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ARICEPT 23: An Unusual Dose Means More Dollars for Drug Companies

By Dan C. Bolton, Keller, Fishback & Jackson LLP. 

With the clock about to run out on patent protection for their blockbuster drug Aricept, prescribed to treat symptoms of Alzheimer’s Disease (AD), two pharmaceutical giants, Pfizer, Inc. and Eisai Inc., came up with a brazen idea to dodge patent expiration and continue to reap profits.

The plan was a new 23 mg dose of Aricept (Aricept 23) that could not be reached by combining the soon to be generic and less expensive 5 mg and 10 mg doses.  This scheme would ensure three more years of exclusivity and sole marketing rights for the pharmaceutical companies, along with a continued revenue stream, for the new 23 mg dose.Aricept 23

Aricept 23, however, failed three of the four efficacy measures in the single clinical study submitted by Eisai (the one it barely passed was clinically meaningless), and was panned by FDA reviewers, who found that the 23 mg dose was no more effective than the 10 mg dose, and were especially alarmed by the increase in dangerous, and potentially fatal, risks for elderly patients in the grip of advanced AD.

Despite the recommendation by the reviewers that Aricept 23 not be approved, and its lack of efficacy and increased dangers over the lower dose, Aricept 23 was approved.  With this approval, Pfizer and Eisai revved up a relentless marketing and advertising campaign that continues to this day, the core of which is to misrepresent the safety and efficacy of the clever new dose, and prey on a vulnerable elderly patient population, their families and caregivers, who are desperate to try anything to help their loved ones.

Aricept 10, National Institutes of Health

Aricept 10, National Institutes of Health

The History of Aricept

Aricept is the best-selling drug in the world to treat symptoms of AD.  Aricept was also the best-selling drug for Eisai, accounting for 60% of its revenue in the United States before the loss of patent protection for the 5 mg and 10 mg doses.  The drug is co-marketed in the United States with Pfizer, Inc.  It is a blockbuster drug that has generated billions of dollars in revenue for Pfizer and Eisai since its approval in the United States.

Aricept was first approved by the FDA on November 25, 1996, for the treatment of mild to moderate AD, at a dose of 5 mg or 10 mg once a day.  On October 13, 2006, Aricept was approved for severe AD at a dose of 10 mg once a day.

On July 23, 2010, just a few months before patent expiration in November 2010, Aricept 23 was approved for moderate to severe AD.  This occurred even though Aricept 23 received highly critical reviews from both the FDA clinical and statistical reviewers (both clinical and statistical reviewers recommended against approval).  And the one clinical study submitted to support the efficacy of Aricept 23 failed to establish that the dose had any clinically meaningful benefit beyond a lower dose, and in fact, presented more serious and life threatening risks to AD patients.

Source: NIH

Source: NIH

Aricept 23 study fails to meet multiple efficacy endpoints

Under federal law, new doses of previously approved drugs, not reproducible from currently marketed doses, may be given a three year period of exclusivity during which generic competitors are not permitted to manufacture and sell the same new dose.  Eisai sought approval for an unusual 23 mg dose—a dose that would be entitled to marketing exclusivity since it could not be reached by combining the 5 mg and 10 mg pills.

When the FDA met with Eisai in March 2007, it agreed to Eisai’s request for the submission of a single efficacy study.  The FDA and Eisai both agreed that the proposed 23 mg dose of Aricept would be considered effective, and would be approved, only if it was shown to have statistically significant superiority over the 10 mg dose on both cognitive and global functioning measures.  The global functioning measure is important since it confirms that any cognitive measure is clinically meaningful; that is, an improvement that patients, healthcare professionals and/or caregivers notice.

eisaiIn September 2009, Eisai submitted its New Drug Application (NDA) to market Aricept 23 to the FDA. 

In support of its NDA, Eisai submitted the results of a single efficacy study (Study 326) that compared the safety and efficacy of Aricept 23 against 10 mg Aricept.  The study did not have a placebo control, and significantly, did not include a group taking 20 mg of Aricept (which would not be entitled to marketing exclusivity since the dose is reproducible from existing dosages).

The study showed a small but statistically significant difference on a cognitive measure, but no statistically significant difference in global functioning.  The improvement in the cognitive measure was only 2.2 points over the 10 mg dose on a 100 point scale.

The study also had two secondary endpoints that were designed to provide support for the primary endpoints.  The study showed no statistically significant treatment difference on the two secondary measures.  Thus, in three of four tests comparing Aricept 23 to 10 mg Aricept, no significant difference was found between the two doses on a cognitive or functional level, and the fourth test resulted in patients on Aricept 23 scoring a meager two points higher on a 100-point scale.  In sum, the only “evidence” of efficacy was, as the FDA described it, a “numerically small” two-point increase on a large 100-point scale, and on every other measure Aricept 23 was no more effective than the lower dose.aricept ad by communications company

Aricept 23 study shows increase in dangerous risks

Not only was Aricept 23 without meaningful clinical benefit in comparison to the 10 mg dose, the study established that the dose was associated with an alarming and significant increase in risk to patient safety.  Study subjects taking the 23 mg dose had a higher incidence of all adverse events.  In particular, the use of Aricept 23 was associated with a much higher incidence of vomiting, which in patients with AD, can lead to pneumonia, massive gastrointestinal bleeding, esophageal rupture, or death.

There was a significant increase in adverse events with Aricept 23, compared to the 10 mg dose.  Vomiting occurred in 2.5% of patients on 10 mg, and climbed over three-fold to 9.2% of patients on the 23 mg dose.  Nausea occurred in 3.4% of patients in the 10 mg group, and jumped to 12% of patients on Aricept 23.  Diarrhea occurred in 5.3% of patients on 10 mg, and increased to 8.3% of patients on the higher dose.  Fatigue occurred in 0.8% of patients on 10 mg and rose to 2.4% of patients on Aricept 23.  In fact, all eight of the most commonly occurring adverse events increased in frequency with the 23 mg dose.  More than twice the percentage of patients in the 23 mg dose group (19%) discontinued participation in the study because of adverse effects compared to the 10 mg dose group (8%).

The FDA’s medical reviewer concluded that “the results of Study 326 did not satisfy the pre-specified criteria for demonstrating the efficacy of the higher dose…I recommend that this application, which seeks approval of Aricept in a new dose strength of 23 mg administered once daily, for the treatment of moderate to severe dementia of the Alzheimer’s type not be approved.”  The FDA statistical reviewer concurred, stating that “…the data from this trial does not seem to provide enough support for the efficacy of [Aricept 23].”

Despite the failure of Study 326 to demonstrate the efficacy of Aricept 23 on the agreed upon criteria, and the FDA staff recommendation that approval be denied, the Director of the FDA’s Division of Neurology Products approved the application for Aricept 23 on July 23, 2010.  He did so even though he agreed that Aricept 23 did not show greater efficacy on the global measure, in comparison to the 10 mg dose, “I also believe the results do not support a conclusion that the 23 mg dose group offers a greater benefit on overall functioning that the 10 mg dose.”

Experts outside the FDA who treat AD have also recognized the lack of efficacy and increased risk of Aricept 23.  A researcher at the Mayo Clinic wrote that “not only does donepezil 23 mg/day increase the likelihood of unacceptable gastrointestinal side effects, it provides no clinical benefits.  Aricept 23 mg is about 10 times more costly per pill than donepezil 10 mg.”

Pfizer, NBC News Washington

Pfizer, NBC News Washington

Conclusion

Since the approval of Aricept 23, and its launch in August 2010, Pfizer and Eisai have embarked on an aggressive marketing campaign to collect as much revenue as possible from the 23 mg dose.  This is in spite of the fact that it has no more efficacy than a lower, less expensive dose, and poses substantially more risks, including death, to elderly and disabled AD patients.  AD patients, families and caregivers who were duped into spending money for an expensive drug, with no more efficacy and much more risk than generic  Aricept, should be entitled to restitution for the conduct of Pfizer and Eisai in marketing Aricept 23.

###

 

Dan C. Bolton is Of Counsel in the Los Angeles office of Keller, Fishback & Jackson LLP.  The firm represents plaintiffs nationwide in pharmaceutical and medical device litigation, including Aricept 23, hernia and transvaginal mesh, hip implant, and power morcellation cases.  Mr. Bolton oversees the pharmaceutical and medical device practice.

13 Comments

  1. kitty says:

    Human testing must be stopped on all levels. AD folks don’t have the cognitive ability to get thru a vomiting episode.

  2. Sandy says:

    It amazes me and yet it doesn’t what these companies will do just to make money! What amazes me more is even though the staff was going to deny the drug the director approved any ways!! It my opinion there had to be some pay off to make this happen. It is pathic that this is allowed to happen to unknown innocent people. Our America is as corrupt as many others. We just like to pretend it is not! These patients will believe that this drug is going to help them when in fact it will not do any better than the other drug! Just like mesh products!! We believed it would help us and yet it has destroyed not only our own bodies but our marriages and our lives!!,

    When will this ever stop!! I guess never until the end of time because no one can make these kinds of things stop.

  3. Ronald James says:

    Check Hilary and Obamas pockets these crooks are raping us and liberals just smile and say do me some more. The government is corrupt and we need a revolution to get criminal people out these agencies

    • MarieAnn says:

      So true Ronald! Corrupt people in charge for sure…. I had heard the J & J gave more to the Obama campaign than the Republican candidates…not that the Reps are that much better at honesty. Yes we need a revolution of sorts, we need people with integrity and honesty running office, Not the status quo, who only care about the next election and not about getting this country back on track.

    • kitty says:

      Isn’t it ODD that Mrs Obama isn’t enraged over the use of plastics in women’s reproductive organs.

      Was J&J involved in some administrative way at the hospital she worked for in Chicago? Was she the CEO at that hospital?

  4. David says:

    The Aricept 23 mg dose’s “[association] with an alarming and significant increase in risk to patient safety” – “without meaningful clinical benefit in comparison to the 10 mg dose” – is much like the current, indiscriminate abuse of surgical mesh across its indications for use. For surgical mesh, however, unlike Aricept”s use of the efficacy of the 10 mg dose comparator (the control) – to contrast the 23 mg dose for “meaningful clinical benefit” – the threshold of a mesh indication’s gold standard native tissue repair (before the onslaught of the mesh industry’s predatory marketing tactics) could be reclaimed (and should have been maintained –not forgotten), to use its efficacy as the control, to contrast a clinically meaningful non-mesh benefit – without “an alarming and significant increase in risk to patient safety” which is associated with mesh use.

    To quote Todd Heniford, M.D., formed American Hernia Society President, in the 2007 Ethicon/ Johnson & Johnson DVD, The Benefits of Lightweight Meshes In Ventral Hernia Repair: “Prior to using mesh consistently in hernia repair the recurrence rates were somewhere around 50% for a typical ventral hernia. For groin hernias they approached perhaps 25%. With the use of mesh — everyday in hernia repair we have been able to drop those rates of recurrences for ventral hernias to less than 10%. And, for groin hernias certainly less than 5%.”

    NOTE: I am assuming that Dr. Heniford’s 25% percent recurrence rate for groin hernias (inguinal hernias) was in reference to the recurrence following primary repairs….As in the paper “Hernia – A Collagen Disease?” (referenced below), this “25% [is] for the repair of recurrent [inguinal] hernias”. If he is not referring to primary inguinal repairs, then a more accurate number may be “10% – 15% of patients who will have a recurrence” (via past general surgeons’ competency…still humanly possible) following a primary repair (also stated below) in the paper: “Can we be sure that the meshes do improve the recurrence rates?”

    Specifically, focusing on groin hernias or inguinal hernias, the most common type of hernia, they “represent 80% of all external abdominal wall hernias” (as stated on The Shouldice Hospital’s website). To reiterate from above – Dr. Heniford stated that before the “everyday” use of mesh recurrence rates for “groin hernias […] approached perhaps 25%”. And, now with the “everyday” use of mesh “less than 5%”.* This would be about a 20% window of increased surgeon efficacy resulting from current, “everyday,” indiscriminate surgical mesh abuse.** That would equate to about 20 more patients out of 100 that would not have a recurrence of an inguinal hernia repaired with mesh. This disproportionate industry “success,” is however, also with the understanding that now instead of benefiting 75 patients out of 100 – by fixing their hernias without the life-long/life-destroying risks of mesh – you unwarrantedly subjected 100% of the patient population to the outcome of that risk.*** (There is not even a rationale that “the greater patient good” is being severed when a best, one-sided surgeon practice fixates on the 20 patients who “needed mesh”…“20%” only when using Dr. Heniford’s own statistics.)

    Much like using Aricept’s 5 mg and 10 mg doses, inherent mesh risk could be mitigated by tailoring the treatment approach to match a patient’s need –the current “unmet patient need”: to not be subjected to unwarranted/unreasonable mesh risk resulting from its current, indiscriminate surgeon abuse as the best industry practice. While the risk/benefit threshold for Aricept could balance benefit between the 5 mg and 10 mg dose ranges (or combination there of) –to mitigate the unreasonable, mathematically derived deceptive risk of the 23 mg dose, likewise with mesh, unwarranted device risk could be mitigated at the threshold of responsible surgeon use –to thereby, address the legitimacy of unmet patient need not surrogate, illegitimate surgeon/manufacturer need to exploit patient vulnerability.

    * In the hernia literature, as it would relate to long-term and not a short-term hernia recurrence rate, research studies have found that the use of mesh is only delaying the onset of a recurrence of a hernia in the 10% – 15% of patients who will have a recurrence. “Constant rates of re-operations” (referring to an inguinal repair) “of about 15% in most western countries imply that 85% of the patients after suture repair (Bassini or Shouldice) will not undergo a re-operation for a recurrent hernia during their lifetime.” — (Can we be sure that the meshes do improve the recurrence rates?, Uwe Klinge, Carsten J. Krones, 12/2004)…

    …“Despite technical improvements, the rate of inguinal hernia recurrence – which might be regarded as a subgroup of inguinal hernia recurrence – is estimated to be approximately 10% worldwide, with an increase up to 25% for the repair of recurrent hernias. Primary incisional hernias have an incidence of 10% – 20%…” — (Hernia – A Collagen Disease?, R. Rosch, k. Junge, P. Lynen, P.R. Mertens, U. Klinge and V. Schumpelick, 2003)…

    …“In contrast to grandiose expectations, both groups [mesh and suture repairs of incisional hernias] showed a linear rise of the accumulating rate of re-operations, which was simply delayed for 2 years in the mesh group.” — (Can we be sure that the meshes do improve the recurrence rates?, Uwe Klinge, Carsten J. Krones, 12/2004)

    ** As it would not relate to this 20% patient mesh “need” (as stated above by Dr. Heniford) the Shouldice Hospital in Thornhill, Ontario Canada (a facility specializing only in the repair of hernias) states on their website their time tested hernia repairs are meant to last a patient’s lifetime and they are able to achieve a “rate of infection, complications and recurrence [of …] less than 0.5% for primary inguinal hernia repairs” without mesh use.

    In the hernia literature, as it would not relate to this 20% patient mesh “need,” in the 2004 study, The Shouldice herniorrhaphy in the treatment of inguinal hernias: A prospective study on 775 patients, one surgeon performed the Shouldice repair on 775 patients at a 2% rate of recurrence, with a 7 year follow-up. — (J.L. Porrero, M. Hidalgo, A. Sanjuanbenito, C. Sanchez-Cabezudo)

    In a 2003 study called 10 Years’ Controlled Results of Suture Repair, the conclusion of that study was, “Ten years after Shouldice repair, 97% of the patients are free of recurrence. These results indicate that there is no need to abandon the Shouldice technique with local anesthesia as the standard procedure for primary inguinal hernia repairs.” — (Ch. Tons, A. Schachtrupp, J.Hoer, A. Marx, G.Arlt and V. Schumpelick)

    *** In the hernia literature, as it would relate to chronic pain and complications, it is understood (by industry and by Dr. Heriford himself, as a coauthor) that there is a statistic as high as 63% for patients to experience chronic pain and complications following the modern mesh hernia repair: “Depending on the definition, chronic groin pain has been reported in up to 63% of patients 1 year after open inguinal hernia repair. Chronic groin pain can have serious deleterious effects on the quality of life, utilization of health care resources, and societal impacts on work performance. With the prevalence of this problem, a definitive solution is needed for optimal management of this patient population.” — (Combined open and laparoscopic approach to chronic pain following open inguinal hernia repair, 24, Febuary 2005. M.J. Rosen, Y.W. Novitsky, W.S. Cobb, K.W. Kercher, B. Todd Heniford)

    – The PROBLEM resulting from indiscriminate surgeon mesh abuse (a manmade “treatment” plague) cannot be address looking down the tunnel-vision of the laparoscopic approach, necessitating the indiscriminate abuse of surgical mesh, before or after the fact of the premeditation of that patient abuse (consented to or not).

    – The ANSWER: The Shouldice Hospital’s responsible use of mesh (as a last resort) is a role-model, of patient-orientated medicine, which the hernia industry should again follow as its gold standard of care. The lost efficacy of the Shouldice repair in current clinical practice, should disperse the ignorance…of the lack of surgeon competency – with current surgeon need – to indiscriminately abuse patients, with surgical mesh, in own best interest.

    • David says:

      To restated from above: Upon this industry recognition of “the prevalence of […the post-operative chronic groin pain] problem…,” and then with a widespread industry acceptance that “…a definitive solution is needed…”* to address “this problem” rationally/logically–with causal thinking: “Could it be that in regards to this higher statistic of chronic pain, that the major change in the technique of hernia repair that has evolved over the most recent two decades-the widespread use of implanted prosthetic mesh, whether needed or not-is the cause?”** Could the solution (derived from the pervious understanding) then be as simple as the following, again above stated, ANSWER: “the Shouldice inguinal hernia repair may have a role in open primary herniorrhaphy to decrease the risk of chronic groin pain.”***

      As referenced below, this “prospective trial of primary inguinal hernia repair” was performed “by surgical trainees”. This would indicate to me that it would be humanly possible to also retrain current surgeons – trained to indiscriminately abuse patients with surgical mesh (as their own best practice), to put the needs of their patients before their own regressions (even if that surgeon was further regressively trained in the laparoscopic approach…because on an open surgical approach that surgeon would now have the ability to mitigate their past inappropriate/patient abusive, indiscriminate mesh abuse).

      And, with regards to the manufacturers’ “need”: Does more industry effort equate to less risk for a patient (via the patients’ effectiveness benefit)? This non-innovative industry effort problem for patients, in my opinion, is because “the 510(k) predicate device debris felid” can be likened, in the device manufacturer’s mind, to “the field of dreams”. In that, if they can dream it up, they can regurgitate their “substantial equivalence” (“SE”) device back out into the marketplace, via the “least burdensome” 510(k) pathway….To then market their belief that their “SE” device is “better,” or not as risky/dangerous then the next manufacturer’s non-approved device….To again try to grab a bigger share of the market place to maximize their profit too. And, even more so…their 510(k) ambitions can then become reality when they are able to split the past “SE” of “the [510(k)] predicate device,” used for comparison (via citing multiple predicate devices), to thereby turn “the 510(k) predicate device debris felid” into “the Mad Hatter’s recipe book”.

      * Combined open and laparoscopic approach to chronic pain following open inguinal hernia repair, 24, Febuary 2005. M.J. Rosen, Y.W. Novitsky, W.S. Cobb, K.W. Kercher, B. Todd Heniford

      ** Annals of Surgery, Groin Pain After Hernia Repair – Robert E. Condon, MD, MS, FACS, 2001

      *** A prospective trial of primary inguinal hernia repair by surgical trainees, B.W. Miedema, S.M. Ibrahim, B.D. Davis, D.G. Koivunen, 2003

  5. David says:

    FOOTNOTE: the Johnson & Johnson/Ethicon DVD – The Benefits of Lightweight Meshes in Ventral Hernia Repair was shown by Bruce Rosenberg, with the National Meshoma Foundation, to CDRH Director, Dr. Jeffery Shuren, M.D., J.D. and other meeting attendees, during a November 9, 2010 meeting I attended (over four years ago now) at the FDA’s White Oak Campus in Silver Spring, Maryland. That meeting, in my opinion, fulfilled the intent of making the FDA formally aware in 2010 of the greater surgical mesh industry’s knowledge, and Johnson & Johnson/Ethicon knowledge in particular, of the numerous known complications which follows the dangerous, permanent implantation of synthetic surgical mesh into the human body. (Several meeting attendees raised their hands, when asked, indicating they had already seen this DVD.)

    This DVD was shown (prior to the November 9th FDA meeting) on July 29, 2010, during a meeting Mr. Rosenberg and I attended with Kate Leone, Senior Health Counsel for Senator Harry Reid at the U.S. Capitol. The purpose of that meeting was to not only show this DVD, but more importantly discuss “the failure of the FDA’s 510(k) clearance process to adequately protect the American public from the severe injuries and complications that result from the use of synthetic surgical mesh” (as stated in my July 29, 2010 letter to the Senators of the 111th U.S. Congress).

    This DVD was again shown on November 10, 2010 (the day after the November 9th FDA meeting), during a meeting Mr. Rosenberg and I attended with William A. McConagha, (former) Health Policy Advisor for Senator Tom Harkin and Ms. Leone at the Hart Senate Office Building. As stated in my November 26, 2010 letter to Mr. McConagha, following up on that November 10th meeting, “during [that] meeting Bruce and I expressed our increasing concern for the safety of surgical patients following the implantation of synthetic surgical mesh. The overuse and unethical misuse of surgical mesh by the medical community is indiscriminately subjecting all patients to a lifetime of risk and a grossly, unjustifiable high statistic of harm.”

  6. kitty says:

    It almost seems like the families of these Alzheimer patients are being

    tricked into taking “THE NEW Treatment” what bothers me is hearing about the side effects. —-seeing an old frail patient going in their diaper with diarrhea or throwing up. The vomiting is heartbreaking to hear about—a little Ole lady not knowing what’s going on.

  7. lou says:

    Hey Dan, are you setting up the stage for a class action?

  8. Dan Bolton says:

    Yes, Lou, we are investigating a potential class action. If I can answer any questions, please contact me. Thank you.

    • Barbara says:

      I told my Neurologist that I was worried about memory loss (started after the 7years of mesh rotting/replaced with more mesh). Without thinking twice he wrote me a RX for Aricept.After about a week, I found myself in a rage over little things.I remembered when working as an RN in charge of an Alziemers Wing in Nursing Home and how patients often had melt downs. Would stand up after a meal and have liquid stool (sorry) running all over them. There are only about 3 drugs for AD. I would rather die than completely lose my dignity. FDA is a “Government Sham”. Always has been. Lots of medicine does more harm than good. Best example: Cures for Cancer….CUT(surgery) Burn(radiation}POISON(Chemo. FDA SUCKS

  9. Dorothy Carpenter says:

    I would like to join this discussion

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