FDA Warns Pfizer Over Geodon Trial Overdosing
46 CommentsBy Ed Silverman // April 21st, 2010 // 6:49 am
The drugmaker was cited for failing to properly monitor pediatric clinical trials in which at least 13 children with bipolar disorder experienced overdosing that led to restless legs, tremors, involuntary facial movements and skin petechiae, which results from bleeding under the skin. The FDA cited Pfizer in an April 9 warning letter that noted the problem was originally found during FDA reviews in 2005.
The FDA wrote that “Pfizer failed to properly ensure monitoring of the study referenced above. As a result of inadequate monitoring, widespread overdosing of study subjects at multiple study sites was neither detected nor corrected in a timely manner,” according to the letter.
For instance, the FDA cited an internal Pfizer document dated Oct. 3, 2007 and entitled “Safety Information on Affected Subjects,” whicd noted that an additional six pediatric subjects in the study at two different sites experienced overdosing. And these occurred in June, July and August 2007 - several months after Pfizer supposedly retrained study monitors on correct dosing procedures.
This is the sort of episode that bolsters criticism of the deal in which drugmakers were awarded patent extensions for agreeing to run pediatric trials. Moreover, this is also the same drugmaker that was fined $301 million for improperly marketing Geodon for unapproved uses; unapproved patients, including children, and for higher doses than approved by the FDA (see here). The unfortunate take-away message suggests a disregard for children, although Pfizer says it takes the situation seriously and maintains it has instituted new procedures to prevent a recurrence.
In its letter, the agency noted the inspection is part of its Bioresearch Monitoring Program, which includes inspections designed “to evaluate the conduct of research and to ensure that the rights, safety, and welfare of the human subjects of those studies have been protected.” The Pfizer inspection was performed due to “significant violations found during inspections of several clinical investigators” involved in the trial.
Lisa Van Syckel
“Pfizers says it takes the situation seriously”
If they had, these children wouldn’t have been harmed. Had Pfizer, had any respect for the safety and welfare of these children, they would have thrown those clinical trial investigators under the bus.
Lisa Van Syckel
Pfizer should make public, the names of those clinical investigarors who where responsible for overdosing these children. As Senator Grassley would say, “Sushine makes the best disinfectant”.
AnneS
“…13 CHILDREN with bipolar disorder experienced overdosing that led to restless legs, tremors, involuntary facial movements and skin petechiae, which results from bleeding under the skin. ”
Why are we letting pharmaceutical companies experiment on our children?
Justice in MI
This is getting into Constant Gardner territory.
Suzanne
Do a search on http://www.clinicaltrials.gov. I found a Pfizer-sponsored peds trial for this drug that should give you an idea of who they work with.
pharmavet
It’s finally time to end the pediatric exclusivity game and simply require pediatric studies as a requirement for NDA approval, period.
patrons99
Well stated, AnneS -
“Why are we letting pharmaceutical companies experiment on our children?”
As another example, just have a look at the current pediatric vaccination schedule.
A particular concern should be the mandated Hepatitis B jabs given to infants, before their blood-brain barrier is functionally intact. Personally, I believe that is criminal.
Lisa Van Syckel
Pharmavet, I agree with you 100%!!! Stupak had addressed that issue extensively during Congressional Hearings in 2004, Unfortunately, Pharma got its way.
Lisa Van Syckel
The clinical trials.gov only list the principal investigator, and I noticed that the NIMH is colaborating with Pfizer on one of these studies. Sure hope they arent using my tax dollars for this Barbaric treatment for kids.
Lisa Van Syckel
According to the associated press,”29 Children” received overdoses!!!
patrons99
JiM,
Yes, indeed. The Constant Gardener and the phrase “guinea pigs” comes to mind. Here is yet another example where the reality is actually worse than the fiction…courtesy of the global pharma consortium (cartel). Pharma’s legion of shills don’t seem to mind…it’s business as usual.
Stephany
The disregard for children by the drug companies is as bad as the FDA, after all, the FDA still approves the drugs for younger and younger children (such as Abilfy and Risperdal), let’s not forget Grassley questioned the drug trial protocol of Joseph Biederman (of the Childhood Bipolar theory mafia at Mass General and Harvard)when he trialed Risperdal in 5 year olds…and Lilly’s Zyprexa was trialed on 5 year olds as well.
It’s an industry, and the people behind the money making drugs did not take the ‘Oath’ to do no harm, so of course why should they care?!
I’d like to know just WHO watches over the children? the FDA does not…..
This is a health crisis in America, the drugging of children is becoming an every day part of life….and it is quite alarming.
As a parent who has a child who has been harmed as a result of psych meds and a wrong dianosis, and years of research and seeing the skewed data, the buried data, internal documents and drug pimps such as Nemeroff and Biederman get away with millions of dollars for promoting these drugs….call me a skeptic!!
Suzanne
http://www.clinicaltrials.gov/ct2/show/NCT00181922?term=geodon&age=0&rank=10
Stephany
For an extensive article about the drugging of children in America
http://bipolar-stanscroniclesandnarritive.blogspot.com/2010/04/america-psychiatric-drugging-of-our.html
Stephany
Suzanne’s link to the trial verifies what I thought, without even having to look….
Principal Investigator: Joseph Biederman, MD Massachusetts General Hospital
patrons99
In another recent pharmalot thread, JimK said it best:
“As the evidence on the newer drugs continue to demonstrate that the risks far outweigh the benefits it seems that the 21st century pharmaceutical companies are merely government endorsed “patent medicine” salesmen and women.”
http://www.pharmalot.com/2010/04/the-fda-may-halt-the-avandia-safety-study/#comment-490961
Suzanne
Stephany, not saying this is *the* trial in question. Still, it’s a familiar name.
Stephany
He’s in pretty much all of the drugs for kids trials, either him or his minions, Wozniak, et al.
It’s all connected, there’s a money trail that always leads to these people, and all promoting the drugs for kids regime, in my opinion, seriously this is a crisis, and it’s happening on a daily basis, and the children will suffer as innocent victims as part of a corrupt and unethical industry for profit.
patrons99
“…Pfizer says it takes the situation seriously and maintains it has instituted new procedures to prevent a recurrence.”
A little bit off-topic, but possibly of interest to the medical historians amongst us:
http://www.mc.vanderbilt.edu/biolib/hc/nostrums/
http://www.google.com/images?client=firefox-a&rls=org.mozilla:en-US:official&channel=s&hl=en&q=patent+medicine&um=1&ie=UTF-8&source=univ&ei=FCbPS4OcHIKQ8gSQk8W2Dw&sa=X&oi=image_result_group&ct=title&resnum=4&ved=0CCAQsAQwAw
Nothing has really changed over time! Our mistakes keep getting repeated. If anything, the present-day situation is much than it was a century ago.
Suzanne
I assume it is the same in all peds specialties - a handful of studies done by one or two researchers.
patrons99
Generally speaking, this kind of thing happens in ALL medical specialties. Probably ghost-written studies on behalf of a study group. Sooner than later these ghost-written studies are distilled into ghost-written medical practice “guidelines”. It’s a vicious cycle. Our law makers are fooled. Many practicing physicians are fooled. Many patients are fooled. The public health suffers. The federal and state healthcare fisc suffers. Everybody looses, except Pharma.
It seems that whatever is good for pharma is now universally “good” for the country. Why else would our government and mainstream media continue to endorse “everything-pharma” ? There are now beyond reproach. They have become untouchables. They cannot do anything wrong. If they do err, it’s permissible. This is the new status quo, a baseline that makes us ever more dependent on pharma. There is no end in sight.
Salmon
Pfizer was responsible for the pediatric studies with the recently approved pediatric studies for asenapine (Saphris). The FDA review indicates that Pfizer may have intentionally used excessively large kids (e.g 200 lb twelve year olds) and a short study duration (10 days) to minimize the detection of dose and time related toxicities.
Other studies in the review show that liver damage was dose and time dependent in adults and 10 fold increases in transaminases occurred as early as day 6 when high doses were swallowed.
The statements at the advisory committee meeting indicates that as a sublingual formulation Saphris is likely to be used in young children. Plus the review suggests that swallowing of drug in this population is likely to be a safety issue.
The review also shows that liver tests were not submitted that were obtained while patients were on asenapine during a very high dose study. Only labs before and after subjects were on drug were reported. Plus even though the review documents that the labs were requested they were never provided.
The review also shows Larry Alphs, a Pfizer VP, as possibly responsible for not reporting a death to the IND as required by law.
Asenapine is very similar to olanzapine (Zyprexa). Even though the background package for the advisory committee that recommended approval for pediatric bipolar documented 2 deaths in children due to liver failure within a year or so of beginning treatment and likely due to excessive dosing. The stated reason by FDA and Lilly for making Zyprexa second line behind Geodon in children is because of weight gain.
Salmon
patrons99
Wow! Salmon, your comment is stunning. I’m blown away by it. This needs a thorough investigation.
Generally speaking, in situations similar to this one, shouldn’it be asked: Was there willful malfeasance? If deaths and liver failures were hidden or misrepresented, it’s one for criminal division DOJ and FBI. I’m reminded of The Fugitive with Harrison Ford. And yes, your comment is very relevant to a pharmalot post of Ed’s from yesterday:
http://www.pharmalot.com/2010/04/feds-consider-banning-execs-for-fraud/
Again, generally speaking, in instances similar to this one, shouldn’t it be asked: Was there more than just garden-variety fraud? Does anyone buy the mistake argument? Was there an agreement? Was there concerted action?
There is a certain similarity here to a death in an asthma research study, that I believe should have thoroughly investigated, but it was probably just ignored…swept under the carpet.
http://www.opednews.com/articles/Was-Asthma-Clinical-Resear-by-Robert-Davidson-091126-883.html
Salmon
The following is taken verbatim from the FDA review document which is on the FDA website.
2.3.3 Recommendations re: Criminal Investigations
Per instructions from OCP management (Dr. Mehta) any recommendations (or communications)
regarding criminal investigations from this reviewer first obtain approval from the management chain of command. This constitutes a formal request to FDA management and recommends criminal investigation of individuals in various companies and organizations for failure to report deaths, attempting to mislead
reviewers by various devices that are apparently intended to obfuscate and hide data required for review and that are needed to make safety assessments that would effect approval, and potentially sales and reimbursements…
Consequently this reviewer believes that the following section of federal law may have been potentially
violated:
SEC. 301. [21 USC §331] Prohibited Acts.
(ii) The falsification of a report of a serious adverse event submitted to a responsible person (as defined under section 760 or 761) or the falsification of a serious adverse event report (as defined under section 760 or 761) submitted to the Secretary, (see §3.5.1.2 and §3.5.1.6).
There are more than instance which will require more time to cite appropriately and will be communicated only to the appropriate criminal investigators.
This reviewer believes the following laws may have also been violated; these include possible violations of law by FDA personnel. (N.B. This list does not encompass all potential violations). Per instructions from Dr. Mehta this reviewer requests that these concerns be referred to the appropriate criminal investigators.”
The list includes
18 USC Sec. 1512 - Witness Tampering
and
18 USC Sec. 1518 - Obstruction of criminal investigations of health care offenses
So it looks unlikely that anything was ever referred to the criminal investigators.
patrons99
@ Salmon,
“So it looks unlikely that anything was ever referred to the criminal investigators.”
Do you mean FDA investigators or DOJ investigators? The reviewer cites possible violations of federal law. Who dropped the ball? Why are they being given a “free pass”?
There could be a huge story here. This kind of thing is a microcosm of much of what is wrong with pharma and FDA. There is an incredible story here! The reality of what actually transpired must see the light of day.
Senator Grassley is correct in his view that sunshine is best disinfectant.
Justice in MI
I look forward to Salmon’s answer re: who didn’t pursue this. I’m going to guess it was FDA’s Office of Criminal Investigation, which is, in essence, its liaison with DOJ.
patrons99
This is certainly not the first time that federal investigators dropped the ball, in a situation similar to this one. Let there be light.
http://www.scribd.com/doc/17300805/Document-19-Amended-Complaint-and-Exhibits
http://www.scribd.com/doc/17300758/07-Cv-01530-Filed-Complaint-TXSD
Nancy
Pfizer co-sponsored a study of rapid versus slow dose titration of ziprasidone in the treatment of pediatric bipolar disorder from February 2007 to November 2009. The anticipated enrollment was 60. However, according to ClinicalTrials.gov, the actual enrollment was 45. Why?
I found no publication results for this study.
For more information, go to ClinicalTrials.gov and search for NCT00622739. Scroll down to More Information, and then click on History of Changes. Uncheck the Hide features for additional information.
Skeptical
The biggest question I have is who leaked the name of the drug (geodon). In the actual warning letter posted on the FDA website, Geodon was redacted.
Jack Friday
http://pharmagossip.blogspot.com/2010/04/joe-biedermans-god-complex.html
Justice in MI
re: Skeptical’s question, this is not a warning letter; this was part of the $2.3 B bust. Geodon was also included and named, along with Pfizer’s other three illicitly promoted drugs, in the DOJ announcement last Fall.
Justice in MI
whoops–take that back; was conflating the two cases.
Nancy
Patrons99, thank you for posting.
“…by virtue of propinquity of clinical research subjects and specialty practice patients, prescreens could take place at no cost…this arrangement invited denial of appropriate care to specialty practice patients without their consent, so as to qualify them by ‘prescreen’ for study participation.”
How does the patient/family member know the physician acted in their best interests? Take the following situation….
http://tinyurl.com/24ybgyt
Salmon
It says Pfizer right in the letter which is posted on the FDA’s Website.
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm208976.htm
Salmon
patrons99
Who dropped the ball? JiM, you may be right. History seems to have repeated itself.
http://www.scribd.com/doc/17300818/Letter-of-October-17-2001-from-the-Department-of-Health-and-Human-Services-
Why, you ask ? Because FDA has shown a repeated pattern of regulatory malfeasance over the last two decades: specifically, repeated failures to investigate and failures to prosecute clinical research fraud. FDA resists mightily doing anything that will substantively injure the franchise (pharma). We have seen this time and time again. The is particularly true, when multiple NDAs, sNDAs, and multiple marketed drugs are involved.
The system is broken. I have been saying this for close to a decade now. I have tried repeatedly to call federal and state regulatory attention to this problem. Should it come as any real surprise to us that dangerous drugs (e.g. ketek, raxar, LABAs, neuraminidase inhibitors) continue to gain expedited market approvals, under PDUFA timelines, and remain in the market place even after strong safety signals (e.g. deaths, hospitalizations, neuropsychiatric events) and/or allegations of clinical research fraud?
http://content.nejm.org/cgi/content/full/356/16/1601
http://www.lawyersandsettlements.com/case/ketek_antibiotic_side_effects.html
http://www.opednews.com/articles/genera_martha_r_060801_jama_scandal_and_ket.htm
http://www.theepochtimes.com/n2/content/view/17498/
Justice in MI
The critiques of FDA we hear today, almost verbatim, go back forty years–at least to the 1970s. Check out the Dorson Committee report from that era. Re: critical reviewers being suppressed, we read, in part:
“The disserters were effectively suppressed, primarily by resort to involuntary transfers. Moreover, management’s execution of this policy was often untruthful, usually unkind, sometimes unlawful, and consistently unprofessional.” (Review Panel on New Drug Regulation, 1977)
1977. As I’ve said before, it’s too easy, if not without some basis, to blame FDA itself. Blame also Congress and several administrations of both parties for knowing the reality allowing it to go on, and on, and on.
ex-FDAer
Interesting.
During the 70’s there were the Kennedy Hearings on Lilly’s Use of prisoners for initial drug testing.
A few years ago Bob Temple, the head of medical policy at FDA, was quoted as saying that everything that’s happening now will blow over and nothing will come of it just like the Kennedy Hearings.
Evelyn Pringle
The doctor who prescribed the drugs to Gabriel Meyers, the Florida 7-year-old who hung himself about a year ago, received a warning letter from the FDA in February 2010 about violations in clinical trials.
I was just comparing the letter to Dr Punjwani to the one Pfizer got and the trials and the injured participants sound eerily similar.
I resent that the FDA seems to intentionally write these letters in some kind of code to make it nearly impossible to know for sure if they are discussing the same issues.
Here’s the link for people who want to judge for themselves:
http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm202862.htm
Justice in MI
Yup. The Dorsen report was one result of the Kennedy hearings of the 70s. Even it speaks ambivalently, oscillating between the kind of language above and language which seems to want to make everything seem OK.
Temple knows the history, whatever else.
Salmon
Evelyn they do have codes. The code (b)(4) is used to indicate a redaction of information based on a specific exemption under the Freedom of Information Act.
Skeptical
This definitely was a warning letter. That’s how the wires picked it up. Did someone internally within PFE inadvertently leak the name of the drug to the press? If so, I hope they are looking for another job!!!
Salmon
Skeptical,
Please read the warning letter on the FDA website that Evenlyn provides. You will see that
patrons99
@ Nancy 2:18 AM -
“How does the patient/family member know the physician acted in their best interests? Take the following situation….”
Without specific reference to any particular clinic, I provide the following short answer:
The patient/family member does not know the physician acted in their best interests. The potential for mischief is enormous whenever a specialty clinic uses its own patients as a source of patients to be entered into clinical research studies, at the same facility. This type of combination specialty practice/research practice arrangement:
(a) invites denial and withholding of appropriate care to patients in order to qualify them for entry into research studies, without the need to obtain a properly administered informed consent,
(b) invites medically-unnecessary procedures to be performed and billed to 3rd party payers, despite these procedures representing “prescreens” without informed consent,
( c) invites a temporal-discordance (postdating) between the “prescreen” and the signing of the formal informed consent for study participation, so as not to have to repeat, either the prescreen or execution of the formal informed consent,
(d) invites the performance of a “pre-pre-screen” by the front office staff (e.g., telephone receptionist, etc),
(e) invites manipulation of the patients’ clinical history so as to qualify them, and not inadvertently disqualify them, for one clinical research study after another, at a single research/practice facility, i.e., the use of “study-buddies” who often become dependent on the clinic for income, “free” drug samples, and/or specialty “care”,
(f) invites hiding the incidence of pre-screening failures for study participation, so as not to call attention to these failures to 3rd party payors, or to FDA,
(g) creates referral bias of ongoing clinical research studies,
(h) greatly accelerates study subject enrollment, at no cost (in either time or money) to study sponsors (pharma),
(i) invites simultaneously defrauding several branches of the U.S. Department of Health and Human Services (FDA, Medicare, Medicaid, Tricare, and various commercial payers).
How prevalent is the use of such “cross-over” and “study buddies” in various specialty practices around the country? Does such a practices, i.e. cross-over and study buddies, effectively defraud medicare to the benefit of pharma? Why is the true incidence of screening “failures” no where to be found? Who actually “pays” for screening “failures”? How valid is the clinical research coming out of such specialty clinics?
Nancy
@ patrons99 7:15 AM
In 2009 the Seton Hall University School of Law Center for Health & Pharmaceutical Law & Policy published a White Paper on the sticky, tricky problems illuminated in your post. Read more here:
http://tinyurl.com/28dhqak
The authors found that “Potential participants can be harmed by recruitment practices that insufficiently inform them of the risks of the study, ignore medical conditions that place them at risk in the trial, or encourage them to discontinue or forego a treatment regimen likely to be better for them than the regimen being evaluated in the trial. Manufacturers have also conducted studies as a way of introducing physicians to their products and obtaining the physicians’ brand loyalty, rather than as a genuine scientific inquiry [Kevin P. Hill et al., The ADVANTAGE Seeding Trial: A Review of Internal Documents, 149 Annals Internal Med. 251, 251-58(2008)]…Even if enrollees are not physically harmed in these studies, they are asked to participate in research that is a sham, violating the trust they have placed in the researchers who recruited them. Such studies undermine the integrity of the research enterprise; public revelation of the studies is likely to diminish willingness to participate in research.”
The process of obtaining sufficient data during investigations of such malignant medical practices is tricky due to the sensitive nature of the information. As well, stakeholders in the research enterprise withhold information in order to protect business interests.
Allegations of violations of state medical practice acts are easily dismissed because state medical boards are deprived of sufficient evidence to prove that a violation occurred. These allegations become a historical part of medical board files and remain statutorily confidential. The appeal process is long, arduous, and expensive. In the meantime patients, research volunteers, and benighted study personnel remain unaware of the risks.
patrons99
Nancy -
“Allegations of violations of state medical practice acts are easily dismissed because state medical boards are deprived of sufficient evidence to prove that a violation occurred.”
State medical boards are nearly always ineffectual. They don’t want to “make waves” or “rock the boat”. From first hand personal experience, I can tell you that a BOMEX (board of medical examiners) will “punt” on certain matters, claiming that (a) they do not have jurisdiction over the subject, or (b) that they cannot act while there is ongoing litigation. This tactic amounts to simply “sweeping the matter under the carpet” and hoping that the matter will just “quietly go away”.
Quite often, a BOMEX will act, or not act as was the case here, in conjunction with a state Attorney General’s office and with federal regulators. Again, stalling techniques are employed to the great detriment of the “whistleblower”, the at-risk public, state and federal healthcare budgets (the “fisc”), ongoing clinical research study databases in support of multiple NDAs and sNDAs, and postmarketing drug safety surveillance, nationwide.
It is not at all serendipitous that many dangerous drugs gain expedited market approvals by FDA under PDUFA timelines, and then remain in the marketplace, long after significant safety signals are identified. Are there victims of this subterfuge? I have no doubt whatsoever that there are “endangered and dead” victims. The system is completely broken and there is no end in sight.
http://www.scribd.com/doc/17300781/January-4-2001-AZ-BOMEX-Receipt-of-Complaint
http://www.scribd.com/doc/17300794/Feb-19-2002-Arizona-State-Board-of-Medical-Examiners-Letter
http://www.scribd.com/doc/17350742/Nov-6-2008-Arizona-Attorney-General-Letter
http://www.scribd.com/doc/17300818/Letter-of-October-17-2001-from-the-Department-of-Health-and-Human-Services-
“In the meantime patients, research volunteers, and benighted study personnel remain unaware of the risks.”
The study personnel (clinical research coordinators and a specialty care nurse) were well aware of the risks to the study subjects, specialty patients, and ethical transgressions which were too numerous to count. Several of the clinical research coordinators and the R.N., on more than one occasion, came to me and expressed their concerns. We could all have simply walked away from it.
“The appeal process is long, arduous, and expensive.”
No kidding!
Nancy
@ patrons99
“From first hand personal experience, I can tell you that a BOMEX (board of medical examiners) will ‘punt’ on certain matters, claiming that (a) they do not have jurisdiction over the subject, or (b) that they cannot act while there is ongoing litigation.”
I have experienced this as well, and I am writing an appeal to the state medical board.
“The study personnel (clinical research coordinators and a specialty care nurse) were well aware of the risks to the study subjects, specialty patients, and ethical transgressions which were too numerous to count.”
I have no doubt this was the case. In my experience investigators who chose not to follow the rules preferred to employ study personnel (data technicians and study coordinators) who were not inclined to challenge substandard clinical and research practices. Study personnel who were at risk for manipulation by the investigator were inexperienced, in need of recommendation letters for graduate school, or fearful of losing their positions.
I believe the Institutional Review Board personnel worked under similar conditions. For example, administrators declined to participate in the voluntary accreditation program offered by the Association for the Accreditation of Human Research Protection Programs, Inc., which requires (among other things) that study personnel are well-versed in good clinical practice in research.