Tag Archives: GMP

India’s Drug Quality Concerns: Is Light At The End of The Tunnel In Sight Now?

Posted on by
Reply

A brief chronology of some recent events on issues pertaining to patient-health-safety with drugs, as captured below, would possibly generate a mixed feeling for many. This includes a serious concern about, especially generic drug quality safety standards in India, on the one hand, and a ray of hope in the tools available to patients to know more about drugs that they have been prescribed. In this article, I shall dwell on this area. My intent is to bring to the fore the vital point – Is the beginning of the end of a long dark tunnel in sight now?

 A chronology of some recent events:

As reported on July 16, 2023, while talking on the subject, “Pharmaceutical Quality — What are we missing?”, the Drug Controller General of India (DCGI) made a notable comment. He, reportedly, said that the poor quality of drugs exported from India to foreign countries had tarnished the image of the country in the international market. The DCGI further added, pharmaceutical quality has become a subject of discussion on the global platform and the international community has started doubting whether India is capable of making quality pharmaceuticals for the global population.

He underscored, “We boast of our country as the pharmacy of the world, but it seems that it is too difficult to maintain the top position for long. If the position is lost, it will be painful and difficult to restore the faith of the international community. Further, we will lose the opportunity to serve the whole humanity of the world. The responsibility of the loss will not only fall on the manufacturers, but equally on all the stakeholders.”

Alongside, a news report on August 01, 2023, brings some hope in this regard, which I shall elaborate in course of this deliberation.  

A long saga of events: 

Yes, as it appears from the following backdrop:

Over the last several decades, there have been many instances where international drug regulators, including the U.S. FDA, expressed concerns about the quality standards of Indian manufactured drugs. These concerns have generally been related to specific manufacturing facilities – ranging from top domestic manufacturers to smaller ones, raising an uncomfortable apprehension – does India produce ’World-Class’ medicines, for all? 

About a decade ago, one of the most well-known cases was in 2013 when the U.S. FDA issued an import alert on products from the Ranbaxy Laboratories facility in India due to data integrity and manufacturing quality issues. This led to significant scrutiny of other Indian pharmaceutical companies as well. Issues related to data integrity, product quality, and good manufacturing practices lead to inspections, warning letters, import alerts, or other regulatory measures.

It continued. For example, around that time, even Sun Pharmaceutical Industries, one of India’s largest pharmaceutical companies, received a warning letter from the U.S. FDA in 2015 (Source: U.S. FDA). Similarly, Wockhardt, another top Indian pharmaceutical company, faced regulatory scrutiny in 2013 when the U.S. FDA issued an import alert and seized products manufactured at their facility in India. The FDA raised concerns about violations of good manufacturing practices and data integrity issues at the facility. This led to recalls of several products and affected the company’s reputation. (Source: Reuters).

As the juggernaut kept moving, on  December 08, 2016, I wrote in this blog, “Even Smaller Countries Now Question Indian Drug Quality Standard.” On March 04, 2023, the Mint reported, “Death of children in Gambia linked to consumption of India made cough syrups, as the US CDC report states.”  

As I write, the veracity of impact of such incidences remains as serious, if not more, although instances seem to be much fewer. For instance, as reported by Reuters on August 01, 2023: “India has directed Riemann Labs, a manufacturer linked to cough syrup deaths in Cameroon, to stop manufacturing activities, the country’s health ministry said in a statement on Tuesday.”

Thus, On May 27, 2019, I again wrote about: “Drug Quality Imbroglio And ‘Culture of Bending Rules’ in India” in this blog– and that was not the first time I flagged this menace in the country against patient safety.

Even big Indian pharma continued to be struggling with GMP issues:

Big Indian pharma companies are also involved in issues related to lapses in high drug quality standards even recently. Such as, even in 2021, Dr. Reddy’s Laboratories, received a warning letter from the U.S. FDA after an inspection of their manufacturing facility in India. The letter cited violations of good manufacturing practices, data integrity issues, and inadequate investigations of product complaints. Source: The Economic Times). Just a year before, in 2020, the U.S. FDA noted several observations related to good manufacturing practices and quality control. (Source: Moneycontrol).

Drug regulators fight the fire as and when it comes up:

Both the state drug regulators and the Drug Controller General of India (DCGI) fight the fire at the respective manufacturing locations, as and when these come up. No significant actions on the ground for patient safety against such drugs were visible on the ground.  

For example, as reported on August 03, 2023: “Following recent incidents of several countries reporting deaths allegedly linked to “contaminated” India-manufactured drugs, the government has set a deadline for mandatory implementation of the Good Manufacturing Practices (GMP) which were revised in 2018, bringing them on par with World Health Organization (WHO) standards.”

The government ponders making technological interventions for patients:

There are early signs of the government trying to embrace technology for patients’ safety. For example on November 17, 2022, the Union Health Ministry released a gazette notification no 823Eimplementing the Drugs (Eighth Amendment) Rules, 2022, making it mandatory for pharmaceutical companies to affix a QR code on the pack of top 300 formulations from August 1, 2023. A QR code, as reported, will contain the unique product identification code, generic name of the drug, brand name, name and address of the manufacturer, batch number, date of manufacture, expiry date and manufacturing license number.

This was part of the Ministry’s ‘track and trace’ mechanism, and of course, an intent at that time. However, a specific timeline for implantation has now been clearly enunciated.

This time it’s a two-pronged action:

For the first time, I think, a two-pronged action has been announced by the government – an enabling action for patients on the one hand against a strong punitive measure for the errant drug manufacturers on the other:

According to the above gazette notification of the Union Ministry of Health, on August 01, 2023, the central government announced stricter regulations for drug authentication and transparency by imposing mandatory QR codes on drugs. This will be effective from the same day. Patients will now be able to check the QR code on their medicines to ensure their authenticity. 

On August 03, 2023, the government set a deadline for adopting WHO-standard good manufacturing practices for drug manufacturers. Companies with a turnover of over Rs 250 crore will have to implement the revised GMP within six months, while medium and small-scale enterprises with turnover of less than Rs 250 crore will have to implement it within a year. 

Conclusion:

Besides all important patient safety, there are, at least, three other important factors for manufacturing high quality drugs for all and on an ongoing basis, sans lapses, as below:

  • Patients’ trust in the healthcare system relies on the availability of reliable medication. When patients have confidence in the drugs they are prescribed, they are more likely to comply with treatment regimens, leading to better health outcomes. 
  • A strong pharmaceutical sector that focuses on safe and effective drugs can foster economic growth by generating revenue, creating jobs, and attracting investments. It can also stimulate research and development efforts.
  • A reputation for producing quality drugs can boost India’s position as a global leader in pharmaceuticals, attracting international collaborations and partnerships.

Which is why, from the entire perspective, as above, amid India’s drug quality concerns, I reckon, one may still tend to wonder now – Is a light in sight now at the end of the dark and long tunnel? 

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.

 

Draft Pharma Policy 2017 Ticks The Right Boxes: A Challenge Still Remains

Posted on by
Reply

Pharma policy is not a panacea to address all related issues, neither for the patients nor the industry, in general. As I see it, it’s no more than a critical cog in the wheel of the overall macro and the micro health care environment in India. Regardless of this fact, and notwithstanding virtually inept handling of previous pharma policies in many critical areas, each time a new policy surfaces, it generates enough heat for discussion.

Interestingly, that happens even without taking stock in detail of the success or failure of the previous one. A similar raging debate maintaining the same old tradition, has begun yet again with the Draft Pharma Policy 2017. This debate predominantly revolves around the direct or indirect interests of the industry, and its host of other associates of various hues and scale.

Having said that, the broad outline of the 18-page draft policy 2017 appears bolder than previous ones in several areas, and has ticked mostly the right boxes, deserving immediate attention of the Government. One such aspect I discussed in my previous article, titled “Draft Pharma Policy 2017 And Branded Generics,” published in this blog on August 28, 2017.

There are obviously some loose knots in this draft policy, a few are contentious too, such as the changing role of National Pharmaceutical Pricing Authority (NPPA), which apparently is doing a reasonably good job. I also find its link with several important national initiatives, especially ‘Make in India’, ‘Digital India’ and ‘Skill development’. Above all, the draft policy reflects an unambiguous intent to stop several widely-alleged business malpractices – deeply ingrained in various common, but important industry processes and practices that include, pharma sales and marketing, serious quality concern with many loan licensing manufacturers, and even in the issues related to ‘Product to Product (P2P) manufacturing.

The Department of Pharmaceuticals (DoP) reportedly commenced the preliminary rounds of discussion on August 30, 2017, where the Ministry of Health, the Ministry of Environment and the Department of Commerce also participated in the deliberation. In this article, I shall not go into the speculative areas of what ought to or ought not to come finally, instead focus on the key challenges in making the pharma policy meaningful, especially for the patients, besides the industry.

Policy implementation capability:

Whatever may be the net outcome of these discussions, and the final contours of the National Pharma Policy 2017, the implementation capability of the DoP calls for a thorough overhaul, being the primary challenge in its effective implementation. Since 2008, several illustrious bureaucrats have been at the helm of this important department, but nothing substantial seems to have changed in the comprehensive implementation of pharma policies, just yet. Concerned stakeholders continue to wait for a robust patented drug pricing policy, or for that matter even making the Uniform Code of Pharmaceutical Marketing Practices (UCPMP) mandatory, which, going by what the DoP officials had reportedly hinted at many times, should have been in place by now.

The core reason for the same could well be due to a structural flaw in the constitution of DoP under the Ministry of Chemicals and Fertilizers, instead of making it a part of the Ministry of Health. The reason being to create a greater synergy in the implementation of both the Pharma and Health Policies, in a more meaningful way. But, that could be a topic of a separate discussion, altogether.

Initial adverse impact on the pharma industry:

Some of the following proposals, as articulated in the draft pharma policy 2017, are likely to cause initial adverse impact on the performance of the industry, especially considering the way the industry, in general, has been operating over a long time:

  • No brand names for single molecule drugs
  • Mandatory UCPMP with heavy penal provisions
  • e-prescriptions facilitating greater usage of less expensive high quality drugs with only generic names
  • Mandatory BE/BA studies for all generic drug approvals
  • GMP and GLP requirements in all manufacturing facilities
  • Restrictions on loan-licensing and P2P manufacturing.

Initial retarding impact, out of the above measures, may be felt on pharma revenue and profit growth, increase in overall manufacturing cost, and more importantly on the long term strategic game plans of most pharma players, in one way or the other.

The Government is aware of it:

Nevertheless, to make a significant course correction through policy interventions, in curbing widely reported alleged marketing and other malpractices, dubious quality standards of many drugs, and sufferings of many patients with high out of pocket drug expenditure, the Government apparently firmly believes that such an outcome is unavoidable, although need to be minimized. The following paragraph detailed in the Annual Report 2016-17 of the Department of Pharmaceuticals, vindicates the point:

“The domestic Pharma market witnessed a slowdown in the ongoing financial year owing to the Government’s efforts to make medicines affordable. The impact of this can be seen in the industry’s financials as well. The drugs & pharmaceuticals industry reported poor sales performance for two consecutive quarters ended September 2016. Sales grew by a mere 2.9 per cent in the September 2016 quarter, after a sluggish 2.5 per cent growth registered in the June 2016 quarter. The industry’s operating expenses rose by 5.4 per cent during the September 2016 quarter, much faster than the growth in sales. As a result, the industry’s operating profit declined by 5.4 per cent. Operating margin contracted by 185 basis points to 21.1 per cent. A 3.4 per cent decline in the industry’s post-operating expenses restricted the decline in its net profit to 0.8 percent. The industry’s net profit margin contracted by 160 basis points to 13.7 per cent during the quarter.”

Just the pharma policy won’t increase access to health care or drugs:  

Just a pharma policy, irrespective of its robustness, is unlikely to increase access to health care or even medicines, significantly, despite one of the key objectives of the draft pharma policy 2017 being: “Making essential drugs accessible at affordable prices to the common masses.” This articulation is nothing new, either. It has been there in all pharma policies, since the last four decades, but has not been able to give the desired relief to patients, till date.

Pharma and Health Policies need to work in tandem:

To be successful in this direction, both the Pharma and the Health Policies should be made to work in unison – for a synergistic outcome. This is like an individual musician creating his or her own soothing music, following the exact notations as scripted by the conductor of a grand symphony orchestra. The orchestrated music, thus created is something that is much more than what a solo musical player will be able to create.

This is exactly what is not happening in the health care ecosystem of India, over decades, and continues even today. Each of the Pharma and Health policies are implemented, if at all, separately, apparently in isolation to each other, while the holistic picture of health care remains scary, still progressing at a snail’s speed in the country!

The predicament of the same gets well reflected in a World Bank article that states:

“In India, where most people have dug deep into their pockets to pay doctors, pharmacies and diagnostic centers (or ‘out-of-pocket spending’) as the norm for a long time, vulnerability to impoverishment caused by medical expenses remains high. Though government health spending is estimated to have steadily risen to 30% of the country’s total health expenditure – up from about 20% in 2005 – and out-of-pocket payments have fallen to about 58%, dropping from 69% a decade ago, these levels are still high and not commensurate with India’s level of socioeconomic development. In fact, the average for public spending on health in other lower middle-income countries is more than 38%, while in China, government spending accounts for 56% of total health expenditure.”

Affordable drug – just one parameter to improve its access :

While ‘making essential drugs accessible at affordable prices to the common masses’ is one of the top objectives of the draft pharma policy. The degree of its success is intimately linked with what the National Health Policy 2017 wants to achieve. It promises ‘improved access and affordability, of quality secondary and tertiary care services through a combination of public hospitals and well measured strategic purchasing of services in health care deficit areas, from private care providers, especially the not-for profit providers.’

The Health Policy 2017 also states: ‘Achieving a significant reduction in out of pocket expenditure due to health care costs and achieving reduction in proportion of households experiencing catastrophic health expenditures and consequent impoverishment.’ It is no-brainer to make out that reducing out of expenses on drugs is just one element of reducing overall out of pocket expenditure on overall health care. When there is no, or very poor access to health care for many people in India, improving access to affordable drugs may mean little to them.

A major reason of the ongoing ‘Gorakhpur Hospital’ tragedy, is not related to access to affordable drugs, but access to affordable and a functioning public health care system nearby. In the absence of any adjacent and functioning Government health facilities, the villagers had to commute even 150 to 200 kilometers, carrying their sick children in critical conditions to Gorakhpur. The question of access to affordable drugs could have arisen, at least, for them, if the country would not have lost those innocent children due to gross negligence of all those who are responsible for such frequent tragedies.

Thus, improving access to affordable essential drugs, as enunciated in the pharma policy, depends largely on improving access to affordable and quality public health care services. Both are intertwined, and require to be implemented in unison. Without the availability of affordable health care services, the question of affordable essential drugs would possibly be akin to putting the cart before the horse.

Conclusion:

The degree of resistance, presumably from the industry and its associates, to have a new and robust National Pharma Policy that meets the related needs and aspirations of the nation, in an inclusive manner, is generally much more than any National Health Policy, for obvious reasons.

As several proposed changes in the draft pharma policy 2017 appear radical in nature, its grand finale, I reckon, will be more interesting. At the same time, navigating through the waves of tough resistance, coming both from within and outside, will possibly not be a piece of cake, either, for the policy makers achieve the stated goals. Nevertheless, in that process, one will get to watch where the final decision makers give-in or dilute the proposals, and where they hold the ground, supported by a solid rationale for each.

Thus, the bottom line is: Where exactly does the challenge lie? In my view, both the National Health Policy 2017, and the Draft Pharma Policy 2017 mostly tick all the right boxes, especially in ‘making essential drugs accessible at affordable prices to the common masses’.

However, the fundamental challenge that still lies ahead, is to effectively translate this noble intent into reality. It would call for making both these policies work in tandem, creating a synergy in pursuit of meeting the nation’s health and socioeconomic needs on access to affordable health care for all, including medicines.

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.

 

Draft Pharma Policy 2017 And Branded Generics

Posted on by
Reply

In its first reading, the 18-page draft Pharma Policy, 2017 gives me a sense that the Government has followed the much-desired principle of ‘walk the talk’, especially in some key areas. One such space is what Prime Minister Modi distinctly hinted on April 17, 2017, during the inauguration function of a charitable hospital in Surat. He clearly signaled that prescriptions in generic names be made a must in India, and reiterated without any ambiguity whatsoever that, to facilitate this process, his government may bring in a legal framework under which doctors will have to prescribe generic medicines.

Immediately following its wide coverage by both the national and international media, many eyebrows were raised regarding the feasibility of the intent of the Indian Prime Minister, especially by the pharma industry and its business associates, for the reasons known to many. A somewhat muted echo of the same could be sensed from some business dailies too, a few expressed through editorials, and the rest quoting the views on the likely ‘health disaster’ that may follow, if ‘branded generics’ are not prescribed by the medical profession. Obviously, the main apprehension was centered around the ‘shoddy quality parameters’ of unbranded generic drugs in India. It’s a different matter though, that none can possibly either confirm or pooh-pooh it, backed by irrefutable data with statistical significance.

Be that as it may, making high quality generic drugs accessible to most patients at affordable prices, avoiding any possible nexus between the doctors and pharma companies, which could jeopardize the patients’ economic interest, deserves general appreciation, shrill voices of some vested interests notwithstanding.  Nonetheless, if the related proposals in the new pharma policy come to fruition as such, it would be a watershed decision of the government, leaving a long-lasting impact both on the patients, as well as the industry, though in different ways, altogether.

I raised this issue in my article titled, “Is Department of Pharmaceuticals On The same Page As The Prime Minister?”, published in this blog on May 15, 2017. However, in today’s discussion, I shall focus only on how has the draft pharma policy 2017 proposed to address this issue, taking well into consideration the quality concerns expressed on unbranded generics, deftly.

Before I do that, let me give a brief perspective on ‘brand name drugs’, ‘generic drugs’, ‘branded generics’ and ‘unbranded generic drugs’. This would basically serve as a preamble to arrive at the relevance of ‘branded generic’ prescriptions, along with the genesis of safety concern about the use of un-branded generic drugs.

No definition in Indian drug laws:

Although, Drugs and Cosmetics Act of India 1940 defines a drug under section 3 (b), it does not provide any legal definition of ‘brand name drugs’, ‘generic drugs’, ‘branded generic drugs’ or ‘un-branded generics’.  Hence, a quick landscaping of the same, as follows, I reckon, will be important to understand the pertinence of the ongoing debate on ‘branded generic’ prescriptions in India, from the patients’ health and safety perspectives:

‘Brand name’ drugs:

Globally, ‘brand name drugs’ are known as those, which are covered by a product patent, and are usually innovative New Chemical Entity (NCE) or a New Molecular Entity (NME). Respective innovator pharma companies hold exclusive legal rights to manufacture and market the ‘brand name drugs’, without any competition till the patents expire.

Generic drugs:

Post patent expiry of, any pharma player, located anywhere in the world, is legally permitted, as defined in the Intellectual Property Rights (IPR) regulations, to manufacture, market and sell the generic equivalents of ‘brand name drugs’. However, it’s a global norm that the concerned generic manufacturer will require proving to the competent drug regulatory authorities where these will be marketed, that the generic versions are stable in all parameters, and bioequivalent to the respective original molecules. According to US-FDA, a ‘generic drug’ will require to be the same as the original ‘brand-name drug’ in dosage, safety, strength, quality, purity, the way it works, the way it is taken and the way it should be used.

‘Branded generic’ drugs:

Branded generics are generic molecules marketed and prescribed by their respective brand names. Around 90 percent of generic formulations are branded generics in India, involving heavy sales and marketing expenditure in various forms, which has become a contentious issue today in India. The reason being, although branded generics cost significantly more than unbranded generics, the former variety of generic drugs are most preferred by the medical profession, as a group, in India. Interestingly, there is no difference whatsoever in the marketing approval process between the ‘branded generics’ and other generic varieties without any brand names.

Unbranded generic drugs:

Unbranded generic drugs are those, which are sold only in the generic names, sans any brand name. I reiterate, once again, that there is no difference in the marketing approval process between the ‘branded generics’ and ‘unbranded generic medicines’.

The core issue:

The whole debate or concern related to both efficacy and safety on the use of unbranded generic drugs in India stems from a single regulatory issue, which is widely construed as scientifically improper, and totally avoidable. If this subject is addressed in a holistic way and implemented satisfactorily in the country, by and large, there should not be any worthwhile concern in prescribing or consuming single ingredient unbranded generic drugs in India, which generally cost much less than their branded generic equivalents.

This core issue is primarily related to establishing bioequivalence (BE) with the original molecules for all generic formulations, regardless of whether these are branded or unbranded generic drugs. Thus, positive results in bioequivalence studies, should be a fundamental requirement for the grant of marketing approval of any generics in India, as is required by the regulators of most countries, across the world.

This has been lucidly articulated also in the publication of the National Institute of Health (NIH), USA, underscoring the critical importance of generic drugs in healthcare is unquestionable. The article says: “it is imperative that the pharmaceutical quality and ‘in vivo’ performance of generic drugs be reliably assessed. Because generic drugs would be interchanged with innovator products in the market place, it must be demonstrated that the safety and efficacy of generics are comparable to the safety and efficacy of the corresponding innovator drugs. Assessment of ‘interchangeability’ between the generic and the innovator product is carried out by a study of ‘in vivo’ equivalence or ‘bioequivalence’ (BE).”

The paper further highlights, “the concept of BE has, therefore, been accepted worldwide by the pharmaceutical industry and national regulatory authorities for over 20 years and is applied to new as well as generic products. As a result, thousands of high-quality generic drugs at reduced costs have become available in every corner of the globe.”

Why is BE not mandatory for marketing approval of all generic drugs in India?

It is intriguing, why is this basic scientific and medical requirement of proving BE is not mandatory for granting marketing approval of all generic drugs at all time, without any exception – covering both branded generics and their unbranded equivalents, in India.

As I have already deliberated on this subject in my article titled “Generic Drug Quality: Cacophony Masks An Important Note, Creates A Pariah ”, published in this blog on May 08, 2017, I shall now proceed further to relate this critical issue with the Draft Pharma Policy 2017.

Brand, branding and branded generics:

Nevertheless, before I focus on the draft pharma policy 2017, let me skim through the definitions of a ‘brand’ and the ‘branding process’, in general, for better understanding of the subject.

American Marketing Association defines a brand as: ‘A name, term, design, symbol, or any other feature that identifies one seller’s goods or services as distinct from other sellers.’ Whereas, ‘The Branding Journal’ articulates: ‘A brand provides consumers with a decision-making-shortcut when feeling indecisive about the same product from different companies.’

Business Dictionary describes the ‘branding process’ as: ‘Creating a unique name and image for a product in the consumers’ mind, mainly through advertising campaigns with a consistent theme. Branding aims to establish a significant and differentiated presence in the market that attracts and retains loyal customers.’

How does it benefit the branded generic consumers?

One thing that comes out clearly from the above definitions that brands, and for that matter the branding process is directed to the consumers. Applying the branding process for generic drugs, the moot question that surfaces is, how does it benefit the pharma consumers, significantly?

Besides, the branding process being so very expensive, adds significant cost to a generic drug, making its price exorbitant to most patients, quite disproportionate to incremental value, if any, that a branded generic offers over its unbranded equivalents. Thus, the relevance of the branding process for a generic drug, continues to remain a contentious issue for many, especially where the out of pocket expenditure for medicines is so high, as in India.

Marketing experts’ view on the branding process for drugs:

An interesting article titled ‘From Managing Pills to Managing Brands’, authored by the Unilever Chaired Professor of Marketing and a research fellow at INSEAD, published in the Harvard Business Review made the following observations on brands and the branding process for drugs:

“…It takes a huge investment to build a successful brand, consumer goods manufacturers try to make their brands last as long as possible. Some consumer products—notably, Coca-Cola, Nescafé, and Persil (a European laundry detergent) -  have stayed at the top for decades. That’s not to say the products don’t evolve, but the changes are presented as improvements and refinements rather than as breakthroughs.”

“In the pharmaceutical business, by contrast, a new product is always given a new name. Drug companies believe that only by introducing a new name can you signal to the market that the product itself is new. Unfortunately, this approach throws out the company’s previous marketing investment entirely; it has to build a new brand with each new product. That may not have mattered when pharmaceutical companies could rely on a large, high-margin market for each drug they wheeled out. But in a crowded market with tightening margins, the new-product, new-brand strategy is becoming less and less feasible.”

The above observations when applied to expensive ‘branded generics’, which are nothing but exact ‘me too’ varieties among tens other similar formulations of the same generic molecule, do not add any additional value to the patients, in a well-functioning drug regulatory environment.

Hence, to reduce the out of pocket drug cost significantly, Prime Minister Modi hinted at bringing an appropriate legal framework to address this critical issue, which gets well-reflected in the draft pharma policy 2017, as I read it.

Six key features of the draft pharma policy related to ‘branded generics’:

Following are the six key features enshrined in the draft pharma policy 2017 to translate into reality what the Prime Minister spoke about on this subject in Surat on April 17, 2017.

1. Bio-availability and Bio-equivalence tests mandatory for all drug manufacturing permissions:

For quality control of generic drugs, Bio-availability and Bio-equivalence tests (BA/BE Tests) will be made mandatory for all drug manufacturing permissions accorded by the State Drug Regulator or by the Central Drug Regulator. This will be made compulsory even for the future renewals of manufacturing licenses for all.

2. WHO GMP/GLP mandatory for all drug units:

The government shall ensure to get the World Health Organization’s Good Manufacturing Practices (GMP) and Good Laboratory Practices (GLP) adopted by all manufacturing units.

3. No branded generics for single ingredient off-patent molecules:

The government will pursue the policy of sale of single ingredient drugs by their pharmacopeial name/salt name. To keep the identity of the manufacturer, the manufacturer would be allowed to stamp its name on the drug package. For patented drugs and Fixed Dose Combination (FDCs) drugs the brand names may be used.

4. ‘One company – one drug – one brand name – one price’:

The principle of ‘one company – one drug – one brand name – one price’ would be implemented for all drugs.

5. Aid and assistance to prescribe in generic names:

To aid and assist the registered medical practitioners in prescribing medicines in the generic names, e-prescription will be put into operation whereby the prescriptions will be computerized and the medicine name will be picked up from a drop-down menu of salt names.

6. UCPMP to be made mandatory:

The marketing practices of several pharmaceutical companies create an unfair advantage. To provide a level playing field, the regulation for marketing practices which is at present voluntary will be made mandatory. Penalty will be levied for violations and an agency for implementation would also be assigned.

Conclusion:

I have focused in this article only on those specific intents of the government, as captured in the draft pharma policy 2017, to reduce the out of pocket expenses on drugs for the Indian patients, which is currently one of the highest in the world. This area assumes greater importance to many, keeping in mind what Prime Minister Modi hinted at in this regard on April 17, 2017. If implemented exactly as detailed in the policy draft, this specific area would have a watershed impact both on the patients, as well as, the pharma companies, including their related business associates, lasting over a long period time.

Far reaching consequential fall outs are expected to loom large on the way pharma players’ strategic business processes generally revolve round ‘branded generics’ in India. I hope, the Plan B of many predominantly branded generic players is also receiving final touches on the drawing board by now, as this aspect of the draft policy proposal can in no way be construed as a bolt from the blue, catching the industry totally off-guard. That said, would the same changes as proposed in the draft pharma policy 2017, if and when implemented, be a ‘wow’ moment for patients?

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.

 

Data Manipulation: Leapfrogging Dangerously Into Clinical Trial Domain

Posted on by
Reply

Over the last several years, repeated allegations of gross data manipulative practices, detected by global drug regulatory agencies, such as USFDA and MHRA, have shaken the Indian pharma exporting companies hard.

This has been hurting the overall business performance of most of these players, considerably, besides other consequential fallouts

Significant numbers of pharma manufacturing facilities of different scale and size have been receiving ‘Import Alerts/Warning Letters’, at regular intervals, from the overseas drug regulators. All such steps have resulted in refusal of entry of medicines manufactured in those plants into the importing countries. As on date, most of these bans are for the United States (US), some for the United Kingdom (UK) and now a fresh one that covers all the 28 countries of the European Union (EU).

Consequently, the drug export performance of the country has started moving south, as I indicated in my blog post of September 29, 2014, titled “Make in India…Sell Any where in The World”: An Indian Pharma Perspective.

While looking at the future, the situation seems to be even more concerning than what is generally envisaged today, as it involves many homegrown local pharma behemoths, including the topper of the Indian pharma league table – Sun Pharma.

Time to take the bull by the horns:

These are regular and serious episodes of allegedly deliberate wrong doings involving life saving medicines. It is about time that without further delay the Indian Government and the country’s drug regulators accept unequivocally that there is something fundamentally wrong in this area that needs to be set right urgently.

To come out of this peril soon, competent authorities need to first ascertain without squandering much time on the utopian “conspiracy theory”, whether this seemingly uncontrollable issue falls under:

  • Technical incompetence
  • Inadequate resource deployment
  • Or just an outcome of generally all pervasive and a very Indian “Jugaad” mindset

It could well be a mix of all the three above factors in different proportions.

‘Data manipulation’ dangerously leapfrogging into clinical trial domain:

So far, incidences of alleged data falsification were restricted mostly to drug manufacturing activities. Alarmingly, it has now leapfrogged into the immensely important domain of ‘Clinical Trials’, based on which the drug regulators decide on the ‘Marketing Approval’ of medicines for patients’ consumption, wherever required.

If the Government does not nip it in the bud, ruthlessly and now, it has the potential to heavily impact the innocent patients even costing their precious lives.

What it means commercially?

According to Pharmaceutical Export Promotion Council (Pharmexcil), the Indian pharmaceutical industry could lose around US$1 – US$1.2 billion worth of exports due to the latest decision of the European Union to ban 700 generic drugs that earlier received European Union (EU) clearance for sale in their member countries.

According to Pharmexcil, Europe accounts for US$3 billion out of total Indian pharma exports of US$15.4 billion, which includes both APIs and formulations. This is the first time, when there has been a negative growth in pharma exports to the EU.

Unrolling the GVK Bio saga:

On July 22, 2015 Federal Institute for Medicines and Medical Products of Germany reportedly posted the notice (in German language) of ban of 700 generic drugs effective August 21, 2015. This ban would be applicable to all 28 EU member nations.

Accordingly, from the above date, all these drugs of both the Indian and multinational companies for which clinical trials were done by India’s Hyderabad based GVK Biosciences, cannot be distributed or sold by pharma companies, wholesalers, drug stores and other outlets in the EU, as indicate in the above notice. This would be the largest ban of generic drugs imposed by the European Union, as it comes into effect.

This ban is reportedly the ultimate outcome of an inspection in 2014 by the French authorities of the GVK site that handled the clinical trials for those 700 drugs. The French inspectors found that a number of electrocardiograms were falsified by GVK Bio employees as part of 9 approval studies between 2008 and 2014.

Following this finding, earlier on January 23, 2015, by a Press Release, the European Medicines Agency (EMA) had announced that a number of medicines for which authorization in the European Union (EU) was primarily based on clinical studies conducted at GVK Biosciences in Hyderabad, India, should be suspended.

Though GVK Bio has disputed the claims, it has reportedly set aside up to US$6.5 million for new studies on these drugs.

Indian Government blames ‘vested interests supporting Big Pharma’!

Interestingly, on July 23, 2015, The Financial Express reported, “the Modi government has asked the heads of India’s diplomatic missions in EU member countries and at the European Commission (EC)-level to take up the issue with the concerned authorities and ensure that it is not ‘blown out of proportion’ by ‘vested interests’ supporting the Big Pharma (innovator drug companies).”

However, it is even more interesting that earlier on April 16, 2015, quoting the CEO of GVK Biosciences Private Limited Reuters reported, “India may go to the World Trade Organization (WTO) if the European Union does not reconsider a decision to suspend the sale of about 700 generic drugs that were approved based on clinical trials by GVK Biosciences.”

It is noteworthy, despite the above public announcement, between April and July 2015, India has not lodged any complaint to the WTO on this mega ban in EU, involving clinical trials conducted by GVK Biosciences.

In my view, any tangible immediate outcome of the Indian diplomatic move, particularly on this ban in the EU, as reported above, appears rather unlikely, if at all.

The rigmarole continues:

The narrative of alleged gross falsification of sensitive clinical trial data does not end here. Almost replicating what happened earlier with frequent incidences of drug manufacturing data manipulation, the same rigmarole now leapfrogs into another important domain with similar intensity.

On June 30, 2015, close on the heels of the above GVK Biosciences saga, the World Health Organization issued a ‘Notice of Concern’ after inspection of Chennai-based Contract Research Company, Quest Life Sciences facility.

It also brought to light, critical deviations from GCP (Good Clinical Practices), over data integrity, subject safety and quality assurance and in gross violation of procedures during clinical trials for HIV drugs, such as, Lamivudine, Zidovudine and Nevarapine dispersible tablets from Micro Labs.

WHO inspectors reportedly found that “two-thirds of electrocardiograms performed on patients were duplicates with dates and names changed by the company”.

The WHO letter also underscored, “These issues appear to be systemic in nature and occurring many times over a significant period of time, and not only as a one-time incident for the study submitted to WHO.”

Again, almost depicting the past, there does not seem to be any perceptible and strong regulatory interventions in India in this regard, event after the above ‘Notice of Concern’ from the WHO.

Could assume a snowballing effect:

This situation may eventually assume a snowballing effect, when data related malpractices in clinical trials would catch up with drug manufacturing related data manipulation detected by the foreign drug regulators in India. I have just given an example of its continuation in the clinical trial domain.

The following are a few examples of just the last six months of 2015 of the continuation of the same in the drug manufacturing area:

Cadila Pharmaceuticals Limited:

In a letter dated February 25, 2015 to Cadila Pharmaceuticals Limited, the USFDA wrote that in the pharma manufacturing facility of the company, located at 294 GIDC Industrial Estate, Ankleshwar, Gujarat, their (USFDA) investigator identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of Active Pharmaceutical Ingredients (APIs). Those deviations cause the APIs manufactured there to be adulterated, in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with CGMP.

Emcure Pharmaceuticals Ltd.:

On July 13, 2015, by an ‘import alert’ posted on its website, the USFDA announced that the regulatory agency had barred imports from Hinjewadi manufacturing plant in Maharashtra of Emcure Pharmaceuticals Ltd., after their inspection revealed the company was not meeting manufacturing quality standards.

Aurobindo Pharma Ltd.:

Again, according to a July 22, 2015 media report, “Hyderabad-based Aurobindo Pharma is the latest addition to an expanding list of Indian drug firms that have come under the scanner of the US health regulator.” In this case also the USFDA reportedly raised issues related to the quality management systems of the company.

Business sustainability could be in jeopardy:

There are ample evidences that manipulations of specified drug quality standards, are making even the large home grown pharma companies to pay through the nose. In fact, it has already cost some of these companies an arm and a leg, at times jeopardizing even their very existence. One such company is Ranbaxy. The issues related to data fudging of Ranbaxy have been so complex and widespread that its recent acquirer Sun Pharma has already started struggling to keep its neck above water with this brand new acquisition.

According to July 27, 2015 media reports, GVK Biosciences are also in parleys to sell the business, following EU drug regulators’ serious allegations of clinical trial data manipulation at its Hyderabad facility.

Again, media reports of July 30, 2015 indicated that hit by the USFDA imposing import ban on three of its manufacturing facilities, Ipca Laboratories reported 86 per cent decline in net profit for first quarter ended June 30, 2015.

Though, some domestic pharma companies are still out of it, with grace, if this overall menace remains unchecked and not intervened by the Government, it could cost the nation dear, at least when it comes to near term exports business growth and global disrepute for the delinquency.

Are medicines for domestic consumption safe and effective?

When such rampant data manipulation can take place for ‘export quality’ of drugs, what about the quality standards of medicines, which are manufactured for consumption of local patients?

Despite intense furore on this subject, Indian drug regulators at the Central Drugs Standard Control Organization (CDSCO), very strangely, do not seem to be much concerned on this critical issue, at least, as perceived by majority of the stakeholders. It appears from the precedents, our drug regulators seem to act promptly, mostly when the Supreme Court of the country directs them for any specific action for public interest.

Considering blatant violations of GMP and GCP standards that are increasingly coming to the fore related to ‘export quality’ drugs in India, and that too only after the inspections by the foreign drug regulators, the following questions float at the top of my mind:

  • Why no such warnings are forthcoming at all from the Indian drug regulators?
  • Does it mean that the level of conformance to GMP and GCP is hundred percent for all medicines manufactured and clinically evaluated in India for the consumption of local patients?
  • If yes, why such incidences are not uploaded to the CDSCO website, just like USFDA?
  • If not, why?

Conclusion:

Increasing incidences of repeated GMP and GCP violations by the Indian drug exporters, as enunciated mostly by the USFDA, MHRA and now EMA are, in turn, fueling the apprehensions of many Indian stakeholders on the quality manufacturing and clinical evaluation of those drugs in the country.

In the critical public health safety area, there does not seem to be any room for diplomatic maneuvering by the Government, whatever is its financial impact on the drug exports performance of India.

This can be corrected, only if the Indian pharma industry and the Government, in tandem, wish to move in the right direction. Searching for justifications within imaginary ‘vested interests’ and self-created ‘conspiracy theory’ would be futile and counterproductive.

Making the wrongdoers swallow strong bitter pills would help salvaging the seemingly uncontrollable regulatory situation. Additionally, it would stop inviting disrepute to the country that the world was referring to, even until recently, as the ‘pharmacy of world’.

Any attempt to trivialize the situation, could meet with grave consequences  and prove to be foolhardy. The emerging scenario ultimately may even compel the local doctors and hospitals to avoid prescribing drugs of those companies involved in such wrong doings against patients’ interests. This actually happened earlier with Ranbaxy, though briefly. It is also possible that many erudite patients on their own may request the doctors to prescribe equivalent drugs of pharma MNCs, enjoying better brand equity in this regard.

Drug quality related avoidable malpractices and attempted hoodwinking to regulators, are taking place at a time when Prime Minister Modi is going global to give a boost to his much publicized ‘Make in India’ campaign.

In the current aspirational business climate of the country, it is an irony that alleged ‘Data Manipulation’, which was so far confined to pharma manufacturing activities in India, instead of getting mitigated, is now leapfrogging into the related clinical trial domain too, with utter disregard to patients’ health safety interest and the reputation of the country.

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

Posted on by
Reply

“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.

USFDA ‘Import Bans’: The Malady Calls For Strong Bitter Pills

Posted on by
Reply

It is a matter of pride that Indian pharmaceutical industry is the second largest exporter of drugs and pharmaceuticals globally, generating revenue of around US$ 13 billion in 2012 with a growth of 30 percent (Source: Pharmexcil).

Though sounds awkward, it is a reality that India is a country where ‘export quality’ attracts a premium. Unintentionally though, with this attitude, we indirectly accept that Indian product quality for domestic consumption is not as good.

‘Export quality’ being questioned seriously:

Unfortunately today, increasing number of even ‘export quality’ drug manufacturing units in India are being seriously questioned by the regulators of mainly United States (US) and the United Kingdom (UK) on the current Good Manufacturing Practices (cGMP) being followed by these companies. In many instances their inspections are culminating into ‘Import Bans’ by the respective countries to ensure dug safety for the patients.

Are drugs for domestic consumption safe?

Despite intense local and global furore on this subject, Indian drug regulators at the Central Drugs Standard Control Organization (CDSCO), very strangely, do not seem to be much concerned on this critical issue, at least, not just yet. Our drug regulators seem to act only when they are specifically directed by the Supreme Court of the country.

A recent major incident is yet another example to vindicate the point. In this case, according to media reports of November 2013, the Drug Controller General of India (DCGI) has ordered the Indian pharma major Sun Pharmaceuticals to suspend clinical research activities at its Mumbai based bio-analytical laboratory, after discovering that the company does not have the requisite approval from the central government for operating the laboratory. The DCGI has decided not to accept future applications and will not process existing new drug filings that Sun Pharma has made from the Mumbai laboratory until the company gets an approval.

Considering the blatant violations of cGMP standards that are increasingly coming to the fore related to ‘export quality’ of drugs in India, after inspections by the foreign drug regulators, one perhaps would shudder to think, what could possibly be the level of conformance to cGMP for the drugs manufactured in India solely for the local patients.

This question comes up as the record of scrutiny on adherence to cGMP by the Indian drug regulators is rather lackadaisical. The fact that no such warnings, as are being issued by the foreign regulators, came from their local counterpart, reinforces this doubt.

USFDA ‘Import Bans’:

Be that as it may, in this article let me deliberate on this particular drug regulatory issue as is being raised by the USFDA and others.

It is important to note that in 2013 till date, USFDA issued ‘Import Alerts/Bans’ against 20 manufacturing facilities of the Indian pharmaceutical exporters, sowing seeds of serious doubts about the overall drug manufacturing standards in India.

The sequence of events post USFDA inspection: 

Let us now very briefly deliberate on the different steps that are usually followed by the USFDA before the outcomes of the inspections culminate into ‘Import Alerts’ or bans.

After inspections, depending on the nature of findings, following steps are usually taken by the USFDA:

  • Issue of ‘Form 483’
  • The ‘Warning letter’
  • ‘Import Alert’

Revisiting the steps: 

Let me now quickly re-visit each of the above action steps of the USFDA.

‘Form 483’: 

At the conclusion of any USFDA inspection, if the inspecting team observes any conditions that in their judgment may constitute violations of the Food, Drug and Cosmetic (FD&C) and other related Acts, a Form 483 is issued to the concerned company, notifying the firm management of objectionable conditions found during inspection.

Companies are encouraged to respond to the Form 483 in writing with their corrective action plan and then implement those corrective measures expeditiously. USFDA considers all these information appropriately and then determines what further action, if any, is appropriate to protect public health in their country.

The ‘Warning Letter’:

The ‘Warning Letter’ is a document usually originating from the Form 483 observations and results from multiple lacking responses to Form 483 requiring quick attention and action. It may be noted that higher-level USFDA agency officials and not the investigator issue the ‘Warning Letters’.

‘Import Alert/ Ban’:

‘Import Alerts’ are issued whenever USFDA determines that it already has sufficient evidence to conclude that concerned products appear to be adulterated, misbranded, or unapproved. As a result, USFDA automatically detains these products at the border, costing the related companies a lot of money. The concerned company’s manufacturing unit remains on the import alert till it complies with USFDA cGMP.

What happens normally?

Most of the USFDA plant inspections are restricted to issue of Form 483 observations and the concerned company’s taking appropriate measures accordingly. However, at times, ‘Warning Letters’ are issued,  which are also mostly addressed by companies to the regulator’s satisfaction.

Import Bans are avoidable: 

Considering the above steps, it is worth noting that there is a significant window of opportunity available to any manufacturing facility to conform to the USFDA requirements by taking appropriate steps, as necessary, unless otherwise the practices are basically fraudulent in nature.

The concern:

Currently, there is a great concern in the country due to increasing frequency of ‘Import Alerts’.  As per USFDA data, in 2013 to date, about 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.

The matter assumes greater significance, as India is the second-largest supplier of pharmaceuticals to the United States. In 2012, pharmaceutical exports from India to the US reportedly rose 32 percent to US$ 4.2 billion. Today, India accounts for about 40 percent of generic and Over-The-Counter (OTC) drugs and 10 percent of finished dosages used in the US.

Ranbaxy cases: ‘Lying’ and ‘fraud’ allegations: 

In September 2013, after the latest USFDA action on the Mohali manufacturing facility of Ranbaxy, all three plants in India of the company that are dedicated to the US market have been barred from shipping drugs to the United States. The magnitude of this import ban reportedly impacts more than 40 percent of the company’s sales. However, Ranbaxy has a total of eight production facilities across India.

This ‘Import Alert’ was prompted by the inspection findings of the USFDA that the Mohali factory of Ranbaxy had not met with the cGMP.

Other two plants of Ranbaxy’s located at Dewas and Paonta Sahib faced the same import alerts in 2008, and are still barred from making drug shipments to the US.

The import ban on he Mohali manufacturing facility of Ranbaxy comes after the company pleaded guilty in May 2013 to the felony (criminal) charges in the US related to drug safety and agreed to pay a record US$ 500 million in fines.

In addition, the company also faced federal criminal charges that it sold batches of drugs that were improperly manufactured, stored and tested. Ranbaxy also admitted to lying to the USFDA about how it tested drugs at the above two Indian manufacturing facilities.

Heavy consequential damages with delayed launch of generic Diovan:

The ‘Import Alert’ of the USFDA against Mohali plant of Ranbaxy, has resulted in delayed introduction of a cheaper generic version of Diovan, the blockbuster antihypertensive drug of Novartis AG, after it went off patent.

It is worth noting that Ranbaxy had the exclusive right to sell a generic version of Diovan from September 21, 2012. 

Gain of Novartis:

This delay will help Novartis AG to generate an extra one-year’s sales for Diovan. This is expected to be around US$ 1 billion, only in the US. This development prompted Novartis in July this year to raise its profit and sales forecasts accordingly.

Wockhardt cases: Non-compliance of cGMP

Following Ranbaxy saga, USFDA inspection of Chikalthana plant of Wockhardt in Maharashtra detected major quality violations. Second time this year USFDA noted 16 violations of cGMP in the company’s facility. Earlier, in July 2013, the Agency issued a ‘Warning Letter’ and ‘Import Alert’ banning the products manufactured at the company’s Waluj pharmaceutical production facility.

Moreover, in September 2013, Medicines and Healthcare Products Regulatory Agency (MHRA) had pulled the GMP certificate of the company’s unit based in Nani Daman, after an inspection conducted by the UK regulator showed poor manufacturing standards. 

Again, in October 2013, the MHRA withdrew its cGMP certificate for the Chikalthana plant of Wockhardt. This move would ban import of drugs into the UK, manufactured in this particular plant of the company.

However, MHRA has now decided to issue a restricted certificate, meaning Wockhardt will be able to supply only “critical” products from these facilities. This was reportedly done, as the UK health regulator wants to avert shortage of certain drugs essential for maintaining public health. The impact of the withdrawal of cGMP certificate on existing business of the company can only be ascertained once Wockhardt receives further communications from the MHRA.

Earlier in July 2013, MHRA had reportedly also imposed an import alert on the company’s plant at Waluj in Maharashtra and issued a precautionary recall for sixteen medicines made in this unit.

RPG Life Sciences cases: allegedly ‘Adulterated’ products: 

In June 2013, USFDA reportedly issued a ‘Warning Letter’ to RPG Life Sciences for serious violation of cGMP in their manufacturing plants located at Ankleshwar and Navi Mumbai.

USFDA investigators had mentioned that “These violations cause your Active Pharmaceutical Ingredients (APIs) and drug products to be adulterated …the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with cGMP.”

Strides Arcolab case: Non Compliance of cGMP

In September 2013, Strides Arcolab announced that its sterile injectable drug unit – Agila Specialties (now with Mylan) had received a warning letter from the USFDA after its inspection by the regulator in June 2013. However, Strides Arcolab management said, “the company was committed to work collaboratively and expeditiously with the USFDA to resolve concerns cited in the warning letter in the shortest possible time.”

USV case: allegation of ‘data fudging’: 

Recently, USFDA reportedly accused Mumbai-based drug major USV of fudging the data.

After an inspection of USV’s Mumbai laboratory in June 2013, the US drug regulator said the company’s “drug product test method validation data is falsified”. The USFDA has also reprimanded USV for not training its staff in cGMP.

Probable consequences: 

USFDA import bans and a similar measure by the UKMHRA would lead to the following consequences:

  • Significant revenue losses by the companies involved, till the concerned regulators accept their remedial actions related to cGMP.
  • Increasing global apprehensions about the quality of Indian drugs.
  • Possibility of other foreign drug regulators tightening their belts to be absolutely sure about cGMP followed by the Indian drug manufacturers, making drug exports from India more difficult.
  • Huge opportunity cost for not being able to take advantage from ‘first to launch’ generic versions of off patent blockbuster drugs, such as from Diovan of Novartis AG.
  • Indian patients, including doctors and hospitals, may also become apprehensive about the general quality of drugs made by Indian Pharma Industry, as has already happened in a smaller dimension in the past.
  • Opposition groups of Indian Pharma may use this opportunity to further their vested interests and try to marginalize the Indian drug exporters. 
  • MNCs operating in India could indirectly campaign on such drug quality issues to reap a rich harvest out of the prevailing situation.
  • Unfounded ‘foreign conspiracy theory’ may start gaining ground, prompting the Indian companies moaning much, rather than taking tangible remedial measures on the ground to effectively come out of this self created mess.

Conclusion: 

Repeated cGMP violations made by the Indian drug exporters, as enunciated by the USFDA, have now become a malady, as it were. This can be corrected, only if the reality is accepted without attempting for justifications and then swallowing strong bitter pills, sooner.

Thereafter, the domestic pharma industry, which has globally demonstrated its proven capability of manufacturing quality medicines at affordable prices for a large number of patients around the world and for a long time, will require to tighten belts for strict conformance to cGMP norms, as prescribed by the regulators. This will require great tenacity and unrelenting mindset of the Indian Pharma to tide over the crisis.

Any attempt to trivialize the situation, as indicated above, could meet with grave consequences, jeopardizing the thriving pharma exports business of India.

That said, any fraud or negligence in the drug quality standards, for whatever reasons or wherever these may take place, should be considered as fraud on patients and the perpetrators must be brought to justice forthwith by the DCGI, with exemplary punitive measures.

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.