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Seems Merck can’t get a break. First there is the ongoing Vioxx mess and then there was a positive development with the approval of Gardasil vaccine for cervical cancer followed by the Center for Disease Control (CDC) recommendation that it be given to all girls age 11-12. Now, the LA Times is reporting on the growing concern and beginnings of lawsuits regarding Fosamax (alendronate sodium), Merck’s treatment for osteoprosis.

Another Merck Drug Is Under Legal Attack - Los Angeles Times

It seems that Fosamax and other compounds in its class called bisphosphonates are linked to a condition called osteonecrosis. This is a rare condition which leads to deterioration of the jaw bone which can be extremely painful and debilitating. The question is, was this something Merck should have foreseen and is it something that should have been picked up earlier.

FDA has a Office of Drug Safety (ODS) Postmarketing Safety Review that was issued in August of 2004. The conclusion was that additional language should be added to the labels under adverse events. Here is a blog posting from Drug Injury Watch blog concerning this.

Here’s a screenshot of a search on Google for Fosamax (click the image for a larger view). Note that two of the three sponsored results at the top are for lawsuits and of the first seven ads on the right, three are for law firms.

The same search on Yahoo! yields three of four results at the top for lawyers and only one out of eight for ads on the right column.

Google trends is also interesting in that three FL cities; Miami, Orlando, and Tampa all are in the top ten cities searching for this terms. This is most likely due to the fact that the law firm of Levin, Papantonio, Thomas, Mitchell, Echsner, & Proctor, P.A. located in Pensacola, FL. One of their lawyers has filed over 30 lawsuits so far and expects to file more than 300 by the end of the summer.

My take, this is going to be another major pain for Merck. It will be interesting to see how this develops in the coming months. Another thought is that at least two other companies Novartis [Zometa (zoledronic acid] )and Procter and Gamble [Actonel (risedronic acid)] have similar problems with similar drugs but don’t seem to be getting the negative press that Merck is receiving (they are however being looked at for lawsuits also).

Other news sources:

• Yahoo! News Search Results for fosamax osteonecrosis
• fosamax osteonecrosis - Google News

Blog sources

• Google Blog Search: fosamax osteonecrosis
• fosamax osteonecrosis - Sphere

Technorati Tags: alendronate, drug safety, Fosamax, Merck

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I’ve mentioned several times in this blog that sometimes pharma takes a short term approach and takes a position that really paint themselves into a corner. Recently Viropharma seemed to exhibit this same behavior.

Philadelphia Inquirer | 07/03/2006 | ViroPharma wants to stop FDA from easing generics rules

Basically, according to this article, ViroPharma is trying to prevent the FDA from approving a generic version of their antibiotic Vancocin (vancomycin) capsules which is used to treat various infections and particularly infections of Clostridium difficile which has recently been in the news. It is one of the few treatments specifically for this bacteria which lately has become more common. This is the bacteria involved in the recent deaths regarding RU-486 but it has been common in other situations as well including deaths after normal normal child birth.

After reading the article something didn’t seem to be right or was missing, so I decided to look into this in more detail. Here’s what I found.

Here is the first letter from the CEO of Viropharma to the FDA (pdf) and here is the second (pdf). Michel Rosen (CEO of Viropharma) also sent a letter directly to the FDA acting commissioner Andrw von Eschenbach. They claim that since Vancomycin is a drug of last resort and that if it is more widely available then resistance is likely and therefore a generic version should not be approved. They also argue that a simple dissolution test is not sufficient for a variety of reasons.

Here is the Viropharma web page regarding this. For those of you with a scientific background, I highly recommend the scientific evidence pdf.

I fully understand Viropharma’s position that they only have one product (licensed from Eli Lilly) and need to protect it but I think they are going about it in the wrong way (remember my mantra; do the right thing, for the right reason, in the right way). The process for small molecule drugs to become generic is well established. Also one sponsor of a ANDA (Biotechnology Equity research) requested guidance from the Office of Generic Drugs (OGD) and OGD has given specific guidance on what needs to be done to establish bioequivalence, at least in terms of dissolution. Another sponsor (Infinium Capital Corp) also requested guidance from the OGD Division of Bioequivalence and received the same information, basically a dissolution test. Viropharma is arguing (pretty convincingly) that the drug can not be judged based solely on dissolution of capsules. After reading their arguments, I tend to agree that some limited clinical trial testing may be needed.

Another reading of the situation (which is probably closer to the truth) is that FDA was answering a specific question about dissolution (since we don’t get to see the original question it is hard to judge) and are not saying this is all that is required. I really think that the FDA wasn’t saying that if the capsules dissolved in a certain timeframe under certain conditions that was all that was required.

Basically, if the OGD has indeed changed the criteria for bioequivalence of generic drugs without any sort of process or scientific input, it is indeed disturbing. I personally think this is a case of misunderstandings and miscommunication which will hopefully be cleared up soon.

While Viropharma may indeed be in the right, this sort of approach reinforces the view in the public’s mind that pharmaceutical companies are greedy and put profits ahead of everything else, even if in this case they may have very good reasons for doing so. While their scientific argument is persuasive, it wasn’t addressed to the average consumer who views pharma skeptically to say the least. It really boils down to do you let the media handle you or do you handle the media. I think Viropharma should do a better job of managing the information flow. Other than posting the way too technical scientific and legal arguments, I’ve not seen much from the company in terms of getting their message out to the general public.

Other Sources

• ViroPharma Submits Scientific Arguments In Supplement To Vancocin Petition For Stay Of Action
• Viropharma argues to stop copying of Vancocin | Reuters.com

• Prescribing Information for Vancocin from the FDA website (pdf)
• General information about Clostridium Difficile

Technorati Tags: FDA, Vancocin, vancomycin, ViroPharma

Email Ed Vawter

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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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A recent article in the International Herald Tribune regarding patents and the poor caught my eye.

How drug patenting fails the world’s poor - Business - International Herald Tribune

The article covers a recent meeting of the World Health Organization (WHO) which brings up the fact that some think the current system is inadequate . The solution put forth by WHO is for governments to develop and finance an alternative drug development and distribution system for the developing world. While the goal may be admirable, I don’t think any government should be in the drug development business. Making affordable medicines for the developing world is a tough issue but making the government the drug maker I don’t think will help. Not only that, but if a government develops a drug, then who is the watchdog to ensure the drug is safe and efficacious? Not the government since this would be a conflict of interest. A better approach in my opinion is to create incentives for companies to develop drugs that would be beneficial to these developing countries in much the same way that the Orphan Drug Act has helped to bring drugs to the market that help small patient populations. However, as always these need to be carefully crafted to avoid creating loopholes that some may take advantage of.

Another problem is developing drugs for diseases that are only prevalent in developing countries. A prime example is malaria; little to no research is being done by any of the big pharma companies in this area. Since there isn’t much money to be made, why would companies invest the years of development into a drug that is unlikely to ever make a profit? I better approach is to find ways to decrease costs in all areas including regulation. Would it be better to decrease oversight and possibly have less safe drugs make it to market in poorer countries under the rational that they would likely die anyway? And then some are upset that more and more clinical trials are being performed in these poorer countries and worried about them being taken advantage of. It would seem that performing the clinical trials in some of these countries would be a benefit to them.

My answer to the question in the title is NO. However, that doesn’t mean changes don’t need to be made to help those who are less fortunate. I don’t claim to have all the answers, but I think it needs to be addressed in a manner that benefits all involved. Determining the amount of benefit each should receive is where the real problem lies.

Other Resources

• IPcentral Weblog: WHO or Whom?
• The Manila Times Internet Edition | OPINION >
• New Scientist Breaking News - Trade talks fail to deliver drugs to world’s poor

Technorati Tags: drug patents

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The following article appeared recently in the Washington Post.

Petitions to FDA Sometimes Delay Generic Drugs

The article talks about the use of what is called a citizen’s petition to delay entry of generics into the market so that a brand name drug can continue to have it’s exclusivity. The FDA has information about providing feedback to on it’s website.

The process involves filing a petition with the FDA and then it can take anywhere from months to a year or more before there is action on the FDA’s part. This in essence gives the brand name drug an extension on it’s exclusivity.

One of my basic tenants of living is to do the right thing for the right reason in the right way (and this includes at the right time). If one of these is out of balance, there will be problems. In this case, we are talking about intent (the right reason). However, determining why someone does something especially in a technical context, can be quite difficult.

In this particular case, it may well be that the brand name company has the most information about the drug over the years of development and is most likely in a good position to determine if there is a potential problem. However, the FDA should also be an expert with even more experience since they see all drugs at various stages of development and have access to knowledge that is not publicly available. However, I’ve also been around the industry long enough to recognize that sometimes companies use this sort of loop hole to their advantage. I personally think this has to do with the legalistic interpretation instead of the moralistic one. While I realize companies are in business to make money, I also realize they have to keep the confidence of consumers. Practices such as this and the misuse of filings in the FDA orange book show to me that companies emphasize the short term gains without realizing the longer term negative effects of the bad publicity. This may be because consumer confidence does not show up in any accounting statements.

One of the things I think might help is to improve the FDA’s response time to these petitions. According to the article the FDA is taking steps internally to shorten the time for rulings on these petitions. There were no details given as to what these changes may be so we will be a wait and see if there really is a quicker response. I think this is an issue that will not disappear anytime soon and probably won’t change until Congress gets involved. And with the current political situation, I think that it highly unlikely.

Technorati Tags: drug safety, FDA

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