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There has been some talk recently of improving the drug development process by including the use of biomarkers. Now, I’ll be the first to admit this is somewhat out of my area of expertise; I’ve always been involved on the manufacturing side, but I wonder if the FDA will really quickly buy into this approach. I know from my experience in developing oncology drugs that the FDA wanted to see an increase in overall survival; that is the gold standard as it should be. The company I worked for suggested several surrogates mainly to get a good idea of who the drug may help and to determine more quickly if development should be discontinued. The feedback was that the FDA would not be considering such data in our filings.

So, maybe biomarkers will work for other areas, but my experience in oncology was that the FDA still wanted to see overall survival. But then maybe it will slowly change as more evidence comes in.

Resources:

• RedOrbit - Health - Research and Markets: The FDA is Encouraging the Use of Biomarkers in Clinical Trials and, in a Few Cases, Requiring the Development of Companion Diagnostics
• The FDA Is Encouraging The Use of Biomarkers In Clinical Trials
• Safety Biomarkers Help to Reduce Drug Attrition

Technorati Tags: biomarkers, FDA

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MeTHF is an interesting solvent and a useful alternative to THF. One of the primary differences is that MeTHF is not miscible with water whereas THF is. This means that at the end of a reaction, you can add an aqueous quench and work up the reaction without having to add another solvent. MeTHF also gives clean phase splits whereas THF mixed solvents can give problems with emulsions and long sitting times to get clean phase splits.

MeTHF has some other interesting properties as well. Bromo derived Grignards are more soluble in MeTHF than in THF itself. It is also more easily dried. Not only can it serve as a replacement for THF, but it also has been used as a replacement for dichloromethane (pdf) which is a big advantage.

The main drawback currently is price. I quick check of Aldrich gives a 2L bottle of 2-mehyltetrahydrofuran for $165. By contrast, a 2L bottle of THF is only $88.90. I think the price will come down if more people start using it. After all, it comes from furfural which comes from corn and is renewable. Also with ethanol being considered as a fuel alternative, the ability to increase capacity for 2-methyltetreahydrofuran can be increased and the price will certainly come down.

Here is the page from Penn Speciality Chemicals with a lot more information on MeTHF.

For a reference on MeTHF for replacing dichloromethane: David H. Brown Ripin, Synlett 2003, No. 15, p 2353.

Technorati Tags: THF, solvent change, solvents

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This article reports on significant advances reported by GlalxoSmithKline on their work with a potential bird flu vaccine.

GSK Reports Significant Advance in H5N1 Pandemic Flu Vaccine Program

The main point is that they have managed to get a very good immune response from a low dose level. Here’s the key qoute from the press release.

The vaccine, which uses a proprietary adjuvant, enabled over 80% of subjects who received 3.8 micrograms of antigen to demonstrate a strong seroprotective immune response. This level of seroprotection meets or exceeds target criteria set by regulatory agencies for registration of influenza vaccines. Efficacy results at these levels of antigen dosage have also not been reported for any other H5N1 vaccine in development to date, including those using other adjuvants such as alum.

This is truly a breakthrough since getting enough vaccine to treat enough people has long been a major concern.

Technorati Tags: bird flu, drug development, GlaxoSmithKline, H5N1

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I want to talk about a couple of alternative solvents that get overlooked quite a bit in organic synthesis. The first is diethoxymethane (DEM; CAS [462-95-3]).

It has several uses based on it’s properties. First, it is a very good solvent fr Grignards and other organometallic reactions due to its low water levels typically less than 150 ppm (water solubility in DEM is 1.3% w/w). It llso has limited solubility in water; 4.2% w/w. It also has a low boiling ponit (88 °C) and Another attractive property is that DEM azetropes with ethanol (bp 74 °C, 58% DEM) and with water (bp 75 °C, 90% DEM).

It does tend to form peroxides after being opened and it is flammable (flashpoint of -5 °C). It is stable to base but does decompose under strong acid conditions.

While the solvent has been known for some time, it has only in the past ~6 years been commercially available in large quantities (55 gal drum to railroad tankcars from Eastman). It is in general a good replacement for dichloromethane, tetrahydrofuran, glyme (1,2-dimethoxyethane), and methylal (1,1-dimethoxymethane).

Here’s some information from Eastman Chemical and a publication from a few years ago in Org. Process Res. and Dev. 2001, 5, 127.

Eastman Chemical Information

Applications of Diethoxymethane as a Versatile Process Solvent and Unique Reagent in Organic Synthesis

Another solvent that gets overlooked is 1,3-dimethyl-2-imidazolidone (DMEU or DMI; CAS [80-73-9]). This can be used as a replacement for the highly toxic HMPA as a dipolar aprotic solvent.

It is very similar to 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone [7226-23-5] but has a lower boiling point.

It is similar to dimthylformamide but tends to be more stable. It is stable to alkali metals and strong bases and has a boiling point of 225 °C. Mitsui Chemicals America has a nice site with information on 1,3-dimethyl-2-imidazolidone including physical properties, chemical properties and some applications.

I have used both of these in my past and have been happy with the results and hope others will consider them for future projects.

Technorati Tags: process development, solvents

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The first sentence of this article caught my eye.

What if you organized an important cancer clinical trial and nobody came? That scenario could become a reality for oncology researchers across the United States, new research shows.

Clinical Trials for Cancer Running Out of Volunteers - Yahoo! News:

The article goes on to say that in order to complete all of the 679 trials at all phases for lung, breast and prostate cancer you would need 238,000 patients. That corresponds to half of all cancer incidences. This means that at least half of people diagnosed with cancer would need to participate in a clinical trial and note that the 238,000 needed only covers breast, lung, and prostate cancer!

I don’t dispute the numbers and based on my experience this is pretty close to true. However, It should be noted that they picked the three types of cancer that have the largest number of trials currently. I do know from a project I was involved in for non-small cell lung cancer it was deemed impossible to get enough patients in the US and western Europe in the required timeframe. Therefore, the trial ended up recruiting world-wide in South America, India and eastern Europe.

Cancer trials tend to be the current trend for a couple of reasons. One, there are some types of cancer that meet the unmet medical need as defined by the FDA and drugs to treat these are given special consideration. A lot of this came about from the AIDS activism in the 80’s. Also, cancer tends to be a highly profitable area for drugs. I’ve not seen recent numbers for drug sales broken down by therapeutic area but I’m sure oncology is high on the list.

The question is what, if anything needs to be done. I tend to think that the numbers aren’t as bleak as it has ben made out to be.
One thing is better education of oncology doctor as to what is available, especially for patients who don’t respond otherwise. Let’s hope this isn’t a trend and merely a momentary decline.

Technorati Tags: drug development, clinical trials

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I’ve read many articles recently about attempts to improve the whole drug development process and much of the focus seems to be on the drug discovery side. While I agree that drug discovery can be made more efficient, I think that this may just result in moving the bottleneck to the development arena, an area that in general from my experience gets somewhat overlooked in terms of how do we make development (making clinical trial materials) more efficient. I do think that the decoding of the human genome will eventually result in more potential target for drug discovery and help to focus their efforts in the future since most of the low lying fruit has already been picked. I think many people were overly optimistic as to how long it would be before the decoding of the human genome would lead to something concrete.

A large part of the problem is you don’t want to spend an inordinate amount of effort developing a great route to a compound, only to have it fail in the clinic. Determining failure in the clinic as soon as possible is imperative before they get into the large and expensive phase III trials. However, by the time it is clear that the drug will indeed succeed, it is usually determined (mainly by management and regulatory departments) to be too lately to make any changes to the route. This invariably leads to an inefficient processes being rolled out commercially. One of the reasons for that is the amount of work required to change a commercial route once it is validated and filed. I truly think more effort needs to be dedicated to getting a workable process in place for making changes to allow for

Process analytical technology (PAT) will help if it can be economically done by retrofitting current facilities. Expecting companies to scrap investment in facilities and equipment just to incorporate PAT is unlikely to happen. However, if PAT could be easily retrofitted into existing equipment it would certainly be more widely adopted.

Note that the bulk active post approval changes guidance has been removed from the FDA Guidance website since it was reported in the Federal Register on June 1, 2006 that they were “inconsistent with the agency’s initiative, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century (CGMP Initiative). However, looking through the CGMP Initiative nothing directly addresses the issue of what needs to be done if a change is to occur after approval. I for one sincerely hope this is an area of development that is looked at in more detail to allow for changes to occur which could improve the quality and efficiency of producing bulk active ingredients.

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A recent article in Chemical & Engineering News (June 19, 2006) brought back to mind some thoughts from my early career with a major pharmaceutical company. This special issue covers many different areas of the drug industry and tries to answer the question “Where does pharma go next?”

C&EN Special Issue: An Industry in Transition

I just want to comment on one item covered in the article Pharma In Flux. Here’s the pertinent part:

Wyeth, on the other hand, is among the major drug companies that have instituted a comprehensive series of targets for each stage of drug development. The plan, put in place by Robert Ruffolo, president of Wyeth Research & Development, emerged in response to Wyeth’s sagging pipeline in the late 1990s (C&EN, Feb. 16, 2004, page 22). It called for Wyeth to introduce 12 new drugs to early-stage development each year, up from an average of three in the late 1990s; to file eight Investigational New Drug Applications (INDAs) with FDA per year, up from an average of two; to begin Phase III clinical trials on at least two new candidates per year; and to market two new drugs per year.

While setting goals such as this is admirable, in my experience it has created many more problems than it solves. Being on the development side of things, what I saw was the following. Drug discovery, in order to meet these goals, would toss over the wall into the development side whatever compound they had when they approached their deadline for a drug in a given therapeutic area. They always seemed to come up with one just before the deadline. This was then developed regardless of how poor a candidate it truly was. Then, the drug discovery chemists were given bonuses and/or company-wide recognition and the process development folks left to try and figure out how to pull off the difficult feat of developing a potential commercial route to a poorly selected compound.

Now, in my experience development always managed to find a way to make the compound but that doesn’t make the process efficient. My experience was that development was not allowed input into what we would like to see in a drug candidate even though we were drug discovery’s internal customer. Now, I realize that the goals of drug discovery are different from those in development, but I do think allowing for input from development would have been useful. There were some things that were done to make the process more efficient. A development chemist went to each of the drug discovery group meetings (one of the reasons for having early development and drug discovery at the same geographic site) in order to get a heads up on what way be coming our way in the future and to learn what had been done that worked as well as what was tried that didn’t work. However, my impression was that this was a one way street with information flowing in one direction only. Any ideas and suggestions from development to drug discovery was generally met with little interest or outright skepticism. Also, the data packages that development received from drug discovery did not contain the kind of information that was needed in order to move the project forward. Much time was spent in gathering basic information that should have been made available in the transfer package but wasn’t (TLC’s with solvent systems; NMR data, etc.). In some cases, drug discovery experiments had to be repeated to get basic information . Some of this was because drug discovery did not understand what development did bit in other cases, they didn’t want to know. About the only time drug discovery embraced development was when they had a core compound identified and the kilo labs was making large amount of the core for drug discovery to make various derivatives.

What is needed is a more objective criteria of what drugs should be developed and not a focus on simply hitting certain numbers. When only numbers were talked about, I never saw drug discovery fail to meet the goal. In my 5.5 years at this major pharma company, I never did see any objective criteria developed to determine what drug candidate should be moved into development. Hopefully this is changing, but I’ve not seen any first hand evidence of this.

Technorati Tags: process development, drug development

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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.

Technorati Tags: design of experiments, process development

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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

Technorati Tags: process development, telescope reactions

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The European Medicines Agency (EMEA) has recommended approval of Sanofi-aventis’ Accomplia (rimonabant) weight loss drug. While not binding, the EU usually follows the recommendation within three months. This means it may be approved by the end of July. It should be noted that the EMEA did not recommend approval of Accomplia for smoking cessation.

Also, the FDA sent an approvable letter in Feb to Sanofi-aventis for weight loss but also did not think the drug worked for quitting smoking. It is unclear when it may be approved in the US. The NDA was filed in June 2005 so it may happen by the end of 2006.

The interesting thing about rimonabant is that it works by a new mechanism different from most other drugs by blocking a pleasure center in the brain.

Wikipedia has a nice article on rimonabant. Two article are available for those seeking more information; one from the New England Journal of Medicine (free) and the other from the Lancet (registration required). Drug Development Technology also had a nice article on rimonabant.

Technorati Tags: rimonabant

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