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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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February 11, 2014

Drug Discovery in India

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Posted by Derek

Molecular biologist Swapnika Ramu, a reader from India, sends along a worthwhile (and tough) question. She says that after her PhD (done in the US), her return to India has made her "less than optimistic" about the current state of drug discovery there. (Links in the below quote have been added by me, not her:

Firstly, there isn't much by way of new drug development in India. Secondly, as you have discussed many times on your blog. . .drug pricing in India remains highly contentious, especially with the recent patent disputes. Much of the public discourse descends into anti-big pharma rhetoric, and there is little to no reasoned debate about how such issues should be resolved. . .

I would like to hear your opinion on what model of drug discovery you think a developing nation like India should adopt, given the constraints of finance and a limited talent pool. Target-based drug discovery was the approach that my previous company adopted, and not surprisingly this turned out to be a very expensive strategy that ultimately offered very limited success. Clearly, India cannot keep depending upon Western pharma companies to do all the heavy lifting when it comes to developing new drugs, simply to produce generic versions for the Indian public. The fact that several patents are being challenged in Indian courts would make pharma skittish about the Indian market, which is even more of a concern if we do not have a strong drug discovery ecosystem of our own. Since there isn't a robust VC-based funding mechanism, what do you think would be a good approach to spurring innovative drug discovery in the Indian context?

Well, that is a hard one. My own opinion is that India only has a limited talent pool as compared to Western Europe or the US - the country still has a lot more trained chemists and biologists than most other places. It's true, though, that the numbers don't tell the story very well. The best people from India are very, very good, but there are (from what I can see) a lot of poorly trained ones with degrees that seem (at least to me) worth very little. Still, you've still got a really substantial number of real scientists, and I've no doubt that India could have several discovery-driven drug companies if the financing were easier to come by (and the IP situation a bit less murky - those two factors are surely related). Whether it would have those, or even should, is another question.

As has been clear for a while, the Big Pharma model has its problems. Several players are in danger of falling out of the ranks (Lilly, AstraZeneca), and I don't really see anyone rising up to replace them. The companies that have grown to that size in the last thirty years mostly seem to be biotech-driven (Amgen, Biogen, Genentech as was, etc.)

So is that the answer? Should Indian companies try to work more in that direction than in small molecule drugs? Problem is, the barriers to entry in biotech-derived drugs are higher, and that strategy perhaps plays less to the country's traditional strengths in chemistry. But in the same way that even less-developed countries are trying to skip over the landline era of telephones and go straight to wireless, maybe India should try skipping over small molecules. I do hate to write that, but it's not a completely crazy suggestion.

But biomolecule or small organic, to get a lot of small companies going in India (and you would need a lot, given the odds) you would need a VC culture, which isn't there yet. The alternative (and it's doubtless a real temptation for some officials) would be for the government to get involved to try to start something, but I would have very low hopes for that, especially given the well-known inefficiencies of the Indian bureaucracy.

Overall, I'm not sure if there's a way for most countries not to rely on foreign companies for most (or all) of the new drugs that come along. Honestly, the US is the only country in the world that might be able to get along with only its own home-discovered pharmacopeia, and it would still be a terrible strain to lose the European (and Japanese) discoveries. Even the likes of Japan, Switzerland, and Germany use, for the most part, drugs that were discovered outside their own countries.

And in the bigger picture, we might be looking at a good old Adam Smith-style case of comparative advantage. It sure isn't cheap to discover a new drug in Boston, San Francisco, Basel, etc., but compared to the expense of getting pharma research in Hyderabad up to speed, maybe it's not quite as bad as it looks. In the longer term, I think that India, China, and a few other countries will end up with more totally R&D-driven biomedical research companies of their own, because the opportunities are still coming along, discoveries are still being made, and there are entrepreneurial types who may well feel like taking their chances on them. But it could take a long longer than some people would like, particularly researchers (like Swapnika Ramu) who are there right now. The best hope I can offer is that Indian entrepreneurs should keep their eyes out for technologies and markets that are new enough (and unexplored enough) so that they're competing on a more level playing field. Trying to build your own Pfizer is a bad idea - heck, the people who built Pfizer seem to be experiencing buyer's remorse themselves.

Comments (30) + TrackBacks (0) | Category: Business and Markets | Drug Development | Drug Industry History | Who Discovers and Why


COMMENTS

1. Keith Robison on February 11, 2014 1:59 PM writes...

Given that India has a very different (and highly varied) population, the spectrum of rare diseases is likely quite different there & it might be useful to search for them -- but perhaps only profitable for an Indian start-up if the therapies can also be resold in developed economies.

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2. Pharmaheretic on February 11, 2014 2:13 PM writes...

I see that ramu is playing gungadin. While that is not surprising, I always had trouble understanding the rationale of trying to suck up to people who look down on you.

On a related note, has the very well qualified author of this blog ever been closely involved in the discovery of an innovative lead that made it to the market? If "western" (polite term for white) scientists are so good at drug discovery, why are the pipelines of big pharma so empty of game changing drugs right now?

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3. Curious Wavefunction on February 11, 2014 2:25 PM writes...

I would say one of the best strategies would be to do phenotypic screening against extracts from traditional Indian medicines. I think there's a lot of potential value in some of those (as also in traditional Chinese medicine).

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4. CMCguy on February 11, 2014 2:59 PM writes...

Perhaps India can have a funding model for R&D Start-ups by having large export tariff applied on drugs sold to 3rd World counties under compulsory licensing. I don't have any real idea on how much this diversion of IP covered sales amounts to however almost every time I've seen this topic mentioned the superseded patented drug was supplied from India (based on more mature quality expectation than Chinese sources)

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5. G on February 11, 2014 3:07 PM writes...

Tropical diseases that are ignored by most researchers, and yet help rare westerners, and the millions of others that contract the variety of disease that have huge impacts.

Funding could possibly be sourced from NGOs, and others.

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6. Anonymous on February 11, 2014 3:52 PM writes...

The shortage of cash for research in India is probably a blessing, because it forces more creativity and entrepreneurial thinking to develop a new and more efficient R&D engine, rather than just throwing a lot more money into the same old broken R&D engine of big pharma. I agree that phenotypic screening with natural products (combined with good Indian medicinal chemists) seems to be a good way forward.

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7. Anonymous on February 11, 2014 4:07 PM writes...

Derek, you do realize that Humira, the world's top-selling drug was originally discovered and developed in Britain, right? As were monoclonal antibodies, DNA, molecular biology and most of the basic knowledge on which virtually all drugs are based.

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8. Anonymous on February 11, 2014 4:09 PM writes...

Right now, establishing a home-grown biopharma industry in India is not possible. I don't care who is funding it, they are going to want return on investment. What prevents India's government from declaring even a home-grown drug too expensive and subject to compulsory licensing? Until there is uniform and reliable respect for IP, it just isn't going to happen.

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9. Anonymous on February 11, 2014 4:21 PM writes...

@8: Who said Indian companies can only sell their products in India? If they can find a cheaper way to develop safe and effective drugs, then they actually stand a better chance than most western pharma companies.

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10. Anonymous on February 11, 2014 4:42 PM writes...

"The alternative (and it's doubtless a real temptation for some officials) would be for the government to get involved to try to start something, but I would have very low hopes for that, especially given the well-known inefficiencies of the Indian bureaucracy."

This is already happening under the banner "Open Source Drug Discovery" (OSDD). It's a massive government operation involving target selection, HTS, optimization of cellular potency, hit to lead, candidate selection and beyond. The whole thing is funded by the Indian government and the program is run by CSIR, which is the equivalent of NIH in India. They are focusing on TB targets. Have not seen much yet in terms of novel chemical entities, but they could be making progress. I wish them well and hopefully a new TB drug with a new mechanism of action will come out of this. Given the less impressive results of the TB programs at AstraZeneca, Bangalore which perhaps influenced the recent site closure, OSDD is currently the only major engine for TB drug development in India.

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11. Farmaheretic on February 11, 2014 4:46 PM writes...

@2- Pharmaheretic. well said. you are being too polite with the "well qualified" description.

Try blogging like DL and see if anyone can or has time to discover ....

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12. David Borhani on February 11, 2014 5:00 PM writes...

@7: It pays to get your facts straight.

Humira (a.k.a. "D2E7"; see Salfeld et al., WO 97/29131) was born of a collaboration between BASF/Knoll and Cambridge Antibody Technology (CAT). The collaboration was initiated by BASF Bioresearch Corporation (BBC), the BASF/Knoll subsidiary located in Massachusetts as part of BASF's response to the restrictive 1989 German "gene law".

As Bob Kamen, the leader of BBC has noted, CAT did phage libraries and initial screening of scFv candidates, and BBC did conversion of clones to full length mAbs, mammalian expression, and everything else, with support from Knoll in Germany. Significant optimization, extensive additional preclinical characterization, and of course development of the impressively high-volume and high-yielding production capabilities were performed largely at BBC, in Worcester, MA. See: The Humira Story.

It is thus a bit of a stretch to write that Humira was "discovered and developed in Britain".

Note that BASF Pharma/Knoll was well-positioned to initiate the CAT collaboration, having had previously developed the murine anti-TNF antibody MAK-195, which was marketed for a time as an anti-sepsis drug under the tradename Segard, and having had formed a collaboration with Biogen to develop recombinant TNF in oncology. The concept of a creating a fully-human anti-TNF mAb to further advance the stunning clinical findings of Marc Feldmann and Ravinder Maini on the efficacy of a murine anti-TNF mAb in rheumatoid arthritis was one of Bob Kamen's great achievements.

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13. Anonymous on February 11, 2014 5:09 PM writes...

'Advice is a form of nostalgia. Dispensing it is a way of fishing the past from the disposal, wiping it off, painting over the ugly parts and recycling it for more than it is worth'

The developing world should be forging a new path altogether, not shackled by what the west thinks it knows (and the pipelines it does not have to show for it)

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14. Pete on February 11, 2014 5:33 PM writes...

I have big doubts about the commercial viability of drug discovery even in the developed world and my advice to a country like India would be to be clear about expectations. Non-Indian venture capitalists will be wary of putting money into India where drug discovery expertise is thin on the ground, bureaucracy is heavy and getting any profits out of the country may not be straightforward.

Not-for-profit drug discovery for diseases in which western pharma has little interest would be one option although this would require government/charity funding. Some of the early stage stuff could be done in universities and/or research institutes. Some thought would need to be given to what activities would benefit from some centralization. Screening (for leads as opposed to running project assays), pharmacokinetic studies and databases all come to mind in this context. If it's not for profit then IP-driven timescales become less of an issue. The basic idea would be to seed the drug discovery programs with some screening hits, see how the hits are exploited and be ready to move on the best compounds. Possibly even room for some commercial activity within this framework?

There is an Open Source Drug Discovery (OSDD)initiative in India and it'd be interesting to hear what they have to say.

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15. Cato the Elder on February 11, 2014 5:45 PM writes...

@2 "gungadin" and "western" (polite term for white)".... are you for real? It isn't racism when you fairly assess a region's capabilities. If anything Derek is being overly charitable in this post

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16. Bakshi on February 11, 2014 10:43 PM writes...

Indian drug industry wants to make quick money by selling cheap generic drugs.They have trader (banya) mentality and are not willing to spend money on innovative drug discovery. There is plenty of talent available in India to carry out drug discovery in India.

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17. Insilicoconsulting on February 11, 2014 10:47 PM writes...

With personal experience of working at large pharma, startups and CRO's in India, I do feel we are quite up-to discovering therapies here. The human talent pool is there.

Of course, due to sheer numbers , just like in IT it makes sense that top 20% WILL be comparable to top western scientists, middle 40 percent will be average and the rest....

However , just like its difficult to replicate siliconvalley even in europe, establishing a startup culture is difficult here. More so in Drug disc. The mentality for many years has been to get a well paying safe job. Societal pressures are huge (stability, marriage, own home etc).

Another factor is self belief. Or rather, the lack of it. People here with the same calibre as ones who make it as CEO's of top American/European, when in India behave in a different manner.

The current drug discovery model which requires enormous investments both in the preclinical/clinical sides is of course a major hindrance. India needs to get creative in the regulatory norms and the eay discovery is done here.

Government has been playing a small role in encouraging startups in such sectors, but needs to go the whole hog. Huge amount of money is wasted in central government research institutes (CSIR labs to wit just like the UK). This needs to be diverted.

The patent system surely did not exist in its present form since the beginning. Like the IT counterparts realize its not fair and balanced. Like marriage, it may be a necessary evil but needs prenups to prevent abuse. Especially when it concerns emerging economics and poorer countries.

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18. Iwasachocolateseller on February 12, 2014 3:26 AM writes...

Enforceability of contracts.
Essential for R&D in any industry. Get that right and India then stands a chance of becoming a real global player across many, many industries and not just a cheap outsourcing hub.

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19. Will on February 12, 2014 7:53 AM writes...

Leaving aside questions of pharmacokinetics, are there any disease states which could only be treated by small molecule, and not biologic apis? Or, (at least in theory) is everything treatable by biologics

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20. Lyle Langley on February 12, 2014 9:37 AM writes...

@19, Will...
As of right now, most people will tell you that CNS indications would be tough to treat via biologics without some sort of delivery into the brain. There are CNS indications that do not necessarily need CNS penetration (e.g., MS); but for something like SZ, the reigning dogma is small molecules are the only treatment. If a delivery system can get the biologic into the brain, then that may change (some have tried intranasal delivery as well). But, I guess, in theory, there would be a limit - in practice, may be different...

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21. Anon8 on February 12, 2014 9:45 AM writes...

@16, Spot on! Several people have touched on many issues herein and all true! India and the so called many drug companies there can never be a power house for drug discovery, NME in a given therapeutic area etc. given its past. Most drug companies in India are family owned and they are not very eager to part away and give control to the qualified individuals to run the show. During one of my trip a person (CEO) at the top opined that he could make more money by investing in a real estate market (ROI).

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22. marcello on February 12, 2014 11:55 AM writes...

I think China, obviously with higher wealth and more efficient state sponsoring, has a much better shot at it.

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23. Piero on February 13, 2014 4:01 AM writes...

Not exactly related (dimensions are quite different), but in some way this is reminding me the situation here in Italy back in the 70s-80s, at least as for what I'm told by older colleagues

There were a strong chemistry tradition, very good researchers, quite good efforts in drug discovery, both by Italian companies and by multinational corporations local branches; these last had a strong incentive because the goverment cut their taxes and let them have better prices if they had research facilities here (so that they didn't care much in effect for what was to be found as the expenses were covered just by that), and I'm told this is also happening in India where companies establish local branches and labs to try to gain the market and have good relation with the government.

Well, guess what happened?
There's almost no more drug discovery nowadays by either of the Italian (too costly, not enough results) or multinational (no more advantages) companies

Permalink to Comment

24. Piero on February 13, 2014 4:32 AM writes...

Not exactly related (dimensions are quite different), but in some way this is reminding me the situation here in Italy back in the 70s-80s, at least as for what I'm told by older colleagues

There were a strong chemistry tradition, very good researchers, quite good efforts in drug discovery, both by Italian companies and by multinational corporations local branches; these last had a strong incentive because the goverment cut their taxes and let them have better prices if they had research facilities here (so that they didn't care much in effect for what was to be found as the expenses were covered just by that), and I'm told this is also happening in India where companies establish local branches and labs to try to gain the market and have good relation with the government.

Well, guess what happened?
There's almost no more drug discovery nowadays by either of the Italian (too costly, not enough results) or multinational (no more advantages) companies

Permalink to Comment

25. Davet on February 13, 2014 6:12 PM writes...

Lack of IP protection is often seen as something that just hurts foreign companies, but it can have strongly negative effects on innovation in local companies as well. If the legal system doesn't protect innovation or other forms of IP, it doesn't. This has hurt India for decades.

Here's an example from China: the producer of a Chinese-produced movie determined that their legal DVD had 0.5% market share in China. Hence, even though US DVDs are widely pirated there, at least US companies can make a profit in their home market, i.e., the US. In contrast, the lack of IP protection in China also prevents Chinese movie producers from growing because they have little chance in their home market.

India can continue to ignore patents or require companies to disclose their IP and this will help maintain a lack of innovation.

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26. sepisp on February 14, 2014 4:57 AM writes...

Paradoxically, the Swiss chemical and pharma industry was launched by ignoring German patents. Not getting stuck to a monopolist manufacturer makes the economy more, not less efficient. A patent is an evil government intervention and a "feudal" monopoly (no matter its benefits) and that should be recognized in any analysis of the topic.

Ridiculously enough, Finland is on some sort of a U.S. State Department blacklist because we have contract manufacturers that make U.S. patented APIs. They're sold in countries where there no corresponding U.S. patent, so it's perfectly legal. But, the U.S. wants to enforce American law abroad, too, so they act like that. Canada(!) is on the same list for the same reason.

Maybe the question here is that is it realistic to assume a certain type of business model, like the "discover and patent" model, can be applied to all countries. It could be that drug discovery indeed shouldn't be done in India. There's neither a paying market nor revenue security. You don't sell sand in Sahara either.

For instance, drug discovery could be funded with a mechanism completely separate from the general patent system. Currently, revenue from drug discovery is directly tied to the sales of an individual drug. Instead, you could tax all drugs and then allocate the revenue to the companies doing the discovery as a political decision. Unfortunately that would be possible only in Finland, New Zealand and other low-corruption countries. But, corruption is not a force of nature; Finland was definitely politically corrupt up to the early 1980s. Maybe India should do something about it; it's been already shown it can be done.

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27. Psp on February 18, 2014 2:55 PM writes...

Some Indian companies like Glenmark have done a good job of home-grown innovative R&D. As speculated, the bio R&D is being done in Switzerland due to lack of local expertise, whereas the Indian chemistry talent is being utilized for NCE research in Mumbai. There are some signs of success - with a novel antibody outlicensed to Sanofi in 2010 and Thomson calling it 'The one to watch out for' last year.

Similar is Biocon.

Permalink to Comment

28. Psp on February 18, 2014 2:59 PM writes...

Some Indian companies like Glenmark have done a good job of home-grown innovative R&D. As speculated, the bio R&D is being done in Switzerland due to lack of local expertise, whereas the Indian chemistry talent is being utilized for NCE research in Mumbai. There are some signs of success - with a novel antibody outlicensed to Sanofi in 2010 and Thomson calling it 'The one to watch out for' last year.

Similar is Biocon.

Permalink to Comment

29. Psp on February 18, 2014 3:04 PM writes...

Some Indian companies like Glenmark have done a good job of home-grown innovative R&D. As speculated, the bio R&D is being done in Switzerland due to lack of local expertise, whereas the Indian chemistry talent is being utilized for NCE research in Mumbai. There are some signs of success - with a novel antibody outlicensed to Sanofi in 2010 and Thomson calling it 'The one to watch out for' last year.

Similar is Biocon.

Permalink to Comment

30. Swapnika on February 20, 2014 2:34 AM writes...

Thanks to Derek for hosting my question, and to everyone who chimed in! I've cross-posted this discussion on my blog as well.

Permalink to Comment

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