New Clinical Trial Regime Deserves Support, Sans Threats

Posted on January 30, 2014 by Tapan Ray

Recent Supreme Court intervention compelling the Union Government to enforce stringent regulations both for approval and conduct of Clinical Trials (CT) in India, has unfortunately met with some strong resistance with stronger words. Some of these voices are from credible experienced sources and the shriller ones are mostly from vested interests with dubious credentials. However, it is also a fact that this interim period of process change in CT has resulted in around 50 per cent drop in new drug trials in the country, pharma MNCs being most affected.

Brief background:

The earlier system of CT in India created a huge ruckus as many players, both global and local, reportedly indulged in widespread malpractices, abuse and misuse of the system. The issue was not just of GCP or other CT related standards, but mostly related to ethical mind-set or lack of it and rampant exploitation of uninformed patients/volunteers, especially related to trial-related injuries and death All these are being well covered by the Indian and international media since quite some time.

The Bulletin of the World Health Organization (WHO) in an article titled, “Clinical trials in India: ethical concerns” reported as follows:

“Drug companies are drawn to India for several reasons, including a technically competent workforce, patient availability, low costs and a friendly drug-control system. While good news for India’s economy, the booming clinical trial industry is raising concerns because of a lack of regulation of private trials and the uneven application of requirements for informed consent and proper ethics review.”

Earlier system did not work:

Just to give a perspective, according to a report quoting the Drug Controller General of India (DCGI), 25 people died in clinical trials conducted by 9 pharma MNCs, in 2010. Unfortunately, families of just five of these victims received” compensation for trial related deaths, which ranged from an abysmal Rs 1.5 lakh (US$ 2,500) to Rs 3 lakh (US$ 5,000) to the families of the diseased.

This report also highlighted that arising out of this critical negligence, the then DCGI, for the first time ever, was compelled to summon the concerned nine pharma MNCs on June 6, 2011 to question them on this issue and give a clear directive to pay up the mandatory compensation for deaths related to CTs by June 20, 2011, or else all CTs of these nine MNCs, which were ongoing at that time or yet to start, will not be allowed.

The 9 pharma MNCs summoned by the DCGI to pay up the mandatory compensation for deaths related to CTs were reported in the media as Wyeth, Quintiles, Eli Lilly, Amgen, Bayer, Bristol-Myers Squibb (BMS), Sanofi, PPD and Pfizer.

The report also indicated that after this ultimatum, all the 9 MNCs had paid compensation to the concerned families of the patients, who died related to the CTs. However, the situation did not change much even thereafter.

Indictment of Indian Parliamentary Committee:

On May 8, 2012, the department related ‘Parliamentary Standing Committee (PSC)’ on Health and Family Welfare presented its 59th Report on the functioning of the Indian Drug Regulator – the Central Drugs Standard Control Organization (CDSCO) in both the houses of the Parliament.

The report made the following scathing remarks on Central Drugs Standard Control Organization (CDSCO) under 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.”

Catalytic change with tough norms:

The intervention of the apex court heralded the beginning of a catalytic changing process in the CT environment of India. The court intervention was in response to a Public Interest Litigation (PIL) filed by the NGO Swasthya Adhikar Manch calling for robust measures in the procedural guidelines for drug trials in the country.

In an affidavit to the Court, the Government admitted that between 2005 and 2012, 2,644 people died during CTs of 475 New Chemical Entities (NCEs)/New Molecular Entities (NMEs), with serious adverse events related deaths taking 80 lives.

Accordingly, changes have been/are being made mostly in accordance with the recommendations of Professor Ranjit Roy Chaudhury Experts Committee that was constituted specifically for this purpose by the Union Ministry of Health.

Prof. Ranjit Roy Chaudhury experts committee in its 99-page report has reportedly recommended some radical changes in the CT space of India. Among others, the report also includes:

Setting up of a Central Accreditation Council (CAC) to oversee the accreditation of institutes, clinical investigators and ethics committees for CTs in the country.

Only those trials, which will be conducted at centers meeting these requirements, be considered for approval by the DCGI.

All modifications in the procedural norms and guidelines for CTs are expected to protect not just the interest of the country in this area, but would also ensure due justice to the volunteers participating in those trials.

The DCGI has now also put in place some tough norms to make the concerned players liable for the death of, or injury to, any drug trial subject. These guidelines were not so specific and stringent in the past. There are enough instances that CT in India, until recently, had exploited poor volunteers enormously, many of which reportedly did not have any inkling that the efficacy and safety of the drugs that they were administering were still undergoing tests and that too on them.

With those radical changes to the rules of the Drugs and Cosmetics Act, 1940, pertaining to CT, it is now absolutely mandatory for the principal investigator of the pharmaceutical company, unlike in the past, to reveal the contract between the subject and the company to the DCGI. Besides, much reported process of videography of informed consent ensuring full knowledge of the participant has already been made mandatory. Further, any death during the process of CT would now necessarily have to be reported to the DCGI within 24 hours.

A report quoting the Union Minister of Health has highlighted that, “Earlier, the informed consent of the persons on which the trials had been conducted was often manipulated by the companies to the disadvantage of the subjects,”

Reaction to change:

With the Government of India tightening the norms of CT, the drug trial process and the rules are undergoing a metamorphosis with increased liability and costs to the pharma players and Contract Research Organizations (CROs). The reaction has been moderate to rather belligerent from some corners. One such player reportedly has publicly expressed annoyance by saying: “The situation is becoming more and more difficult in India. Several programs have been stalled and we have also moved the trials offshore, to ensure the work on the development does not stop.”

There were couple of similar comments or threats, whatever one may call these, in the past, but the moves of the Government continued to be in the right direction with the intervention of the Supreme Court.

No reverse gear:

Thus, coming under immense pressure from the Indian Parliament, the civil society and now the scrutiny of the Supreme Court for so many CT related deaths and consequential patients’ compensation issues, the Government does not seem to have any other options left now but to bring US$ 500 million CT segment of the country, which is expected to cross a turnover of US$ 1 Billion by 2016, under stringent regulations. Thus any move in the reverse gear under any threat, as mentioned above, appears unlikely now.

Experts believe that the growth of the CT segment in India is driven mainly by the MNCs for easy availability of a large treatment naive patient population with varying disease pattern and demographic profile at a very low cost, as compared to many other countries across the world.

Conclusion:

If the DCGI loosens the rope in this critical area and even inadvertently allows some pharmaceutical players keep exploiting the system just to keep the CT costs down only for commercial considerations, judiciary has no option but to effectively intervene in response to PILs, as happened in this particular case too.

The new system, besides ensuring patients’/volunteers’ safety, justice, fairplay and good discipline for all, will have the potential to help reaping a rich economic harvest through creation of a meaningful and vibrant CT industry in India in the long run, simultaneously benefitting millions of patients, as we move on. However, the DCGI should ensure to add reasonable speed to the entire CT approval process, diligently.

Taking all these into consideration, let all concerned support the new CT regime in India, sans any threats…veiled or otherwise.

By: Tapan J. Ray

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

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

Posted on January 13, 2014 by Tapan Ray

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

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

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

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

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

A long overdue decision for patients’ health safety:

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

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

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

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

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

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

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

Good for patients:

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

Great for Pharma:

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

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

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

A similar past issue still haunts:

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

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

Conclusion:

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

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

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

By: Tapan J. Ray

The ‘TINA Factor’: A Hotspot for Patented Drugs

Posted on December 16, 2013 by Tapan Ray

An article published in a global business magazine on December 5, 2013 mentioned that Marijn Dekkers, the CEO of Bayer AG reportedly has said at the Financial Times Global Pharmaceutical & Biotech Conference held this month that:

“Bayer didn’t develop its cancer drug, Nexavar (sorafenib) for India but for Western Patients that can afford it.”

The head honcho deserves kudos for revealing his mind upfront, while inviting two quick questions, as follows:

If that is so, why did Bayer launch Nexavar in India?
Did Bayer have any other alternative or choice for not doing so, other than negotiating for a ‘Voluntary License’?

As Bayer already had decided against any ‘Voluntary License’ for Nexavar in India, the simple answer to both the questions is : There Is No Alternative (TINA). And…that’s my ‘TINA Factor’, now a hotspot for patented drugs in India.

I shall dwell on it below, just in a short while.

Bellicose stance for high drug prices and more stringent patent regime:

Everybody acknowledges, beyond even an iota of doubt, that the contribution of the global pharmaceutical industry in the ongoing fight of mankind against diseases of all kinds, is commendable and exemplary.

However, over a period of time, as the low hanging fruits of pharma R&D are in the process of getting all plucked, raw commerce mainly driven by likes of “The Wall Street” quarterly expectations, have started overriding public health considerations involving a large section of the society, across the world, including India.

In this evolving scenario, healthcare has to be extended to almost everybody in the society by the respective Governments in power with strong support from the pharma industry. Instead, to utter dismay of many, the later seems to have opted for a bellicose stance. Their lobby groups appear to be power playing with all might in the corridors of power, to make the product patent regime of faster growing emerging markets more and more stringent, restricting smooth entry of affordable generic or biosimilar drugs increasingly difficult.

Underlying reasons for Big Pharma’s near obsession to have in place an ever stringent patent regime, defying all public health interest particularly of the developing countries, I reckon, are mainly three-fold:

Grant of product patent for any innovation irrespective of triviality
To have absolute pricing freedom for patented drugs for unlimited profits
To enjoy and extend product monopoly status as long as possible

Probably, to camouflage these intents, the reasons for high prices of patented drugs are attributed to the over-used buzz-words – fostering and re-investing in innovation, which is more often underscored as frightfully expensive.

Fair enough, in that case, let the high cost of R&D be appropriately quantified involving independent experts and made known to public. It will then not be like a jig saw puzzle for people to understand the real intent or the truth behind high drug prices. Thereafter, practical solutions need be fleshed-out putting the bright brains and minds together to make new medicines affordable to patients, across the world.

Most probably, that is not to happen, unless a legally binding system of disclosure of expenses is made mandatory for R&D, just as the ‘Physician Payment Sunshine Act’ of the United States demands public disclosure of gifts and payments made to doctors by the pharma players and allied businesses.

On the contrary, incessant efforts by vested interests still continue to keep the patented drug prices beyond the reach of common man. The following are just some very recent examples:

Another ‘defiant move’ in drug pricing:

In another recent development, US-FDA on December 6, 2013 approved Sovaldi (sofosbuvir) of Gilead Sciences Inc. This new drug is reported to be a cure for chronic infection with hepatitis C virus, without co-administration of interferon.

According to the report of July 2013 of the World Health Organization (WHO), about 150 million people are chronically infected with hepatitis C virus, and more than 350, 000 people die every year from hepatitis C- related liver diseases, across the world.

Most interestingly, Gilead Sciences have reportedly decided to keep the price of Sovaldi at a staggering US$ 1,000 (Rs. 62,000) -a-day for one tablet to be continued for 12 weeks. Thus the cost of a three month course of treatment with Sovaldi would be a mind boggling sum of US$ 84,000 (Rs.L 5.21), just for one patient.

It is worth noting that the above price/table of Sovaldi, as decided by Gilead Sciences, has started culminating into a storm of protest, almost immediately, even in the United States (US). The biggest drug benefits manager in that country – Express Scripts Holding Co. in a decisive move to drive down spending on the medicines, reportedly plans to start a price war when Sovaldi comes to market next year or early in 2015 wearing a price tag of US$ 1,000 a pill.

Further, on this seemingly defiant pricing strategy, that too for a life saving drug affecting patients belonging to all strata of the society, ‘Doctors Without Borders’ have reportedly commented: “Using patents to block affordable versions of sofosbuvir and pricing this drug out of reach of the most vulnerable groups who need it most is simply putting profits before people’s lives.”

Brewing a fresh initiative for more stringent high drug price regime:

To foist stricter pharmaceutical patent regime, making access to affordable drugs for the world’s poor increasingly challenging, an initiative is reportedly brewing afresh led by the United States (US).

Ministers of Trade from 12 countries initiated a discussion on December 6, 2013 at Singapore to meet the US deadline of forging a deal on the proposed ‘Trans-Pacific-Partnership (TPP)’ before the end of 2013.

These twelve countries – Australia Brunei, Canada, Chile, Japan, Malaysia, Mexico, New Zealand, Peru, Singapore, USA and Vietnam, contributing 40 percent of the world economy, are expected to hammer out the TPP deal first, though other countries may hitch on thereafter.

However, after 4 days of intense negotiation, the US-led TPP talks ended on December 10, 2013, without beating into shape any deal. These countries would reportedly meet again on January 2014, in contrast to earlier plan.

The global human right groups like ‘Medicins Sans Frontieres (MSF)’ and ‘Doctors Without Borders’ have reportedly commented, “The ‘Data Protection’ period will prevent drug regulatory agencies in TPP signatory countries from referencing data needed to approve lower-cost generic versions of a protected drug, delaying competition that would lead to cheaper prices”.

In a poll commissioned by ‘Avaaz’ – a global advocacy group, reportedly 62 percent of Americans, 63 percent of Australians, 70 percent of New Zealanders, and of 75 percent Chileans opposed limiting access to generic medicines through the patent proposal in TPP.

Quite expectedly, the powerful US pharma lobby group ‘Pharmaceutical Research and Manufacturers of America (PhRMA)’ said, “It was necessary for companies to recover investments and conduct further research into new cures”.

Breath of fresh air:

The good news is that some prudent developments are also seen around in the midst of a monopolistic drug pricing scenario, offering a breath of fresh air. Some countries around the world, including an important payor in the Unites States, National Institute for Health and Care Excellence (NICE) of UK which assesses the value of drugs for NHS use, and even ‘National Development and Reform Commission (NDRC)’ of China, have now started taking note and proactive measures in different ways on monopolistic high drug prices.

A recent report highlighted that ‘National Development and Reform Commission (NDRC)’ of China would examine and regulate the price-related monopolistic practices of six industries operating in the country, including pharmaceuticals and would crack down wherever they find excessively high prices.

Can India insulate itself from pricing onslaught?

Despite growing global pressure against ‘putting profits before people’s lives’, one may arguably expect more such initiatives spearheaded by Big Pharma to make the patent regime, of especially the emerging markets, more stringent in the years ahead.

That said, ‘The TINA Factor’, which I shall now dwell upon, would probably help reinforcing the protective shield of Indian patent regime against foreseeable assaults with strategies quite similar to as cited above, denying access to new life saving drugs to most of the general population of the country.

‘The TINA Factor’ and three ‘Alternatives’ available to MNCs:

Since enactment of patient-friendly patent laws by the Parliament of India effective January 1, 2005, many global pharma companies and their lobby groups have been continuously expressing immense displeasure and strong anger in many ways for obvious reasons, just as the CEO of Bayer AG did recently.

There are, of course, a few exceptions, such as Sir Andrew Witty, the global CEO of GlaxoSmithKline (GSK), who has been publicly expressing balanced views on this subject in several occasions, so far.

Being driven by anger and possibly desperation any MNC may wish to choose one of the following three ‘Alternatives’ available to them:

Alternative 1: Do not apply for the product patent in India at all.

‘The TINA Factor’: In that case the product will be made available in a platter for the generic players to copy.

Alternative 2: Obtaining the relevant patent from the Indian Patent Office (IPO), do not launch the patented product in India.

‘The TINA Factor’: After three years from the date of grant of patent, as per the statute, the said product could become a candidate for CL on the ground that the patented invention has not been worked in India.

Alternative 3: Launch the product only at the international price.

‘The TINA Factor’: If any patented new product is not available to patients at a ‘reasonably affordable price’ or ‘reasonable requirements’ of patients with respect to the patented invention are not satisfied, again according to statutes, interested parties are free to apply for CL to the IPO, following the steps as specified in the Act. Moreover, the Government itself may issue CL in national emergencies or ‘extreme urgency’ for non-commercial use.

Considering the ‘TINA Factor’, it appears, if the new products do not conform to the ‘Indian Patents Act’ and are NOT launched with ‘reasonably affordable prices’ or ‘reasonable requirements’ of patients are NOT met with these new drugs, the possibility of their legal generic entry at much lower prices is rather high in India. CL granted by the IPO for Bayer’s Nexavar to NATCO vindicates this point.

Summing-up effects of the ‘TINA Factor’:

Many would now reckon that the ‘TINA Factor’, being a hotspot for patented drugs in India, has the potential for getting adopted by many other countries in not too distant future. Two of its palpable effects, as felt in the country so far, may be summed-up as follows:

It leaves no option to any MNC, other than launching their new products in India, especially after obtaining relevant patents from the IPO.

It also squashes apprehensions of many that discontented Big Pharma would be able stop launching patented new products in India, depriving a large number of patients of the country.

Conclusion:

‘The TINA Factor’, thus created by the lawmakers, is expected to remain undiluted, unless commensurate changes are made in the Indian Patents Act.

Not withstanding the reported anger expressed by the CEO of Bayer AG or recently reported ‘absurd pricing’ of Sovaldi, or even for that matter, fresh attempts that are now being made to cobble together a TPP deal, patented new products would continue to be launched in India, as they will receive marketing approval from the Drug Controller General of India (DCGI).

Any possibility of dilution of the ‘TINA Factor’ seems remote now, though powerful overseas pharma lobby groups are investing heavily for a change to take place in various ways.

It also does not seem likely, at least in the near to mid-term, that India would be a party to its ‘Patents Act’ diluting any ‘Free Trade Agreement’ or remain unmoved with high drug prices like, US$ 1000/tablet for life saving drugs like sofosbuvir, more so, if those are considered essential medicines in the country.

Come 2014, it appears improbable that any new Union Government would be able to garner enough numbers in the Parliament to amend Indian Patents Act, buckling under pressure of powerful lobby groups, directly or indirectly, and daring to ignore public sentiment on this sensitive issue.

Considering all these, the point to ponder now:

While abhorring pro-patients ‘Patents Act’ of India, can the Big Pharma come out with any viable alternative today for NOT launching their life saving patented new drugs in the country with the ‘TINA Factor’ prevailing?

By: Tapan J. Ray

Pharma Horizon: Cloud, Rainbow And Smear

Posted on December 9, 2013 by Tapan Ray

Some recent papers contemplated that the patent cliff for blockbuster drugs has already reached the zenith and early signs of recovery should be visible from 2013 onwards. However, from analysis of the currently available data, contrary to the above belief, I reckon, the downtrend in global pharma is far from over, not just yet.

One of the telltale signs of this slump is near-term patent expiry of today’s blockbuster drugs, the impact of which will continue to keep the global pharma sky overcast with clouds for some more time, especially in absence of replaceable equivalents. Interestingly, on the flip side, a beautiful rainbow, as it were, also takes shape in the horizon, ushering-in a hope to a large number of patients for improved access to newer drugs, just as it does to the generic players for accelerating business growth.

That’s the good part of it, though for the generic drug industry. However, the bad part of the emerging scenario gives rise to a lurking fear of gloom and doom, emanating from self-created evitable smears and taints, blended in vessels of despicable mindsets.

Clouds:

While having a glimpse at that following table, the underlying impact of the dark clouds looming large on the global pharma horizon cannot just be wished away:

Total Patent Expiry:

Year	Value US$ Billion
2015	66
2014	34
2013	28
2012	55
Total	183

(Compiled from FiercePharma data)

Thus, the negative impact from sales lost to patent expiry of blockbuster drugs of today, though declined from US$ 55 billion in 2012 to US$ 28 billion in 2013, the same would start climbing-up again to US$ 66 billion in 2015.

If we take a look at the product-wise details, the picture pans out as under:

Top 10 ‘Patent Expiry’ in 2014:

No.	Brand	Company	Disease	Sales 2012 US$ Million	Expiry
1.	Copaxone	Teva	MultipleSclerosis	3996	May 2014
2.	Nexium	AstraZeneca	Acid peptic	3994	May 2014
3.	Micardis/HCT	BoehringerIngelheim	Hypertension	2217	Jan 2014
4.	Sandostatin LAR	Novartis	Cancer	1512	June 2014
5.	Exforge/HCT	Novartis	Hypertension	1352	Oct 2014
6.	Nasonex	Merck	Resp. Allergy	1268	Jan 2014
7.	Trilipix	Abbvie	Anti-lipid	1098	Jan 2014
8.	Evista	Eli Lilly	Osteoporosis	1010	Mar 2014
9.	Renagel	Sanofi	Chronic Kidney Disease	861	Sep. 2014
10.	Restasis	Allergan	Chronic Dry Eye	792	May 2014

(Compiled from FiercePharma data)

The above figures, therefore, do reinforce the hypothesis that the following factors would continue to make the best brains of global pharma burning the midnight oil in search of sustainable strategic blueprints, at least, for some more time:

- Mostly, high growth emerging markets of the world are generic drugs driven

- Increasing cost containment pressure of Governments and/or other payor

- Challenges from Intellectual Property (IP) and Market Access related issues

- Declining R&D productivity

- Shift in overall focus for new drugs on expensive biologics

- Markets turning more Volatile, Uncertain, Complex and Ambiguous (VUCA)

Current strategy to deliver shareholder-value not sustainable:

Since last several years, one has witnessed, despite slowing down of sales growth, big pharma players, by and large, have not failed in delivering impressive shareholder returns. This has been possible mainly due to ruthless cost cutting across the board, restructuring of operational framework and taking measures like, increase in dividends and share repurchases.

These strategic measures, though laudable to keep the head above water, are just not sustainable over a period of time sans strong cashﬂow.

Thus, for a long haul, robust and consistent business growth with commensurate impact on the bottom-line generating smooth cashflow, is imperative for all these companies.

In this difficult ball game of developing sustainable cutting-edge strategies at an equally challenging time, the consolidation process within the industry would gain further momentum, where only the fittest corporations, led by great corporate brains, would manage to survive and thrive.

However, who all would successfully be able to squarely face the moments of truth, triumphantly seizing the opportunities frozen in time, in the fast changing paradigm of a seemingly VUCA world, is not more than a matter of speculation now.

The Rainbow:

As stated above, while this canopy formed with dark clouds keeps looming large at the global pharma horizon, a beautiful rainbow is simultaneously seen taking shape for the domestic Indian drug manufacturers to cash-on with well-orchestrated strategic measures. One of the critical success requirements for this sprint, is touching the tape in the finishing line to become first to introduce generic versions of the patent expired drugs, especially in the US market.

Indian pharma players have already demonstrated in the past that they do have the wherewithal of making such rare opportunities meaningful by offering affordable new drugs of high quality standards to a large number of patients, while simultaneously accelerating growth of their respective business operations.

Proven acumen even in biologics:

India has recently proven its acumen in the area of biologics too, by developing a biosimilar version of the complex biologic drug – Trastuzumab (Herceptin) of Roche, used for the treatment of breast cancer, and that too in a record time.

As is known to many, earlier in 2013 Roche decided not to defend its patents on Herceptin in India, which reportedly recorded local sales of about US$ 21 million in 2012. Many people opined at that time, it would not be easy for any company to develop biosimilar version of Trastuzumab, mainly due to the complexity involved in its clinical development. Hence, some diehards kept arguing, Roche would not be commercially impacted much for taking the above decision, at least in the near to mid term.

Surprising almost everybody, Biocon and its MNC partner Mylan not only developed an affordable biosimilar version of Trastuzumab successfully, but also got its marketing approval from the Drug Controller General of India (DCGI), thereby immensely benefitting a large number of breast cancer patients in India and hopefully even beyond.

Keeping ‘Eye on the ball’?

Details of ANDA status from the USFDA source probably indicate that several Indian players have started gearing up to move in that direction at a brisk pace, keeping their eyes well fixed on the ball.

The following table further indicates that in 2012 India ranked second, after the United States (US) in terms of number of ANDA approvals and in 2013 till October India ranks number one, overtaking the United States (US):

ANDA’s Granted in 2012 and upto October 2013):

Country	ANDA 2012	ANDA (October 2013)	Total Since 2007
United States	183	119	1191
India	196	138	993
Switzerland	20	12	134
Israel	28	13	133
Canada	27	13	116
Germany	20	6	107
UK	11	15	95
China	7	10	29

Smears:

Unfortunately, just out side the frame of the above kaleidoscope, one can see large spots of self created slimy smears, which can make the ‘Rainbow’ irrelevant, maintaining the horizon as cloudy even for the Indian generic players.

Continuous reports from US-FDA and UK-MHRA on fraudulent regulatory acts, lying and falsification of drug quality data by some otherwise quite capable Indian players, have just not invited disgrace for the country in this area, but also reportedly prompted regulators from other nations trying to assess whether such bans might suggest issues for drugs manufactured for their respective countries, as well.

Such despicable mindsets of the concerned key players, if remain unleashed, could make Indian Pharma gravitating down, stampeding all hopes of harvesting the incoming opportunities.

We have one such ready example before us and that too is not an old one. The ‘Import Alert’ of the USFDA against Mohali plant of Ranbaxy, has already caused inordinate delay in the 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.

Another report of November 2013 states, “The Drug Controller General of India has ordered Sun Pharmaceutical, the country’s largest drug maker by market capitalization to suspend clinical research activities at its Mumbai based bio-analytical laboratory, a move that could slow down the company’s regulatory filings in India and possibly overseas as well.”

The outcome of such malpractices may go beyond the drug regulatory areas, affecting even the valuations of concerned Indian pharma companies. According to a recent report Strides Arcolab will not get US$ 250 million of the US$ 1.75 billion anticipated from the sale of its injectable drugs unit to Mylan Inc unless regulatory concerns at Agila Specialities in Bangalore are resolved.

Thus the smears though for now are confined to a few large manufacturing units of Indian Pharma, including some located overseas, may eventually play the spoil sport, trashing all hopes seen through the rainbow in the bins of shame.

Conclusion:

In the balance of probability, I believe, the clouds of uncertainty would continue to loom large over the global pharma, at least, till 2015.

However, in the midst of it, heralds a ‘never before opportunity’ for Indian pharma to cash on the early fruits of forthcoming patent expiries of today’s blockbuster drugs, not just for them, but for patients at large.

Already demonstrated capabilities of the homegrown players, trigger expectations of making it happen. The encouraging trend of grant of ANDAs in the US further reinforces this belief.

Despite all these, a lurking fear does creep in. This evitable fear finds its root in repeated fraudulent behavior of some Indian drug manufacturers, seriously compromising with cGMP standards of global drug regulators, including lying and falsification of data generated, thus playing a spoil sport by ‘snatching defeat from the jaws of victory’, as it were.

That said, the question to ponder now is: In the ‘Pharma Horizon’ what would ultimately prevail in the short to medium term, especially in the Indian context – Clouds, The Rainbow or Smears?

By: Tapan J. Ray

Are We Taking Safe and Effective Medicines?

Posted on November 13, 2013 by Tapan Ray

The above headline is in no way intended to mean that this discussion is on spurious or counterfeit drugs.

Today’s deliberation is on the licensed drugs, which are manufactured in India, for the patients of the country, by the manufacturers holding valid drug licenses from the Indian regulators.

Close on the heels of my article titled, “USFDA ‘Import Bans’: The Malady Calls For Strong Bitter Pills “, another equally serious incident related to drug safety, came to the fore.

Fabricated data from the Contract Manufacturer of large companies:

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

GuruFcure, which started operations in 2007 and calls itself “one of the leading pharmaceutical formulation manufacturers in India”, reportedly manufacture drugs for the leading pharma MNC and Indian companies and Indian companies such as:

Abbott
Alkem
Glenmark
Wockhardt
Unichem
Intas Pharma, among others.

Though, as per media report, Wockhardt and Glenmark said that these two companies are not currently associated with GuruFcure, the fact remains that they did market drugs produced by this contract manufacture in the past and the patients consumed those drugs against doctors’ precriptions.

Large players need to set examples:

The largest pharmaceutical company in India with highest share of the Indian Pharmaceutical Market – Abbott, has also been reported to get some of their drugs manufactured by this contract manufacturer.

Not a solitary example:

Just prior to this incident, in November 8, 2013, the DCGI reportedly 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.

Tardy regulatory system fuels apprehensions:

In India, many large, medium and small units get their products from the contract drug manufacturers. As compared to the USFDA inspection data, there are virtually no public data available on the details of inspections carried out at these plants by the drug regulators indicating the level of cGMP compliance.

Health being a state subject in India, State Drug Controllers should play a critical role in ensuring drug safety for patients through regular inspection of these manufacturing facilities on cGMP compliance.

Conclusion:

If cGMP violations can take place for drug exports, despite rigorous compliance checks by the foreign drug regulators, what could possibly happen when the same system is so tardy in India?

While the MNCs boast on their highest drug regulatory compliance standards, even for contract manufacturers, why do they keep relationships with those getting caught for fraudulent practices, is equally difficult to fathom.

One may possibly describe such incidents as just aberrations. However, that conclusion can only be drawn, when we have Drug Controllers’ cGMP inspection data for a large number of drug manufacturing units in India with details. Unfortunately, that is not the case, in any way.

In such an environment in India, the moot question that comes at the top of mind, “Are we taking safe and effective drugs, whenever required?”

By: Tapan J. Ray

Supreme Court Suspends New Drug Trials in India…Time to Shape Up?

Posted on October 14, 2013 by Tapan Ray

On September 30, 2013, with a damning stricture to the Drug Regulator, the Supreme Court, in response to a Public Interest Litigation (PIL) filed by the NGO Swasthya Adhikar Manch, stayed approvals for 162 applications for local Clinical Trials (CTs) of new drugs approved by the Drugs Controller General of India (DCGI) earlier.

The apex court of the country granted the DCGI two weeks time to furnish evidence to the court that adequate patients’ safety and other related mechanisms have been put in place for CTs of all New Chemical Entities (NCEs) and New Molecular Entities (NMEs) in the country.

According to reports, during July and August 2013, the DCGI received 1,122 CT applications, out of which, 331 related to approval of global CTs. The New Drug Advisory Committee (NDAC) approved 285 drugs in AIDS, oncology, cardiology, neurology, psychiatry, metabolism and endocrinology therapy areas. Finally, 162 drugs received the green signal from the DCGI. Now all these trials have come to a halt.

At the same time, the court also directed the Ministry of Health to come out with a plan within 10 weeks to strengthen the regulatory framework for CTs in India based on various suggestions received from the state governments, other stakeholders and experts groups.

A casual approach?

Just to recapitulate, prior to this, on January 3, 2013, against the PIL, the bench of Honorable Justices R.M Lodha and A.R Dave of the Supreme Court reportedly observed that uncontrolled Clinical Trials (CT) are creating ‘havoc’ to human lives causing even deaths to many subjects in India.

In an interim order, the bench directed the Government that CTs could be conducted only under the supervision of the Health Secretary of India. Holding the Government responsible, the bench further observed, “You (Government) have to protect health of citizens of the country. It is your obligation. Deaths must be arrested and illegal trials must be stayed.”

Thereafter, though the Health Secretary of India approved the above 162 CTs, presumably following the above Supreme Court directive, it is an irony that when asked by the Apex Court, the government could not immediately explain precisely what systems and mechanisms have been put in place for proper conduct of these 162 CTs. It sought 2 weeks’ time to justify the action taken by the drug regulator in this regards.

Compromise on patients’ safety continues unabated:

During another hearing early in October 2013 on a petition filed by the NGO ‘Swasthya Adhikar Manch regarding violations of norms during CTs, the Supreme Court reportedly sought details from the Union Government on the irregularities during the drug trial using Human Papilloma Virus (HPV) vaccines by the Seattle (USA) based organization PATH in Andhra Pradesh and Gujarat states of India.

This intervening application by the NGO was based on the 72nd Parliamentary Standing Committee (PSC) on Health and Family Welfare report dated August 30, 2013, where it was recommended that action should be taken against PATH, state governments of Andhra Pradesh, Gujarat, Indian Council of Medical Research (ICMR) and other government officials including Drug Controller General of India (DCGI) for alleged violations on the subject.

The report highlights, HPV vaccines were given to 14,091 girls in Khammam district of Andhra Pradesh and 10,686 girls in Vadodra, Gujarat. These girls were between age group of 10 and 14, of which seven girls died due to such illegal vaccine trials.

Eventually, these trials were stopped, but only after the matter received media attention.

As per reports, the vaccines were provided by two pharma MNCs – Merck and GlaxoSmithKline through PATH. It also stated as follows:

“Vaccines were given to children irrespective of age in the case of Merck’s Gardasil vaccine. While permission was given to use GSK’s Cervarix vaccine in children of 10 to 14 years, CTs had been conducted on subjects in the age group of 18 to 35 years. Thus the safety and well being of subjects were completely jeopardized.”

No options but to shape-up:

It is worth mentioning, the above PIL had alleged that large scale drug trials being conducted across the country, mainly by the pharma MNC, are using Indian patients as ‘guinea pigs’, as it were. The NGO also told the Supreme Court that several pharmaceutical companies continue to conduct CTs quite indiscriminately, in various states of India, endangering lives of poorly/un-informed trial subjects.

In an affidavit to the Court, the Government admitted that between 2005 and 2012, 2,644 people died during CTs of 475 NCEs/NMEs with serious adverse events related deaths taking 80 lives.

Thus, coming under immense pressure from the civil society and now the scrutiny of the Supreme Court for so many CT related deaths and consequential patients’ compensation issues, the Government does not seem to have any other options left now but to bring US$ 500 million CT segment of the country, which is expected to cross a turnover of US$ 1 Billion by 2016, under stringent regulations.

CT related deaths in India:

As per the Ministry of Health following are the details of deaths related to CTs registered in India from 2008 to August 2012:

Year	Total no of deaths	CT related deaths	Compensation paid to patients:
2012 (up to August)	272	12	NA
2011	438	16	16
2010	668	22	22
2009	737	NA	NA
2008	288	NA	NA

It is estimated that over the last four years, on an average, 10 persons have died every week in India related to CT.

DCGI hauled-up 9 MNCs on patients’ compensation:

It is worth noting, absolutely unacceptable level of compensation, by any standard, are being paid by the concerned companies, including large MNCs, for the lives lost during CTs.

According to another report quoting the Drug Controller General of India (DCGI), 25 people died in clinical trials conducted by 9 pharma MNCs, in 2010. Unfortunately, families of just five of these victims received” compensation for trial related deaths, which ranged from an abysmal Rs 1.5 lakh (US$ 2,500) to Rs 3 lakh (US$ 5,000) to the families of the diseased.

This report also highlighted that arising out of this critical negligence, for the first time ever, the then DCGI was compelled to summon the concerned nine pharma MNCs on June 6, 2011 to question them on this issue and give a clear directive to pay up the mandatory compensation for deaths related to CTs by June 20, 2011, or else all CTs of these nine MNCs, which were ongoing at that time or yet to start, will not be allowed.

The 9 pharma MNCs summoned by the DCGI to pay up the mandatory compensation for deaths related to CTs were reported as Wyeth, Quintiles, Eli Lilly, Amgen, Bayer, Bristol-Myers Squibb (BMS), Sanofi, PPD and Pfizer.

The report also indicated that after this ultimatum, all the 9 MNCs had paid compensation to the concerned families of the patients, who died related to the CTs.

Prior indictment by Indian Parliamentary Committee:

The report made the following scathing remarks on CDSCO under its point 2.2:

Action just not enough yet:

Acting on the damning stricture by the Supreme Court, the Ministry of Health by a gazette notification of January 30, 2013 made the norms of compensation to patients participating in CTs more stringent. ‘Patient Compensation’ was proposed to include injury or death, even if those are not related to the drugs being tested in the CTs.

Understandably, reacting to this notification, some pharma companies, industry lobby groups and also Clinical Research Organizations (CROs) expressed concerns in areas like:

Lack of distinction between study-related injuries and non-study related injuries.

Use of placebos in placebo-controlled trials.

Lack of any arbitration mechanism in case of disagreement on causality/quantum of compensation and also lack of clarity on who constitutes the Expert Committee and its composition.

In addition, the DCGI requested the stakeholders’ to share their inputs to the independent experts advisory committee chaired by Prof. Ranjit Roy Chaudhury along with six other distinguished members namely, Dr V. P. Kamboj, Dr BT Kaul, Dr Vasantha Muthuswamy, Dr Mira Shiva  and Dr Uma Tekur, to help formulating policy, guidelines and SOPs for approval of NCEs/NMEs and procedures for CTs, including the conduct of ethics committees, the accreditation of trials sites, inspections of trials sites, the ongoing monitoring of trials and banning of drugs. The Government on February 6, 2013 constituted this Committee.

This decision of the regulator, though under pressure, was praiseworthy. Unfortunately nothing substantially changed on the ground for CTs in India even thereafter, as no substantive action has yet been taken on the above expert committee recommendations.

The report of the experts committee:

Prof. Ranjit Roy Chaudhury experts committee in its 99-page report has reportedly recommended some radical changes in the CT space of India. Among others, the report includes the following:

Setting up of a Central Accreditation Council (CAC) to oversee the accreditation of institutes, clinical investigators and ethics committees for CTs in the country.

Only those trials, which will be conducted at centers meeting these requirements, be considered for approval by the DCGI.

For speedy clearance of applications, a broad expertise based Technical Review Committee (TRC) will replace 12 New Drug Advisory Committees (NDACs), which are currently functioning for NCE/NME approvals.

The TRC would be assisted, as required, by appropriate subject experts selected from the ‘Roster of Experts’.

For any Adverse Effects (AEs) or Serious Adverse Effects (SAEs) during a CT, the sponsor investigator will be responsible for providing medical treatment and care to the patient at its/their cost till the resolution of the AEs/SAEs.

This is to be provided irrespective of whether the patient is in the control group, placebo group, standard drug treatment group or the test drug administered group.

A Special Expert Committee should be set up independent of the Drug Technical Advisory Board (DTAB) to review all drug formulations in the market and identify drugs, which are potentially hazardous and/or of doubtful therapeutic efficacy.

A mechanism should be put in place to remove these drugs from the market by the CDSCO at the earliest.

Though some of the above provisions were vigorously objected by the industry during stakeholders’ consultations, the committee in its final report has upheld those recommendations.

The main worry – costs of CTs will go up:

CTs, as we know, are of critical importance for obtaining marketing approval of any new drug and at the same time forms a major cost component in the new drug development process, across the world.

Any savings in this area, both in terms of time and money, will add significantly to the profit margin of the product. In that context, the above suggestions, if implemented to create a safety net for the patients participating in CTs, will make these trials more expensive for the concerned companies with increased liability.

Hence, we hear a hue and cry, especially from the pharma MNCs. This is mainly because, India was, thus far, a low cost CT destination for them with virtually no liability for the drug trial patients. This is because, the poor and ill-informed subjects are left in the lurch by many companies exploiting the gaping holes existing in the fragile CT system of the country. After the intervention of the Supreme Court in this regard, some foreign players have reportedly suspended their CTs in India for reasons best known to them.

Exploitation of CT regulations:

The system of CT in India has created a huge ruckus, as it has long been tainted with widespread malpractices, abuses and misuses by many players, both global and local. The issue is not just of GCP or other CT related standards but more of an ethical mind-set and well-reported rampant exploitation of uninformed patients, especially in case of trial-related injuries or even death.

The Bulletin of the World Health Organization (WHO) in an article titled, “Clinical trials in India: ethical concerns” reported as follows:

Industry reactions:

Very interestingly, there have been a divergent sets of reactions from the industry on this issue.

An influential section in the CT space of the country has reacted, with gross indiscretion, to the most recent SC order banning CTs for NCEs/NMEs till a robust mechanism in India is put in place.

Commenting on the verdict, an industry leader has reportedly said:

“A black day for Indian science and a sad reflection on our judiciary”.

Such comments probably vindicate much talked about crony capitalistic mindset of this class. They do not hesitate a bit to display their scant respect even to the highest judiciary of the country, leave alone their glaring indifference to the important public health interest related issue. All such actions possibly emanate from the intense greed to protect and further the vested interests, not withstanding the gross injustice being meted out to the drug trial subjects as a consequence.

On the other hand, supporting the Supreme Court’s view, The Indian Society for Clinical Research (ISCR) reportedly has said:

“As a professional organization representing clinical research professionals across the stakeholder spectrum, ISCR is fully supportive of the need for a more robust and regulated environment for the conduct of clinical trials in India which ensures the practice of the highest standards of ethics and quality and where patient rights and safety are protected”.  

ISCR further said, “As in every profession and industry, there will always be players who operate at both ends of the spectrum. While we do not condone any irregularities, we must acknowledge, there are several hundreds of clinical trials taking place in the country in compliance with international and local guidelines. There have been over 40 US FDA clinical trial audits done in India with no critical findings reported. There have also been several European regulatory audits of Indian clinical trial sites, again with no critical findings.”

That said, Indian Parliamentary Standing Committee, had commented on a ‘nexus between the industry and the drug regulator’ for continuation of such sorry state of affairs, since long.

‘Industry-pharma nexus’ in the USA too?

Recently, similar tricky relationship between the regulator and the pharma companies was unearthed again with the later paying hefty fees to attend meetings of a panel that advises the US FDA.

The article highlighted, an investigative report in the ‘Washington Post’ found that pharma companies paid as much as US$ 25,000 to attend sessions convened by a scientific panel on painkillers, and has led to claims that the industry was being given an opportunity to influence federal policy in this area.

Expected Government action:

The Supreme Court is expected to hear the matter on October 24, 2013.

Meanwhile, the Ministry of Health reportedly held meetings with concerned officials to chalk out the strategy before the Court, when this case would come up for hearing after two weeks.

The report says, the Government is planning to place before the court a comprehensive plan with details of the existing mechanism and ongoing efforts like, bringing the the new Drugs and Cosmetic (Amendment) Bill 2013 and incorporation of Prof. Ranjit Roy Chaudhury expert committee recommendations, to plug the loopholes in the new drug trial mechanism of the country.

Conclusion:

While the importance of CTs to ensure better and more effective treatment for millions of patients in India is immense, it should not be allowed at the cost of patients’ safety, under any garb. If the regulator overlooks this critical factor and some pharmaceutical players keep exploiting the system, judiciary has no option but to effectively intervene in response to PILs, as happened in this particular case too.

Thus, I reckon, appropriate safety of human subjects participating in CTs and a fairplay in compensation, whenever justified, should be non-negotiable for the indian drug regulator. Despite reactions with indiscretion from a section of the industry, the Supreme Court is absolutely right to direct the DCGI to stop CTs for all NCEs/NMEs until the apex judiciary is satisfied that a robust system is in place for such trials in India. This will ensure, the scientific objectives of the CTs are properly achieved without any compromise on patients’ safety.

Breaking the nexus decisively between a section of the powerful pharmaceutical lobby group and the drug regulator, as highlighted even in the above Parliamentary Committee report, the Ministry of Health should, without any further delay, put in place a robust and transparent CT mechanism in India, come what may.

This well thought-out new system, besides ensuring patients’ safety and fairplay for all, will have the potential to help reaping a rich economic harvest through creation of a meaningful and vibrant CT industry in India, simultaneously benefitting millions of patients, as we move on.

That said, the moot question still remains: Will the drug regulator be able to satisfy the Supreme Court, as the two weeks expire, that appropriate mechanisms are in place to resume smooth conduct of CTs for the new drugs in India?

By: Tapan J. Ray

FDC Saga: Defiant Manufacturers, Sloppy Regulators and Humongous Inaction

Posted on July 15, 2013 by Tapan Ray

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

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

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

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

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

The WHO Model:

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

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

Thus, FDCs:

Need to demonstrate clinical efficacy and safety beyond the individual drugs when given alone.

Need to ‘demonstrate bioequivalence of the single combined dose unit with the components administered in the same doses separately but concomitantly’.

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

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

A major disadvantage:

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

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

Market attractiveness for FDCs in India:

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

% Share
Drug	2008	2009	2010	2011
Plain	55	55	55	54
Combinations	45	45	45	46
Domestic Market: USD 13 Billion; MAT Apr 2013

Source:IMS

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

A messy regulatory situation:

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

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

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

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

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

Patients’ safety – the foremost concern:

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

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

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

Untangling the messy knot:

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

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

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

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

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

The saga continues:

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

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

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

Current scenario:

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

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

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

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

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

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

Conclusion:

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

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

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

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

By: Tapan J. Ray

Is Fraud or Negligence in Drug Quality Standards Not a Fraud on Patients?

Posted on June 3, 2013 by Tapan Ray

As we know, a substance is called a drug when it has scientifically proven and well documented efficacy and safety profile to reduce both mortality and morbidity of patients. Any fraud or negligence in the drug quality standards, for whatever may be the reasons or wherever these take place, is a fraud on patients and should warrant zero tolerance.

A perception survey on drug quality:

According to a poll released in 2010 by the ‘Pew Charitable Trusts’s Prescription Project’ of the United States:

More than three out of four voters are confident that prescription drugs made in the USA are free from contamination

While less than one in 10 feel confident about medications made in India or China.

54 percent of Americans distrusted Indian drugs and 70 percent distrusted Chinese drugs.

“When you buy a shirt, it will say right on the label where it was made, but when you get a pharmaceutical, you don’t know.”

Despite all these, the survey points out that in 2007, 68 percent of the ingredients of all drugs sold worldwide came from India or China, as compared to 49 percent in 2004.

Experts comment that USFDA does not have either people or resources required to monitor manufacturing in the geographically widespread locations, as these are today.

Recent spate of charges against Indian pharmaceutical companies – a vindication?

Recent spate of charges against some top ranked Indian companies, will further dent the image of India not just in the United States or Europe, but also as a pharmacy of high quality yet low cost generic drugs for the developing countries of the world.

In May 2013, well known India-based pharma major Ranbaxy reported to have pleaded guilty to criminal charges of manufacturing and distributing some adulterated medicines, produced at its Paonta Sahib and Dewas, facilities and agreed to US$ 500-millon settlement. Can this be considered as a vindication of the above perception on the quality of ‘made in India’ drugs?

The view of WHO:

Interestingly the World Health Organisation (WHO) even after the above USFDA indictment has commented that at present it has no evidence that Ranbaxy manufactured medicines that are currently prequalified by WHO are of unacceptable quality.

Indian drug regulator initiates action:

It is good to know that the Drugs Controller General of India (DCGI) and the Ministry of Health will reportedly decide the way forward in this matter on completion of a fact-finding study initiated by the Central Drugs Standards Control Organization (CDSCO) on the subject.

Other incidents in India:

Following are examples of other reported serious regulatory violations involving the domestic pharmaceutical companies:

No.	Year	Company	Issue	Status
	2009	Lupin	USFDA warning for Mandideep plant	Resolved in 2010
	2010	Claris Life Sciences	USFDA ban products for manufacturing norms violations	Ban revoked in 2012
	2011	Zydus Cadila	USFDA warns Co. over Moraiya, Gujarat Facility	Ban revoked in 2012
	2011	Dr Reddy’s	USFDA bans sale of drugs from Mexico facility	Ban revoked in 2012
	2013	Jubilant Life Sciences	Gets USFDA warning for Canada facility	Company taking corrective steps
	2013	Wockhardt	Banned from exporting products from its Aurangabad factory to the US due to quality concerns	In discussion

Source: The Economic Times (May 22, 2013), Financial Express (May 25, 2013)

Though some other countries also have faced bans from exporting products, it cannot be taken, I reckon, as any consolation by anyone.

A Mumbai Hospital demonstrated the mood of zero tolerance:

The above expression of good intent should not just remain as a ‘lip service’. Indian drug regulator is expected to take a leaf out of all these allegations and initiate appropriate audit as required. Otherwise, exhibiting zero tolerance, like Jaslok Hospital of Mumbai, many other institutions will ask their doctors not to prescribe products of these companies to protect patients’ interest. More hospitals reportedly are mulling similar action against Ranbaxy.

IMA expresses apprehension:

Even ‘The Indian Medical Association (IMA)’ has reportedly asked the DCGI to investigate quality of medicines manufactured by Ranbaxy.

It happens in the ‘heartland’ too just as in the ‘hinterland’:

Contrary to the above poll released in 2010 by the ‘Pew Charitable Trusts’s Prescription Project’, pointing accusing fingers, in this respect, exclusively to India and China, may not be just fair. Incidents of such regulatory violations are not just restricted to Indian pharmaceutical companies either. Unfortunately, these happen with the global majors too.

None of these should be condoned in any way by anyone and attract as much global publicity, public wrath and zero tolerance, as all these would possibly deserve.

Following are some examples:

No	Company	Issues with USFDA	Consent decree signed (year)	Issue status	Penalty amount
	Schering-Plough	GMP violations affecting four manufacturing sites and 125 products	Yes (2002)	Closed (2007)	$500 Mn.
	GlaxoSmithKline	Manufacturing deficiencies found at Puerto Rico facility	Yes (2005)	Pending	$650 Mn. Bond
	Wyeth	GMP violations at plant in Pennsylvania and New York which were producing FluShield	Yes (2000)	Pending	$297 Mn. Plus 18.5% of sales of FluShield
	Abbott Labs	Non-conformance with quality system regulations for in vitro diagnostic products at an Illinois facility	Yes (1999)	Pending	$212 Mn.
	Boehringer Ingelheim	To bring its Ohio facility into compliance with regulatory requirements	Yes (2013)	Pending	Not specified

Source: Financial Express (May 25, 2013)

Further, in December 1998 the US FDA reportedly had stopped shipments of Abbott Laboratories’ clot-busting drug Abbokinase till the company had resolved undisclosed manufacturing problems at its plant. Abbott subsequently resolved this to the satisfaction of the drug regulator.

Even end May 2011, the USFDA reportedly raised concerns about contamination of drugs of the American pharmaceutical major – Hospira, at its Indian manufacturing facility.This issue was highlighted as the latest in a string of manufacturing and quality problems dogging the company since 2010.

American lawmakers demand thorough review of USFDA oversight procedures:

Pressure has reportedly started mounting in the United States for a thorough review into the effectiveness of oversight procedures for all bulk drugs and formulations manufactured in foreign facilities.

Simultaneously, there is also a specific demand for an in-depth review of all actions of the US regulator for so many years, which allowed Ranbaxy’s ‘massive fraud to remain unchecked’.

Beyond regulatory oversight, need robust internal system driven model as a fire-wall:

To address such issues only drug regulators interventions may not be just enough, maintaining total integrity of ‘Supply Chain’ of an organization proactively in a well structured, fool-proof and a system-driven way, will continue to play the most critical role. This will help creating ‘fire-wall’, which will be difficult to breach.

The scope of Supply Chain:

The scope of ‘Supply Chain’, which is comprised of the entire network of entities from vendors who supply raw and packaging materials, manufacturers who convert these materials into medicines, together with warehouses, distributors, retailers and healthcare centers who will reach these medicines ultimately to patients exactly the way these will deserve.

Thus, just not in the manufacturing process, any breach of security at any place of the supply chain can cause serious problems to patients.

Accordingly, pharmaceutical companies need to adequately invest along with appropriate staff training programs to ensure that the Supply Chain Integrity is maintained, always.

Supply Chain Security (SCS) is critical:

SCS, therefore, deserves to be of prime importance for the pharmaceutical companies across the globe. Recent high profile SCS related cases, as mentioned above, have exposed the vulnerability in addressing this global menace effectively.

All pharmaceutical players should realize that not just ‘show-off’, an effective integrated approach is of paramount importance to eliminate this crime syndicate, which is taking lives of millions of patients the world over.

Mixing-up counterfeit drugs with this menace may not be prudent:

Shouting for counterfeit drugs involving mainly intellectual property related issues, may be important, but will in no way help resolving self-created menaces arising out of breach of supply chain integrity endangering million of lives, in another way.

Though an expensive process, can’t be compromised:

It is worth repeating, securing pharmaceutical supply chain on a continuous basis is of critical importance for all the pharmaceutical players across the globe. However, the process will no doubt be expensive for any company.

Like other industries, in the pharmaceutical sector, as well, cost effective procurement is critical, which entices many pharmaceutical players, especially, in the generic industry not to go for such expensive process just to maintain the SCS.

A serious SCS related tragedy:

I would like to reinforce my argument on the importance of SCS with the following example of the ‘Heparin tragedy’ where the supply chain integrity was seriously violated with ‘ingeneuity’.

In the beginning of 2008, there were media reports on serious adverse drug events, some even fatal, with Heparin, a highly sulfated glycosaminoglycan of Baxter International. Heparin is widely used as an injectable anticoagulant. Baxter voluntarily recalled almost all their Heparin products in the U.S. Around 80 people died from contaminated Heparin products in the U.S. The US FDA reported that such contaminated Heparin was detected from at least 12 other countries.

A joint investigation conducted by Baxter and the US FDA ascertained that the Heparin used in batches associated with the serious adverse drug events was contaminated with Over Sulfated Chondroitin Sulfate (OSCS). It was reported that Heparin Scientific Protein Laboratories, Changzhou, China supplied Heparin to Baxter.

The cost of OSCS is just a fraction of the ingredient used in Heparin. Being driven by the criminal profiteering motive the manufacturers in Changzhou, China had reportedly used OSCS for highly sulfated glycosaminoglycan, as the former could not be detected by the pharmacopeia test in use, until 2008. This is because OSCS mimics Heparin in the pharmacopeia test. Post this criminal event, at present, all over the world more specific pharmacopeia test methods have been adopted for Heparin.

Stakeholders need to be extremely vigilant:

Considering all these, pharmaceutical players and the drug regulators from across the world should put proper ‘fool proof’ systems in place to eliminate the growing menace of criminal adulteration of APIs, drug intermediates, excipients entering in the supply chain together with preventing any breach in their logistics support systems.

Apprehension against generic drugs as a class:

Taking advantage of the situation, one can possibly say, as some vested interests have already started propagating that generic equivalents of the branded drugs are really not quite the same in quality.

However, the point that cannot be ignored is the comment of a senior USFDA, who was quoted in the same article saying, “I have heard it enough times from enough people to believe that there are a few products that aren’t meeting quality standards.“

Generic drug manufacturers should make serious note of such comments and act accordingly to allay prevailing lurking fear on the use of generic medicines, in general, though small in number.

Conclusion:

Following the recent series of incidents including that of Ranbaxy, the image of India as a low cost generic drugs manufacturer of high quality could get adversely impacted. Although there are enough instances that such things happen in the developed world, as well, including the United States.

Moreover, in the backdrop of high decibel quality concerns raised by USFDA, the level of apprehension regarding effectiveness of generic drugs made in India may increase significantly, unless some tangible, well thought out and highly publicized remedial measures are taken forthwith.

The decision of Jaslok Hospital, Mumbai advising their doctors for not using Ranbaxy products to patients on the same ground, will further strengthen the public apprehension.

Whatever may be the reason, as long as any company is in the business of manufacturing medicines, there should be demonstrable zero tolerance on any compromise, fraud or negligence in the drug quality standards. Any fraud and negligence in drug quality, I reckon, is virtually a fraud against humanity.

That said, changing mindset towards a strong corporate governance by walking the talk, all pharmaceutical companies must guarantee safe and high quality medicines to the society, come what may.

This, I believe, could be achieved by putting in place a robust SCS system and ensuring that this is not compromised in any way… anywhere…ever… for patients’ sake…both globally and locally.

By: Tapan J. Ray

PILMAN

A Tapan Ray Website

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