28 March 2008

by Ronald E. Kavanagh, B.S.Pharm., Pharm.D., Ph.D. - shirak@verizon.net

I'm the parent of a child with severe ADHD and I'm also a pediatric clinical psychopharmacologist who just happens to be an FDA reviewer. Previously I worked at Merck where I was also involved with neuropsychiatric drug development and regulation.

Unfortunately government rules and regulations are so restrictive that if I discuss anything that is substantially based on information I've learned through my job I could face disciplinary procedures including being fired and even criminal prosecution. Consequently, I need to be circumspect regarding anything I write.

However, in the course of keeping up with the scientific literature on my own time and using my own resources I have serendipitously come across information that has allowed me to understand what is going on between the pharmaceutical industry and the FDA. Consequently, I believe I am now in a position to openly discuss my personal concerns and opinions as a private citizen without violating any government rules or regulations.

Recently the government admitted a link between vaccinations, autism, and underlying genetic disorders of mitochondrial metabolism. Additionally a number of articles in last week's March 19th edition of the Journal of the American Medical Association provide insight into FDA's critical path initiative. This information in combination with other articles I've come across reveal the overriding strategy behind what's occurring.

Mitochondria produce and help store energy for tissues by metabolizing sugars, fats, and even proteins. They're most active in those tissues that need the most energy including the brain, heart, liver, and muscles. This is likely why certain diseases frequently occur together, such as mental illness, cardiovascular disorders, diabetes, and lipid disorders. It also explains why drugs used to treat any one of these illnesses may cause serious and even lethal side effects in other organs that have significant mitochondrial activity.

Thus if you know the particular genetic defects that effect mitochondria in addition to being able to figure out why certain individuals don't respond to current treatments, you can come up with new treatments they may responds to. Plus you should be able to find targets for treating other diseases that mimic the side effects, in addition to the stated rationale of being able to predict who will have significant adverse reactions to drugs. Drug companies have now publicly admitted that they've known and have been working on this for years. In fact it's clear to me that they've been working on it since the early 1990's at least.

In order to deliver on this promise of 'personalized medicine' there have been a number of legal, regulatory, political, practical, and scientific hurdles that have had to be overcome. One of the most daunting is the collecting and sifting through the huge amounts of information that needs to be analyzed. There are literally hundreds if not thousands of interconnecting pathways involved that need to be examined. These can range from the mitochondrial enzymes themselves to cellular proteins that help transport fats and other substances across cell membranes, to detoxifying antioxidants. Yet for each individual gene there can literally be hundreds of different mutations with varying degrees of effect.[1]

The easiest way to detect the genetic defects of interest is to collect genetic information on the people who have certain adverse reactions to drugs. For example diabetes and metabolism disorders with the antipsychotic ZyprexaR from Lilly, or the cardiac toxicity with the antidepressant PaxilR from Glaxo. However, more typically the side effects of interest are much rarer such as the hepatotoxicity with the antidiabetic agent troglitazone, which was removed from the market, or the suicidality that occur with antidepressants, anticonvulsants, and even with Retin A which is used for acne. For each of the possible hundreds of mutations that might be responsible for these side effects you may need genetic information from possibly a 1000 individuals with the same side effect and the same genetic defect.

Since these side effects occur infrequently, no one company can collect sufficient information in a reasonable amount of time. Consequently, the 'Big Pharma' companies are pooling their genetic information from their different drugs under the auspices of the FDA.[2] This has all been occurring under the FDA's critical path initiative,[3] and partly appears to be why 'Big Pharma' and the FDA have been slow to acknowledge dangerous drugs in labeling and remove them from the market. It might even be partly behind why more and more dangerous drugs are being approved. This genetic data mining is also behind the recent big push to update FDA's science base, particularly in genomics and data analysis,[4] and to upgrade FDA's information technology infrastructure.

By combining this data with proteomic data and the recent 'safety first' initiative which includes an associated culture change to have medical personal in practice report side effects and to have improved reporting by the FDA to the public. Targets and biomarkers for chronic diseases like diabetes can be detected. The safety first initiative with also increase reporting adverse effects to the public and that a genetic test is available.

This will allow 'Big Pharma' to not only sell a drug but they also can sell genetic testing for every single person prescribed the drug, plus there a numerous patent and marketing advantages, including the possibility of selling the same test over and over.

However there are also some disadvantages which can be circumvented by conducting studies in places such as India. [5] <> ,[6] Thus there are likely additional advantages for the pharmaceutical industry if the FDA opens branch offices overseas that may eventually dwarf in importance the improvement in monitoring of manufacturing sites.

I didn't appreciate what was occurring under the mantel of 'translational medicine' until just over two months ago, and when I did, my initial thought was well they're at the point now where they're beginning to tell people about the safety issues they have been denying for years and if I go public now there's little chance I'll be able to help the people who have been hurt and I may wind up hurting even more people.

So I began to think how I could help uncover these genetic defects and by doing so help protect patients. As I thought about this as a scientist, I came up with a list of criteria for a study design that included the following: young otherwise healthy individuals who may be at increased risk for eventually developing the full range of diseases of interest, large numbers of patients, good reporting of adverse events, collection of genetic and laboratory information, as many people in as short a time as possible, examine drugs that are especially prone to cause these side effects, use of high doses as the dose is likely related to the risk, and have a population that's at high risk of having concurrent viral infections because virus infections speed up mitochondria and may precipitate these adverse events and diseases.[7]

When reflecting on this I realized that this described the use of psychoactive medication in children. A number of other things then began to fall into place. The screening of inborn errors of metabolism in children,[8] the mental health screening of children,[9] the FDA policies on off-label use,[10] FDA's safety review of ConcertaR a few years ago that would have overemphasized the well known phenomenon of psychosis in some patients, which I now believe may have been an attempt to promote the idea of a relationship of ADHD and bipolar illness, and the announcement by the National Institute of Mental Health recommending that children with ADHD should be placed on antipsychotics for symptoms that may suggest bipolar spectrum disorder.[11]

Even though these drugs haven't even been studied or shown effective for hypomania associated with bipolar II disorder which is much more severe. Plus all the pediatric requirements in the recent Food and Drug Administration Amendments Act, including forced use of genetic tests and the associated forced labeling changes for companies with drugs for pediatric use which is most likely to be employed against small firms,[12] as well as other changes in labeling policy.[13]

This month there are many FDA policy changes that are being discussed, and President Bush has repeatedly said it's a sprint to the finish. He's even issued two executive orders recently. One that has the result that if Dr. Von Eschenbach and Secretary Leavitt were to be removed it wouldn't affect the changes that are being implemented at the FDA, and second eliminating earmarks so that even if Congress tells FDA they have to spend money on improving safety instead of implementation of the critical path, FDA can ignore Congress and continue to spend money to implement this plan.

Consequently, I'm afraid that if some actions are not taken immediately it will be too late and we will soon be looking at an epidemic of inappropriately medicated and maimed children. People may be willing to take risks for themselves, but they shouldn't be able to force unneeded risks and injury on the most defenseless people in society just so they can reap the monetary and health benefits that are derived from the suffering of others.

Ronald E. Kavanagh, B.S.Pharm., Pharm.D., Ph.D.

Disclaimer: This article contains my personal opinions as a private citizen. No official support or endorsement of this article by the Food and Drug Administration is intended or should be inferred."

Please include disclaimer if this is published.

_____

[1]
http://www.seahorsebio.com/news-and-events/webinars/webinar-dykens-10-16-07. html

[2] http://www.fda.gov/bbs/topics/news/2006/NEW01337.html

[3] http://www.sciencedirect.com/science?_ob=ArticleURL <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T64-4PGH4KM-2&_u ser=10&_coverDate=09%2F30%2F2007&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_ acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4b8c6546d9f6db62c753 08061504dd11> &_udi=B6T64-4PGH4KM-2&_user=10&_coverDate=09%2F30%2F2007&_rdoc=1&_fmt=&_orig =search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10& md5=4b8c6546d9f6db62c75308061504dd11 Important article see bottom of page 10

[4] http://www.cdc.gov/genomics/hugenet/default.htm

[5]
http://ipmall.info/hosted_resources/gin/DFernandez_Pharmacogenomics_051003.p df

[6] http://www.larta.org/lavox/articlelinks/2005/050103_ip.asp

[7] http://www.fda.gov/medwatch/safety/2008/prezista_DHCP.pdf

[8]
<http://www.nichd.nih.gov/about/overview/approp/testimony/dir_FY2008.cfm> http://www.nichd.nih.gov/about/overview/approp/testimony/dir_FY2008.cfm

[9] <http://www.surgeongeneral.gov/topics/cmh/childreport.htm> http://www.surgeongeneral.gov/topics/cmh/childreport.htm

[10] http://oversight.house.gov/story.asp?ID=1641

[11]
http://www.nimh.nih.gov/science-news/2007/bipolar-spectrum-disorder-may-be-u nderrecognized-and-improperly-treated.shtml

[12] http://www.fda.gov/oc/initiatives/fdaaa/PL110-85.pdf

[13] http://oversight.house.gov/story.asp?ID=1698