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Drug Quality Imbroglio And ‘Culture of Bending Rules’ in India

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“Bottle Of Lies Exposes The Dark Side Of The Generic-Drug Boom” – re-emphasized the book, released in May 2019.  This confirms, the raging debate on the questionable quality of many generic drugs manufactured in India and involving several top domestic pharma companies, is a never-ending one. Numerous articles also ascribe many different reasons to this saga, leaving an overall impression – as if, blindfolded persons are trying to describe an elephant, touching and feeling different parts of the animal’s body, each at a time.

Let me illustrate the point with the Bloomberg article of January 31, 2019. It reported, “Culture of ‘Bending Rules’ in India Challenges U.S. Drug Agency.” And further commented: ‘The FDA confronts creative improvisation in the world’s largest generic-drug exporter.’ Curiously, according to the above report it seems to be a general belief among many, even within India.

This article will take into account the above apprehension – specifically raised against Indian drug manufacturers of both branded and non-branded generics. Accordingly, my focus will be on just three points – as possible causative factors for this critical issue:

  • Is it an India specific concern – thus related to ‘Indian cultural mindset’? or it’s a global issue, involving both Indian multinational drug manufacturers.
  • Is it a systematic attempt to create a perception bias against low-cost generic drugs, worldwide?
  • Are generic drug makers resorting to such unacceptable shortcuts due to increasing margin pressure?

Having deliberated these points, I shall try to outline a set possible remedial measures to address this issue in a holistic way, ensuring a win-win outcome. Let me first explore, whether or not this issue is specific to India, involving Indian drug manufacturers.

Is the issue India specific?

Is the issue of questionable quality of generic drugs, irrespective of whether they carry a brand name or not restricted to the shores of India? One can find its answer in the same report, as quoted above. A yearlong investigation by Bloomberg News into the generic-drug industry concluded, ‘FDA inspections at factories from West Virginia to China have found reason to doubt the data meant to prove drugs are safe and effective.’

One possible reason for such perception could be, since India is predominantly a branded generic market, voices decrying ‘questionable’ safety and efficacy of cheaper non-branded generic drugs, are too loud. Nevertheless, amidst all this, who’s who of branded generic manufacturers continue getting caught on the wrong foot by overseas regulators in the quality quagmire. Ironically, multinationals are also included in it.

Multinationals are also included in such quality quagmire:

There are several examples of non-compliance to requisite drug quality standards by multinational drug companies. Let me illustrate the point with an example that involves a top global pharma player.

The March 04, 2019 ‘Warning Letter’ of US-FDA for the Irungattukottai (Tamil Nadu) plant of Pfizer in India, clearly said: “Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture.”

This is not a solitary example of Pfizer’s generic hospital injectables manufactured in this plant. According to a media report dated July 17, 2018, twice before US-FDA had cited manufacturing and testing issues in this facility, containing 11 observations of the regulator, such as, workers “manipulated test sample weights to obtain passing results” for both batches of raw materials and finished product. It is a different matter that the company, later on, decided to close this plant for commercial reasons. Be that as it may, negative perception of generic drug quality is indeed an issue that needs to be addressed without further delay, holistically.

Studies have captured negative perception of generic drugs:

That this is a perception, has been well – elucidated along with its implications, in several studies. A few of which are as below:

A BMJ article concluded: “A significant proportion of doctors, pharmacists and lay people hold negative perceptions of generic medicines. It is likely these attitudes present barriers to the wider use of generics.” It further added, “Negative perceptions of medicine quality along with other drivers contribute towards choosing more expensive medicines in the private sector.”

Endorsing this point, yet another BMJ article inferred: “Negative perceptions of generic medicines and preferential promotion of branded medicines over generics by pharmaceutical companies could influence prescriber behavior and affect trust in healthcare provided in public services. To succeed, access to medicine programs need to systematically invest in information on the quality of medicines and develop strategies to build trust in healthcare offered in government health services.”

Again, in a separate survey of over 2700 physicians on perceptions of generic drugs, more than 23 percent of respondents expressed negative perceptions about their efficacy and nearly 50 percent. reported negative perceptions of generic drug quality. In the same survey, patients also expressed concerns that the lower cost of generics is associated with reduced medication quality.

Although, the above survey was conducted in the United States, the current situation in India, I reckon, is no different, but with one caveat. Here, preferential promotion of branded generic medicines over cheaper non-branded equivalents, by the respective drug manufacturers, could significantly influence prescriber behavior. Therefore, the question that follows: Is this perception-creation based on facts?

Is the negative perception fact-based?

Although, even the US-FDA clearly states that: ‘A generic medicine works in the same way and provides the same clinical benefit as its brand-name version”, I did try to find some conclusive evidence depicting brand name drugs are superior to their cheaper generic equivalents. While doing literature searches, two types of results emerged – there are studies that do not find any significant difference between generic drugs and their branded equivalents. At the same time, a few other studies do suggest that there is a difference between these two, but admitting that these studies are not conclusive. Let me give below examples of each.

No quality difference found between generic drugs and the branded variants: 

I shall quote here three studies, out of which one is India specific. The analysis reported in the above BMJ article, found that ‘the generic and branded variants of the medicines tested were of comparable quality.’

Another study, published by PLOS Medicine on March 13, 2019 also said, “In this study of 8 drug products conducted using 2 large US commercial insurance databases, we observed that use of generics provided comparable clinical outcomes as the brand products.”

An India specific researchon the same also reported, most generic and branded drug users believed that their drugs were effective in controlling their ailments with no significant difference in reported adverse effects and drug adherence.

Slightly different results were also reported with generics, but not conclusive:

One such study questioned, whether generic drugs are truly equivalent to the brand-name versions.This article was published on January 2019 by Harvard Health Publishing with the title, “Do generic drugs compromise on quality?”

This article quoted a Canadian study, published in the October 2017 issue of ‘Circulation: Cardiovascular Quality and Outcomes’, which found that patients who took generic versions of three different blood pressure medications in the months after the generic drugs became available saw increased rates of drug-related side effects.

Was it due to a perception bias?

To ascertain whether or not there is a perception bias, let us look into the following details of the same study along with its conclusion.

In this study, the researchers ‘looked at the numbers of emergency room visits and hospitalizations for 136,177 individuals ages 66 and over (60% of them women) who used any of three blood pressure medications: losartan (U.S. brand name Cozaar), valsartan (Diovan), and candesartan (Atacand). The investigators examined data for the periods 24 months before and 12 months after the generic versions of these medications went on the market. And found that before the generic versions became available, about one in 10 people taking the blood pressure drugs had to go to the emergency room or be hospitalized each month. In the month after each of the generics went into use, the rates of these adverse events went up: 8% for losartan, almost 12% for valsartan, and 14% for candesartan.’ The study authors commented, this might suggest performance differences between the brand-name and generic drugs.

However, analyzing this study, the Harvard article suggested further probe on the question: Did it result from quality problems with the generic versions of these medications or were there other factors that occurred in this time frame?

Another research, aimed at finding, whether patients are more adherent to generic statins than brand-name statins (lovastatin, pravastatin, or simvastatin) and whether greater adherence improves health outcomes, also concluded, “An 8% reduction in the rate of the clinical outcome was observed among patients in the generic group versus those in the brand-name group.” This also wasn’t a conclusive one, either.

Nevertheless, the key point of a ‘perception bias’, is captured in a separate study, where the researchers did find higher rates of psychiatric hospitalization for patients taking generic and AG escitalopram and sertraline, compared with those who initiated the brand-name product. Importantly, they noted that these outcomes were likely due to either residual confounding or generic perception bias.

No quality difference also found between branded and non-branded generics in India:

There are studies, which captured no quality difference between branded generics and non-branded generics in the country. One such India specific study concluded: “Quality of branded-generics is same as for their branded version. The study highlights the need to modify the drug price policy, regulate the markups in the generic supply chain, conduct and widely publicize the quality testing of generics for awareness of all stakeholders.”

Thus, so far, we have seen in this article that concern on quality of generic drugs is neither India specific, nor is it related to ‘Indian cultural mindset.’ And this is, undoubtedly, a global issue, involving both Indian and multinational drug manufacturers. There are also ample evidences available that a systematic attempt is being made to create a perception bias against low-cost generic drugs, worldwide. Let us now look at the third possible causative factor, as I listed above.

Is it due to margin pressure on generic drugs?

The answer to this question was deliberated in an article titled, ‘Generic drug makers feel pinch as prices crumble,’ published in the Financial Times on August 17, 2017. Quoting a top global financial analyst, it reported – global generic drug industry, where Indian manufacturers are major players,has maintained roughly 30 per cent operating margins over a long period of time, with improvements year on year. But, since last few years, there has been a margin degradation, which may possibly further go down – even lower than what it is today.

The article further highlighted, a round of consolidation among their main customers in the US: the wholesalers, have escalated the problem.  Many of these groups have clubbed together to form “mega buyers”, known as general purchasing organizations, that can command large discounts. Moreover, for the US market, another area of ‘concern’ is that the US-FDA has identified boosting competition in the generics market as one of its main priorities. As this reform opens up, it could squeeze the generic drug margins further.

Many envisage that intense cost cutting measures, could have transgressed in the drug quality assurance area, aggravating this issue. Although, it needs to be verified through credible studies, curiously, some signs of improvement in this area has recently been reported.

That said, there appears to be a strange coincidence between recent reports on Indian drug makers showing improvement in USFDA inspection outcomes and attempts to increase generic drug companies and some of their top executives slapped with price-fixing lawsuits in the U.S.This needs to be studied further.

The way forward:

The negative perception of generic drugs, in general, and non-branded generic drugs, in particular, is most likely a well-crafted business issue, rather than a genuine patient safety concern. It calls for an immediate two-pronged approach:

  • Vigorous awareness and educational campaigns on safety and efficacy of generic drugs targeted to patients, medical and paramedical professionals.
  • New regulatory measures, especially the following five:

- No pricing pressure or price control in any form of generic drugs

- Abolish brand names for generic drugs

- Make generic prescription compulsory to boost intense competition and thereby     reducing the price.

- Restrict the number of ingredients in FDC not more than two or three

- Make Uniform Code of Pharmaceutical Marketing Practices (UCPMP) mandatory.

Conclusion:

Thus, the questionable quality of generic drugs is not an India specific concern and involves both Indian multinational drug manufacturers. This is also evident from the analysis, as quoted above, that underscores, ‘FDA inspections at factories from West Virginia to China have found reason to doubt the data meant to prove drugs are safe and effective.’ Many studies have revealed that there is a systematic attempt to create a perception bias against low-cost generic drugs, worldwide.

A sequence of remedial measures, as described above, also include fostering competition, instead of introducing government controls on prices of generic drugs with stringent regulatory oversight being in place.

Thus, the so called ‘belief’ that the ‘culture of bending Rules’ is culpable for dubious generic drug quality in India, is more akin to a strong perception, prevailing in India, rather than based on any scientific analysis related to this issue. This ought to change with a well-coordinated intervention – for patients’ health interest sake.

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.

Escalating Antibiotic Resistance, And Thwarting Ban Of Irrational FDCs

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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   

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.

Ease of Doing Pharma Business in India: A Kaleidoscopic View 

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Ensuring ease of doing any ethical business activity in India, is a new focus area of the Government and is very rightly so. Creating ease of doing ethical pharma business too, falls under this overall national objective.

In this article, restricting myself to the drug sector, I shall deliberate on various aspects, which are now being considered by the pharma industry, related to the ‘ease of doing pharma business in India’. My discussion would cover all subsets of pharma players, irrespective of whether they fall under Multinational (MNC) or purely homegrown Indian companies, with different scales of operations – large, medium, small, or micro. 

To help the Government facilitating the ‘‘ease of doing pharma business in India’, it is just not enough to make the business models for all subsets of the Indian pharma sector looking ethical, conforming to all relevant laws, policies, rules and norms. Each pharma player need also to maintain an ongoing strict internal vigil, religiously, to ensure that the requirements of high quality clinical development, manufacturing and selling practices for effective, safe and rational medicines, are properly understood and strictly followed by all the employees within the organization.

A Kaleidoscopic View:

The above situation is something that ought to happen, as the Government keeps striving to improve the ‘ease of doing pharma business’ in India. However, while looking through a Kaleidoscope, as it were, the colors of industry expectations in this area keep changing rapidly, as the new contentious issues keep emerging. Consequently, the ground reality of assessing the same, by a large section of the pharma players in India, seems to veer only around different types of just self-serving demands, expecting those to act as a powerful tailwind pushing their business interests rapidly forward.

Such expectations keep surfacing, rather frequently, from all the subsets of the pharma industry, be they MNCs and their trade associations or the Companies of purely Indian origin and their trade bodies. The accusation to the Government pertaining to all these issues, is a common one: ‘Where is the ease of doing pharma business in India?’

Citing even some recent incidents, they are voicing with equal gusto, that the root causes of all these problems lie miles outside the pharma industry. The causative factor, they indicate, is rooted at the very doorsteps of the Government, as its ministries initiate tough action to root out corruption in the pharma industry as concurrent measures, disturbing their business comfort zones, and upsetting the apple carts. 

The Government has its task cut out:

I hasten to add that I have no intention to paint it as a confrontation between the Government and the pharma industry, in any way. The Government is also facing the brunt from the various stakeholders, relentlessly, for its utter negligence of public health care, and public expenditure over it.

The impact of this Government indifference, though also comes on the patients, the industry does not seem to have much to crib over it as a direct impediment to the ‘ease of doing pharma business’ in India.

Probably as a diversionary tactic, the industry keeps using this critical Government inaction in the hope of diverting the public, or media attention from its own alleged business malpractices, even at a time when these are being covered both by the national and international media, regularly. Nevertheless, the industry credibility on these issues, seems to have started waning fast, as the genie is out of the bottle.

A common punching bag of all industry dissatisfaction on the Government:

It is worth noting that despite some key differences between the MNC and Indian pharma companies, which I shall discuss later, the common punching bag of the industry dissatisfaction on various Government decisions, always has been the lack of ‘ease of doing pharma business’ in the country.

This discontentment may be well justified. I have no qualms about it. However, when this dissatisfaction gets tagged with some recent Government action, taken to protect public health interests and does not have much to do with the ‘ease of doing ethical pharma business’, many eyebrows are obviously raised.

Against some of these critical patient-centric actions, the industry continues to express its annoyance in unison, while for some other Government decisions, it speaks in different voices – some are happy ones, and the others are not so. However, the common thread of expression of all such dissatisfactions is always linked with the lack of ‘ease of doing business’ in India.

A. Where the pharma Industry in India speaks in unison: 

I shall now give two major examples of the key Government decisions, that have irked the entire pharma industry immensely, and makes it voicing that those Government actions grossly violate the fundamental requirements of its smooth running of business. Is that fair? Let me analyze that below with these two examples:

1. Drug price control:

The industry, by and large, opines that individual drug company should be allowed to decide the way it would price any drug, as the market forces, especially for generic drugs, would determine its price.

Indian Parliament, the Supreme Court of India, the Government in power at different times, most of the independent experts and the NGOs, on the contrary, consider drug price control is necessary in India, especially for essential drugs. It makes high quality essential medicines affordable and accessible to the general population.

National Pharmaceutical Pricing Authority (NPPA) has also announced and explained that the competition does not work on controlling prices for pharma products, where the consumers are not the decision makers. The key prescribing decision makers for the patients are the doctors, who are mostly and unethically influenced by the drug companies having vested interest in making such decisions. This unholy nexus has been widely alleged globally, and also established through umpteen number of studies of high credibility.

Nevertheless, the doctors, from across the globe, including in India, have long disputed that any payments, if and when they receive from pharmaceutical companies, have no relationship to how they prescribe drugs.

A March 17, 2016 study of ProPublica has conclusively established that: “The more money doctors receive from drug and medical device companies, the more brand-name drugs they tend to prescribe. Even a meal can make a difference.” This study may be in the context of the Unites States, but India in this in this regard is no exception, as captured even in the parliamentary Committee reports.

Thus, conceding to high voltage pharma advocacy, made on the pretext of ‘encouraging innovation’ and ‘ease of doing business in India’, if any Government contemplates the abolition of drug price control in India is, it would make not just essential drugs inaccessible to a large section of society, but encourage blatant corrupt practices. This caution has come, besides many others, also from a Parliamentary Committee report, unambiguously. Incidentally, the present Government too strongly speaks against corruption, in any form.

Thus, I reckon, if the industry believes that the price control of essential drugs, which are for public health interest, goes against ease of doing pharma business in India, so be it.

2. Manufacturing and selling of irrational FDCs:

A Fixed Dose Combination (FDC) drug may appear irrational to drug regulators and well-qualified experts, after necessary scientific scrutiny, for various reasons. This may happen, primarily because of the following reasons:

  • When the medical rationale of the FDC along with the ingredient details, submitted to the regulatory authority for marketing approval, are considered scientifically inappropriate.
  • When the evolving medical science establishes the irrationality of the FDC after a period of time.
  • When the analysis of ‘Adverse Drug Event’ reports from the ongoing Pharmacovigilance studies signals a red alert.
  • Widespread uncontrolled misuse or abuse of FDCs, where the consumers’ health risks far outweigh the drug benefits, as provided in the drugs Act, for public health interest.
  • Some regulatory loopholes were misused by the drug manufacturers in the past to get the irrational FDCs approved by the State Drug Authorities, violating the new FDC regulatory approval Policy.

Any irrational FDC so identified by the drug regulators and experts, by putting a system of scrutiny in place, must be banned forthwith, in public health interest. There should not be any scope of negotiation with drug manufacturer to make the bans effective.

Incidentally, realizing the gravity of public health risks posed by irrational FDCs, even the NPPA has reportedly decided to review afresh all new applications for price fixations of FDC and examine their safety and efficacy profile.

Moving towards this direction, the NPPA Chairman, has reportedly sent back more than 200 applications for price fixation of FDCs, instructing the concerned manufacturing and marketing companies to apply again with a declaration that their formulations are not “irrational.” It was also reported that the price regulator has also brought under the lens third-party drug makers and pharma companies that outsource to them, to check illegal sales of irrational FDCs and spurious drugs.

Two key questions being raised now:

Despite all these, the industry keeps repeating, especially, the following two questions, which are worth looking at, one by one: 

1.  Why is the ban now?

I discussed the issue of FDC ban in my previous article in this Blog on March 21, 2016 titled, “The Recent Ban On Irrational FDCs: History Repeats Itself”.

In the above article, I also argued that large section of the industry and its associations are protesting against the Government ban of 344 irrational FDCs, and questioning vigorously, even outside the Delhi High Court – ‘why is the ban now?’

The point ‘why now’ is absolutely irrelevant, as not taking any action ever, against a wrong doing ignored over a long period time for whatever reasons, does not confer any regulatory legitimacy to an irrational FDC formulation to be considered as a rational one for all time to come, and thereby, exposing patients to serious health risks, knowingly.

2.  Why is this ban so sudden, and in some cases after decades?

Sudden banning of drugs, which are in the market for a long time, is not a recent Indian phenomenon in India. In 2011, according to a report, in the world’s largest pharma market – the United States, the FDA banned 500 prescription drugs that had been on the market and working for decades. USFDA ban also happened suddenly, and that includes cough syrups too.  Thus, it is intriguing, why is this fuss created by the Industry in India now? 

In the midst of it, one odd, knee-jerk, apparently ‘spoon-fed’ and ill-informed editorial in some Indian business daily, raises more questions about its real intent, rather than help finding answers to the poorly sketched problems.

I would hope, the Government would stay firm and be able to convince the Delhi High Court today, i.e. on March 28, 2016, with its robust data-based arguments, accordingly.

Be that as it may, in my perspective, if the industry still believes that bans of irrational FDCs to protect public health interest, as decided by the independent experts after long and structured deliberations, would go against ‘ease of doing pharma business’ in India, so be it. 

B. Where the pharma industry in India speaks in different voices:

As stated above, there are several other key areas, where the MNC and Indian Pharma players have sharp differences in their perspectives. Despite these differences, the aggrieved section does not even blink a bit to attribute those Government actions to the lack of ‘ease of doing pharma business’ in the country.

 In this area, I shall give just the following three examples: 

1. The Patents Act:

MNCs say that section 3 (d) of the Indian Patents Act 2005, which is aimed at curbing patent ever-greening or frivolous inventions, is against the ease of doing business in India. However, the Indian Pharma players, do not think so, at all. Similar disagreement also exists in other critical areas too, such as, ‘Data Exclusivity (DE)’ and ‘Compulsory Licensing (CL)’.

Thus, in my opinion, if some ‘public health interest’ related provisions of the robust Indian Intellectual Property (IP) Act, such as, section 3 (d), DE and CL, are considered as going against the ‘ease of doing pharma business in India’ by the MNCs, so be it.

2. Mandatory Uniform Code of Pharma Marketing Practices (UCPMP):

Need to have a mandatory UCPMP, though, is reportedly supported by the MNCs, Indian pharma players do not seem to be quite in sync with this idea. I am not sure, whether the delay in the announcement of mandatory UCPMP, almost in every 3 months, has any coincidence with it or not. However, the reality is, no one still knows clearly, when would it definitely come, if at all.

Media reports on pharma MNC support to mandatory UCPMP, and repeated reiteration that its members in India rigidly follow the IFPMA Code of Marketing Practices, though commendable, seem to grossly lack in credibility.

Interestingly, despite the existence of this code and high-decibel vouch for its rigid conformance, maximum number of MNCs have been fined billions of dollars, by the Government in various countries, for alleged gross marketing and other business malpractices. It has been happening over a long period of time, and is being reported by the international media, frequently.

What is really happening, especially, on the so called total support of ethical marketing practices by the MNCs? Are they trying to create just good optics by craftily framing and supporting such showpiece codes, and blatantly defying these to achieve self-serving goals? The voice gets shriller, even when they are being levied hefty fines, after getting caught red handed, as reported by the global media? I guess, the future would ultimately unfold the reality. But would it, at all?

The Indian Scenario: 

Even in India, such alleged marketing malpractices involving even a top pharma MNC have often been reported by the media. Just to illustrate, “Prescribe a drug maker’s medicine and get a free vacation”, reported a news article. There are several other similar reports too. Hence, the credibility of pharma MNC statements regarding strict conformance to ethical marketing codes, ably formulated by the well-known pharma trade associations, such as, IFPMA, appears to be very low, if exists at all.

The well-reputed medical Journal BMJ in one of its articles titled, “Corruption ruins the doctor-patient relationship in India”, published on May 8, 2014, expressed serious concern on this issue.

It concluded that corruption, kickbacks and the nexus between doctors and pharmaceutical firms are rampant India. This eventually prompted the BMJ, in June 2014, to launch a campaign reportedly called ‘Corruption in Medicine’.

On this issue, way back in May 08, 2012, even the Indian Parliamentary Standing Committee on Health and Family Welfare in its 58th Report, placed before the Parliament on May 08, 2012, expressed its serious concern.

Indian lawmakers, recommended in the report that the Department of Pharmaceuticals (DoP) should take decisive action, without further delay, in making the UCPMP mandatory, so that effective checks could be ensured on ‘huge promotional costs’ and the resultant add-on impact on medicine prices. Unfortunately, despite a change in the Government in 2014, UCPMP has still not been mandatory.

It is anybody’s guess, despite all these reports, what type of external pressure, if at all, the DoP is still facing to put in place a robust mandatory UCPMP with strong deterrent measures.

Under this backdrop, in my view, if mandatory UCPMP having enough teeth, to curb ongoing blatant marketing malpractices to protect patients’ health interest in India, is considered by any as going against the ‘ease of doing pharma business in India’, so be it. 

3. Drug manufacturing quality:

Enough discussions have already been made on import ban of USFDA from over 45 drug manufacturing facilities of Indian Companies, of all sizes and scale of operations, on the ground of drug quality standards. USFDA considered drugs manufactured in those banned facilities are unsafe for the consumption of American patients. Some other foreign drug regulators, from the developed countries, have also taken similar action.

Taking advantage of this development, it was reported that attempts are indirectly being made to establish that MNC marketed generic drugs are superior to similar ones, manufactured even by the large Indian drug producers.

The fact, apparently, is quite different. MNCs operating in India has not come under the USFDA scanner in this regard as much, probably not because of their far superior drug manufacturing quality standards in India, as compared to even the best of their Indian counterparts. I reckon, it is mainly because, very few MNC drug manufacturing facilities in India export India manufactured drugs for consumption in the United States. 

It may not, therefore, make any real sense to conclude that MNC marketed generic drugs in India, either manufactured my themselves or under loan & license or under a third party, are generally better in quality than the similar ones manufactured even by the large Indian manufacturers. 

In any case, I feel that there is a huge scope for Indian drug regulators to ensure uniformly high drug quality standards. This is necessary for Indian patients’ health and safety. There also should be stringent regular quality audits in all drug manufacturing facilities in India, where non-conformance with prescribed standards would attract serious punitive measures. The Union Ministry of Health, together with the State Governments would require increasing the number of auditors accordingly.

However, the reality is, many Indian drug manufacturers have expressed that maintaining stricter drug manufacturing standards (cGMP) would involve huge expenditure, which they will not be able to afford. Consequently, this would go against the ‘ease of doing pharma business’ in India.

Again, in my view, if the stringent regulatory requirements for maintaining high drug manufacturing standards in India to protect public health interest, is considered as going against the ‘ease of doing pharma business’ in India, so be it.

Conclusion:

Improving ‘ease of doing pharma business’ in India is an absolute necessity, just as all other businesses. Pharma sector deserves it very badly too, as it has been experiencing excruciating delay in multiple regulatory clearances. Single window clearances of all applications, with a much greater sense of urgency, without bureaucratic red tapes and avoiding other unnecessary delays, is certainly the way forward for India. It would require urgent policy reforms, maintaining a right balance between, public, consumers and business interests.

Pharma sector is not all villain, either, by any yardstick. It is instrumental in saving and improving the quality of lives of so many people across the globe, since a very long time, with its both innovative and generic medicines. All must acknowledge it, and the Government does it too, openly, several times. 

That said, the space of focus of the pharma industry appears to be getting increasingly narrowed down to more of its self-serving acts, and in their hard selling, through hugely expensive advocacy campaigns, even at the huge cost of attracting frequent self-defeating scathing criticisms, across the world.

At the same time, the Governments in different times hugely disappointed its citizens, in charting a clear road map for quality and affordable health care for all in India, along with appropriate budgetary allocations and policy reforms, and thereafter, in its implantation with military precision.

However, that doesn’t mean, in any way, while facilitating ‘ease of doing pharma business’ in India, the Government would turn a blind eye on the rapidly breeding corruption in the pharma business practices, and give in to unjustified industry muscle-flexing, sacrificing the health interest of its citizens in the country.

While looking through this Kaleidoscope, it appears to me, if the pharma sector considers the appropriate Government actions to protect public health interest, against the unacceptable industry practices, would also go against the ‘ease of doing pharma business’ in India… Well, so be it.

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.

 

Booming Sales Of Unapproved Drugs: Do We Need “Safe In India” Campaign For Medicines?

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“To sin by silence when they should protest makes cowards of men”                      - Abraham Lincoln

Not just the Federal Drug Administration of the United States (USFDA), global concerns are being expressed regularly about the laxity of drug regulatory and clinical trial standards in India, exposing patients to health safety related risks.

The problem is significantly more with the Fixed Dose Combination (FDC) Drugs for various reasons. This is worrisome because; the domestic market for FDCs is very large and growing much faster, in sharp contrast to the western world. For example, in 2011-12 FDCs accounted for more than half of all NSAID and oral anti-diabetic drug sales, and one-third and one-fifth of anti-psychotic and anti-depressant/benzodiazepine sales, respectively, according to a recent study.  Both the domestic and multi-national pharma players market FDCs in India

Alarmingly, a plethora of FDCs unapproved by the drug regulators of India on their rationality, efficacy and safety, have flooded the domestic pharma market, in large quantities.

All such drugs are being actively promoted by the respective pharma players, widely prescribed by the doctors, openly sold by the chemists and freely consumed by the patients without any apprehension or having no inkling of the magnitude of the possible health hazards that such drugs might cause, both in short and long term.

Public health safety hazard arising out of this scenario does not seem to have ever been estimated by the Indian drug regulators, despite indictments even by the Parliamentary Standing Committee, nor is there any properly functional system in place to capture such data for meaningful analysis.

As the saying goes ‘better late than never’, a credible report on this menace has just been published on May 12, 2015 by independent experts, which I shall discuss in this article.

Is the situation out of control?

On the ground, the situation seems to be out of control of even the Central Drugs Standard Control Organization (CDSCO).

This is vindicated by a March 2013, written reply of the Minister for Health and Family Welfare, where the Government reportedly informed the Lok Sabha (the lower House of the Parliament) that in twenty three cases of new FDC, licenses have been granted by the State Licensing Authorities (SLAs) without the mandatory approval of the DCGI and action will be taken in all these cases.

However, no one seems to know, as yet, what action the Government has taken against those errant officials.

The latest investigative report on the criticality of the situation:

The May 12, 2015 issue of “PLOS Medicine” – a Peer-Reviewed Open-Access Journal, published the results of an investigation on CDSCO approval for and availability of oral FDC drugs in India from four therapeutic areas – analgesia (non-steroidal anti-inflammatory drugs (NSAIDs), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics).

This study was done based on the Department Related Parliamentary Committee on Health and Family Welfare’s 2012 Report, stating that manufacturing licenses for large numbers of FDCs had been issued by state authorities without prior approval of the CDSCO in violation of rules, and considered that some ambiguity until 1 May 2002 about states’ powers might have contributed to this worrying consequences.

I shall also discuss the above Parliamentary Committee report in this article.

Booming sales of unapproved drugs: 

‘PLOS Medicine’ report highlighted the following:

A. They obtained information on FDC formulations approved between1961 and 2013 in each therapeutic area from the CDSCO.

B. FDC sales details were obtained for the period 2007 to 2012 from PharmaTrac database of drug sales in India. Over the five years included in the time-trend analysis, FDCs accounted for an increasing proportion of total sales volumes. By 2011–2012, FDCs accounted for more than half of all NSAID and oral anti-diabetic drug sales, and one-third and one-fifth of anti-psychotic and anti-depressant/benzodiazepine sales, respectively.

C. Of the 175 FDC formulations marketed in India in the therapeutic areas studied, only 60 (34 percent) were approved. 

Out of these, percentages of approved formulations are as follows:

-       80 percent of 25 marketed metformin FDC formulations

-       27 percent of 124 NSAID FDC formulations

-       19 percent of 16 anti-depressant/benzodiazepine FDC formulations

-       30 percent of 10 anti-psychotic FDC formulations

D. In 2011–2012, percentages of FDC sales volumes arising from unapproved formulations was:

-       43 percent for anti-psychotics

-       69 percent for anti-depressants/benzodiazepines

-       28 percent for NSAIDs

-       0.4 percent for metformin

E. Formulations including drugs of which use is banned or restricted internationally accounted for 13.6 percent and 53 percent of NSAID and anti-psychotic FDC sales, respectively.

F. While “ambiguity” in the rules prior to 2002 was advanced as a reason for some FDCs having been marketed without a record of central approval, the researchers identified no ambiguity, and in fact, following an amendment to the rules in May 2002 that extended the requirements on approval applicants, new FDCs continued to be marketed without a record of central approval.

The suggestions:

The ‘PLOS Medicine’ report concluded with the following suggestions:

Unapproved formulations should be banned immediately, prioritizing those withdrawn or banned internationally, and undertaking a review of benefits and risks for patients.

To ensure long-term safety and effectiveness of new medicines marketed in India, as well as transparency of the approval process, amendments in India’s regulatory processes and drug laws are called for. A review should be undertaken of the safety and effectiveness of FDCs currently available in India.

Indian lawmakers too pointed out this embarrassing regulatory laxity:

This saga of drug regulatory laxity in general and for the FDCs in particular, is continuing since quite a while. This is despite the fact that the Department Related Parliamentary Committee on Health and Family Welfare presented its 59th Report of 118 pages in total on the functioning of the Indian Drug Regulator – the Central Drug Standards Control Organization (CDSCO) in both the houses of the Parliament on May 08, 2012.

The report begins with a profound observation:

Medicines apart from their critical role in alleviating human suffering and saving lives have very sensitive and typical dimensions for a variety of reasons. Prescription drugs are the only commodities for which the consumers have no role to play. Nor are they able to make any informed choices, except to buy and consume whatever is prescribed or dispensed to them, because of the following reasons:

  • Drug regulators decide which medicines can be marketed
  • Pharma companies either produce or import drugs that they can profitably sell
  • Doctors decide which drugs and brands to prescribe
  • Consumers are at the mercy of external entities to protect their interests

The ‘Mission Statement’ of CDSCO is ‘Industry Oriented’ and not ‘Patient Focused:

Very interestingly, the lawmakers’ report highlights, citing the following examples, how out of line the ‘Mission Statement’ of CDSCO is, as compared to the same of other countries, by being blatantly industry oriented instead of safeguarding Public Health and Safety interests :

Drug Regulator

The ‘Mission Statement’
1.

CDSCO, India

 Meeting the aspirations…. demands and requirements of the pharmaceutical industry.
2.

USFDA, USA

 Protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs.
3.

MHRA, UK

 To enhance and safeguard the health of the public by ensuring that medicines and medical devices work, and are acceptably safe.
4.

TGA, Australia

 Safeguarding public health & safety in Australia by regulating Medicines…

Consequently, the Parliamentary Committee took a strong exception for such utter disregard and continued neglect of patients’ interest by the Drug Regulator of India. It recommended immediate amendment of the ‘Mission Statement’ of CDSCO incorporating in very clear terms that the existence of the organization is solely for the purpose of protecting the best interest of patients and their safety. It is needless to say, thereafter it would call for its stringent conformance with high precision.

A scathing remark against CDSCO:

The parliamentary Committee report made the following scathing remarks on CDSCO in its point 2.2:

“The Committee is of the firm opinion that most of the ills besetting the system of drugs regulation in India are mainly due to the skewed priorities and perceptions of CDSCO. For decades together it has been according primacy to the propagation and facilitation of the drugs industry, due to which, unfortunately, the interest of the biggest stakeholder i.e. the consumer has never been ensured.”

Allegation of possible collusion:

The report also deliberates not only on the utter systemic failure of CDSCO along with the DCGI’s office to enforce the drug regulations effectively, but also towards a possible collusion between CDSCO and the pharmaceutical industry to implement a self-serving agenda by hoodwinking the system. This is a very serious allegation, which needs to be thoroughly probed and the findings of which should be made public for everybody’s satisfaction.

The committee, therefore, felt that effective and transparent drug regulation, free from all commercial influences and callous enforcement of rules and laws, are absolutely essential to ensure safety, efficacy and quality of drugs keeping just one objective in mind, i.e., welfare of patients.

Do we need “Safe in India” campaign for drugs?

Do we need a well-hyped “Safe in India” campaign for drugs? Looking around, at least conceptually, the answer is probably ‘yes’…Seriously…I am not joking!

The reason being, despite scathing remarks of the Parliamentary Standing Committee in 2012, apparently no systematic enquiry has been undertaken by the CDSCO to ascertain the reason for continuation and the veracity of this menace, just yet.

A very significant number of unapproved medications still remain undetected by the drug regulators and continue to be abundantly available, frequently prescribed, openly sold and freely consumed by the patients without even an iota of doubt regarding possible health safety hazards that these prescription drugs might cause.

May 2015 ‘PLOS Medicine’ Report helps unraveling the underbelly of the drug regulatory scenario in India, along with its systemic decay, which fails to halt the possible serious health safety hazards that Indian patients are exposed to.

India’s image as an emerging ‘pharmacy of the world’ for cheaper generic drugs has already been dented with a number of ‘import bans’ from the US and UK for flouting the specified drug manufacturing quality standards.

The saga of ‘import bans’ for Indian drugs, together with this critical health safety related menace, probably necessitates an effective launch of a “Safe in India” campaign for medicines, in general, by the Government.

This initiative gains additional importance, as painstakingly developed reputation of the Indian drug exporters, including the largest domestic players, has now been dented. It needs to be revamped, sooner.

I addressed a related issue in my blog post of February 3, 2014, titled “FDA ‘Import Bans: Valuing Drug Supply Chain Security For Patients’ Safety.”

Conclusion:

Effective resolution of this critical issue demands high priority at the highest level of the decision making process of the Government, with commensurate sense of urgency.

Keeping that in mind, would it be a bad idea, if just like “Make in India” campaign of the Prime Minister; “Safe in India” campaign for medicines is also undertaken with equal gusto and monitored by the top echelon of the country’s rejuvenated governance machinery?

This initiative would probably help sending the very contextual ‘shape up or ship out’ signal to the drug regulators, both at the Center and also in the States to erase the prevailing menace for good.

In that process, it would eventually allay the public health safety concern with the ‘Made in India’ drugs, coming out of ‘Make in India’ campaign, not just in the country, but also beyond its shores.

The speed of action in this situation is the essence. Otherwise, the following golden words of wisdom as enunciated by Abraham Lincoln would keep haunting us, till the remedial measures taken by the Government become palpable on the ground:

“To sin by silence when they should protest makes cowards of men”

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.

NDDS as New Drug: Good for Patients, Great for Pharma

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The Ministry of Health of India has reportedly decided to amend Rule 122 (E) of the Drugs and Cosmetics Rules, 1945 to categorize the New Drug Delivery Systems (NDDS), including ‘Controlled Release (CR)’ or ‘Modified Release (MR)’ formulations, whether a copy of studied and approved drugs or a new one, as ‘New Drugs’.

After the amendment, all vaccines and recombinant DNA (r-DNA) derived drugs would also fall under this nomenclature. Accordingly, to obtain ‘Marketing Approval’, such formulations would be subjected to requisite studies, including ‘Clinical Trials (CT), as specified for ‘New Drugs’ under the Drugs and Cosmetics Act of India.

It has however been clarified though, that these applications will not be treated as Investigational New Drugs (IND) and the Central Drugs Standard Control Organization (CDSCO) shall prepare appropriate regulatory guidelines for all NDDS formulations.

The main reason for the amendment is possibly much late realization of CDSCO that such formulations are vastly different from each other with respect to both efficacy and toxicity.

Besides, it has been widely alleged that some pharma companies in India, mainly to hoodwink the Drug Price Control Orders (DPCO) in the past, used to switch over from ‘Immediate Release (IR)’ formulations to products with CR/MR technology of the same molecule. However, that loophole has since been plugged in DPCO 2013, creating almost a furore in the industry.

A long overdue decision for patients’ health safety:

As stated earlier, this is indeed a long overdue decision of the Indian drug regulatory policy makers, solely considering patients’ health interest.

The primary reason being, any NDDS formulation with CR/MR technology is designed to release the drug substance in a controlled manner with high precision to achieve desired efficacy and safety, quite unlike its IR equivalent, if available in the market. It is important to note that inappropriate release of the drug in any CR/MR formulation would result in lesser efficacy or increased toxicity, jeopardizing patients’ health.

Process followed by US-FDA for CR/MR formulations:

In the United States, for marketing approval of such products, FDA usually requires submission of New Drug Applications (NDAs) providing details based on the evidence of adequate drug exposure expressed by blood levels or dose, and the response framework validated by clinical or surrogate endpoint(s).

US-FDA has three types of NDAs for MR drug products:

  • IR to CR/MR switch
  • MR/CR to MR/CR switch with unequal dosing intervals
  • MR/CR to MR/CR switch with equal dosing intervals

For switching from an IR to a CR/MR product, which is more common in India, the key requirement is to establish that the new CR/MR product has similar exposure course of the drug as compared to the previously approved IR product, backed by well-documented efficacy and safety profile. If not, one efficacy and/or safety trial would be necessary, in addition to three clinical pharmacology studies.

Good for patients:

The good news for patients is that, being categorized as ‘New Drugs’, all NDDS formulations, without any exceptions whatsoever, would henceforth obtain marketing approval only from the Drug Controller General of India (DCGI), after having passed through intense data scrutiny, instead of State Drug Authorities where getting a manufacturing license of such formulations is alleged to be a ‘child’s play’. Thus, with the proposed amendment, efficacy and safety concerns of CR/MR formulations are expected to be addressed adequately.

Great for Pharma:

Currently, while fixing the ‘Ceiling Prices (CP)’ under DPCO 2013, National Pharmaceutical Pricing Authority (NPPA) treats CR/MR formulations at par with IR varieties of the same molecules having the same dosage strength.

Thus, categorization of all NDDS formulations as ‘New Drugs’, irrespective of the fact whether these are copies of studied and approved drugs or new ones, would be lapped up by the manufacturers from product pricing point of view. All these formulations, after the proposed amendment, would go outside the purview of drug price control under Para 32 (iii) of DPCO 2013, which categorically states that the provisions of this order shall not apply to:

“A manufacturer producing a ‘new drug’ involving a new delivery system developed through indigenous Research and Development for a period of five years from the date of its market approval in India.”

A similar past issue still haunts:

Similar callousness was exhibited in the past, while granting marketing approval for a large number of highly questionable Fixed Dose Combination (FDC) drugs by the same drug regulators. Unfortunately, that saga is still not over, not just yet. 

All these irrational FDC formulations, even after being identified so by the Drug Technical Advisory Board (DTAB), have been caught in the quagmire of protracted litigations. Consequently, such dubious products are still being promoted by the respective pharma players intensively, prescribed by the doctors uninhibitedly, sold by the chemists freely and consumed by patients ignorantly. With ‘pharmacovigilance’ being almost non-functional in India, the harmful impact of these drugs on patients’ health cannot just be fathomed.

Conclusion: 

With the above examples, it is quite clear that technological precision of high order is absolutely imperative to manufacture any effective CR/MR formulation. In addition, stark regulatory laxity in the marketing approval process for these drugs is a matter of great concern.

In such a scenario, one could well imagine how patients’ health interests are being compromised by not formalizing and adhering to appropriate regulatory pathways for marketing approval of such drugs in the country, since decades.

That said, as the saying goes “Better Late, Than Never”. The ‘New Drug’ nomenclature of all CR/MR formulations or for that matter entire NDDS as a category, including vaccines and recombinant DNA (r-DNA) derived drugs, would now hopefully be implemented in India, though rather too late, a much welcoming decision nevertheless.

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.

FDC Saga: Defiant Manufacturers, Sloppy Regulators and Humongous Inaction

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“TO SIN BY SILENCE WHEN THEY SHOULD PROTEST MAKES COWARDS OF MEN”       – Abraham Lincoln

The ghost of untested, irrational and even of bizarre kind of Fixed Dose Combination (FDC) drugs, which continue to be launched, promoted, prescribed and sold freely across the length and breadth of India, has started haunting the Ministry of Health of India, yet again, in 2013. 

Though the issue originated decades ago, in 1988 appropriate ‘Rule’ of the Drugs and Cosmetics Act of India was amended suitably to have a firm regulatory grip over this situation. Despite this much awaited amendment, the situation almost went astray with incessant market entry of a large number untested FDC medicines of dubious medical rationale.

A free for all situation, as it were, in the FDC arena, continued to be facilitated by blatant laxity on the part of, especially, the state drug regulators by allowing unfettered market entry of such drugs, ignoring the CDSCO directive.

On the other hand, the Central Drugs Standard Control Organization (CDSCO), despite its statutory powers,  continued to suffer from humongous inaction untill the issue resurfaced again in 2007 and then of course, now in 2013.

The WHO Model:

The 2005 ʹProcedure to update and disseminate the WHO Model List of Essential Medicines, Criteria for Selection’ includes the following statement regarding Fixed Dose Combination products (FDCs):

ʺMost essential medicines should be formulated as single compounds. Fixed‐dose combination products are selected only when the combination has a proven advantage over single compounds administered separately in therapeutic effect, safety, and adherence or in delaying the development of drug resistance in malaria, tuberculosis and HIV/ AIDS.ʺ

Thus, FDCs:

  • Need to demonstrate clinical efficacy and safety beyond the individual drugs when given alone.
  • Need to ‘demonstrate bioequivalence of the single combined dose unit with the components administered in the same doses separately but concomitantly’.

‘Adherence’ aspect of WHO Model for FDCs is also important. Problems with ‘adherence’ could lead to inadequate and inconsistent dosing, which in turn could lead to development of drug resistance.

With robust and unquestionable medical rationale, FDCs are expected to provide superior efficacy and improved compliance without causing any untoward risk to patients.

A major disadvantage:

However, one of the major disadvantages with the FDCs is lack of flexibility in adjusting dose of individual ingredients, even if it is required for some patients. Internationally, most popular example is the FDCs of antiretroviral drugs for HIV infected patients like, Combivir, Trzivir, Kaletra etc.

Interestingly, in India there are FDCs for almost all disease areas from allergic disorders to Wolf-Parkinson-White syndrome (exaggerated), as it were.

Market attractiveness for FDCs in India: 

The domestic market for FDCs is very large and growing much faster, in sharp contrast to the western world. The following table will vindicate this point:

% Share

Drug

2008

2009

2010

2011

Plain

55

55

55

54
Combinations

45

45

45

46

Domestic Market: USD 13 Billion; MAT Apr 2013

Source:IMS

Thus, because of growing market demand, pharmaceutical companies in India tend to market FDCs of all different permutations and combination, at times even crossing the line of any ‘sound medical rationale’. For this reason, we find in the website of ‘Central Drugs Standard Control Organization’ (CDSCO), the banned list of so many FDCs.

A messy regulatory situation:

Introduction of new FDCs does not only warrant a ‘sound medical rationale’ but also ‘strict conformance to all prescribed regulatory requirements’ for patients’ interest. 

To check unfettered market introduction of potentially harmful FDCs, the Ministry of Health issued a Notification in September 1988, including FDCs in Rule 122 E of the Drugs & Cosmetics Rules (D&CR) 1945.

In effect, it removed the powers of the State FDAs to give manufacturing or marketing approval of FDCs. After the notification was issued, all manufacturers/marketers of all new FDCs are required to apply only to the Drug Controller General of India (DCGI) under Rule 122E of the D&CR 1945 as a new drug, along with the stipulated fees by way of a Treasury Challan.

Since this entire process entails appropriate regulatory data generation, besides  time and expenses involved, the above ‘Rule’ was continuously and deliberately broken and manufacturing and marketing approvals for various types of FDCs falling under ‘new drug’ category were regularly sought and granted by the State Drug Controllers.

Many believe that the State FDAs were equally responsible for knowingly flouting the Law, as were the pharmaceutical manufacturers.

Patients’ safety – the foremost concern:

Despite serious concerns expressed by a Parliamentary Standing Committee, this complicity resulted in the market being flooded with ‘irrational combinations’ which posed a real threat to patients’ interest and safety. The State FDAs were reminded of the notification by the earlier DCGI.

294 FDCs were banned by the DCGI in 2007. Thereafter, the important issue of patients’ interest and safety got converted into a legal quagmire, as many FDC manufacturers chose to go to the court of law to protect their business interest and also managed to obtain a ‘Stay’ order from the Madras High Court. The matter is still subjudice.

Be that as it may, those 294 FDCs banned by the Ministry of Health of India on health and safety grounds continue to be promoted, prescribed and sold to patients across India without any hindrance, whatsoever.  

Untangling the messy knot:

As the issue got entangled into prolonged litigations, the CDSCO took initiative of resolving this contentious issue again in 2009 with the help of an expert committee, involving the manufacturers.

This subcommittee cleared 48 FDCs under ‘similar FDCs already approved’, after discussing the merits and demerits, including pharmacodynamics, pharmacokinetics, side effects, dosage, medical rationale etc. of each ingredient and the combinations. The decision of the Sub Committee was then submitted to the Drug Technical Advisory Board (DTAB).

After formal approval of DTAB, these combinations are construed to be new drugs and any company wishing to market/manufacture the formulation would require submitting its Application in Form 44 to the DCGI to get approval in Form 45.

This decision was expected to send a clear signal to all concerned that resorting to any form of shortcuts to bypass strict adherence to prescribed regulatory requirements, could seriously jeopardize patients’ interest and safety. The same process was subsequently followed for the balance 142 FDCs, as well.

Thereafter, a special committee was again appointed by the CDSCO in 2013 to look into this matter in a holistic way. However, such sporadic knee-jerk reactions have failed to deliver any tangible results in this area – not just yet.

The saga continues:

Even after the above critical decision of the DTAB the saga still continues.

In March 2013, by a written reply, the Minister for Health and Family Welfare reportedly informed the Lok Sabha (the lower House of the Parliament) that in twenty three cases of new FDC, licenses have been granted by the State Licensing Authorities (SLAs) without the mandatory approval of the DCGI and action will be taken in all these cases.

However, no one seems to know, as yet, what action the Government has taken against those errant officials.

Current scenario:

Recently, the Directorate General of Health Services (DGHS) by a notification to State Drug Controllers has reportedly ordered all manufacturers of new FDC products, licensed locally before October 2012 without CDSCO permission, to submit safety and efficacy data prior to 30 August 2013.

This decision of DGHS has created a furore within the concerned FDC manufacturers, yet again, the possible outcome of which is yet to be ascertained.

The State Drug Controllers had issued manufacturing licenses for these FDCs prior to October 2012. At that time concerned manufacturers were given 18 months time period to prove efficacy and safety of these medicines to the DCGI. Regrettably, as per the above report, the DCGI has confirmed that he has received hardly any response from the FDC manufacturers till date on this regulatory requirement.

CDSCO has also stated that manufacturers, who will fail to submit the required data by the deadline run the risk of having their products banned from the market.

Before this, the State Drug Controllers were informed about this requirement on January 15, 2013.

At this point it is worth mentioning, the DCGI in October 2012 had reportedly also barred the State Drug Controllers from granting manufacturing licenses to pharmaceutical companies under brand names of the drugs, directing them to strictly issue licenses under generic name of the molecule. Additionally, he also asked the state licensing authorities not to grant licenses to combination drugs, which are technically ‘new drugs’ and fall within the domain of DCGI only.

Conclusion:

This logjam with FDCs certainly cannot continue in perpetuity, neither should such regulatory sloppiness be acceptable to any right thinking stakeholder.

All blatant violations of Drugs and Cosmetics Act of India must be stopped forthwith and the violators be brought to justice without delay. Patients’ health interest, as required by the drug regulators, is non-negotiable.

The order of DGHS asking all manufacturers of new FDCs, licensed locally before October 2012 without CDSCO permission, to submit safety and efficacy data prior to 30 August 2013, should not follow recently reported Pioglitazone type of volte face, once again, under similar outside pressure.

It is high time now for the Government to bring the unending saga of  irrational and harmful FDCs, orchestrated by defiant manufacturers, encouraged by sloppy regulators and catalyzed by humongous systemic inaction, to its logical conclusion, for patients’ sake. 

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.

 

 

Pioglitazone Conundrum: Should The Drug Regulator Step Over The Line?

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Recent order of the Indian drug regulator to withdraw all formulations of the well known, yet controversial, anti-diabetic drug – Pioglitazone from the domestic market has created a flutter in the country, ruffling many feathers at the same time.

Withdrawal of any drug from the market involves well-considered findings based on ongoing robust pharmacovigilance data since the concerned product launch. To ascertain long-term drug safety profile, this process is universally considered as important as the processes followed for high quality drug manufacturing and even for R&D.

A paper titled, “Withdrawing Drugs in the U.S. Versus Other Countries” brings to the fore that one of the leading causes of deaths in the United States is adverse drug reaction. Assessing enormity and impact of this issue, the United Nations General Assembly for the first time in 1979 decided to publish a list of banned pharmaceutical products that different countries may use for appropriate decisions keeping patients’ safety in mind, as they will deem necessary from time to time.

An interesting finding:

Quite interestingly, the paper also highlights:

“There are a number of pharmaceuticals on the market in the USA that have been banned elsewhere and similarly, there are some drug products that have been banned in the United States, but remain on the market in other countries.”

Different policies in different countries:

The reason for the above finding is mainly because, various countries follow different policies to address this important health related issue. For example, though the United States will withdraw drugs based on the decision taken by its own FDA, it will also compare the action taken by countries like, UK, Japan, Australia and Sweden on the same subject.

However, many experts do believe that United Nations must take greater initiative to make all concerned much more aware about the UN list of dangerous drugs, which should be continuously updated to expect the least.

Need transparency in pharmacovigilance:

Pharmacovigilance has been defined as:

“The task of monitoring the safety of medicines and ensuring that the risks of a medicine do not outweigh the benefits, in the interests of public health.”

An article on Pharmacovigilance by A.C. (Kees) van Grootheest and Rachel L. Richesson highlights as follows:

“The majority of post marketing study commitments are never initiated, and the completion of post marketing safety studies (i.e., phase IV studies) declined from 62% between 1970 and 1984 to 24% between 1998 and 2003.”

Thus, in many countries, due to lack of required transparency in the pharmacovigilance process, harmful drugs continue to remain in the market for many years before they are withdrawn, for various reasons.

The above paper strongly recommends, “While there might be monetary benefits for each country in keeping these drugs on the market, the U.N. must step up the visibility of the withdrawal of dangerous drugs list.”

Recent Pioglitazone withdrawal in India:

Recently in India, the Ministry of Health under Section 26A of the Drugs and Cosmetics Act, 1940 has suspended the manufacture and sale of Pioglitazone, along with two other drugs, with immediate effect, through a notification issued on June 18, 2013.

As per the Drugs and Cosmetic Rule 30-B, import and marketing of all those drugs, which are prohibited in the country of origin, is banned in India. Just as in the United States, the Ministry of health, while taking such decisions in India, compares long-term safety profile of the concerned drugs in countries like, USA, UK, EU and Australia.

A Parliamentary Standing Committee of India has already indicted the drug regulator for not taking prompt action on such issues to protect patients’ treatment safety.

Pioglitazone: the risk profile:

In India:

A leading medical journal (JAPI) cautions:

“Given the possible risk of bladder cancer, physicians have to be extremely careful about using pioglitazone indiscriminately in the future.”

The JAPI article continues to state:

“We require more robust data on the risk of bladder cancer with pioglitazone and Indian studies are clearly needed. Till that time, we may continue the use of this drug as a second or third line glucose-lowering agent. In all such cases, the patient should be adequately informed about this adverse effect and drug should be used in as small a dose as possible, with careful monitoring and follow up.”

In the USA:

In 2011 The US FDA as a part of its ongoing safety review of pioglitazone informed physicians and the public that use of this drug for more than 12 months is linked to an increased risk of bladder cancer.

The USFDA review is reportedly based on “an ongoing 10-year observational cohort study as well as a nested, case-control study of the long-term risk of bladder cancer in over 193,000 patients with diabetes who are members of the Kaiser Permanente Northern California (KPNC) health plan.”

Based on this finding US FDA directed that physicians should:

  • Not use pioglitazone in patients with active bladder cancer.
  • Use pioglitazone with caution in patients who have a prior history of bladder cancer, adding, “The benefits of blood sugar control with pioglitazone should be weighed against the unknown risks for cancer recurrence.”
  • Tell patients to report any signs or symptoms of “blood in the urine, urinary urgency, pain on urination, or back or abdominal pain, as these may be due to bladder cancer.”
  • Urge patients to read the pioglitazone medication guide.
  • Report adverse events involving pioglitazone medicines to the FDA MedWatch program.

The moot point:

Considering the above US FDA directives in the Indian context, the moot point therefore is, whether it will be possible for the drug regulator to ensure that physicians and the patients in India follow such steps for drug safety with pioglitazone?

In Canada:

Another new Canadian study has again reportedly linked Pioglitazone with risks of bladder cancer and cautioned, “physicians, patients and regulatory agencies should be aware of this association when assessing the overall risks and benefits of this therapy.”

Pioglitazone and its combinations banned in France and Germany:

After a government-funded study, tracking diabetics from 2006 to 2009, concluded that Pioglitazone increases bladder cancer risk, the French Medicines Agency (FMA) announced withdrawal of Pioglitazone along with its fixed-dose combination with Metformin, as well.

FMA also advised doctors to stop prescribing Pioglitazone, plain or in combination, and asked patients, who are on this drug to consult their doctors immediately.

Simultaneously, German health authorities also acted on similar lines.

An intriguing comment by the Indian drug regulator:

Keeping all these in view, it is indeed intriguing to note that the Indian drug regulator is reportedly open to re-examine the case of pioglitazone and revoking its ban in India, if strong scientific evidences emerge in support of safety and efficacy of the drug.

However, the question then comes up is what more new scientific evidences that the Indian drug regulator is now expecting, especially when the pharmacovigilance studies are almost non-existent in India?

Moreover, such comments of the drug regulator not only prompt raising doubts about the fragility and hastiness of his own decision of banning Pioglitazone in India, but also amply demonstrate lack of seriousness in his part on this extremely important decision on drug safety?

‘Drug Product Liability Claims’ in India virtually non-existant:

In most of the developed countries, appropriate regulations are in place for product liability claims.

Under this law, if any patient suffers injury in any form while administering  a pharmaceutical drug, the patient concerned is eligible to make pharmaceutical-drug-based product liability claims, which usually involve a huge amount of money by any imaginable standard.

These claims are based on:

  • Improperly marketed pharmaceutical drugs. This category includes:

- Failure to provide adequate or accurate warnings regarding a dangerous side effect.

- Failure to provide adequate instructions on safe and appropriate use of the drug.

- The “bad advice”, which may have been given by the manufacturer or by a doctor, pharmacist, sales rep, or some other medical provider.

In the United States drug safety and effectiveness related litigations reportedly also include:

-        Criminal and civil complaints brought by the U.S. Department of Justice.

-        Lawsuits brought by state Attorney Generals and private plaintiffs under state consumer protection acts and other causes of action.

In India, closer to the above system there is a law in paper, named as “Products Liability”. This law deals with the liability of manufacturers, wholesalers, distributors, and vendors for injury to a person or property caused by dangerous or defective products. The aim of this law is to help protecting consumers from dangerous or defective products, while holding manufacturers, distributors, and retailers responsible for putting into the market place products that they knew or should have known were dangerous or defective. However, in reality, there are hardly any damages slapped by consumers on to the manufacturers in India under this ‘Product Liability’ law.

It may sound however bizarre, but is a hard fact that many drugs in Fixed Dose Combinations (FDCs) had never even gone through any form clinical trials on human volunteers before they were for the first time allowed to be marketed in India by the drug regulators.

In absence of any active steps taken by the government to educate and encourage patients to make use of this law, patients, by and large, would continue to pay a heavy price for their ignorance, keeping their mouth shut all the way, while using:

- Defectively manufactured pharmaceutical drugs.

- Pharmaceutical drugs with dangerous side effects.

- And even improperly marketed pharmaceutical drugs.

As stated before, it is worth repeating, neither is their any functional pharmacovigilance system in place in India.

Drug product liability suit for Pioglitazone in the United States:

Just to cite an example, one report indicates:

“According to court filings, all of the Actos (Pioglitazone) lawsuits pending in the Western District of Louisiana allege Takeda Pharmaceuticals failed to provide adequate warnings to doctors and patients regarding the drug’s association with an increased risk of bladder cancer. Last month (April, 2013), the nation’s first trial involving Actos bladder cancer allegations ended with a Los Angeles Superior Court jury awarding $6.5 million to a plaintiff who was diagnosed with the disease after taking the drug for four years”. However, the judge overseeing the case granted Takeda Pharmaceuticals’ request to set aside the verdict.

The report also indicates, ‘more than 1,200 Actos bladder cancer claims are pending in the Louisiana litigation. Additional Actos lawsuits have been filed in state litigations in California and Illinois.’

Indian doctors and manufacturers protest together against Pioglitazone ban:

It is equally intriguing to note, despite serious life threatening side-effect and restricted usage profile of Pioglitazone, as established internationally through robust and large clinical studies, both the doctors and the Pioglitazone manufacturers in India are urging the government to lift ban on this drug immediately, keeping the silent patient community in the front line, as usually happens all over.

A news report highlighted that ‘doctors flayed the ban on anti-diabetes drug Pioglitazone and requested the Centre to reverse its decision in interest of patients.’

Another media report highlighted, major drug makers are strongly opposing the move of the government to ban Pioglitazone, in India.

Conclusion:

Without generating another set of robust evidence proving contrary to what has been already concluded in the United States and EU based on strong supporting pharmacovigilance data, if the Indian drug regulator revokes the ban of Pioglitazone, it will be construed as a huge compromise with patients’ safety interest with this drug.

This issue assumes even greater importance, when the ‘drug product liability’ system is almost dysfunctional in India.

The other alternative of the drug regulator is to revoke the ban, wilting under combined pressure of the manufacturers and doctors and ask for safety warnings trying to emulate, as it were, what has been done by the US FDA.  

In which case, with full knowledge that it is virtually impossible for any one to comply with the above US FDA requirements in India, will the drug regulator not step over the line, yet again?

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.

Prescribing medicines by generic names…a good intent… but is it a practical proposition in India?

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Parliamentary Standing Committee for Health and Family Welfare in their recommendation to the ‘Rajya Sabha’ of the Indian Parliament on August 4, 2010, recommended prescription of medicines by their generic names.

This recommendation appears to be based on the premises that the cost of ‘Brand Building’ exercise of the generic drugs in India, including varying degree of presumably ‘high sales and marketing expenditure’ incurred by the formulators towards such efforts, can be easily eliminated to make medicines available to the common man at much cheaper prices.

This recommendation, on the face of it, makes immense sense. However, the moot question remains, “Is it a practical proposition to implement in India?”

In the following paragraphs, let me try to deliberate on this important issue.

Generics and Branded Generics:

As we know generic name is the actual chemical name of a drug. The brand name is selected by the producer of a formulation and is built on various differential value parameters for its proper position in the minds of health professionals as well as the patients. Thus, brand name offers a specific identity to the generic drug.

The prevailing situation in India:

In India, over 50% medicines prescribed by the physicians are for Fixed Dose Combinations (FDCs), spanning across almost all therapeutic categories. Thus, it could be difficult for them to prescribe such medicines in the generic name and could equally be difficult for the chemist to dispense such prescriptions.

Moreover, in case of any mistake of dispensing the wrong drug by the chemist inadvertently, the patients could face serious consequences. It is well known, the concentration of ingredients in the fixed dose combination of any two medicines, many a times, differs from manufacturer to manufacturer. There are over 50,000 odd formulations in the Indian pharmaceutical market and it would be almost impossible for any doctor to keep track of exact concentrations of each of these drugs and prescribe in their right strengths.

Current prescription practice:

Currently doctors use brand names to differentiate one such formulation from the others. Different brands of even single ingredient medicines may have inherent differences in their formulations like, in the drug delivery systems (controlled/sustained release), kind of coatings allowing dissolution in different parts of alimentary canal, dispersible or non-dispersible tablets, chewable or non-chewable tablets etc. Since doctors are best aware of their patients’ conditions, they may wish to prescribe a specific type of formulation based on specific conditions of the patients, which may not be possible by prescribing only in generic names.

Other Patients related issues:

Patients also could face other difficulties due to generic prescribing. As is known, different brands of FDCs may have different proportions of same active ingredients. If chemists do not know or have the exact combination prescribed by the doctor in their shops, thye would possibly substitute with a different combination of same drugs, which could well be less effective or even harmful to the patients.

Conclusion:

Prescriptions by generic names instead of brand names could likely to lead to substitution of the medicines at the chemists’ outlets because of the reasons, as mentioned above.

Thus, the major concern with generic prescriptions is that a chemist will then make the choice of the manufacturer while dispensing a medicine. There could only be one criterion for the choice of such medicines by a chemist i.e. to select what gives them highest margin of profit. In such a case, the ultimate decision making authority for the prescription medicines shifts from the physicians to the chemists, which could make the situation far worse for the patients. For the interest of the patients, it is, therefore, extremely important that the government, regulators, physicians, chemists and even the patients’ groups are aware of such risks.

Considering all these risk factors, in my view, if the prescriptions of medicines are made mandatory by their respective generic names in India, it could compromise with patients’ safety, very significantly.

By Tapan Ray

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