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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

« More On Doing Away With Patents | Main | Which World Do We Live In, Anyway? »

April 4, 2006

Once More Into the Patent Breech

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Posted by Derek

Man, is everyone going at it hammer and tongs in the comments sections to the last two posts. There are a lot of good issues being raised, along with some interesting invective. But (as several people have noted), we're conflating several issues here.

On the subject of me-too drugs, I've already said a lot of what I have to say on the subject, and it can be found in that category over on the right. Looking over the comments, I tend to agree with SRC's take on the subject, although I'm pretty sure that my blood pressure doesn't go up as high as his does. A point that he makes, that many of these drugs are the sign of roughly simultaneous development (rather than sequential) is something a lot of people don't think about.

That said, there are some sequential me-toos, of varying degrees of utility. I've gone on about Clarinex/Claritin and Nexium/Prilosec here before, because I think that those are the two most egregious within-the-same-company examples. See this post on Sepracor for some others - come to think of it, they're involved in the Clarinex example, too, much to Schering-Plough's sorrow. It's fine with me if insurance companies decide that they don't want to pay for these things without a clear demonstration of medical need. If the market isn't big enough, companies won't develop such drugs. I'm in favor of as many pricing signals being sent as possible, all up and down the business.

Then there's the whole "how much does the federal research budget subsidize Big Pharma?" question. I'm going to have to pull that one out and deal with it - again - but not tonight. I continue to think that if you haven't been through the process, it can be difficult to realize just how long, twisty, and expensive the path between a great initial paper in Nature and a great drug on the market really is.

But these two issues have become thoroughly tangled up with the "can patents be improved" question. There have been some good suggestions scattered throughout the comments: longer granted terms for unmet medical needs, for example. If you try to apply these things too slickly, you open the way into terrible arguments, but for conditions where there isn't an existing therapy, the case should be clear. But isn't this exactly what the Orphan Drug Act is supposed to already do for us? There may not be as much uncaptured benefit here as we're thinking.

I wonder if there could be a (presumably shorter) fixed patent term that only starts once a compound comes to market, to deal with those long-gestation-period drugs that companies worry about getting involved with. You could also imagine adding onto a patent's term if the company agrees to do further studies (data to be made completely available,) which discover further utility (especially against competitor compounds?) But there's lots of arguing room in any scheme like that, too. And I could easily imagine companies carefully timing their investigations in order to stretch the patent out in the most lucrative way possible. (There was a similar suggestion in there for time limits to various milestones, tied to patent terms).

Coming up with incentives that can't be easily gamed isn't trivial, and it's a problem that's much larger than the patent debate.

Comments (16) + TrackBacks (0) | Category: Patents and IP


COMMENTS

1. Bruce Hamilton on April 5, 2006 1:19 AM writes...

I'll try to avoid generalising too much, but the global Pharma industry is diverse, and innovation is often purchased by larger players, and academia/federal are not the only sources of innovation.

It's worth considering the recent merging of medium players to big players. Some data I've seen shows big companies take fewer novel candidates through the approval process than the smaller entities did.

Big pharma take a serious interest in monitoring new drug candidates from many sources, and quickly licensing drug applications from smaller players - many of whom rely on those milestone payments to fund their research.

The funders of the smaller innovative companies also want their company to find a serious hit that will encourage the larger pharma companies to buy into ( or all of ) the smaller firm. as that frees up the venture money for others.

There is also mutual benefit - small innovative firms often have little regard for regulatory disciplines, and large pharma has serious experience in guiding products to commercialisation.

Why would large pharma risk developing highly bioactive molecules ( eg cancer cytotoxins ), as they are the chemicals that tend to have serious physiological side effects ( prime lawyer food ), whereas a me-too headache tablet may generate far more revenue for far less risk.

It's not my field, but I assume the research and regulatory approval for me-too drugs are presumably cheaper/quicker?. If not they should be, modelling must have some use other than discovery.

In the fields I've worked in ( toxins ) most innovation has been from small companies who often capture and develop off-shore or unusual ideas. The big companies will licence or buy the IP.

The need for orphan drug incentives is because the cost of unconstrained regulatory approval is very high - perhaps more effort should be done to reduce that, or make it appropriate to the target population?.

With regard to some of the numbers, I thought the cost of bringing a drug to market mainly occurs in Phase III, both with regard to process development and clinical testing?. The costs should only be those assocaited with that compound, and not include all the failed candidates of that company ( those written off sunk costs often get partially offset by useful tax credits ).

My suggestion to improve the patent process would be to allow broad initial claims, but for a very short defined time period - matching the discovery, preclinical period. The claim then lapses.

Allowing the claims and detail to be refined within a certain time at each stage ( Phase 1, II, III ), so by early-mid PIII both the manuafcturing process and the product applications should be tightly locked down. Then the final commercialisation patent would begin, and the length would be determined case by case.

I expect that would encourage much more partnering in the early phases ( with other small specialist firms ). It may even encourage some new firms to take products all the way through with partners, but many could just stop at PIII.

Big pharma would continue to outsource much of the high-risk discovery, and try to pick winners from those smaller pools. The cost of buying such IP would increment at each stage, depending on the perceived uniqueness and utility of the IP ( process and application ).

What I'm proposing is that the IP is available for purchase at several points in the timeline.
A plethora of me-toos would just keep the overall sector price the same, but more widely distributed over candidates.

Lucrative drugs will foster competitors very quickly, but the original player will have factors that contingency into the price paid.

Bruce Hamilton

Permalink to Comment

2. Palo on April 5, 2006 3:12 PM writes...

Derek, in refering to me-too drugs you say that you believe "many of these drugs are the sign of roughly simultaneous development". How many is 'many'? It would be interesting to know the ratio of simultaneous vs. sequential.

I agree with a lot of your discussion on potential solutions to the patenting problem. I think demanding that me-too drugs are compared in trials against known competitor compounds is a sensible idea that many proposed. It would discourage frivolous me-toos while improving the maketability of those that are truly an advantage

Permalink to Comment

3. Daniel Newby on April 5, 2006 8:10 PM writes...

Palo said "I think demanding that me-too drugs are compared in trials against known competitor compounds is a sensible idea that many proposed."

The trouble is, with most drugs we care more about side effects, drug interactions, dosing schedules, and off label uses. For example, consider the blood-pressure drug propranolol (Inderal). If it were being studied for the first time today, under the scheme proposed, it would go down in flames. Its therapeutic effect is utterly boring, with very little advantage over its competitors. However it is also decent at preventing migraines, and remarkably benign when used to treat anxiety symptoms, both of which would not show up in a Phase III trial for blood pressure.

That's they way with a lot of drugs. Their real utility doesn't show up until they have been out there bouncing around in zillions of patients. This is particularly true for central nervous system drugs, where idiosyncratic responses are the rule.

A data point on the Nexium/Prilosec debate: Nexium is a capsule containing loose pellets, while Prilosec is a hard tablet that must not be crushed. This is not a small difference for folks who have trouble swallowing.

Permalink to Comment

4. Theodore Price on April 5, 2006 10:12 PM writes...

Palo, I can't speak for Pharma in general, but, in my feild of pain neuroscience, I am aware of at least 5 companies that are furiously working on the exact same targets (at least 2 of them, which is alot considering there are about 3 currently utilized targets for analgesics). One of them is going to beat everyone else to the market with the first one and then others are going to follow suit. I suppose these will appear to be me-toos, but I agree with Derek, that type of classification is unfair. BTW, I'm in academia and have zero pharma funding, by the way.

Permalink to Comment

5. Palo on April 6, 2006 11:24 AM writes...

Daniel,
maybe we can have placebo and competitor trials? I realize that's expensive, and there is where, maybe, other proposals like taking the clinical trial business away from companies might be a good idea.

On the Nexium bit: wouldn't an obvious solution then be to have Prilosec as capsule containing loose pellets instead of 'developing' a new drug?

Permalink to Comment

6. Palo on April 6, 2006 11:30 AM writes...

Theodore, you say:
I am aware of at least 5 companies that are furiously working on the exact same targets

Drugs against the same target are not necessarily me-too. The whole concept of me-too is the development of a similar drug after someone filed a patent for a compound against that target.

That's why I asked Derek the question, because he seemed to suggest that some of the me-too are actually just coincidently similar compounds, accidental me-too if you want. I'd like to know how many of those are there.

Permalink to Comment

7. Kay on April 6, 2006 11:56 AM writes...

"I wonder if there could be a (presumably shorter) fixed patent term that only starts once a compound comes to market, to deal with those long-gestation-period drugs that companies worry about getting involved with."

If anything could slow the pace of progress within the larger companies, then this would seem to be a contender.

Permalink to Comment

8. Sebastian Holsclaw on April 6, 2006 3:44 PM writes...

I still don't understand the fascination with "me-too" patents. If it really is a useless "me-too", why do you care? If it is so useless, patenting it doesn't get in the way of research and the consumer can buy the cheaper (due to competition) original alternative that has fewer (or no) years left on its patent.

Permalink to Comment

9. Palo on April 6, 2006 5:16 PM writes...

Sebastian, I never called me-toos 'useless', I called them 'unnecessary'. My whole point all across this blog is that me-toos are a waste of resources (research and marketing) that I wished pharma used in true innovation. I also wished it was harder to get a patent for frivolous me-toos.

Your point about the economics of me-toos ignores the huge distortion that billions of dollars spent on marketing plays in replacing the original compound with the new more expensive me-too.

We all know that without all the misleading marketing that tells the consumer there is something better about the me-too, and without the different forms of bribery of doctors and hospitals that pharma uses, frivolous me-toos would not find a market.

Permalink to Comment

10. Sebastian Holsclaw on April 6, 2006 6:02 PM writes...

"We all know that without all the misleading marketing that tells the consumer there is something better about the me-too, and without the different forms of bribery of doctors and hospitals that pharma uses, frivolous me-toos would not find a market."

What about insurance companies selecting away from allegedly unnecessary me-toos?

Permalink to Comment

11. Theodore price on April 6, 2006 6:41 PM writes...

Palo,

For one of the targets, several of the companies came up with nearly identical compounds prior to the first patent. The companies that got beat to the patent office then started scurrying about the "patent space" that was not covered by that initial patent and started filling up other uncovered areas. At least three of the companies have compounds, that are patented, that are based on ureas. I'm no organic chemist, but I have seen most of the publications that have come out on compounds that are headed to trials (at least that is what they say -- I have no idea if its true) and all the compounds look remarkably similar to me; however, I wouldn't call them me-toos. I'd be willing to bet that mulitple versions of antagonists against the target will come to market, and who knows if the first to patent will be the first to market, not to mention which will eventually be best (and for which subset of patients).

Permalink to Comment

12. Palo on April 6, 2006 6:50 PM writes...

Theodore, as I said, in the case you mention I wouldn't call the me-too either...
It sounds like fair competition in which the investment made in innovative research resulted in similar results... that's fine with me.

Permalink to Comment

13. Palo on April 6, 2006 6:53 PM writes...

What about insurance companies selecting away from allegedly unnecessary me-toos?

That seems the direction the whole me-too thing might go. I hope that's the case. That would be a great dis-incentive for me-toos.

Permalink to Comment

14. Anonymous on April 6, 2006 8:48 PM writes...

That's why I asked Derek the question, because he seemed to suggest that some of the me-too are actually just coincidently similar compounds, accidental me-too if you want. I'd like to know how many of those are there

Palo, this may be more realistic than you imagine. The chemical libraries against which these targets are screen are hardly unique in big-pharma. There are obviously differences, but having seen *lots* of screening data it's shocking how much overlap there actually is.

Permalink to Comment

15. Robert Paci on April 7, 2006 12:22 AM writes...

I think we need to be clear on the working definition of me-toos so we're not talking past each other.

May I propose, from my memory of work in pharma, that they are follow-on drugs in a class that have the same mechanism of action as the lead drug.

To illustrate:

Prozac is the lead SSRI, and Zoloft, Paxil, and Celexa are "me-toos".
Imitrex is the lead triptan, and Amerge, Zomig, Relpax, and Axert are "me-toos".

Insurers tend to like more drugs coming into a class because any new "me-too" that can't prove superiority to the lead will generally be launched at a lower price.

I will conceed that it is fair to consider Clarinex, Nexium, etc. as "me-toos", but it should be understood that the key charge leveled at pharma concerns the primary definition.

Permalink to Comment

16. Buddha on April 7, 2006 10:25 AM writes...

Robert,
Maybe I am splitting hairs here but I would be more inclined to call Zoloft et. al second generation SSRI's. Me-too's implies (in my mind) that there is marginal benefit over the oringinal drug. One could argue that Zoloft and the others have definite benefits over Prozac (decreased half-life, improved SE profile etc.)

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