It has always been my understanding that the manufacture, sale, and distribution of prescription pharmaceuticals is and always has been tightly controlled by the federal government to protect the ultimate consumer from harm. Although there may be side effects, these medications are intended to make you better.
If we begin to doubt the things of which we are absolutely sure, it raises many questions. In fact, there is a very real possibility that some of the medications you are taking are making you sicker than the illness you are treating. Yet, very few of us question the purity of our medications because we know how tightly prescriptions are controlled and regulated.
A very dangerous assumption, it seems.
In Part One of How Good Are Your Drugs?, I looked at the wholesalers of pharmaceuticals, and the ease of which adulterated and counterfeit drugs can enter the mainstream.
Here, we look at the manufacturers and their ability to co-opt FDA regulations for their own financial gain, leaving the patient at risk from the medications intended to make them well.
Where the FDA Is Dropping the Ball
In June 2006, the House Committee on Oversight and Government Reform issued a report entitled Prescription for Harm – The Decline in FDA Enforcement Activities. The report was requested by and prepared for Congressman Henry Waxman. In it are some disturbing results, including these three from the Committee’s web site:
1. FDA enforcement actions have declined under the Bush Administration. The number of warning letters issued by the agency for violations of federal requirements has fallen by over 50%, from 1,154 in 2000 to 535 in 2005, a 15-year low. During the same period, the number of seizures of mislabeled, defective, and dangerous products has declined by 44%.
2. FDA headquarters officials have routinely rejected the enforcement recommendations of career field staff. Internal agency documents show that in at least 138 cases over the last five years involving drugs and biological products, FDA failed to take enforcement actions despite receiving recommendations from agency field inspectors describing violations of FDA requirements.
3. FDA’s record keeping and case tracking practices are inadequate. Although the Federal Records Act and internal agency procedures require FDA to keep records that document agency enforcement decisions, FDA does not appear to comply with these requirements. FDA’s response to Committee requests for relevant enforcement documents was haphazard, incomplete, and untimely. FDA officials explained that FDA could not provide prompt and complete responses because the agency lacks a system that enables it to track enforcement recommendations from field offices.
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Article comments
1 - Stanley
I think the writer of this article selected a very poor example of the FDA's enforcement oversight. If anything the FDA was a bit overzealous in this case.
Elspar is produced by a submerged fermentation process using a strain of E. coli with a mutation that causes it to produce more asparaginase (an enzyme) than the wild type of E. coli. The mutation is naturally occurring and over time the culture will start to revert back to the wild type and make less asparaginase. It is a routine process in microbiology to re-isolate the organism and re-select the mutant strain at periodic intervals. This re-isolation is what was cited by the FDA. What the FDA interpreted as a "change in the production process" was actually a routine practice that is performed in fermentation facilities every day.
It should also be noted that it is not as easy as to shut down a process every time the manufacturer and the FDA disagree. Elspar is a life-saving chemotherapy agent that has a very short shelf-life. Shutting down the process would deny patients access to this drug while Merck and the FDA argue semantics. If the FDA believes that an issue is serious enough, they have no problem stepping in and shutting down a facility. This was not the case in the example given.
There are plenty of warning letters on the FDA website that the writer could have chosen to use as examples in his essay. Of course, most of them do not involve companies which have high profile litigation problems stemming from a completely unrelated issue. Merck is an easy target right now; Mr. Vassar could have spent a little more time searching for a more deserving victim.
2 - Stanley
I almost forgot. The writer also got the mechanism of action of asparaginase completely wrong. Asparaginase is NOT a protein that resembles nutrients cancer cells need to grow and it does NOT thwart cancer growth because cells absorb the drug instead of nutrients.
Asparaginase is simply an enzyme that breaks down extracellular asparagine, an amino acid necessary for normal cellular function. Cancer cells typically rely on exogenous sources of asparagine for survival because they lack the cellular machinery to manufacture asparagine internally. Normal cells retain the ability to manufacture asparagine internally. By denying the cancer cells the extracellular asparagine that they need for survival, the cancer cells are destroyed while sparing most normal cells.
Since this article is listed under the heading of "News", it is incumbent upon the author to present accurate information.
Another point that the author fails to mention is that asparaginase is considered an orphan drug. This means that the patient population for this drug is very limited and the manufacturer produces it mainly for humanitarian, not financial, reasons. If you were to examine Merck's annual report you will probably not find asparaginase anywhere in Merck's sales figures. To insinuate that any process improvements were made for financial reasons is ludicrous.
3 - Rick Vassar
Stanley,
Thanks for the comments. I enjoy the discussion.
Unfortunately, you defeat your own arguments. If there are procedures for altering the production, you cannot unilaterally sidestep the process because of the perceived greater good. That's untenable.
As for Merck, I didn't make them an easy target. They put that on their back on their own. I am just reporting what I see. All the technical information was provided via public record; either the FDA, the SEC or Merck/Ovation themselves.
Rick Vassar
4 - Christopher Rose
Rick, can you please make the url in the comments window complete by sticking http:// at the beginning. The site sends people to an error page otherwise. Thanks.
5 - Stanley
Rick,
In your article you wrote, "It is also unclear how long prior to the February 2005 inspection that these deficiencies existed." Is it possible that this “problem” had always existed and was never raised as an issue during previous FDA inspections? Could it also be possible that this was not due to an oversight by the FDA, but rather a difference in interpretation by FDA inspectors? This is a common obstacle faced by the pharmaceutical manufacturing industry. You can read the regulations as many times as you like, but you are never able to anticipate the differing opinions of individual inspectors. In fact, some inspectors will actually contradict the findings from a previous inspection. The best you can do is use your best judgment, error on the side of caution whenever possible, and try to keep abreast of the current regulatory environment. It is not as black and white as you try to make it appear. The regulations are often vague, contain numerous updates, and require a great deal of interpretation. This is the reason that most pharmaceutical companies employ so many people in their regulatory affairs departments. This is also part of the reason that the FDA allows time for manufacturers to respond to a 483 or warning letter.