QDIS Blog

Seems Ketek (telithromycin) made it back in the news a couple of weeks ago.

Enrollment of Children in Drug Study Is Halted - New York Times:
Enrollment of children in drug study suspended - Children’s Health - MSNBC.com

I’ve previously posted about Ketek and how some in Congress, particularly Senator Charles Grassley (R-IA) were concerned about why the FDA approved Ketek when some involved with some studies were found guilty of fraud. Here’s an excerpt from The Blotter (from ABC news):

The study with the forged test results was conducted at a former weight loss clinic in Gadsden, Alabama. Dr. Maria Anne Kirkman-Campbell is serving five years in prison for falsifying safety test results on Ketek.

A former nurse, Michelle Snedeker, told ABC News she was ordered to forge documents and report data on people who had not even been given Ketek. The doctor was paid $400 for each of the 407 subjects that she enrolled for the study.

It has been thought to cause liver problems (not an uncommon occruance for drugs since this is where they are usually metabolized) and now studies in children have been halted. It should be made clear that the FDA is not talking about taking the drug off the market but is performing a safety review, although some officials it seems do have serious concerns. Here’s an exceprt from the New York Times article:

Yesterday, The Times cited internal food and drug agency memorandums that said some safety officials said the F.D.A. should consider forcing Sanofi-Aventis to remove Ketek from the market, severely restrict its use or add a prominent warning label about its potentially fatal side effects.

It is interesting to note the company line regarding why the trials were halted. Here it is from the New York Times article:

The company denied that the studies of the drug, Ketek, were halted because of safety concerns and said that it was only trying to ensure that the trials complied with Food and Drug Administration requirements.

According to Clintrials.gov, there are four studies and all have been halted. Heres the list of the trials:
Clinical Trial: TELI COM - Telithromycin in Children With Otitis Media
Clinical Trial: Comparative Study to Evaluate the Efficacy and Safety of Telithromycin Given Once Daily Versus Cefuroxime Axetil Given Twice Daily in Children With Middle Ear Infections
Clinical Trial: TELI TON - Telithromycin in Tonsillitis
Clinical Trial: TELI TAD - Telithromycin in Tonsillitis in Adolescents and Adults

It should be noted that ketek was approved in 2004 and as of april 2006, there have been 110 reported cases of liver problems associated with Ketek, so the number is likely higher since some cases certainly go unreported.

More news results on Ketek (these are sorted by date in both cases):

Yahoo! News Search Results for ketek
ketek - Google News

And here is some search results from other bloggers (also sorted by date):
Yahoo! Search Results for ketek (blog results)
Google Blog Search: ketek antibiotic

The interesting thing on this is that the earliest blog entry mentioning Ketek was back on 21 Mar 2005 for Google blog search and only 13 days ago in Yahoo’s blog search. The earliest news on Ketek in Google dates back to May 22 and for Yahoo the same date.

Regarding the blog search results it is interesting to note how many times Ketek is mention with regard to causing nausea or other possible side effects. Now, I wouldn’t but much faith in random posting to journals and diaries posted on the Internet, but it is worth noting. Now these could happen for a variety of reason and many would not be related to the drug. Still it is more antecedent evidence of possible problems.

Google trends is another interesting way to look at this event. Here’s the graph of search volume. I do think something is wrong with Google trends since it doesn’t report any news events and there have been several including ones found through a Google news search. The two blips in 2004 are certainly related to it’s approval

The interesting thing is the Houston, TX result for both Ketek and telithromycin. My bet (based on previous experience) is that there is a law firm in Houston working on a lawsuit related to Ketek.

Technorati Tags: antibiotics, drug safety, Ketek, telithromycin

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The Mercury News had a good article recently on patients hopes for lower costs of biologics drugs such as human growth hormone and other such drugs.

New drug approval raises hope for cheaper medicine

I think the hope may be premature and that there is most likely not going to be a flood of biogenerics. The FDA has made it clear that they don’t consider the approval of Omnitrope ® (somatropin) to be a biogeneric and actually use the phrase “follow on protein product”. I don’t think the American public is going to see biogenerics anytime soon and I predict it will take action in Congress to get this moving forward. I do believe the issue of how you get a biogeneric on the market needs to be addressed; what is the process and what testing or clinical trials need to be done to protect the public but also keeping in mind that the high cost of biologics means some patients will not get treatment. It is always a balancing act; protecting the public vs the impact of people not being able to afford their medicines. The US decided back when the generics drug business was given a process by which to get cheaper medications on the market, that was the way we wanted to control prices; by allowing and facilitating competition. I think we need a process for biogenerics and it should have been started several years ago.

However, I feel the FDA needs to get back on track and improve it’s reputation first and foremost. But this shouldn’t be used as a excuse for not attempting to make progress on biogenerics. However, working on a process for biogenerics before working on its reputation is a path to failure in my opinion.

Technorati Tags: biogenerics, FDA, somatropin

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Boy does the plan B fiasco keep getting stranger and stranger. I’ve posed on it several times as has Mark Sedak over at Eye on FDA. Here is the latest from the New York Times.

Ex - FDA Chief: Agency Meant to OK Plan B - New York Times:

Mark has a post specifically dealing with this latest news and has some very good questions that need to be answered. The question I have is how can Dr. Crawford say with a straight face that he couldn’t figure out how to enforce an age limit for the OTC version of plan B?! Maybe he should talk to the Bureau of Alcohol Tobacco and Firearms for advice on how they deal with sales of cigarettes or alcohol and see how they deal with it. That excuse is just ridiculous.

Here’s link to Dr. Crawford’s testimony (pdf).

Here’s links to a page on the Center for Reproductive Rights containing other pdf’s of other people testimony who were involved in the plan B discussions.

Testimony of Dr. Janet Woodcock (Part 1)

Testimony of Dr. Janet Woodcock (Part 2)

Testimony of Dr. Steven Galson (Part 1)

Testimony of Dr. Steven Galson (Part 2)

Also, former commissioner Mark McClellan was deposed on June 13th (2 days ago) but those transcripts are not yet available. I haven’t had time to read through them all, but since they are in pdf format, you can easily search them electronically. If I find anything interesting, I’ll be sure and post.

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The New York Times had an article a few weeks back that caught my eye and I haven’t had a chance to post about it.

Rising Diabetes Threat Meets a Falling Budget - New York Times:

Further diabetes articles from the New York Times.

One of the fastest rising diseases today is diabetes. Now for those not familiar with diabetes, there are basically two types; Type 1 (which use to be called juvenile diabetes) and Type 2 (use to be called adult onset). Now I am familiar with Type 1 since my wife has been diabetic for many years now. The interesting fact is that diabetes has risen quite a bit in recent years.

Detailed data from the Center for Disease Control (CDC) is available with breakdown by age and other factors.

The sad fact though is that money for diabetes related issues is going down even though over 225,000 Americans are affected and the number continues to grow. Another fact is that almost b50% of the people who have diabetes don’t know it and usually don’t until they require hospitalization for complications or another reason and it then gets caught. Diabetes is the primary underlying cause for kidney disease, blindness and non-trauma related amputations.

Graphic: Falling Behind in Research Spending

Some interesting facts:

$ per case for West Nile disease: $16,936
$ per case for Lyme disease: $1,415
$ per case for diabetes: $68

This is based on 14.7 million cases of diabetes reported in 2004 but does NOT include the estimated 6.1 million undiagnosed cases.

Here are many other new articles recently on diabetes.

American Diabetes Association Home Page

Yahoo news search result.
Google news search results.
MSN news search results

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Many articles in the chemical literature use the words “optimized” or optimal” conditions in the report. Most of these in my experience are NOT optimized but rather a set of conditions were investigated and the best results obtained are then used. Out of curiosity, I looked at articles published in the following American Chemical Society (ACS) journals:

• Journal of Organic Chemistry (JOC)
• Journal of the American Chemical Society (JACS)
• Organic Letters (OL)
• Organic Process Research and Development (OPRD)

I choose these four since they are the major organic journals from the ACS and I happen to have subscriptions to all of them. A search of these journals for “optimized” or optimal” in the title or abstract from Jan 2000 to June 2006 resulted in 1065 hits. Searching within those results for those articles containing the word “statistical” results in 144 articles that actually used design of experiments (DOE) to determine the optimal conditions. This means that only about 13.5% of those claiming to be optimal or optimized actually are. I’m sure that if this was expanded to other journals the results would most likely be even lower. This is because the journal OPRD tends to publish quite a few very good articles describing the use of designed experiments resulting in a bias to the high side. My best guess is that including more journals would give a lower percentage of around 8-10%. It should be obvious that the vast majority of those claiming to be optimal really aren’t. They are probably pretty good, but certainly can’t be said with confidence to be the best conditions.

In the normal practice, a variety of solvents are chosen and then the best one selected and this is used to further optimize the conditions such as base. This “one factor at a time” process is quite common but ignores the interaction between the solvent and other conditions such as concentration, temperature, catalyst, reagent (i.e. base), etc. Also, at the end of an “optimization” performed using one factor at a time, you still don’t know for sure if you have found the best conditions. You only know that this set of conditions of those studied gave better results than the other conditions (but not necessarily the best). If a designed experiment is used, then you can arrive at a model for the system and predict where in the experimental space the best reaction conditions are, even if that set of conditions were not part of the design (however, you should always check and make sure this predict is correct). The use of designed experiments allows for the development of mathematical models (typically a quadratic equation) to predict results within the space studied. You can also study as many results as are of interest.

One reason DOE has not been used extensively is that you typically have to change your system to fit a design from a book or article. More recently, computer generated designs have overcome some of this although my experience is that most compute generated deigns are not of the best quality. They typically are what are called D-optimal designs and these designs concentrate on giving the narrowest confidence limits on the b coefficients. This means they are good at finding out how important a certain factor is, but are not the best for predicting the results which is typically what is of interest in industry. Here is an equation for a hypothetical example of a system looking at temperature (T), concentration (C) and catalyst (K).

Result = b0 + (b1 x T) + (b2 x C) + (b3 x K) + (b4 x T x C) + (b5 x T x K) + (b6 x C x K) + (b7 x T^2) + (b8 x C^2) + (b9 x K^2)

A D-optimal design will give you the best value for each of the b’s. This is good in cases where you may be studying eight or ten factors and you want to know the critical process parameters; say the three most important. They do not necessarily give the best results for the prediction of the result.

I-optimal designs however, are generated such that the best possible prediction of the result is what is of interest. It may not be entirely obvious but these are indeed different. Sometimes they may be the same but that is not necessarily the case.

QD information Services offers you the chance to use I-optimal designs that are specific for your set of circumstances. If you want to study four solvents and concentration as well as only three temperatures then we can provide you with an I-optimal design for that. If you are interested in a customized experimental design, feel free to send me an email and we can discuss your specific needs. We also offer help in analyzing the results and finding the true optimal conditions.

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One of the primary tools available to the process development chemist to simplify a reaction sequence is to run multiple steps without isolating and purifying the intermediates. This is commonly referred to as “telescoping” reactions. The reasons for telescoping are many; limiting contact with a potentially hazardous compound, reducing cycle times, and reducing pollution and emissions among others. Some concerns are finding the correct solvent to allow the reactions to proceed as well as ensuring no reduction in quality occurs (no new impurities or elevated levels of known impurities). There can be cases where a new impurity is generated but others are eliminated and the new impurity is easily removed.

The Eli Lilly process group recently published an example os using telescoping to reduce toxic and odorous emissions. The first two steps involve formation of a sulfur ylide and the formation of a cyclopropane ring. Initially the steps were in two different solvents (acetone and MeCN). The major concern here is the use and emission of Me2S.

After screening several solvents it was found that both reactions would take place in MeCN and that DBU was the best base of those studied. I do have some concerns about how this was carried out, but that’s a story for another post. They determined the solvent first, then the base, and finally the addition times. This ignores the possibility of interactions between base, solvent and additions times. I better way is to use a designed experiment to determine the correct combination. It could be that one of the other bases with another solvent might give a better result.

Using MeCN as solvent and DBU as the base with quick addition of both DBU and the cyclopentenone gave good results (58% yield).

Process Development of (1S,2S,5R,6S)-Spiro[bicyclo[3.1.0]hexane-2′,5′-dioxo-2,4′-imidazolidine]-6-carboxylic Acid, (R)–Methylbenzenemethanamine Salt (LSN344309) Org. Process Res. Dev. 2006, 10, 28–32

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Seems Europe has approved ATryn (an anticlotting drug) which is produced in the milk of genetically modified goats. GTC Biotherapeutics is the company behind this although Genyme is representing them in European regulatory issues.

Reuters: Goat-derived drug cleared in Europe
Boston Globe: GTC gets surprise boost from EU

The clinical trials in the US are almost compete and it should go to the FDA sometime in the first half on 2007. The process involves inserting a gene into the goat before they are born which causes them to produce a human protein that can be purified and tuned into an injectable drug for humans. The disease ATryn treats is fairly rare (about 60,000 cases in the US or about 1 in 5,000) and therefore an excellent candidate to be produce in animals. The economics of producing this complex of a product in a standard biotech factory would most likely be prohibitive with that few patients.

This situation, where an animal is used to produce a drug, has lead to the term “pharming” since the goats are in essence a walking, eating drug factory. It is nice to see fruits of the efforts to produce drugs in animal milk that started over 20 years ago.

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Coming from the process development side of the pharmaceutical industry I’m always interested in being able to efficiently model a process from the small scale to the large scale. A recent paper describes the researchers experience with scaling the drying process from a 200 g scale in a rotary evaporator (yes, than can be used for drying solids as well as stripping solvent) to a 1000 kg scale in three different types of driers.

Modeling the Scale-Up of Contact Drying Processes: Org. Process Res. Dev., 10 (3), 409 -416, 2006.

It should be noted that the model is not universal; only 5 of the 8 systems investigated worked. It also should be pointed out that there is still quite a bit of unpredictability. If, during the evaporation, the material forms one large lump (not an uncommon occurrence) then the model doesn’t work. The two other cases that failed were also due to aggregation during the drying process. While this aggregation can be reduced by reducing the rotation speed, this also slows down the drying process and resulted in longer drying times.

While this paper outlines a useful approach, processes such as drying still depend very much on the product itself.

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Most chemists know that a solvent change can have a dramatic effect the course of a reaction but what is not commonly appreciated is that a change of solvent can dramatically reduce impurities formed in a reaction and make the subsequent purification much easier or allow it to be eliminated entirely. I recently came across an example of this sort of can be seen in the following article:

The Synthesis of a Novel Inhibitor of B-Raf Kinase (Org. Process Res. Dev. 2006, 10, 70–77)

The reaction of 7-hydroxyisoquinoline with (CF3SO2)2O in EtOAc–pyridine gave the triflate in moderate yield (48%) after an aqueous work-up and a thin-film vacuum distillation. Quite a bit of material is lost in the course of the distillation due to the use of ethylene glycol which was used as a lubricant and to solubilize pyridinium salts.

Changing the reaction solvent from EtOAc to t-BuOMe led to more efficient removal of the salts during the aqueous work-up, the use of less ethylene glycol which gave a higher yield (75-85%) as well as allowing the distillation to proceed at a lower temperature. All this from a simple change from EtOAc to t-BuOMe.

I’ll be honest, this wasn’t the reason this article first caught my eye. I read it because I noticed they used a Negishi coupling in their synthesis. I received my PhD from Purdue University under the supervision of Dr. Negishi and spent quite a bit of time working on this sort of coupling back in the late 80’s. I’m always pleased to see the words “Negishi coupling” and “uneventful” in the same sentence. It was interesting, although disturbing, to see some of the same problems we experienced back 20 years ago. This includes control of temperature for the Li halogen exchange and that the Pd catalyst nature is vital. It would have been interesting to look at other ligands. My experience is that trifurylphosphine instead of triphenylphosphine sometimes gives much better results. It would also be interesting to investigate using the Pd catalyst for the amination as well (Buchwald coupling) instead of dealing with the hydrogen evolution resulting from deprotonation of the amine with NaH and then coupling with the aryl chloride.

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Back in mid-May, Neurocrine Bioscience received both good and bad news from the FDA regarding their insomnia medication Indiplon.

Neurocrine Receives Approvable Letter for indiplon Capsules and Non-Approvable for indiplon Tablets for the Treatment of Insomnia: Financial News - Yahoo!

The capsules were approved, but the tablets were not. The capsules were a lower dose (5 and 10 mg) whereas the tablets were 15 mg. It was also interesting that the FDA admitted to not having time to review all of the information submitted in the new drug application (NDA). Although not specified, I certainly hope that the reason for not approving the 15 mg tablets was simply because they hadn’t reviewed that data. If this is the case, it is good to see the FDA go ahead and send the approvable letter for the capsules and not hold those up.

Neurocrine has listed on their web page the webcast response to the FDA letter but it appears to no longer be available. It will be interesting to see how the insomnia market share will develop since their have been several recent entrants in this area such as Lunesta and the Ambien (which has been around for quite some time). I personally have used Ambien and it works well for me, especially for dealing with jet lag when traveling to Europe on business.

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