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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: Twitter: Dereklowe

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May 2, 2008

"Not Useful" Means "Not Approvable", Right?

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Posted by Derek

One recent drug industry setback I haven't noted around here - well, OK, to be more specific, it's a Merck setback, and boy must they be getting sick of those - is the FDA's "not approvable" letter for the Singulair/Claritin combination pill.

As the folks at the InVivoBlog note, it sure was hard, from one perspective, to see that one coming. After all, Claritin (loratadine) has an exemplary safety record and has been on the market for many years now, and Singulair (montelukast) has been selling in the billions of dollars as a stand-alone drug. No doubt many people have taken, and are taking, the two as separate pills. So you combine them and get a "not approvable": right.

The In Vivo people speculated that this might be a safety problem, since the agency has been mighty jumpy about that area recently, but Merck has now told them that safety and tolerability weren't raised in the FDA letter.

Well, what does that leave? Manufacturing? Hardly possible, given the way that these two drug substances are already being cranked out. That, as far as I can see, leaves good old efficacy. You could always argue that putting the two compounds into one pill improves patient compliance, etc., if the combination itself is useful in the first place. But in this case, I'd guess that the problem is that the combo has turned out to offer no benefit over either drug taken alone. Hard to make a case under those circumstance, it is.

And if you look into the history of a Singulair/Claritin idea, that appears to be just the problem. As the Wall Street Journal's Health Blog notes, the companies had already found no benefit for seasonal allergies, compared to either drug standing alone. Supposedly they were able to come up with some sort of nasal congestion data (what a joy that must be) that showed an edge this time, but yikes - how desperate do you have to be to take things to that point, after you've already seen no benefit in the main endpoints?

So why are Merck (and Schering-Plough) spending money on this kind of last-gasp line extension? Surely there are better places to burn cash. I've never been sympathetic to the argument that money spend on promotion is somehow stolen from R&D, but this sort of thing is another matter. Stupid R&D most definitely steals money from smarter R&D, and here's some of it that's made off with the swag.

Comments (10) + TrackBacks (0) | Category: Drug Development


1. Analytical Scientist on May 2, 2008 9:00 AM writes...

I 100% agree with your conclusions. I had heard rumors of the lack of benefit for combination of the two drugs for years, and I was wondering why this combo was going forward.

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2. Jose on May 2, 2008 12:31 PM writes...

It seems absurd that Merck would push a marginal project for so long, but why does the FDA care? If it really is safe and effective, isn't it up to doctors and/or market forces to decide how useful it could be? Perhaps Merck's recent lapses in good judgment come into consideration?

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3. SteveSC on May 2, 2008 2:52 PM writes...

So the standard has evolved from "safe and effective" to "more safe and more effective"? That's an innovation killer for sure. I agree with Jose, why should the FDA care if a new drug has the same safety and efficacy profile as an existing drug as long as the marketing people avoid superiority claims? All this does is protect incumbents from competition.

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4. Petros on May 2, 2008 3:07 PM writes...

In reviewing new therapies for rhinitis some years back I remember commenting on the lack of additional efficacy of this combo and was also amaazed to see that it progressed to a NDA.

Having worked for years in the LT antagonist area I was startled, after the early clinical data, how Merck have succeeded in marketing Singulair to the hilt (contrast Accolate and Onon) despite certain highly eminnet respiratory physicians questioning the ethics of using Singulair in preference to inhaled steroids for the treatment of asthma!

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5. retread on May 2, 2008 4:30 PM writes...

I didn't like combination drugs for the treatment of epilepsy (particularly the initial treatment). Phelantin (a combination or phenobarbital and dilantin (phenytoin) ) was used a lot by a colleague in the 70s. If a rash developed you lost the use of both drugs. If you did need both, it was better to optimize the dose of each separately (this was before we had accurate blood levels to go on - believe it or not).

Inhaled (cortico)steroids if extensively used, lead to systemic complications (such as cataract and worse) -- at least that was the thinking as of 11/00 when I retried. Perhaps, like much in medicine, old truths are not the new truths.

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6. befuddled on May 2, 2008 6:15 PM writes...


Inhaled corticosteroids are supposed to pose some risk, or so I was told by a pulmonary specialist not too long ago. Enough of a risk that it's not thought to be worth using them to tamp down the persistent inflammation seen in asthma unless it's fairly severe.

Which came as a surprise to me. I had thought the inhaled versions were supposed to be much safer than the systemic drugs.

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7. d. on May 3, 2008 8:30 AM writes...

Merck wasn't pushing for this one at all, it was coming from the Schering-Plough half of the Schering-Plough/Merck joint venture. The joint venture is more famous for its little simvastatin/ezetimibe combo (Vytorin), but the rights to the loratadine/montelukast combo were given at the same time.

The SP side wanted this to go through since revenue from the combo pill would be split 50/50 between SP and Merck while Singulair revenue goes to Merck alone. For the joint venture the cost of the trials & application were small compared to the possible benefit of getting a piece of the montelukast business.

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8. S Silverstein on May 3, 2008 9:52 PM writes...

Why the "let's create a new drug by mixing two existing ones" tactics?

As an old Jewish coin dealer who had every coin imaginable in stock used to say, "You can't do business very well from an empty wagon."

As for marketing budgets not detracting from R&D, I don't know about that.

Unless the R&D money instead goes to buy good computers.

After all, don't chemists and other scientists toil in discovery so IT people can have excellent computers?

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9. Petros on May 5, 2008 3:07 AM writes...

The risks of side effects from modern inhaled steroids are minimal, contrast the older agents, and the second bisggest selling drug in the world (GSK's Advair) is an inhlaed steroid combo product/ A second such combo product (AZ's Symbicort) had acheived blockbuster sales even before US approval.

The latest streoids, not used in such combos yet, are even safer with respect to unwanted side-effect potential.

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10. emjeff on May 5, 2008 9:19 AM writes...

"Inhaled corticosteroids are supposed to pose some risk, or so I was told by a pulmonary specialist not too long ago. Enough of a risk that it's not thought to be worth using them to tamp down the persistent inflammation seen in asthma unless it's fairly severe.

Which came as a surprise to me. I had thought the inhaled versions were supposed to be much safer than the systemic drugs."

"Less risk" does not equal "No Risk" . All drugs have side effects. However, glucocorticoids have horrendous AEs when administered at high oral doses(osteoporosis, Cushings,etc), whereas the inhaled steroids do not have these effects.

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