Les Propheties Pharmaceuticale : Prophesying on where the pharmaceutical outsourcing is headed

It is either an after-effect of all that powwow with the old-worldly Chippewa (the ‘real-Indians’, who aren’t Indian really ;-)) in the round house OR, it’s the paradoxical audacity stemming from my ironic inability to predict my own future!! - Either way…….,

......I have this compelling urge to play an oracle for once & mouth some prophecies!

My prophesying though is limited to pharmaceutical manufacture, outsourcing & is inspired by what’s going on right now all around in the pharmaceutical industry. While on first-look most of the recent happenings appear to be standalone in nature, there is a tangible pattern that isn’t too tough to decipher. My attempt is merely to speculate on what this pattern means for pharmaceutical manufacturing scenario, a few years from now, albeit a little prophetically.

Listed below are a some of my observations, statements & surmises (not still prophecies....), in no particular order, based on a handful but trend-indicative news alerts that I received over the past two weeks;

• Big pharma shutting-down small molecule manufacturing sites but investing in Biologics facilities - Merck, Pfizer, Novartis, AstraZeneca etc in shutting-down mode & Roche, Genzyme (Sanofi) et al in investment spree

• CMOs & Pharma companies scramble to strengthen ADC manufacturing capabilities in an apparent response to the visible thrust by drug developers to biologify (sic) unsuccessful small molecule candidates as ADCs & reposition them as targeted therapy candidates - SAFC, Lonza & Roche strengthening ADC capacities

• Indications that compulsory license issuance in developing countries is driven more by ‘access to cost-effective first-line therapies’ than ‘access to later-generation therapies’  - Indian Patent office Upholding CL for Imatinib & rejecting CL application for Dasatinib

• Federal complicity (vis-à-vis’ regulatory) with the innovator belief that biosimilar is an Oxymoron – The recent passage of SB-598 bill constraining use of biosimilars by State of California

• Regulators mellowing, but playing-safe with approval of biosimilars? - The first ever biosimilar approval by EMEA is for Remicade (infliximab) indicated in the ‘relatively non-fatal” auto-immune disorders

• Geographical re-alignment and consolidation of biosimilar manufacturing assets - Dr. Reddy’s  signing a deal for getting it’s biosimilars manufactured & marketed within the USA by Merck-Serono; Lonza’s scrapping of biosimilar venture with Teva and it’s going slow on India expansion; DSM launching a large-scale biosimilar facility in Australia et al

• The increased focus of Big-pharma on having a lean & integrated supply chain for their off-patent assets – As indicated by the on-going race of backward-integration by formulation CMOs & forward integration by API CMOs

• Drug Discovery & Development (primarily chemistry, biology & clinical) service providers progressively getting consolidated within NA, EU with clinical development centers in low-cost countries – As indicated by the flurry of activity each passing day

• Clinical API synthesis tending to be retained within the shores by the partly to de-risk late-stage regulatory risks & mostly to engage residual in-house R&D facilities – As indicated by the outsourcing strategy adopted by most Big & Mid-sized pharma

• Spurred-on by increasing regulatory wariness, high focus by the outsourcer' on ensuring supply chain integrity for key Intermediates and starting material for both marketed as well as developmental drugs – As indicated by the uncharacteristically massive press-coverage of  WuXi successfully facing a FDA pre-approval inspection for the ‘Intermediate’ of a new drug under review for approval

While the observations tell a story of their own, here’s my promised prophecy in the form of three quatrains, which very unlike the good old Nos’, I went about decoding myself – so much for my quest to be understood in my lifetime!

Quatrain 1

Decoded:

The Indian &/or Chinese CMO/ CDMO/ CROs will see the outsourcing getting limited to;

·        Manufacture of generic, low-tech (applicable to DP) small molecule, high volume & predominantly disease-maintenance/ management therapeutics (as against curative therapeutics)

·        Manufacture of (ideally integrated) potent, cytotoxic therapeutics    

·        Non-GMP/ GMP manufacture of key intermediates requiring large capacities/ ~ economies of scale of both patent-case & generic APIs for big/ mid-sized pharma

·        Large-scale manufacture of OTCs & Medicinal Products (components of med devices)

·        Early development (preclinical through PIII) of investigational drugs belonging to small/ mid & big-pharma (since this stage demands a lean-cost model)

·        Late-stage development (leading to NDA) of investigational drugs for small/ virtual biotechs

Quatrain 2

Decoded:

The North American, European CMO/ CDMO/ CROs will see the consolidation of the following opportunities in their favor;

·        Manufacture of Biologics, Biosimilars(authorized?)  

·        Manufacture of high-tech, specialty small-molecule APIs (ADCs, PDCs et al); formulations & devices

·        Late-stage development (leading to NDA) of investigational drugs for Mid & Large-sized pharma

·        Integrated Drug-discovery, development for Big pharma

Quatrain 3

Decoded:

Finally & a tad controversially – the Indian pharmaceutical players (& probably Chinese too) in general will aggressively pursue;

·        Compulsory licensing opportunities for the first-line therapies of small-molecule drugs for the NON-orphan disease segments

·        Biosimilar/ biogeneric development (for potential global alliances) and for eventual direct commercialization (with likely alliances again..) within India – with emphasis on curative biologics for non-fatal disease segments not addressed by small-molecule therapeutics    

As is evident, this list of predictions is by no means exhaustive & is only a brief compilation based on some core-opportunity types focused on within the outsourcing domain.

I know Nostradamus has more detractors than believers, so go ahead and flame me, I’m all game! ............ Only, make sure your rebuttals are in Quatrains too…., Just kidding :-)

    

Shouldn't all pharmaceutical professionals too take the Hippocratic Oath?

The news about the generic drug maker Ranbaxy Labs pleading guilty to felony charges related to drug safety and its acceptance of $500 million in civil and criminal fines created an unprecedented buzz in the world-wide web. The most incisive piece by far appears to be “the epic inside story of long-term criminal fraud at Ranbaxy.....” By Katherine Eban on CNN Money.

No horror story is complete without its share of seedy alleys, murky dealings & closed cup-boards that contain multitudes of hidden skeletons - this too has. Even as all the digging is indeed required towards a total expose’, the associated spill/ shoot-out of emotional rhetoric is threatening to harm the still-early but the strong trend of genericization of global medicare.

Can we raise above the rhetoric of branded drugs v/s generic drugs; first-world v/s third-world & address the core issue of why medical frauds happen & what can be done to plug these? 

My Comment on the above article:

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A very compelling narrative & an alarmingly scary proposition…. 

I fully agree with the majority opinion here that the consequences of a fraud this big should be equally big for the company in question. But again, I also endorse the opinion of a few others like Sam Werbalowsky, Dan Miller et al who have pointed out that Ranbaxy isn't a standalone case in the shameful history of pharmaceutical frauds & that the focus should be on ethical business of all Pharma & not just the generic players as Ranbaxy – It is important to underscore this particular aspect at this juncture since the tone & tenor of this otherwise brilliant piece makes it prone to being construed as a platform for demonizing the generic medicine vis-a-vis' branded drugs. 

A quick look at the list of infamy here & here establishes that the common thread running through all is the disturbing trend of the best-of-the-organizations taking a call of preferring earnings over ethics at critical decision points. Another common aspect among all is the seeming complicity of a vast number of employees at all levels of the organization to misrepresenting a fact or manipulating an outcome. This shows that the problem is not just at the top decision making levels but is endemic at all levels of hierarchy & there’s this shocking apathy all through to what amounts to ethical behavior of an average worker/ employee in a pharmaceutical organization.

Given the complete insulation of an average pharmaceutical employee to the consumer-end of the spectrum & hence insulation from the consequences of any wrong-doing, I'm a little sceptical as to what will motivate these people to be vigilantes of public health & safety at their work place, pardon my cheekiness here, whether or not that involves whistle-blower benefits – THIS apparent lack of ownership of public health & safety in pharmaceutical manufacturing world is what I believe is the real core problem.

While there may be much creative reasoning & some complex solutions to the above core problem, I’d like to keep it simple & say that the reason is a lack of any formal sensitization of a pharmaceutical industry worker prior to or during his/ her employment on her/ his own accountability to public health & safety in general & the solution I hence propose is to instil this accountability in all pharmaceutical employees by way of a Hippocratic Oath that unfortunately is currently merely confined to medical practitioners & decreasingly so.

Food for thought.

Ref: my earlier post at:

http://vishrasayan.blogspot.in/2013/03/factors-influencing-global-prospects.html

Factors Influencing the Global Prospects & Investor Attractiveness of Indian Pharmaceutical Industry

Most ‘Indian Pharma Outlook’ reports from the likes of McKinsey & PwC  almost exclusively focus their policy & regulatory scenario call-outs on aspects that bear an impact on entry & exit strategies of global pharmaceutical companies - which is understandable given they form the healthcare client-base of these consulting organizations. Not much information is however available when it comes to information on the policy & regulatory landscape within India that has a bearing on the commercial prospects of Indian pharmaceutical companies globally & one that can influence the investor sentiment/ emotion driving it.

Inspired by CNN Money’s beautifully minimal ‘Fear & Greed Index’, I set about categorizing and analysing the three most debated India-specific pharmaceutical policy & trade issues in the past few months. Thus categorized as low, elevated & high risk, these three issues broadly mapped out the boundaries of factors influencing ‘Global Prospects & Investor Attractiveness of Indian Pharmaceutical Industry”.

I

COUNTERFEIT MEDICINE

Lack of candor in acknowledging a local & global menace of counterfeit drugs

FDA website says “Counterfeit medicine is fake medicine. It may be contaminated or contain the wrong or no active ingredient. They could have the right active ingredient but at the wrong dose. Counterfeit drugs are illegal and may be harmful to your health” – While US Pharmacopeia broadly uses the same definition, it extends the scope of fake to the drugs that are “deliberately mislabelled” and with “fake-packaging” - Now, while the definitions do not say so, it is an inferred & accepted norm within the regulatory, federal & industry circles within USA, EU most other developed economies that any drug approved for a certain geography/ country if found to be distributed, marketed in another geography where it hasn’t obtained any approval makes that drug a counterfeit too.

In what could be explained within ten lines of text as above & given this is a definite public health issue, it’s confounding how so much energy is spent by so many espousing interpretations of varied hues on what doesn’t amount to a counterfeit. A recent news item in TOI showcases how a whole country’s credibility could take a beating with misinformed defence of an ill-articulated official position. The gentleman in the referred article states "Counterfeit is essentially an intellectual property issue referring to falsely packaged products that violate trademarks, but it is not necessarily about the quality of the medicine" - almost affecting that a counterfeit with a real API a lesser crime" – If this is indeed the official position of Indian on counterfeits, it sure needs work.

Factors at play

From the consumer’s perspective it could be Cost differential of counterfeits vis-à-vis’ branded formulations & No-hassles (online) access of Prescription drugs. From the counterfeiter’s perspective, it’s all about monetizing the existence of a vast ill-informed & gullible market 

& then there is this legacy of distrust & malice……

While there is/ was a definite basis to suspect & investigate role of India connection to the counterfeits, for a larger part of the last decade FDA, PhRMA, SOCMA & EFCG and the various allied task-forces went on an extended witch hunt, not entirely without dishonourable motives (read: SOCMA, EFCG; NA/ EU manufacturers losing out to outsourcing to India), for Indian knockoff offenders & in the bargain tarnishing the image of many ethical Indian organizations that in some instances were completely unaware of their product getting trans-shipped through parallel/ secondary import channels (ref. the PhRMA report on counterfeit drug statistics quoting 2008 data)

*Image courtsey: from a Forbes article about Indian companies adaptng the mobile verification systems in a big way

Pros & Cons

↑ ZILCH: There can absolutely be nothing positive about;

• A fake drug with a spurious drug &/OR
• A counterfeit with a real drug &/OR
• A true generic in an unauthorized territory 

↓ CREDIBILITY: Any knee-jerk reactions such as the above, based impractically on a painful legacy, may end up sounding like a tacit Indian support to counterfeit industry and will severely harm the genuine promise Indian generic industry holds and is pursuing

↓ PUBLIC HEALTH: The above cynical approach to addressing global concerns on counterfeits can easily get rubbed off within the Indian context & the consequent confusion can be used by counterfeiters to take root & rot the whole public health system within India

↓ NET IMPACT ON INDIAN PHARMA:  This is a no-brainer really, with zero positive & two negatives; this is a present & imminent danger to the credibility of Indian pharmaceutical Industry.

What could Indian Pharmaceutical industry & policy makers do to address the above aspects/ issues?

Ironically a lot of Indian response to any dialog on counterfeits still seems to be based on the sole concept that some of the "real-API counterfeits' are traceable to India & many a time, without the manufacturing company realizing so  - while this may still be a relevant grouse, it still cannot be the sole discussion point whenever someone mentions counterfeits.

From a global perspective, Counterfeits, even if they use “real API” should still be eliminated from supply chain owing to the following consequences* (adapted from a USP DQI presentation) of their existence;

• Diminished trust in health care system
• Waste of financial resources
• People go untreated—leads to prolonged illness or, possibly, death
• Sub-potent treatment can lead to resistance and treatment failure

India Pharma Industry, policy makers should shed the baggage of the hurtful past & acknowledge explicitly to the world community that the above concerns are applicable for control of counterfeits on the Indian soil too & hence both internally & externally India will deal with all dialog on counterfeit medicine FIRST as a public safety debate & THEN as a trade debate.

Looking ahead

The regulators & industry in developed countries such as USA & EU, UK should also look beyond the greed-driven commerce as the trigger for the existence of counterfeits & acknowledge that the  reasons can be equally economical, triggered by the need for affordable medicine for the outlier population that is neither covered by the state nor by the insurance companies. This aspect is bound to be helped by the current winds of genericization blowing through USA & Europe and this trend will hopefully and naturally topple the cheap counterfeit applecart – Having said that tackling counterfeits should be the primary corporate social responsibility of the pharmaceutical industry worldwide.

II

COMPULSORY LICENSING

The not so surprising enthusiasm for the compulsory Licensing route to introduction of 'copy cats'

Back in March 2012, Natco Pharma opened the gates (or Pandora's box depending upon which side of fence one is..) with their successful bid for the Compulsory License of Sorafenib Tosylate (Nexavar) using the provisions set out in the TRIPS agreement. The recent endorsement of this decision by IPAB seems to have ushered-in the growth-phase of CLs with BDR Pharmaceuticals of Mumbai filing an application for Dasatinib and the grapevine says quite a few as this are lined up in the immediate future, in India & overseas.

While CLs are being looked into seriously by other developed countries too, what complicates it in the Indian context is the sheer price difference that makes the royalty on sales to the innovator a trifling formality and the sheer size of the lost opportunity for the innovator huge (size of Indian population).  The case-in-study being Nexavar again wherein Bayer’s price is 35 times the Natco’s price & the 7% royalty Bayer was granted, wouldn’t even pay for their lawyers fee at the initial sales volume.

Factors at play

Cost effective access to newer therapeutics in India, Compliance with global IPR norms (both prescribed & inferred) and last but not the least, A really big (read: 1.2 billion population) market opportunity, the surface of which has been hardly scratched.

Pros & Cons

↑ SOCIA IMPACT:  The Indian population will have economical access to technologically superior later-date drugs

↑ FINANCIAL IMPACT: Opening up of a new market in India for these newer therapies hitherto not adopted owing to a steep price barrier

↓ CREDIBILITY: The Indian pharmaceutical industry's credibility will take a hit if the trend catches up in a big & uncontrolled fashion - The obvious impact will be a gradual deceleration of outsourcing to India & more specifically withdrawal of contract manufacturing of proprietary drugs in India by innovators affected by the CL (which could be all within a very short-span)

↓ NET IMPACT ON INDIAN PHARMA: At the current stage, I’d believe Indian industry as a whole has more to lose w.r.t. loss of outsourcing pie than the money generated out of the CL drugs.

Also, despite a large price differential & given the drug use in India is still physician controlled & not state-sponsored or paid for by the insurers, the innovator companies are likely to resort to a sustained campaign through physicians to color the local copy-cat as a 'compromised medicine' & thus can significantly and negatively impact the Indian company's anticipated fortunes – Improbable as this may sound, this indeed happened a few years ago in the vaccine domain with the MNCs spoiling the retail-dreams of the local contenders using their sheer financial-muscle & reach to influence the physician** against the local vaccine.

**My daughter’s pediatrician forcefully opposed my suggestion to go-in for a Hep-B vaccine from a good Indian company & insisted that he wouldn't suggest we compromising on the quality of the vaccine and that we should instead opt for the pricier but reliable MNC  - Ironically, a decade later this Indian company was acquired by the very same MNC :-))

What could Indian Pharmaceutical industry & policy makers do to address the above aspects/ issues?

A transparent, public evaluation of the application & a greater scrutiny of the "need"/ "essentiality" of a certain new drug vis-a-vis further price rationalization drugs that have already fallen off the patent cliff.

Possession of validated process for the said drug by the applicant at the time of application to be deemed as an automatic disqualification - to mean, since this indicates that the applicant reaching out to the innovator for a licence has been done without an intent to get one & hence that refusal of a license by the innovator is not sufficient basis of the Indian generic company to go in for a CL route

In effect create a higher barrier to incoming applications & thus walling-out contestable awards that bring no incremental benefit neither to the industry nor to the consumer

Looking ahead

While at the face of it this may look like essentially an opportunity for Indian generic players, I tend to believe that pretty soon the global generic giants will join the game through strategic alliances, acquisitions et al & eventually even innovators would themselves monetize the trend by introducing authorized "cheap" generics - “Cheap” being the keyword, as it is eminently evident from the Nexavar price differential, a mere 20-30% reduction wouldn’t really sway the regulatory sentiment in favour of innovator.

III 

ENHANCED VISIBILITY

Gearing up for better transparency, eventually

Even as articulation of a position is still a challenge for India in some key policy areas as above, Visibility, mostly aided by cyberization of governance is getting bigger & better in India each day. While digital governance may be an emerging global phenomenon, what makes it unique in the Indian context is that this amounts to a tentative first step towards transparency, a beast that India is struggling to tame for many years now.

Specific to healthcare, within the past four months the Indian patent authority (CGPDTM) has issued draft guidelines for processing patent applications pertaining to Biotechnology; Biological Material & Traditional Knowledge. What makes this interesting is the public review & dialog to aid the process of finalizing the guidelines.

Factors at play

The acknowledgement of a consensus approach to policy making; The concept an of enforcement designed & driven by the stakeholder universe; An attempt to encourage innovation within India by providing clarity on patentability aspects & finally, a rather brave attempt to forestall patent walling-in attempts by companies & to prevent encroachments on traditional knowledge

The pros & cons

↑ ENABLING BUSINESS CLIMATE – As a country that conducts business transactions in English, India already has an inherent advantage with respect to visibility & transparency. The increased digital visibility will go a long way in helping India consolidate this advantage & give a much needed differentiator vis-à-vis the omnipresent Chinese competition

↑ IMPROVED BUSINESS ETHIC – Each step in this direction will help India better its ranking on the transparency international’s corruption index – in part the visibility through digital governance itself is an outcome of higher awareness, wariness of the Indian citizen towards corruption in public & corporate life

↓ DELAYED POLICY MAKING – Though my initial thought was to say nothing negative here, I realize that the Indian problem with ‘clear articulation of a policy’ can be further compounded by the diversity of information received through feedback, debates et al & thus potentially delay the legislation of the guidelines

↑ NET IMPACT ON INDIAN PHARMA – Overall any favourable changes in governance will always translate as a better business/ investor sentiment, eventually

What could Indian Pharmaceutical industry & policy makers do to address the above aspects/ issues?

Indian pharma would do good to dive head-long into this process of deliberation on policies; guidelines etc. and partake in creating an enabling framework. On their part, the policy makers, government should proactively solicit participation of Industry and fine-tune the guidelines in light of practical business considerations.

Looking ahead

As stated earlier, enhanced visibility is the tentative first step towards transparency – it’d be ideal for all stakeholders to do whatever they could to sustain this forward momentum & help India shed the stereotypical image of a difficult third world country.

While I stopped at three, there are some other important factors that can impact the prospects of Indian pharma in some measure - a quick visual representation of these factors is as follows;

One recurring theme in the above discussions is a need for emergence of clearly articulated and transparently evaluated policies which then could be implemented in spirit.

Where no other motivation works the lure of commerce does, well in most cases. While this may sound dogmatic, it is a valid reason for an economy increasingly dependent on globalization & externalization. I wish & hope the Indian Pharmaceutical Industry will play a major role in setting the house in order & thus achieve and sustain their much deserved success world-over.

Has the rise of an Indian sun in drug discovery horizon turned out a no-show? OR is it a mere eclipse?

Looking up on google to put together my next post, I typed out the text “Drug discovery prospects India” and the top most hit was that of a 2012 Current Science study that went on to explain how the authors figured that the prospects are poor for original drug discovery in India. Not quite the encouraging start I was hoping for.., I scrolled further down and I find the counter poser, a report by Kauffman, no less, that predicted a bright future for drug discovery in India way back in 2008.

While the 2012 article, incidentally by Indian authors, isn’t necessarily a very brightly designed study and the Kauffman analysis isn’t exactly reeking of academic rigor, together these reports do raise the pertinent question of, if the rise of the Indian sun in drug discovery horizon turned out a no show? or is it a mere eclipse?

To part validate the above hypothesis, I went about tracking the flow of funds into life science enterprises within India in the past four years – some observations;

• Considering the 2012 article slams the quality of innovation of Indian CROs,  the discovery services companies ironically cornered >40% of all the investment made in past three years
• The investments into medical devices & diagnostics pretty much followed the global trend which has been incremental over years  
• Manufacturing organizations, both biotech & small molecule attracted some investment, I’d guess a sentiment again aided by a hope of continued & incremental global outsourcing
• Drug discovery organizations receiving venture capital rank at the very bottom of the list at 8% (as against 30% globally)

Even a cursory scan of the existing drug discovery strategies within Indian firms throws up the following aspects;

• A lot of ‘me too’ approaches/ platforms, including choice of target protein that may have already lost out the race to the plethora of US/EU innovator organizations
• Continuing the above line, a lack of novelty of approach, something that’d make an investor sit-up and take notice
• Incomplete, inadequate composition of scientific-leadership teams  i.e. key functional leaders & a sound advisory board
• A surprising lack of in-licensed drug candidates in the portfolios vis-à-vis’ efforts on building novel molecules from scratch
• A similar lack of high pedigree academic partnerships, Indian as well as overseas
• Last but not the least, a surprising lack of any focused attempt to use make use of the India-specific advantages like drug discovery based on Traditional & complementary medicine et al

As with most SWOTs, all the above weaknesses can be worked on and converted into opportunities. Looking at the diaspora of top-notch Indian chemists, molecular biologists, bio-physicists, pharmacologists across the globe making highly innovative & astute contributions to the drug discovery, development & clinical evaluation, I’d readily dismiss any talk of Indians not being up to it when it comes to path breaking innovation – only there is a definite need to re-purpose Indian drug discovery enterprise model, if I may say so & probably this is true for most other domains even.

      

Now, who’ll bell the cat? I say why not the investing universe?  of all geographies and domains out there, Indian drug discovery enterprise is where there's a crying, albeit unacknowledged, need for some astute thought leadership and strategic oversight so as to build, nurture & steer the foggy but promising entrepreneur pool - and who better than the venture capitalist to assume this constructive role, shift the paradigm & eventually partake the fruit of success?

Food for thought.

AFTER THOUGHT:

It’s about time the IRR of an Indian discovery organization is determined by the sheer value of the IP & portfolio it generates and NOT on whether the company is incorporated in Boston, Basel or Singapore.