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.

SCM: Embracing Technology For Patients’ Safety

Posted on December 18, 2017 by Tapan Ray

Supply Chain Management (SCM) in the pharma industry is generally perceived as a logistic function, just in most other industries, involving the distribution of medicines from manufacturing plants, right up to pharma distributors. Thereafter, it becomes the responsibility of the respective distributors to reach these to the wholesalers, who cater to the needs and demand of retail chemists.

In tandem, pharma SCM is also playing a key role in reducing overall cost of drugs, improving the profit margin, and to some extent their affordability to a larger number of patients. This process involves efficient procurement of right products of the right quality, transporting them in the right condition, delivering them at the right location in right time, with optimal inventory carrying cost.

That said, today’s reality demands the SCM to cover much larger space. This calls for taking in its fold even those critical parameters that go beyond the realm of business performance – protecting the health and safety interests of patients, effectively. In that sense, SCM plays a pivotal role pharma business operation, having a potential to make a profound impact in the lives of many, quietly.

Coming out of the cocoon of narrowly defined distribution or logistic functions, pharma SCM, in many countries, has started rediscovering itself, as a multi-dimensional and multi-factorial business necessity, keeping patients within its core focus area, always.

I wrote on ‘The importance of Supply Chain Integrity’ and ‘Maximizing value of a new product launch with an innovative Supply Chain Management System’ in this blog on November 29, 2010 and August 30, 2010, respectively. Thus, in this article, I shall dwell on the role of pharma SCM in ensuring patients’ health and safety, embracing modern technology.

Current concerns:

Gradual transformation of SCM with high-tech interventions is visible now, but in a sporadic way. Speedy development initiatives in this area need to be more inclusive, everywhere. This is a paramount requirement of the pharma business, that has been prompted by serious breaches in the SCM process, affecting patients’ health, safety and security, besides impacting the brand image.

Manifestations of these get reflected in the instances like, availability of substandard and counterfeit drugs, or large product recalls, or quality issues with APIs and excipients escaping SCM scrutiny.

W.H.O says, it’s now all-pervasive:

The availability of substandard and falsified medical products, although is a menace to the society, seems to be all pervasive. The November 2017, Fact Sheet of the World Health Organization (W.H.O) recognizes this fact. The paper categorically states that no country has remained untouched by this issue – from North America and Europe to sub-Saharan Africa, South East Asia, and Latin America. Thus, this hazard, once considered a problem limited to developing and low-income countries, is no longer so.

The leading factors: ‘poor governance and weak technical capacity’:

The W.H.O study titled “Public health and socioeconomic impact of substandard and falsified medical products” released in November 2017 invited rather embarrassing media headlines, such as “India among countries where 10% of drugs are substandard.” Some of the most common medicines consumed in India, such as Combiflam and D-Cold were also found as sub-standard by Central Drugs Standard Control Organization (CDSCO) – as this news item reports.

Commenting on the possible reasons for this menace, W.H.O underscored that such substandard and falsified medical products are most likely to reach patients in 3 important situations. These are, constrained access to high quality and safe medical products, poor governance, and weak technical capacity.

The most important and viable option to effectively address this drug-safety threats is innovative applications of state of the art technology platforms. Many pharma players, are gradually realizing it through experience. Quite in unison, various Governments, India included, are also contemplating to follow the same path. Some nations are enacting robust laws for strict compliance of the remedial measures, as charted out by the respective drug authorities.

Harnessing technology as an enabler:

I reckon, harnessing modern technology will facilitate putting in place a robust ‘Track and Trace’ in the SCM, through product ‘serialization’, to effectively address this menace. As many would know, pharma serialization broadly means that each medicinal product pack will carry a Unique Identifier (UID), that can be tracked and traced till the same reaches the end-user.

The process may start with the key ‘touch points’ of a drug before it reaches the patients, such as suppliers, formulators, carrying and forwarding agents (C&FA) or distributors, wholesalers and retailers. This can be extended backwards, as well, to make the drug-sourcing process safer, which is also of crucial importance.

Leveraging technology for patient safety:

Realizing the importance of drug-safety needs of patients, many drug regulators, even in the developed markets, are leveraging technology as a key enabler in the SCM value chain to effectively address this issue. There are several recent global examples of achieving this specific objective. One such example comes from the top pharma market in the world – the United States.

Where the ‘Track and Trace System’ came as a law:

To ensure greater drug-safety for patients in the country, the oldest democracy of the world decided to introduce the ‘Track and Trace System’ in the SCM process by enacting a robust law. Accordingly, in December 2016, the US-FDA released the final guidance on the implementation of the Drug Supply Chain Security Act (DSCSA).

Under this law an electronic ‘Track and Trace System’, through product ‘serialization’, will be put in place in the United States. As reported in the ‘Pharmacy Times’, DSCSA comes into force to regulate transactions between dispensers, pharmacies, and also among manufacturers, repackagers, wholesale distributors, third-party logistics providers, and trading partners, from November 24, 2017.

Following DSCSA, on June 30, 2017, the agency issued a draft guidance for the industry, titled Product Identifier Requirements Under the Drug Supply Chain Security Act – Compliance Policy. It informed the manufacturers and other supply chain stakeholders that “although manufacturers are to begin including a ‘product identifier’ on prescription drug packages and cases on November 27, 2017, the FDA is delaying enforcement of those requirements until November 2018 to provide manufacturers additional time and avoid supply disruptions.”

The US-FDA explains ‘product identifier’, as follows:

A unique identity for individual prescription drug packages and cases, which will allow trading partners to easily trace drug packages as they move through the supply chain.

Includes the product’s lot number, expiration date, a national drug code (or NDC), and a serial number. The serial number is different for each package or case. This creates a unique identifier – human and machine readable – to enable product tracing throughout the supply chain and enable all trading partners to better detect illegitimate products within the supply chain.

The US drug regulator clarified that the compliance policy outlined in the draft guidance applies solely to products without a product identifier that are introduced into commerce by a manufacturer between November 27, 2017 and November 26, 2018.

Several other countries also realizing its criticality:

Besides the United States, several other countries are harnessing high technology to make the SCM system more robust to ensure patient safety. Some of these include, EU, South Korea, Brazil and China, South Korea and Argentina. India too has initiated action in this area, but only for exports, as on date. Intriguingly, drug-safety for patients within the country doesn’t seem to be on the ‘must do’ list of the law and policy makers of the country, just yet.

‘Track and Trace’ system in India:

As stated above, the ‘Track and Trace’ system in India for drugs is currently applicable only to pharma exports. By a notification dated January 05, 2016, the Directorate General of Foreign Trade (DGFT) made encoding and printing of unique numbers and bar codes as per GSI Global Standard mandatory. This would cover tertiary, secondary and primary packaging for all pharmaceuticals manufactured in India and exported out of the country to facilitate tracking and tracing.

However, for drugs in the domestic market, although a draft proposal was circulated to the stakeholders in June 2015, but no significant progress has yet been made on its implementation in India.

Conclusion:

Availability of potentially harmful substandard and counterfeit drugs is posing a threat to public health and safety, almost in all countries across the world, with a varying degree, though. The November 2017, Fact Sheet of the World Health Organization (W.H.O) also highlighted this issue with a great concern.

A robust SCM systems, built on modern technological platforms are now receiving encouragement from the Governments in many countries, to contain this menace. Accordingly, lawmakers are formulating tough laws, and the drug regulators are specifying the requirements that need to be built into the pharma SCM mechanism.

Some pharma players, on their own, are further raising this bar, while framing their internal compliance norms for SCM. They realize that besides responding to patients’ health and safety needs, it is necessary for the commercial consideration too, alongside the company’s reputation.

Although, India is included among those countries where 10 percent of drugs are substandard, as the W.H.O reports, no such regulatory mechanism has been made mandatory within the Supply Chain to cover drugs in the domestic market, as yet. Interestingly, the DGFT has made the ‘Track and Trace’ mechanism only for the exporters, probably for patients’ health safety of the importing countries! Neither has the majority of domestic pharma manufacturers voluntarily implemented it, demonstrating ‘Patient-Centricity’.

Making SCM robust, weaving into it the drug-safety needs of patients, is a necessity in India too. When a large number of countries, including BRICS nations, are embracing modern technology to achieve this goal, why isn’t India doing so – intriguing…No…?

By: Tapan J. Ray

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

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.

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

Nutraceuticals: Still An Oasis Amidst Well-Regulated Pharmaceuticals

Posted on November 28, 2016 by Tapan Ray

On November 24, 2016, the food-safety watchdog of India announced that health supplements or Nutraceuticals cannot be sold as ‘medicines’ anymore. This new regulatory standard has been set for the manufacturers of Nutraceuticals and food supplements, and is aimed at controlling mislabeling of such brands. The fine prints of the notification are yet to be assessed.

On the face of it, this new announcement seems to be a good step, and would largely address a long-standing issue on the such products. Prevailing undesirable practices of labeling some pharma brands as food supplements or Nutraceuticals, with some tweaking in the formulations, mainly to avoid the risk of price control, is also expected to be taken care of by the food-safety authority of India, while granting marketing approval.

Nevertheless, it is often construed that off-label therapeutic claims, while promoting these products to the doctors, help achieving brand positioning objective as medicines, though indirectly. Appropriate authorities in India should probably resolve this issue, expeditiously.

In this article, I shall focus on the rationale behind different concerns over the general quality standards, claimed efficacy and safety profile of Nutraceuticals and food supplements, in general, and how the regulatory authorities are responding to all these, slowly, albeit in piecemeal, but surely.

The ‘gray space’ is the issue:

The close association between nutrition and health has assumed a historical relevance. Growing pieces of evidence, even today, suggests that nutritional intervention with natural substances could play an important role, especially in preventive health care. The World Health Organization (WHO) has also highlighted that mortality rate due to nutrition related factors in the developing countries, like India, is nearly 40 percent.

However, as one of the global consulting firm of repute has aptly pointed out, “At one end of this natural nutrition spectrum, are functional foods and beverages as well as dietary supplements, aimed primarily at maintaining health. On the other, more medical end of the spectrum, are products aimed at people with special nutritional needs. In the middle, is an emerging gray area of products that have a physiological effect to reduce known risk factors, such as high cholesterol, or appear to slow or prevent the progression of common diseases such as diabetes, dementia or age related muscle loss.”

This gray space between Pharmaceutical and Nutraceuticals, therefore, holds a significant business relevance, from various perspectives.

An Oasis amidst highly-regulated pharmaceuticals:

Mostly because of this gray space, several pharma companies and analysts seem to perceive the Nutraceutical segment virtually an oasis, lacking any transparent regulatory guidelines, amidst well-regulated pharma business. This perception is likely to continue, at least, for some more time.

Such pattern can be witnessed both within the local and global pharma companies, with some differences in approach, that I shall deliberate later in this article.

However, regulators in many countries, including India, have started expressing concerns on such unfettered manufacturing, marketing and other claims of Nutraceuticals. Many of them even ask, do all these Nutraceuticals deliver high product quality, claimed effectiveness and safety profile to their consumers, especially when, these are promoted by several pharma companies, though mostly off-label, to generate physicians’ prescriptions for various disease treatments?

Not just domestic pharma companies:

This concern is not restricted to the domestic companies in India.

Global pharma players, who generally believe in scientific evidence based medicines, have been reflecting an iffiness towards Nutraceuticals. For example, whereas both Pfizer and Novartis reportedly hived off their nutrition businesses, later Pfizer invested to acquire Danish vitamins company Ferrosan and the U.S. dietary supplements maker Alacer. Similarly, both Sanofi and GlaxoSmithKline also reportedly invested in mineral supplements businesses that could probably pave the way of the company’s entry into medical foods.

However, it is worth underscoring that generally the consumer arms of global pharma companies focus on OTC, and Nutraceuticals do not become an integral part of the pharma business, as is common in India.

Interestingly, not very long ago, Indian pharma industry witnessed a global pharma major virtually replicating the local marketing model involving Nutraceuticals. It also became an international news. On August 24, 2011, ‘Wall Street Journal (WSJ)’ reported that ‘Aventis Pharma Ltd. (now Sanofi India) agreed to buy the branded nutrition pharmaceuticals business of privately held Universal Medicare Pvt. Ltd for an undisclosed amount, as its French parent Sanofi looks to expand in the fast-growing Indian market.’

Universal Medicare, which posted about US$ 24.1 million revenue in the year ended March 31, 2011, will manufacture these branded Nutraceutical products and Aventis will source them from Universal Medicare on mutually agreed terms. Around 750 of the Universal Medicare’s employees also moved to the French Company along with its around 40 Nutraceutical brands, the report said.

If all these acquired brands, do not fall under the new FSSAI guidelines related to the required composition of food supplements and Nutraceuticals in India, it would be worth watching what follows and how.

Nutraceuticals are also promoted to doctors:

Let me reemphasize, India seems to be slightly different in the way most of the pharma companies promote Nutraceuticals in the country. Here, one can find very few standalone ‘Over the Counter (OTC)’ pharma or Nutraceutical product company. For this reason, Nutraceutical brands owned by the pharma companies, usually become an integral part of their prescription product-portfolio. Mostly, through off-label promotion Nutraceuticals are often marketed for the treatment or prevention of many serious diseases, and promoted to the doctors just as any other generic pharma brand.

Need to generate more scientific data based evidences:

A 2014 study of the well-known global consulting firms A.T. Kearney titled, “Nutraceuticals: The Front Line of the Battle for Consumer Health”, also recommended that ‘a solid regulatory framework is crucial for medical credibility, as it ensures high-quality products that can be relied on to do what they say they do.’

This is mainly because, Nutraceuticals are not generally regarded by the scientific community as evidence based medicinal products, going through the rigors of stringent clinical trials, including pharmacokinetics and pharmacodynamics studies, and is largely based on anecdotal evidence. Besides inadequacy in well-documented efficacy studies, even in the areas of overall safety in different age groups, other side-effects, drug interactions and contraindications, there aren’t adequate scientific evidence based data available to Nutraceutical manufacturers, marketers, prescribers and consumers.

There does not seem to be any structured Pharmacovigilance study is in place, either, to record adverse events. In this scenario, even the ardent consumers may neither realize, nor accept that Nutraceuticals can cause any serious adverse effects, whatsoever.

From this angle, the research study titled, “Emergency Department Visits for Adverse Events Related to Dietary Supplements”, published in the New England Journal of Medicine (NEJM) on October 15, 2015, becomes very relevant. The paper concluded as follows:

“More than 23,000 emergency department visits annually in the United States from 2004 through 2013 were for adverse events associated with dietary supplements. Such visits commonly involved cardiovascular adverse effects from weight-loss or energy herbal products among young adults, unsupervised ingestion of micronutrients by children, and swallowing problems associated with micronutrients among older adults. These findings can help target interventions to reduce the risk of adverse events associated with the use of dietary supplements.”

Fast growing Nutraceutical industry continues to remain largely unregulated. It persists, even after several previous studies had revealed dangerous levels of harmful ingredients, including amphetamine, in some Nutraceuticals.

Indian regulatory scenario:

In India, the ‘Food Safety and Standards Authority of India (FSSAI)’, established under the Food Safety and Standard Act of 2006, is the designated Government body responsible for the regulation and approval of Nutraceuticals in the country.

In July 2015, FSSAI proposed draft regulations for Nutraceuticals, Functional Foods, Novel Foods and Health Supplements for comments from all stakeholders within the stipulated time limit. This draft regulation defines Nutraceuticals as follows:

“Nutraceuticals means a naturally occurring chemical compound having a physiological benefit or provide protection against chronic disease, isolated and purified from food or non-food source and may be prepared and marketed in the food-format of granules, powder, tablet, capsule, liquid or gel and may be packed in sachet, ampoule, bottle, etc. and to be taken as measured unit quantities.”

In this draft FSSAI also proposed that therapeutic claims of Nutraceuticals and all such foods are required to be based on sound medical and nutritional evidence, backed by scientific as well as clinical evidence.

In 2011, FSSAI constituted a product approval committee, whose members were supposed to use similar parameters as drugs, to assess Nutraceuticals for this purpose. However, FSSAI had to jettison this idea, in compliance with the order dated August 19, 2015 of the Supreme Court questioning the procedure followed for approvals by the food regulator.

In April 2016, FSSAI restricted enforcement activity against Nutraceuticals and health supplement companies to only testing of products till new standards are notified.

The latest regulatory developments:

There are, at least, the following two recent developments reflect that the regulatory authorities, though trying, but are still grappling with the overall product quality, efficacy and safety concerns for Nutraceuticals:

Responding to the growing demand for regulatory intervention in this important matter, on November 30, 2015, by a gazette notification, the Government of India included phytopharmaceutical drugs under a separate definition in the Drugs & Cosmetics (Eighth Amendment) Rules, 2015, effective that date.

Again, on November 24, 2016, FSSAI reportedly announced that health supplements or Nutraceuticals cannot be sold as ‘medicines’ anymore. This new regulatory standard set for the manufacturers of Nutraceuticals and food supplements is aimed at controlling mislabeling of such brands. On its enforcement, every package of health supplement should carry the words ‘health supplement’ as well as an advisory warning ‘not for medicinal use’ prominently printed on it.

It further added: “The quantity of nutrients added to the articles of food shall not exceed the recommended daily allowance as specified by the Indian Council of Medical Research and in case such standards are not specified, the standards laid down by the international food standards body namely the Codex Alimentarius Commission shall apply.”

However, these regulations will be enforced from January 2018.

Curiously, in September 2016, National Institutes of Health in United States announced plans to put some more scientific eyes on the industry, the NIH reportedly announced plans to spend US$ 35 million to study natural products, ranging from hops to red wine’s resveratrol to grape seed extract. The new grants, reportedly, are expected to fathom the basic science behind many claims that Nutraceuticals can improve health.

The market:

The August 2015 report titled, ‘Indian Nutraceuticals, Herbals, and Functional Foods Industry: Emerging on Global Map,’ jointly conducted by The Associated Chambers of Commerce and Industry of India (ASSOCHAM) and the consulting firm RNCOS, estimates that the global Nutraceuticals market is expected to cross US$ 262.9 billion by 2020 from the current level of US$ 182.6 billion growing at Compound Annual Growth Rate (CAGR) of about 8 percent.

Driven by the rising level of awareness of health, fitness and changing lifestyle pattern, increasing co-prescription with regular drugs, and focus on preventive health care, India’s Nutraceuticals market is likely to cross US$ 6.1 billion by 2020 from the current level of US$ 2.8 billion growing at CAGR of about 17 percent, the report states.

The United States (US) has the largest market for the Nutraceuticals, followed by Asia-Pacific and European Union. Functional food is the fastest growing segment in the US Nutraceutical market, followed by Germany, France, UK and Italy in Europe.

Conclusion:

Today, both manufacturing and marketing of Nutraceuticals keep charting in a very relaxed regulatory space, in India. There are no robust and transparent guidelines, still in place, for product standardization and scientifically evaluate the safety and efficacy of all these products on an ongoing basis. Neither is there any stringent requirement for conformance to the well-crafted cGMP standards.

The reported discussions within the Union Ministry of Ayush for setting up a structured regulatory framework, within the CDSCO, for all Ayush drugs and to allow marketing of any new Ayurvedic medicine only after successful completion of clinical trials to ensure its safety and efficacy, are indeed encouraging. This may be followed for all those Nutraceuticals, which want to be promoted as medicines, claiming direct therapeutic benefits.

Be that as it may, November 24, 2016 announcement of FSSAI, that health supplements or Nutraceuticals cannot be sold as ‘medicines’ anymore to control mislabeling of such brands, is a step in the right direction.

Another major issue of many pharma brands being put under Nutraceuticals with some tweaking in formulations and labelled as food supplements, would also probably be largely addressed, as FSSAI would continue to be the sole authority for marketing approval of Nutraceuticals.

However, it is still not very clear to me, as I am writing this article, what happens to those Nutraceutical brands, which are already in the market, with compositions not conforming to the new FSSAI norms. Fairness demands reformulation and relabeling of all those existing Nutraceuticals, strictly in conformance to the new guidelines, and obtain fresh approval from FSSAI. This will help create a level playing field for all Nutraceutical players in India.

While there is a pressing need to enforce a holistic regulatory discipline for the Nutraceuticals to protect consumers’ health interest, the commercial interest of such product manufacturers shouldn’t be ignored, either. This is primarily because, there exists enough evidence that proper nutritional intervention with the right kind of natural substances in the right dosage form, could play an important role, especially in the preventive health care.

As the comprehensive regulatory guidelines are put in place, Nutraceuticals not being essential medicines, should always be kept outside price control, in any guise or form. In that process, the general pharma perception of Nutraceutical business, as an ‘Oasis’ amidst well-regulated and price-controlled pharmaceuticals, would possibly remain that way, giving a much-needed and well-deserved boost to this business.

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

Counterfeit Drugs In India: A Malady Much Deeper

Posted on October 24, 2016 by Tapan Ray

Many debates and discussions continue being lined up in India almost regularly, generally by the pharma trade associations, besides a few others, on the issue of counterfeit drugs. A good number of these events are sponsored by the global and local anti-counterfeit product manufacturers and the related service providers, presumably to get a captive pharma audience. By and large, these gatherings are well publicized, and very rightly so, to focus for a while on this growing menace in the country.

One of the key objectives of such proceedings, I reckon, besides recommending the immediate action steps for the government in saddle, is to encourage the manufacturers of high quality drugs to protect their brands from the onslaught of counterfeiters through anti-counterfeit measures. Several of these involve a state of the art non-cloning technology. The core message that gets filtered-through, in most of these occasions is, if the suggested steps are followed by the drug companies with the related products and services, these won’t just help protect the patients’ health interest, but also provide a boost to the top and bottom lines in the pharma business, significantly.

There are no qualms about this initiative, not at all. Nonetheless, can this be considered a holistic approach to tackle the menace of counterfeit drugs, especially by the pharma players in India, and considering various other different ways the menace keep striking the patients, so surreptitiously?

Thus, in this article, my point of focus will be on a critical question, which is not asked with the same vigor always in many of the above events: Hasn’t the malady of counterfeit drugs in India spread much wider, and taken its root considerably deeper?

Counterfeit drugs and what it includes?

According to the World Health Organization (W.H.O), there is currently no universally agreed definition among its member states in what is widely known as ‘Counterfeit medicines’. Nevertheless, W.H.O does indicate that the term ‘counterfeit’ is widely used to include falsified, unlicensed, falsely packaged, stolen and substandard medical products. Jurisdictions across the world define counterfeit medicines in many different ways.

It’s worth noting here, according to W.H.O, substandard medical products also belong to this category. In 2009, W.H.O defined ‘substandard’ drugs as “genuine medicines produced by the manufacturers authorized by the NMRA (national medicines regulatory authority) which do not meet quality specifications set for them by national standards”.

Hence, notwithstanding whatever will be accepted as the general consensus of the W.H.O members on the definition of counterfeit drugs, from the patients’ perspective, any drug failing to meet with the claimed efficacy, safety and quality standards, should come under the same ‘category definition’, including substandard drugs.

Controversy over the term ‘Counterfeit’:

Many W.H.O member countries believe that the term counterfeit is closely associated and legally defined within the Intellectual Property (IP) legislation, and concentrates on trademark protection. Consequently, usage of this terminology has been perceived to have reduced the focus from what is first and foremost a public health issue. Thus, it has become quite important for W.H.O to separate the different categories of what is widely used as ‘counterfeit drug’, for the purpose of analysis and identifying strategies, to effectively address the issue of the public health menace that such activities give rise to.

Types of counterfeit drugs:

A Review Article titled “Anti-counterfeit Packaging in Pharma Industry” dated February 17, 2011, published in the “International Journal of Pharmacy and Pharmaceutical Sciences”, divided the types of counterfeit mechanisms into five categories, in which drugs are manufactured or distributed without proper regulatory clearance, and do not meet the determined standards of safety, quality, and efficacy:

No active ingredient (43 percent)
Low levels of active ingredient (21 percent)
Poor quality drugs (24 percent)
Wrong ingredients (2 percent)
Wrong packaging or source (7 percent)

This particular article will dwell mainly on a very important segment in this category – the substandard or poor quality drugs.

The magnitude of the problem:

On May 17, 2016, a Research Article titled, “Public Awareness and Identification of Counterfeit Drugs in Tanzania: A View on Antimalarial Drugs”, published in ‘Advances in Public Health’ – a peer-reviewed, open access journal that publishes original research articles, highlighted something that should cause a great concern not just for the Indian drug regulators, but also the Indian pharma manufacturers, in general.

The research paper, besides other points, underscored the following:

“Currently, it is estimated that 10–15 percent of the global drugs supplied are counterfeit. The prevalence is higher in developing countries in Africa and in parts of Asia and Latin America where up to 30–60 percent of drugs on the market are counterfeit. India is a major supplier of poor quality drugs whereby 35–75 percent of fake/counterfeit drugs globally originate from India.”

Another report of ‘Pharmexcil’ dated October 04, 2010 also states: “According to the Organization for Economic Cooperation and Development (OECD), 75 percent of fake drugs supplied world over have origins in India, followed by 7 percent from Egypt and 6 percent from China. India is also a leading source of high quality generic and patent drugs in the legitimate commerce worldwide. Since drugs made in India are sold around the world, the country’s substandard drug trade represents a grave public health threat that extends far beyond the subcontinent.”

Substandard drugs: a potential crisis in public health:

An article with the above title, published in the British Journal of Clinical Pharmacology on November 29, 2013 cautioned on the potential crisis in public health with substandard drugs, as follows:

“Poor-quality medicines present a serious public health problem, particularly in emerging economies and developing countries, and may have a significant impact on the national clinical and economic burden. Attention has largely focused on the increasing availability of deliberately falsified drugs, but substandard medicines are also reaching patients because of poor manufacturing and quality-control practices in the production of genuine drugs (either branded or generic). Substandard medicines are widespread and represent a threat to health because they can inadvertently lead to health care failures, such as antibiotic resistance and the spread of disease within a community, as well as death or additional illness in individuals.”

Hence, the potential of health crisis with various substandard drugs is quite similar to other types of counterfeit drugs.

Substandard drugs and small pharma players:

As I said before, the malady of counterfeit, fake and substandard drugs are spreading much wider and deeper in India. What’s happening around today in this area prompts us to believe, it may no longer be proper to keep all the large pharma manufacturers away from the ambit of discussion on substandard or counterfeit drugs. This apprehension is raising its head, as it is generally believed that only small, unknown, or fly-by-night type of drug manufacturers, are responsible for substandard, fake or counterfeit drugs. Whereas, the reality seems to be different. There are now ample reasons to believe that even some large drug manufacturers, both local and global, who have been caught by the regulator for the same wrongdoing, are also equally responsible for causing similar adverse health impact on patients.

Substandard drugs and large pharma players:

That the issue of substandard drugs is quite widespread in India, involving both global and local pharma players – small and large, is also quite evident from the following report, published in the May 14, 2016 edition of the well-reputed national daily – Hindustan Times:

“A day after French major Sanofi announced a recall of some batches of its popular painkiller Combiflam, India’s drug regulator said over 102 medicines have been highlighted for quality concerns and withdrawal in the last five months. The list includes several popular painkillers.”

The report also indicated that these are generic medicines, both with and without brand names, such as, CIP-ZOX of Cipla, Orcerin of MacLeod Pharma, Zerodol-SP of Ipca Laboratories, Pantoprazole of Indian Drugs and Pharmaceuticals Ltd and Norfloxacin of Karnataka Antibiotics & Pharmaceutical Ltd. According to the public notices of the Central Drugs Standard Control Organization (CDSCO), these batches were manufactured in June 2015 and July 2015, and carried expiry dates of May 2018 and June 2018.

The CDSCO also reportedly said that in notices posted on its website in February and April, 2015, it found some batches of Combiflam to be “not of standard quality” as they failed disintegration tests. The point to note is, according to the US-FDA, disintegration test is used to assess the time it takes for tablets and capsules to break down inside the body and are used as a quality-assurance measure.

“All drugs listed under the drug alert list should be recalled with immediate effect. We have found some serious problems with the making of the drug because of which we have highlighted quality concerns. Hence, recall is necessary for all companies,” GN Singh, the Drug Controller General of India (DCGI), reportedly told the above newspaper.

Should the ‘intent behind’ be considered as the key differentiating factor?

This takes me to another question: What’s the ‘intent behind’ manufacturing substandard drugs? It is not difficult to make out that the only ‘intent behind’ manufacturing substandard drugs by illegal, some small or fly-by-night type of drug operators would be to make quick money, by cutting corners, and criminally falsifying the entire process.

Until recently, I used to strongly believe that those large manufacturers who are getting caught for releasing substandard drugs to the market, have made sheer mistakes, and these are no more than minor aberrations. However, recent findings by the US-FDA, after rigorous manufacturing quality audit of several production facilities of large and small generic drug producers of India, make me wonder whether this thin differentiating line of ‘intent behind’ manufacturing substandard drugs, though still exists, has started getting blurred. The foreign regulators have imposed import ban on drugs produced in those facilities on the ground of willingly compromising drug quality, and grossly falsifying data.

I am not going into those much discussed details here, once again, as the drugs involved in the above cases are meant for exports and the import bans, by the foreign regulators were aimed at protecting the health and safety of citizens of those countries. In this article my focus is on India, and health interest of the local Indian population.

Thus fathoming a different ‘intent behind’ manufacturing substandard drugs, especially by the large and well-known manufacturers, is the real challenge. What sort of anti-counterfeit events will be able to possibly address this perturbing issue, that is now getting revealed much faster than even before?

Who in India ensures that all drugs are safe?

Possibly none, not even the drug regulators and the enforcers of the drug laws, as a number of national and international media reports reveal. General public doesn’t get any assurance from any authorities that the medicines sold by the drug retail outlets, pan India, are all standard quality and genuine.

At the same time, it is equally challenging for anyone to ascertain, with absolute certainty, that it’s a counterfeit, substandard or a fake drug, in whatever name we call it, is responsible for avoidable suffering or even death of an individual. In such a sad eventuality, one has no other choice but to accept that the causative factor was either a wrong diagnosis of the disease, or delayed onset of treatment.

Is CDSCO still in a denial mode?

It’s an irony that the government sources often highlight that the incidence of substandard, spurious or fake drugs in India has declined from around 9 percent in the 1990s, to around 5 percent in 2014-15, quoting the CDSCO sample survey findings.

Nevertheless, while looking at the same CDSCO survey results of the last four years – from 2011-12 to 2014-15, the incidence of spurious and substandard drugs in India appears to be static, if not marginally increased, as follows:

Year	Tested Samples	Substandard Samples	Spurious or Adulterated samples	% Failed
2011-12	48,082,00	2,186.00	133.00	4.82
2012-13	58,537.00	2,362.00	70.00	4.15
2013-14	72,712.00	3,028.00	118.00	4.32
2014-15	74,199.00	3,702.00	83.00	5.10

Source: Central Drugs Control Organization (CDSCO)

In my view, these CDSCO results should be taken perhaps with dollops of salt, not merely the sample size for these surveys is too small, but also the complexity involved in the collection of the right kind of samples that will always pass the acid test of independent experts’ scrutiny. Right representational sample size – state-wise, is so important, primarily considering that India is the world’s third-largest pharmaceutical market by volume, consumes 383 billion medicines per annum, according to a 2015 Government report, and is quite a heterogeneous pharma market.

A September 06, 2016 media report well captured the palpable hubris of the Government on this worrying subject. It quoted the Drug Controller General of India (DCGI) – Dr. G N Singh as saying: “This is an encouraging trend when it comes to comparing Indian made generics with that produced in regulated markets. This will help us dispel the myth that India is a source of substandard drugs as compared to any other regulated market.”

Interestingly, other studies and reports do indicate that this menace could well be, at least, thrice as large.

Be that as it may, according to an October 22, 2016 media report, CDSCO is expected to release the findings of the latest survey on ‘spurious drugs’ in India by end October 2016.

Two recent good intents of CDSCO:

Apparently, as a response to the widespread public criticism on this issue, despite being in a denial mode earlier, CDSCO has recently expressed two good intents to address this issue, as follows:

As reported on October 18, 2016, it has sent a recommendation to the Union Ministry of Health to amend the Drugs & Cosmetics Act to facilitate implementation of bar coding and Unique Identification Number (UIN) on every pack of domestic pharma products.

To ensure consistency and uniformity in the inspection process, on May 26, 2016, by a Public Notice, it issued a new draft checklist of ‘Risk Based Inspection of the Pharma Manufacturing Facilities’ for verification of GMP compliance as per the provisions stated under Schedule M of Drugs and Cosmetics Rules, 1945, and sought suggestions from the stakeholders. This checklist would be used by drug regulatory enforcement agencies as a science based tool. It also envisaged that the pharma industry would find this checklist useful for self-assessment.

Let’s now wait and watch, to get to know the timeline of translating these good intents into reality on the ground, and the impact that these decisions will make to reverse the current worrying trend of counterfeit and substandard drugs in India.

Conclusion:

The malady of counterfeit or substandard drugs is not just India centric. Various credible sources have estimated that around a million people fall victim to such so called ‘medicines’, each year. However, unlike many other countries, India still doesn’t have any structured and effective regulatory or other mechanisms, not even any spine-chilling deterrent, in place to address this public health menace of humongous implications.

That said, besides serious health hazards, the adverse financial impact of substandard drugs on patients is also significant. Such drugs, even when non-fatal, are much less effective, if not ineffective or trigger other adverse reactions. Thus, a longer course of treatment, or switching over to a different medication altogether, may often be necessary, multiplying the cost of treatment.

In that sense, substandard, spurious, fake or counterfeit drugs, in whatever name one describes these, increase the disease burden manifold, besides being life-threatening. This issue assumes greater significance in India, where 58.2 percent of the total health expenditure is incurred out-of-pocket by a vast majority of the population. Medicines alone, which are mostly purchased from private retail outlets, across India, account for between 70 and 77 per cent of the individual out of pocket health spending, according to a W.H.O report.

High decibel campaigns on various anti-counterfeit technology solutions for fast selling, or expensive brands of large pharma companies, whether sponsored by placing the commercial interest at the top of mind, or even otherwise, are welcome, so are the two recent good intents of the Union Government, in this area.

However, the desirable proactive focus on curbing the menace of substandard medicines in India, which cause similar health risks as any other type of counterfeit drugs, does not seem to be as sharp, not just yet, barring the pharma export sector. Nor does this issue attract similar zest for a meaningful discourse related to patients’ health and safety within the country, as associated with various other anti-counterfeiting technology solution oriented events. The anomaly remains intriguing, especially when the malady spreads, with its root reaching deeper.

By: Tapan J. Ray

Clinical Trials: Critical Need To Improve Patient Participation With Informed Consent

Posted on April 18, 2016 by Tapan Ray

On April 13, 2016, an article in the Wall Street Journal (WSJ) titled, “Clinical Trials Need More Subjects” underscored an important point that the rate at which the clinical researchers are able to recruit and retain patients for ‘Clinical Trials (CT)’, has now hit an all-time low. This is vindicated by studies that indicate less than 10 percent of Americans now participate in clinical trials, and only 3 to 5 percent of patients sign up for trials of new cancer therapies, in the largest CT market of the world.

As a result, about 40 percent of CTs do not recruit enough patients to meet their goals, the article highlights. Consequently, a large number of pharma industry sponsored CTs are now, reportedly, moving away from the United States. India should, therefore, take note of this development and pull up the socks.

If similar situation gets replicated in other countries too, and persists, it would be very unlikely that critical and credible medical and scientific knowledge that can significantly improve the treatment outcomes in many serious disease conditions could be meaningfully gathered and put to practice. Its other serious fallouts too, are also not terribly difficult to imagine.

A key medical research tool:

In pursuit of the advancement of medical knowledge and patient care, CT of drugs is universally considered to be a key medical research tool, as it is the best way to learn what works best in treating various types of diseases. It goes without saying that drugs for all new types of treatments would need to be discovered first through a long and painstaking process of discovery research. These are then purified, and tested in preclinical studies, before a final decision is taken for commencement of CT on human against preset parameters, as deemed necessary.

While going through this stringent process some drugs are found to be safe and effective on human subjects and some others are not, on the contrary may be harmful.

There lies the crucial importance of CT for all scientific evidence based medicines. According to the Department of Health & Human Services of the United States, Clinical research is done only if doctors don’t know:

whether a new approach works well with people and is safe and
which treatments or strategies work best for certain illnesses or groups of people

CT, though a small part in the important and lengthy process of developing newer treatments, significantly helps the health care decision makers to decide on the treatments that work best for any patient.

Broad types:

Pharmaceutical companies usually sponsor CT for new drugs and treatments, which are carried out by the designated research teams, consisting of doctors and other related professionals in different specialized areas.

There are 4 phases in any CT, which are broadly as follows:

Phase I: Here, for a new treatment, an investigational drug is tested for the first time in small numbers, usually between 20 and 100, on healthy volunteers, to identify the proper dosage ranges for drug administration, while critically monitoring its method of absorption, adverse effects and toxicity profile.

Phases II: This phase, just as Phase I studies, also tests the drug on, usually between 100 and 300 patients, suffering from the targeted disease conditions. Safety is the main goal of this phase of CT and is programmed towards adjusting treatment doses, monitoring the common side effects, and whether patient’s disease condition improve as a result of the drug. These studies are usually randomized and double-blinded, where neither the patient nor the researchers would know whether a patient is receiving the investigational drug, or a placebo, or a standard treatment.

Phase III: In this phase, the investigational new drug goes through rigorous testing of safety, efficacy, and proper dosage levels in a large group of subjects, which may even exceed several thousand, with a specific illness or disease. The key objective is to enable the doctors to evaluate the safety and effectiveness of the treatment for various groups of patients, such as, men versus women, elderly versus young, besides many others.

Phase IV: Such studies are done after the drug receives the marketing approval from the drug regulator. The basic objective of these trials is usually to monitor whether the treatment offers desired benefits or gives rise to long-term side effects, which were not seen in the phase II and III trials. This phase may involve even several hundreds and thousands of patients.

It is worth noting that CT is essential to obtain marketing approval for any new treatment, as required by the drug regulators in the different countries, and takes around 6 to 8 years.

The role of patients:

Patients play a critical role in the entire scientific value chain of any drug evaluation process, especially on human. It is absolutely necessary, particularly in the regulated markets of the world, that all medicines are fully vetted through highly regulated, stringently monitored and well-scrutinized CTs, to ensure safety and effectiveness of each new drug and treatment for the patients.

No CT can take place sans the willingness and informed consent for participation of thousands of patients for any such studies held across the world. Without adequate patient participation in a CT, the drug performance data may also not be credible and thus acceptable to the drug regulator. This would, consequently, make it impossible to bring any new drug for prevention or treatment of various, often life threatening, disease conditions.

Major reasons for not enough patient participation:

There are many reasons for not enough patients volunteering to participate in the CT, even in India. Some of the major reasons have been identified as follows:

Patients often are not aware that such trials also offer a treatment option. In many cases, their doctors too may not be explaining it effectively to them, as a part of their professional discourse. Several studies conclude that trust in a physician is a main reason patients decide to participate in CT.

Some patients, after reading media reports, interacting with some NGOs and also from word of mouth, mistrust the CT process and suffer from fear of being a guinea pig.

At times, complicated protocols, and eligibility requirements may also be discouraging.

Many patients, especially in India, are not very clear about the exact insurance (financial) cover the study provides for them, along with other payments for the care that they would receive during the trial, or for any drug-related long term untoward incident even after completion of the CT.

All these need to be effectively addressed.

India attractiveness for CT:

The number of CT conducted in India had increased with a rapid pace till 2012, driven by cost arbitrage, treatment-naïve patient population, qualified English speaking medical research professionals that the country offers. According to available reports, in 2009, outside the United States, India was the second most preferred country to conduct CT. Incidentally, at that time, the CT guidelines in India were too loose, quite discretionary, patient-unfriendly and with many gaping holes. This scenario has changed dramatically since 2013, with consequent adverse impact on the number of CT in India.

A 2009 study conducted by Ernst & Young and the Federation of Indian Chambers of Commerce and Industry of India (FICCI), states that India participates in over 7 percent of all global phase III and 3.2 percent of all global phase II trials. The major reasons of India attraction of the global players to conduct CT in the country, were highlighted as follows:

Cost of Clinical Trial (CL) is significantly less in India than most other countries of the world
Huge treatment-naïve patient pool with different disease pattern and demographic profile
Easy to enroll volunteers, as it is not very difficult to persuade poor and less educated people as ‘willing’ participants. This may not be so easy now with the recent amendment of CT guidelines.

However, there is an urgent need for a world class capacity building in this area to reap a rich harvest.

Improving CT regulations in India:

Not so long ago, it came to light with the help of ‘Right To Information (RTI)’ query that more than 2,000 people in India died as a result of Serious Adverse Events (SAEs) caused during drug trials from 2008-2011 and only 22 of such cases, which is just around 1 percent, received any compensation. That too was a meager average sum of around US$ 4,800 per family.

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

This gloomy situation is now gradually improving. According to an August 2015 research article titled “Impact of new regulations on clinical trials in India”, published in International Journal of Clinical Trials, 2015 Aug; 2 (3): 56-58, there was a need of strict vigilance and regulations for conducting CT in India, which was much easier than in North America or Europe. In India, the trial participants were exploited because of illiteracy, poverty and lack of awareness of their basic rights in this area. The Central Drugs Standard Control Organization (CDSCO) has now taken a noteworthy step by launching online Clinical Trial Registry-India (CTRI) ensuring accountability, transparency and information sharing on clinical trials in the public domain.

Followed by a tough intervention of the Supreme Court in 2013, Indian Government brought in amendments to the CT guidelines of Schedule Y, in December 2014 which came into force effective June 2015. These long-overdue amendments are expected to strengthen the CT process in India and effectively protect the rights, desired safety and general well-being of the participating subjects, while generating authentic clinical data for new drugs or treatment.

Informed consent:

Obtaining informed consent of the participating patients, is absolutely necessary for the researchers. This has recently been made stringent in India effective June 07, 2013. From that date, to make the sCT process transparent and ensure requisite confidentiality, an audio-visual recording of the ‘informed consent’ process has been made mandatory in the country.

A valid consent would mean that the participants have well understood the risks and benefits of the treatment during the CT period and after, along with the general procedures that he or she would need to undergo during the given time-frame.

However, the question that is still being debated, primarily because of the continuing challenge in defining in each case, beyond any scope of doubt, what should be universally considered as an adequate level of information given to the patients to obtain consent of participation in the CT.

Financial compensation process:

Currently, the calculation of financial compensation, wherever applicable, is based on a well-defined formula. This system has been made mandatory for the sponsor in India for any trial related injuries or death. Such compensation has to be paid, even when the trial related injury is discerned after the completion of the CT. The concerned participants would receive this compensation over and above the free medical management of injury, which in any case has to be provided by the sponsor.

Hence patient safety and compensation related issues pertaining to CT in India have, to a great extent, been addressed, though there is still more scope for improvement on an ongoing basis.

Another major issue still to be addressed:

It is generally expected that when CT of a new drug is conducted by the global pharma players in India with the participation of Indian patients, the same drug when launched in other countries would also be made available in India for the benefit of Indian patients.

Unfortunately, the situation is not so, as indicated by a paper titled, “A critical appraisal of clinical trials conducted and subsequent drug approvals in India and South Africa”, published in the BMJ Open on August 31, 2015.

The objective of this study was to assess the relation between the number of clinical trials conducted and respective new drug approvals in India and South Africa.

The study found that out of CTs with the participation of test centers in India and/or South Africa, 39.6 percent (India) and 60.1 percent (South Africa) CTs led to market authorization in the EU/USA, without a New Drug Application (NDA) approval in India or South Africa.

The paper concluded, despite an increase in CT activities, there is a clear gap between the number of trials conducted and market availability of these new drugs in India and South Africa. Hence, the drug regulatory authorities, investigators, institutional review boards and patient groups should direct their efforts to ensuring availability of new drugs in the market that have been tested and researched on their population, the article suggested.

I hope, the CDSCO would take remedial measures to address this situation, soon.

Indian pharma players should get their act together:

In view of the international media reports on alleged ‘CT data fudging’ by some of the larger Indian players in the pharma and relator sectors, there is an urgent need of the Indian pharma players to get their acts together, without any further delay.

On April 15, 2016, Reuters reported, “India’s Alkem Laboratories has been accused by Germany’s health regulator of fudging data on clinical trials of an antibiotic and brain disorder drug, becoming the third Indian firm to be scrutinized since 2014 for suspected manipulation of trial data.” However, a day later Alkem said that it was submitting suitable clarifications to the European Medical Agency (EMA).

Be that as it may, if the allegation for such gross violations of basic ethical standards is true, it would bring shame not just to the companies concerned, but also to India as a trusted source for pharma products and services. Such alleged foul play has the potential to ultimately shatter the stakeholders’ confidence, including patients, on CTs done by the Indian players, both for the local and global markets.

Conclusion:

At the long last, after a grueling experience and tough intervention of the Supreme Court of India, CTs conducted in India are now reasonably well regulated and generally seem to comply with ethical requirements and standards. The question of human ‘guinea pigs’ and its associated concerns have also been adequately addressed by the CDSCO now.

Gradually improving the CT regulatory environment in India, barring some avoidable aberrations, offers some significant direct and indirect benefits to all concerned. Indian pharma is, therefore, expected to handle this sensitive opportunity with great care and following the highest ethical standards.

This, in turn, would help bring to the market robust evidence-based new drugs and treatment for many types of diseases, and at the same time could facilitate their early access to many patients, at a time of dire need.

Through increasing access to CT, the participating patients would be able to avail several important benefits, such as, new and still unavailable treatment options, especially for those serious ailments, where other existing drugs either are not working effectively with satisfactory results, not affordable to many, or not working at all. In that sense, CT could offer to a sizeable number patients several other treatment options to choose from, especially, for many life-threatening diseases. This important benefit needs to be explained to the patients from credible sources, and thus merits serious consideration by the practicing medical professionals.

However, it is also a fact, particularly, in India that some people are lured to, or voluntarily enroll themselves for CT with an objective to make some extra money. Let me hasten to add that there are many other patients for whom the compensation for participation in the CT is no more than just an extra bonus.

Hence, improved patient participation with informed consent, to avail an important medical option in the disease treatment process, encouraged by the doctors without having any vested interest, has a great potential to create a win-win situation, for all concerned.

By: Tapan J. Ray

PILMAN

A Tapan Ray Website

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