Data Integrity Issue Haunts Again With Covid Vaccine?

On March 22, 2021, by a media release, AstraZeneca announced that its ‘US Phase III trial of AZD1222 demonstrated statistically significant vaccine efficacy of 79% in preventing symptomatic COVID-19 and 100% efficacy at preventing severe disease and hospitalization.’

Quite unexpectedly, on March 23, 2021, the above claim on AstraZeneca’s Covid-19 vaccine, triggered a rare post-midnight statement by the National Institute of Allergy and Infectious Diseases (NIAID) of the United states. It rekindled a lurking fear of many, yet again, on the issue of questionable data integrity within the drug industry, in general.

This News Release articulated: “Late Monday, the Data and Safety Monitoring Board (DSMB) notified NIAID, BARDA, and AstraZeneca that it was concerned by information released by AstraZeneca on initial data from its COVID-19 vaccine clinical trial.”

The concern was on the possible inclusion of outdated information from that trial, ‘which may have provided an incomplete view of the efficacy data.’ It urged AstraZeneca to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as soon as possible.

Later on that very day, AstraZeneca released another statement saying: “The numbers published yesterday were based on a pre-specified interim analysis with a data cutoff of 17 February. We have reviewed the preliminary assessment of the primary analysis and the results were consistent with the interim analysis. We are now completing the validation of the statistical analysis.”

The company further emphasized, “We will immediately engage with the independent data safety monitoring board (DSMB) to share our primary analysis with the most up to date efficacy data.” And also added that AstraZeneca intends to issue the results of the primary analysis within 48 hours.

However, the impact of the NIAID’s announcement on the unfurling of AstraZeneca’s Covid-19 vaccine in the U.S, is yet to be ascertained. It’s also still unknown what this news could mean for the vaccine’s alleged efficacy. Be that as it may, it all happened at a time when millions of people, in many countries of the world, including India, have already taken, at least, the first dose of this vaccine.

In this article, I shall deliberate on broader aspects of this critical issue and its relevance in the present case. However, before doing so, let’s try to figure out, why data integrity still remains a major concern of many experts in this area.

Why data integrity is still a major issue:

There are many studies that raised serious concern in this area, over a period of time. For example – ‘Dozens of recent clinical trials may contain wrong or falsified data’ – was claimed by the research paper that was discussed in ‘The Guardian’ on June 05, 2017.

This study reviewed data from 5,087 clinical trials, published during the past 15 years, in two prestigious medical journals – JAMA and the New England Journal of Medicine, and six anesthesia journals. In total, 90 published trials had underlying statistical patterns that were unlikely to appear by chance (or be termed as ‘unforced error’) in a credible dataset, the paper concluded.

Even my own article of September 30, 2019 deliberated on various facets of ‘data integrity’ involving novel therapy, across the world. There, I quoted one of the top medical experts related to the above paper, saying: “It’s very scary that we may be treating patients based on false evidence.” He further added: “It may be the case that certain treatments may need to be withdrawn from use.”

The ghost of a recent example still haunts:

Not so long ago, much reported fallout from Novartis’ alleged data manipulation fiasco with its billion-dollar gene therapy Zolgensma, shook all concerned. So much so, that the Company CEO had to pledge during an investor conference that: ‘the company will be more proactive in reporting data integrity issues to the FDA.’

He also added, Novartis has responded to the FDA’s Form 483 and is making documents available as requested, while reiterating that the data manipulation uncovered at the San Diego site “does not impact the safety, efficacy or quality of Zolgensma.”

The key point to ponder, therefore, especially in AstraZeneca’s Covid-19 vaccine case – is the same ghost haunting us, yet again?

Is it happening again? 

One may, possibly, find some cue of the answer to this question while looking at what followed after ‘validation of the statistical analysis’ by AstraZeneca, as it was promised by the company. Interestingly, the following day, after apparently a thorough analysis, the data released by AstraZeneca, re-iterated effectiveness of its COVID-19 vaccine, which apparently, is broadly similar to the results released earlier.

The Company highlighted therein, ‘US Phase III primary analysis confirms safety and efficacy,’ with the following points:

  • 76% (earlier shown as 79%) vaccine efficacy against symptomatic COVID-19
  • 100% efficacy against severe or critical disease and hospitalization
  • 85% efficacy against symptomatic COVID-19 in participants aged 65 years and over.

It may continue to remain unclear to many – whether or not there was some suspected issue of data integrity – till the answers, at least, to the following questions are made public:

  • Why did the data and safety monitoring board for the trial write a harsh letter to AstraZeneca on its claim, and copied the leadership of NIAID and the Biomedical Advanced Research and Development Authority?
  • As the proof of the pudding is in its eating, why there will even be a slight downward revision in the rate of efficacy of AstraZeneca Covid-19 vaccine?

Conclusion:

wrote in this blog, way back on August 03, 2015 that data manipulation issues are dangerously leapfrogging into clinical trial domain, even in India. As a result, many domestic drug players had to pay a heavy price – in terms of drug import bans by USFDA and other regulators. Several questions on the quality of efficacy and safety of Indian generic drugs were also raised in many developed countries. A number of best-selling books were also written on this issue.

Some may recall, just ahead Covid pandemic struck, trial data of a highly complex and very expensive gene therapy was also questioned by the US-FDA, for the same reason. However, on March 31, 2020, on completion of its review of the information, records of the inspection, the evidence collected, and the firm’s corrective actions, US-FDA stated: “Objectionable conditions were found and documented but the objectionable conditions observed during the inspection do not meet the threshold for regulatory action.”

Almost in a similar line, after the NIAID decided to make its data related concern public on AstraZeneca Covid-19 vaccine, its head, Anthony Fauci, reportedly, characterized this issue as “an unforced error.” This is indeed a cryptic comment. The root cause of this entire saga with details is still awaited.

Interestingly, the term “unforced error’ is widely used in Tennis, and means, ‘a mistake in play that is attributed to one’s own failure rather than to the skill or effort of one’s opponent.’ From this perspective, after AstraZeneca’s statement of clarification on its Covid-19 vaccine data, the concern on its phase three trial data would possibly be put to rest. At least for now, let’s not see the ghost of data integrity for this vaccine, where there doesn’t seem to be any.

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.

 

Combating Covid Pandemic: When ‘Something Is Better Than Nothing’

As the new Coronavirus overwhelms the world, since its global outbreak, up until November 29, 2020, over 1,458,305 people have died from this pandemic. Understandably, the Governments in all countries are frantically searching for some robust remedial measures to prevent these unfortunate deaths, besides protecting livelihoods of a vast majority of people.

For this purpose, experts considered effective preventive measures, such as vaccines could help taming this menace, alongside existing personal prevention measures. Accordingly, scientists around the world, have are hard to accelerate development and manufacturing of safe and effective Covod-19 vaccines, within the prescribed guidelines. Equally important is the fact these vaccines must be safe with predictable effectiveness- for all age groups.

The good news is, vaccines are now a distinct possibility in the near future, with the positive interim Phase III clinical trial reports pouring in. It gets reflected in the remark of the Director General of the World Health Organization (WHO), on November 23, 2020, at the media briefing on Covid-19. He said: There is now real hope that vaccines – in combination with other tried and tested public health measures – will help to end the pandemic.

Interestingly, amid these reports, a lurking fear of many experts also surfaces – on the impact of possible side effects, that Covid vaccine may cause, besides their medium to long term efficacy in human subjects. But, with the mounting number of deaths, near collapse of the global economy, including India, there isn’t any more time to watch and wait.

Apparently, all governments now want some scientifically relevant vaccines, instead of nothing. This article will deliberate on the one hand – an unprecedented achievement, alongside some critical concerns – voiced even by the Indian Prime Minister. Let me begin with the apprehensions, as expressed by some domain experts on some rough edges, as it were, in the process of its development.

Queries on vaccine dosing, efficacy, safety and testing:

On November 23, 2020, AstraZeneca and Oxford reported interim results of their vaccine with the average efficacy of 70% prevention. This sounded good to many, as it falls within the expectations of above a 50% standard that the FDA had set for Covid vaccines. However, the puzzling part in this result was – bigger (standard) doses of the vaccines were less efficacious. The vaccine was only 62% effective in a group that got two full doses spaced about a month apart. But among about 2,700 people who got a half-dose followed by a full, the number rose to 90%, the report highlighted. This incident prompted several questions about the most effective dose of AstraZeneca and Oxford vaccine, including its safety record and the approach to testing. Consequently, apprehensions surfaced whether the Drug regulators will clear it, based on the currently available data.

It now appears, AstraZeneca ‘s Covid-19 vaccine is ‘headed for an additional global trial as the drug maker tries to clear up the uncertainty and confusion surrounding favorable results in its current study.’ Incidentally, in India - AstraZeneca and Oxford vaccine will be manufactured by Pune-based Serum Institute of India (SII) under a collaborative arrangement. Let me now dwell on a broader as aspect in this space.

Could current Covid vaccines become useless in the future?

There isn’t an iota of doubt that developing Covid vaccine in ten months, which otherwise takes around ten years – is an unprecedented achievement. However, there are several other important areas in this space, where pundits have expressed uneasiness through various articles.

One such paper is titled, ‘Don’t rush to deploy COVID-19 vaccines and drugs without sufficient safety guarantees,’ published in the Nature on March 16, 2020. According to the author, a critical point in this regard is to consider ‘the potential for emerging and re-emerging Coronaviruses to cause future outbreaks.’

This is because, ‘the virus behind COVID-19 might mutate in ways that would make previously effective vaccines and antivirals useless.’ Testing vaccines and medicines without taking the time to fully understand safety risks, could bring unwarranted setbacks during the current pandemic, and into the future. ‘Despite the genuine need for urgency, the old saying holds – ‘measure twice, cut once’, the author commented.

The article concluded by suggesting, ‘any regulatory agency considering ways to accelerate treatments into testing should also weigh up how likely these drugs are to work beyond this particular Coronavirus.’ Moreover, according to the WHO, it’s too early to know if COVID-19 vaccines will provide long-term protection.

Possible side-effects of COVID-19 vaccines:

As people’s hopes swell, expecting Covid vaccines to ultimately end the deadly global pandemic, experts caution about their reported – annoying and unpleasant side effects. The November 12, 2020 paper – ‘Time to Discuss Potentially Unpleasant Side Effects of COVID Shots? Scientists Say Yes,’ published by the Kaiser Health News (KHN), also articulated similar apprehension.

It said, most Covid vaccines, including much publicized ones from Pfizer and Moderna, will require two doses to work, injections that must be given weeks apart, as company protocols show. Scientists anticipate the shots will cause enervating flu-like side effects — including sore arms, muscle aches and fever — that could last days and temporarily sideline some people from work or school.

Even with the Pfizer vaccine, which is touted to be over 90% effective, 1 in 10 recipients would still be vulnerable. There could also be a possibility that a vaccine may not suit everyone due to side-effects, especially the most vulnerable elderly population. That means, at least in the short term, as population-level immunity grows, people can’t stop social distancing and throw away their masks, the report emphasized. Even Prime Minister Modi has informed the nation about possible side effects of Covid vaccines.

PM Modi also warns of possible vaccine side-effects:

Being adequately briefed on the above perspectives related to Covid vaccines, the PM has also warned the nation about the possible side-effects. This is probably to ensure that the unpleasant experience of side-effects, after being administered the first dose, do not catch the population off-guard. Mostly because, no one should miss the second dose of vaccine for the same.

He said, during a recent video conference with the state chief ministers, ‘like many other popular medicines, any COVID-19 vaccine could lead to side-effects in some people.’ Emphasizing that both speed and safety are equally important in launching a vaccine, he assured that ‘the government would only go by science in finalizing a vaccine for the country.’

Is something better than nothing?

In the current situation, it appears so, as there is no other alternatives, except maintenance of social distancing, frequent hand sanitizing and wearing masks while outdoors. The Prime Minister also articulated sans any ambiguity: ‘Whatever vaccine makes it through the world’s certified processes, we will have to accept them and move ahead.’

In the meantime, he urged the states to keep distribution infrastructure, such as cold storages ready, the report said. Interestingly, according to Serum Institute CEO Adar Poonawalla, India could approve the emergency use of the Oxford-AstraZeneca COVID-19 vaccine by December 2020.

That said, for mass vaccination of the population across India, another factor that is extremely important to decide which vaccine to go for – is the required storage temperature of various Covid Vaccines under development.

Required cold chain storage temperature of various Covid vaccines:

Required cold chain storage temperatures of various Covid vaccines are as follows:

Company

Type

Doses

Effectiveness*

Storage

Oxford-AstraZeneca Viral Vector (genetically modified virus) Two 62-90%** Regular fridge temp.
Moderna RNA (part of virus genetic code) Two 95% -20C up to six months
Pfizer-BioNTech RNA Two 95% -70C
Gamaleya (Sputnik V) Viral Vector Two 92% Regular fridge temp.

Source: Respective Companies, WHO – BBC News. *Preliminary Phase III results. **Two full doses: 62%, A half dose followed by a full dose: 90%, Average: 70%

From the above table, it appears, from the perspective of continuous cold chain storage facility of vaccines – till these are administered to each person, Oxford-AstraZeneca and Russian Sputnik vaccines will be more practical, despite issues with them. Viewing from this perspective, as well, it appears ‘something is better than nothing’ term can be applied in this area, as well.

Conclusion:

The Covid pandemic continues to worry India, immensely. As on November 29, 2020 morning, India recorded a staggering figure of 9,393,039 of Coronavirus cases with 136,733 deaths. The threat of subsequent waves for further spread of Covid infection now looms large in many states.

Unprecedented speed in developing vaccines to effectively combat Covid Pandemic has created some initial issues. Some of these Covid vaccine challenges include, vaccine side effects, its future usefulness, or challenges towards maintaining required stringent cold chain storage requirements, especially in a country like India. Powder version of Covid vaccines, in the future, would possibly resolve this issue for all countries, across the world.

Currently, in tandem with keeping the cold-chain distribution infrastructure ready, at least, for vaccines that require regular fridge temperature, there is a need to make people aware of Covid vaccine side-effects. Otherwise, after getting first shot of a Coronavirus vaccine, many people may get so scared of its side effects that they may not come back for the second dose. If this happens, the very purpose of mass vaccination will get defeated.

However, from the Indian perspective, Covid vaccines that the country, hopefully, will shortly get, may not be the best, out of the available ones, in terms of safety and efficacy. But, for combating Covid Pandemic across India at this juncture, I reckon, the good old dictum still holds good – ‘something is better than nothing.’

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.

 

Pharma’s Dual Challenge – To Save Lives And Livelihood

“Jaan hai to jahan hai” (If you have life, you have the world). Prime Minister Modi - with a skillful tweak, used the couplet of the 18th century poet - Mir Taqi Mir, while announcing the criticality of 21-day national lockdown from March 24, 2020 due to Covid-19 global pandemic. Many Indians lapped up this concept, considering it as a short haul sacrifice to save lives. Possibly, because the Prime Minister had said at that time, ‘Mahabharata battle won in 18 days, war against Coronavirus will take 21 days.’

As the Covid-19 went on a rampage despite the national lockdown, the Prime Minister, on April 11, 2020, changed it to ‘jaan bhi and jahan bhi’ (life also, the world also). This slogan seems to be more relevant in the emerging scenario.

After over a couple of months stringent national lockdown, the necessity and urgency of restarting active life started assuming a priority status for all concerned. But, the restarting process won’t be a piece of cake either – for anybody. As it would not only involve saving lives, but also – ensuring proper means of livelihood, making the industries gradually return to normal, and thereby revival of the country’s economy.

Dr. Ashish Jha, Director of the Harvard Global Health Institute, has summarized the nature of this challenge concisely, as quoted by the article – ‘Five key questions about India’s rising Covid-19 infections.’ This was published by BBC News on June 15, 2020. Acknowledging that India is in a very difficult situation, Dr. Jha said, “We are still early in the pandemic and we have a good year or so to go before we turn the corner. The question is what is the plan to get India through the next 12 to 16 months?”

Like many other industries, this is an arduous task to accomplish even for the drug industry, and for that matter – by any country. From the pharma industry perspective, I reckon, the commencement of the ‘restarting’ process, would pose a tough and dual challenge for many players – for different reasons. The current expectations require them going much beyond developing and delivering effective drugs and vaccine to win the Covid-19 war, and include the following, as well:

  • The population needs to develop either a vaccine-induced or a herd immunity, for a long-term protection against Covid-19. Pharma companies can facilitate the former one.
  • The entire population should have access to scientific evidence-based Coronavirus drugs and vaccine – at a price that most people can afford, to achieve the goal of vaccine-induced immunity.

In this article, I shall explore the ground issues in this area while confronting this dual challenge by the pharmaceutical industry, in general.

Developing herd immunity not an option for India: 

As it is known to many, even without an effective vaccine, it is possible for the population to develop a herd immunity. However, in this situation, a very large population will need to get infected, with its consequent impact on healthcare infrastructure and people’s lives. But, it will possibly be foolhardy to even think about this option, particularly for any country, such as India.

Dr. Ashish Jha in the above article on the BBC News, has also captured this challenge, aptly. He articulated, ‘India cannot wait for 60% of its people to get infected to achieve herd immunity and stop the virus. ‘That would mean millions of people dead. And that is not an acceptable outcome.’ Moreover, India’s Covid-19 infection curve has not started flattening – there is no consistent and steady decline, just yet. Thus, a vaccine-induced immunity seems to be the only prudent choice for the country.

Other reasons why an early intervention is necessary:

A national lockdown in India was certainly necessary to save lives. However, its prolonged duration of over 3 months, has caused a widespread confusion, anxiety, and fear among the public regarding the disease. Consequently, it has created several unintended social consequences, such as disease related stigma, discrimination, besides triggering several serious health hazards. The World Health Organization (W.H.O) also recognizes this problem.

Instances of stigma and discrimination against medical personnel – doctors and health care workers are common and have already been reported. Similarly, those working in aviation, especially on flights that were sent to bring the Indians back from COVID-19 affected foreign land, also met the same fate. Interestingly, such instances are not uncommon even within various housing societies for high income groups and communities. The stigma associated with COVID-19 is real and here to stay, at least for some time.

Serious health hazards like, panic, depression and anxiety have also gone viral as the nation was observing lockdown. Experts, reportedly, have opined that the fear of contracting viruses, compulsorily going to institutional quarantine centers and rising number of deaths, among others, are big triggers for all. Many believe, various communications – formal and informal – to keep people indoors, have given rise to such unintended consequences involving average Indians.

These developments further reinforce the critical need for an early therapeutic intervention in the disease treatment and prevention areas, such as an effective vaccine, where pharma can deliver what it does the best, and sooner.

Green shoots of overcoming the first challenge are visible:

Although, the world has not reached there, just yet, some green shoots of overcoming the first challenge with scientific-evidence-based drugs and vaccine, are now in sight. Treating Covid-19 effectively with the old warhorse – dexamethasone at a very affordable price, is almost a reality today. W.H.O has also called to ramp up dexamethasone production for Covid-19 patients.

Meanwhile, a few other drugs, such as remdesivir and favipiravir have also received marketing authorization of DCGI for treatment of Coronavirus in India. Similarly, Oxford University and AstraZeneca’s experimental Covid-19 vaccine have, reportedly, entered the final stages of clinical trials. Scientists are now in the final assessment of how well the vaccine works in protecting people from becoming infected by the virus.

A shift in the most vulnerable population poses another tough challenge:

As the need to restart the economy of the country becomes paramount, alongside the urgency of saving lives and livelihood, a shift in the most vulnerable population for Covid-19 infection is clearly visible.

As many would know, Coronavirus pandemic started with the more affluent class of the society who mainly travel abroad for work or studies. However, it is now spreading fast in the lesser privileged social strata, including poor migrant labors and other marginalized population. The spread now spans across from affluent communities, right through densely populated slum areas. The trend keeps going north, as each day passes, as of now.

In such a situation, to contain the disease effectively, Covid-19 drugs and vaccine must be accessible and affordable to all. Making this requirement another tough challenge for the pharma industry – as and when the therapies receive marketing approval of drug regulators.

Recently available drugs are expensive, even in India:

From the recent trend it appears, unlike hydroxychloroquine or dexamethasone, most of these emergency use Covid-19 drugs, such as remdesivir or favipiravir may not be accessible and affordable to a vast majority of the population, as discussed below.

Like remdesivir, favipiravir is also, reportedly, the subject of at least 18 clinical trials involving more than 3,000 patients across India, USA, Canada, Italy, China, France, UK and other countries. Encouragingly, for the Oxford University developed Coronavirus vaccine, Serum Institute is expected to price it at Rs.1,000 per vaccine. Thus, for a family of 4 persons, it would cost around Rs. 4000. Be that as it may, lets have a look at the comparative clinical efficacy of cheaper and relatively expensive repurposed older drugs, against their respective costs.

Comparative efficacy and cost of a cheaper and expensive repurposed drugs: 

While comparing the relative clinical efficacy of cheaper and relatively expensive repurposed drugs – against their respective costs, some interesting facts surface, as follows:

According to the reported results, published by FiercePharma in an article on June 24, 2020, dexamethasone treatment led to a 35 percent reduction in death rate among patients on invasive mechanical ventilation and 20 percent for those receiving oxygen without invasive ventilation. The dose used was, 6 mg of dexamethasone in a single dose per day – either orally or via intravenous injection – for ten days at a stretch. Whereas, the cost of Dexamethasone (0.5mg) in India, for a strip of 30 Tablets, is around Rs.6.00.

Similarly, the same article reported, remdesivir has been found to reduce the death rate among severe patients to 7.7 percent from 13 percent for placebo, a difference that was not statistically significant.Whereas, remdesivir in India, will cost around Rs 5,000-6,000/dose. And its recommended dose for adults and pediatric patients weighing 40 kg and higher, is a single loading dose of 200 mg on Day 1 followed by once daily maintenance doses of 100 mg from day 2 up to 5 to 10 days.

Similarly, favipiravir will be available in India as a 200 mg tablet at a Maximum Retail Price (MRP) of Rs 3,500 for a strip of 34 tablets. Whereas, its recommended dose is 1,800 mg twice daily on day one, followed by 800 mg twice daily up to day 14, according to its manufacturer.

An interesting fallout of Dexamethasone study:

An interesting fallout of the dexamethasone study on arriving at a fair price for remdesivir for treating Covid-19 patients, is worth noting. The Institute for Clinical and Economic Review (ICER) had earlier highlighted the “cost-effectiveness” benchmark price of remdesivir ranges from $4,580 to $5,080. However, ‘a new scenario analysis assuming the likely incorporation of dexamethasone as standard of care, produces a lower benchmark price range for remdesivir of $2,520 to $2,800.’

Conclusion:

As on June 28, 2020 morning, crossing half a million mark, the recorded Coronavirus cases in the country have reached 529,577 with 16,103 deaths. And the climb continues. In the context of the same disease, a publication of the London School of Economics and Political Science (LSE) had recently articulated: ‘In less than 3 months, COVID-19 has become a global pandemic of proportions we have not experienced this century. This has led to some of the largest economies in the world racing to develop a vaccine to combat the disease. However, in this time of urgency, patent laws may conflict with the equal provision of these future medicines worldwide.’

In sync with this sentiment, apprehensions of profiteering on drugs, tests, or vaccines used for the COVID-19 pandemic are mounting in almost all countries. Governments are now being encouraged to suspend and override patents and take other measures, such as price controls, to ensure availability, reduce prices and save more lives.

According to reports, Canada, Chile, Ecuador and Germany have already taken steps to make it easier to override patents by issuing ‘compulsory licenses’ for COVID-19 medicines, vaccines and other medical tools. Similarly, the government of Israel issued a compulsory license for patents on a medicine they were investigating for use for COVID-19.

From the industry, a strong demand for fiscal stimulus, such as the removal of the Health Cess and Customs Duty, to support patient access to critical medical products, is also gaining momentum, alongside the early release of Government payment to providers.

Thus, while exploring the dual challenge lying ahead for many pharma companies – to save both lives and livelihood – delivering effective drugs and vaccine may probably be an easier task than improving access to those – for all, in a meaningful way.

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

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.

 

FDC Saga: Defiant Manufacturers, Sloppy Regulators and Humongous Inaction

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

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

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

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

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

The WHO Model:

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

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

Thus, FDCs:

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

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

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

A major disadvantage:

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

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

Market attractiveness for FDCs in India: 

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

% Share

Drug

2008

2009

2010

2011

Plain

55

55

55

54

Combinations

45

45

45

46

Domestic Market: USD 13 Billion; MAT Apr 2013

Source:IMS

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

A messy regulatory situation:

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

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

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

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

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

Patients’ safety – the foremost concern:

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

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

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

Untangling the messy knot:

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

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

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

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

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

The saga continues:

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

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

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

Current scenario:

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

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

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

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

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

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

Conclusion:

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

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

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

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

By: Tapan J. Ray

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

 

 

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

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

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

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

An interesting finding:

Quite interestingly, the paper also highlights:

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

Different policies in different countries:

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

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

Need transparency in pharmacovigilance:

Pharmacovigilance has been defined as:

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

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

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

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

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

Recent Pioglitazone withdrawal in India:

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

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

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

Pioglitazone: the risk profile:

In India:

A leading medical journal (JAPI) cautions:

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

The JAPI article continues to state:

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

In the USA:

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

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

Based on this finding US FDA directed that physicians should:

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

The moot point:

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

In Canada:

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

Pioglitazone and its combinations banned in France and Germany:

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

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

Simultaneously, German health authorities also acted on similar lines.

An intriguing comment by the Indian drug regulator:

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

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

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

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

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

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

These claims are based on:

  • Improperly marketed pharmaceutical drugs. This category includes:

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

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

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

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

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

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

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

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

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

- Defectively manufactured pharmaceutical drugs.

- Pharmaceutical drugs with dangerous side effects.

- And even improperly marketed pharmaceutical drugs.

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

Drug product liability suit for Pioglitazone in the United States:

Just to cite an example, one report indicates:

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

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

Indian doctors and manufacturers protest together against Pioglitazone ban:

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

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

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

Conclusion:

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

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

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

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

By: Tapan J. Ray

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

Balancing IPR with Public Health Interest: Brickbats, Power Play and Bouquets

It is now a widely accepted dictum that Intellectual Property Rights (IPR), especially pharma patents, help fostering innovation and is critical in meeting unmet needs of the patients.

However, the moot question still remains, what type pharmaceutical invention, should deserve market exclusivity or monopoly with overall freedom in pricing, keeping larger public health interest in mind.

In line with this thinking, for quite sometime a raging global debate has brought to the fore that there are quite a large number of patents on drug variants that offer not very significant value to the patients over the mother molecules, yet as expensive, if not more than the original ones. In common parlance these types of inventions are considered as ‘trivial incremental innovations’ and described as attempts to ‘evergreening’ the patents.

The terminology ‘evergreeningusually ‘refers to a strategy employed by many pharmaceutical companies to extend their market monopoly by slightly changing the existing molecules and obtaining new patents to continue to enjoy market exclusivity and pricing freedom, which otherwise would not have been possible.

Path breaking or jaw-drooping ‘W-O-W’ types of innovations are not so many. Thus most of the patented drugs launched globally over the last several decades are indeed some sort of ‘me-too drugs’ and generally considered as ‘low hanging fruits’ of R&D, not being able to offer significantly greater value to patients than already exiting ones. Many of these drugs have also achieved blockbuster status for the concerned companies, backed by high voltage marketing over a reasonably long period of time. It is understandable, therefore, that from pure business perspective why serious global efforts are being made to push the same contentious system in India too.

Example of some of these molecules (not necessarily in the written order), are as follows:

  • Cemetidine – Ranitidine – Famotidine – Nizatidine – Roxatidine (to treat Acid-peptic disease)
  • Simvastatin – Pravastatin – Lovastatin – Pitavastatin – Atorvastatin – Fluvastatin – Rosuvastatin (to treat blood lipid disorder)
  • Captopril – Enalepril – Lisinopril – Fosinopril – Benzapril – Perindopril – Ramipiril – Quinalapril – Zofenopril (Anti-hypertensives)

However, pharmaceutical companies do argue that such ‘incremental innovations’ are the bedrock for growth of the pharmaceutical industry and are essential to continue to fund pharmaceutical research and development.

An interesting paper:

A paper titled, “Pharmaceutical Innovation, Incremental Patenting and Compulsory Licensing” by Carlos M. Correa argued as follows:

  • Despite decline in the discovery of New Chemical Entities (NCEs) for pharmaceutical use, there has been significant proliferation of patents on products and processes that cover minor, incremental innovations.
  • A study conducted in five developing countries – Argentina, Brazil, Colombia, India and South Africa has:
  1. Evidenced a significant proliferation of ‘ever-greening’ pharmaceutical patents that    can block generic competition and thereby limit patients’ access to medicines.
  2. Found that both the nature of pharmaceutical learning and innovation and the interest of public health are best served in a framework where rigorous standards of inventive step are used to grant patents.
  3. Suggested that with the application of well-defined patentability standards, governments could avoid spending the political capital necessary to grant and sustain compulsory licenses/government use.
  4. Commented, if patent applications were correctly scrutinized, there would be no need to have recourse to CL measures.

A remarkable similarity with the Indian Patents Act:

The findings of the above study have a striking similarity with the Indian Patents Act. As per this Act, to be eligible for grant of patents in India, the pharmaceutical products must pass the ‘two-step’ acid test of:

  • Following the inventive stepDefined under Section 2(ja) of the Patents Act as follows:

“Inventive step” means a feature of an invention that involves technical advance as compared to the existing knowledge or having economic significance or both and that makes the invention not obvious to a person skilled in the art.

  • Passing scrutiny of Section 3(d) of the law: It categorically states, inventions that are a mere “discovery” of a “new form” of a “known substance” and do not result in increased efficacy of that substance are not patentable.

Supreme Court of India clarifies it:

The Honorable Supreme Court of India in page 90 of its its landmark Glivec judgement has clearly pronounced that all ‘incremental innovations’ may not be trivial or frivolous in nature. However, only those ‘incremental innovations’, which will satisfy the requirements of both the above Sections of the Act, wherever applicable, will be eligible for grant of patents in India. 

An opposite view:

Another paper presents a different view altogether. It states that incremental improvements on existing drugs have great relevance to overall increases in the quality of healthcare.

With the progress of the pharmaceutical industry, such drugs have helped the physicians to treat diverse group of patients. They also represent advances in safety, efficacy along with newer dosing options significantly increasing patient compliance.

The paper claims that even from an economic standpoint, expanding drug classes represent the possibility of lower drug prices as competition between manufacturers is increased’.  It states that any policy aimed at curbing incremental innovation will ultimately lead to a reduction in the overall quality of existing drug classes and may ultimately curb the creation of novel drugs.

Pricing:

Experts, on the other hand, argue, if patents are granted to such ‘incremental innovations’ at all, their prices need to be determined by quantifying ‘Incremental Value’ that patients will derive out of these inventions as compared to the generic versions of respective original molecules.

Use of such drugs may lead to wasteful expenditure:

A large majority of stakeholders also highlight, though many of such drugs will have cheaper or generic alternatives, physicians are persuaded by the pharma players to prescribe higher cost patented medicines with the help of expensive avoidable marketing tools, leading to wasteful expenditure for all. The issue of affordability for these drugs is also being raised, especially, in the Indian context.

  • The ‘2012 Express Scripts Canada Drug Trend Report’ unfolded that the use of higher-cost medications without offering additional patient benefits resulted in waste of $3.9 billion annually in Canada.
  • Another recent Geneva-based study concluded as follows:

Evergreening strategies for follow-on drugs contribute to overall healthcare costs. It also implies that policies that encourage prescription of generic drugs could induce saving on healthcare expenditure. Healthcare providers and policymakers should be aware of the impact of evergreening strategies on overall healthcare costs.”

  • Some other studies reportedly revealed, “Medicines sold in France are 30 times more expensive than what it costs pharmaceutical companies pay to manufacture them.” Industry observers opine, if that is happening in France what about India? Quoting experts the same report comments, “If pharmaceutical companies are forced to follow moral and human values, it could save the tax payer at least 10 billion euros, an amount which could fill up the deficit of the national health care system.
  • Yet another article questioned, “What if a physician is paid speaking or consulting fees by a drug maker and then prescribes its medicine, even if there is no added benefit compared with cheaper alternatives?

More debate:

According to a paper titled, ‘Patented Drug Extension Strategies on Healthcare Spending: A Cost-Evaluation Analysis’ published by PLOS Medicine, European public health experts estimate that pharmaceutical companies have developed “evergreening” strategies to compete with generic medication after patent termination. These are usually slightly modified versions of the existing drugs.

Following are some brands, which were taken as examples for evergreening:

S.No.

Evergreen

Medical Condition

Original Brand

1.

Levocetirizine (Vozet) Allergies Cetirizine (Zyrtec)

2.

Escitalopram (Lexapro) Depression Citalopram (Celexa)

3.

Esomeprazole (Nexium) Acid reflux Omeprazole (Prilosec)

4.

Desloratadine (Clarinex) Allergies Loratadine (Claritan)

5.

Zolpidem Extended Release (Ambien CR) Insomnia Zolpidem (Ambien)

6.

Pregabalin (Lyrica) Seizures Gabapentin (Neurotonin)

Source: Medical Daily, June 4, 2013

In this study, the researchers calculated that evergreening – where pharmaceutical companies slightly modify a drug molecule to extend its patent, had cost an extra 30 million euros to the healthcare system in Geneva between 2000 and 2008. The authors argue that ‘evergreening’ strategies, “more euphemistically called as ‘life cycle management’ are sometimes questionable benefit to society.”

As the paper highlights, in this scenario the companies concerned rely on brand equity of the original molecule with newer and more innovative marketing campaigns to generate more prescriptions and incurring in that process expenses nearly twice as much on marketing than on research and development.

Brickbats:

In this context, recently a lawmaker rom America reportedly almost lambasted India as follows:

I’m very concerned with the deterioration in the environment for protection of US intellectual property rights and innovation in India. The government of India continues to take actions that make it very difficult for US innovative pharmaceutical companies to secure and enforce their patents in India.“ 

On this, the Indian experts comment, if the situation is so bad in India, why doesn’t  America get this dispute sorted out by lodging a formal complaint against India in the WTO, just as what India contemplated to do, when consignments of generic drugs of Indian manufacturers were confiscated at the European ports, alleging those are counterfeit medicines.

Yet another recent news item highlighted a “concerted effort, which involves letters from US corporations and business groups to the president, testimony by Obama administration officials before Congress, and lawmakers’ own critiques, came ahead of US secretary of state John Kerry’s trip to India later this month (has already taken place by now) for the annual strategic dialogue, which will precede Prime Minister Manmohan Singh’s visit to Washington DC in September.”

The report stated, the above letter complained that over the last year, “courts and policymakers in India have engaged in a persistent pattern of discrimination designed to benefit India’s business community at the expense of American jobs … Administrative and court rulings have repeatedly ignored internationally recognized rights — imposing arbitrary marketing restrictions on medical devices and denying, breaking, or revoking patents for nearly a dozen lifesaving medications.” 


At a recent Congressional hearing of the United States, a Congressman reportedly expressed his anger and called for taking actions against India by saying,

“Like all of you, my blood boils, when I hear that India is revoking and denying patents and granting compulsory licenses for cancer treatments or adopting local content requirements.”

Indian experts respond to these allegations by saying, patent disputes, patent challenges, revocation of patents, compulsory licensing etc. are all following a well-articulated judicial process of the country, where Indian government has hardly any role to play or intervene. American government and lawmakers are also expected to respect the rule of law in all such cases instead of trying to denigrate the Indian system.

The Power Play:

This short video clipping captures the Power Play in America on this matter.

The Government of India responds:

Ministry of Commerce and Industries of India reportedly countered the allegations of the United States over patents to the US Trade Representive arguing that the Indian IPR regime is fully TRIPS-compliant and Indian Patents Act “encourages genuine innovation by discouraging trivial, frivolous innovation, which leads to evergreening”.

Countries adopting the Indian model:

The above report also highlighted as follows:

  • Argentina has issued guidelines to reject ‘frivolous’ patents.
  • Peru, Columbia, other South American countries have placed curbs.
  • Philippines has similar provisions.
  • Australia is contemplating making the law tougher.

Revised report of Dr. R. A. Mashelkar Committee:

Even the revised (March 2009) ‘Report of the Technical Expert Group (TEG) on Patent Law Issues’, the TEG, chaired by the well-known scientist Dr. R.A. Mashelkar, in point number 5.30 of their report recommended as follows:

“Every effort must be made to prevent the practice of ‘evergreening’ often used by some of the pharma companies to unreasonably extend the life of the patent by making claims based sometimes on ‘trivial’ changes to the original patented product.  The Indian patent office has the full authority under law and practice to determine what is patentable and what would constitute only a trivial change with no significant additional improvements or inventive steps involving benefits.  Such authority should be used to prevent ‘evergreening’, rather than to introduce an arguable concept of ‘statutory exclusion’ of incremental innovations from the scope of patentability.”

Bouquets:

As stated above, many experts across the world believe, the criticism that Section 3 (d) is not TRIPS Agreement compliant is unfounded, as no such complaint has been lodged with the World Trade Organization (WTO) in this matter, thus far. The safeguards provided in the patent law of India will help the country to avoid similar issues now being faced by many countries. Importantly, neither does the section 3(d) stop all ‘incremental innovations’ in India.

Quoting a special adviser for health and development at South Centre, a think tank based in Geneva, Switzerland, a recent report indicated, “Many developing countries will follow India’s example to protect the rights of their populations to have access to essential medicines”.

Yet another report quoting an expert articulates, “India’s top court’s decision affirms India’s position and policy on defining how it defines inventions from a patenting point of view for its development needs. It challenges the patenting standards and practices of the developed countries which are the ones really in much need of reform.

The Honorable Supreme Court in its Glivec judgment has also confirmed that such safeguard provisions in the statute are expected to withstand the test of time to protect public health interest in India and do not introduce any form of unreasonable restrictions on patentability of drug inventions.

Conclusion:

Not withstanding the report of the US-India Business Council (USIBC) titled ‘The Value of Incremental Innovation: Benefits for Indian Patients and Indian Business’, arguing for abolition of section 3(d) of the Indian Patents Act to pave the way for patentability for all types of incremental innovations in pharmaceuticals, realistically it appears extremely challenging.

As the paper quoted first in this article suggests, denial of patents for inventions of dubious value extending effective patent period through additional patents, is a significant safeguard to protect public health interest. This statutory provision will also pave the way for quick introduction of generics on expiry of the original patent.

Taking all these developments into active consideration, keen industry watchers do believe, for every effort towards balancing IPR with Public Health Interest, both brickbats and bouquets will continue to be showered in varying proportion together with the mounting pressure of power play, especially from the developed world and still for some more time.

However, in India this critical balancing factor seems to have taken its root not just deep and strong, but in all probabilities - both politically and realistically, the law is now virtually irreversible, come what may.

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.

 

 

Does the Landmark Glivec Judgment Discourage Innovation in India?

No, I do not think so. The 112 pages well articulated judgment of the Supreme Court of India delivered on April 1, 2013, does not even remotely discourage innovation in India, including much talked about ‘incremental innovation’. This landmark judgment reconfirms the rules of the game for pharmaceutical innovation, as captured in the Indian Patents Act 2005.

When one reads the judgment, point 191 in page number 95 very clearly states as follows:

“191. We have held that the subject product, the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act but that is not to say that Section 3(d) bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It will be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought in the patent regime by deletion of section 5 from the Parent Act. That is not said in this judgment.”

Thus all ‘incremental innovations’, which some people always paint with a general broad brush of ‘evergreening’, should no longer be a taboo in India. The judgment just says that Glivec is not patentable as per Section 3(d) of Indian Patents Act based on the data provided and arguments of Novartis.

To me, the judgment does also not signal that no more Glivec like case will come to the Supreme Court in future. It vindicated inclusion of Section 3(d) in the amended Indian Patents Act 2005.

It is interesting to note that honorable Supreme Court itself used the terminology of ‘incremental innovation’ for such cases.

That said, I find it extremely complex to imagine what would have happened, if the judgment had gone the opposite way.

A critical point to ponder:

The judgment will also mean that all those products, having valid product patents abroad, if fail to meet the requirements of Section 3(d), will not be patentable in India, enabling introduction of their generic equivalents much sooner in the country and at the same time causing a nightmarish situation for their innovators.

However, this again, in no way, is an outcome of this judgement or a new development, as stated above. It is just vindication of the intent behind inclusion of Section 3(d) in the amended Indian Patents Act, when it was enacted by the Parliament of India in 2005.

Patentability of ‘Incremental Innovations’ in India:

Patentability criteria for any ‘incremental innovations’ has been defined in the Section 3(d) of the Indian statute as follows:

“The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.

Explanation: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.

Supreme Court interpretation of the term “Efficacy” in Section 3(d): 

The Honorable Supreme Court in page 90 of its above order under point 180 stated that in case of medicines, efficacy can only be “therapeutic efficacy”, which must be judged strictly and narrowly. The interpretation goes as follows:

180. “What is “efficacy”? Efficacy means ‘the ability to produce a desired or intended result’. Hence, the test of efficacy in the context of section 3(d) would be different, depending upon the result the product under consideration is desired or intended to produce. In other words, the test of efficacy would depend upon the function, utility or the purpose of the product under consideration. Therefore, in the case of a medicine that claims to cure a disease, the test of efficacy can only be “therapeutic efficacy”.

The Honorable Court under the same point 180 further elaborated:

“With regard to the genesis of section 3(d), and more particularly the circumstances in which section 3(d) was amended to make it even more constrictive than before, we have no doubt that the “therapeutic efficacy” of a medicine must be judged strictly and narrowly…Further, the explanation requires the derivative to ‘differ significantly in properties with regard to efficacy’. What is evident, therefore, is that not all advantageous or beneficial properties are relevant, but only such properties that directly relate to efficacy, which in case of medicine, as seen above, is its therapeutic efficacy.” 

Based on this interpretation of Section 3(d), the Honorable Supreme Court of India ordered that Glivec does not fulfill the required criteria of the statute.

The rationale behind Section 3(d):

A report on ‘Patentability of the incremental innovation’ indicates that the policy makers keeping the following points in mind formulated the Indian Patents Act 2005:

  • The strict standards of patentability as envisaged by TRIPS pose a challenge to India’s pharmaceutical industry, whose success depended on the ability to produce generic drugs at much cheaper prices than their patented equivalents.
  • A stringent patent system would severely curtail access to expensive life saving drugs to a large number of populations in India.
  • Grant of a product patents should be restricted only to “genuine innovations” and those “incremental innovations” on existing medicines, which will be able to demonstrate significantly increased efficacy over the original drug.

IPA challenges: 86 pharmaceutical patents granted by IPO fall under Section 3(d):

study by the ‘Indian Pharmaceutical Alliance (IPA)’ indicates that 86 pharmaceutical patents granted by the IPO post 2005 are not breakthrough inventions but only minor variations of existing pharmaceutical products and demanded re-examination of them.

Possible implications to IPA challenge:

If the argument, as expressed above in the IPA study, is true by any stretch of imagination, in that case, there exists a theoretical possibility of at least 86 already granted product patents to get revoked. This will invite again another nightmarish situation for innovators.

Examples of revocation of patents in India:

On November 26, 2012, the Intellectual Property Appellate Board (IPAB) reportedly denied patent protection for AstraZeneca’s anti-cancer drug Gefitinib on the ground that the molecule lacked invention.

The report also states that AstraZeneca suffered its first setback on Gefitinib in June 2006, when the Indian generic company Natco Pharma opposed the initial patent application filed by the global major in a pre-grant opposition. Later on, another local company, GM Pharma, joined Natco in November 2006.

After accepting the pre-grant opposition by the two Indian companies, the Indian Patent office (IPO) in March 2007 rejected the patent application for Gefitinib citing ‘known prior use’ of the drug. AstraZeneca contested the order through a review petition, which was dismissed in May 2011.

Prior to this, on November 2, 2012 the IPAB revoked the patent of Pegasys (Peginterferon alfa-2a) – the hepatitis C drug of the global pharmaceutical giant Roche.

Though Roche was granted a patent for Pegasys by the Indian Patent Office (IPO) in 2006, this was subsequently contested by a post-grant challenge by the large Indian pharma player – Wockhardt and the NGO Sankalp Rehabilitation Trust (SRT) on the ground that Pegasys is neither a “novel” product nor did it demonstrate ‘inventiveness’, as required by Section 3(d) of Patents Act of India 2005.

It is worth noting, although the IPO had rejected the patent challenges by Wockhardt and SRT in 2009, IPAB reversed IPO’s decision revoking the patent of Pegasys.

Similarly the patent for liver and kidney cancer drug of Pfizer – Sutent (Sunitinib) granted by IPO in 2007, was revoked by the IPAB in October, 2012 after a post grant challenge by Cipla and Natco Pharma on the ground that the claimed ‘invention’ does not involve inventive steps.

Patent challenges under section 3(d) may come up even more frequently in future:

Some observers in this field have expressed, although ‘public health interest’ is the primary objective for having Section 3(d) in the Indian Patents Act 2005, many generic companies, both local and global, have already started exploiting this provision as a part of their ‘business strategy’ to improve business performance in India, especially when an  injunction is usually not being granted by the honorable Courts for such cases on public health interest ground.

Thus, as stated above, there is likely to be many more cases like, Glivec coming before the Supreme Court in the years ahead.

Another related development of the last week:

It has been reported that American pharma major MSD has last week filed a suit in the Delhi High Court against Indian pharma major – Glenmark for alleged patent violation of its leading anti-diabetic drugs Januvia and Janumet. In this case also no interim injunction has reportedly been granted to MSD by the Honorable Delhi High Court.

Glenmark has stated through a media report, “It is a responsible company and has launched the products after due diligence and research.” The company has also announced that their version of the molecule named Zita and Zita Met will be available to patients at a 20 percent discount to MSD’s price.

Hence, once again, the Indian court to decide, the balance of justice would now point to which direction.

Government has no role to play – patent challenge is a legal process across the world:

The proponents of ‘no change required in the Section 3(d)’ argue, ‘Patent Challenge’ is a legal process all over the world, the Government has hardly got any role to play in settling such disputes. The law should be allowed to take its own course for all disputes related to the Patents Act of the country, including Section 3(d).

They also opine that India must be allowed to follow the law of justice without casting aspersions on the knowledge and biases of the Indian judiciary for vested interests.

That said, there is certainly an urgent need to add speed to this legal process by setting up ‘Fast-track Courts’ for resolving all Intellectual Property (IP) related disputes in a time bound manner.

Arguments against Section 3(d):

Opposition to the Section 3(d) counter-argues by saying, this is a critical period for India to help fostering an appropriate ecosystem for innovation in the country. This group emphasizes, “Providing the right incentives for incremental pharmaceutical innovation can move India forward on this path and encourage the development of drug products that meet the needs of Indian patients. Reforming Section 3(d) to encourage and protect incremental pharmaceutical innovation would create such incentives and help India become a true powerhouse of innovation.”

Another group says that the main reason in favor of Section 3(d) being the provision will prevent grant of frivolous patents, the ultimate fallout of which will result in limited access to these drugs due to high price, is rather irrelevant today. This, they point out, is mainly because the Government is now actively mulling a structured mechanism of price negotiation for all patented drugs to improve their access to patients in India.

Importance of ‘Incremental Innovation’ in India:

Incremental innovations are indeed very important for the country and have been benefiting the patients immensely over decades, across the world.

A report titled, “The Value Of Incremental Pharmaceutical Innovation” highlighted as follows:

  • As per the National Knowledge Commission, while 37.3% of Indian companies introduced breakthrough innovations in recent years, no fewer than 76.4% introduced incremental innovations.
  • 60 percent of the drugs on the World health Organization’s essential Drug list reflect incremental improvements over older drugs.

The report indicates some of the benefits of ‘Incremental Pharmaceutical Innovation’ for India as follows:

  1. Improved quality of drug products, including products that are better suited to India’s climate.
  2. Development of treatments for diseases that are prevalent in India for which new drug discovery is currently limited or otherwise inadequate.
  3. Increasing likelihood that for every therapeutic class, there is a treatment to which an Indian patient will respond.
  4. Development of the R&D capacity and expertise
 of Indian pharmaceutical companies.
  5. Reduction of healthcare and other social costs in India through improved drug quality and selection.
  6. Increased access to medicine as a result of price competition.

The study concluded by saying that Section 3(d) potentially precludes the patenting of hundreds of incremental pharmaceutical innovations that Indian companies are attempting to patent and commercialize outside India.

There are umpteen numbers of examples that can ably demonstrate, ‘incremental innovation’ of the pharmaceutical innovators help significantly improving the efficacy and safety of existing drugs. All such innovations should in no way be considered “frivolous” as they have very substantial and positive impact in improving conditions of the ailing patients.

Be that as it may, the Supreme Court judgment has categorically mentioned that all ‘Incremental innovations’ should conform to the requirement of the Section 3(d) of the statute.

West should learn from India’s high patent standards”

An article appeared just yesterday written by a well-regarded Indian economist recommended, “West should learn from India’s high patent standards”. It observed that    over-liberal patent system of the West is now broken and it should learn from India’s much tougher patent system.

Patent monopolies needs to be given only for genuine innovations, as defined in the Indian Patents Act 2005, where the public benefits clearly exceed the monopoly cost.

The author concluded by saying, “This means setting a high bar for innovation. High standards are desirable for patents, as for everything else.”

View of the Glivec inventor: 

In another interview titled, “If you erode patents, where will innovations come from?” Dr Brian Druker, whose work resulted in the development of Glivec, re-emphasizing the need for R&D by the pharmaceutical industry, commented,  “I’m going to stay away from the legal judgment … but as a physician, I do recognize that the advances will come from new products, not modifications.

Are discordant voices out of step with time?

The interpretation of the Section 3(d) of the statute by the Honorable Supreme Court of India is the last word for all, despite a few voices of discord from within and mostly outside India. These voices, many would reckon, could well be out of step with time, especially in relatively fast growing, modern, independent, thinking and assertive young  India.

Conclusion:

In my view, nothing materially has changed on the ground before and after the Supreme Court judgment on the Glivec case so far as the Indian Patents Act is concerned and also in its interpretation.

While encouraging all types of innovations, including incremental ones and protecting them with an effective IPR regime are very important for any country. No nation can afford to just wish away various socioeconomic expectations, demands and requirements not just of the poor, but also of the growing middle class intelligentsia, as gradually getting unfolded in many parts of the globe.

Available indicators do point out that the civil society would continue to expect in return, just, fair, responsible and reasonably affordable prices for the innovative medicines, based on the overall socioeconomic status of the local population.

This critical balancing factor is essential not only for the progress of the pharmaceutical industry, but also to alleviate sufferings of the ailing population of the country, effectively.

For arguments sake, in an ideal scenario, if the Central and State Governments in India decide to buy such drugs to supply to all patients free of cost, just like any ‘welfare state’, will even the Government be able to afford these prices and fund such schemes in India?

It is, therefore, now widely expected that innovator pharmaceutical companies, which play a pivotal role in keeping population of any nation healthy and disease free to the extent possible, should also proactively find out ways to help resolving this critical issue in India, working closely with the Government of 1.2 billion Indians, including other concerned stakeholders.

In that context, the landmark Supreme Court judgment on the Glivec case has vindicated the need of striking a right balance between encouraging and protecting innovation, including incremental ones and the public health interest of India.

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.