Probably, considering the unfathomable scope of the body’s own repairing toolbox with SC, Prime Minister Narendra Modi reportedly called on Indian biologists to motivate school children for pursuing a career in stem cell research.

Let me now go back for a moment to Multiple Sclerosis (MS) as I am aware of this this disease condition rather closely. One of our close family friends who was a very senior official in one of the top multinational corporations of the world, had to give up his job prematurely being a victim to this serious illness. In that sense, this particular news item rekindles a new hope for many to look for a better quality of life while managing many other diseases of such kind, all over the world, including India.

‘The Telegraph’ reported: in so far, the largest long-term follow-up of SC transplantation treatment study of MS, which was spearheaded by Imperial College London, established that 46 per cent of patients who underwent this treatment did not suffer a worsening of their condition for five years. The treatment works by destroying the immune cells responsible for attacking the nervous system. This is indeed a very significant development in the space of medical research.

This new treatment, called autologous hematopoietic stem cell transplantation (AHSCT), was given to patients with advanced forms of MS who had failed to respond to other medications. However, the researchers noted that the nature of the treatment, which involves aggressive chemotherapy, carried “significant risks”.

It’s worth recapitulating here that MS is caused by the immune system malfunctioning and mistakenly attacking nerve cells in the brain and spinal cord, leading to problems with movement, vision, balance and speech. It’s a lifelong condition and often causes serious disability, with no cure still in sight. The disease is most commonly diagnosed in people in their 20s and 30s, although it can develop at any age.

A new hope with a game changing potential:

The above study of SC transplantation conducted by Imperial College London in MS, is just a recent example, among scores of major steps being taken in this frontier of medical science in preparation of a decisive battle against many more life-threatening and serious debilitating diseases.

No doubt that various treatments involving stem cells are generally considered a novel and rapidly advancing medical technology. However, in a small number of developed countries, such as the United States (US), a number medical procedures with stem cells are being practiced since around last three decades. Bone marrow transplant is the most widely used stem-cell therapy in this area, which was first performed in 1968.

According to California Institute for Regenerative Medicine (CIRM) and various other medical literature, SC treatment has the game changing potential for successful use to:

Replace neurons damaged by spinal cord injury, stroke, Alzheimer’s disease, Parkinson’s disease or other neurological problems
Produce insulin that could treat people with diabetes and heart muscle cells that could repair damage after a heart attack, or
Replace virtually any tissue or organ that is injured or diseased

Thus, stem cells offer limitless possibilities, such as tissue growth of vital organs like liver, pancreas. Today there are many diseases for which no effective treatment still exists, besides giving symptomatic relief, such as Multiple Sclerosis, Parkinson’s disease, Alzheimer’s, severe burn, spinal cord injury. There is a host of other diseases, including several chronic ailments, such as diabetes, heart ailments, rheumatoid arthritis, or some types of cancer, which can’t just be reversed, however, could be managed with a lifelong treatment. For most of these diseases, and several others involving tissue degeneration, SC therapy has the potential to be a huge life and a game changer. It may involve, besides patients, several industries, including pharmaceuticals and biotech sectors.

Major stem cell sources and some key milestones:

Medical scientists and researchers have conclusively established that stem cells are the master cells of any human body. These are undifferentiated cells of the same lineage, retaining the ability to divide throughout life and grow into any one of the body’s more than 200 cell types. Some of the major sources of stem cells in the human body are bone marrow, cord blood, embryonic cells, dental pulp and menstrual blood.

As captured by ‘ExploreStemCells’ of UK, some key events in stem cell research include:

1978: Stem cells were discovered in human cord blood
1981: First in vitro stem cell line developed from mice
1988: Embryonic stem cell lines created from a hamster
1995: First embryonic stem cell line derived from a primate
1997: Cloned lamb from stem cells
1997: Leukemia origin found as hematopoietic stem cell, indicating possible proof of cancer stem cells
1998: University of Wisconsin isolated cells from the inner cell mass of early embryos and developed the first embryonic stem cell lines.
1998: Johns Hopkins University derived germ cells from cells in foetal gonad tissue; pluripotent stem cell lines were developed from both sources.
1999 and 2000: Scientists discovered that manipulating adult mouse tissues could produce different cell types. This meant that cells from bone marrow could produce nerve or liver cells and cells in the brain could also yield other cell types.

All these discoveries were exciting for rapid progress in the field of stem cell research, along with the promise of greater scientific control over stem cell differentiation and proliferation. Currently, many more research studies are underway in globally acclaimed institutions and other boutique laboratories exploring the possibility of wide scale use of SC therapy, even in the treatment of several chronic diseases, including diabetes and heart disorders.

A controversy:

The controversy related to SC research mainly involves Embryonic Stem Cells (ESC) and raises several difficult questions for a speedy resolution. As articulated by the ‘Genetic Science Learning Centre’ of the University of Utah, these are mainly:

Does life begin at fertilization, in the womb, or at birth?
Is a human embryo equivalent to a human child?
Does a human embryo have any rights?
Can destruction of a single embryo be justified to provide a cure for a countless number of patients?
Since ESC can grow indefinitely in a dish and can, in theory, still grow into a human being, is the embryo really destroyed?

However, in 2006 scientists learned how to stimulate a patient’s own cells to behave like embryonic stem cells. These cells are reducing the need for human embryos in research and revealing exciting new possibilities for stem cell therapies, according to this Centre.

Stem cell research in India:

India has pursued SC research since over a couple decades reasonably supported by the Government, especially the Department of Biotechnology (DBT), besides several remarkable initiatives from the private sector. Ethical guidelines in this regard are also in place, so also are the National Guidelines for Stem Cell Research in India. These guidelines are aimed at obtaining licenses from the Drug Controller General of India (DCGI).

Further, in a major move to regulate and oversee the activities by streamlining SC research in the country, the Government has also set up an Institutional Committee for Stem Cell Research and Therapy (IC-SCRT) and the National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT). This necessitates the researchers on human stem cells, both institutions and the individuals, to be registered with NAC-SCRT through IC-SCRT. To ensure that the concerned companies and individuals follow the National Guidelines, these committees will review, approve and monitor each research project in this area. It now calls for even greater focus from all other stakeholders to help accelerate growth of this niche segment of medical science for patients’ benefits.

SC transplantations using umbilical cord blood and bone marrow for treating neurological, hematological, hepatic and cardiac disorders are being pursued by some well-known medical institutions, such as, AIIMS, PGI Chandigarh, CMC Vellore, AFMC Pune, Manipal Hospital Bangalore. For example, AIIMS, reportedly, undertook a major multi-center trial to look at the role of stem cells in repairing tissue damaged during acute heart attacks, where other treatment process, including a cardiac bypass surgery fails to adequately improve the heart function. Similarly, Shankar Netralaya in Chennai has successfully carried out limbal stem cell transplantations for restoring vision to several patients.

That said, this is a cost intensive area of research, which involves expensive equipment, reagents and other consumables. Moreover, ensuring continuous training for SC researchers and clinicians also poses a major problem. Greater international collaboration in this area, and increasing number of Public-Private-Partnership (PPP) could accelerate the progress of India in this hugely promising area of medical science, reaping a rich harvest for a large patient population of the country.

Stem cell banking:

SC banking is a fast-developing area in this field, especially designed for SC therapy. As not many patients are not currently as much aware or interested in SC therapy as they ought to, it may not appear as an immediate requirement for many. However, an encouraging trend is fast catching up, especially within some enlightened persons, to have in a bank a large reserve of their own or their baby’s stem cells that would be available for any medical emergencies or more effective treatment options, in the future.

It assumes increasing importance because, as we age, illness and the natural process of aging could reduce the number of stem cells available to regenerate organs, muscles and bone. At that time, while treating a serious illness or a grave injury, a person may have fewer adult stem cells that have the collective power to make an effective healing response to SC therapy.

In that context, SC banking provides a great opportunity to store, multiply and utilize a newborn’s or even an adult person’s younger and healthy stem cells for SC therapy during any medical emergency, such as a serious accident or a crippling illness, at a later stage in life.

There are broadly the following two types of SC banking facilities are now available in India:

A. Cord blood stem cell banking:

This is type of SC banking is the process of collecting, processing, cryogenically freezing and preserving the ‘Cord blood’ that remains in the vein of the umbilical cord and placenta at the time of birth, for potential future medical use during SC therapy. Stems cells extracted from the umbilical cord blood have been shown to be more advantageous than those extracted from other sources such as bone marrow. These banked stem cells are considered as a perfect match for the lifetime of the donor baby, and for other family members, as well. This is significant as there exists a greater chance for success in a stem cell transplant between siblings than with unrelated donors and recipients.

B. Adult stem cell banking:

Some state-of-the-art adult stem cell banking services are either already available or in the process of coming up in many places of the world, including India. As an individual’s fat (adipose tissue) is an important source of adult stem cells, with the application of a high precision medical technology of separating, multiplying, and storing adult adipose tissue-derived mesenchymal stem cells for autologous use by physicians, ‘Adult stem cells are stored in these banks.

The good news is, increasing awareness in this area has now started prompting many parents, and also some adults to bank or store their own SC and the baby’s cord blood rich with a specific types of stem cells, that can be utilized, at a later date, in a variety of SC therapy while treating many life-threatening and debilitating diseases, if required.

Types of stem cell therapy:

There are two major types of SC therapies, and both are available in India:

Autologous stem cell therapy: uses the adult patient’s own stem cells obtained from the blood, bone marrow.

Allogenic stem cell therapy: uses donated stem cells, but faces chances of donor stem cell rejection.

As articulated in the revised stem cell guidelines, stem cells can’t be offered to patients in India as ‘therapy’ unless these are proven effective and safe supported by unequivocal clinical trial data and approved by the DCGI. Otherwise, these can be used only in ‘clinical trials’ as will be approved by the DCGI. The only exception to this is the use of haematopoietic (blood forming) stem cells for treating blood disorders, which is considered as ‘a proven therapy,’ according to available reports.

The Market – Global and India:

September 14, 2015 issue of ‘The Pharma Letter’ stated based on a recent report that the global stem cells market was valued at US$ 26.23 billion in 2013, and is estimated to be worth US$ 119.52 by 2019, registering at a Compounded Annual Growth Rate (CAGR) of 24.2 percent. Whereas, in India, the stem cell market is expected to be around US$ 600 million by 2017. Another report, titled ‘India Stem Cells Market Forecast & Opportunities, 2020’ of ‘Pharmaion’, states that stem cells market in India is expected to grow at a CAGR of over 28 percent during 2015 – 2020.

In terms of services offered, stem cells market in India has been segmented into two main categories, namely SC banking, and SC research. The latter dominated the market in 2014, and is likely to continue its dominance through 2020. Adult stem cells accounted for the majority share in India’s SC market in 2014, as a lot of research being carried out using adult stem cells, besides growing adult stem cell banking and other associated applications in therapeutics.

The major growth drivers for SC market are: increasing patient awareness, an increase in the approval for clinical trials in stem cell research, growing demand for stem cell banking services,

Government support, rising investments in research, and ascending trend of development for regenerative treatment to meet unmet medical needs.

The first stem cell based product approval in India:

On May 30, 2016, a Press Release of ‘Stempeutics Research’ of Bengaluru announced that for the first time in India, DCGI has granted limited approval for manufacturing and marketing of its allogeneic cell therapy product named Stempeucel® for the treatment of Buerger’s Disease – a rare and severe disease condition affecting the blood vessels of the legs, which finally may require amputation. Stempeucel® treatment is designed to enhance the body’s limited capability to restore blood flow in ischemic tissue by reducing inflammation and improving neovascularization. The prevalence of Buerger’s Disease is estimated to be 1,000,000 in India and two per 10,000 persons in the EU and US, as the release stated. Stempeutics Research’ is a company of Manipal Education & Medical Group and a Joint Venture with Cipla Group.

Conclusion:

Research on stem cells, across the world, is taking rapid strides. It has already demonstrated its healing power in changing many human lives either by significantly stalling the progression of several serious ailments, such as Multiple Sclerosis (MS), or reversing the disease conditions, such as serious damage to the heart caused by massive myocardial infarction.

An increasing number of stem cell banks coupled with growing public and private investments in stem cell research, positive narratives are getting scripted for this space in India. With rapidly growing middle class population and comparatively less stringent rules and regulations, India is emerging as a perfect destination for many more global and local stem cell banking companies. Consequently, the stem cell market in the country is expected to witness robust growth in the coming years.

However, only future research on stem cells will be able to unravel whether an Alzheimer’s victim will get back the stolen memory; a cancer patient won’t have to mentally prepare to die of cancer anytime soon, besides spending a fortune towards cancer therapy; an insulin dependent diabetic will no longer require insulin; an individual with damaged heart won’t have to continue with lifelong medication, and it goes on and on.

Nevertheless, if it does… and God willing – it will, ‘Stem Cell Therapy’ would not just be a life changer for many patients, it will be a game changer too for several others, including the pharma, biotech companies and many more within the healthcare sector. If any skeptic still asks, will it really happen? My counter question, in response, will be: Why not?… Why the hell not?

By: Tapan J. Ray

Even Smaller Countries Now Question Indian Drug Quality Standard

Posted on December 5, 2016 by Tapan Ray

India has over 135 US-FDA approved pharmaceutical manufacturing units, at present. This number is very significant ranking second behind the United States, and was driving the growth of generic drug exports in the top pharma market of the world. Riding on the wave of such stellar progress, a hubris seems to have set in the related operational areas of many Indian pharma players, especially the drug exporters.

This incredible ride continued, until a first major jolt shook all concerned in this business. It came first in the form of an unprecedented hefty fine for wrong doing, followed by the US- FDA ‘import bans’ of several drugs, manufactured around 44 different Indian drug-making facilities, since over the last five years.

The first major jolt:

Not so long ago, just in 2013, quality related concerns with generic drugs exported from India came to the fore, after Ranbaxy reportedly pleaded guilty and paid a hefty fine of US$ 500 million for falsifying clinical data and distributing ‘adulterated medicines’ in the United States.

Thereafter, US-FDA banned drug imports from Ranbaxy and Wockhardt, manufactured in all those facilities that failed to conform to its cGMP quality standards.

Those are the stories for generic formulations. It then covered the Active Pharmaceutical Ingredients (API) too. On January 23, 2014, USFDA notified Ranbaxy Laboratories, that it is prohibited from manufacturing and distributing APIs from its another Indian manufacturing facility in Toansa. With this step, erstwhile Ranbaxy had virtually no access to the top pharmaceutical market of the world.

Was it for raising the bar of quality norms?

Many of us felt and expressed that ‘import bans’ of Indian drugs due to failing quality parameters, manufactured in certain facilities of largely Indian pharma companies, are mostly due to higher stringent quality norms of the US-FDA, the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA). Nevertheless, this argument does not carry much weight, as an exporter will always have to conform to the set quality standards of the importers, whatever these are.

Indian drug regulator too made a much avoidable remark:

Unfortunately, amid such a scenario, instead of taking appropriate transparent and stringent measures, the Drug Controller General of India (DCGI) was quoted by the media saying, “We don’t recognize and are not bound by what the US is doing and is inspecting. The FDA may regulate its country, but it can’t regulate India on how India has to behave or how to deliver.”

The DCGI made this comment as the then US-FDA Commissioner Margaret Hamburg was wrapping up her a weeklong maiden trip to India, in the wake of several ‘Import Bans’ arising out of repeated cGMP violations by some large domestic generic drug manufacturers. Whereas, Hamburg reiterated the need for the domestic drug manufacturers conform to the USFDA quality standards ensuring health and safety for American patients, the DCGI’s above comment appears rather arrogant, out of tune, and was avoidable, to say the least. Instead, some serious corrective regulatory measures should have followed.

On the above comments of the DCGI, the American Enterprise Institute reportedly reacted by saying, “Indian drug regulator is seen as corrupt and colliding with pharma companies…”.

Smaller countries initiated similar action:

It now appears that this situation is going from bad to worse and malady is much deeper. Smaller countries, such as Vietnam, have recently banned products of a sizable number of domestic pharma exporters.

On September 5, 2016, a leading business daily of India reported: “Close on the heels of Prime Minister Narendra Modi’s visit to Vietnam to strengthen bilateral ties, including defense, security and trade, the ministry of commerce and industries is planning to set up a committee, along with the Central Drugs Standard Control Organization (CDSCO), to inspect Indian pharmaceutical companies which have been banned from Vietnam for exporting sub-standard drugs.”

In 2014, the Drug Regulatory Authority of Vietnam ‘red-listed’ about 50 pharma companies for alleged regulatory non-compliance in their manufacturing practices. The names included, some big names of Indian pharma industry.

Overall pharma market size of Vietnam is estimated over US$ 2 billion, and expected to grow to US$ 8 billion by 2020. A significant chunk of Vietnam’s pharmaceutical market comprises of generic drugs, where India used to be a major exporter. In the recent years, however, Indian pharmaceutical product exports to Vietnamese market have dipped considerably, reflecting the effects of the ban, with exports declining by 12 percent to US$ 146 million in 2015-16 from US$ 165 million in the previous fiscal year, the report said.

It was envisaged, especially after the Prime Minister’s visit to Vietnam, this situation will improve notably. However, just as what happened with the USFDA on related issues, there has been no change in the overall situation in this case, either.

Further, on November 23, 2016, yet another Indian Business news daily reported that 39 Indian drug companies have been blacklisted by Vietnam for quality standard violations, along with some others in Bangladesh and South Korea. The Vietnamese regulator has listed the names of all blacklisted companies on its website, without specifying in detail the exact reason behind the bans. The Indian products include, antibiotics and anti-rabies vaccine, among others. The latter was also reportedly banned by the World Health Organization (WHO), in January 2016.

What is more intriguing, despite the Union Ministry of Health and the Ministry of Commerce and Industries of India being aware of it, the issue seems to have drifted beyond reasonable control of the Indian regulators.

Some local companies still not acting:

On Feb 24, 2016, the US and the EU drug regulators reportedly called upon India’s pharmaceutical sector to step up efforts to improve manufacturing standards, and ensure the reliability of data, if it wishes to maintain its dominance in the generic drug industry. In the report, the director of the office of surveillance at the USFDA – Russell Wesdyk was quoted saying, “some Indian companies are still not taking enough steps to identify risks and failures at their firms.”

“Data integrity really sounds-off alarm bells for us. If you see data integrity on the surface, there is likely a lot going on underneath,” the foreign drug regulators reportedly commented.

These comments are profound, especially considering that India supplies about 33 percent of medicines sold in the United States, and nearly a quarter sold in the UK. Similar Indian drug quality related issues are now being raised by even smaller countries.

How safe are drugs for domestic consumption?

Many reasons may be attributed to quality concerns on Indian generics in the United States. Nonetheless, another question that surfaces alongside, if cGMP violations can take place for drug exports, despite rigorous compliance checks by the foreign drug regulators, what could possibly happen when the same system is so tardy in India? Are we consuming safe and effective drugs, whenever required, even within the country?

No one seems to have the right answer to this question, be because of various reasons. One such reason, out of various others, could well be how robust is data quality generated by the contract manufacturing companies? These are the core quality related issues, and can’t just be wished away, under any pretext.

Some examples:

On November 12, 2013, the DCGI was quoted saying that the investigative team of the drug regulator concluded that all the data submitted by Puducherry-based contract drug manufacturer ‘GuruFcure’, while seeking approval for manufacturing seven fixed dose combination drugs, are ‘fabricated’ and not ‘authentic’.

‘GuruFcure’, which started operations in 2007, and calls itself “one of the leading pharmaceutical formulation manufacturers in India”, reportedly used to manufacture drugs for some leading pharma MNC and Indian companies, such as: Abbott, Alkem, Glenmark, Wockhardt, Unichem, Intas Pharma, among others.

Though, as per the above media report, Wockhardt and Glenmark said that they were no longer associated with ‘GuruFcure’ at that time, the fact remains, they did market drugs produced by this contract manufacture in the past, and the patients consumed those drugs against doctors’ prescriptions. The saga continues unabated, even today.

On November 28, 2016, a major national English daily reported with a video clip that, following a crackdown since March this year, the drug regulators of seven states have alleged that 27 medicines, sold by 18 major drug companies in India, including Abbott, GSK, Sanofi, Sun Pharma, Cipla, Torrent, Alkem, Emcure and Glenmark Pharma, are of substandard quality, citing grounds such as false labelling, wrong quantity of ingredients, discoloration, moisture formation, failing dissolution test and failing disintegration test. Such allegations, though supported by laboratory test results, needs to brought to their logical conclusion. This is mainly because, media reports of this nature fuel lurking apprehension on the overall drug quality standards in India, leading to serious compromise with patients’ health and safety.

Conclusion:

Against this rather gloomy backdrop, a ray of hope comes from a report that CDSCO has started training Indian drug manufacturers in good manufacturing practices, as it tries to address concerns of the USFDA, and other drug regulators, effectively.

Quoting the DCGI, who has now apparently resolved to put together proper practices and regulation in place for the pharma industry, the report says that CDSCO has hired 500 personnel, and is expected to further train employees of other units, to ensure that high quality medicines are manufactured in the country.

These officials will visit drug manufacturing hubs of the country over the next three to four years and train employees in producing quality medicines, following proper procedures and maintaining records. I hope, this will include contract manufacturers too. The question would remain: What happens when these regulatory lapses do not take place out of ignorance or lack of experience or expertise, but are purely intentional to cut corners?

Alleged dubious quality of many drugs manufactured in India is a critical issue, both within the country and with several foreign drug regulators, such as US-FDA, EMA and MHRA, among others. It affects all those who consume such drugs.

Today, even smaller countries are questioning Indian drug quality to protect their patients’ health interest. Thus, everything, when clubbed together, sends a strong signal to the Indian drug regulator to come out of its denial mode, walk the talk, and act decisively to safeguard the interest of Indian patients too.

By: Tapan J. Ray

Escalating Antibiotic Resistance, And Thwarting Ban Of Irrational FDCs

Posted on November 21, 2016 by Tapan Ray

September 2016 ‘Fact Sheet’ of the World Health Organization (W.H.O) raised a red flag on fast increasing incidence of Antimicrobial Resistance (AMR). It poses a serious threat to global public health, more than ever before. Consequently, effective prevention and treatment of an ever-increasing and complex range of infections caused by bacteria, parasites, viruses and fungi are becoming more and more challenging.

In this situation, various medical procedures, such as, organ transplantation, cancer chemotherapy, diabetes management and major surgery like, caesarean sections or hip replacements, invite much avoidable a very high element of risk.

Further, a July 2014 paper titled ‘Antibiotic resistance needs global solutions’, published in ‘The Lancet’ reports increase of incidences of drug-resistant bacteria at an alarming rate. In fact, antibiotic resistance is one of the most serious threats in the history of medicine, and new antibiotics and alternative strategies should be sought as soon as possible to tackle this complex problem.

Another more recent paper titled ‘Fixed-dose combination antibiotics in India: global perspectives’, published in ‘The Lancet’ on August, 2016 finds that nowhere in the world this problem is as stark as in India. It emphasizes that the crude infectious disease mortality rate in India today is 416.75 per 100,000 persons, which is twice the rate prevailing in the United States. Misuse, or rather abuse, of Antibiotics is a major driver of resistance. In 2010, India was the world’s largest consumer of antibiotics for human health, the paper says.

Thus, this critical issue calls for urgent action across all government sectors and the society, in general, as W.H.O cautions.

The Devil is also in irrational antimicrobial FDCs:

The reasons for the fast spread of antimicrobial resistance are many, and each one is well documented. One such factor is the use of irrational antimicrobial FDCs. Some of these have already been banned by the Union Government of India, though continue to be manufactured, promoted, prescribed, sold and consumed by the innocent patients unknowingly.

In this article, I shall focus on the banned FDCs of such kind, highlighting how the consequential serious threat to public health and safety is repeatedly getting lost in the cacophony of protracted court room arguments against these bans.

Irrational FDCs and antimicrobial resistance:

That ‘irrational’ FDCs of antibiotics very often hasten the spread of antimicrobial resistance, is now a well-documented fact.

The ‘National Policy for Containment of Antimicrobial Resistance in India 2011’ clearly recognizes that: “Antimicrobial resistance in pathogens causing important communicable diseases has become a matter of great public health concern globally including our country. Resistance has emerged even to newer, more potent antimicrobial agents like carbapenems.” The Policy also recommends removal of irrational antibiotic FDCs from the hospital drug list.

‘The Lancet’ article of August, 2016, as mentioned above, also reiterates, while citing examples, that “Studies of several antibiotic combinations, such as meropenem and sulbactam, have reported no additional advantage over their individual constituents, and have been reported to cause toxic reactions and promote resistance. Despite repeated investigations into the shortcomings of some FDCs, such drugs are still being manufactured and promoted on the Indian drug market.”

Why does it matter so much?

Corrective regulatory measures to contain the spread of antibiotic resistance are absolutely necessary in India, for the sake of the patients. According to a paper titled ‘Antibiotic Resistance in India: Drivers and Opportunities for Action’, published in the PLOS Medicine on March 2, 2016: “Out of around 118 antibiotic FDCs available in the Indian market, 80 (68 percent) are not registered with the Central Drugs Standard Control Organization (CDSCO). Moreover, 63 (19 percent) of around 330 banned FDCs are antibiotics.”

The global relevance:

Such regulatory bans of antimicrobials FDCs in India are important from a global perspective too, as ‘The Lancet’ article of August 2016 observes.

The article recapitulates that the ‘New Delhi metallo-β-lactamase’ – an enzyme that causes bacteria to be resistant to antibiotics, was first reported in India in 2008 and is now found worldwide. The growth of worldwide trade and travel has allowed resistant microorganisms to spread rapidly to distant countries and continents. In addition, some of these banned FDCs in India are reported to be exported to African and Asian countries too.

That said, each country will also need to play a significant role to curtail the abuse or misuse of antibiotics, locally. I find a glimpse of that in England, besides a few other countries.

A research paper of Antibiotic Research UK and EXASOL dated November 12, 2015, concluded that overall antibiotic prescriptions are coming down across England. However, the same paper also articulated that in the deprived areas of the country, such as Clacton-on-Sea, antibiotic prescribing rates are almost twice the national average.

Some big MNCs are no different:

In the Government’s ban list of irrational FDCs even some top brands of pharma MNCs feature, including antibiotic FDC of antibiotics. For example, on Mar 14, 2016, Reuters reported that one of the largest pharma MNCs operating in India – Abbott Laboratories, was selling a FDC of two powerful antibiotics Cefixime and Azithromycin, without approval of the DCGI. This could possibly be a legacy factor, arising out of its acquisition of a good number of branded generic drugs, together with their management, from a domestic pharma company. Abbott, otherwise is well regarded by many as a distinguished global institution, practicing high standards of business ethics and values, across the world.

Be that as it may, this powerful antibiotic cocktail that poses huge health risk to patients has reportedly not received marketing approval in the major global pharma markets, such as, the United States, the United Kingdom, Germany, France or Japan.

The Reuters report also elaborates that the drug ‘had been promoted and administered as a treatment for a broad array of illnesses, including colds, fevers, urinary tract infections, drug-resistant typhoid and sexually transmitted diseases.’ It also found chemists who were selling the drug to prevent post-operative infection and for respiratory problems. After the ban, the company has reportedly stopped manufacturing and sales of this antibiotic FDC.

Irrational FDC ban – a significant corrective measure:

Keeping all this in perspective, the regulatory ban on irrational FDCs of antibiotics on March 10, 2016, along with products falling in several different therapy areas, was a significant regulatory measure, among many others, to contain the menace of AMR in India.

Unfortunately, quite a lot of these formulations are still in the market, actively promoted by their manufacturers and widely prescribed by the doctors, till date. This is mainly because, to protect the revenue and profit generated from these brands, concerned pharma companies have obtained an injunction from various high courts against the ban, which was notified by the Government, earlier.

Thwarting FDC ban – a key issue:

Looking back, 294 FDCs were banned by the DCGI in 2007. At that time also, the same important issue of patients’ health, safety and economic interest got caught in an intriguing legal quagmire. As a result, implementation of the Government’s decision to ban of these irrational FDCs got delayed, indefinitely.

Added to this, irrational antimicrobial FDCs featuring in the ban list of March 10, 2016, got trapped in exactly the same legal battle, yet again. Thus, repeated stalling of Government ban on irrational FDCs, including antibiotics, continue to remain a key health and safety issue in India.

The latest development:

In September 2016, the Union Government has reportedly moved the Supreme Court of India in defense of its March 2016 ban on irrational FDCs.

In its petition, the Union Government has reportedly urged that all cases against the orders related to ban of ‘irrational’ FDCs, now being heard in various High Courts across the country, be transferred to the apex court and heard as a single case. The move is expected to cut any ambiguity that could arise from differing verdicts between high courts.

In case of a verdict favoring the ban of all the notified irrational FDCs, scores of patients will be benefited by not just falling victims to possible health menace arising out of such unjustifiable drugs, as the Government argues, but also due to expected containment of rapid spread of deadly antimicrobial resistance in the country.

Conclusion:

With the ban of irrational FDCs, the Union Ministry of Health has taken one of the much-needed steps to restrict antibiotic resistance in India, besides addressing other health and financial menace caused by such drugs.

The support of the Apex court of India to urgently resolve this legal jig-saw-puzzle, would also help control, though not in a holistic way, the scary antibiotic resistance challenge in India. In that process India would possibly be able to contribute its little bit towards the antibiotic resistance challenge, across the world, if we consider the ‘New Delhi metallo-β-lactamase’ case as a glaring example in this area.

It is, therefore, widely expected that for the greater public interest, the honorable Supreme Court may view this important health and safety issue accordingly, while pronouncing its final verdict. If and when it happens, hopefully soon, the prevailing industry practice in the country to make profits with dubious drug cocktails sans any robust medical rationale, basically at the cost of patients, can’t possibly be thwarted any longer, and will be effectively implemented on the ground.

By: Tapan J. Ray

PILMAN

A Tapan Ray Website

Tag Archives: DCGI

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For Improving Drug Quality in India – A Bizarre Intent

Generic Drug Quality: Cacophony Masks An Important Note, Creates A Pariah

In a Quandary of Drug Quality, Price Control, Innovation and Patient Interest in India

Stem Cell Therapy in India: A Potential Game Changer in Disease Treatment

Even Smaller Countries Now Question Indian Drug Quality Standard

Escalating Antibiotic Resistance, And Thwarting Ban Of Irrational FDCs