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

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

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

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

A key medical research tool: 

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

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

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

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

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

Broad types: 

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

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

  • Phase I: Here, for a new treatment, an investigational drug is tested for the first time in small numbers, usually between 20 and 100, on healthy volunteers, to identify the proper dosage ranges for drug administration, while critically monitoring its method of absorption, adverse effects and toxicity profile.
  • Phases II: This phase, just as Phase I studies, also tests the drug on, usually between 100 and 300 patients, suffering from the targeted disease conditions. Safety is the main goal of this phase of CT and is programmed towards adjusting treatment doses, monitoring the common side effects, and whether patient’s disease condition improve as a result of the drug. These studies are usually randomized and double-blinded, where neither the patient nor the researchers would know whether a patient is receiving the investigational drug, or a placebo, or a standard treatment.
  • Phase III: In this phase, the investigational new drug goes through rigorous testing of safety, efficacy, and proper dosage levels in a large group of subjects, which may even exceed several thousand, with a specific illness or disease. The key objective is to enable the doctors to evaluate the safety and effectiveness of the treatment for various groups of patients, such as, men versus women, elderly versus young, besides many others. 
  • Phase IV: Such studies are done after the drug receives the marketing approval from the drug regulator. The basic objective of these trials is usually to monitor whether the treatment offers desired benefits or gives rise to long-term side effects, which were not seen in the phase II and III trials. This phase may involve even several hundreds and thousands of patients.

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

The role of patients:

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

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

Major reasons for not enough patient participation:

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

  • Patients often are not aware that such trials also offer a treatment option. In many cases, their doctors too may not be explaining it effectively to them, as a part of their professional discourse. Several studies conclude that trust in a physician is a main reason patients decide to participate in CT.
  • Some patients, after reading media reports, interacting with some NGOs and also from word of mouth, mistrust the CT process and suffer from fear of being a guinea pig.
  • At times, complicated protocols, and eligibility requirements may also be discouraging.
  • Many patients, especially in India, are not very clear about the exact insurance (financial) cover the study provides for them, along with other payments for the care that they would receive during the trial, or for any drug-related long term untoward incident even after completion of the CT.

All these need to be effectively addressed. 

India attractiveness for CT:

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

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

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

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

Improving CT regulations in India:

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

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

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

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

Informed consent:

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

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

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

Financial compensation process:

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

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

Another major issue still to be addressed:

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

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

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

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

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

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

Indian pharma players should get their act together:

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

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

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

Conclusion:

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

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

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

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

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

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

By: Tapan J. Ray 

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.

Nutraceuticals: Make The Fragile Regulatory Space Robust, Soon

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In the space between drugs and nutrition, there is an intriguing ‘gray area’ with significant business relevance, especially in India.

In a related publication, A.T. Kearney – a leading global management consulting firm has elaborated it as below:

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

Falling in the middle of the spectrum, a large number of Nutraceuticals clearly blur the line between food and drugs, in many cases. In India, there is no clearly defined legal and regulatory status for such Nutraceuticals, just yet.

Why a robust regulation required for Nutraceuticals? 

The scholarly article of S.H. Zeisel (Professor of Nutrition, University of North Carolina at Chapel Hill Nutrition) titled, “Regulation of Nutraceuticals,” Science 5435, 1853–1855 (1999) highlighted that in many cases when the dosages of food supplements exceed those of a normal diet, there could well be a drug-like bioactivity of a nutrient.

An example of the nutrient tryptophan may suffice to illustrate this point briefly. At higher dosage tryptophan can exhibit drug-like activity, as it is the precursor of serotonin, which is extensively used to treat insomnia. Many of such points are yet to draw the regulators’ attention in India as much as it should, as yet.

Marketing drugs as ‘food supplements’?

Marketing drugs as food supplements to evade Drug Price Control Order (DPCO) by some pharma players, of all sizes and scale of operation, is not an uncommon practice in India. The National Pharmaceutical Pricing Authority (NPPA), reportedly, pointed it out sometime around 2009.

Not just for pricing reason, but more importantly for consumers’ health and safety, the Central Drugs Standard Control Organization (CDSCO) should address this issue now with a greater sense of urgency, as the market for Nutraceuticals and health supplements is reportedly growing at a brisk pace today. According to a Frost & Sullivan report, the total Indian Nutraceuticals market in 2015 was expected around US $ 5 billion. 

In the absence of any clear and robust regulatory guidelines, most Nutraceutical products, with a spectrum of therapeutic claims, are virtually self-categorized as food supplements, which are not covered under the Drugs and Cosmetics Acts in India.

Currently in the country, Nutraceuticals and functional foods are covered under the definition of ‘food’ as per Section 22 of Food Safety & Standards Act (FSSA), 2006. These food products have been categorized as Non-Standardized/Special Food Products. Accordingly, Food Safety and Standards Authority (FSSAI) of India have described Nutraceuticals as:

“Naturally occurring chemical compound having a physiological benefit or provide protection against chronic disease, isolated and purified from food or non-food source.”

Though categorized as nutritional supplement, the product packs of such Nutraceuticals usually do not carry any “FSSAI’ logo, which signifies conformance to the food safety standards of India, for the benefit of consumers.

Recommendations are many, but no comprehensive action yet:  

To give an example, many Nutraceuticals contain vitamins in varying quantity. However, most of these products seem to carefully avoid Schedule V guidelines for vitamin content to avoid being categorized as drugs, and thereby coming under strict regulatory requirements. Self-categorizing these products as ‘food supplement’, helps bypassing this issue, as on date.

Such ongoing practices related to Nutraceuticals need to be viewed keeping in perspective, some of the recent key recommendations made by the Drugs Technical Advisory Board (DTAB) of the CDSCO, on Schedule V related formulations.

The minutes of the 70th. meeting of the Drugs Technical Advisory Board (DTAB) held on August 18, 2015, recorded the acceptance of the report of its sub-committee on vitamins, which recommended, among others, some of the following guidelines:

  • Ingredients which are covered under the range as prescribed under schedule “V” of the Drugs and Cosmetics Rules for Tablets, capsules, granules are 18 classified as a drug, while those powders like Farex, Oats and Cereal fortified vitamins are exempted from the provisions of chapter IV under schedule K of Drugs and Cosmetics Rules.
  • Ingredients which fall below the range as prescribed under schedule “V” shall be classified as food. However, if there is a claim for treatment, mitigation or prevention of any diseases or disorder, then it will be classified as a drug. 
  • Ingredients which are within Recommended Daily Allowance (RDA) levels, but fall under the range as prescribed under schedule V Drugs and Cosmetics Rules shall be classified under drug as it is already mentioned in the rules. 
  • Products containing ingredients which are neither covered under Schedule V nor fall within RDA, these can be classified as unprovable products under Drugs and Cosmetics Rules, unless otherwise specifically permitted by the Licensing Authorities of drugs based on major purpose of the item (like food/drug).
  • Whenever there are additional ingredients than those given in schedule V, including some of herbal ingredients, a separate and conscious view has to be taken about the safety and efficacy of the drug
  • Any product containing herbal ingredients shall be dealt with by the food or drug authority based on the above principles. 

The same subcommittee, on June 12, 2015, after discussing each of some specified products, with a claim of falling in non-drug category, as per directions of the Hon’ble High Court of Patna, recommended categorization of some of the well-known brands brands, such as, Revital (Ranbaxy) and A to Z capsules (Alkem) as drugs. The sub-committee report was then uploaded in the CDSCO website for stakeholders’ comment.

Could there be ‘irrational FDC ban’ like an issue with Nutraceuticals?

The answer to this question is anybody’s guess at this point of time. However, such a possibility can be just wished away either.

This lurking fear stems from the recent notification of FSSAI dated March 30, 2016, which states as follows:

“It has been decided that till the standards of Nutraceuticals, food supplements and health supplements are finally notified, the enforcement activities against such food business operators may be restricted to testing of these products with respect to requirements given in the draft notification on such products of September 9, 2015″.

However, it clarifies that the companies will get an exemption, if such products were available in the market before the Food Safety and Standards Act came into effect in 2011, or if product approval was pending on August 19, 2015.

The key objective of the above September 9, 2015, FSSAI draft notification was to ensure that Nutraceuticals, health and food supplements and other such products are not sold as medicines with therapeutic claims. Thus, asking the industry players to send their suggestions and objections to the proposal, this draft notification indicates, among others, that all such products should: 

  • Adhere to the proposed permissible limits of various minerals, vitamins, plant or botanical-based ingredients, among others.
  • Adhere to the proposed list of food additives used in all these categories of products, besides labelling norms, every package must carry the words “Food” or “Health Supplement” and prominently display “Not for Medicinal Use” on the label. 
  • Give a disclaimer on the package that the food or health supplement should not be used as a substitute for a varied diet.
  • Clearly indicate on the label that “this product is not intended to diagnose, treat, cure or prevent any disease”, besides information on recommended dosages, among others.

As this notification is expected to cover all products, which are marketed as food supplements, many Nutraceuticals manufacturers, reportedly, fear that it could effectively mean a ban on virtually all those brands, self-categorized as food or nutritional supplement, and launched post 2011.

If it happens, the saga of ban of a large number of irrational Fixed-Dose Combinations (FDCs) of drugs, that includes some top-selling pharma brands and is now sub judice, could get extended to the Nutraceuticals sector too. 

Nonetheless, the bottom-line is that a robust mechanism to effectively regulate and monitor Nutraceuticals in India, is yet to see the light of the day. 

Crazy marketing of Nutraceuticals: 

Despite regulatory and marketing restrictions to the therapeutic claims for this category of drugs, Nutraceuticals are mostly promoted to the doctors, just as any other ethical pharma products in India.

Consequently, these are widely prescribed by the medical profession, not just as nutritional supplements, but also for the treatment of disease conditions, ranging from obesity to arthritis, osteoporosis, cardiovascular conditions, diabetes, anti-lipid, gastrointestinal conditions, dementia, age-related muscle loss, pain management and even for fertility. All these are generally based on off-label therapeutic claims of the respective manufacturers.

Being advertised in the mass media too:

To illustrate this point, I would give an example of a well known brand in India. As I see from the Government records, i.e. from the minutes of the 68th meeting of the DTAB sub-committee held on June 12, 2015 that it had recommended Revital’s (Ranbaxy) categorization under drug.

As we all know that, as per drugs and Cosmetics Act of India, drugs cannot be advertised in the mass media, except Schedule K drugs, such as Aspirin and paracetamol. In that sense, I find it difficult to fathom, how is Revital then, which highlights a naturally occurring substance fortified with vitamins and minerals, advertised even on the Television, along with a top celebrity endorsement?

A recent notification on phytochemicals:

As I mentioned in my article in this Blog on December 21, 2015, titled “Nutraceuticals: A Major regulatory Step That Was Long Overdue”, partly responding to the growing demand for regulatory intervention in this important matter, on November 30, 2015, by a gazette notification, the Government of India included phytopharmaceutical drugs under a separate definition in the Drugs & Cosmetics (Eighth Amendment) Rules, 2015, effective that date.

This regulatory action followed the rapidly growing use of these drugs in India, which includes purified and standardized fraction with defined minimum four bio-active or phytochemical compounds.

On the ground, this significant regulatory measure would require the pharma players to submit the specified data on phytopharmaceutical drugs, along with necessary applications for conduct clinical trial or import or manufacture of these products in the country. 

However, this is no more than half-measure in this direction. Hopefully, this will be followed by final action on the DTAB recommendations on vitamins, and final notification of FSSAI on standards of Nutraceuticals, food and health supplements. A well-integrated action of the CDSCO and FSSAI, would possibly help to contain the unregulated proliferation of various types of Nutraceutical products coming into the Indian market, prescribed by the doctors and consumed by the people, sans any scientific evidence based efficacy, safety and quality standards.

Manufacturers’ business interest also can’t just be ignored:

While there is a pressing need to enforce regulatory discipline for claimed efficacy, safety and high quality standards for the Nutraceuticals to protect consumers’ health interest, commercial interest of such drug manufacturers can’t also just be ignored. If that happens, it will be unfair.

Thus, one of the ways to encourage the manufacturers to expand this market, I reckon, could well be categorizing the Nutraceuticals offering health benefits, under a separate category altogether, which will be kept out of any form of drug price control.

Conclusion:

The manufacturers of Nutraceuticals still keep charting in a very relaxed regulatory space. Currently, there is no robust and transparent process in place to standardize and scientifically evaluate safety and efficacy of these products on an ongoing basis. This scenario should not be allowed to continue, any longer.

Appropriate control of standardized Nutraceutical manufacturing, regular monitoring of the same and scientific evidence-based marketing approval process of all such products, therefore, require to be well-well regulated. The requirement for stringent conformance to the set cGMP standards would ensure desired safety, efficacy and high quality of nutraceutical products for the consumers.

The recent decisions of the Union ministry of Ayush for setting up a structured regulatory framework, within the CDSCO, for all Ayush drugs and to allow marketing of any new Ayurvedic medicine only after successful completion of clinical trials to ensure its safety and efficacy, are indeed encouraging.

Just as Ayurvedic products, all Nutraceuticals, not being essential medicines, should always be kept outside price control in any form. It should happen in tandem with the Government’s taking a bold step to make the prevailing fragile regulatory space for the Nutraceuticals a robust one, creating a win-win situation for all. 

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.

 

The Recent Ban On Irrational FDCs: History Repeats Itself

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The recent regulatory ban on a large number of irrational Fixed Dose Combination (FDC) drugs is not a new incident in India. A similar mega ban was announced even before, about nine years ago. Intriguingly, the saga continues, for various reasons, without any tangible outcome for the patients on the ground.

On March 11, 2016, the latest ban, again on a large number of irrational FDCs, was notified. It caused a flutter and an immediate sharp adrenaline rush to the impacted drug companies and was soon followed by an interim stay order, again by an honorable High Court of the country.

Thus, when I connect the past dots with the latest one, on mega ban of irrational FDCs in India, a similar sequence of events gets unfolded, following each of such ban notifications of the Government.

Looking back, 294 FDCs were banned by the DCGI in 2007. At that time too, the important issue of patients’ health, safety and economical interest, got converted into a legal quagmire. Many adversely affected FDC drug players chose to go to the court of law to protect their business interest, and also successfully managed to obtain a ‘Stay’ order from the Madras High Court.

Consequently, those 294 irrational FDCs, banned by the Union Ministry of Health on health and safety grounds, continued to be promoted, prescribed and sold to patients across India, without any hindrance, whatsoever.

The matter continues to remain sub judice, as we deliberate the issue here. Thus, whether the recent gazette notification on the ban of irrational FDCs would immediately be implemented, unlike the past ban, or the history would repeat itself, is indeed a big question mark, at this juncture.

Would this ban have similar outcome?  

As discussed, close to a decade after the serious legal fall-out of the ban of 294 irrational FDCs in 2007, another mega ban of 344 irrational FDCs has been announced by the Government, through a Gazette Notification dated March 11, 2016. Some well known brands, such as, Corex, Phensedyl, Crocin Cold and Flu, D-Cold Total, Nasivion and Vicks Action 500 Extra, among others, reportedly come under this ban now. Here is the complete list of 344 banned FDCs.

According to the Government, the reason for banning these drugs is that ‘they involve risk to humans and safer alternatives were available.’

Nevertheless, manufacturers of some of these mega brands have again obtained an interim injunction on the ban for their respective products, from the Delhi High Court.

Sometime during the day, i.e. on March 21, 2016, the honorable Delhi High Court is expected to take up this patient-centric issue. It apparently smacks a blatant self-serving interest of the concerned irrational FDC manufacturers, that defeats the core purpose and value of pharma products for their users.

Like most other issues, the Court directive on this issue, as well, would ultimately prevail, without any shade of doubt.

Is it a ‘bolt from the blue’ for the pharma industry? 

Many industry watchers feel that this recent ban has not come as a ‘bolt from the blue’ for the pharma players, at all, as is being claimed by a section of the pharma industry. Even the Union Ministry of Health has, reportedly, clarified the following points on the recent notification:

  • “We have tried to bring objectivity to the issue by roping in the best of scientists to study the effects of these FDCs.”
  • “Show cause notices were also issued to more than 344 companies and they were given time to make further representations after the expert committee gave their recommendations. Some of them did not even care to respond. Everybody was given ample opportunity. After that, the move was initiated. It was done after much examination.”
  • “It is necessary and expedient in the public interest to regulate by way of prohibition of manufacture for sale, sale and distribution for human use, of the said drugs in the country.”

It is worth noting, at least, one of these well known pharma brands was, reportedly, banned in one of our neighboring countries – Sri Lanka, in 2012, for wide-spread drug misuse, long after its marketing approval in the country.

Some key events leading to the recent ban: 

Besides the above articulation by the Union Ministry of Health, it is worth noting, especially, the following key developments to ascertain, whether this ban came suddenly to the irrational FDC manufacturers, and without any prior warning or appropriate communication:

  • The issue of manufacturing licenses being granted by some states for FDCs without prior approval of Central Drugs Standard Control Organization (CDSCO), was first discussed by the Drugs Technical Advisory Board (DTAB) in the year 2000, though without any major tangible outcome till 2007. 
  • In 2007, Government banned 294 FDCs, and the consequent court proceedings had ‘Stayed’ this ban.
  • Expressing huge concern on pharma malpractices related to irrational FDCs, the Parliamentary Standing Committee on Health and Family Welfare in its 59th report (2012) also had flagged this issue. The lawmakers observed in the report that manufacturing licenses for large numbers FDCs were being issued by the State Drug Authorities, without prior approval of the Central Drugs Standard Control Organization (CDSCO), in violation of rules. The committee also noted that multiple FDCs, which are available in India had been rejected by the drug regulators in Europe, North America, and Australia, while for many others never had marketing approval applications submitted outside India (Section 7 of [6]).
  • Subsequently, in June 2013, CDSCO  announced the “Policy Guidelines for Approval of Fixed Dose Combinations (FDCs) In India.”
  • According to CDSCO, just 1193 FDCs were approved by the DCGI, since 1961 till November, 2014. Thus, all drug manufacturers should clearly know, which FDC has been approved by the DCGI, and when, leaving no scope for any ambiguity in this area. Thus, there should be no problem in total conformance to the above ‘FDC Policy Guidelines’ by these drug producers.
  • In the same year – 2013, a public notice was also, reportedly, issued, calling all those drug players manufacturing FDCs to apply with the requisite fee, in the prescribed form to the DCGI office, providing the required details.  
  • In 2014, a six-member committee, chaired by Prof. (Dr.) Chandrakant Kokate, Vice Chancellor, KLE University, Jawaharlal Nehru Medical College, Belgaum, Karnataka, was formed to expedite the review process of the applications. 
  • The Kokate Committee has, reportedly, reviewed about 6,600 FDCs, so far, and classified them under four categories – irrational, require further deliberations, rational and require additional data generation. 
  • According to a report, 963 FDCs were found under the irrational category, providing reasons in detail for each. 
  • In 2016, the Government finalized its action, based on the Report of Kokate Committee and also the response received (or still not received despite requests) from the concerned FDC manufacturers.
  • The March 11, 2016 Gazette Notification banned 344 ‘irrational’ FDCs, ruffling many feathers, but understandably to protect patients’ health interest.
  • On March 14, 2016, in response to an appeal against this ban through a writ petition, first by Pfizer, the Delhi High Court reportedly granted the company a stay, pending the next court hearing on March 21, 2016. Subsequently, several such stay orders by the honorable Delhi High Court have been issued with the same date of hearing. 
Adverse health and economic impact on patients:

Besides serious health risks, the patients also suffer from a huge adverse economical impact, in rupee value terms, by consuming much avoidable irrational FDC formulations, which are generally more expensive than single ingredient drugs, if taken separately at times of necessity or convenience.

The ban of 344 FDCs is estimated to cover over 2,500 brands, in different therapy categories, including chronic diseases, where medicines are taken for a long period of time. Thus, a large number of patients were consuming these irrational formulations for a long period of time without any inkling of their necessity and more importantly serious adverse health impact that these irrational FDCs could cause.

To quantify how much have the patients collectively spent on these banned medicines, in the rupee value terms, I shall quote from the estimates of one of the well reputed and much quoted pharma retail audit and market research organization of India – AIOCD Pharmasofttech AWACS Pvt. Ltd.

According to its report of March 13, 2016, Indian Pharmaceutical Industry would lose Rs. 3,838 Crore (MAT), which is 3.1 percent of the turnover of the Indian Pharmaceutical Market (IPM), when calculated based on the retail sales of these FDCs in the last 12-month period.

Paraphrasing the same finding, one can logically conclude that Indian patients withstood an adverse economic impact of Rs. 3,838 Crore in a 12-month period, by spending on these unnecessary and irrational FDCs of dubious value, besides health risks. 

To my surprise, some of the MNC pharma players contribute a major chunk to this avoidable expenditure of the patients, besides associating and avoidable health risks.

Quoting similar credible data, it is also possible to give company-wise break-up in this area, which, in my view, may not be meaningful here.

Two Critical issues to address:

Although, a lot of water has since flown down the bridges, a large number of irrational FDCs are still in the market, exposing patients to possible health hazards and economical hardship.

In this blog, I discussed this core issue in two of my articles, one on July 15, 2013 titled, “FDC Saga: Defiant Manufacturers, Sloppy Regulators and Humongous Inaction”, and the other on May 18, 2015 titled, “Booming Sales Of Unapproved Drugs: Do We Need ‘Safe In India’ Campaign For Medicines?”.

I reckon, the following two would still remain the critical issues, which need to be addressed, expeditiously, once and for all, for patients’ sake: 

  • Stringent compliance with the latest CDSCO requirements by all the manufacturers of FDCs in India must be ensured. Any non-conformance should attract strong punitive measures, through a transparent process.
  • Whether such drugs are being widely misused, creating a grave risk for health and other safety hazards, must be ascertained periodically, based on credible data.
An important example:                         

Just the other day, Reuters reported that one of the largest pharma companies operating in India, was selling a FDC of the antibiotics cefixime and azithromycin, without approval of the DCGI.

Interestingly, this particular FDC has reportedly not received marketing approval in the major global pharma markets, such as, the United States, the United Kingdom, Germany, France or Japan.

After the ban of this irrational FDC, the company was compelled to stop manufacturing and sales of this powerful antibiotic cocktail that poses huge health risk to patients.

This Reuters report also states, 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.

Many doctors and health experts have been saying that the spread and misuse of antibiotic combinations may be contributing to antibiotic resistance in India.

FDC approval must be hard evidence-based:

Since all pharmaceutical products, whether available as a single ingredient, or FDC formulations, are globally considered as ‘Evidence-Based Medicines’. Such evidences are established through robust, stringent and well regulated clinical trials for obtaining marketing approval from the drug regulators, unlike most ‘traditional medicines’.

Following this well-established global norm, and as recommended by even the World Health Organization (WHO), all irrational FDCs must be identified through a transparent and medical science-based process, and banned forthwith by the Government.

Establishing safety and efficacy for all FDCs through clinical trials, just like any other single ingredient drug, introduced for the first time in India, whenever it happens or had happened in the past, inadvertently or otherwise, should be a ‘must happen’ regulatory requirement, for all time to come.

Profit making interest through introduction of a plethora of irrational FDCs, should never be allowed to overshadow patients’ health and economical interest.

The bogey of even ‘25 to 30-year-old FDCs’ now being banned: 

Some section of the industry is also raising this point, vociferously, protesting against the bans of their respective old and top-selling FDC brands, which have now been considered by the Government as irrational, and questioning: ‘why now?’

This point is irrelevant, as not taking action ever, against a wrong doing allowed over a long period time, does not make an irrational FDC formulation a rational one, for all time to come.

Moreover, this recent action of the drug regulator can not be considered as unique either. With the advancement of medical science, in the past years too, the DCGI issued banned notifications, covering many old FDCs, considering those ‘irrational combinations’ at a given point of time, such as, analgin + pitofenone, vitamins B1 + B6 + B12, cyproheptadine + lysine, just to name a few.

Conclusion:

As is known to many, pharmacovigilance is still at a very nascent stage in India. Consequently, ‘Adverse Drug Reactions (ADR)’ or ‘Adverse Drug Events’ reporting are still abysmally poor in the country. No information on ‘Adverse Drug Events’, as claimed by the manufacturers of these irrational FDCs, should, therefore, in no way mean that these drugs are safe and efficacious and beyond any reasonable doubt.

Although the laxity of the drug regulator in this area can’t also be condoned, in any way, the enormity of the risks posed by irrational FDCs to the innocent patients, is indeed mind boggling.

If the manufacturing and sale of all irrational FDCs are not legally stopped, even after a long and rigorous scientific and medical scrutiny by the experts, the patients in the country would, unfairly, continue to remain exposed to huge health and economic risks, without any fault of theirs. This is exactly what happened in 2007 also, when, after the stay order of the ban notification for 294 irrational FDCs by the honorable Madras High Court, all those FDCs continued to be promoted, prescribed and sold to patients across India, unhindered… but at whose cost?

Yet again, the gazette notification of the Government on the recent ban on 344 FDCs, has gone for judicial scrutiny, at least, for some money spinning key brands of the large pharma players.

This time, however, there is one significant difference, the Government seems to be far more assertive and committed to ensure that only safe medicines are available in the market, despite reported intense advocacy by the industry. This commitment on the part of the Government is also evident from the media report that the (DGCI) has again sent a new list of additional 1,200 FDCs for a probe to the panel, which recommended the ban of 344 irrational FDCs in the last week, and that too, after the court stay order on the latest ban.

Further, a senior a senior official in the Health Ministry has, reportedly, reiterated that the Government will stand firm on its decision, and will support the ban with robust data, in the Delhi High Court.

Would history repeat itself, this time now? We, at least, would get a sense of it, as the proceeding of the honorable Delhi High Court commences today, on this issue.

Either way, it will possibly send a clear signal, whether the triumph of commercial profit motive with irrational FDCs would continue, unabated, over patients’ health, safety and economic interests, at least in the foreseeable future. 

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.

 

For Drug Safety Concern: “Whistleblower’s Intention Should Be Nationalistic”

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In the recent weeks, three significant developments related to the Pharmaceutical Industry in India, have triggered rejuvenated concerns in the following critical areas: 

A. Overall drug safety standards in the country

B.  Self serving interest, rather than patients’ interest, dominate the prescribing decisions

C. Government assurance to American Trade Organization on ‘Compulsory License (CL)’ in India. 

These important issues fall under three key regulatory areas of India, as follows:

  • The Central Drugs Standard Control Organization (CDSCO)
  • The Medical Council of India (MCI)
  • The Indian Patent Office

It is worth mentioning here that the Department Related Parliamentary Committee on Health and Family Welfare in its 59th Report, placed before both the houses of the Parliament on May 08, 2012, on the functioning of the Central Drug Standards Control Organization (CDSCO), begins with the following observations:

Medicines apart from their critical role in alleviating human suffering and saving lives have very sensitive and typical dimensions for a variety of reasons. They are the only commodity for which the consumers have neither a role to play nor are they able to make any informed choices except to buy and consume whatever is prescribed or dispensed to them, for the following reasons:

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

Most importantly, all these concerns, if not properly clarified and appropriately addressed by the Government, soon enough, have the potential to create an adverse snowballing impact on the uniform access to affordable quality medicines, for all sections of the society in India.

Under this backdrop, I shall discuss in this article briefly, my perspective on each of these critical areas, as they are today, and not just the drug safety concerns.

The headline of this article is expected capture not only the prevailing mood of some key regulators, but also their inertia to address critical healthcare concerns and above all how the core public health related issues are getting lost, and the trivial ones are gradually occupying the center stage.

A. Overall drug quality and safety  standards in India:

A Public Interest Litigation (PIL) suit, filed against the Drugs Consultative Committee and the Central Drugs Standard Control Organization (CDSCO), was listed on the Supreme Court website for hearing on March 11, 2016.

The PIL has been filed by one Dinesh Thakur, requesting the Supreme Court to lay down guidelines by which manufacturers could be made liable for violating drug standards and also give a direction to the government to set up a ‘Drug Approvals Review Committee’ for examining criminality in the manner in which faulty drug approvals were granted. 

Many may recall that the same Dinesh Thakur worked for Ranbaxy from 2003 for two years, and is now the Chief Executive of MedAssure Global Compliance based in Florida, US. Thakur’s Company now advises pharma manufacturers on drug safety and quality standards.

As reported by Reuters, Thakur had earlier exposed how the erstwhile largest drug maker of India, Ranbaxy Laboratories, failed to conduct proper safety and quality tests on drugs and lied to regulators about its procedures. Consequently, USFDA fined Ranbaxy US$500 million for violating federal drug safety laws, and making false statements to the US regulator.

This news report further states: “Indian Parliamentary Committee, thereafter, reportedly demanded an investigation and the drugs regulator committed to one in 2013. Thakur received a statement from the health ministry last year, seen by Reuters, showing no inquiry had begun.”

On the last Friday, however, the Supreme Court of India refused to entertain this PIL of Dinesh Thakur, saying it does not have time to adjudicate academic issues, such as, need for guidelines to regulate quality of medicines.                                                  

The core issue:

The core issue here is not at all the above PIL, not at the very least. The issue is the much reported concern being expressed, over a period of time, regarding the drug safety standards in India. The reasons include breach of of data integrity, and gross violation of the ‘Good Manufacturing Practices’ standards. Such instances are being detected, almost regularly, by the foreign drug regulators, in several manufacturing facilities run by many large and small Indian drug producers.

It is well vindicated by the fact that around 45 Indian drug manufacturing plants have been banned by the USFDA alone, from shipping generic drugs to the United States, as these were considered unsafe for consumption of patients in the US. Some other foreign regulators too had taken similar action, citing similar reasons. The USFDA website specifies the details of gross violations made in each of these cases.

Ironically, all such facilities can manufacture and sell their drugs in India, as they conform to the quality requirements of the Indian drug regulator. Consequently, the Indian patients consume even those medicines, which are considered unsafe by the USFDA for American patients, innocently, as and when prescribed by the doctors.

Arising out of these incidents, when asked about the drug safety standards in India, and the public health-safety, instead of giving credible and action oriented answers for public reassurance, some of the apparently brazen replies of the DCGI are quite stunning for many stakeholders, both within and outside the shores of India.

I would now quote below just a few of those replies, just as examples. 

“…Whistleblower’s Intentions Should Be Nationalistic” -  DCGI:

According to Reuters, it has received the following response from the Drug Controller General of India (DCGI), on the above PIL related to the drug safety standards in India:

“We welcome whistleblowers, we have got great respect, but their intentions should be genuine, should be nationalistic… I don’t have any comment on this guy.”

Thus, many industry watchers feel that in a situation like this, the honorable Supreme Court of India would possibly require to intervene, just as what it did on alleged ‘Clinical Trial’ malpractices in the country or for drug price control, solely for public health interest.

The same attitude continues:

Such brazen response of the Central Drug Regulator, and that too on a serious subject, is indeed bizarre. It becomes increasingly intriguing, as the same attitude continues without any perceptible meaningful intervention from the Ministry of Health.

For example, on February 22, 2014, in the midst of a more intense scenario on a similar issue, instead of taking transparent and stringent measures, the DCGI was quoted by the media commenting:

“We don’t recognize and are not bound by what the US is doing and is inspecting. The FDA may regulate its country, but it can’t regulate India on how India has to behave or how to deliver.”

On February 26, 2014, presumably reacting to the above remarks of the DCGI, the American Enterprise Institute reportedly commented, “Indian drug regulator is seen as corrupt and colliding with pharma companies…”

Such apparently irresponsible and loose comments keep continuing, despite the 2012 report of the Parliamentary Committee of India alleging collusion between some pharmaceutical companies and officials of the CDSCO, which oversees the licensing, marketing and trials of new drugs. The report also commented that the agency is both chronically under-staffed and under-qualified.

Some possible remedial measures:

As the saying goes, “better late than never”, considering all these continuing developments, it is about time to reconsider some of the key recommendations of Dr. R. A. Mashelkar Committee on a similar subject and make amendments in the relevant Act accordingly, soon, to facilitate creation of a robust with high accountability ‘Central Drugs Authority (CDA)’. It would introduce a centralized licensing system for drug manufacturing, along with stringent drug safety standards; besides, sale, export and distribution of drugs. Perhaps, the draft bill on CDA is now lying in the heap of archival documents with the change in Government.

Why does India need CDA?

I believe, the formation of a robust CDA with high accountability, besides meeting with drug safety concerns, would provide the following significant benefits, both to the Industry and also to the Government:

  • Achieving uniform interpretation of the provisions of the Drugs & Cosmetics Act & Rules
  • Standardizing procedures and systems for drug control across the country
  • Enabling coordinated nationwide action against spurious and substandard drugs
  • Upholding uniform quality standards with respect to exports to foreign countries from anywhere in India
  • Implementing uniform enforcement action in case of banned and irrational drugs
  • Creating a Pan-Indian approach to drug control and administration
  • Evolving a single-window system for pharmaceutical manufacturing and research undertaken anywhere in the country.

B.  Self serving interest dominates the prescribing decision: 

That the self serving interest, rather than patient interest, dominate the prescribing decision, was vindicated by a key announcement of the Medical Council of India (MCI) last month.

In February 2016, apparently succumbing to continuous and powerful external pressure, the MCI announced an amendment in a clause of its Code of Ethics Regulations 2002, exempting doctors’ associations from the ambit of its ethics code, as applicable to doctors now across the country. Prior to the amendment, this section used to read as: “code of conduct for doctors and professional association of doctors in their relationship with pharmaceutical and allied health sector industry”.                      

In other words, it means that the professional associations of doctors will no longer come under the ambit of ethics regulations, legitimizing their indulgence in the identified unethical and corrupt practices, by receiving gifts in cash or kind from the pharma or healthcare industry.

A large section of the key stakeholders believes that this amendment would help creating an additional large space for the pharmaceutical marketing malpractices to thrive, unabated, at the cost of patients.

The latest report of the Parliamentary Standing Committee on MCI:

In its 92nd Report, the Department-Related Parliamentary Standing Committee on Health and Family Welfare titled, “The Functioning of Medical Council of India”, presented to the Rajya Sabha and laid on the Table of Lok Sabha on 8th March, 2016, the Committee observed on this amendment as “an action that is ethically impermissible for an individual doctor cannot become permissible, if a group of doctors carry out the same action in the name of an association.”

The report also noted the failure of MCI to instill respect for a professional code of ethics in the medical professionals and take disciplinary action against doctors found violating the code of Ethics, etc.

The Committee called for a complete restructuring of the MCI, since it believes that the Council has failed as a regulator of medical education and the profession. Casting serious aspersions on the functioning of the MCI, the house panel of the Parliament recommended that the Act under which the MCI was set up be scrapped and a new legislation be drafted “at the earliest”. 

The report castigated the health ministry:

The lawmakers castigated the Health Ministry in this report saying, “The committee also finds it intriguing that instead of intervening to thwart attempts of MCI at subverting the system, the ministry meekly surrendered to MCI.”

While summing up, the report states, “the Committee exhorts the Ministry of Health and Family Welfare to implement the recommendations made by it in this report immediately and bring a new Comprehensive Bill in Parliament for this purpose at the earliest.”

How will it pan out now?

I reckon, it will now be immensely interesting now for all concerned to follow, how does the Government deal with this report to curb, among others, the strong interference of mighty and powerful vested interests to continue with the rampant pharma marketing malpractices, at the cost of patients in India.

C. Reported Government assurance on ‘Compulsory License’: 

On March 3, 2016, a media report quoted a submission by the US Chamber of Commerce to the office of the US Trade Representative (USTR) as follows:

“While the Government of India has privately reassured (American) industry that it would not use compulsory licenses for commercial purposes, a public commitment to forgo using (this) would enhance legal certainty for innovative industries.”

This is an interesting development, primarily because there are a number of legal provisions for granting Compulsory Licenses (CL) in the Indian Patents Act 2005, including, when a drug is not widely available, extremely expensive and some other situation. In some these provisions, law should follow its own course and there is no legally permissible scope for Government’s administrative interference. Grant of CL for Nexavar of Bayar is one such example, and incidentally, that’s the sole CL that India has granted, so far, from the date of amendment of the country’s Patents Act in 2005. 

Thus, a blanket assurance of not invoking any of the provisions of the CL, as provided in the Indian Patents Act 2005, if true, would possibly require to pass through intense legal scrutiny, as that would adversely impact the access to key medicines in a necessary situation, for the public health interest.

So far, India has amply demonstrated to all, time and again, that the country does not grant a CL at the drop of a hat. That situation should continue to encourage and protect innovation. 

Nevertheless, “a written public commitment to forgo using the CL provisions for enhancing legal certainty for innovative industries,” as demanded by the US Chamber of Commerce, appears to be unreasonable, goes against the spirit of India’s Patents Act, and perhaps is not legally tenable either, unless the IP Act is amended accordingly in the Parliament.

Conclusion:

All these three areas, as discussed above, are critical from the healthcare perspective of the country.

Ironically, while deliberating on the subject, the capability, credibility and competence of some of the key regulators of the country, are being repeatedly questioned. These doubts emanate not just from Tom, Dick and Harry, but from an illustrious spectrum of constitutional institutions of India, spanning across the lawmaking Parliament, through its various committee reports, to the ultimate legal justice provider – the Supreme Court of India, through is various orders and key observations.

Regrettably, in this specific space, which is primarily related to healthcare, nothing seems to be changing on the ground, since long. The same tradition continues, without any visible sense of urgency, even from the Government.

On the contrary, we now read a new genre of comments, even from a key regulator, on the stakeholder concerns. For example, reacting to concern on drug safety standards, instead of articulating tangible actions to usher in a perceptible change, the chief action taker reportedly specified a totally judgmental and an outlandish requirement: “…Whistleblower’s intentions should be Nationalistic.”

Together with these incidents, the key public healthcare concerns of India too, are now apparently getting drowned in the high decibel ‘Nationalistic’ versus ‘Anti-nationalistic’ cacophony. But, the hope still lingers… for a change…for our nation’s sound health!

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.

‘Fake Drugs Kill More People Each Year Than Terrorism In The Last 40 years’

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In this article, I shall deliberate on ‘fake medicines’ that we may at times land up into buying, without any inkling that instead of curing or managing the ailments, these products can push us into serious health hazards, quite contrary to what we and our doctors hope for.

One may term these substances as ‘Counterfeit’, ‘Fake’, ‘Spurious’ or ‘Sub-standard’ drugs, or in whatever other names one may wish to. The bottom-line is that such products in the guise of drugs could precipitate very serious and life-threatening health crisis for patients. This mindless game has already become both a global and local health menace, though in varying degrees and parameters in different countries.

According to INTERPOL, large sums of money are involved with these transnational criminal enterprises. Fake drug makers, who run this deadly trade undercover, use sophisticated tools and technologies and are well equipped to operate stealthily.

Deploying requisite wherewithal, this growing threat to public health and safety needs to be addressed expeditiously by all concerned and in tandem. Curbing this menace would call for great concerted focus in approach and execution of a fool-proof strategy with military precision.

At this stage, I reckon, we should not clutter the subject by mixing it up with other commercial considerations, such as Intellectual Property (IP) related matter, for which appropriate laws and mechanisms are already in place.

CBI underscores veracity of the problem:

Under the above backdrop, a Central Bureau of Investigation (CBI) Press Release dated June 24, 2015 announced that the First Indo-French Workshop on “Combating Counterfeit Medicine” for Police Officers, Investigators and other officers was held on 23 and 24 June 2015 in New Delhi.

The event was organized in collaboration with the French Embassy; Institute of Research Against Counterfeit Medicines, France; Central Office Against Environmental & Public Health Violations, France and Central Fight Against Harm to the Environment And Public Health (OCLAESP) and was hosted by the CBI. Mr. Anil Sinha, Director, CBI inaugurated the workshop.

‘Fake Drugs Kill More People Each Year than Terrorism’:

In his inaugural address, Mr. Sinha made a startling revelation, when he said, according to an estimate of INTERPOL; fake medicines kill more people in a year than those who have died in the past 40 years as a result of terrorism.

Just a few years ago, INTERPOL reportedly estimated that while more than 65,000 people were killed in over 40 years in transnational terrorist incidents, the estimates of deaths caused by fake medicines range from tens of thousands to hundreds of thousands annually.

Quoting Ronald Noble, the erstwhile Secretary General of INTERPOL another report says, “40 years of terrorism has killed about 65,000 people, while 200,000 people died from the use of counterfeit drugs last year alone, and that’s just in China.”

Both crime and big money are involved in this life-threatening menace. Citing an example the CBI Director said, ‘One illicit online pharmacy network, which was dismantled by US authorities in 2011, managed to earn USD 55 million during two years of operations’.

In India, we have already read about the raids conducted by Mumbai FDA in April 2015 on similar unauthorized online pharmacies in the country. Following this development, the Drug Controller General of India has announced his yet another good intent to look into this issue with the help of a trade organization.

I shall also discuss, very briefly though, about problems associated with online pharmacies related to fake drugs, the world over.

More problems in the developing nations:

The CBI Director also articulated in his address, “Though the ramification of this menace is worldwide, it is more pronounced in developing and under developed nations.”

Sometime back in 2006, a study published by the then International Medical Products Anti-Counterfeiting Task Force (IMPACT) indicated that in countries like, the USA, EU, Japan, Australia, Canada and New Zealand, the problem is less than 1 percent. On the other hand, in the developing nations like parts of Asia, Latin America and Africa more than 30 percent of the medicines are counterfeits.

The above ‘Task Force’ also reported as follows:

“Indian pharmaceutical companies have suggested that in India’s major cities, one in five strips of medicines sold is a fake. They claim a loss in revenue of between 4 percent and 5 percent annually. The industry also estimates that spurious drugs have grown from 10 percent to 20 percent of the total market.”

‘Fake Drugs’ are more in countries with weak regulatory enforcement:

It has been observed that the issue of fake drugs is more common in those countries, where the regulatory enforcement mechanism is weak. India, I reckon, is one such country.

Interestingly, the Ministry of Health in India does not even recognize that fake Drugs are a growing menace in the country. This is vindicated by its latest report of 2009 on this subject.

The above report titled, “Report on Countrywide Survey for Spurious Drugs”, published by CDSCO on behalf of Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India in 2009, concluded as follows:

“In view of above observations and data obtained from the manufacturers, after physical verification of all the drug samples and subsequent chemical analysis report on the representative of samples taken at random, it may be concluded that:

(i)             The extent of spurious drug in retail pharmacy is much below the projections made by various media, WHO, SEARO, and other studies i.e. only 0.046 % (11 samples out of 24,136 samples).

(ii)           Extents of substandard drugs among the branded items are only 0.1 % {Out of two thousand nine hundred seventy six (2976) unsuspected samples, 03 samples do not conform to claim with respect to Assay on chemical analysis}”

It is an irony that the drug regulators in India mostly keep demonstrating an ‘Ostrich Syndrome’ – refusing to acknowledge this menace that is blatantly obvious. They apparently believe that no health hazards due to prevalence of fake drugs exist in the country.

On the other side – many worrying reports:

Though the Government of India tends to wash its hands off on the very existence of this menace with the survey reports as above, following are just a few examples from other reports raising concerns on this critical issue in India:

  • A July 2014 ASSOCHAM report titled, “Fake and Counterfeit Drugs In India –Booming Biz” states that fake drugs constitute US$ 4.25 billion of the total US$ 14-17 billion of domestic pharmaceutical market. If the fake drugs market grows at the current rate of 25 percent, it will cross US$ 10 billion mark by 2017.
  • A May 2012 study published in ‘The Lancet’ reported that over one in three anti-malarial drugs sold in southeast Asia are fake while a third of samples in sub-Saharan Africa failed chemical testing for containing too much or too little of the active ingredient, potentially encouraging drug resistance. Around 7 percent of the drugs tested in India was found to be of poor quality with many being fake. India reportedly records 1.5 million cases of malaria every year.
  • A February 2012 report of ‘The National Initiative against Piracy and Counterfeiting’ of FICCI highlighted that the share of fake/counterfeit medicines is estimated at 15- 20 percent of the total Indian pharmaceutical market.
  • A 2011/12 report of the US Customs and Border Protection highlighted: “India and Pakistan both made it to top 10 source countries this year due to seizures of counterfeit pharmaceuticals. Pharma seizures accounted for 86 percent of the value of IPR seizures from India and 85 percent of the value of IPR seizures from Pakistan.”

DCGI intends to justify his moot point yet again:

In view of all these worrying reports and amid concerns around the quality of medicines being manufactured in India, in January 2015, the Drug Controller General of India (DCGI) proposed carrying out a nation-wide survey using methodology prepared by the Indian Statistical Institute, Hyderabad to assess the prevalence of fake and substandard drugs.

In the 2015 survey, around 42,000 locally made drug samples would be drawn from across the country throughout the rest of this year, which would include 15 therapeutic categories of drugs featuring in the National List of Essential Medicines (NLEM), 2011.

As I mentioned before, according to the DCGI this survey would “tell the world that our drugs are of quality”.

I discussed a similar issue titled, ‘Are We Taking Safe And Effective Medicines‘ in this Blog on November 13, 2013.

‘Fake Drugs’ and Online drug sales:

Before I touch upon this point and at the very outset, let me submit that in this article I shall not discuss on the merits or demerits of online pharmacies and the need of such e-outlets in India.

That said, it is now widely believed, backed by hard data that the Internet is increasingly assuming an attractive niche in the global diffusion of ‘fake drugs’.

Unlike India, some countries already support the business of legal online pharmacies by charting a transparent regulatory mechanism in place. For example in the United States all Internet pharmacies have to be licensed in the country. All their States require this. The general rule is, if an Internet pharmacy is offering to ship drugs into a particular state, they have to be licensed (but not necessarily located) there.

However, if an Internet pharmacy is shipping prescription drugs to individuals in the US from outside the US, that is absolutely illegal.

Some institutions in the US developed an accreditation system for Internet pharmacies. The official seals of these institutions, require to be posted on pharmacies’ website as a warrantee.

It is important to note that these institutions operate only at the national level and due to differences in domestic laws in different countries, it is difficult for any of them to provide customers with reliable information concerning the quality of pharmaceuticals, in general, available online.

Status of online pharmacies in India:

Although online sales of pharmaceuticals are totally illegal in India till date, there seems to be several such pharmacies still operating in the country.

It is generally believed that the impact of the Internet on ‘fake drugs’ business models is real. Thus, enforcement strategies need to be very stringent.

It is precisely for this reason, on April 17, 2015, Maharashtra’s Food and Drugs Administration (FDA) reportedly raided the premises of e-commerce major Snapdeal.com for allegedly selling medicines, including prescription drugs.

Immediately thereafter, the company announced that it has delisted the drugs on its portal and is assisting the FDA in the investigation.

Taking note of the prevailing scenario of illegal online sales of prescription drugs through e-commerce sites in India, DCGI office has reportedly started studying the existing regulations internationally to come out with a set of rules for online pharmacies. Meanwhile, DCGI has reportedly appointed the Federation of Indian Chambers of Commerce and Industry (FICCI) as the nodal agency for consolidating the guidelines.

Be that as it may, experts believe that online sale of drugs should be permitted in India only with strict and well thought out norms, which are enforceable hundred percent, anywhere within the country. Stringent guidance should be formulated in the amendment bill, 2015 of Drugs & Cosmetics Act & Rules, accordingly.

Conclusion:

Keeping this emerging scary scenario in perspective on the menace of fake drugs, the message of the CBI Director in this regard must be noted by the Government with all seriousness…continuing ‘all is well’ signals from the DCGI, not withstanding.

All stakeholders of the pharmaceutical industry must be made aware, on a continuous basis, of the health hazards posed by fake medicines in India.

As the penetration of Internet keeps increasing at a galloping speed in the country, unregulated online sales of ‘fake drugs’ in the guise of ‘licensed medicines’, pose a very real threat to public health and safety. If and when online sales of medicines are legalized, enforcement of all rules and laws in this regards need to be very stringent with exemplary punitive actions prescribed, for even slightest violations.

In tandem, the DCGI and other regulatory and enforcement agencies in the states, healthcare professionals, patients, all pharmaceutical manufacturers, drug distributors, wholesalers and retailers should join hands to play a proactive role in curbing the menace of ‘fake medicines’ that victimize the innocent patients.

No Wolf in sheep’s clothing must be allowed coming anywhere in the near vicinity…at all.

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.

“Make in India” Image of Pharma Needs An Early Makeover

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“It is never too late to be what you might have been” - George Elliot

The chronicle of events since the last couple of years or so, related to ‘Make in India’ image of the local drug industry, have been instrumental to significantly slowing down the scorching pace of pharma exports growth of the country.

The Union Ministry of Commerce estimates that India’s export of drugs and pharmaceuticals may hardly touch US$16 billion in 2014-15, against US$14.84 billion of last financial year. This would mean that pharma exports growth would just be around 5 percent, against the projected number of 10 percent for the year. This is a significant concern, as pharma exports contribute around 40 percent to the total value turnover of the sector.

Despite this fact and couple of other important reasons, as I shall discuss below, about 45 percent of listed pharma stocks in India have reportedly more than doubled in the past one year. The current tail wind in the domestic pharma market could possibly have contributed to this aberration.

According to AIOCD Pharmasofttech AWACS, the last financial year started in April 2014 with 7.3 percent domestic retail pharma growth, which accelerated to 20.9 percent in March 2015, as the year ended.

High level of optimism and positive sentiments, thus generated in this process, possibly prompted many to ignore even some of the critical storm signals for the domestic pharma industry in its totality.

Declining pharma exports growth – A key challenge:

In 2014, pharmaceutical exports contributed 39 percent to the sector’s total value turnover. Consistently strong export performance over the last few decades, has catapulted the local drug industry in the not so common trajectory of the net foreign exchange earner for India. It is worth noting, though pharma exports grew at a rate of just 1.2 per cent to reach in 2013-14, it registered a CAGR of 21 percent over the last decade.

Some analysts estimate, the chances of Indian pharma exports touching even US$16 billion in 2014-15 are indeed challenging, especially considering low growth recorded by some of the large Indian pharma companies, including Ranbaxy, Dr. Reddy’s Laboratories and Lupin, especially in the US market.

Mounting pricing pressure:

Consolidation process of pharmacy players in the US market is also affecting the profit margins of the Indian drug exporters.

Some key examples are:

  • Global alliance among three large pharmacy distributors – Walgreen, Alliance Boots and Amerisource –Bergen, in early 2013
  • Joint venture between the second largest US wholesale distributor, Cardinal Health, and CVS Caremark in December 2013
  • US pharmacy McKesson’s announced acquisition of US distributor Celesio in January 2014.
  • On April 9, 2015, Bloomberg reported that Walgreens Boots Alliance Inc.’s acting Chief Executive Officer Stefano Pessina has expressed his intent to do more deals, just months after being on the saddle of the biggest US drugstore chain.

As a result, a few dominant pharmacy players emerged with hard bargaining power, exerting tough pricing pressures on the generic drug companies and that too in a market that has been facing already facing cutthroat generic price competition.

Consequently, according to published reports, the prices of generic drugs, in general, declined by around 20 to 30 per cent over the past 19 months, in the US.

Vulnerability in the key market:

According to IBEF March 2015, the United States (US) has been the prime importer of pharmaceuticals from India, accounting for over 25 per cent of Indian pharmaceutical exports, followed by the European Union and Africa at second and third positions, respectively.

India exports over US$4 billion of pharmaceutical products to the US, out of its annual exports of around $15 billion. Large domestic companies, such as Ranbaxy, Sun Pharma and Lupin account for around US$3 billion of exports to the US and the balance comes from a large number of other Indian pharma players.

Government sites 3 reasons:

According to the Union Ministry of Commerce, there are reportedly three key reasons for the pharma export falling short of target in the financial year 2014-15, namely:

-       Delayed regulatory approvals

-       Consolidation of pharmacy players in North America (discussed above)

-       Steep depreciation of currencies in emerging markets such as, Russia, Ukraine and Venezuela

A major controllable concern seems to be out of total control:

While articulating the above three factors, the Union Ministry of Commerce seems to have missed out a very important one that has been instrumental in perpetuating the recent slow down of Indian pharma exports, significantly. It is very much a controllable too, unlike the other three, though appears to be virtually out of total control of the domestic pharma companies.

Fortunately, media kept harping on it. PTI News of January 11, 2015 reported, while Indian pharma exports expected to touch a turnover US$16 billion in 2014-15, many Indian pharmaceutical companies continue to face regulatory action by the USFDA for alleged violation of ‘Good Manufacturing Practices (GMP)’ and other irregularities at the respective drug manufacturing facilities in different parts of the country.

This report observed, a number of Indian drug-makers, including Ranbaxy, Sun Pharma, IPCA Labs, Wockhardt and Dr. Reddy’s Laboratories faced sanctions of the USFDA over different issues ranging from hygiene levels in the plant and concealment of data on failed tests to even fabrication of records. As a result, in several cases, these companies have been barred from selling their drugs in the US and other countries.

The issue involves the very top:

Sun Pharma, post acquisition of Ranbaxy, tops the pharma league table in India with around 9 percent of domestic market share.

It is much well known though, that the US drug regulator has already imposed a ban on import of medicines into the US, produced at its key constituent Ranbaxy’s India-based factories. Earlier, certain drugs produced at its Dewas plant of Ranbaxy were also barred from export to the entire EU region for non-compliance to GMP norms.

On its own, the acquirer – Sun Pharma has also faced USFDA ban on import of products made at its Karkhadi plant in Gujarat.

Taking all these into consideration, one can probably argue that the ‘Make in India’ issue for Indian pharma is humongous and quite a widespread one. Its adverse impact is very much palpable even at the very top.

The root cause:

The root cause of non-conformance of specified GMP standards probably dwells deep within the mindset of the concerned companies, as comes in the narrative of a whistleblower. In that case, the speed of progress of Indian pharma exports’ revival, alongside the industry image makeover, would possibly face a strong and silent headwind.

Pharma sector needs a health check:

On April 16, 2015, ET Intelligence Group commented that “High-flying pharma sector may be in need of a health check”, further reinforcing the case for re-rating of, especially, the export-oriented pharma sector.

The report underscored, that foreign brokerages Bank of America Merrill Lynch and CLSA have flagged concerns about valuations in pharma priced to perfection leaving little room for error. According to data from Bloomberg, since last week, ‘buy’ recommendations by analysts have dropped in stocks like Sun Pharma, Lupin, Cipla, Ipca Labs, Cadila Healthcare, Aurobindo Pharma and Torrent Pharma.

Smacks of irrational exuberance?

The article emphasized that the pharma growth story has now moved to being one that ‘smacks of irrational exuberance’.

The unprecedented interest in the sector has had the effect of shirking off negatives, like regulatory clamps by US FDA, price control, and currency fluctuations in the emerging markets and delay in drug approvals in the US.

The saga still continues:

Triggered by a whistleblower report and confirmed by a number of different adverse plant audit findings, the USFDA has stepped up scrutiny of India make generic drugs, over the last two years. It is worth noting that Indian generic drug players supply round 40 percent of such medicines sold in the United States.

As we discuss the subject, Indian pharma players continue to receive the warning letters from the USFDA, related to breach of GMP standards.

Lamentably enough, significant parts of the same continue to be the data integrity issues. Even in 2014, some large domestic players including, Sun Pharmaceuticals, Cadila Pharma and Orchid Pharma came under scrutiny of the US drug regulator.

Most recently in March 2015, USFDA banned most imports from the Ipca plants, in Pithampur in Madhya Pradesh and Silvassa in Dadra and Nagar Haveli, for non-compliance of GMP standards. Earlier, in January 2015, the US regulatory agency reportedly banned imports from another Indian manufacturing plant of Ipca.

India tops the list on the US import alerts:

According to USFDA data, from 2013 onwards, over 20 drug manufacturing facilities across India attracted ‘Import Alerts’ as against seven from China, two each from Australian, Canadian and Japanese units and one each from South African and German facilities.

Unfortunately, despite intense local and global furore on this subject, the Central Drugs Standard Control Organization (CDSCO) of India, very strangely, do not seem to be much concerned on this critical issue, at least noticeably enough, besides making some occasional public statements on its working together with the USFDA in this regard.

I discussed similar subject in my blog post of September 29, 2014 titled “Make in India…Sell Anywhere in The World: An India Pharma Perspective.

Conclusion:

As it appears to me, the USFDA import bans related to breach of GMP standards, including ‘Data Integrity’, are mostly unrelated to knowledge deficiency of any kind – technical or otherwise, in the teams handling large drug manufacturing plants of India.

The details, as listed in the USFDA website, indicate that a large number of such incidents are related to falsification of data in the critical documentation process.

Earlier in this article, I termed the problem as very much controllable with the right kind of mindset to set things right, without probably resorting to cost-saving short cuts.

Prime Minister Modi, even during his very recent trips to France, Germany and Canada, passionate appealed to all, including pharma investors both local and global, to “Make in India” and “Sell Anywhere in The World” (exports). This call deserves to be responded with the right spirit and mindset and not just with lip services.

Failure to effectively address the patients’ safety requirements related issues of the foreign drug regulators, such as USFDA, and any direct or indirect attempt to categorize this plight as international ‘conspiracy’ of any kind, could jeopardize India’s interest in pharma exports, for a much longer while.

There is not even an iota of doubt today that “Make in India” image of Indian pharma has suffered a huge set back, at least in the largest and most valuable pharmaceutical market of the world.

As the well acclaimed English novelist George Elliot once said, “It is never too late to be what you might have been”, Indian pharma industry urgently needs an image makeover in this critical area…through a demonstrable change in mindset for doing things right…in every occasion and situation, always.

This is critical, as loss of credibility and reputation too frequently can push a pharma company virtually out of major international business for good… its current clout, might and financial power, not withstanding.

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.