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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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« Does Glucophage Make Alzheimer's Worse? | Main | Your Paper Is A Sack Of Raving Nonsense. Thank You. »

February 26, 2009

Ranbaxy in Trouble

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Posted by Derek

There are reports this morning that the FDA is halting further review of drug applications from one of the largest generic drug manufacturers, India's Ranbaxy. It appears that some test results submitted to the agency have been found to be falsified. Update: here's the FDA's complaint (PDF).

I'm not seeing any details on what sorts of numbers look to have been cooked, or how the FDA caught on - more may come to light later. But it's for sure that this is trouble no company needs, and behavior no company should engage in. It's going to be especially hard in this case, because Ranbaxy (and India) have been trying to prove themselves as major, trustworthy players in the industry. I would have put the company in that category already, unfortunately, until this.

But it's important to remember that US companies have had their own compliance issues with manufacturing over the years - ask Schering-Plough about that, among others. Until we have more details about what's going on, I think it would be prudent to hold off on the "see what those cheap foreign plants will try to get away with" rhetoric. Who knows, that may come later.

Comments (39) + TrackBacks (0) | Category: Current Events | The Dark Side


COMMENTS

1. Hap on February 26, 2009 12:51 PM writes...

Lots of companies have had compliance issues, either out of a lack of clarity in the policies, or confusion, or trying to cut costs. Falsifying documents, though, seems significantly worse, because it's a conscious mistake, and everything that comes out of a company involves documents (because the FDA doesn't have the money to test everything), and if they can't trust your documents, you have nothing to sell. (Can we trust your efficacy data? How about your supply chains?)

This seems like a stupid mistake to make, if it is falsification and not something else. It shouldn't tar any other Indian companies, and there will probably be plenty with products of their own, but it won't do Ranbaxy any good at all, let alone the Japanese company (Takeda?) who bought them.

Permalink to Comment

2. alig on February 26, 2009 1:27 PM writes...

A year or 2 ago another generic drug company was caught falisfying their data. The FDA made them recall all of their drugs (it was in the 20-30 range) and they went bankrupt.

Permalink to Comment

3. processchemist on February 26, 2009 1:42 PM writes...

About data falsification, this one stands in between the hexacyclinol case and these news about Ranbaxy: last OPRD features a dispute between scientists at Lundbeck and Dr Reddy's chemists; the Lundbeck people checked a patent and an article (published by OPRD) about escitalopram synthesis, and found that the chemistry published by Dr Reddy's can't be reproduced (a key intermediate covered by Dr Reddy's patent too).
Lunbeck has a great curriculum about aggressive legal protection of his IP (with an apparent great teaming between chemists and lawyers), maybe a little too aggressive, but if you read the papers and let the data speak the conclusions are obvious... and the consequent legal action too.

Permalink to Comment

4. Spiro on February 26, 2009 2:30 PM writes...

Processchemist,

The amateurishness of Dr Reddy's chemists in that fuss will become legendary. Had they not published the OPRD, Lunbeck's chemists would probably not have had the necessary data to start their offensive.
Another lesson Reddy's chemists should haven taken from JJLaClair : when you publish "dubious" data, never ever try and justify your data...

Permalink to Comment

5. Hap on February 26, 2009 2:43 PM writes...

When you publish in a journal known for rock-solid preps, you ought to realize that someone is probably going to actually try your reactions, and if they can't work, someone is going to realize it.

The articles look like entertaining reading.

Permalink to Comment

6. Sili on February 26, 2009 3:46 PM writes...

or how the FDA caught on
What are the odds that this is a fabricated charge by a competitor? These are difficult times. Permalink to Comment

7. Hap on February 26, 2009 4:01 PM writes...

I don't know - if the FDA is making the statement themselves (as the article says), that would (or ought to) imply that they made some test of the claim themselves rather than simply taking it as truth based solely on the word of a competitor.

If the FDA is acting as a tool in drug trade wars, it is unlikely to help their status, let alone drug companies in the US who may benefit from the perceived safety of the drugs because of FDA oversight. If thy're acting on the behalf of foreign generics competitors, well, that would make even less sense.

I would have figured a competitor would have dropped hints from "unnamed sources" that Ranbaxy was under investigation for document falsification - it's kind of hard to get people to stake their reputations on bogus claims in public.

Permalink to Comment

8. Jeremy on February 26, 2009 7:22 PM writes...

See what those cheap foreign plants will try to get away with!!!!

Permalink to Comment

9. anon on February 26, 2009 8:47 PM writes...

And this from the Indians, who are WAY more reliable than....another really big asian country.

Permalink to Comment

10. milkshake on February 26, 2009 9:23 PM writes...

I don't think Indian chemists are on average way more reliable than Chinese. I have had good experience with reproducibility of synthetic publications coming from all-Chinese groups - and I have had very many Chinese lab colleagues over the years and not even once I saw anything that would make me doubt their credibility. But I saw crap-loads of irreproducible or mis-interpreted stuff from Hyderabad. (And I had some unfavorable personal experiences too, with Indian dudes that fabricated their results). It got to the point that when I search literature and come across a reaction precedent reaction published by an all-Indian group - that cannot be independently corroborated - I tend to disregard it.

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11. Compliance Analyst on February 27, 2009 8:47 AM writes...

Read the AIP sent to Ranbaxy:
http://www.fda.gov/cder/drug/infopage/ranbaxy/Ranbaxy_AIP.pdf).

This wasn't a competitor, or simple mistakes. These are repeat violations and errors. You don't make that many erros on "accident".

There is a history of other companies falsifying data, e.g. Able, Leiner Health Care, Actavis, etc. With the recent history of large ticket items killing people and more items being imported from China and India, the scrutiny of products from these countries is going to be huge.

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12. Chem on February 27, 2009 10:01 AM writes...

Taking one or two incidents (do not not know it is true or not utile revealed)I think milkshake is clearly do not like Indians.
No professional scientist write like that about fellow workers. Imaginations with out true out come is dangerous.

Permalink to Comment

13. Chem2 on February 27, 2009 10:03 AM writes...

Taking one or two incidents (do not not know it is true or not untile revealed)I think milkshake is clearly do not like Indians.
No professional scientist write like that about fellow workers. Imaginations with out true out come is dangerous.

Permalink to Comment

14. Hap on February 27, 2009 11:29 AM writes...

First trolls and now sock puppets. I guess In The Pipeline (or Milkshake) has hit the big time.

Permalink to Comment

15. anon-e on February 27, 2009 11:31 AM writes...

Milkshake wrote:

"and I have had very many Chinese lab colleagues over the years and not even once I saw anything that would make me doubt their credibility."

I disagree. I have personally seen fraud in synthesis perpetrated by both Indians and Chinese--and both were equally belligerent when confronted with the "facts".


I dont think one group is more culpable in this vs another. And who is to say that the frequency of these misdeeds is greater for these group vs any Anglo, African or other group? Has this been examined via systematic analysis of the literature to lead to this conclusion?

I cannot believe in this age of instant data circulation/scrutiny, that any scientist would try to get away with any sort of fabrication or manipulation of data. There must be intense pressure to do so which supersedes the fear of exposure.

Permalink to Comment

16. Colbert on February 27, 2009 11:35 AM writes...

Milkshake's reactions (no pun) seem to be influenced by the Indians he has worked with. I have worked with several Indian chemists here in the US and have had an excellent experience with them. A recent kinase inhibitor drug and HIV protease inhibitor drug were actually named after the Indian scientists who co-discovered them (Dasatanib and Darunavir). I think the problem, as Milkshake alluded to, lies with Indian groups working in India. First it was Chaterjee, then that guy from South India who fabricated 60 papers recently, then the Mehta paper in Org. Lett. and now the Ranbaxy and Dr. Reddy debacles. More Indians need to get out of India!

Permalink to Comment

17. pc on February 27, 2009 12:21 PM writes...

Although so far there appears no real scientific statistic figures measuring the reliability of the chemistry (medichem included) related literature from various ethnic groups, I guess many experienced practitioners would know empirically whether to trust a given publication by looking at where the authors are based. In fact I'll bet it's the first unconscious reaction for many to take a look at who the authors are and where they are from when given a publication.

#10 Milkshake, as a Chinese, thank you!!!

Permalink to Comment

18. Chem2 on February 27, 2009 12:49 PM writes...

Jeremy used same words "cheap foreign plants"
quoted by Derek. Thats kind of wiered.
Thes are the Companies making
cost effective generics and providing to the people those who can not even dream of buying except suffering to die. See in africa and other countries who are mainly precribing/using who's generics.
One has to accept the reality but taking the negative side is easy.

Permalink to Comment

19. Hap on February 27, 2009 1:23 PM writes...

I am assuming #8 was trying to be funny. I hope.

Having a competitive market for generics helps if you know what you're getting. Bad product sold cheaply is probably worse than no product at all - if the former case, you think you're getting something helpful and are unlikely to try other things that would actually help, while in the latter case you know where you stand, even if your position is not good.

Permalink to Comment

20. processchemist on February 27, 2009 1:33 PM writes...

"Companies making
cost effective generics and providing to the people those who can not even dream of buying except suffering to die"

And this demonstrates that a company can make money with the poors and the poorests, following the laws that rules these markets, nothing else. It's business, not humanitarism.
The same company can't be justified if, to grab a rich slice of the richest market, break the laws here applied. By the way, the western companies (I'm talking about generic API producers) are subjected to these rules since the rules exist (rules about quality and IP protection). And this is one of the major causes of their higher prices.

Permalink to Comment

21. milkshake on February 27, 2009 1:54 PM writes...

Busting process patents for making generics is necessity in poor countries - I worked with a guy who (among other things) circumvented the Tamoxifen manufacturing route in ICI patents, and thus made it available in Eastern Bloc. For his efforts he ended up in protracted litigation with ICI - the company tried to invalidate his patent and also filed counter-suit for infringement on their own patents. This was a hardball tactics on the ICI part to keep generics off the market. It ended up in international arbitration eventually. The patent example procedures actually got reproduced side-by-side, by independent party, to ascertain whether or not they qualified as "new and unexpected', and outside of what demonstrated by the ICI patent examples. It was a huge headache but he prevailed in the end because his procedures were reliable.

Permalink to Comment

22. Chem2 on February 27, 2009 2:25 PM writes...

"And this demonstrates that a company can make money with the poors and the poorests, following the laws that rules these markets, nothing else. It's business, not humanitarism."

processchemist; this is totally misinterpretation to the statement posted.
Every country has its own laws, its not only US is following the rules. Every country has its own rule to to properly scrutinize the product quality.

If you talk about laws there is no reports that any one died of taking these generic drugs manufactured by Ranbaxy. Dr. knows the quality of the product what to prescribe at the time needed.
Saving lives is great humanatarian than talking about laws/business.
Every pharmaceuticals company in the world is after making the money heavly. At least some companies making doing business in a cost effective manner is better business than selling expensive product at the time needed.

Permalink to Comment

23. Hap on February 27, 2009 2:43 PM writes...

The other shoe is, of course, where they got those drugs - someone else had to find them and test them and make sure they worked before they became salable, and if they were, only then were their generics were actually worthwhile to make. If you can't make money selling the originals, then there won't be any generics to sell.

Falsifying your data under the guise of making your drugs cheaply doesn't fit any definition of "following the rules" I am aware of.

Sorry for calling you a sock puppet, though - I thought you were a clone of the previous commenter.

Permalink to Comment

24. processchemist on February 27, 2009 2:50 PM writes...

@CHem2

"Saving lives is great humanatarian than talking about laws/business."

I don't want to start a flame, but this is rhetoric, and it's purely specular to the "See what those cheap foreign plants will try to get away with!!!!".
Please, DON'T talk about ethics: the picture is much different from "Evil western big pharma vs naive asian producers saving lifes". And the majority of the readers of this blog is perfectly aware of it.

Permalink to Comment

25. Chem2 on February 27, 2009 2:51 PM writes...

milkshake now not only hate Indians but he diverted the discussion by talking about Tamoxifen issues and talk about "poor countries".
Here debate is the quality of the products/Chemists from India is question.

I have seen so many patents/publications they are all repetation of one another and misleading preparaations. Indians are not smart enough to dispute on such publications.

Permalink to Comment

26. Chem2 on February 27, 2009 4:13 PM writes...

We know these blogs are "rhetoric" but you lit the flame insted of debating fairly/professionally/scientifically.

Permalink to Comment

27. CMC Guy on February 27, 2009 4:56 PM writes...

Chem 2 "Here debate is the quality of the products/Chemists from India is question."

Taken as an event this comes down to one company, and perhaps only one of their facilities, that looks like it had serious systematic flaws in QC/QA function based on the FDA letter. Although appears to have been mostly poor records transcriptions there were elements that were totally inconsistent with fundamental GMP (dating practices). It does not matter if no one was "injured" and that material in question met initial quality by attempting to file/sell in USA certain demands were triggered (BTW MDs and public have no idea of the quality as assume the FDA approval means automatic reliability)

At the same time Ranbaxy is one of bigger/best known suppliers of generics to the West and with the current scrutiny of imports it makes everyone look bad as "representative" supplier. Reputations of India and China companies are already particularly concerning as they have "duel GMP systems" one supporting internal supply (relatively lax) and another (much better) compliance. So Indian Chemists further damaged by this.

Note I have successfully outsourced materials from both India and China and know quality is possible but you have to work closely to develop and maintain relationships to make sure is done appropriately to Western standards. I have also know both good and bad chemists from India and China (and USA, Canada, Europe, Russia, etc.) although in some countries the lines are often more blurred because of inherent factors.

milkshake you often tell stories of the bad nature of communistic/socialistic systems but the behavior noted in #21 (perhaps description is misleading of circumstances) falls into that realm where a State can itself or allow others to violate IP for "providing medicines to the poor". While understandable is some senses there are usually accommodations that can get made without the downright theft that happens.

Permalink to Comment

28. MTK on February 27, 2009 5:39 PM writes...

If companies from other countries do not want to conform to rules and regulations that US and European governments demand, then let them. If poorer countries are willing to take advantage of these lower priced, and quality, products, let them also. It's a market that I'd rather not be involved in and one that dooms the companies to forever be stuck in those markets, but that's their choice. As long as they're shut out of higher standard markets, they can have it.

I don't have any doubt that many people who otherwise wouldn't be able to afford some medicines will get some. (Although, it's hard to imagine that the demand for a statin, an antidepressent, or any other chronic treatment to be very high in a third world country.) I also have no doubt that a catastrophe will eventually occur, but that was the risk all parties were willing to take.

This will, of course, require increased enforcement in the higher standard countries to make sure that these cheaper lower quality products don't get smuggled in, but that can be avoided.

And Chem 2, quality is not an outcome, it's a process. The process assures good outcomes, so as CMC notes, it's irrelevant that no one was harmed. Yet. If you've got a bad process, eventually you will have a bad outcome.

And I'll also agree with others that the whole humanitarian motive is a bunch of bull. Oh yeah, if only we could get Lexapro into the hands of world's poorest!

Permalink to Comment

29. Chem2 on February 27, 2009 6:11 PM writes...

MTK you talk about the process and I myself witnesses few GMP and cGMP labs in west and I know what the quality of process are. When it comes to Asia it has different laws and regulations. First you have to go and witness the facilities and standards before come to this kind of discussion.

Permalink to Comment

30. milkshake on February 27, 2009 6:19 PM writes...

If I remember correctly ICI did not have adequate composition-of-matter protection for tamoxifen in Europe because the history of the drug was long and convoluted and for quite some time they were not very serious about developing it (it was initially intended as a contraceptive but it failed). The composition-of-matter european patents date from early 60s so they already expired. ICI had a big IP hole in Europe so they tried to use their manufacturing procedure patents to prevent it from going generic there. As we know this is pretty futile as there is always a workaround.

Permalink to Comment

31. MTK on February 27, 2009 6:49 PM writes...

Chem2,

I said I had no problem with other countries having their own standards. If you don't want to conform to ICH, be my guest. Just don't try and sell your stuff in countries with standards you don't want to adhere to.

If you want to be in the game, you have to play by the rules, simple as that.

And I don't care that you've witnessed GMP in the West. Your "no harm, no foul" defense indicates you do not have a real understanding of what GMP quality is about.

Permalink to Comment

32. Hap on February 27, 2009 7:24 PM writes...

If you're willing to lie to the FDA about comparatively minor issues, how can they trust that your drugs work as designed or are as pure as you say they are? Getting caught lying doesn't make people more likely to trust you - it makes them wonder what else you might be lying to them about.

Try that "no harm, no foul" line on your wife or boss and see how far that gets you.

Permalink to Comment

33. Chem2 on February 27, 2009 7:25 PM writes...

MTK it is clear that you did not understand my context. Read it again. What ever unrelated issues you bring in your next post I do not care and I leave at this point.

Permalink to Comment

34. Chem2 on February 27, 2009 7:34 PM writes...

Hap
"Try that "no harm, no foul" line on your wife or boss and see how far that gets you".

You are completly lost your mind.
You may do such things, I am sure you are doing this otherwise you will not get this idea.

Permalink to Comment

35. CMC Guy on February 27, 2009 8:13 PM writes...

milkshake thanks for the elaboration as makes more sense and acceptable tone to the story. As indeed having developed a couple work-a-rounds myself agree there is almost always a way to circumvent processes in Patents.

Chem2 not sure I follow your context either as you are the one espousing tangential info to support whatever you think you are saying. The context is Ranbaxy wants to provide material for US Markets and therefore must comply with the FDA, and the obviously did not do so adequately. The result, stereotyping as it may be, decreases view of other Indian suppliers who operate from same India GMPs base.

Permalink to Comment

36. MTK on February 27, 2009 8:45 PM writes...

Chem2,

I think I understand you perfectly.

Let me recap some of the things you have said:

"there is no reports that any one died of taking these generic drugs manufactured by Ranbaxy".

That's "the no harm, no foul" defense I spoke of. Indicates misunderstanding of the term "quality" in a manufacturing sense.

"Dr. knows the quality of the product what to prescribe at the time needed. "

Once again, indicates ignorance of what quality means. Doctors have no idea about quality in manufacturing of drugs. To even think so is laughable.

"I myself witnesses few GMP and cGMP labs in west and I know what the quality of process are"

Let me continue beating this dead horse. You clearly don't grasp the concept of quailty as it pertains to manufacturing. It is not how well you run chemistry, so to speak of "quality of process" is incorrect. Quality IS a process.

"Indians are not smart enough to dispute on such publications."

Indicates complete and utter ignorance. Period.

Permalink to Comment

37. Sili on February 28, 2009 2:23 PM writes...

Thanks for the clarification.

Somehow it's a little comforting to know that this is at least ... well, real and not a case of fabricated backstabbing.

Permalink to Comment

38. brwnsuga on March 1, 2009 11:12 AM writes...

yes, I beleive that they tired to falsify the records. I work for some of these cpmapnies and I see what they do to get the product to market.

Ranbaxy is no different. Does any one in upper mangement know how to tell the TRUTH!!!!!

Permalink to Comment

39. milkshake on March 2, 2009 10:03 PM writes...

Here is a more detailed writeup on the shenanigans at Ranbaxy plant:

http://www.nature.com/news/2009/090302/full/news.2009.130.html

It was apparently going on at least since 2006 and the data fabrication was getting progressively brazen.

As Gandhi says, "in the end deceivers deceive only themselves"

Permalink to Comment

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