The Curious Conundrum of New Drugs Approval Process

Posted on January 18, 2016 by Tapan Ray

Fathoming the details of just a short span of time, not going beyond the last 10 years, I find from the published data that many new drugs, such as, Alatrofloxacin, Aprotinin, Drotrecogin alfa, Lumiracoxib, Propoxyphene, Rofecoxib, Rosiglitazone, Sibutramine, Tegaserod, Tetrazepam, were withdrawn from a number of important global markets. Quite a few of those were withdrawn also from the world market.

The key reason for almost all these withdrawals was serious safety concerns for the patients while using these medicines. Interestingly, some of these new molecules were withdrawn even after attaining the blockbuster status, such as Rofecoxib.

Tens of thousands of patients have died only because of this reason, according to reports.

It is widely believed by the experts in this area, if full public disclosure of the entire data of drug clinical trials was made, most of these new drugs would not have seen the light of the day and without putting many patients’ health safety in jeopardy.

All this is a part of a curious conundrum in the new drug approval process, across the world, for various reasons. In this article, I would try to dwell on this issue.

Voices against this ‘unethical practice’ getting louder:

On December 22, 2015, ‘CBC News’ published an interesting article, titled “Researcher issues ‘call to action’ to force release of hidden drug safety data: Bringing drug industry data into the light of public scrutiny.”

The article echoed the same belief of other global experts and, in fact, went a step forward. It categorically reiterated, if full disclosure of the entire data of drug clinical trials is made public, medical practice might have been quite different.

To drive home this point, the article cited the example of the arthritis drug rofecoxib (Vioxx), which has been linked to tens of thousands of deaths related to heart attacks.

It highlighted, although this risk was very much known to the regulatory authority of the United States, the relevant data was not released to the public for an impartial scrutiny.

Quoting different sources, the paper observed, almost half of the drug trials remain secret and the studies that are published, overwhelmingly report results that make the drug in question look good.

Independent experts’ views differed from the innovator companies:

In some cases, when researchers were able to see what is hiding in the filing cabinets of the drug innovator companies, a different picture altogether emerged on the overall profile of those drugs.

One group looked at 12 antidepressants, comparing the published studies with the internal US FDA assessments. They found that 94 per cent of the published studies were positive, as compared to 51 per cent, when they included all of the studies assessed by the drug regulator.

Based on a detailed study, the authors concluded, without considering all the data, drug effectiveness can often be exaggerated, leading doctors and patients to assume that the medications work better than what they actually do. The ongoing practice of the drug players may help them to significantly diminish the risks, related to the benefits offered by these medicines.

A few months ago, another group analyzed the data from an unpublished drug company study about the effect of Paxil on teen depression and found that the drug did not work and was not safe for the patients. This result completely contradicted the original, unpublished study on this drug.

A crusader emerged in Canada:

Interestingly, the same article, as above, states that Mathew Herder , the health law associate professor at Dalhousie University in Halifax, Canada is now taking up the fight. He is now “calling on other doctors, researchers and journalists to bombard Ottawa with their own demands for drug industry data, using the new legislative lever called the ‘Protecting Canadians from Unsafe Drugs Act,’, which was passed late last year in Canada.

He has also created a template to help doctors, researchers and journalists access drug safety data at Health Canada. Herder reportedly could even include biomedical researchers, doctors who prescribe medicine, investigative journalists pursuing questions about drug safety, and other activists and patient groups.

This example is worth imbibing elsewhere.

The ‘Rule Books’ are in place, though with loopholes:

To curb such alleged patient unfriendly practices of the innovative drug manufacturers, while obtaining the marketing approval of new drugs, various rules and procedure were put in place, by various authorities.

I shall deliberate below a few of these rules, and enough loopholes therein, enabling the interested parties to hoodwink the external experts, at the cost of patients.

International Clinical Trials Registry Platform:

Much before Herder, following a ministerial summit on Health Research in 2004, a World Health Assembly Resolution passed in 2005 called for unambiguous identification of all interventional clinical trials. This resolution led to the establishment of the ‘World Health Organization (WHO) International Clinical Trials Registry Platform’. It collates information on trials that have been notified in a network of clinical trial registries.

According to W.H.O, “The registration of all interventional trials is a scientific, ethical and moral responsibility”.

In the latest version of the Declaration of Helsinki, it reiterates, “Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.”

It unambiguously states, “Researchers have a duty to make publicly available the results of their research …. Negative and inconclusive as well as positive results must be published or otherwise made publicly available”.

Understandably, W.H.O statement underscores, “There is an ethical imperative to report the results of all clinical trials, including those of unreported trials conducted in the past.”

It is worth mentioning here that on January 1, 2015, by a new policy on publication of clinical data, ‘European Medicines Agency (EMA)’ also decided to proactively publish all clinical reports submitted as part of marketing-authorization applications for human medicines, by the by pharmaceutical companies.

Big Pharma's serious apprehensions on greater Public transparency:

Before finalization of the above policy, EMA sought comments on its draft from various state holders. On September 5, 2013, in its remarks on the draft, ‘The European Federation of Pharmaceutical Industries and Associations, EFPIA’ expressed its apprehension about the public health safety oriented proactive move by the EMA as follows:

“We are worried by a move towards greater transparency of clinical trials data that appears to be putting transparency – at whatever cost – ahead of public health interests. Our detailed response to the EMA draft policy speaks to this concern. While EFPIA values other voices and opinion in the conversation surrounding clinical trials data, we believe there are better alternatives than what the EMA is presenting.”

This is of course understandable. That said, it also gives satisfaction to note that EMA did not wilt under any pressure on this score, whatever the anecdotal might of the external force be.

Gross non-compliance, endangering patients’ health safety:

Although, the standards and requirements of “Public Disclosure of Clinical Trial Results” have been well specified now, and even in most of the Big Pharma websites one can find disclosure norms of clinical trial data, their overall compliance on the ground, is still grossly inadequate, endangering patients’ health safety.

An article published in the BMJ Open on November 12, 2015 titled, “Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012”, well captured the magnitude of this issue.

Nevertheless, the study analyzed just a subset of drugs approved in a single year, 2012. The researchers only examined whether clinical trials were registered and reported, not what that data suggested about how the drugs worked.

The paper reported the results as follows:

“In 2012, the US FDA approved 39 novel new medicines, known as NMEs, and 35 novel drugs. Combining these lists, the FDA approved a total of 48 new drug entities, 15 of which were sponsored by 10 large pharmaceutical or biotechnology companies with market capitalizations valued over US$19 billion. A total of 342 trials were conducted to gain regulatory approval of the 15 drugs, 24 of which were excluded from our analysis, leaving 318 trials involving 99 599 participants relevant to our study, a median of 17 trials per drug.”

Based on the findings, the authors concluded asunder:

“Trial disclosures for new drugs remain below legal and ethical standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal and ethical standards and the quality of medical knowledge.”

Simultaneously, The Washington Post in an article of November 12, 2015, titled, “How pharma keeps a trove of drug trials out of public view”, summarized this report by highlighting to the general public that one third of the clinical trial results that US FDA reviewed to approve drugs made by large pharmaceutical companies in 2012, were never publicly reported.

Unethical practices skewing medical science:

On July 25, 2015, ‘The Economist’ published an article titled, “Spilling the beans’. It highlighted again that the failure to publish the results of all clinical trials is skewing medical science.

This article also brought to the public attention that half of the clinical trial results are never published over several decades. It broadened the discourse with the observation that this specific unwanted practice, distorts perceptions of the efficacy of not just drugs, but devices and even surgical procedures too, in a well planned and a systematic manner. What is most important to note is, it has seriously compromised with patients’ health interest, across the world.

It keeps on happening, as there are no firm obligations on the part of drug companies for making public disclosure of all such data, both for and against, though all these data are required to be filed with the regulatory authorities. Hence, the overall assessment of the drugs, weighing all pros and cons, is just not possible for any outside expert agency.

For granting necessary marketing approval, the designated authorities, at least theoretically, ensure that the drugs are reasonably safe, and have, at least, ‘some beneficial effects’. However, the prescribing doctors would continue to remain ignorant of the untold facts, the article states.

According to ‘The Economist’, although in the United States the relevant laws were modified, way back in 2007, to address this issue, it still remains as a theory, the actual practices in this regard are mostly not so.

Despite vindication no tangible outcome yet:

As I said earlier, this fact got vindicated through extensive research by the ‘BMJ Online’ article and many other contemporary medical publications.

For example, the evidence released earlier on April 10, 2014 by the Cochrane Collaboration of London, UK, also shows that a large part of negative data generated from the clinical trials of various drugs were not disclosed to the public.

Again, like Vioxx, though the US FDA was aware of all such data, for a well known drug Tamiflu, unfortunately the prescribing doctors were not. As a result, the U.S. Centers for Disease Control and Prevention (CDC), which doesn’t have the same access to unpublished data as the regulators, recommended this medicine not being able to evaluate it holistically.

However, as the findings from the unpublished clinical trials eventually surfaced, CDC expressed serious apprehension on the overall efficacy of Tamiflu, quite contrary to the assessment of the concerned big pharma player.

Hence, despite quite a large number of vindications by the experts, no tangible outcome has been noticed on this pressing issue, just yet.

Conclusion:

Based on all this discussion, the moot question that springs up: Why do the doctors still prescribe such drugs, even after being aware of the full facts?

In this regard, an article titled, “Big Pharma Plays Hide-The-Ball with Data”, published in the Newsweek on November 13, 2014 raised a very valid question.

It commented, even if Tamiflu does nothing, and there is just a slight chance of life-threatening side effects, why was it approved by the US FDA, in the first place?

Even more intriguing is: Why do the doctors continue prescribing these, especially after the Cochrane Collaboration took the Tamiflu’s maker, Roche, to task about many of its claims, in April 2014.

Incidentally, the Cochrane Collaboration is widely regarded as one of the most rigorous reviewers of health science data. It takes results of multiple trials, looks for faults and draws conclusions. It doesn’t accept funding from businesses with a stake in its findings.

The answer to this question may perhaps be too obvious to merit any elaborate discussion here.

Be that as it may, this curious conundrum of ‘New Drug Approval’ with ‘Partial Public Disclosure of Clinical Trial Data’ needs to effectively addressed, without further delay. If not, patients’ health interest would continue to get seriously compromised with the continuation of prevailing laxity in its implementation process by the drug regulators.

By: Tapan J. Ray

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

Nutraceuticals: A Major Regulatory Step That Was Long Overdue

Posted on December 21, 2015 by Tapan Ray

Currently in India the nutraceutical products segment, with surrogate or off-label therapeutic claims, is growing at a reasonable pace.

Many such products are now being directly promoted to the medical profession, just like any other modern medicines, with therapeutic claims not being supported by robust clinical data that can pass through scientific or regulatory scrutiny.

For such use of nutraceutical products, I raised the following two questions in my article on this Blog titled, “Nutraceuticals with Therapeutic Claims: A Vulnerable Growing Bubble Protected by Faith and Hope of Patients” on August 27, 2012:

What happens when the nutraceutical products fail to live up to the tall claims made by the respective manufacturers on their efficacy and safety profile?

Are these substances safe in those conditions, even when not enough scientific data has been generated on their long term toxicity profile?

Importance of robust clinical data for any product with therapeutic claims:

For similar claim of therapeutic efficacy in the treatment of a disease condition, any drug would require establishing its pharmacokinetics and pharmacodynamics with pre-clinical and clinical studies, as stipulated by the drug regulators. Some experts believe that these studies are very important for nutraceutical products as well, especially when therapeutic claims are made on them, directly or indirectly. This also because, these substances are involved in a series of reactions within the body.

Similarly, to establish any long term toxicity problem with such products, generation of credible clinical data, including those with animal reaction to the products, both short and long term, using test doses several times higher than the recommended ones, is critical. These are not usually followed for nutraceutical products in India, even when therapeutic claims are being made.

Some experts in this field, therefore, quite often say, “A lack of reported toxicity problems with any nutraceutical should not be interpreted as evidence of safety.”

The current status:

Currently in India, nutraceuticals, herbals and functional foods are covered under the definition of ‘food’ as per Section 22 of Food Safety & Standards Act, 2006. These food products have been categorized as Non-Standardized/special food products. Neither was there any properly framed guidelines related to manufacturing, storage, packaging & labeling, distribution, sales, claims and imports, nor any legal fear of counterfeiting.

A recent reiteration of the need of regulatory guidelines for nutraceuticals:

In a study on ‘Indian Nutraceuticals, Herbals, and Functional Foods Industry: Emerging on Global Map,’ jointly conducted by The Associated Chambers of Commerce and Industry of India (ASSOCHAM) and RNCOS and released by ASSOCHAM on August 17, 2015 the above key apprehensions on the lack of any kind of regulatory guidelines for the approval and monitoring of products falling under this segment, were reiterated.

The market:

According to the above study, the global nutraceuticals market is expected to cross US$ 262.9 billion by 2020 from the current level of US$ 182.6 billion growing at a compound annual growth rate (CAGR) of about 8 percent.

United States (US) has the largest market for the nutraceuticals, followed by Asia-Pacific and European Union. Functional food is the fastest growing segment in the US nutraceuticals market. Germany, France, UK and Italy are the major markets in the European Union for nutraceuticals. Japan (14 percent) is the major consumer of nutraceuticals in Asia-Pacific, followed by China (10 percent).

The Indian nutraceuticals market is at a nascent stage now, but fast emerging. India accounts for around 1.5 percent of the global market. However, the above study forecasts that due to rising awareness of health and fitness and changing lifestyle, India’s Nutraceuticals market is likely to cross US$ 6.1 billion by 2020 from the current level of US$ 2.8 billion, growing at a compound annual growth rate (CAGR) of about 17 percent.

Phytochemicals in nutraceuticals:

Phytochemicals have been broadly defined as chemical compounds occurring naturally in plants. A large number of phytochemicals, either alone and/or in combination, are currently being used as nutraceuticals with significant impact on the health care system, claiming a number of medical health benefits, including prevention, treatment and even cure of many types of diseases.

The most recent regulatory intervention:

Responding to the growing demand for regulatory intervention in this important matter, on November 30, 2015, by a gazette notification, the Government of India included phytopharmaceutical drugs under a separate definition in the Drugs & Cosmetics (Eighth Amendment) Rules, 2015, effective that date.

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

On the ground, this significant regulatory measure would necessarily require the pharma players to submit the specified data on the phytopharmaceutical drug, along with the application to conduct clinical trial or import or manufacture in the country.

The salient features of the notification:

I am summarizing below, only the salient features of the detail notification for obtaining regulatory approval of these drugs in India:

A. Data to be submitted by the applicant:

A brief description or summary of the phytopharmaceutical drug giving the botanical name of the plant:

- Formulation and route of administration, dosages

- Therapeutic class for which it is indicated

- The claims to be made for the phytopharmaceutical product.

- Published literature including information on plant or product or phytopharmaceutical drug, as a traditional medicine or as an ethno medicine and provide reference to books and other documents, regarding composition, process prescribed, dose or method of usage, proportion of the active ingredients in such traditional preparations per dose or per day’s consumption and uses.

- Information on any contraindications, side effects mentioned in traditional medicine or ethno medicine literature or reports on current usage of the formulation.

- Published scientific reports in respect of safety and pharmacological studies relevant for the phytopharmaceutical drug intended to be marketed.

- Information on any contraindications, side effects mentioned or reported in any of the studies, information on side effects and adverse reactions reported during current usage of the phytopharmaceutical in the last three years, wherever applicable.

- Present usage of the phytopharmaceutical drug , – to establish history of usages, provide details of the product, manufacturer, quantum sold, extent of exposure on human population and number of years for which the product is being sold.

B. Human or clinical pharmacology information

C. Identification, authentication and source of plant used for extraction and fractionation

D. Process for extraction and subsequent fractionation and purification

E. Formulation of phytopharmaceutical drug applied for

F. Manufacturing process of formulation

G. Stability data

H. Safety and pharmacological information

I. Human studies

J. Confirmatory clinical trials

K. Regulatory status in other countries

L. Marketing information, including text of package inserts, labels and cartons

M. Post marketing surveillance (PMS)

N. Any other relevant information that will help in scientific evaluation of the application

Conclusion:

Prior to the above gazette notification, companies marketing nutraceutical products in general and phytochemical products, in particular, used to operate under a very relaxed regulatory framework.

Such products are currently promoted with inadequate disclosure of science based information, particularly with the surrogate therapeutic claims, which are based merely on anecdotal evidence and forms a part of intensive off-label sales and marketing efforts on the part of respective marketing players. It continues to happen, despite the fact that off-label therapeutic claims for any product are illegal in India, just like in many other countries.

Appropriate measures now being taken by the Government on phytochemical drugs, are expected to further plug the regulatory loopholes for off-label therapeutic claims without any robust scientific evidence. This particular regulation would also, hopefully, help curbing marketing malpractices to boost sales turnover of such products.

Considering all this, it appears that this is a major regulatory step taken by the Indian Government that was, in fact, very long overdue. Implemented properly, this would ensure predictable health outcomes and improved safety standards for most of the nutraceutical products, solely keeping patients’ health interest in mind.

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.

‘Repurposing’ Older Drugs: Has The Process Started Rolling?

Posted on October 26, 2015 by Tapan Ray

On October 22, 2015, BBC News reported, “The world’s largest clinical trial to examine whether aspirin can prevent cancers returning has begun in the United Kingdom (UK).”

About 11,000 people, who have had early bowel, breast, prostate, stomach and esophageal cancer will be involved in this study with one tablet a day dosage for five years. This trial is being funded by ‘The Charity Cancer Research, UK’ and ‘The National Institute for Health Research (NIHR).’

The scientists feel, if it works, this ‘repurposing’ of an older and much-known drug would be a “game-changing” one. It would then be able to provide a cheap and effective alternative to prevent recurrence of cancer to a large number of cancer survivals. Interestingly, no global pharma players are involved in this cancer prevention research, as yet.

Aspirin was developed by Bayer way back in 1897 for pain and inflammation. Thereafter, the scientists found a ‘repurpose’ in its use as an anti-platelet drug for treating and preventing heart attacks and strokes.

Similarly, the anti-inflammatory drug Ibuprofen, which was developed by Boots in the 1960s for the treatment of rheumatoid arthritis, is now showing promises that it can help protect against Parkinson’s disease.

Again, a number of studies claim that statins, a cholesterol-reducing drug, can help prevent Alzheimer’s Disease, resulting in low levels of beta-amyloid. Further research needs to be done in this area, as this finding has not been universally accepted, just yet.

All such commendable initiatives, throw open a relevant question for debate: ‘Can the existing drugs be re-examined in a systematic manner to discover their other possible radically new usages at a much lesser treatment costs to patients?’

In my view, available data emphatically prompts the answer ‘Yes’ and I shall deliberate on on that in this article.

‘Repurposing’ older drugs:

The Oxford Dictionary meaning of ‘repurpose’ is: ‘Adapt for use in a different purpose.’

Accordingly, the process of discovering new usages of older drugs is often called by many scientists as ‘repurposing’.

Currently, we come across various articles reporting a number of such new initiatives. This process is safer, much less expensive and takes much lesser time.

These laudable R&D initiatives needs encouragement from all stakeholders, especially from the Government. Given proper focus and attractive financial and other incentives, more and more players are expected to get attracted to a different genre of innovation. It is a whole new ball game of discovering new purposes of old and cheaper drugs with known and well-documented long term safety profile.

Some old drugs with ‘new purpose’:

The following table gives an example of some well known older drugs, for which fresh R&D initiatives discovered their new purpose of treatment, at a much cheaper cost:

Drug	Old Indication	New purpose
Amantadine	Influenza	Parkinson’s Disease
Amphotericin	Antifungal	Leishmaniasis
Aspirin	Inflammation, pain	Antiplatelet
Bromocriptine	Parkinson’s disease	Diabetes mellitus
Bupropion	Depression	Smoking cessation
Colchicine	Gout	Recurrent pericarditis
Methotrexate	Cancer	Psoriasis, rheumatoid arthritis

(Source: Indian Journal of Applied Research, Volume: 4, Issue: 8, August 2014)

A clarion call to join this movement:

The well-known researcher, Dr. Francis S. Collins, the Director of the National Institutes of Health (NIH) in a TED talk (video) strongly argued in favor of ‘translational research’ to produce better drugs, faster. To make this process to work successfully Francis Collins hopes to encourage global pharmaceutical companies to open up their stashes of drugs that have already passed safety tests, but that failed to successfully treat their targeted disease.

He wants to study, how drugs approved for one disease could successfully treat another or more ailments and also gave examples of the following drugs, which I am quoting below, as such:

Raloxifene: The FDA approved Raloxifene to reduce the risk of invasive breast cancer in postmenopausal women in 2007. It was initially developed to treat osteoporosis.
.
Thalidomide: This drug started out as a sedative in the late fifties, and soon doctors were infamously prescribing it to prevent nausea in pregnant women. It later caused thousands of severe birth defects, most notably phocomelia, which results in malformed arms and legs. In 1998, thalidomide found a new use as a treatment for leprosy and in 2006 it was approved for multiple myeloma, a bone marrow cancer.
.
Tamoxifen: This hormone therapy treats metastatic breast cancers, or those that have spread to other parts of the body, in both women and men, and it was originally approved in 1977. Thirty years later, researchers discovered that it also helps people with bipolar disorder by blocking the enzyme PKC, which goes into overdrive during the manic phase of the disorder.
.
Rapamycin: This antibiotic, also called sirolimus, was first discovered in bacteria-laced soil from Easter Island in the seventies, and the FDA approved it in 1999 to prevent organ transplant rejection. Since then, researchers have found it effective in treating not one but two diseases: Autoimmune Lymphoproliferative Syndrome (ALPS), in which the body produces too many immune cells called lymphocytes, and lymphangioleiomyomatosis, a rare lung disease.
.
Lomitapide: Intended to lower cholesterol and triglycerides, the FDA approved this drug to treat a rare genetic disorder that causes severe cholesterol problems called homozygous familial hypercholesterolemia last December.
.
Pentostatin: This drug was created as a chemotherapy for specific types of leukemia. It was tested first in T-cell-related leukemias, which didn’t respond to the drug. But later NIH’s National Cancer Institute discovered that the drug was successful in treating a rare leukemia that is B-cell related, called Hairy Cell Leukemia.
.
Sodium nitrite: This salt was first developed as an antidote to cyanide poisoning and, unrelated to medicine, it’s also used to cure meat. The National Heart, Lung, and Blood Institute is currently recruiting participants for a sodium nitrite clinical trial, in which the drug will be tested as a treatment for the chronic leg ulcers associated with sickle cell and other blood disorders.

Zidovudine (AZT): The first antiviral approved for HIV/AIDS in 1987.

Farnesyltransferase inhibitor (FTI): This was used to successfully treat children with the rapid-aging disease Progeria in a 2012 clinical trial.

“None of these drugs could have been developed without collaborations between drug developers and researchers with new ideas about applications, based on molecular insights about disease,” Dr. Collins said.

The examples that I have given, so far, on ‘repurposing’ older drugs are not exhaustive, in any way, there are more such examples coming up almost regularly.

The key benefits:

The key benefits of ‘repurposing’ older drugs may be summarized as follows:

Ready availability of the starting compound
Previously generated relevant R&D data may be used for submission to drug regulators
Makes clinical research more time-efficient and cost-effective
Possibility of much quicker market launch

Slowly gaining steam:

On November 27, 2012, ‘The Guardian’ reported that a number of university-based spin-outs and small biotech companies are being set up in the United States to find new purpose for old drugs. They express interest especially, on those drugs, which were shelved as they did not match the desired efficacy requirements, though showed a good overall safety profile.

Such organizations, take advantage of the declining cost of screening, with some compound libraries, such as, the Johns Hopkins library, which includes 3,500 drugs, available for screening at a small charge, the report highlighted.

Quoting a specialist, the report stated, “Existing drugs have been shown to be safe in patients, so if these drugs could be found to work for other diseases, then this would drastically reduce drug development costs and risks. Of 30,000 drugs in the world, 25,000 are ex-patent – it’s a free-for-all.”

‘Repurposing’ may not attract many pharma players, Government should step in:

Notwithstanding the clarion call of Dr. Francis Collins to global pharma players for their active participation in such projects, I reckon, the positive response may not be too many, because of various reasons.

Although, ‘repurposed’ drugs offer similar or even greater value to patients than any comparable ‘me-too’ New Chemical/Molecular Entity (NCE/NME), there may not possibly be any scope here for ‘Obscene Pricing’, such as ‘Sovaldi’ and many others, as some experts feel. And that’s the reality.

Moreover, new usages of the same old molecule, in all probability, may not get any fresh Intellectual Property (IP) protection in India, either.

Hence, considering the health interest of patients, in general, the Government should assume the role of ‘prime mover’, primarily to set the ball of ‘repurposing of older drugs’ rolling in India. This has already started happening in some of the developed countries of the world, which I shall dwell upon here.

Funding clinical development for ‘repurposing’:

Let me give a couple of examples of funding such admirable initiatives in two different countries.

I have already mentioned above that the clinical development for ‘repurposing’ Aspirin in the prevention of cancer, is being funded by the charity Cancer Research UK and the National Institute for Health Research (NIHR).

In a similar initiative, National Institutes for Health (NIH) of the United States, launched the ‘National Center for Advancing Transnational Sciences (NCATS), in May 2012.

New Therapeutic Uses program of NCATS helps to identify new uses for drugs that have undergone significant research and development by the pharma industry, including safety testing in humans. NIH claims that ‘using drugs that already have cleared several key steps in the development process gives scientists nationwide a strong starting point to contribute their unique expertise and accelerate the pace of therapeutics development.’

By pairing researchers with a selection of specific drugs, NCATS program tests ideas for new therapeutic uses, ultimately identifying promising new treatments for patients. Funding for this purpose is done by NCATS through NIH. For example, In July 2015, NCATS planned a funding of around US$3 million to support four academic research groups to test a selection of drugs for new therapeutic uses, as follows:

Type 2 diabetes
Glioblastoma (one of the most aggressive brain tumors in adults)
Acute myeloid leukemia (an aggressive blood cancer)
Chagas disease (a neglected tropical disease that causes heart, digestive and neurological problems)

According to NIH, each award recipient will test a selected drug for its effectiveness against a previously unexplored disease or condition. The industry partners for these projects are AstraZeneca and Sanofi.

Can it be done in India?

Of course yes, provided the Government considers health care as one its priority focus areas with commensurate resource deployment of all kinds for the same.

As things stand today, India still remains beyond any visibility to give a tangible shape to this specific concept of ‘repurposing’ of older drugs. There does not seem to be any other valid reason why similar model of funding can’t be followed locally too, for this purpose.

The nodal agency to spearhead such initiatives, and to create appropriate groundswell to help gain a critical mass, may well be the ‘Council of Scientific & Industrial Research (CSIR)’ or any other body that the Government decides in consultation with domain experts, together with reasonable financial incentives for commercialization of new usages at an affordable cost.

Conclusion:

As we all know, many people, across the world, are currently going through the pain of seeing their loved ones suffer, and even die, from serious ailments, the treatments of which either do not exist or when exist, the therapy costs may be out of reach of a vast majority of patients. In tandem, the R&D pipeline of the global pharma industry is gradually drying up.

In a situation like this, drug ‘repurposing’ that is directed towards meeting unmet medical needs of patients of all types irrespective of financial status, needs to be increasingly encouraged and pursued as a critical solution to this growing problem.

The good news is that some global pharma majors, though very few in number, have now expressed their intention to salvage their failed molecules and are open to help explore whether such drugs may work in other disease conditions.

India seems to be still miles away from this space, and a bit directionless too. That said, the country is scientifically quite capable of making up the lost ground in this area, provided the Government decides so, garnering requisite wherewithal.

Thus, in my view, the process of ‘repurposing’ older drugs has already started rolling in some major countries of the world, in a well structured manner with requisite funding in place. Tangible outcomes are already noticeable today, with some examples quoted in this article.

As Dr. Francis Collins said, collaborations between drug developers and researchers with new ideas about applications, based on molecular insights about disease are critical in the way forward to achieve this cherished goal in a sustainable manner.

By: Tapan J. Ray

Data Manipulation: Leapfrogging Dangerously Into Clinical Trial Domain

Posted on August 3, 2015 by Tapan Ray

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

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

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

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

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

Time to take the bull by the horns:

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

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

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

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

‘Data manipulation’ dangerously leapfrogging into clinical trial domain:

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

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

What it means commercially?

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

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

Unrolling the GVK Bio saga:

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

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

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

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

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

Indian Government blames ‘vested interests supporting Big Pharma’!

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

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

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

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

The rigmarole continues:

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

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

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

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

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

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

Could assume a snowballing effect:

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

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

Cadila Pharmaceuticals Limited:

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

Emcure Pharmaceuticals Ltd.:

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

Aurobindo Pharma Ltd.:

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

Business sustainability could be in jeopardy:

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

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

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

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

Are medicines for domestic consumption safe and effective?

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

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

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

Why no such warnings are forthcoming at all from the Indian drug regulators?

Does it mean that the level of conformance to GMP and GCP is hundred percent for all medicines manufactured and clinically evaluated in India for the consumption of local patients?

If yes, why such incidences are not uploaded to the CDSCO website, just like USFDA?

If not, why?

Conclusion:

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

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

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

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

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

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

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

By: Tapan J. Ray

Pharma Outlook 2015: A Glimpse Of Some Drivers and Barriers

Posted on January 5, 2015 by Tapan Ray

Looking ahead, the brand new year 2015 appears quite interesting to me both from the global and also from the local pharmaceutical industry perspective. In this article I shall try to give a glimpse of some of the important drivers and barriers for success of the industry as the year unfolds, based on recent and ongoing developments.

Let me start with the global outlook of 2015, where in the midst of all gloom and doom of the past years, I notice formation of a distinct and new silver lining, mainly due to the following two reasons:

1. Record number of new drugs approval in 2014 spanning across10 therapy areas:

As indicated in its website, USFDA has approved 41 novel medicines in 2014, which is 14 more than the previous year and is the second highest after 1996 that witnessed 53 approvals. Many of these new drugs are with blockbuster potential.

According to another report, the European Medicines Agency (EMA) has also recommended 82 new medicines in 2014, which though includes generic drugs in its list. However, this number too shows an increase from 79 in 2013 and 57 in 2012.

According to January 02, 2014 report from Forbes, very interestingly, infectious diseases dominated with 12 approvals (27 percent), cancer with 8 approvals (18 percent), followed by rare diseases with 5 (11 percent). Just two of these new approvals are for Hepatitis treatment and the rest are for bacterial, fungal, viral, and parasitic infections.

AstraZeneca received the highest number of 4 approvals followed by Eli Lilly with 3.

2. Patent expired blockbuster drugs in 2015 would have low generic impact:

Though drugs worth sales turnover of US$ 44 billion would go off patent in 2015, patent expiries will have minimal impact on the top line as 2015 sales will grow close to four times that of patent losses. Following are the top 10 drugs among those:

No.	Brand	Company	Disease	Sales2013 (US$ Bn)	Patent Expiry
1.	Lantus	Sanofi	Diabetes	7.9	Feb 2015
2.	Abilify	Otsuka/Bristol-Myers Squibb	Schizophrenia/ Other neurological conditions	7.8	April 2015
3.	Copaxone	Teva	Multiple sclerosis	4.33	Sept 2015
4.	Neulasta	Amgen	Infection reduction in cancer patients on chemotherapy	4.4	Oct 2015
5.	Tracleer	Actelion	Pulmonary arterial hypertension	1.57	Nov 2015
6.	Namenda	Actavis	Alzheimer’s disease	1.5	April 2015
7.	Avodart/Jalyn	GSK	Benign prostatic hypertrophy	1.34	Nov 2015
8.	Zyvox	Pfizer	Gram-positive bacterial infections	1.35	May 2015
9.	AndroGel	Abbvie	Low testosterone	1.03	Early 2015
10.	Synagis	AstraZeneca	Monoclonal antibody to prevent respiratory syncytial virus infection in infants	1.1	Oct 2015

(Compiled from FiercePharma data)

As a significant number of these drugs are biologics, such as Lantus, Abilify, Neulasta and Synagis, the generic impact on those large brands, post patent expiry, would be minimal, at least, for several more years.

However, Lantus sales could soon be impacted, as its biosimilar versions from Boehringer Ingelheim and Eli Lilly have already received approval in Europe, and may be launched in the United States, as well.

Biosimilar versions of other drugs that will go off patent in 2015, do not seem to be anywhere near launch soon to make immediate dent in the sales of the original biologics. I had deliberated on various possible reasons for delay in biosimilar entry, especially in the US, in my earlier blog post of August 25, 2014, titled “Scandalizing Biosimilar Drugs With Safety Concerns”

Taking all these into consideration, EvaluatePharma has estimated that out of patent expiry related sales turnover of US$44 billion, just around US $16 billion would get impacted in 2015 by their generic equivalents.

Global market outlook 2015:

According to IMS Health, spending on medicines will reach nearly $1,100 billion in 2015 with a growth rate of 3-6 percent over the last five-year period.

According to EvaluatePharma, the overall outlook of the global pharma industry in 2015 and beyond is expected to be as follows:

A dozen products launched in 2015 are forecast to achieve blockbuster sales by 2020

Drugs treating high cholesterol and heart failure will dominate the field with a combined 2020 sales forecast of US$8 billion

Sovaldi and its combination product Harvoni will take the number one worldwide seller spot with forecasted sales of $15.3 billion in 2015

Patent expiries will have minimal impact on the top line as 2015 sales will grow close to four times that of patent losses

Financing climate appears friendly and deals will continue at a steady pace but M&A activity unlikely to match the frenzy of 2014

Moreover, Oncology therapy area brings a huge promise with novel immuno-oncology drugs. As Reuters have reported, Merck & Co’s Keytruda and Bristol-Myers Squibb’s Opdivo, which work by blocking a protein called Programmed Death receptor (PD-1), are the first in a coming wave of immuno-therapies that analysts believe could generate annual sales of more than US$30 billion a year.

Indian pharma industry outlook 2015:

Indian pharmaceutical industry, dominated by branded generic drugs, is estimated to register a turnover of around US$ 33.8 billion with an average growth of 10.3 percent in 2014 – 2018 period, according to Deloitte. Increasing number of diagnosis and treatment of chronic ailments, fuelled by ascending trend in the per capita income, would be the key factors to drive this double-digit growth rate.

In 2013-14, pharma exports of the country with a turnover of US$ 14.84 billion grew at a meager 1.2 percent, which is the slowest growth in nearly the last 15 years. Pharmexcil attributed its reason to USFDA related regulatory issues and increasing global competition. India still stands exposed in this area, unless meaningful corrective measures are taken forthwith. It is worth noting, although India exports drugs to over 200 countries in the world, the United States (US) alone accounts for about 25 percent of India’s pharma exports.

Key issues and challenges in ‘The Exports Front’:

Generic drugs currently contribute over 80 percent of prescriptions written in the US. Around 40 percent of prescriptions and Over The Counter (OTC) drugs that are sold there, come from India and account for around 10 per cent of finished dosages in the US.

Almost all of these are cheaper generic versions of patent expired drugs, which are mainly produced in around 200 USFDA approved drug-manufacturing facilities located in India. Hence, India’s commercial stake in this space is indeed mind-boggling.

Indian drug exports were taking place satisfactorily without any major regulatory hitches since quite some time. Unfortunately, over the last few years, mostly the Federal Drug Administration of the US (USFDA) and the United Kingdom (UK)’s Medicines and Healthcare Products Regulatory Agency (MHRA) have started raising serious doubts on the quality of medicines manufactured in India, creating an uncertainty on drug exports in those countries.

To overcome this critical issue and keep marching ahead with distinction in the drug exports front, Indian pharma would require to successfully dealing with the following two areas:

A. Data integrity:

Since quite a while, USFDA has been raising serious concerns on ‘Data Integrity’ in their previously approved production facilities of a large number of Indian pharma players. The details of each of these concerns are available in the USFDA website.

This worrying development is now posing a huge threat to future growth potential of Indian drug exports, as in this area the Indian government had set an objective, in its strategy document, to register a turnover of US$ 25 billion in 2014-15. In all probability, it would fall far short of this target at the end of this fiscal, predominantly for related reasons. However, the good news is, considering the criticality of the situation, the Indian government is now working with the USFDA to resolve this problem.

I discussed a part of this area in my Blog Post of September 29, 2014 titled “Make in India…Sell Any Where in The World”: An Indian Pharma Perspective

B. Credibility of Clinical Trial Data from India:

Credibility of ‘Clinical Trial Data’ generated by the domestic players in India, has also become a cause of great concern, as the regulators in France, Germany, Belgium and Luxembourg suspended marketing approval for 25 drugs over the genuineness of clinical trial data from India’s GVK Biosciences.

Key issues and challenges in ‘The Domestic Front’:

Though 2015 would also witness the following important issues and challenges, meeting with this challenge of change should not be difficult with a proper mindset and right strategies:

A. The Drug Price Control Order 2013 (DPCO 2013):

Change in the mechanism of drug price control from earlier ‘cost based’ to newer ‘market based’ one and the specified provisions to neutralize inflationary impact of the input costs on the bottom line, based on the WPI, have already been considered as welcoming changes for the industry. As a result, despite implementation of the DPCO 2013, the pharma shares continued to do well in 2014 despite doomsayers’ predicaments, not just in the past, but even today.

I believe, the DPCO 2013 would not cause any significant negative impact further in 2015 on the performance of pharma companies, as the price controlled drugs would in all probability continue to be around 20 percent of the total pharma market. Moreover, now annual price increases are linked to the WPI for the controlled products and the companies can increase prices of remaining 80 percent of decontrolled products, upto 10 percent every year, irrespective of inflationary trend.

That said, due to huge inter-brand price differences, in July 2014 the National Pharmaceutical Pricing Authority (NPPA) had brought under price control 50 more cardiovascular and anti-diabetic drugs in addition to 348 drugs that featured under price control in the DPCO 2013.

If the pharma players do not take note of such abnormal inter-brand price variation of the same drugs without meaningful reasons, there could possibly be further move by the NPPA in this direction.

Additionally, any mechanism for patented products’ pricing, if announced in 2015, would have far-reaching impact, especially on the MNCs marketing such drugs.

B. Unethical practices in Clinical trial:

In the Clinical Trial arena of India, responding to a Public Interest Litigation (PIL), the Supreme Court of the country and separately the Parliamentary Standing Committee had indicted the drug regulator and charted out some action areas. The Parliamentary Committee in its report had even mentioned about a nexus existing between the drug regulator and the industry in this area.

Driven by the directives of the Apex Court of the country, the union ministry of health of the government of India has already strengthened some areas of past laxity in drug regulatory control, such as mandatory registration of clinical trials, constitution of committees to oversee the trial approval, its execution and above all ethical treatment of patients, including compensation.

Although, these are all requisite measures to create an appropriate longer-term eco-system for clinical trials in India, it has reportedly ruffled many feathers, such as CROs in the country who work mainly for pharma MNCs and some global pharma players too. This is mainly because of inordinate delays in drug approvals during the regulatory rectification process, besides cost of clinical trials going up. An orderly drug regulatory environment must prevail, instead of allegedly ‘free for all’ clinical trial environment in the country, costing many innocent lives and livelihoods. Responding to this changing clinical trial environment, some MNCs have already articulated that they are reconsidering their drug trial strategy in India and some Indian players, possibly with vested interests and echoing similar sentiments, are also saying that they would shift their clinical trial projects out of India, which would adversely impact the country’s clinical trial industry.

Be that as it may, it appears now that under the directive of the Supreme Court of the country, the decisions taken by the government in clinical trial area are irreversible, for the long-term interest of the country.

C. Intellectual Property (IP) issues:

Reacting to some well-justified measures taken by India in the IP area to make healthcare affordable to all, the US and its some key allies, continuously pressured by their powerful pharma lobby groups, continue to push India hard to broaden the IP protections. ‘Big Pharma’ lobbyists are reportedly trying to compel India to amend its IP laws that would suit their business interest at the cost of patients.

Fortunately, many stakeholders, including media, have started raising their voices against such strong-arm tactics, further fueling the credibility erosion of ‘Big Pharma’ and creating important pressure groups for the government.

Simultaneously, concerned pharma MNCs are also seeking legal recourse over issues mainly related to the section (3d) and Compulsory Licensing of the Indian Patents Act. However, most of the judicial verdicts vindicate the quality of decisions taken by the Indian Patent Office (IPO) in these areas.

Though very unlikely, any amendment or tweaking of the existing patent laws of India in 2015 would provide an unfair advantage to MNCs with negative impact on public health interest.

D. Uniform Code of Pharmaceutical Marketing Practices:

Compared to the actions that are now being taken by the law enforcers overseas against pharmaceutical marketing malpractices, India has been showing a rather lackadaisical attitude in these areas, until recently. It astonishes many that unlike even China; no pharmaceutical company has been investigated thoroughly and hauled up by the government for alleged bribery and other serious allegations of corrupt practices.

However, frequent reporting by the Indian media had triggered a debate in the country on the subject. A Public Interest Litigation (PIL) on this subject is now pending before the Supreme Court for hearing in the near future. It is worth noting that in 2010, ‘The Parliamentary Standing Committee on Health’ also had expressed its deep concern by stating that the “evil practice” of inducement of doctors by the pharma companies is continuing unabated as the revised guidelines of the Medical Council of India (MCI) have no jurisdiction over the pharma industry.

The Government, until recently, has shown no active interest in this area either, though the new Union Health Minister, J.P. Nadda decried the unethical nexus between the doctors and pharma companies, amounting violations of medical ethics in the country. He reportedly has stated that in majority of the cases, the pharma companies are luring the doctors by giving gifts and other benefits for prescribing the brand of medicines of their choice to the patients.

As the saying goes, ‘better late than never’, on December 12, 2014, the Department of Pharmaceuticals (DoP) of the Government of India announced details of the ‘Uniform Code of Pharmaceutical Marketing Practices (UCPMP)’, which would be effective across the country from January 1, 2015 for all pharma players to implement, across India.

However, I reckon, the document in its current form is rather weak in its effective implementation potential. Meaningful and transparent deterrent measures to uphold public health interest are also lacking. The entire process also deserves a well-structured monitoring mechanism and digital implementation tools that can be operated with military precision. I discussed this issue in my Blog Post of December 29, 2014, titled “India’s Pharma Marketing Code (UCPMP): Is It Crafted Well Enough To Deliver The Deliverables?”

On UCPMP a survey done by E&Y has highlighted the following points, besides other areas:

More than 50 percent of the respondents are of the opinion that the UCPMP may lead to manipulation in recording of actual sampling activity.

Over 50 percent of the respondents indicated that the effectiveness of the code would be very low in the absence of legislative support provided to the UCPMP committee.

90 percent of the respondents felt that pharma companies in India should focus on building a robust internal controls system to ensure compliance with the UCPMP.

In my view as well, the self-regulatory measures prescribed in the UCPMP of the DoP are unlikely to make any significant impact in 2015, unless pharma companies start focusing on building robust internal controls system to ensure compliance with the UCPMP.

Conclusion:

I would now put on the balance of probabilities, the new ‘Silver Linings’ of the Global pharmaceutical industry as discussed above, the issues and challenges of 2015 for the Indian pharma and also other important factors that I have not been able to discuss in this article. The overall emerging picture depicts that the pharma industry, both global and local, would fare much better than what it did in the recent past, provided the industry, as a whole, does not continue to ignore the storm signals outright.

Thus, based on the available data, the year 2015, as appears to me, would provide an enormous opportunity with promises of an interesting time ahead that the pharmaceutical industry should try to leverage on…and then cherish it for a long while…most probably as a turning point of the same ball game with different success requirements.

By: Tapan J. Ray

Nutraceuticals: An Emerging Opportunity in The Gray Area Between Pharma And Nutrition

Posted on November 17, 2014 by Tapan Ray

Close association between nutrition and health has assumed a historical relevance. Growing pieces of evidence, even today, suggests that nutritional intervention with natural substances could play an important role, especially in the preventive healthcare. The World Health Organization (WHO) too has highlighted that mortality rate due to nutrition related factors in the developing countries, like India, is nearly 40 percent.

The ‘Gray Area’:

In the space between pharmaceutical and nutrition, there is an emerging ‘gray area with 50 shades’ having significant business relevance.

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

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

Evolution of the terminology ‘Nutraceuticals’:

Dr. Stephen DeFelice of the ‘Foundation for Innovation in Medicine’ coined the term ‘Nutraceutical’ from “Nutrition” and “Pharmaceutical” in 1989. The term nutraceutical though is now being commonly used in marketing such products has no regulatory definition, other than dietary or nutritional supplements.

It is interesting to note that the dietary supplement industry defines nutraceuticals as, “any nontoxic food component that has scientifically proven health benefits, including disease treatment and prevention.”

Probably because of this reason, it is often claimed by the manufacturers of nutraceutical products that these are not just dietary supplements, but also help in the prevention and/or treatment of many disease conditions.

In India, nutraceuticals are mostly promoted to the doctors just as any other ethical pharma products. These are also prescribed by the medical profession, not just as nutritional supplements but also for the treatment of disease conditions, ranging from obesity to arthritis, osteoporosis, cardiological conditions, diabetes, anti-lipid, gastroenterological conditions, dementia, age-related muscle loss, pain management and even fertility. All these are generally based on off-label therapeutic claims of the respective manufacturers.

Currently, this particular category of nutraceutical products, despite being out of price control and operating within much relaxed regulatory environment, is showing just a moderate growth trend in India.

The market:

According to a report of Frost & Sullivan, the global nutraceutical market has clocked maximum growth in the last decade.

Nutraceuticals as an industry emerged in the early 1990s. However, from 2002 to 2010 has been the key growth phase for the industry. From 1999 to 2002, the nutraceutical industry grew at an Annual Average Growth Rate (AAGR) of 7.3 percent, while from 2002 to 2010, the AAGR doubled to 14.7 percent, in line with the Indian Pharma Market (IPM).

The penetration of nutraceuticals in India was around 15 percent in 2013. In the same year, the turnover of the global nutraceuticals market was around US $168 billion in which India had a demand share of around 2 percent, i.e. around US $2 billion.

Growing at a Compound Annual Growth Rate (CAGR) of 17.1 percent, the Indian market is expected to reach US$ 4 billion by 2018. China, Southeast Asia, and India are the fast-growing markets, with each experiencing growth in double digits.

In the last couple of years functional beverages have emerged as a fastest growing category for the Indian market, with many companies expanding their portfolio in the segment. This category is expected to grow at a CAGR of 21.7 percent by 2018.

However, in terms of ingredients, especially plant extracts and phytochemical, Indian manufacturers have entrenched their place as suppliers, both locally as well as globally.

Some other key findings of this report are as under:

India is currently a nascent market for nutraceuticals, without a robust business model in place. Both MNCs as well as domestic companies in the pharmaceutical and food and beverage space have tested the market with a variety of launches, with some degree of success.

The existence of alternative medicines in India, and the Indian consumer’s belief in them, could provide a platform for the nutraceutical industry to cash on.

The Indian consumers’ awareness about conventional nutraceutical ingredients such as omega-3 fatty acids or lutein is very limited. The nutraceutical manufacturers would require spreading awareness about their products to the Indian masses, much more effectively.

As compared with the developed countries such as the USA, Europe, and Japan, the percentage of population consuming nutraceuticals in India is much low. The middle to high income groups are the dominant consumers of functional foods and beverages along with dietary supplements, while the lower income groups consume mainly prescription-based dietary supplements.

Health awareness and an increase in the penetration of organized retail stores are expected to play a major role in driving the nutraceuticals’ consumption in India.

Current regulations in India:

The Food Safety and Standards Act (FSSA) of India, 2006 predominantly regulate manufacturing, storage, distribution, sale and import of nutraceuticals in India. Unlike pharma products, no other regulations are still in place, though the government reportedly is in the process of inviting suggestions from the stakeholders on the subject.

Experts feel that FSSAI needs to play a more important role in defining standards to streamline the operations for nutraceuticals business in India, which should include, besides others, the following:

Quality of raw materials
Safe manufacture of product with cGMP standards
Health claims
Labeling
Distribution & storage

In the absence of comprehensive regulations many companies are unable to decide on necessary investments that will be required for this business in the longer term.

Currently, nutraceuticals are much less expensive to develop, manufacture, market and distribute, offering a rainbow of business opportunities in the healthcare space.

A brand ‘New Ministry’ in place:

In all likelihood, renewed measures would now be taken to bring nutraceuticals under the mainstream healthcare.

It appears more feasible today than ever before, as the Prime Minister Modi, with an eye on reviving indigenous and traditional medicine has recently created a brand new ministry with a Minister of State (Independent Charge) at the helm to look after Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homeopathy (AYUSH).

Need to generate robust clinical data:

In this context, a relatively new development is worth noting. It has been reported that all new traditional medicines will need to undergo clinical trials before their regulatory marketing approval in India. However, it has also been amply clarified that “such products will include only the new patented drugs and not the classical formulations that find mention in India’s ancient texts, some of which are 5,000 years old.”

I reckon, for all nutraceutical formulations with specific therapeutic efficacy and safety claims, there is a need to generate supportive robust clinical data for the patients’ long term health interest.

Therapeutic efficacy of a drug in the treatment of a disease condition is established with pharmacokinetic, pharmacodynamics, other pre-clinical and clinical studies. Some experts believe that these studies are very important for nutraceutical products too, particularly when therapeutic claims are made on them, as these substances undergo a series of reactions within the body.

Similarly, to rule out any long-term toxicity problem with such products, generation of credible clinical data is again critical. At present, these are not usually followed for nutraceutical products in India, even when therapeutic claims are made.

The experts, therefore, quite often say, “A lack of reported toxicity problems with any nutraceutical should not be interpreted as evidence of safety.”

Regulatory requirements for nutraceuticals in the USA:

In America, the Congress had passed the ‘Dietary Supplement Health and Education Act’ in 1994. This act allows ‘functional claims’ to dietary supplements, like “Vitamin A promotes good vision” or “St. Johns Wort maintains emotional well-being”, as long as the product label contains a specific disclaimer that the FDA has not evaluated the said claim and that the product concerned is not intended to diagnose, treat, cure or prevent disease.

The above Act bestows some important responsibility on to the doctors, who are required to provide specific and accurate scientific information for nutraceutical products to their patients. This process assumes critical importance, as the patients would expect the doctors to describe to them about the usefulness of nutraceutical products as alternatives to approved drugs. In such cases, if any doctor recommends a dietary supplement instead of pharmaceutical products, the doctor concerned must be aware of the risk that the patient’s health may suffer, for which the affected patient could sue the doctor for malpractice.

Indian Health Ministry should take note of these points for ethical promotion of nutraceuticals in India.

Sanofi considered nutraceuticals as a business opportunity in India:

So far in India, Sanofi is the only Pharma MNC that has entered into nutraceuticals business in a big way. Sniffing the market opportunity in this segment, the French major acquired the nutraceuticals business of Universal Medicare Private Ltd of worth Rs.110 Crore, in August 2011. The nutraceuticals product portfolio of Universal Medicare included more than 40 brands from cod liver oil capsules, vitamins/mineral supplements and antioxidants to liver tonics.

Ambivalence of Pharma MNCs:

According to A.T. Kearney report, unlike food industry, the global pharma industry has approached nutraceuticals with a ‘great deal of ambivalence’.

Pfizer and Novartis have sold their nutrition businesses.While the same Pfizer that sold Wyeth Nutrition to Nestle, invested an undisclosed sum to acquire Danish vitamins company Ferrosan and the dietary supplements manufacturer of the United States, Alacer, reinforcing what was already a billion-dollar business enterprise.

On the other hand GlaxoSmithKline (GSK) and Novartis have recently announced a joint venture for consumer products business, which could probably be a stepping-stone to get into nutraceuticals. Who knows?

Food companies leading nutraceuticals business:

The A.T. Kearney report also states that at present the food companies, and not the pharma players, are in the lead, accounting for about 90 percent of nutraceuticals sales with expertise in branding, consumer market expertise and access to mass distribution channels.

A few consumer companies have also inked partnership with pharma companies. For example, Coca-Cola and Sanofi have partnered to sell health drinks in French pharmacies.

Conclusion:

Nutraceuticals business, as many believe, is an emerging opportunity in the ‘Gray Area’ between pharmaceuticals and nutritional product classes. So far, the food companies have been charting this frontier that remained uncharted by a large majority of the pharma players. This is mainly because the success requirements for nutraceutical products, including dietary supplements, are quite different.

That said, a transparent and well-charted regulatory pathway for nutraceuticals, especially for formulations with therapeutic claims, would have a significant impact on its future growth potential in India.

Many nutraceutical products in the country with specific therapeutic claims do not seem to have supporting robust clinical data, leave aside being peer reviewed and published in the reputed international journals on the claims for safety or efficacy.

The entry of one of the global majors, Sanofi, having a clear focus on Evidence Based Medicines (EBM), ushers in a new hope and promise to get the loose knots tightened in this important area, while driving the business growth of the category.

Just as EBM, scientific ‘Evidence Based Nutraceuticals (EBN)’ with therapeutic claims, should be the centerpiece of consumer confidence and interest in this emerging niche of healthcare business in 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.

“Make Global Pharma Responsible in Homeland for Objectionable Conduct in Clinical Trials Elsewhere”

Posted on February 12, 2014 by Tapan Ray

In the context of his recent meeting with Commissioner Margaret A. Hamburg of US-FDA, the Drug Controller General of India (DCGI) reportedly expressed his concern to ‘The Economic Times’ on the ‘objectionable conduct’ of global pharma in new drug trials in India, as follows:

“US and other global drug makers who conduct clinical trials at different locations across the globe need to be made responsible in their home country for their objectionable conduct in clinical trials elsewhere.”

He further added:

“While conducting trials, drug makers cannot discriminate on the basis of nationality, because patient safety is top priority for every regulator – US or India”

The above report also mentioned that there is already a law in place in the United States that makes companies accountable in their homeland, if they are found to be indulging in corruption overseas.

‘Uncontrolled clinical trials are causing havoc to human life’:

That is exactly what the Supreme Court of India observed last year in response to a Public Interest Litigation (PIL) filed by the Human Rights group ‘Swasthya Adhikar Manch (SAM)’.

At the same time, revoking the power of the ‘Central Drugs Standard Control Organization (CDSCO)’ under the Drug Controller General of India (DCGI), the apex court directed the Health Secretary of India to be personally responsible for all ‘Clinical Trials (CT)’ of new drugs conducted in the country in order to control the ‘menace’ of poorly regulated trials on a war-footing.

Earlier in May 2012, the Parliamentary Committee on Health and Family Welfare in its report on the CDSCO, also stated as follows:

“There is sufficient evidence on record to conclude that there is collusive nexus between drug manufacturers, some functionaries of CDSCO and some medical experts.”

Inaction on CT related deaths:

According to the Ministry of Health, between 2005 and 2012, around 475 new drugs were approved for CT, out of which only 17 obtained the regulatory approval for market launch. Though 57,303 patients were enrolled for CT, only 39,022 could complete the trials. During CT, 11,972 patients suffered Serious Adverse Events (SAE) and 2,644 died. 506 SAEs out of the total and 80 deaths had clearly established link to CTs. However, only 40 out of 80 trial related deaths had their respective families meagerly compensated.

An independent investigation:

Interestingly, an investigation in 2011 by ‘The Independent’, a newspaper of global repute, also highlighted the recruitment of hundreds of tribal girls for a drug study without any parental consent.

Stringent regulatory action followed:

Following high voltage indictments, alleging wide spread malpractices, from all corners – the Civil Society, the Supreme Court and the Parliament, the Ministry of Health constituted an experts committee last year chaired by Professor Ranjit Roy Chaudhury. The committee, after due consultation with all stakeholders, submitted its report recommending a robust process for CTs in India. Besides many other, the experts committee also recommended that:

CTs can only be conducted at accredited centers.

The principal investigator of the trial, as well as the Ethics Committee of the institute, must also be accredited.

If a trial volunteer developed medical complications during a CT ‘the sponsor investigator’ will be responsible for providing medical treatment and care.

Further, in October 2013, the Supreme Court reportedly ordered the government to video record clinical trials of new drugs, making it even tougher for pharma MNCs and the CROs to avoid responsibility on informed consent of the participating volunteers, as required by the regulator.

Consequent industry uproar and recent Government response:

Following all these, as the ball game for CTs in India changed significantly, there were uproars from Big Pharma, the CROs and their lobbyists crying foul.

As the caustic comments and the directive of the Supreme Court of India triggered the regulatory changes in CT, the Union Ministry of Health did not have much elbowroom to loosen the rope. Consequently, the pharma industry and the CROs reportedly made some angry comments such as:

“The situation is becoming more and more difficult in India. Several programs have been stalled and we have also moved the trials offshore, to ensure the work on the development does not stop.”

In response to shrill voices against the stringent drug trial regime in India, Mr Keshav Desiraju, Secretary, Union Ministry of Health and Family Welfare, reportedly said recently:

“While it is not our intention to impose unrealistic barriers on industry, it is equally our intention not to take risks, which may compromise the safety of the subjects of clinical trials.”

During the same occasion, the Union Health Minister Ghulam Nabi Azad also remarked:

“The industry has complained that the regulations are too stringent, but there have also been complaints by parliamentarians, NGOs and others that they are too lax, which the Supreme Court had taken note of.”

He further said without any elaboration, “The Indian regulatory regime governing clinical trials needs to balance the interests of all stakeholders.”

Conclusion:

According to the Indian Society for Clinical Research (ISCR), pharma companies conduct around 60 percent of CTs and the rest 40 percent are outsourced to Contract Research Organizations (CROs) in India.

With the Supreme Court laying stringent guidelines and the regulatory crackdown on CTs, the number of new drug trials in India has reportedly come down by 50 percent. According to Frost & Sullivan, the Indian CT industry was worth US$ 450 million in 2010 -11. Currently, it is growing at 12 percent a year and is estimated to exceed the US$1 billion mark in 2016, with perhaps some hiccups in between due to recent tightening of the loose knots in this area.

Some experts reportedly argue that laxity of regulations and cost arbitrage were the key drivers for global players to come to India for CTs. Thus, there should not be any surprise that with the costs of drug trials going north, in tandem with stringent regulations in the country, some business may shift out of the country. As Mr. Desiraju epitomized in his interview succinctly, as quoted above, this shift would result in much increased costs for the respective companies, which his ministry would ‘regret greatly.’

That said, would the recent anguish of the DCGI, when he expressed “Make global pharma also responsible in their respective homelands for objectionable conduct in CTs elsewhere”, be also construed as a clear signal for shaping up, sooner?

By: Tapan J. Ray

New Clinical Trial Regime Deserves Support, Sans Threats

Posted on January 30, 2014 by Tapan Ray

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

Brief background:

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

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

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

Earlier system did not work:

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

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

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

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

Indictment of Indian Parliamentary Committee:

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

The report made the following scathing remarks on Central Drugs Standard Control Organization (CDSCO) under its point 2.2:

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

Catalytic change with tough norms:

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

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

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

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

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

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

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

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

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

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

Reaction to change:

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

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

No reverse gear:

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

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

Conclusion:

While the importance of CTs to ensure better and more effective treatment for millions of patients in India is immense, it should not be allowed at the cost of patients’ safety, under any garb…not even under any open threat of shifting CTs outside India.

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

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

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

By: Tapan J. Ray

PILMAN

A Tapan Ray Website

Tag Archives: Clinical

The Curious Conundrum of New Drugs Approval Process

Nutraceuticals: A Major Regulatory Step That Was Long Overdue

‘Repurposing’ Older Drugs: Has The Process Started Rolling?

Data Manipulation: Leapfrogging Dangerously Into Clinical Trial Domain

Pharma Outlook 2015: A Glimpse Of Some Drivers and Barriers

Nutraceuticals: An Emerging Opportunity in The Gray Area Between Pharma And Nutrition

“Make Global Pharma Responsible in Homeland for Objectionable Conduct in Clinical Trials Elsewhere”

New Clinical Trial Regime Deserves Support, Sans Threats