Did NZ drug regulator do some laundering for GlaxoSmithKline?

I wrote previously about the hidden bioavailability analysis of GSK's new formulation of Eltroxin (thyroxine). These concerns followed multiple complaints from patients about side effects on the new formulation. Medsafe (the New Zealand drug regulator) had issued an alert, stating that:
"In response to these reports, Medsafe has reassessed the change in Eltroxin formulation and can confirm that the new formulation satisfies all quality, safety, and bioequivalence criteria. In addition, all excipients and excipient quantities present in the new formulation are commonly used in medicines."
GSK stated that
"extensive testing and retesting by GSK has shown that the tablets should be safe and effective when used as prescribed"
However in response to my communications Medsafe refused to discuss what GSK's supposedly "extensive testing" was, the study design or the actual results - citing that the science "is commercial in confidence". Nor it seems were any of the data published in the scientific literature.

Now we have some information about these so called "extensive" tests, courtesy, not of usual science, but through response to a New Zealand parliamentary written question. Still no data, but it now seems that:
  1. Only 36 "test subjects" were studied.
  2. Studies lasted only 48 hours (perhaps long enough to determine bioavailability using measurements of T3 and T4 in blood - but in the absence of any details of study design or the actual results one cannot tell).
  3. It seems that "Almost 25% of the subjects experienced an adverse event when taking the new formulation of Eltroxin, compared to just 8% taking the standard formulation".
Parliamentarians are asking questions.

Member of Parliament Jackie Blue says "the authorities need to explain why this information did not ring alarm bells for them".

My questions would be more fundamental, regardless of the data. Why are we in this position in the first place, and what is the role of a scientific regulator?

See also the excellent Pharmalot on some aspects of this story

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Betty Dong Redux (from Boots to GlaxoSmithKline)

Recent problems with Eltroxin in New Zealand raise memories of a landmark scandal involving the researcher Betty Dong. Eltroxin is the brand name for levothyroxine (also known as thyroxine) as produced by GlaxoSmithKline.

Some history

In 1990, Betty Dong, a researcher at UCSF was funded by Boots Pharmaceuticals to carry out research to compare Boots thyroxine (Synthroid) and generic alternatives of the same drug. She discovered that the Boots drug was no more effective than three cheaper competitor products available at that time. When she tried to publish, Boots threatened to sue. Dong withdrew the manuscript from the JAMA publication process following legal threats. UCSF failed to uphold academic integrity. Company executives then published an inaccurate version of the findings while excluding Dong and threatening legal action. Even then, UCSF remained silent.

Nine years later the sordid details were exposed in the press and Dong’s paper was published. In November 1997 the manufacturer (then Knoll Pharmaceuticals) paid around $100 million to settle dozens of lawsuits charging that the company had cheated consumers. However, the company made a profit of $3billion in inflated costs during the nine year delay. No company executives were prosecuted. The American Thyroid Association failed to take any stance on scientific integrity, leaving, according to Drummond Rennie "the sad impression that the ability of the association to influence these events was weakened by its heavy dependence" on the drug maker’s financial support.

The 2008 Eltroxin problem in New Zealand

Eltroxin is the trade name of thyroxine as sold by GlaxoSmithKline. Over the past few months at least 500 patients in New Zealand complained of a variety of side effects and lack of drug efficacy following reformulation of Eltroxin. Manufacture of the New Zealand supply of Eltroxin had moved from Canada to Germany.

It is not the purpose of this discussion to examine the patient complaints. The resulting news reports can be accessed here, here and here.

The structural aspect of this problem are however interesting.

Generics have to be shown to be chemically identical to the original (usually easy), and to have identical bioavailability under clinically relevant conditions of dosing (often tricky). Generics might differ from each other, but might also vary over time. In normal scientific medicine one would expect such information would be published in the scientific literature (or at the very least would be available for open and full scrutiny).

Medsafe (the New Zealand drug regulator) immediately hit back with an alert which suggested that the GSK product was absolutely fine. They asserted in their alert that:
"In response to these reports, Medsafe has reassessed the change in Eltroxin formulation and can confirm that the new formulation satisfies all quality, safety, and bioequivalence criteria. In addition, all excipients and excipient quantities present in the new formulation are commonly used in medicines."

So I wrote to Medsafe with regard to the evidence underlying their assertions:
Can you please tell me whether
a) the studies to prove bioequivalence of this formulation are published in the scientific literature, or otherwise available?
b) I can have a copy of the study report and findings?

The reply I received was as follows:
To: Aubrey Blumsohn
Subject: Eltroxin Bioequivalence
From: Chris_James@moh.govt.nz
Date: Mon, 8 Sep 2008 12:39:34 +1200

Dear Dr Blumsohn,

Thank you for your email.

In answer to your questions and request for information, I can provide the following:

1. Medsafe is not aware of the bioequivalence study, conducted for the changed formulation of Eltroxin, being available in the scientific literature. I suggest you contact the manufacturer (GSK) for further information.

2. Medsafe evaluated the bioequivalence study and concluded that the change in Eltroxin formulation met all internationally accepted criteria for bioequivalence. Unfortunately, Medsafe cannot currently provide you with the actual study report as this contains data that is "commercial in confidence". For additional information on bioequivalence requirements Medsafe applies, please see our regulatory guidelines at:http://www.medsafe.govt.nz/regulatory/Guideline/medicines.asp

In assessing bioequivalence studies Medsafe also utilises international regulatory guidance, including:
CPMP/EWP/QWP/1401/98. Note for Guidance on the Investigation of Bioavailability and Bioequivalence. Link: http://www.emea.europa.eu/pdfs/human/qwp/140198enfin.pdf. FDA Guidance for Industry, Bioavailability and Bioequivalence, Studies for Orally Administered Drug Products - General Considerations. Link: http://www.fda.gov/cder/guidance/5356fnl.pdf

Medsafe is intending to make more information publicly available on our website shortly, in response to the questions we are being asked.

Yours sincerely,

Chris James
Advisor Pharmacy
Clinical Risk Management, Medsafe
Sector Accountability & Funding Directorate
Ministry of Health

I wrote to GSK asking for the data, but received no response. However in a press statement today GSK states that in their view "extensive testing and retesting by GSK has shown that the tablets should be safe and effective when used as prescribed"

The upshot of all this

  1. A generic drug (or a batch of that generic) may have a problem.
  2. A drug regulator has seen some data which may or may not be relevant to the situation.
  3. Patients, doctors and the public are not allowed to see that information (or to know what studies were carried out). This is because the regulator regards that science as "commercial in confidence". Doctors have to prescribe based on GSK's own evaluation of their supposedly "extensive testing" as well as a guess as to the capability of regulators to evaluate that hidden information.
  4. It is not clear how the studies supposedly seen by the regulator relate to the questions being asked by patients or by doctors. What batches were tested? What tests were carried out? Were there clinical bioavailability studies? What were the study endpoints? Which patients were studied? How many patients were studied? What was the study design? What were the results?
  5. Is the behaviour of GSK and Medsafe really different from the behaviour of Boots and UCSF?
  6. Can we really regard Eltroxin as a science-based product when the science is hidden, and should science-based doctors prescribe it?

Also of interest: The Dilantin story

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Whose mouse is it anyway?

The LA Times has a fascinating article about Disney's copyright claim to Mickey Mouse. The article is relevant to this blog because it is about bullying and legal overkill in an attempt to suppress discussion (including, in one instance, academic discussion).

After the painful experience of losing Oswald the Rabbit, the Disneys "held on to everything they did with a ferociously strong grip".

The discussion about Mickey resulted in a 2003 paper in a University of Virginia legal journal that argued "there are no grounds in copyright law for protecting" the Mickey of those early films. A Disney lawyer "threatened the author with legal action for "slander of title" under California law".

Earlier, Gregory S. Brown, a Disney researcher challenged the arguments of Disney lawyers who wrote that "Mickey Mouse had been created by Walt Disney Co. in 1928". The former archivist knew that the company didn't exist then. Without ruling on the merits of Brown's arguments, the judge tossed it aside as untimely. "He was clobbered with a $500,000 judgment". "His appeal was dismissed when he missed a filing deadline. Disney then seized $20,000 from his accounts" and he was left bankrupt.

They "threatened to sue three Florida day-care centers for painting Disney figures on their walls." They sued a a home-based business for $1 million "after a couple put on children's parties with ersatz Eeyore and Tigger costumes."

In fact "many of Disney's most famous figures were the creations of others, including Cinderella, Pinocchio, Pooh and Snow White, though it has vigorously protected its depictions of them." (A legal dispute with Disney bankrupted the publisher holding the Bambi copyright).

[In my view there is a fundamental difference between Mickey and Avandia (or Zetia, Actonel, Zyprexa, Vioxx, Paxil) as a "product" anyway. A scientific medical product is not simply the molecule (the depiction of the Mouse). A drug product is a scientific package comprising both the molecule and open scientific discussion. Without the honest and transparent science, there is no product at all.]

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Placebo Journal and AccuPringles

The Placebo Journal continues to produce great material. Watch the latest Placebo TV broadcast on product-free pharmaceutical advertising.

I was particularly struck by their promotion of Accupringles from our friends at P&J Pharmaceuticals

Host unlimited photos at slide.com for FREE!

Available in
  • Original
  • Sour Cream and Hydrochlorthiazide
  • Ranch and a Channel Blocker
  • Jalapeno and an ARB
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Pharmaceutical Mergers - Update

I updated the previously discussed historical database of pharmaceutical mergers to include Searle and the Roche Holding acquisitions of Syntex (1994, renamed Roche Bioscience in '95), and recently Genentech.

Please send along any corrections or additions to me at Email.

Here, of interest, is a listing of the eighteen largest pharmaceutical companies as ranked 21 years ago (in 1987). The source is an extremely odd, but interesting book : "Murder By Injection" by Eustace Mullins.
  1. Merck (U.S.) $4.2 billion in sales.
  2. Glaxo Holdings (United Kingdom) $3.4 billion.
  3. Hoffman LaRoche (Switzerland) $3.1 billion.
  4. Smith Kline Beckman (U.S.) $2.8 billion.
  5. Ciba-Geigy (Switzerland) $2.7 billion.
  6. Pfizer (U.S.) $2.5 billion (Standard & Poor's gives its sales as $4 billion.)
  7. Hoechst A. G. (Germany) $2.5 billion (Standard & Poor's lists its sales as $38 Billion Deutschmarks).
  8. American Home Products ( U.S.) $2.4 billion ($4.93 billion according to Standard & Poor's).
  9. Lilly (U.S.) $2.3 billion ($3.72 billion Standard & Poor's).
  10. Upjohn ( U.S.) $2 billion.
  11. Squibb (U.S.) $2 billion.
  12. Johnson & Johnson ( U.S.) $1.9 billion.
  13. Sandoz (Switzerland) $1.8 billion.
  14. Bristol Myers (U.S.) $1.6 billion.
  15. Beecham Group (United Kingdom) $1.4 billion (Standard & Poor's gives $1.4 billion in sales of the U.S. subsidiary $2.6 billion pounds sterling as overall income).
  16. Bayer A. G. (Germany) $1.4 bilIion (Standard & Poor's gives the figure as $45.9 billion Deutschmarks).
  17. Syntex (U.S.) $1.1 billion.
  18. Warner Lambert (U.S.) $1.1 billion (Standard & Poor's gives the figure as $3.1 billion).

I received a huge number of helpful responses including this one:

From: "World Changer" anakahamon@ritternet.com
To: ablumsohn-3@yahoo.co.uk
CC: John Kaminski skylax@comcast.net, JB Campbell jb_campbell@yahoo.com, Christopher Bollyn bollyn.books@yahoo.com, Prothink@yahoo.com, Counter Bias counterbias@yahoo.com.au
Subject: Pharmaceutical Mergers - Scientific Misconduct Wiki
Date: Tue, 2 Sep 2008 14:19:18 -0500

The main thing you need to do with your list is to list all the Jews who own and run the companies.

Given the recent revelations that George Bush is Jewish and attended Sheffield University, can anyone help with the vital task of collating ethnic affiliations of current pharmaceutical CEO's?

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