QDIS Blog

Just wanted to alert readers to a segment of PBS Newshour with an interview with Dr. Andrew von Eschenbach. It has both audio and streaming video of the interview as well as a transcript of the interview.

Online NewsHour: Newsmaker Interview | FDA Overhauls Drug Oversight | January 31, 2007 | PBS:

Several interesting thing I picked out were as follows:

• All the initiatives announced earlier this week will be done within their current budget.
• The pilot program for “report cards” will start in March 2007.
• Reiterated this is a first step in an ongoing processes.

I found this exchange interesting. Margret Warner was trying to get at how the FDA will handle situations where there is disagrement between scientists such as the recent Vioxx case.

MARGARET WARNER: Well, let me ask about a specific examine, because when Congress looked into the Vioxx situation, there was testimony on the Hill that there had been scientists who had expressed misgivings about Vioxx’s safety, and they had been basically overruled or were not listened to by FDA managers. Is that going to be corrected?

DR. ANDREW VON ESCHENBACH: Yes. Well, in the sense that we have to have processes in place where differences of opinion can come forward when there are needs for that to come through, an ombudsman function or be brought for resolution, those processes have to be in place.

The interesting thing is, although he did answer the question (but it was a simple yes or no question) he didn’t have any specfics. In other cases, he had specifics but in this case it was just, we need to have a process.

Overall, I thought it was a good interview and hopefully these initiatives will indeed be the first steps in improving the FDA and drug safety.

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Well yesterday the FDA released a report containing a lot of proposals for improving drug safety. It includes more than a dozen initiatives of various sorts but all related to drug safety.

FDA Reinforces Commitment to Drug Safety (from FDA website; just a press release)
The Future of Drug Safety — Promoting and Protecting the Health of the Public (actual report)

This report outlines the FDA’s response to the Institute of Medicine Report a few months ago and include making “report cards” on unusual side effects. Mark over at Eye on FDA has a great post about this.

This has brought up concerns about patients seeing these “report cards” and stopping taking their medications. I agree this is likely and think it has more to do with helping the general public understand risk and probability. We humans seem to have difficulty with understanding probabilities. I have taught classes on statistics and probability and know that it is difficult to help people gain an understanding.

I think the FDA is trying to head off the changes Congress is likely to make in the Kennedy-Enzi bill (not yet introduced), but that it is likely too little too late to avoid sweeping changes coming from Congress. While I applaud the initiative, I think it is being done with limited enthusiasm and later than many would like. Also, I do think that any Democratic back billed giving increased authority to the FDA will likely lead to a presidential veto if it gets through both houses of Congress.

Until the FDA has the ability to fine drug companies for not following through on their promises of post-marketing studies, I don’t think much will change. They need an ability similar to the EPA to allow the FDA to fine companies for not complying. Right now, the only alternative the FDA has is to remove a product from the market, something I think everyone agree should be a last resort. And it should be meaningful amounts that really make the drug company want to avoid fines. I would purpose that the drug company be fined the equivalent of whatever they earn on a daily basis. As an example, if a drug earns $1 billion in revenue annually, then the fine would be $2.8 million per day for every day late they are in starting a required study. Obviously there should be the ability for the company to present to the FDA why they can’t start a study and if the FDA concurs, then a new date would be set. Otherwise, the FDA starts the fines.

The other obvious need is for more money to be able to adequately do their job. If you look at the amount of the gross domestic product the FDA overseas, and then look at their percentage of the overall budget, it is vastly out of whack.

Here are some other articles on this news.

FDA proposes drug safety “report cards” (from BusinessWeek)
FDA to Monitor Post-Market Drug Safety (from HealthCentral)
PharmaLive: FDA Reinforces Commitment to Drug Safety

Other Resources

Yahoo! News Search Results for FDA drug safety
FDA drug safety - Google News

Other Blog Posting

Google Blog Search: FDA drug safety
FDA: See what people are saying right now on Technorati

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Seems the FDA is banning General Electric (GE) from making X-ray machines due to problems as its plants in both Utah and Massachusetts according to Forbes. The FDA filed a consent decree in US District court in Utah on Friday, January 12, 2007.

FDA Bans GE From Making X-Ray Machines - Forbes.com:

This relates back to problems discovered initially in an inspection in Nov-Dev 2004 and resulted in a warning letter dated Mar 31 2005. Here is the actual warning letter. The FDA found that the devices were:

adulterated within the meaning of Section 501(h) of the Act, in that the methods used in, or the facilities or controls used for manufacture, packing, storage, or installation are not in conformance with the Quality System/Good Manufacturing Practice (QS/GMP) for Medical Devices Regulation, as specified in Title 21, Code of Federal Regulations (21 CFR), Part 820.

And here is the actual FDA announcement;

GE OEC Medical Systems Signs Consent Decree with FDA; Agrees to Correct Manufacturing Deficiencies

Seems the FDA inspection that occurred July-Aug 2005 did not show the required responses to the past warning letter and led to the FDA enforcement. From reading the announcement above it appears that GE did not validate the device design and failed to have a corrective and preventive actions program.

GE stopped shipping the units in September and will not be allowed to distribute them until they pass another inspection. GE have also had to recall several models.

GE Healthcare Press Release

I think it likely you will see more medical device manufacturers come under scrutiny mainly because, from my limited exposure to medical device manufacturers, they do not have as form an understanding of the cGMP requirements as the biotech and pharmaceutical industries do. Also, the concept of “validating the device design” is relatively new and some device manufacturers do not seem to be aware of the guidance documents entitled Design Control Guidance For Medical Device Manufacturers released by the FDA in March 1997 to address this very issue .

Technorati Tags: FDA, FDA enforcement, GE, medical device, cGMP, x-ray machine

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In what could be a nightmare for some pharmaceutical companies, the FDA has notified some pharmaceutical companies that analytical data (primarily bioequivalence) provided in support of some NDAs and ANDA’s may need to be re-evaluated and repeated. Seems during inspections of a Canadian facility of MDS Pharma Services question were raised about the validity of their results.

PharmaLive: FDA Notifies Pharmaceutical Companies to Confirm or Repeat Analytic Studies Used in the Approval of a Number of Drug Products :

FDA Notifies Pharmaceutical Companies to Confirm or Repeat Analytic Studies Used in the Approval of a Number of Drug Products (from FDA website)

Here are the primary areas of concern from the FDA letter.

• Failure to conduct a systematic and thorough evaluation to identify and correct sources of contamination.
• Failure to investigate anomalous results.
• Lack of assay reproducibility between original and repeat results.
• Assay accuracy not assured under the conditions of sample processing.
• Biased manipulation of study data resulting in the acceptance of failed runs (emphasis mine).
• Failure to demonstrate the accuracy of analytical methods with appropriate validation experiments and documentation.

That these were allowed to go on shows a noticeable disregard for cGMP. Most of these are fundamental issues and not even in areas where there is typically disagreement. It is hard for me to fathom how this could go on! Especially troubleing is the bias manipulation item!!

What is even more interesting is it occurred over the course of four years from 2000-2004 but it is only now that the FDA is sending notices to those potentially impacted. What is also interesting to me is that there is no press release about this on MDS’ own news page. The time period covered is four years from 200-2004! While the FDA website has the warning letters they are poor photocopies and in pdf format and hard to read. Here is another source of the FDA letters in a more easily read format.

FDA Warning Letter, MDS Pharma Services (Facility Inspection)
FDA Warning Letter, MDS Pharma Services (BMIS Inspection)

Here is the actual letters the FDA sent to the affected companies:

Letter to sponsor of Pending Abbreviated New Drug Application(s) (ANDAs)
Letter to Sponsor of Approved New Drug Application(s) (NDAs)

On a personal level, one of the drugs mentioned is loratidine the generic name for Claritin. I personally use this and wonder which generic companies are affected. This is the only specfic compound mentioned that I saw but there is likely others.

This should be a warning to many companies when they rely on others for results. I think it will be a blow to MDS Pharma services and find it very confounding that they have yet to get on top of this issue and put out any sort of statement. In light of all this, I certainly would steer any of my clients away from using MDS Pharma Services.

This is also what many refer to as the cockroach syndrome. If you see one, you know there are more in hiding. My question is if this sort of disregard for basic science principals occurs in this instance, there are almost surely other incidents that have not yet been uncovered.

Technorati Tags: FDA, FDA enforcement, FDA inspection, MDS Pharma Services

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I found this article on the FDA from the magazine “The Scientist” interesting and wanted to alert readers to it.

The Scientist : THE FUTURE OF THE FDA

It’s short but covers the main topics of interest and what the future might hold. Hope you enjoy it.

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I hesitated to post about this but then decided I’d leave it to the readers to decide for themselves. This article in the LA Times concerning the FDA and a contract secured via a family connection.

Family tie helps win FDA contract - Los Angeles Times

Normally, I would think much about this but since both people involved were familiar with government contracting , it does appear that they should have known better. Here is the bachground from the article

WASHINGTON — The concerns at the office surfaced not long after their Las Vegas wedding.

Margaret “Margo” Burnette wasn’t pleased with the contractor handling an important data project at the Food and Drug Administration, where she held a senior position. For advice, she turned in summer 2004 to her new husband, Mark A. Boster.

Both had spent most of their careers dealing with government contracts. And Boster, she recalled, had been “ranting about this fabulous company.”

“I did ask Mark, ‘What was the name of that company?’ And I gave the name to my deputy.”

The sequence of events worked out well for Platinum Solutions Inc., of Reston, Va., for whom Boster was a paid advisor.

The FDA dismissed the first contractor and awarded the job to Platinum Solutions. By this fall, the small technology company had collected about $4 million from the project. Last month it won a new, related FDA contract, possibly worth millions more.

This seems like a clear conflict to me and is something that the FDA has come under scrutiny for in the past. Regardless of the final outcome (the FDA looked at it and no violation was found), even the appearance of conflict of interest should be avoided. The article paints a negative picture in my opinion especially since both were well aware of the rules but continue to say they had no regrets and no qualms about the situation. This sort of attitude is what bothers me. At the least, they should have said they wished they had handled it differently and been more upfront.

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The end of the year is always a time for reviewing what the year has held and making resolutions and predictions for 2007. With that in mind, I’d like to present my predictions of what may happen in the pharmaceutical and biotech industries in the year.

1. Biogeneric Regulations: The process for developing biogeneric regulations will get started in the US. This will likely be prompted by an act in Congress. I don’t expect for draft regulations for comment though to come out until sometime in early 2008. I think this is too bad and I personally would like to see regulations in place for comment before the end of 2007.
2. Mergers and Acquisitions: Mergers and big deals will continue in 2007 at full steam. Many of these will involve big pharma acquiring small biotech in order to fill their pipeline. Unfortunately, I don’t think the opportunities will pan out. The problem is that the principals involved in the small biotech that make it a success will not join the big pharma company. They will take their profits and most likley start another small biotech. The big pharma will not get the benefit that they tout to their investors for these purchases and will continue to pay too much for them on th fear that someone else will buy this small biotech instead.
3. Early Stage Deals: More deals will involve earlier and earlier stage products. Big pharma will be more willing to pay big prices for potential drug candidates at earlier stages of development in order to try and fill their pipelines.
4. DTC Advertising: Direct-to-Consumer (DTC) advertising will come under increasing attack and regulations will be enacted to prevent DTC ads in the first year of launching a new drug. Some companies have already said they will do this but I think it will become a matter of law.
5. The FDA: The FDA will be given additional powers to regulate drug post approval. This may include the ability to fine companies if they do not perform agreed upon studies within a certain timeframe.
6. The FDA; The FDA budget will be increase but only by a small amount: not enough to reflect what they actually have to accomplish.
7. Outsourcing: Although outsourcing will continue there will be a new move towards big pharma building R&D centers in China, and India.
8. Drug Imports: Congress will pass regulation to allow drug imports from a limited list of countries. This will be vetoed by the President.
9. Congress will discuss adding the ability for the Government to negotiate with drug companies for drugs covered by Medicare but legislation will fail.
10. Food Safety: Food safety will become an important topic and there will likely be at least one or two more national incidents involving more than 100 people. There will be talk in Congress of combining the USDA and the FDA food safety together but this will not happen.

Well, there they are in print and we’ll see at the end of 2007 how accurate these are.

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I came across this article in the Washigton Post and found it disturbing.

FDA Consolidation Plan May Close Labs - washingtonpost.com:

The article mentions that the FDA will be forming a transition team to discuss which labs should stay open. Although no sites were mentioned specifically in this FDA email dated Dec 6 talked about in the WP article, they do speculate that it involved facilities in Cincinnati, Denver, Detroit, Kansas City, Philadelphia, San Francisco and Seattle.

There is more information on the Public Employees for Environmental Responsibility (PEER) website. They also had an article on this. They have some more information not in the WP article and say that a similar plan was rejected back in 1996 and that then the General Accounting Office (GAO) found the efficiencies questionable and the plan in general vague.

I must say this caught me completely off guard. I’m still not sure what to think but my initial reaction is this is not a good idea. I have always been in favor of localized offices and while the offices will likely stay, the scientific functions may be what are specific being talked about since it mentions labs. My experience is that having scientific functions consolidated can have a positive effect but that effect is failry small and must be weighed against other factors. In this case, having personal in the area who are more familiar with the localized culture and have the ability to quickly respond to a serious situation should one arise.

The supposed goal is to maximize efficiency but I think it more likely involves cost cutting. Given the food safety situation of late and that these labs are involved in those sorts of situation this is particularly disheartening. The PEER article also point out that the FDA FY 07 budget includes a $20 million increase to “expand the network of laboratories that would rapidly and competently analyze samples in the event of a terrorist attack on our nation’s food supply.” While this increase is minimal at best, the fact that it specifically mentions expanding the network of labs is quite a disparity given the fact that the FDA is wanting to consolidate the labs.

This is especially disturbing in light of the closing of satellite EPA libraries recently.

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I’m late on posting this but still wanted to comment on this. An FDA advisory committee came to the conclusion that drug coated stents are not problematic.

ABC News: FDA Panel Finds Drug-Coated Stents ‘Not Detrimental’:

However, there is concern about the massive use of drug coated stents for indications outside of the approval. As many as 66% of the stents are used “off-label”. This is the category that the panel had great concerns over the use.

Here are the summaries from this meeting.

Summary from the Circulatory System Devices Panel Meeting - December 7 & 8, 2006

Again, I think off-label use is valid however I think that there needs to be some sort of check on this. Too many times the off-label use of a drug or in this case a device, accounts for the vast majority of its use. There was a drug at a company I use to work for where ~80% of the sales were for off-label use.

Many times, pharmaceutical and biotech companies will turn to the easiest indication to get approval and hope to get further sales from these other indications for which it is not yet approved. In some cases, there are actually plans to do more studies and get approval for other indications. This is common practice in oncology but I think in other areas there needs to be some sort of regulation. I would suggest that when the off-label use constitutes a certain percentage, the drug companies should be required to get approval for that indication. Now this could have other consequences and one of the biggest concerns would be how do you determine the percentage of off-label use, that is whose’ data do you use. If you rely on the drug companies there may be under-reporting in order to avoid doing further costly studies. However, I think in non-life threatening situations, this could be justified.

Other Resources
FDA Statement on Coronary Drug-Eluting Stents
FDA Heart Health Online - Questions and Answers on Coronary Drug-Eluting Stents
fda drug-eluting stents - Yahoo! Search Results
fda drug-eluting stents - Google Search

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I discover this article originally from Mark Senak over at Eye On FDA blog. This FDA proposal would allow for greater access to experimental drugs as reported in the New York Times.

FDA Proposes Broadening Access to Drugs - New York Times

I am a backer of allowing greater access to experimental drugs but feel that the key in this is the word “appropriate”. While no one would object to this with regard to life threatening conditions such as cancer it is unclear how other situations would be dealt with. One of the point in the proposed rule states that:

modernize applicable regulations to include all circumstances under which access to experimental drugs is permitted.

This seems to be a little overly optimistic to me. I find it hard to believe they could define ALL CIRCUMSTANCES in which this may be appropriate. What about someone who has a respiratory ailment that makes breathing difficult and they have tried all approved therapies without positive results? Maybe it keeps them from being mobile and getting out of their home. If there is an experimental drug that could significantly improve their quality of life would this be allowed? The question basically boils down to what is appropriate and this could indeed vary with regard to aliment and even for given patients having a certain condition. I think rather than trying to state all conditions it might be better to define the process allowing for the use of experimental drugs.

One of my other concerns in this involves the fact that our society today seems to be very litigious. Seems anytime something goes wrong, we look for someone else to hold responsible or to sue. I firmly believe that if a company deliberately withholds information concerning dangers or concerns then they should be held liable. However, in the case of an experimental drug, little may be known and opening it to what use to be called compassionate use may be opening a can of words. I firmly believe individuals should be held accountable for their decisions provided it is an informed decision. I’m not sure how this would be worked out, but I’m sure that this will be an item for discussion.

Technorati Tags: drug safety, FDA, experimental drugs

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