How the FDA forgot the evidence: the case of donepezil 23 mgBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e1086 (Published 22 March 2012) Cite this as: BMJ 2012;344:e1086
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Schwartz and Woloshin (1) argue convincingly that Eisai and Pfizer investigated a 23 mg donepezil (Aricepttm) tablet for efficacy motivated by commercial interest in obtaining FDA approval to market the new dosage as a strategy to compete after patent expiration with the soon to be generic donepezil. The selection of a patented 23 mg tablet seems based on providing practitioners a therapeutic option not achievable with the approved 5 an 10 mg tablets and patients the convenience of a single daily dose. Neither of these assumptions makes any scientific sense to us; in fact, each is contradicted by current knowledge of acetylcholine pharmacology in brain and the pharmacokinetics of donepezil and other acetylcholinesterase inhibitors (AChEI)
A difference of 23 mg from 25 mg or 20 mg dosing almost certainly has no significance for this therapeutic since it has already been shown that wide variations in tissue concentrations of drug and levels of enzyme inhibition occur in a population after administration of 5 and 10 mg doses of donepezil as with other AChEI (2). What has been lacking for the last decades of therapy with donepezil and other ACHEIs is a clear understanding of the relations between dose and AChE inhibition levels, needed to optimize target engagement by the drug and between AChE inhibition levels and patient benefits, the clinical efficacy available with an optimal target engagement. The study by Farlow et al. (3) could have been designed to clarify these issues and to justify a higher than 10 mg qd dose but unfortunately it was not. Eisai and Pfizer instead sponsored a randomized double blind study with 1371 patients at two fixed doses of donepezil 10mg daily or 23 mg daily for 24 weeks. As could be predicted from prior experiences of having to reduce donepezil 10 mg q.d. doses back to 5 mg q.d., patients showing adverse events in the high dose group doubled from 300 (10mg) to 710 and nausea and vomiting, the most common adverse events, were 5-10 times more common in the high dose group.
These classical cholinergic adverse events, increased nausea and vomiting, could have been predicted for a single 23 mg. donepezil from past experiences with AChEI drugs (2). Cholinergic adverse events are already increased with a move from 5 to 10 mg doses of donepezil (2) and in the original developments of AChEI drugs as potential therapies for AD investigators first had to gain control over cholinergic adverse events before efficacy could be demonstrated for the class (2). In our own research we selected to work with metrifonate to take advantage of its irreversible inhibition that provided drug concentration independent stable levels of AChE inhibition over time. We were able to demonstrate that higher levels of ACHE inhibition could be obtained without incurring classical cholinergic adverse events by limiting the reductions in AChE activity to 20% following a dosing of drug (4).There is support for achieving optimal clinical responses with dose increases of AChEI (5) and we do not disagree with research into using higher doses of donepezil to document these benefits and provide to practitioners guidelines for best evidence care. Unfortunately the 23 mg donepezil experience does not achieve this end. Even though donepezil is a long acting AChEI because of its prolonged t ½ elimination, we would be surprised if the 23 mg. tablet did not produce excessive acute percentage reductions in ACHE activity such as we found associated with the onset of classical cholinergic adverse events.
Eisai and Pfizer have done AD patients no service by resurrecting adverse events as an additional incentive to avoid the inconvenience of taking a medication for a chronic illness. It is most probable that that a certain number of patients who have not shown a clinical effect at a lower dose i.e. 10 mg ("non responders" and " weak responders") may show a clinically significant effect at a higher dose; however, the introduction of a 23 mg. tablet does nothing to further this appropriate use of donepezil or other ACHEIs among AD patients.
- A Nordberg, Alzheimer Neurobiology Center, Karolinska Institutet, Stockholm, Sweden
- RE Becker, Aristea Translational Corporation, Freeport, ME, USA
- E Giacobini, Department of Internal Medicine, Rehabilitation and Geriatrics, University of Geneva Faculty of Medicine, Geneva, Switzerland
1. Schwartz LM, Woloshin S. How the FDA forgot the evidence: the case of donepezil 23 mg. BMJ 344e, 1086doi, 2012
2. Giacobini E. Cholinesterase in human brain: the effect of cholinesterase inhibitors on Alzheimer´s disease and related disorders. In: Giacobini E, Pepeu G. The brain cholinergic system in health and disease p. 235-264. Informa Healthcare, 2006.
3. Farlow MR, Salloway S, Tariot PN, Yardley J, Moline ML, Wang Q, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer’s disease: a 24-week, randomized, double-blind study. Clin Ther, 2010; 32:1234-51.
4. Becker RE, Colliver JA, Markwell SJ, Moriearty PL, Unni LK, Vicari S. A Double-Blind, Placebo-Controlled Study of Metrifonate, an Acetylcholinesterase Inhibitor for Alzheimer’s Disease. Alzheimer’s Disease and Associated Disorders. 1996; 10(3):124-131.
5. Nordberg A, Amberla K, Shigeta M, Lundqvist H, Viitanen M, Hellström-Lindahl E, Johansson M, Anderson J, Hartvig P, Lilja A, Långström B and Winblad B. Long-term Tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism and cognitive abilities. Alzheimer Disease and Associated Disorders, 1998;12(3);228-237.
Competing interests: No competing interests
Pill them, bill them. Whose interests are served by regulatory agencies?
Schwartz and Woloshin wisely pointed out that the FDA, despite lack of evidence, granted a new marketing authorization for the 23 mg dose of donepezil (pricept) in Alzheimer’s disease.(1) This allows Pfizer to avoid generic competitors as the patent for donepezil, first approved in 1996, expired in November 2010.
In 2007, the Transparency (sic) Committee of the French High Authority for Health (Haute Autorité de Santé), which is in charge of drugs assessment for reimbursement and pricing, rated donepezil as an “important” (the highest) medical utility and stressed the “structuring role of the drug in the global care of the patients with Alzheimer’s disease”.(2) Again, this challenged clinical evidence.(3) This also contrasted with NICE’s evaluation restricting the donepezil use to clinical trials.(4) However this looks quite similar to a claim made in 2004 by the Pharmaceutical Industries’ Union about “the structuring role of drugs on hospital practices”.(5)
In 2011 the French highest administrative court (Conseil d’Etat) has ruled that guidelines issued by the Haute Autorité de Santé must be withdrawn because it allowed conflicts of interest among its experts.(6) Accordingly, several guidelines including the one concerning Alzheimer’s disease were withdrawn.
1 Schwartz LM, Woloshin S. How the FDA forgot the evidence: the case of donepezil 23 mg. BMJ 2012;344:e108
BMJ 2012; 344 doi: 10.1136/bmj.e1086 (Published 22 March 2012)
Cite this as:
2 Haute Autorité de Santé. Avis de la Commission de la transparence ARICEPT. 20 June 2007. Available at www.has-sante.fr/portail/display.jsp?id=c_594386
3 Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-15
4 National Institute for Health and Clinical Excellence. Technology appraisals, TA111: Alzheimer's disease - donepezil, galantamine, rivastigmine (review) and memantine (TA111) September 2007 Available at http://www.nice.org.uk/TA111
5 Les entreprise du médicament. Chiffres clé. 2004.
6 Lenzer J. French guidelines are withdrawn after court finds potential bias among authors. BMJ 2011;342:d4007
Competing interests: the Haute Autorité de Santé did not renew Dr Braillon as a locum tenens advisor in 2007 because he was “uncontrollable”. This was disclosed from a memo obtained after a court decision in 2011 as the Haute Autorité de Santé also breached the Freedom of Information Act.