Some historyIn 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 ZealandEltroxin 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
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.
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
- A generic drug (or a batch of that generic) may have a problem.
- A drug regulator has seen some data which may or may not be relevant to the situation.
- 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.
- 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?
- Is the behaviour of GSK and Medsafe really different from the behaviour of Boots and UCSF?
- 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