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

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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

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.

A Potential Game Changer For Pharma R&D

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The ghost of ‘Patent Cliff’ has been haunting the ‘Big Pharma’ since quite some time. This situation has been further aggravated by cost containment pressures of various Governments both in the developed and the emerging markets together with contentious issues on Intellectual Property Rights (IPR).

The ‘dream run’ that the innovator companies enjoyed in launching patented products so frequently and making many those blockbuster drugs of billions of dollars, is no longer a reality.

According to the findings of ‘Pharmaceutical R&D returns performance’ by Deloitte and Thomson Reuters of December 2012, the R&D Internal Rate of Return (IRR) of leading pharmaceutical companies had fallen to 7.2 percent in 2012 from 7.7 percent in 2011.

Many would, therefore, tend to believe that the paradigm is changing significantly. The new paradigm in the brand new millennium throws some obnoxious challenges, including some related to IPR, triggering a process of churning in the global pharma industry. Some astute CEOs of ‘Big Pharma’, having a deep introspection, are bracing for restructuring, not just in the business processes, but also in the process of organizational behavior, mindset, ethics and values. Unfortunately, there are many who seem to believe that this giant wheel of change can be put on the reverse gear again with might.

A new PPP initiative in pharma research:

This trying situation calls for collaborative initiatives to achieve both knowledge and cost synergies for a quantum leap in harnessing R&D output.

One such big laudable initiative has come to the fore recently in this arena. Having experienced something like the ‘law of diminishing return’ in pursuit of high resource intensive R&D projects aimed at critical disease areas such as Alzheimer’s, 10 big global pharma majors reportedly decided in February 2014 to team up with the National Institutes of Health (NIH) of the United States in a ‘game changing’ initiative to identify disease-related molecules and biological processes that could lead to future medicines.

This Public Private Partnership (PPP) for a five-year period has been named as “Accelerating Medicines Partnership (AMP)”. According to the report, this US federal government-backed initiative would hasten the discovery of new drugs in cost effective manner focusing first on Alzheimer’s disease, Type 2 diabetes, and two autoimmune disorders: rheumatoid arthritis and lupus. The group considered these four disease areas among the largest public-health threats, although the span of the project would gradually expand to other diseases depending on the initial outcome of this project.

Not the first of its kind:

AMP is not the first PPP initiative of its kind. The Biomarkers Consortium was also another initiative, not quite the same though, of a major public-private biomedical research partnership managed by the Foundation for the NIH with broad participation from a variety of stakeholders, including government, industry, academia, patient advocacy groups and other not-for-profit private sector organizations.

Open innovation strategy of GlaxoSmithKline (GSK) to discover innovative drugs for malaria is yet another example, where GSK collaborated with the European Bioinformatics Institute and U.S. National Library of Medicine to make details of the molecule available to the researchers free of cost with an initial investment of US$ 8 million to set up the research facility in Spain, involving around 60 scientists from across the world to work in this facility. 

Nearer home, ‘Open Source Drug Discovery (OSDD)’ project of the Council of Scientific and Industrial Research (CSIR) is a now a global platform to address the neglected tropical diseases like, tuberculosis, malaria, leishmaniasis by the best research brains of the world working together for a common cause.

Challenges in going solo:

In this context, it is worth mentioning that the CEO of Sanofi, Chris Viehbacher reportedly said in an interview on April 15, 2013 that his company “Won’t push hard to find an Alzheimer’s treatment because the science isn’t advanced enough to justify the costs to develop a drug. Therefore, Sanofi definitely won’t commit major resources seeking to discover an Alzheimer’s therapy.” He further stated, “I think we have to do a lot more basic science work to understand what’s going on. We really, at best, partially understand the cause of the disease. It’s hard to come up with meaningful targets.”

The above report also mentioned that the first Alzheimer’s drugs, should they prove successful, would lead to a market worth US$ 20 billion as estimated in 2012.

Long desired OSDD model:

The new AMP R&D model in the United States seems to have derived its impetus from the “open-source” wave that has swept the software industry. Keeping that spirit unchanged, in this particular ‘open source’ model too, the participants would share all scientific findings with the public and anyone would be able to use these results freely for their own research initiatives.

The collaborators of this PPP project are expected to gain a better understanding of how each disease type works, and thereafter could make use of that collaborative knowledge to discover appropriate new molecules for the target disease areas.

AMP is also expected to arrive at methods to measure a disease progression and its response to treatment much more precisely. This will enable the pharma participants getting more targets right and early, thereby reducing the high cost of failures. Just to cite an example, there have been reportedly 101 failures since 1998 in late-stage clinical trials by Pfizer, J&J and Elan Corp.

Commendable initiative in the uncharted frontier:

The ‘open source’ AMP initiative of ‘Big Pharma’ in the uncharted frontier is indeed very unusual, as the innovative drug companies are believed to be not just quite secretive about the science that they are engaged in, but also near obsessive in pursuing and clinging-on to the Intellectual Property Rights (IPR) through patents for each innovative steps related to potential new drugs.

It is worth noting that like any OSDD model, this PPP agreement also denies the participating players from using any discovery for their own drug research up until the project makes all data public on that discovery.

However, as soon as the project results will be made public, fierce competition is expected all around to develop money-spinning winning drugs.

Participating companies:

Ten pharma companies participating in AMP are reportedly, AbbVie, Biogen Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Eli Lilly, Merck & Co., Pfizer, Sanofi and Takeda. It is good to find within the participants some staunch business rivals. According to a report, a number of foundations, including the American Diabetes Association and the Alzheimer’s Association have also agreed to get involved in the project.

Some key non-participants:

For various different reasons some key pharma majors, such as, Amgen, Roche and AstraZeneca have decided not to participate in AMP.

AMP project and cost:

AMP reportedly has reportedly articulated its intent to: “Map molecular paths that each disease follows and to identify key points that could be targets for treatment. In Type 2 diabetes, for instance, researchers hope to catalog the genetic changes that raise or lower a person’s risk for developing the disease. It also will seek novel methods to measure each disease’s course while assessing if a potential drug is working. Being able to measure a disease’s progress in that way, could speed drug development by raising a company’s confidence that an experimental drug is working, or let it more quickly end a project if a drug isn’t working.”

The participating companies and the NIH have jointly agreed that the AMP would put together a research system on cost sharing basis by pooling the brightest minds who are experts on each disease, along with the best drug discovery laboratories, relevant data and samples from clinical trials to decipher the diseases in ways, which none of these pharma players has been able to achieve just yet on its own.

To achieve all these, the total cost has been estimated at roughly just US$ 230 million, as compared to US$135 billion that the global drug industry claims to spend in a year on R&D.

This should also be seen in context of a study of December 2012 carried out by the Office of Health Economics (OHE), UK with a grant from AstraZeneca, which estimated that the cost of developing new medicine has risen by ten times from US$100 million in the 1970s to as high as US$ 1.9 billion in 2011.

As a head honcho of a global pharma biggie had put it earlier, a large part of these R&D expenses are the costs of failure, as stated above.

Criticism:

As usual, criticism followed even for this path-breaking project. Critics have already started questioning the rationale of the choice of the above four disease areas, with an exception perhaps for Alzheimer’s and wondered whether the participating players are making use of the federal fund to push hard the envelope of their respective commercial intents.

Another new collaborative approach: 

In another recently announced collaborative initiative, though not of the same kind, where Merck & Co has reportedly entered three separate collaboration agreements to evaluate an immunotherapy cancer treatment that is part of a promising new class of experimental drugs that unleash the body’s immune system to target cancer cells.

Conclusion:

There could still be some hiccups in the process of effective implementation of the AMP project. Hope, all these, if any, will be amicably sorted out by the participants of stature for the benefits of all.

Be that as it may, ‘open source’ model of drug discovery, as believed by many, would be most appropriate in the current scenario to improve not only profit, but also to promote more innovative approaches in the drug discovery process.

On May 12, 2011, in an International Seminar held in New Delhi, the former President of India Dr. A.P.J. Abdul Kalam highlighted the need for the scientists, researchers and academics to get effectively engaged in ‘open source’ philosophy by pooling talent, patents, knowledge and resources for specific R&D initiatives from across the world for newer and innovative drugs.

According to available reports, one of the key advantages of the ‘open source’ model would be substantial reduction in the high cost of failures of R&D projects, which coupled with significant saving in time would immensely reduce ‘mind-to-market’ span of innovative drugs in various disease areas, making these medicines affordable to many more patients.

Thus, PPP initiatives in pharmaceutical R&D, such as AMP, are expected to have immense potential to create a win-win situation for all stakeholders, harvesting substantial benefits both for the pharmaceutical innovators and the patients, across the world.

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.

 

 

 

 

R&D: Is Indian Pharma Moving Up the Value Chain?

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It almost went unnoticed by many, when in the post product patent regime, Ranbaxy launched its first homegrown ‘New Drug’ of India, Synriam, on April 25, 2012, coinciding with the ‘World Malaria Day’. The drug is used in the treatment of plasmodium falciparum malaria affecting adult patients.  However, the company has also announced its plans to extend the benefits of Synriam to children in the malaria endemic zones of Asia and Africa.

The new drug is highly efficacious with a cure rate of over 95 percent offering advantages of “compliance and convenience” too. The full course of treatment is one tablet a day for three days costing less than US$ 2.0 to a patient.

Synriam was developed by Ranbaxy in collaboration with the Department of Science  and Technology of the Government of India. The project received support from the Indian Council of Medical Research (ICMR) and conforms to the recommendations of the World Health Organization (WHO). The R&D cost for this drug was reported to be around US$ 30 million. After its regulatory approval in India, Synriam is now being registered in many other countries of the world.

Close on the heels of the above launch, in June 2013 another pharmaceutical major of India, Zydus Cadilla announced that the company is ready for launch in India its first New Chemical Entity (NCE) for the treatment of diabetic dyslipidemia. The NCE called Lipaglyn has been discovered and developed in India and is getting ready for launch in the global markets too.

The key highlights of Lipaglyn are reportedly as follows:

  • The first Glitazar to be approved in the world.
  • The Drug Controller General of India (DCGI) has already approved the drug for launch in India.
  • Over 80% of all diabetic patients are estimated to be suffering from diabetic dyslipidemia. There are more than 350 million diabetics globally – so the people suffering from diabetic dyslipidemia could be around 300 million.

With 20 discovery research programs under various stages of clinical development, Zydus Cadilla reportedly invests over 7 percent of its turnover in R&D.  At the company’s state-of-the-art research facility, the Zydus Research Centre, over 400 research scientists are currently engaged in NCE research alone.

Prior to this in May 14, 2013, the Government of India’s Department of Biotechnology (DBT) and Indian vaccine company Bharat Biotech jointly announced positive results, having excellent safety and efficacy profile in Phase III clinical trials, of an indigenously developed rotavirus vaccine.

The vaccine name Rotavac is considered to be an important scientific breakthrough against rotavirus infections, the most severe and lethal cause of childhood diarrhea, responsible for approximately 100,000 deaths of small children in India each year.

Bharat Biotech has announced a price of US$ 1.00/dose for Rotavac. When approved by the Drug Controller General of India, Rotavac will be a more affordable alternative to the rotavirus vaccines currently available in the Indian market. 

It is indeed interesting to note, a number of local Indian companies have started investing in pharmaceutical R&D to move up the industry value chain and are making rapid strides in this direction.

Indian Pharma poised to move-up the value-chain:

Over the past decade or so, India has acquired capabilities and honed skills in several important areas of pharma R&D, like for example:

  • Cost effective process development
  • Custom synthesis
  • Physical and chemical characterization of molecules
  • Genomics
  • Bio-pharmaceutics
  • Toxicology studies
  • Execution of phase 2 and phase 3 studies

According to a paper titled, “The R&D Scenario in Indian Pharmaceutical Industry” published by Research and Information System for Developing Countries, over 50 NCEs/NMEs of the Indian Companies are currently at different stages of development, as follows:

Company Compounds Therapy Areas Status
Biocon 7 Oncology, Inflammation, Diabetes Pre-clinical, phase II, III
Wockhardt 2 Anti-infective Phase I, II
Piramal Healthcare 21 Oncology, Inflammation, Diabetes Lead selection, Pre-clinical, Phase I, II
Lupin 6 Migraine, TB, Psoriasis, Diabetes, Rheumatoid Arthritis Pre-clinical, Phase I, II, III
Torrent 1 Diabetic heart failure Phase I
Dr. Reddy’s Lab 6 Metabolic/Cardiovascular disorders, Psoriasis, migraine On going, Phase I, II
Glenmark 8 Metabolic/Cardiovascular /Respiratory/Inflammatory /Skin disorders, Anti-platelet, Adjunct to PCI/Acute Coronary Syndrome, Anti-diarrheal, Neuropathic Pain, Skin Disorders, Multiple Sclerosis, Ongoing, Pre-clinical, Phase I, II, III

R&D collaboration and partnership:

Some of these domestic companies are also entering into licensing agreements with the global players in the R&D space. Some examples are reportedly as follows:

  • Glenmark has inked licensing deals with Sanofi of France and Forest Laboratories of the United States to develop three of its own patented molecules.
  • Domestic drug major Biocon has signed an agreement with Bristol Myers Squibb (BMS) for new drug candidates.
  • Piramal Life Sciences too entered into two risk-reward sharing deals in 2007 with Merck and Eli Lilly, to enrich its research pipeline of drugs.
  • Jubilant Group partnered with Janssen Pharma of Belgium and AstraZeneca of the United Kingdom for pharma R&D in India, last year.

All these are just indicative collaborative R&D initiatives in the Indian pharmaceutical industry towards harnessing immense growth potential of this area for a win-win business outcome.

The critical mass:

An international study estimated that out of 10,000 molecules synthesized, only 20 reach the preclinical stage, 10 the clinical trials stage and ultimately only one gets regulatory approval for marketing. If one takes this estimate into consideration, the research pipeline of the Indian companies would require to have at least 20 molecules at the pre-clinical stage to be able to launch one innovative product in the market.

Though pharmaceutical R&D investments in India are increasing, still these are not good enough. The Annual Report for 2011-12 of the Department of Pharmaceuticals indicates that investments made by the domestic pharmaceutical companies in R&D registered an increase from 1.34 per cent of sales in 1995 to 4.5 percent in 2010. Similarly, the R&D expenditure for the MNCs in India has increased from 0.77 percent of their net sales in 1995 to 4.01 percent in 2010.

Thus, it is quite clear, both the domestic companies and the MNCs are not spending enough on R&D in India. As a result, at the individual company level, India is yet to garner the critical mass in this important area.

No major R&D investments in India by large MNCs:

According to a report, major foreign players with noteworthy commercial operations in India have spent either nothing or very small amount towards pharmaceutical R&D in the country. The report also mentions that Swiss multinational Novartis, which spent $ 9 billion on R&D in 2012 globally, does not do any R&D in India.

Analogue R&D strategy could throw greater challenges:

For adopting the analogue research strategy, by and large, the Indian pharma players appear to run the additional challenge of proving enhanced clinical efficacy over the known substance to pass the acid test of the Section 3(d) of the Patents Act of India.

Public sector R&D:

In addition to the private sector, research laboratories in the public sector under the Council for Scientific and Industrial Research (CSIR) like, Central Drug Research Institute (CDRI), Indian Institute of Chemical Technology (IICT) and National Chemical Laboratory (NCL) have also started contributing to the growth of the Indian pharmaceutical industry.

As McKinsey & company estimated, given adequate thrust, the R&D costs in India could be much lower, only 40 to 60 per cent of the costs incurred in the US. However, in reality R&D investments of the largest global pharma R&D spenders in India are still insignificant, although they have been expressing keenness for Foreign Direct Investments (FDI) mostly in the brownfield pharma sector.

Cost-arbitrage:

Based on available information, global pharma R&D spending is estimated to be over US$ 60 billion. Taking the cost arbitrage of India into account, the global R&D spend at Indian prices comes to around US$ 24 billion. To achieve even 5 percent of this total expenditure, India should have invested by now around US$ 1.2 billion on the pharmaceutical R&D alone. Unfortunately that has not been achieved just yet, as discussed above.

Areas of cost-arbitrage:

A survey done by the Boston Consulting Group (BCG) in 2011 with the senior executives from the American and European pharmaceutical companies, highlights the following areas of perceived R&D cost arbitrage in India:

Areas % Respondents
Low overall cost 73
Access to patient pool 70
Data management/Informatics 55
Infrastructure set up 52
Talent 48
Capabilities in new TA 15

That said, India should realize that the current cost arbitrage of the country is not sustainable on a longer-term basis. Thus, to ‘make hay while the sun shines’ and harness its competitive edge in this part of the world, the country should take proactive steps to attract both domestic as well as Foreign Direct Investments (FDI) in R&D with appropriate policy measures and fiscal incentives.

Simultaneously, aggressive capacity building initiatives in the R&D space, regulatory reforms based on the longer term need of the country and intensive scientific education and training would play critical role to establish India as an attractive global hub in this part of the world to discover and develop newer medicines for all.

Funding:

Accessing the world markets is the greatest opportunity in the entire process of globalization and the funds available abroad could play an important role to boost R&D in India. Inadequacy of funds in the Indian pharmaceutical R&D space is now one of the greatest concerns for the country.

The various ways of funding R&D could be considered as follows:

  • Self-financing Research: This is based on:
  1. “CSIR Model”: Recover research costs through commercialization/ collaboration with industries to fund research projects.
  2. “Dr Reddy’s Lab / Glenmark Model”: Recover research costs by selling lead compounds without taking through to development.
  • Overseas Funding:  By way of joint R&D ventures with overseas collaborators, seeking grants from overseas health foundations, earnings from contract research as also from clinical development and transfer of aborted leads and collaborative projects on ‘Orphan Drugs’.
  • Venture Capital & Equity Market:  This could be both via ‘Private Venture Capital Funds’ and ‘Special Government Institutions’.  If regulations permit, foreign venture funds may also wish to participate in such initiatives. Venture Capital and Equity Financing could emerge as important sources of finance once track record is demonstrated and ‘early wins’ are recorded.
  • Fiscal & Non-Fiscal Support: Should also be valuable in early stages of R&D, for which a variety of schemes are possible as follows:
  1. Customs Duty Concessions: For Imports of specialized equipment, e.g. high throughput screening equipment, equipment for combinatorial chemistry, special analytical tools, specialized pilot plants, etc.
  2. Income tax concessions (weighted tax deductibility): For both in-house and sponsored research programs.
  3. Soft loans: For financing approved R&D projects from the Government financial institutions / banks.
  4. Tax holidays: Deferrals, loans on earnings from R&D.
  5. Government funding: Government grants though available, tend to be small and typically targeted to government institutions or research bodies. There is very little government support for private sector R&D as on date.

All these schemes need to be simple and hassle free and the eligibility criteria must be stringent to prevent any possible misuse.

Patent infrastructure:

Overall Indian patent infrastructure needs to be strengthened, among others, in the following areas:

  • Enhancement of patent literacy both in legal and scientific communities, who must be taught how to read, write and file a probe.
  • Making available appropriate ‘Search Engines’ to Indian scientists to facilitate worldwide patent searches.
  • Creating world class Indian Patent Offices (IPOs) where the examination skills and resources will need considerable enhancement.
  • ‘Advisory Services’ on patents to Indian scientists to help filing patents in other countries could play an important role.

Creating R&D ecosystem:

  • Knowledge and learning need to be upgraded through the universities and specialist centers of learning within India.
  • Science and Technological achievements should be recognized and rewarded through financial grants and future funding should be linked to scientific achievements.
  • Indian scientists working abroad are now inclined to return to India or network with laboratories in India. This trend should be effectively leveraged.

Universities to play a critical role:

Most of Indian raw scientific talents go abroad to pursue higher studies.  International Schools of Science like Stanford or Rutgers should be encouraged to set up schools in India, just like Kellogg’s and Wharton who have set up Business Schools. It has, however, been reported that the Government of India is actively looking into this matter.

‘Open Innovation’ Model:

As the name suggest, ‘Open Innovation’ or the ‘Open Source Drug Discovery (OSDD)’ is an open source code model of discovering a New Chemical Entity (NCE) or a New Molecular Entity (NME). In this model all data generated related to the discovery research will be available in the open for collaborative inputs. In ‘Open Innovation’, the key component is the supportive pathway of its information network, which is driven by three key parameters of open development, open access and open source.

Council of Scientific and Industrial Research (CSIR) of India has adopted OSDD to discover more effective anti-tubercular medicines.

Insignificant R&D investment in Asia-Pacific Region:

Available data indicate that 85 percent of the medicines produced by the global pharmaceutical industry originate from North America, Europe, Japan and some from Latin America and the developed nations hold 97 percent of the total pharmaceutical patents worldwide.

MedTRACK reveals that just 15 percent of all new drug development is taking place in Asia-Pacific region, including China, despite the largest global growth potential of the region.

This situation is not expected to change significantly in the near future for obvious reasons. The head start that the western world and Japan enjoy in this space of the global pharmaceutical industry would continue to benefit those countries for some more time.

Some points to ponder:

  • It is essential to have balanced laws and policies, offering equitable advantage for innovation to all stakeholders, including patients.
  • Trade policy is another important ingredient, any imbalance of which can either reinforce or retard R&D efforts.
  • Empirical evidence across the globe has demonstrated that a well-balanced patent regime would encourage the inflow of technology, stimulate R&D, benefit both the national and the global pharmaceutical sectors and most importantly improve the healthcare system, in the long run.
  • The Government, academia, scientific fraternity and the pharmaceutical Industry need to get engaged in various relevant Public Private Partnership (PPP) arrangements for R&D to ensure wider access to newer and better medicines in the country, providing much needed stimulus to the public health interest of the nation.

Conclusion:

R&D initiatives, though very important for most of the industries, are the lifeblood for the pharmaceutical sector, across the globe, to meet the unmet needs of the patients. Thus, quite rightly, the pharmaceutical Industry is considered to be the ‘lifeline’ for any nation in the battle against diseases of all types.

While the common man expects newer and better medicines at affordable prices, the pharmaceutical industry has to battle with burgeoning R&D costs, high risks and increasingly long period of time to take a drug from the ‘mind to market’, mainly due to stringent regulatory requirements. There is an urgent need to strike a right balance between the two.

In this context, it is indeed a proud moment for India, when with the launch of its home grown new products, Synriam of Ranbaxy and Lipaglyn of Zydus Cadilla or Rotavac Vaccine of Bharat Biotech translate a common man’s dream of affordable new medicines into reality and set examples for others to emulate.

Thus, just within seven years from the beginning of the new product patent regime in India, stories like Synriam, Lipaglyn, Rotavac or the R&D pipeline of over 50 NCEs/NMEs prompt resurfacing the key unavoidable query yet again:

Has Indian pharma started catching-up with the process of new drug discovery, after decades of hibernation, to move up the industry ‘Value Chain’?

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.

Open Innovation: Quo Vadis, Pharmaceutical R&D?

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Is the Pharmaceutical R&D moving from the traditional models to much less uncharted frontiers?

Perhaps towards this direction, in November, 2010 in a report titled, “Open Source Innovation Increasingly Being Used to Promote Innovation in the Drug Discovery Process and Boost Bottomline”, Frost & Sullivan underscored the urgent need of the global pharmaceutical companies to respond to the challenges of high cost and low productivity in their respective Research and Development initiatives, in general.

‘Open Innovation’ model, they proposed, will be most appropriate in the current scenario to improve not only profit, but also to promote more innovative approaches in the drug discovery process.  Currently, on an average it takes about 8 to 10 years to bring an NCE/NME to market with a cost of around U.S$ 1.7 billion.

The concept of ‘Open Innovation’ is being quite successfully used by the Information Technology (IT) industry since nearly three decades all over the world, including in India.  Web Technology, the Linux Operating System (OS) and even the modern day ‘Android’ – the open source mobile OS, are excellent examples of ‘Open source innovation’ in IT.

In the sphere of Biotechnology Human Genome Sequencing is another remarkable outcome in this area.

On May 12, 2011, in an International Seminar held in New Delhi, the former President of India Dr. A.P.J. Abdul Kalam commented, “Open Source Drug Discovery (OSDD) explores new models of drug discovery”. He highlighted the need for the scientists, researchers and academics to get effectively engaged in ‘open source philosophy’ by pooling talent, patents, knowledge and resources for specific R&D initiatives from across the world. In today’s world ‘Open Innovation’ in the pharmaceutical R&D has a global relevance, especially, for the developing world of ‘have-nots’.

The ‘Open Innovation’ model: 

As the name suggest, ‘Open Innovation’ or the ‘Open Source Drug Discovery (OSDD)’ is an open source code model of discovering a New Chemical Entity (NCE) or a New Molecular Entity (NME). In this model all data generated related to the discovery research will be available in the open for collaborative inputs. The licensing arrangement of OSDD where both invention and copyrights will be involved, are quite different from any ‘Open Source’ license for a software development.

In ‘Open Innovation’, the key component is the supportive pathway of its information network, which is driven by three key parameters of open development, open access and open source.

As stated earlier, ‘Open Innovation’ concept was successfully used in the ‘Human Genome Project’ where a large number of scientists, and microbiologists participated from across the world to sequence and understand the human genes. However, this innovation process was first used to understand the mechanics of proteins by the experts of the Biotech and pharmaceutical industries.

The Objectives of ‘Open Innovation’: 

The key objective of ‘Open Innovation’ in pharmaceuticals is to encourage drug discovery initiatives, especially for the dreaded disease like cancer and also the neglected diseases of the developing countries to make these drugs affordable to the marginalized people of the world.

Key benefits of ‘Open Innovation’:

According to the above report of Frost & Sullivan on the subject, the key benefits of ‘Open Innovation’ in pharmaceuticals will include:

• Bringing together the best available minds to tackle “extremely challenging”   diseases

• Speed of innovation

• Risk-sharing

• Affordability

Some issues:

Many experts feel that the key issues for ‘Open Innovation’ model are as follows:

  • Who will fund the project and how much?
  • Who will lead the project?
  • Who will coordinate the project and find talents?
  • Who will take it through clinical development and regulatory approval process?

However, all these do not seem to be an insurmountable problem at all, as the  saying goes, ‘where there is a will, there is a way’.

Current Global initiatives for ‘Open Innovation’:

  1. In June 2008, GlaxoSmithKline announced in Philadelphia that it was donating an important slice of its research on cancer cells to the cancer research community to boost the collaborative battle against this disease. With this announcement, genomic profiling data for over 300 sets of cancer cell lines was released by GSK to the National Cancer Institute’s bioinformatics grid. It has been reported that over 900 researchers actively contribute to this grid from across the industry, research institutes, academia and NGOs. Many believe that this initiative will further gain momentum to encourage many more academic institutions, researchers and even smaller companies to add speed to the drug discovery pathways and at the same time make the NCEs/NMEs coming through such process much less expensive and affordable to a large section of the society, across the globe.
  2. The Alzheimer’s  Disease Neuroimaging Initiative (ADNI) is another example of a Private Public Partnership (PPP) project with an objective ‘to define the rate of progress of mild cognitive impairment and Alzheimer’s disease, develop improved methods for clinical trials in this area and provide a large database which will improve design of treatment trials’. 
  3. Recently announced ‘Open invitation’ strategy of GlaxoSmithKline (GSK) to discover innovative drugs for malaria is yet another example where GSK has collaborated with European Bioinformatics Institute and U.S. National Library of Medicine to make the details of the molecule available to the researchers free of cost with an initial investment of US $ 8 million to set up the research facility in Spain involving around 60 scientists from across the world to work in this facility.

‘Open Innovation’ in India: 

In India, Dr. Samir Brahmachari, the Director General of the Council of Scientific and Industrial Research (CSIR) is the champion of the OSDD movement. CSIR believes that for a developing country like India OSDD will help the common man to meet his unmet medical needs in the areas of neglected tropical diseases.

‘Open Innovation’ project of CSIR is a now a global platform to address the neglected tropical diseases like, tuberculosis, malaria, leishmaniasis by the best research brains of the world working together for a common cause.

To fund this initiative of the CSIR the Government of India has allocated around U.S $40 million and an equivalent amount of funding would be raised from international agencies and philanthropists.

Success of ‘Open Innovation’ initiative of CSIR: 

Sometime in late November 2009, I received a communication from the CSIR informing that their OSDD project, since its launch in September 2009, has crossed 2000 registered users in a very short span of time. The pace of increasing number of registered users indeed reflects the confidence that this initiative has garnered among the interested researchers across the world.

CSIR has indicated that the next big leap planned by them in the area of ‘Open Innovation’ is to completely re-annotate the MTb genome for which they have already launched a project titled ‘Connect to Decode’ 2010.

Conclusion: 

Currently pharmaceutical R&D is an in-house initiative of innovator global companies. Mainly for commercial security reasons only limited number of scientists working for the respective innovator companies will have access to these projects.

‘Open Innovation’ on the other hand, has the potential to create a win-win situation, bringing in substantial benefits to both the pharmaceutical innovators and the patients.

The key advantage of the ‘Open Innovation’ model will be substantial reduction in the costs and time of R&D projects, which could be achieved through voluntary participation of a large number of researchers/Scientists/Institutions in key R&D initiatives. This in turn will significantly reduce the ‘mind-to-market’ time of more affordable New Chemical/Molecular Entities in various disease areas.

Thus, to answer to ‘Quo Vadis, Pharmaceutical R&D’, I reckon, ‘Open Innovation’ model  could well be an important direction for tomorrow’s global R&D initiatives to improve access to innovative affordable Medicines to a larger number of ailing patients of the world, meeting their unmet medical needs, more effectively and with greater care.

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.

Open Source Drug Discovery (OSDD) initiative for the tropical diseases by CSIR and cancer by GlaxoSmithKline deserves a big applaud and support from all concerned.

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As the name suggest the ‘Open Source Drug Discovery (OSDD)’ is an open source code model of discovering a New Chemical Entity (NCE) or a New Molecular Entity (NME). In this model all data generated related to the discovery research will be available in the open for collaborative research inputs. The licensing arrangement of OSDD where both invention and copyrights will be involved, are quite different from any ‘Open Source’ license for a software development.

In OSDD, the key component is the supportive pathway of its information network, which is driven by three key parameters of open development, open access and open source.

The Objectives of OSDD:

The key objective of OSDD is to encourage drug discovery initiatives, especially for the neglected diseases of the world to make these drugs affordable to the marginalized people, especially of the developing world.

International initiative:

In June 2008, GlaxoSmithKline (GSK) announced in Philadelphia, “It was donating an important slice of its research on cancer cells to the cancer research community to boost the collaborative battle against this disease.”

With this announcement genomic profiling data for over 300 sets of cancer cell lines was released by GSK to the National Cancer Institute’s bioinformatics grid. It has been reported that around 1000 researchers actively contribute to this grid from across the industry, research institutes, academia and NGOs.

Many believe that the OSDD initiative will gain momentum to encourage many more academic institutions, researchers and even smaller companies to add speed to the drug discovery process and at the same time make the NCEs/NMEs coming through such process much less expensive and affordable to a large section of the society.

On an average it takes about 8 to 10 years to bring an NCE/NME to market with a cost of around U.S$ 1.7 billion.

OSDD in India:

In India, Dr. Samir Brahmachari, the Director General of the Council of Scientific and Industrial Research (CSIR) is the champion of the OSDD movement. CSIR believes that for a developing country like India, OSDD will help the common man to meet his unmet medical needs in the areas of neglected tropical diseases.

OSDD in India is a global platform to address the neglected tropical diseases like, tuberculosis, malaria, leishmaniasis by the best research brains of the world, together.

To fund the OSDD initiative of the CSIR the Government of India has allocated around U.S $40 million and an equivalent amount of funding would be raised from international agencies and philanthropists.

It has been reported that current priority of CSIR in its OSDD program is the tuberculosis disease area.

Why tuberculosis?

The published reports indicate, in every 1.5 minutes one person in India dies of tuberculosis and about 33 percent of the global population is infected primarily with Mycobacterium tuberculosis. The world is still quite far from having an effective vaccine or drug, which can offer long term protection against this dreaded disease.

Partnerships of Industry with belief in Open Source systems and models with CSIR in its OSDD project for tuberculosis, could help finding out a suitable answer to this long standing problem, sooner than later.

Success of OSDD initiative of CSIR:

Late November 2009, I received a communication from the CSIR informing that their OSDD project, since its launch in September 2009, has crossed 2000 registered users. The pace of increase in the number of registered users indeed reflects the confidence this initiative has generated among the interested researchers, the world over.

OSDD community of CSIR has several credits to be proud of including open peer review, open funding review, large number of real time data on open lab notebook.

CSIR has also indicated that the next big leap planned by them is to completely re-annotate the MTb genome for which OSDD has launched ‘Connect to Decode’ 2010 (http://crdd.osdd.net). They initially expected about 150 participants to join, but within a week, they got about 450 participants. That is really the strength of collaboration on OSDD!

Congratulations CSIR and its leader Dr. Samir Brahmachari.

By Tapan 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.

‘Orphan Drugs’ for ‘Orphan Diseases’ – is ‘Open Source Drug Discovery (OSDD)’ platform for discovery research the way forward?

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To meet the unmet needs of common and dreaded diseases intensive R&D activities are being undertaken by the Pharmaceutical Industry, the world over. At the same time, a percentage of human population, however small, also suffers from some rare diseases, for which there are no approved medical treatments even in the twenty first century, for the rich and poor alike.These rare diseases are also termed as ‘orphan diseases’, which are often chronic, progressive, degenerative, life-threatening or disabling. Many patients suffering from such rare diseases are denied their right to get their ailments effectively treated.It is indeed heartening to note that European Organization for Rare Diseases (EURORDIS) and National Alliances announced February 29, 2008 as the first ‘Rare Disease day’. Thereafter, the last day of February has been designated as ‘Rare Disease Day’ worldwide to call attention to the public health issues associated with rare diseases, which have been reported to affect around 30 million patients around the world.

People with rare diseases remain a medically underserved population even in a developed country. We can then well imagine the plight of such patients in India. The ‘Rare Disease Day’ is intended to bring together the patients and families with rare diseases to discuss the need for greater awareness, more research, and better access to diagnosis and treatment. I am not sure how various authorities, including our Government, are deliberating on this healthcare issue.

People suffering from ‘orphan diseases’ often face huge challenges compared to more common diseases. These include delay in getting an accurate diagnosis, few treatment options and difficulty finding medical experts. Many such rare diseases have no approved treatment. Moreover, treatments for ‘orphan diseases’ tend to be in most cases more expensive than treatments for more common diseases.

This year, the “Rare Disease Day” will be observed in India also, on February 28, though these are not very much talked about in our country, nor is there any proper definition in place for such diseases, as yet.

The drugs meant for treating ‘orphan diseases’ have been very appropriately termed as ‘orphan drugs’, mainly due to commercial reasons, as such drugs will be used on much fewer patients with commensurate return on investments towards R&D. Thus spending expensive R&D resources toward such drugs may not make sound commercial sense.

To address this need, in 1983, the Orphan Drug Act was passed by the Congress in the USA to extend financial incentives for companies to develop treatments for rare diseases. Since then, nearly 330 ‘orphan drugs’ and biologics have been approved by the U.S. FDA, which estimates that from 11 to 14 million Americans would benefit from these ‘orphan drugs’. However, despite such commendable measures taken by the US FDA, around 15 million Americans still leave with such ‘orphan diseases’ for which there is no approved treatment.

It is interesting to note that some of these ‘orphan diseases’ are now being diagnosed in India, as well. As India takes rapid strides in medical science, more of such ‘orphan diseases’ are likely to be known in our country.

Thus the moot question is how does India address this issue with pro-active measures? In the USA, even by giving adequate financial incentives, this problem could not be effectively addressed for commercial reasons.

In my view, one of the ways to properly address this issue is to follow the model of our very own the Council of Scientific and Industrial Research (CSIR) for an ‘Open Source Drug Discovery’ (OSDD) program with global partnerships, wherever required. This initiative has been pioneered by the well known scientist and Director General of CSIR Dr. Samir Brahmachari. Andrew Witty, the CEO of GlaxoSmithKline also had mooted a similar idea in another context in not too distant past.

Therefore, to address the issue of ‘orphan diseases’, in my opinion, the OSDD model with partnerships between private, public and academia will not only prove to be a viable and more practical model to discover ‘orphan drugs’, but will also help India to effectively contribute to this important global issue – not just by observing the ‘Rare Diseases Day’ on February 28 or 29, each year.

By Tapan 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.