Kauffman Study – (SSRI) Drugs: More Risks Than Benefits?

Journal of American Physicians and Surgeons Volume 14 Number 1 Spring 2009

SSRI Bombshell by Joel M. Kauffman, Ph.D. Tuesday, March 31st, 2009

Selective Serotonin Reuptake Inhibitor (SSRI) Drugs: More Risks Than Benefits?

Joel M. Kauffman, Ph.D.

ABSTRACT

Anecdotal reports have suggested that selective serotonin reuptake inhibitors (SSRIs) may cause suicidal or violent behavior in some patients. Because of the publicity surrounding certain events, and the numerous lawsuits that have been filed, a review of benefits and risks is needed.

At most 30% of patients receive a benefit from SSRIs beyond the large placebo effect in certain mental conditions, especially depression, according to a recent meta-analysis of published trials. An equally recent meta-analysis of all SSRI trials submitted to the FDA showed a small benefit for the severely depressed patients only. Many early unpublished trials did not show any benefit. Adverse effects are common, occurring in up to 75% of subjects.

Severe adverse effects may be underreported.

Meta- analyses of controlled trials did not include any actual suicides or murders, but only suicidality, some finding, in 1991 and 2007, no evidence even of suicidality.

Other meta-analyses using many of the same trials found that suicidality doubled to 1 in 500 on SSRIs compared with placebo or non-SSRI antidepressants, but did not include any actual suicides or murders. The trial designs were devised by SSRI makers to prevent reports of suicides, by eliminating subjects with the slightest trace of suicidal tendencies. Retrospective studies by others showed actual suicides on SSRIs with a relative risk (RR) of 2–3 compared with non-SSRI antidepressants, with an increased incidence of 123/100,000. Lower doses than the smallest available ones were found to maintain benefits in a majority of patients while reducing risks.

table_03_zoloftbusted1

[PLEASE NOTE THAT THE SSRISTORIES DATABASE REFERRED TO BY DR. KAUFFMAN IN THIS STUDY IS NO LONGER POSTED AT THE URL LISTED ABOVE BUT HAS BEEN MOVED TO THE URL www.ssristories.NET ]

No causal connection between SSRIs and suicide and/or violence has been proved; neither has it been ruled out. Physicians need to be vigilant, and aware of legal precedents that may subject them to enhanced liability when prescribing these drugs. The Genesis of SSRIs Fluoxetine (Prozac in the U.S., see Table 1), introduced in 1988 to combat depression, was the fourth selective serotonin reuptake inhibitor (SSRI) on the U.S. market, after being seriously considered by Eli Lilly as an antihypertensive drug. Unlike the earlier “tricyclics” (amitripyline, clomipramine, dothiepin, imipramine, etc.) and other drug classes, SSRIs acted on the brain to raise levels of the neurotransmitter serotonin without raising the levels of norepinephrine. This was thought to be a benefit in treatment of depression, and later anxiety, panic, social phobia, obsessive- compulsive disorder (OCD) , and many other conditions. The SSRIs listed in Table 1 are among the most frequently prescribed in the U.S., and compete with the five non- SSRIs shown, and others.

ssri-drug-table1

Benefits of SSRIs

A prominent recent meta-analysis of Bridge et al. included 27 trials of SSRIs for three defined mental conditions: major depressive disorder (MDD), OCD, and non-OCD anxiety disorders. Benefits, compared with placebo, were found to be highly statistically significant. For MDD, data from 13 trials showed benefit in 61% vs. 50% on placebo, a gain of 11% absolute (NNT=10), <0.001 for all ages of participants. For OCD, data from six trials showed benefit in 52% vs. 32% on placebo, a gain of 20% absolute (NNT=5), <0.001 for all ages. For non-OCD anxiety, data from 6 trials showed benefit in 69% vs. 39% on placebo, a gain of 30% absolute (NNT=3), <0.001 for all ages. These results represent the maximum expectation of benefit from SSRIs since 22 of the 27 trials were financially supported by SSRI makers, and thus subject to the routinely positive bias of industry-sponsored clinical trials. Jay S. Cohen, M.D., author of the 2001 book , wrote that half his patients did well on fluoxetine, but he noted a high incidence (50%) with side-effects. Cohen also cited a pre-approval study showing that the standard 20 mg per day starting dose helped 65% of patients, while 5 mg helped 54%, so Cohen became one of the pioneers in using lower doses before Lilly made them available. The 1996 entry for paroxetine, at least, confirmed that the 17 most common side-effects were dose-dependent.

In four observational cohort studies of four common SSRIs reported by physicians as part of the prescription-event monitoring program in the UK, with more than 10,000 patients in each drug group, only 36% of the physicians reported fluvoxamine as effective, compared with 60% for fluoxetine, sertraline, and paroxetine. These possible benefit rates, which include the placebo effect, parallel the percentage of patients remaining on the drug for 2 months.

See: Over Dose: the Case Against the Drug Companies

An old trial of placebo for anxious and depressed subjects reduced distress in 43%. Three meta-analyses of the antidepressant literature that appeared in the 1990s independently concluded that two-thirds of the effectiveness attributed to SSRIs is actually placebo effect. In a series of nine controlled studies on hospitalized patients with depression, 57% of those given placebo showed improvement in 2–6 weeks. A 1998 meta-analysis of 47 trials on antidepressant medication including SSRIs indicated that 75% of the response to them was duplicated by placebo. This meta-analysis was criticized on several grounds. Therefore, Irving Kirsch, Ph.D., of the University of Connecticut, with other authors, obtained data submitted to the FDA on every placebo-controlled clinical trial on the six most widely used SSRIs, and published a meta-analysis on 47 trials, finding a small, clinically insignificant effect.

This work was updated in 2008:

Analyses of datasets including unpublished as well as published clinical trials reveal smaller effects that fall well below recommended criteria for clinical effectiveness. Specifically, a meta-analysis of clinical trial data submitted to the U.S. Food and Drug Administration (FDA) revealed a mean drug–placebo difference in improvement scores of 1.80 points on the Hamilton Rating Scale of Depression (HRSD), whereas the National Institute for Clinical Excellence (NICE) used a drug–placebo difference of three points as a criterion for clinical significance when establishing guidelines for the treatment of depression in the United Kingdom. Kirsch et al. concluded that the updated findings from 35 carefully vetted trials suggest that, compared with placebo, the four new- generation antidepressants ( fluoxetine, venlfaxine, nefazodone, and paroxetine) do not produce clinically significant improvements in depression in patients who initially have moderate or even severe depression.

They show statistically significant but clinically minor effects only in the most severely depressed patients. Moreover, the significance of the effect probably is based on a decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new- generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, they write that the decreased placebo response in extremely depressed patients, combined with a response to antidepressants comparable to that of less severely depressed patients, is a potentially important insight that should be investigated further.

Even these unimpressive findings exaggerated the benefits of antidepressants. In three fluoxetine trials and in the three sertraline trials for which data were reported, the protocol allowed replacement of patients who, in the investigators’ judgment, were not improving after 2 weeks. The trials also included a 1–2 week washout period, during which patients were given a placebo prior to randomization. Those whose scores improved 20% or more were excluded from the study. In 25 trials, the use of other psychoactive medication was reported. In most trials, a chloral hydrate sedative was permitted in doses ranging from 500 mg to 2,000 mg per day. Other psychoactive medication was usually prohibited but still reported as having been taken in several trials.

Perhaps such considerations led David Healy, M.D., an SSRI expert, to his conclusion that “…these drugs do not convincingly work….” His evidence came from early unpublished clinical trials whose results were revealed to him at FDA hearings. For fluoxetine, Healy noted four trials with a positive result and four without. For sertraline, only one of five early studies showed benefit. Because of the huge placebo effect, 32–75%, most physicians unfamiliar with the studies revealing this effect are likely, in my opinion, to say that one-third to two-thirds of their patients are improved on SSRIs. This would also explain Dr. Jay S. Cohen’s findings on lower doses of fluoxetine.

SSRIs reportedly interact with 40 other drugs to cause “serotonin syndrome.”

This presents as twitching, tremors, rigidity, fever, confusion, or agitation. Serotonin/norepinephrine reuptake inhibitors (SNRIs) also may cause serotonin syndrome by interactions. Most tricyclic depressants do not have these interactions, with the exception of amitriptyline.

In a controlled trial of paroxetine vs. clomipramine sponsored by GlaxoSmithKline, 75% of the subjects had an adverse effect on paroxetine, 21% had a severe adverse effect, and 13% committed a suicidal act (1 in 8). The 1996 entry for paroxetine lists 17 side-effects with an incidence of ≥ 5% for approved doses.

They are: asthenia, sweating, constipation, decreased appetite, diarrhea (up to 15%), dry mouth (up to 21%), nausea (up to 36%), anxiety, dizziness, nervousness, paresthesia, somnolence (up to 22%), tremor (up to 15%), blurred vision, abnormal ejaculation, impotence, and other male genital disorders. Fully 31 additional side effects with an incidence at least 1% greater than placebo were listed, including uncontrollable yawning.

Murder, suicide, and suicidality were NOT [emphasis added] included.

Nor were they on comparable lists for fluvoxamine, or sertraline. For fluvoxamine, suicide were separately listed as “infrequent.”

For fluoxetine, suicidal ideation was listed as a voluntary report not proved to be drug related. For sertraline, suicidal ideation and attempt were listed separately as “infrequent.”

The entry for venlafaxine was: “…the possibility of a suicide attempt is inherent in depression.” Not found in the was weight gain, which Cohen lists as a serious side effect.

Typical dropout rates in recent trials are claimed to be 5% (see below), but these must be short trials, or trials with a run-in period. In a meta-analysis of 62 earlier trials with a total of 6,000 subjects, the mean total dropout rate and the proportion of dropouts due to side effects appear comparable to results in general practice: total dropout rates of between 30% and 70% have been reported by 6 weeks, of which some 30%–40% are attributed to side effects and the rest to failure of treatment. Early findings of severe adverse effects by SSRI makers came to light only after the class was established. Of 53 healthy volunteer studies on fluoxetine, the results of only 12 were openly reported.

From 35 healthy volunteer studies on paroxetine, pre-launch, the results of only 14 appeared. From 35 pre-launch healthy volunteer studies on sertraline, only seven appeared. Among the unpublished trials, there was one in which all volunteers dropped out because of agitation (akathisia). In published work on sertraline, data excluded material on behavioral toxicity, including at least one suicide of a Adverse Effects of healthy volunteer, and in a different trial, 2 of 20 volunteers became intensely suicidal. This last is consistent with the dropout rate of 5% for agitation alone in actual trials. It is also consistent with Lilly’s animal studies, in which previously friendly cats treated with fluoxetine started growling and hissing—an unheeded warning.

Just a year after fluoxetine was introduced, Bill Forsyth of Maui, Hawaii, had taken it for only 12 days when he committed one of the first murder/suicides attributed to any SSRI.

In the same year Joseph Wesbecker killed eight others and himself in a Louisville, Ky., printing plant where he worked, after 4 weeks on fluoxetine. Yet as early as 1986, clinical trials showed a rate of 12.5 suicides per 1,000 subjects on fluoxetine vs. 3.8 on older non-SSRIs vs. 2.5 on placebo! An internal 1985 Lilly document found even worse results and said that benefits were less than risks. Such documents were released into the public domain by Lilly as part of the settlement in the Wesbecker case. Fifteen more “anecdotes” of murder/suicide, three with sertraline, were listed by DeGrandpre.

Lilly’s denials of a link to murder/suicide on national television and elsewhere cited a sponsored meta-analysis in in 1991, which exonerated fluoxetine as a cause of suicidal acts or thoughts without even mentioning actual murder or suicide. This study included only 3,067 patients of the 26,000 in the clinical trials it utilized. None of the trials had a declared endpoint of suicidality.

Some of the trials had been rejected by the FDA. No mention was made that Lilly had had benzodiazepines co-prescribed to minimizethe agitation that had been recognized with fluoxetine alone. The 5% dropout rate for anxiety and agitation (akathisia) would have taken out the most likely candidates for suicide. Nevertheless, the 1991 study had its intended effect. For example, in 2006 a 900-page tome entitled , which was aimed at attorneys, cited this study, and failed lawsuits concerning SSRIs. The 2007 meta-analysis by Bridge et al. may be influenced by indirect conflicts of interest that are hard to prove based on the financial disclosures.

Their paper pooled excess risk above placebo for “suicidal ideation/suicide attempt” from 27 trials. The excess risk was said to be 0.7% and statistically significant across all indications, but significant within each indication. Of the 27 trials, only five were sponsored by the drug maker, and one of these, the 2004 Treatment for Adolescents with Depression (TADS) study of fluoxetine, had the highest rate of suicidality—7% above placebo. Most of the same trials were used in a meta-analysis by the FDA, which found a statistically significant excess risk of 2% (4% vs. 2% on placebo, 1 in 50 more). Bridge et al. used a random-effects calculation, while the FDA used a fixed-effects calculation.

In commenting on the negative findings, Bridge et al. write: “No study [in our meta-analysis] was designed to examine suicidal ideation/suicide attempt as a study outcome, and in fact most trials were conducted in patients who had been carefully screened to exclude youths at risk.” No actual murders or suicides associated with SSRI use were reported. Did the designs of the studies preclude detection or reporting?

The Bridge meta-analysis was not just a vindication of SSRIs, as communicated to the by Gilbert Ross, M.D., Medical Director of the American Council on Science & Health. Ross went further, commenting that the FDA “Black Box warning” (see below) was counterproductive because it was discouraging the use of antidepressants! Ross speculated that the lethal rampage of the Virginia Tech shooter might have resulted from premature cessation of medications.

SSRIs in general have long lifetimes in the body. Fluoxetine and its active metabolite in particular have a half-life of 16 days, according to the 1996 . In a reexamination of trials in which suicides or attempts during the inadequate washout period were not blamed on the drug, it was shown that the relative risk (RR) of suicidal acts ranged from 3 for sertraline to 10 for fluoxetine.

A concurrent meta-analysis of 24 trials by Kaizar et al. utilized Bayesian statistics, a valid choice, in my opinion, because data do not have to follow a Gaussian or normal curve to yield valid results, and this method can be used to revise probabilities to determine whether a specific effect was due to a specific cause. They found an association between SSRI use and suicidality with odds ratios of 2.3 (95% confidence interval [CI] 1.3-3.8), when the diagnosis was MDD, not OCD, anxiety, nor ADHD. Non-SSRI antidepressants were said to have no association with suicide. This supports the FDA’s findings and requirement, as of October, 2004, for a Black Box warning for all SSRIs, to monitor children and adolescents for suicidality. Kaizar et al. were concerned that there were no completed suicides among 4,487 subjects in the trials; that the trial times were too short at median length of 8 weeks; and that in 10 of the 12 MDD studies, Again, there was no citation of actual suicides associated with SSRIs and no citation of Healy’s work.

Healy reviewed epidemiologic studies that have been cited to exonerate SSRIs. One was analyzed by Healy to show a threefold increase in suicidality compared with other antidepressants.While “treatment-related activation” has been considered primarily with regard to suicidality, it can lead to harm to others as well as to self. Healy summarized data on “hostile episodes” provided by GlaxoSmithKline from placebo-controlled trials with paroxetine in subjects of all ages: 9,219 on paroxetine and 6,455 on placebo. The rubric of “hostility” was used in the trial to code for aggression and violence, including homicide, homicidal acts, and homicidal ideation, as well as aggressive events and “conduct disorders.” No homicides were reported from these trials.

Overall, during both therapy and withdrawal, the RR was 2.1 for hostile events. In children with OCD the RR was 17. Separately, in healthy volunteer studies, hostile events occurred in 3 of 271 subjects on paroxetine vs. none of 138 on placebo. In trials of sertraline on depressed children submitted by Pfizer, 8 of 189 subjects discontinued for aggression, agitation, or hyperkinesis (a coding term for akathisia), compared with 0 of 184 on placebo. In clinical practice, the term akathisia has been restricted to demonstrable motor restlessness, but if that is the only effect, it would have been called dyskinesia according to Healy, who cites four studies linking akathisia to both suicide and homicide.

Actual suicides were combined with suicide attempts in a 2005 meta-analysis of 702 trials of SSRIs vs. either placebo or an active non-SSRI control. Studies were rejected if the citation was a review, a result of duplicate publication, too short, crossover, or had no reporting of actual or attempted suicide. The studies meeting the criteria included 88,000 patients. For attempted suicide, the RR was 2.3 for SSRIs vs. placebo (95% CI, 1.14-4.55). The number needed to treat to harm (sometimes called the “reverse NNT”) was 1 in 684. There was no difference in actual suicide. Of the 702 trials, 104 failed to report adverse events below a certain pre-set limit of 3%, 5%, or 10% of patients. Only 493 trials reported dropout rates, with a mean of 29%, and the mean follow-up time was only 11 weeks. Thus, there was clearly gross underreporting of adverse effects. PDR children and adolescents with an elevated baseline risk of suicide were excluded.

Journal of American Physicians and Surgeons Volume 14 Number 1 Spring 2009 9

More importantly, because actual suicides are involved, Healy cited a study by Donovan et al. that demonstrated a RR=3.4 ( <0.01) for SSRIs compared with all non-SSRI antidepressants involving 222 actual suicides, of which 41 were among patients who had an SSRI within a month of their suicide. Also the British Drug Safety Research Unit recorded more than 110 suicides in 50,000 patients taking an SSRI, an incidence of 219/100,000 compared with 96/100,000 for the non-SSRI mirtazepine (Remeron), an increase of 123/100,000, or 1 in 813 (Table 2). Thus the RR for actual suicide in patients taking SSRIs was 2.3 (or 2.8 for paroxetine). Even here, though, no murders were listed.

In another study cited by Healy, Jick et al. reported 143 actual suicides among 172,598 patients taking antidepressants. The relative risk of suicide in patients taking fluoxetine was 2.1, compared with those taking the tricyclic antidepressant dothiepin. The risk was not age-dependent. SSRI makers keep insisting that there will be more suicides if SSRIs are used as frequently as now. But the RR of 2–3 shown in studies is a number that the number of suicides that may have been prevented, so SSRI use is associated with more suicides, not fewer.

The International Coalition for Drug Awareness in cooperation with the Prozac Survivors Support Group has produced a website on which about 1,600 violent incidents associated with SSRI use are described ( www.ssristories.net ). The first column on the type of incident (murder, school shooting, etc.) is a hot link to a publicly available description of the incident, typically a local newspaper article. A selection of 10 entries (rows) is presented here as Table 3. About 360 suicides are tallied as well as about 400 murder incidents, many of which were multiple murders, each linked to 26 not net includesSSRIs Provide 1,600 Anecdotes of Violence SSRI use (Rosie Meysenburg, personal communication, 2008 .

As the number of “anecdotes” exceeds 1,600—hardly a small number—the association of SSRIs with murder/suicide, often combined, must be taken seriously. The SSRI website was searched to find combined murder/suicide incidents attributed to a specific SSRI. There were three for fluvoxamine, four for citalopram, 10 each for paroxetine and sertraline, and 31 for fluoxetine. Where the studies above substantiated suicide from SSRI use, the total on the SSRI website of 48 simultaneous murder/suicide incidents associated with SSRI use ties together SSRIs and murder. Since there were about two murders per suicide, we may infer that the murder rate on SSRIs could be about 250/100,000. Since no clinical trial involving multiple homicides is ever likely to be run, no firmer evidence is likely to be found. Healy noted that much of the evidence for suicide and murder came from the efforts of journalists and lawyers.
Note that the website carries a prominent warning that “withdrawal can often be more dangerous than continuing on a medication.” Nine violent events cited elsewhere—seven court cases of homicide (one attempted) and two assaults—were associated with specific SSRIs: three with paroxetine, three with sertraline, two with fluoxetine, and one with venlafaxine. Skeptics have cast doubt on whether the prescribed SSRIs were actually taken, especially since many medical records of juveniles were sealed. In the Columbine, Colo., shootings the toxicology report showed “therapeutic” levels of fluvoxamine in one of the shooters. The Red Lake, Minn., shooter had fluoxetine found, according to news items referenced on the website.

A 2004 editorial in by Simon Wessely, M.D., a spokes- man for Eli Lilly, and Robert Kerwin, Ph.D, cited only a single paper by Healy as a source of claims of suicidality that have found a receptive media audience. Tellingly, the only study described at length is by Jick et al. on the correlation of SSRI use and “attempted suicide,” in which the rates on dothiepin, amitriptyline, fluoxetine and paroxetine were not statistically different. Actual suicides in this study (seven on SSRIs) were not mentioned by Wessely and Kerwin, nor were the 143 suicides in Jick’s earlier paper. Jick et al. have been supported partially by GlaxoSmithKline and Pfizer. No study that reported actual suicides on SSRIs was described in detail, let alone refuted. Wessely and Kerwin wrote: “The problem is that depression is unequivocally and substantially associated with suicide and self-harm.” True, but this not the truth.

Table 2. Suicides Related to SSRIs or Mirtazapine

table_02_zoloftbusted1

The legal defense by Lilly, repeated by the media and others, is that any suicides are caused by the condition, depression, not by their drug—whether the violence is associated with short-term drug use, long-term drug use, increased doses, withdrawal, or rechallenge. There is no website, as far as I know, for violent acts committed by persons who never received SSRIs, or for total violent acts; hence the denominator for violent acts is not known. Also unknown is the fraction of potentially violent persons who are treated with SSRIs, or of persons treated with SSRIs who are potentially violent. The published studies on actual suicide, however, compare patients on SSRIs with similar patients on non- SSRI antidepressants or placebo. Children diagnosed with OCD, not depression, also became suicidal on SSRIs, as did healthy volunteers.

Actual two- to threefold increases in suicide rates have been demonstrated as well as they could be. How else could such effects be demonstrated? Who would submit, and what institutional review board or human subjects committee would approve a study explicitly designed to show whether assaultive, homicidal, or other violent behavior increases in subjects prescribed the study drug?

Denial by SSRI makers of culpability for these risks continues to this day. Whether physicians’ acting on the Black Box warnings of 2004 and 2007 for all SSRIs will diminish the incidence of murders and suicides is not yet known. Following the introduction of fluoxetine in 1988, only a year passed before an early user committed multiple murders and suicide; many other examples followed. More than 200 lawsuits have been begun by users of SSRIs and victims’ families charging wrongful death or failure to warn; these have had mixed outcomes. There is now legal precedent for SSRIs as a cause of murder, and the maker of the SSRI is potentially liable for damages, according to David Healy.

Eli Lilly responded with total denial to the lawsuits claiming a link between fluoxetine and violence. Several claims were settled out of court with secret details and no admission of guilt. The Australian David Hawkins was freed from a murder charge by a finding of temporary insanity caused by using sertraline. Tim Tobin of Wyoming won $6.4 million from SmithKline Beecham when a jury found that a murder/suicide committed by Donald Schell was attributable to use of paroxetine. There are four other homicide cases in which the SSRI was deemed to have contributed, resulting in a suspended sentence in one case and an insanity verdict in another.

One case of homicide, with a guilty verdict and a life sentence, followed a judicial ruling that akathisia was associated with SSRI use, but that a causal relationship with homicide could not be argued; thus the link of an SSRI with homicide was disallowed. This was in direct conflict with the findings of the four trials cited above. The SSRI website was searched to find murders related to a specific SSRI whose perpetrators were acquitted based on temporary SSRI-induced insanity. There were two cases with sertraline, four cases with paroxetine, and four cases with fluoxetine. So a precedent has been established for legal recognition that an SSRI can be a cause for murder, and that the drug maker can be found liable for damages. The notices of suicidality for the SSRIs found in the PDR or package inserts before 2004 did not really warn of actual suicide or murder.

200 SSRI-related Lawsuits

The Black Box warning of 2004 about possible suicide in children under 18 years of age did not cover adults or murder at any age, so potential liability for the SSRI makers still exists. In 2007 the warning was extended to persons under age 25 years. David Healy was quoted as saying that the warning was overdue, and that the risk was not likely to disappear above age 25. This was shown by the trials from GlaxoSmithKline on paroxetine cited above.

Antidepressants are extraordinarily difficult to assess for risks or benefits in trials. At most, 11%–30% of patients with depression or related conditions who take SSRIs actually benefited beyond the placebo effect on normal doses. Of the perceived benefit, 32%–67% can be attributed to the placebo effect. Adverse effects, mostly dose-dependent, will appear in up to 75% of patients on normal doses. Of these, studies suggest that suicidality will be observed in an additional 2%–13% (1 in 50 to 1 in 9) of patients on normal doses, beyond what is seen on placebo or many non-SSRI antidepressant drugs. This is sufficiently frequent that a typical prescribing physician should observe examples in routine practice.

The actual suicide rate could be about 123/100,000 (1 in 813) higher in patients on SSRIs than in those on tricyclics or placebo. Studies show that many more suicides are on normal doses of SSRIs beyond what is seen on placebo or many non-SSRI antidepressant drugs. Available data suggest that actual murders may be committed at about the rate of 250/100,000 (1 in 400) SSRI-treated patients beyond what is seen on placebo or many non-SSRI antidepressantdrugs, and that many more murders will be attempted on normal doses as well. While correlation does not prove causation, and results of court trials are not medical science, the data for suicide are solid, and the association of murder with suicide is very suggestive. Now that there is a stronger Black Box warning, physicians who ignore it may be liable for damages; the warning primarily protects the manufacturers of SSRIs. There is obviously great peril in drawing conclusions about causat i on from press report s or court decisions.

While manufacturers have a vested interest in exonerating their drugs, plaintiffs have an interest in blaming it, and defendants in exonerating themselves. We need careful, independent analysis of existing study data. In addition to randomized controlled trials, evidence from basic science ( neuropharmacology) and challenge/dechallenge/rechallenge investigations needs to be sought. Both the public and individual patients are imperiled by an incorrect answer to the pressing questions about these widely prescribed drugs. Future studies may show lower levels of murder and suicide with close supervision, and with better matching of this drug type to patient type.

Conclusionsattemptedsimultaneous
Joel M. Kauffman, Ph.D.

Acknowledgements:
Joel M. Kauffman, Ph.D., professor of chemistry emeritus at the
University of the Sciences, 600 S. 43rd St., Philadelphia, PA 19104-4495,
Contact: kauffman@bee.net.

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Frances E. H. Pane edited the manuscript. David Moncrief piqued my interest by providing a review copy of by Richard DeGrandpre.
The Cult of Pharmacology: How America Became the World’s Most Troubled Drug Culture

Journal of American Physicians and Surgeons Volume 14 Number 1 Spring 2009 11
Potential conflicts of interest: The author has neither a financial interest in any drug mentioned, nor in any alternate treatments for treating any mental illness.

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Donovan S, Kelleher MJ, Lambourn J, Foster T. The occurrence of suicide following the prescription of antidepressant drugs.1999;5:181-192.

Jick SS, Dean AD, Jick H. Antidepressants and suicide.1995;310:215-218.

Wessely S, Kerwin R. Suicide risk and SSRIs. 2004;292:379-381.

Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. 2004;292:338-343.

Carey B. FDA expands suicide warning on drugs. ,May 3, 2007:A17.

J Am Acad Child Psychiatry BMJPsychother PsychosomPLoS Med
BMJ

Drug Injury:Liability, Analysis and Prevention.

Wall Street Journal,Br J Psychiatry Clinical Trials

Basic Business Statistics: Concepts and Applications J Psychiatry Neuroscience

New York Times:Journal of American Physicians and Surgeons Volume 14 Number 1 Spring 2009

USA Trade Name Generic Name:
SSRIs
Celexa
Luvox
Paxil
Prozac
Zoloft
non-SSRIs
Effexor
Remeron
Serzone
Wellbutrin
(UK)
citalopram
fluvoxamine
paroxetine
fluoxetine
sertraline
venlafaxine
mirtazapine
nefazodone
bupropion
dothiepin USA Trade Name Generic Name
SSRIs
Celexa
Luvox
Paxil
Prozac
Zoloft
non-SSRIs
Effexor
Remeron
Serzone
Wellbutrin
(UK)
citalopram
fluvoxamine
paroxetine
fluoxetine
sertraline
venlafaxine
mirtazapine
nefazodone
bupropion
dothiepin

Physicians Desk Reference (PDR)
Joel M. Kauffman, Ph.D.
Table 1. Commonly Prescribed SSRIs and Other Antidepressants Selective Serotonin Reuptake Inhibitor (SSRI) Drugs:
More Risks Than Benefits?

Journal of American Physicians and Surgeons Volume 14 Number 1 Spring 2009 7 Physicians Desk Reference (PDR)
Joel M. Kauffman, Ph.D.
Table 1. Commonly Prescribed SSRIs and Other Antidepressants Selective Serotonin Reuptake Inhibitor (SSRI) Drugs:
More Risks Than Benefits?

Journal of American Physicians and Surgeons Volume 14 Number 1 Spring 2009 7

JAMAwhole12,69210,98313,74112,73450,15013,554

10 dead, 7 wounded: dosage increased one week before rampage
15 year old shoots two teachers, killing one: then kills himself
Columbine High School: 15 dead, 24 wounded
Four dead, twenty injured after Prozac withdrawal
Teen shoots at two students: kills his father
Jury finds Paxil was cause of murder-suicide
Man cleared of charges due to Paxil withdrawal defense
Not guilty by reason of Prozac induced insanity: mother kills daughter
Nine dead, 12 wounded in workplace shooting
11 year old hangs himself: lawsuit

Journal of American Physicians and Surgeons Volume 14 Number 1 Spring 2009

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SSRI Medications

Below is a the drug manufactures BEST GUESS as to how SSRI antidepressants work in your brain. They fully admit that they really don’t know how they work. However, we maintain that the positive effects that patients report come from the stimulant, amphetamine-like, nature of these mind-altering drugs.

Learn the truth about these drugs in “Prozac: Panacea or Pandora?”

What you need to know about serotonin-enhancing medications

Selective Serotonin Reuptake Inhibitors do exactly that: Inhibit the reuptake of serotonin, thus leaving excess serotonin which allows this stimulation to continue. It has long been known that inhibiting the reuptake of serotonin will produce depression, suicide, violence, psychosis, mania, cravings for alcohol and other drugs, reckless driving, etc. [See full list of reactions below]

The most popular drugs that produce this reuptake of serotonin are:

SSRI Antidepressants: Prozac, Serafem, Zoloft, Paxil, Luvox, Celexa, Lexapro

SNRI Antidepressants: Effexor, Remeron, Serzone, Cymbalta

Atypical Antipsychotics: Zyprexa, Geodon, Abilify, Seroquel, Risperdal

Weight Loss Medications: Fen-Phen, Redux, Meridia

Pain Killers: (Any opium or heroin derivative) Morphine, OxyContin, Ultram, Tramadol, Percocet, Percodan, Lortab, Demerol, Darvon or Darvocet, Codeine, Buprenex, Dilaudid, Talwin, Stadol, Vicodin, Duragesic Patches, Fentanyl Transdermal, Methadone, Dextromethorphan (commonly used in cough syrups), etc.

WARNING: Anesthetics can also fall into this group as well as drugs used for other purposes. Always check to see what the mechanism of action is in a drug before combining it with another serotonergic agent or using it soon after the use of a serotonergic agent because the combination of two can cause the potentially fatal reaction known as Serotonin Syndrome. As the main function of serotonin is constriction of smooth muscle tissue, Serotonin Syndrome produces death via multiple organ failure.

“Psychedelic agents mimic the effects of serotonin.”

The brain chemical these drugs increase, serotonin, is the same brain chemical that LSD, PCP and other psychedelic drugs mimic in order to produce their hallucinogenic effects. And remember that psychedelic agents are “a class of compounds with no demonstrated therapeutic use, a history of extensive abuse, and the ability to provoke psychosis. Yet many brain researchers value the psychedelic agents above any of the other psychoactive drugs” because “the research into psychedelic drugs has already enriched our understanding of how the brain regulates behavior.” (Dr. Solomon Snyder, DRUGS AND THE BRAIN). Just how much will these brain researchers learn from our experience with these drugs designed to specifically increase serotonin, the same brain chemical the psychedelic agents mimic to produce their effects?

We know that these drugs interfere with serotonin metabolism (demonstrated by levels of the serotonin metabolite 5HIAA). It is not serotonin that is low in these disorders, it is this by-product 5HIAA, which indicates the level of serotonin metabolism, that is low in depression, suicide, etc. Yet as serotonin (5HT) goes up serotonin metabolism (5HIAA) generally comes down. We already have studies demonstrating at what percentage each of these drugs increase 5HT and decrease 5HIAA. Here are the results of elevated levels of serotonin (5HT) and decreased levels of serotonin metabolism (5HIAA):

Elevated 5HT (serotonin) levels:

  1. schizophrenia, psychosis, mania, etc.
  2. mood disorders (depression, anxiety, etc.)
  3. organic brain disease – especially mental retardation at a greater incident rate in children
  4. autism (a self-centered or self-focused mental state with no basis in reality)
  5. Alzheimer’s disease
  6. old age
  7. anorexia
  8. constriction of the blood vessels
  9. blood clotting
  10. constriction of bronchials and other physical effects

Lower 5HIAA (serotonin metabolism) levels:

  1. suicide (especially violent suicide)
  2. arson
  3. violent crime
  4. insomnia
  5. depression
  6. alcohol abuse
  7. impulsive acts with no concern for punishment
  8. reckless driving
  9. dependence upon various substances
  10. bulimia
  11. multiple suicide attempts
  12. hostility and more contact with police
  13. exhibitionism
  14. arguments with spouses, friends and relatives
  15. obsessive compulsive behavior
  16. impaired employment due to hostility, etc.

All are exactly what patients and their families have continued to report to be their experience on these drugs since Prozac was introduced! These individuals are frantically searching for answers while this research sits right under our noses. Although this is a totally different picture than pharmaceutical marketing departments would have us believe, marketing claims and reality rarely have much in common.

Researchers tell us that five, ten or twenty years later it is not uncommon to find we have another thalidomide on our hands. Raising 5HT (serotonin) and lowering 5HIAA (serotonin metabolism) in such a high number of people can produce very serious, extensive and long term problems for all of society. Even more frightening for the future of our society is the rapidly rising and widely accepted practice of prescribing these drugs to small children and adolescents. This crucial medical research must be addressed openly, without delay, rather than remain buried in seldom read medical research documents as has been the case in the past with other mind-altering medications, once thought to be safe, which were subsequently prohibited by law.

[SOURCE: PROZAC: PANACEA OR PANDORA?, BY ANN BLAKE TRACY]

  • Adverse SSRI Reactions
  • Prozac Package Insert
  • Hyperserotonemia
  • Serotonin Syndrome

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How a New Policy Led to Seven Deadly Drugs

How a New Policy Led to Seven Deadly Drugs

http://www.latimes.com/news/nation/reports/fda/lat_fda001220.htm

By DAVID WILLMAN

WASHINGTON–For most of its history, the United States Food and Drug Administration approved new prescription medicines at a grudging pace, paying daily homage to the physician’s creed, “First, do no harm.”

Then in the early 1990s, the demand for AIDS drugs changed the political climate. Congress told the FDA to work closely with pharmaceutical firms in getting new medicines to market more swiftly. President Clinton urged FDA leaders to trust industry as “partners, not adversaries.”

The FDA achieved its new goals, but now the human cost is becoming clear.

Seven drugs approved since 1993 have been withdrawn after reports of deaths and severe side effects. A two-year Los Angeles Times investigation has found that the FDA approved each of those drugs while disregarding danger signs or blunt warnings from its own specialists. Then, after receiving reports of significant harm to patients, the agency was slow to seek withdrawals.

According to “adverse-event” reports filed with the FDA, the seven drugs were cited as suspects in 1,002 deaths. Because the deaths are reported by doctors, hospitals and others on a voluntary basis, the true number of fatalities could be far higher, according to epidemiologists.

An adverse-event report does not prove that a drug caused a death; other factors, such as preexisting disease, could play a role. But the reports are regarded by public health officials as the most reliable early warnings of danger.

The FDA’s performance was tracked through an examination of thousands of pages of government documents, other data obtained under the Freedom of Information Act and interviews with more than 60 present and former agency officials.

The seven drugs were not needed to save lives. One was for heartburn. Another was a diet pill. A third was a painkiller. All told, six of the medicines were never proved to offer lifesaving benefits, and the seventh, an antibiotic, was ultimately judged unnecessary because other, safer antibiotics were available.

The seven are among hundreds of new drugs approved since 1993, a period during which the FDA has become known more for its speed than its caution. In 1988, only 4% of new drugs introduced into the world market were approved first by the FDA. In 1998, the FDA’s first-in-the-world approvals spiked to 66%.

The drug companies’ batting average in getting new drugs approved also climbed. By the end of the 1990s, the FDA was approving more than 80% of the industry’s applications for new products, compared with about 60% at the beginning of the decade.

And the companies have prospered: The seven unsuccessful drugs alone generated U.S. sales exceeding $5 billion before they were withdrawn.

Once the world’s unrivaled safety leader, the FDA was the last to withdraw several new drugs in the late 1990s that were banned by health authorities in Europe.

“This track record is totally unacceptable,” said Dr. Curt D. Furberg, a professor of public health sciences at Wake Forest University. “The patients are the ones paying the price. They’re the ones developing all the side effects, fatal and non-fatal. Someone has to speak up for them.”

The FDA’s faster and more lenient approach helped supply pharmacy shelves with scores of new remedies. But it has also yielded these fatal missteps, according to the documents and interviews:

1. Only 10 months ago, FDA administrators dismissed one of its medical officer’s emphatic warnings and approved Lotronex, a drug for treating irritable bowel syndrome. Lotronex has been linked to five deaths, the removal of a patient’s colon and other bowel surgeries. It was pulled off the market on Nov. 28.

2. The diet pill Redux, approved in April 1996 despite an advisory committee’s vote against it, was withdrawn in September 1997 after heart-valve damage was detected in patients put on the drug. The FDA later received reports identifying Redux as a suspect in 123 deaths.

3. The antibiotic Raxar was approved in November 1997 in the face of evidence that it may have caused several fatal heart-rhythm disruptions in clinical studies. FDA officials chose to exclude any mention of the deaths from the drug’s label. The maker of the pill withdrew it in October 1999. Raxar was cited as a suspect in the deaths of 13 patients.

4. The blood pressure medication Posicor was approved in June 1997 despite findings by FDA specialists that it might fatally disrupt heart rhythm and interact with certain other drugs, posing potentially severe risk. Posicor was withdrawn one year later; reports cited it as a suspect in 100 deaths.

5. The painkiller Duract was approved in July 1997 after FDA medical officers warned repeatedly of the drug’s liver toxicity. Senior officials sided with the manufacturer in softening the label’s warning of the liver threat. The drug was withdrawn 11 months later. By late 1998, the FDA had received voluntary reports citing Duract as a suspect in 68 deaths, including 17 that involved liver failure.

6. The diabetes drug Rezulin was approved in January 1997 over a medical officer’s detailed opposition and was withdrawn this March after the agency had linked 91 liver failures to the pill. Reports cite Rezulin as a suspect in 391 deaths.

7. The nighttime heartburn drug Propulsid was approved in 1993 despite evidence that it caused heart-rhythm disorders. The officials who approved the drug failed to consult the agency’s own cardiac specialists about the signs of danger. The drug was taken out of pharmacies in July after scores of confirmed heart-rhythm deaths. Overall, Propulsid has been cited as a suspect in 302 deaths.

The FDA’s handling of Propulsid put children at risk.

The agency never warned doctors not to administer the drug to infants or other children even though eight youngsters given Propulsid in clinical studies had died. Pediatricians prescribed it widely for infants afflicted with gastric reflux, a common digestive disorder.

Parents and their doctors had no way of knowing that the FDA, in August 1996, had found Propulsid to be “not approvable” for children.

“We never knew that,” said Jeffrey A. Englebrick, a heavy-equipment welder in Shawnee, Kan., whose 3-month-old son, Scott, died on Oct. 28, 1997, after taking Propulsid. “To me, that means they took my kid as a guinea pig to see if it would work.”

By the time the drug was pulled, the FDA had received reports of 24 deaths of children under age 6 who were given Propulsid. By then the drug had generated U.S. sales of $2.5 billion for Johnson & Johnson Co.

Questions also surround the recent approvals of other compounds that remain on the market, including a new flu drug called Relenza. In February of 1999, an FDA advisory committee concluded that Relenza had not been proved safe and effective. The agency nevertheless approved it. Following the deaths of seven patients, the FDA in January issued a “public health advisory” to doctors.

A ‘Lost Compass’
A total of 10 drugs have been pulled from the market in just the past three years for safety reasons, including three pills that were approved before the shift that took hold in 1993. Never before has the FDA overseen the withdrawals of so many drugs in such a short time. More than 22 million Americans–about 10% of the nation’s adult population–took those drugs.

With many of the drugs, the FDA used tiny-print warnings or recommendations in package labeling as a way to justify approvals or stave off withdrawals. In other instances, the agency has withheld safety information from labels that physicians say would call into question the use of the product.

Present and former FDA specialists said the regulatory decisions of senior officials have clashed with the agency’s central obligation, under law, to “protect the public health by ensuring . . . that drugs are safe and effective.”

“They’ve lost their compass and they forget who it is that they are ultimately serving,” said Dr. Lemuel A. Moye, a University of Texas School of Public Health physician who served from 1995 to 1999 on an FDA advisory committee. “Unfortunately the public pays for this, because the public believes that the FDA is watching the door, that they are the sentry.”

The FDA’s shift is felt directly in the private practice of medicine, said Dr. William L. Isley, a Kansas City, Mo., diabetes specialist. He implored the agency to reassess Rezulin three years ago after a patient he treated suffered liver failure taking the pill.

“FDA used to serve a purpose,” Isley said. “A doctor could feel sure that a drug he was prescribing was as safe as possible. Now you wonder what kind of evaluation has been done, and what’s been swept under the rug.”

FDA officials said that they have tried conscientiously to weigh benefits versus risks in deciding whether to approve new drugs. They noted that many doctors and patients complain when a drug is withdrawn. “All drugs have risks; most of them have serious risks,” said Dr. Janet Woodcock, director of the FDA’s drug review center. She added that some of the withdrawn drugs were “very valuable, even if not lifesaving, and their removal from the market represents a loss, even if a necessary one.” Once a drug is proved effective and safe, Woodcock said, the FDA depends on doctors “to take into account the risks, to read the label. . . . We have to rely on the practitioner community to be the learned intermediary. That’s why drugs are prescription drugs.”

In a May 12, 1999, article co-authored with FDA colleagues and published by the Journal of the American Medical Assn., Woodcock said, “The FDA and the community are willing to take greater safety risks due to the serious nature of the [illnesses] being treated.”

Compared to the volume of new drugs approved, they wrote, the number of recent withdrawals “is particularly reassuring.”

However, agency specialists point out that both approvals and withdrawals are controlled by Woodcock and her administrators. When they consider a withdrawal, they face the unpleasant prospect of repudiating their original decision to approve.

Woodcock, 52, received her medical degree at Northwestern University and is a board-certified internist. She alluded in a recent interview to the difficulty she feels in rejecting a proposed drug that might cost a company $150 million or more to develop. She also acknowledged the commercial pressures in a March 1997 article.

“Consumer protection advocates want to have drugs worked up well and thoroughly evaluated for safety and efficacy before getting on the market,” Woodcock wrote in the Food and Drug Law Journal. “On the other hand, there are economic pressures to get drugs on the market as soon as possible, and these are highly valid.”

But this summer–following the eighth and ninth drug withdrawals–Woodcock said the FDA cannot rely on labeling precautions, alone, to resolve safety concerns.

“As medical practice has changed . . . it’s just much more difficult for [doctors] to manage” the expanded drug supply, Woodcock said in an interview. “They rely upon us much more to make sure the drugs are safe.”

Another FDA administrator, Dr. Florence Houn, voiced similar concern in remarks six months ago to industry officials: “I think the lessons learned from the drug withdrawals make us leery.”

Yet the imperative to move swiftly, cooperatively, remains.

“We are now making decisions more quickly and more predictably while maintaining the same high standards for product safety and efficacy,” FDA Commissioner Jane E. Henney said in a National Press Club speech on Dec. 12.

Motivated by AIDS
The impetus for change at the FDA emerged in 1988, when AIDS activists paralyzed operations for a day at the agency’s 18-story headquarters in Rockville, Md. They demanded immediate approval of experimental drugs that offered at least a ray of hope to those otherwise facing death.

The FDA often was taking more than two years to review new drug applications. The pharmaceutical industry saw a chance to loosen the regulatory brakes and expedite an array of new products to market. The companies and their Capitol Hill lobbyists pressed for advantage: If unshackled, they said, the companies could invent and develop more remedies faster.

The political pressure mounted, and the FDA began to bow. By 1991, agency officials told Congress they were making significant progress in speeding the approval process.

The emboldened companies pushed for more. They proposed that drugs intended for either life-threatening or “serious” disorders receive a quicker review.

“The pharmaceutical companies came back and lobbied the agency and the Hill for that word, ‘serious,’ ” recalled Jeffrey A. Nesbit, who in 1991 was chief of staff to FDA Commissioner David A. Kessler. “Their argument was, ‘Well, OK, there’s AIDS and cancer. But there are drugs [being developed] for Alzheimer’s. And that’s a serious illness.’ They started naming other diseases. They began to push that envelope.”

The wielding of this single, flexible adjective–“serious”–swung wide the regulatory door knocked ajar by the AIDS crisis.

New Order Takes Hold
In 1992, Kessler issued regulations giving the FDA discretion to “accelerate approval of certain new drugs” for serious or life-threatening conditions. That same year a Democrat-controlled Congress approved and President Bush signed the Prescription Drug User Fee Act. It established goals that call for the FDA to review drugs within six months or a year; the pharmaceutical companies pay a user fee to the FDA, now $309,647, with the filing of each new drug application.

The newly elected Clinton administration climbed aboard with its “reinventing government” project. Headed by Vice President Al Gore, the project called for the FDA, by January 2000, to reduce “by an average of one year the time required to bring important new drugs to the American public.” As Clinton put it in a speech on March 16, 1995, the objective was to “get rid of yesterday’s government.”

For the FDA’s medical reviewers–the physicians, pharmacologists, chemists and biostatisticians who scrutinize the safety and effectiveness of emerging drugs–a new order had taken hold.

The reviewers work out of public view in secure office buildings clustered along Maryland’s Route 355. At the jet-black headquarters building, the decor is institutional, the corridors and third-floor cafeteria without windows. The reviewers examine truckloads of scientific documents. They are well-educated; some are highly motivated to do their best for a nation of patients who unknowingly count on their expertise.

One of these reviewers was Michael Elashoff, a biostatistician who arrived at the FDA in 1995 after earning degrees from UC Berkeley and the Harvard School of Public Health.
“From the first drug I reviewed, I really got the sense that I was doing something worthwhile. I saw what a difference a single reviewer can make,” said Elashoff, the son and grandson of statisticians.

Last year he was assigned to review Relenza, the new flu drug developed by Glaxo Wellcome. He recommended against approval.

“The drug has no proven efficacy for the treatment of influenza in the U.S. population, no proven effect on reducing person-to-person transmissibility, and no proven impact on preventing influenza,” Elashoff wrote, adding that many patients would be exposed to risks “while deriving no benefit.”

An agency advisory committee agreed and on Feb. 24 voted 13 to 4 against approving Relenza. After the vote, senior FDA officials upbraided Elashoff. They stripped him of his review of another flu drug. They told him he would no longer make presentations to the advisory committee. And they approved Relenza as a safe and effective flu drug.

Lost Faith in the System
Elashoff and other FDA reviewers discern a powerful message.
“People are aware that turning something down is going to cause problems with [officials] higher up in FDA, maybe more problems than it’s worth,” he said. “Before I came to the FDA I guess I always assumed things were done properly. I’ve lost a lot of faith in taking a prescription medicine.”

Elashoff left the FDA four months ago.

“Either you play games or you’re going to be put off limits . . . a pariah,” said Dr. John L. Gueriguian, a 19-year FDA medical officer who opposed the approval of Rezulin, the ill-fated diabetes drug. “The people in charge don’t say, ‘Should we approve this drug?’ They say, ‘Hey, how can we get this drug approved?’ ”

Said Dr. Rudolph M. Widmark, who retired in 1997 after 11 years as a medical officer: “If you raise concern about a drug, it triggers a whole internal process that is difficult and painful. You have to defend why you are holding up the drug to your bosses. . . . You cannot imagine how much pressure is put on the reviewers.”

The pressure is such that when a union representative negotiated a new employment contract for the reviewers last year, one of his top priorities was to defend what he called the “scientific integrity” of their work.

“People feel swamped. People are pressured to go along with what the agency wants,” said Dr. Robert S.K. Young, an FDA medical officer who in 1998 formed a union chapter to represent the reviewers. “You’re paying for these highly educated, trained people, and they’re not being allowed to do their job.”

Each new drug application is accompanied by voluminous medical data, enough at times to fill 1,000 or more phone books. The reviewers must master this material in less than six months or a year, while juggling other tasks.

“The devil is in the details, and detail is something we no longer have the time to go into,” said Gurston D. Turner, a veteran pharmacologist with the FDA’s scientific investigations division who retired this year. “If you know you must have your report done by a certain date, you get something done. That’s what they [top FDA officials] count, that’s all they count. And that is really, to me, a worrisome thing.”
The FDA did spur reviewers to move at record speed.

In 1994, the FDA’s goal was to finish 55% of its new drug reviews on time; the agency achieved 95%. In 1995, the goal was 70%; the FDA achieved 98%. In 1996, the goal was 80%; the FDA achieved 100%. In both 1997 and 1998, the goal was 90% and the FDA achieved 100%.

From 1993 to 1999 the agency approved 232 drugs regarded as “new molecular entities,” compared with 163 during the previous seven years, a 42% increase.

The time-limit goals quickly were treated as deadlines within the FDA–imposing relentless pressure on reviewers and their bosses to quickly conclude their work and approve the drugs.

“The goals were to be taken seriously. I don’t think anybody expected the agency to make them all,” said William B. Schultz, a deputy FDA commissioner from 1995 to 1999.

Schultz, who helped craft the 1992 user-fee act as a congressional staff lawyer, added: “You can meet the goal by either approving the drug or denying the approval. But there are some who argue that what Congress really wanted was not just decisions, but approvals. That is what really gets dangerous.”

Indeed, the FDA drug center’s 1999 annual report referred to the review goals as “the law’s deadlines.” And, Dr. Woodcock, the center director, elaborated in a subsequent agency newsletter:

“In exchange [for the user fees], FDA makes a commitment to meet certain goals for review times. [The agency] has exceeded almost all of the goals, and it expects to continue to exceed them. Basically, the number of new approved drugs has doubled, and the review times have been cut in half.”

The user fees have enabled the FDA to hire more medical reviewers. Last year, 236 medical officers examined new drugs compared with 162 officers on duty in 1992, the year before the user fees took effect.

Even so, Woodcock acknowledged in an FDA publication this fall that the workloads and tight performance goals “create a sweatshop environment that’s causing high staffing turnover.”

An FDA progress report in 1998, describing the work of agency chemists, said that “too many reviews are coming ‘down to the wire’ against the goal date. . . . This suggests a system in stress.”

Said Nesbit, the former aide to Commissioner Kessler: “The clock is always running, whereas before the clock was never running. And that changes people’s behavior.”

Dozens of officials interviewed by The Times made similar observations.

“The pressure to meet deadlines is enormous,” said Dr. Solomon Sobel, 65, director of the FDA’s metabolic and endocrine drugs division throughout the 1990s. And the pressure is not merely to complete the reviews, he said. “The basic message is to approve.”

Over the last seven years, “there has been a huge shift,” said Kathleen Holcombe, a former FDA legislative affairs staffer and congressional aide who now is a drug industry consultant. “FDA, historically, had an approach of, ‘Regulate, be tough, enforce the law [and] don’t let one thing go wrong,’ ” Holcombe said, adding that now, “the FDA sees itself much more in a cooperative role.”

How Deaths Were Calculated
Reports of adverse drug reactions to the Food and Drug Administration are considered by public health officials to be the most reliable early warnings of a product’s danger. The reports are filed to the FDA by health professionals, consumers and drug manufacturers. The Los Angeles Times inspected all reports filed in connection with seven drugs that were approved and withdrawn since 1993. By hand and by computer, The Times counted 1,002 deaths in which the filer identified the drug as the leading suspect. Since fall 1997, this top category has been termed “primary suspect.” The Times did not count any death in which the drug was identified as the “secondary suspect” or less. The methodology and results were reviewed by Sheila R. Weiss, a former FDA epidemiologist who is an assistant professor at the University of Maryland’s department of pharmacy practice and sciences.

The perception of coziness with drug makers is perpetuated by potential conflicts of interest within the FDA’s 18 advisory committees, the influential panels that recommend which drugs deserve approval or should remain on the market. The FDA allows some appointees to double as consultants or researchers for the same companies whose products they are evaluating on the public’s behalf. Such was the case during committee appraisals of several of the recently withdrawn drugs, including Lotronex and Posicor, The Times found.

Few doubt the $100-billion pharmaceutical industry’s clout. Over the last decade, the drug companies have steered $44 million in contributions to the major political parties and to candidates for the White House and both houses of Congress.

The FDA reviewers said they and their bosses fear that unless the new drugs are approved, companies will erupt and Congress will retaliate by refusing to renew the user fees. This would cripple FDA operations–and jeopardize jobs.

The companies’ money now covers about 50% of the FDA’s costs for reviewing proposed drugs–and agency officials say that persuading Congress to renew the user fees into 2007 is now a top priority.

Yet even if the user fees remain, the FDA is prohibited from spending the revenue for anything other than reviewing new drugs. So while the budget for pre-approval reviews has soared, the agency has gotten no similar increase of resources to evaluate the safety of the drugs after they are prescribed.

“It’s shocking,” said Dr. Brian L. Strom, chairman of epidemiology at the University of Pennsylvania. “How can you say, ‘Release drugs to the market sooner,’ and not know if they’re killing people? . . . It really is a dramatic statement of public priorities.”

More than 250,000 side effects linked to prescription drugs, including injuries and deaths, are reported each year. And those “adverse-event” reports by doctors and others are only filed voluntarily. Experts, including Strom, believe the reports represent as few as 1% to 10% of all such events. “There’s no incentive at all for a physician to report [an adverse drug reaction],” said Strom, who has documented the phenomenon. “The underreporting is vast.”

Even when deaths are reported, records and interviews show that companies consistently dispute that their product has caused a given death by pointing to other factors, including preexisting disease or use of another medicine.

To be sure, a chain of events affects the safe use of a prescription drug: The companies’ conduct of clinical studies; the FDA’s regulatory actions; the doctor’s decision to prescribe; the pharmacist’s filling of a handwritten prescription; the patient’s ability to take the drug as directed. A lapse at any link could prove fatal.

And once a pill is approved by the FDA, the manufacturer often spends heavily on promotion to seize the largest possible market share. This can exacerbate the risk to public health, according to experts.

“Aggressive promotion increases exposure–and doesn’t give you the time to find the problem before patients get hurt,” said Dr. Raymond L. Woosley, pharmacology department chairman at Georgetown University and a former FDA advisory committee member.

When serious side effects emerge, the FDA officials have championed using package labeling as a way to, in their words, “manage” risks. Yet the agency typically has no way to know if the labeling precautions–dense, lengthy and in tiny print–are read or followed by doctors and their patients.

The FDA often addresses unresolved safety questions by asking companies to conduct studies after the product is approved. But the research frequently is not performed–prompting the inspector general of the Department of Health and Human Services to say in 1996 that “FDA can move to withdraw drugs from the market if the post-marketing studies are not completed with due diligence.”

Since that report was issued, the FDA has not withdrawn any drug due to a company’s failure to complete a post-approval safety study. Officials conceded this week that they still do not know how often the studies are performed.

One consequence is that greater risk is shifted to doctors and patients.

For example, Woodcock and her senior aides allowed Rezulin to remain on the U.S. market nearly 2 years after it was withdrawn in Britain in December 1997. The FDA recommended frequent laboratory testing of patients using the drug but had no scientific assurance that the tests would prevent Rezulin-induced liver failure.

“They kept increasing the number of liver-function tests you should have,” noted Dr. Alastair J.J. Wood, a former FDA advisory committee member who is a professor of medicine at Vanderbilt University. “That was clearly designed to protect the FDA, to protect the manufacturer, and to dump the responsibility on the patient and the physician. If the patient developed liver disease and he hadn’t had his [tests] done, somebody was to blame and it wasn’t the manufacturer and it wasn’t the FDA.”

Industry Assurances
Leading industry officials say Americans have nothing to fear from the wave of drug approvals.

“Do unsafe drugs enter and remain in the marketplace? Absolutely not,” said Dr. Bert A. Spilker, senior vice president for scientific and regulatory affairs for the Pharmaceutical Research and Manufacturers of America, in remarks last year to industry and FDA scientists.

But during interviews over the last two years, current and former FDA specialists cited repeated instances when drugs were approved with less than compelling evidence of safety or effectiveness. They also said that important information has been excluded from the labels on some medications.

Elashoff, for instance, was surprised at the labeling for a drug called Prograf, approved in 1997 to prevent rejection of transplanted kidneys. The drug first had been approved in 1994 for use among liver-transplant patients.

The new label notes that Prograf was proved effective in a study of 412 U.S. kidney transplant patients. But no mention is made of the company’s 448-patient European study, in which 7% of the patients who took Prograf died–double the 3.5% death rate among those who received a different anti-rejection drug, documents show.

Contributors to this Report
Design director: Joe Hutchinson
Photographer: Brian Walski
Photo editor: Steve Stroud
Graphics: Rebecca Perry
Graphics editor: Chris Erskine
Researchers: Janet Lundblad, Sunny Kaplan
Editors: Roger Smith, Nan Williams, Steve Devol, Bobbi Olson, Kathie Bozanich
Web site Editors: Sarah D. Wright, Clare Sup

An auditor from the FDA’s scientific investigations unit, Antoine El-Hage, examined the European study results and concluded the “data are reliable.” Elashoff agreed in his review.
Yet the only way for doctors or patients to find that data is to search the medical literature or seek the FDA’s review documents.

Excluding the European study from the Prograf label, Elashoff said, “was just a total whitewash. . . . I think any rational person would reconsider taking this drug if they knew what happened in Europe.”

A spokesman for the manufacturer of Prograf said the company had no objection to including the European study results in the labeling. William E. Fitzsimmons, a vice president of drug development for Fujisawa Healthcare Inc., said the decision to exclude the results was entirely the FDA’s.

“We submitted that data,” he said. “It came down to what the FDA was comfortable putting in the label. We certainly have no interest in trying to hide that information. We presented it at major meetings on transplantation. . . . We’re comfortable with that information being out in the public domain.”

But if the FDA had included the European results in the label, it would have impugned the agency’s basis for approving the new, expanded use for Prograf, according to Elashoff and others.

Asked why the agency excluded the information, Woodcock said the European results were “unreliable and could be potentially misleading to doctors and patients in the U.S. if these were included in the label.”

Copyright 2000 Los Angeles Times

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CELEXA: Youth in India Dies During Clinical Trial

Paragraph 10 reads: “Concerns about the ethics of clinical trials do not exist merely in the realm of speculation. The GVK exposés are not unusual. An increasing number of reports are coming to light of unethical and illegal practices that exploit people’s social and economic vulnerability, subject them to serious risks without their knowledge and consent, and do not even assure them of access to the drugs developed from the trials. Certain types of trials depend on paid volunteers who desperately need money. In Gujarat, unemployed diamond workers and migrants from Uttar Pradesh and Bihar get paid between INR 5000 and INR 20,000 to take part in bioequivalence trials – sums large enough for them to put money over personal safety. Indeed, trial participants may be both financially and socially vulnerable. It is reported that Surender, who died in the Hyderabad felodipine trial, was one of a number of Dalit students being recruited for clinical trials in that city. Likewise, some years ago, a 22-year-old Adivasi youth died in a bioequivalence trial of the antidepressant citalopram [Celexa] by the Sun Pharma Advanced Research Centre in Vadodara. ”

http://www.himalmag.com/Bodies-for-hire;-The-outsourcing-of-clinical-trials_nw3213.html

Bodies for hire; The outsourcing of clinical trials August 2009
By: Sandhya Srinivasan

Medical testing by Western countries is having a staggering impact on India, if only we were to care to pay attention. And the government’s own policies are encouraging this.

Karen Haydock
In November 2008, the Hindustan Times’ LiveMint broke the story of an infant in Bangalore having died after being administered a vaccine in a drugs trial. The Drugs Controller-General of India (DCGI), Dr Surinder Singh, halted the testing, reportedly the first time that the office of the DCGI had taken such action. The trial, for a new pneumonia vaccine, was being conducted by a Hyderabad-based contracted research organisation, GVK Biotech, for the US-based multinational Wyeth Pharmaceuticals. The infant had been recruited from St. John’s Medical College, a reputed private medical institution in Bangalore.

GVK’s spokesperson claimed that the vaccine had nothing to do with the death, as the child had received an approved and widely used vaccine – not the experimental product. However, the DCGI’s investigation revealed that the infant had a heart condition, and that the trial had been meant to be conducted only on healthy babies. According to C M Gulhati, editor of the Monthly Index of Medical Specialities, India and a Delhi-based expert on clinical-trial regulations, the investigation revealed a number of other irregularities as well: the informed-consent document had not been signed before the child was recruited; and the St John’s ethics committee had not been properly constituted, as it was not chaired by an external member to ensure independent functioning.

Yet the infant’s death was not an aberration. In December 2008, 25-year-old K Surender, of Hyderabad, died in a ‘bioequivalence’ trial of a blood-pressure drug, felodipine. Bioequivalence trials test generic versions of drugs to ensure that they are as effective as the original, and involve administering the drug and then monitoring the individual through blood tests and other investigations. These tests are conducted on healthy people who are paid for their participation. The Hyderabad trial also happened to be run by GVK Biotech, which subsequently issued a statement that Surender had simultaneously been part of many bioequivalence studies, with GVK as well as other contracted research organisations. This multiple trial participation could have accounted for his death, argued the company.

Such an explanation is unconvincing. If Surender had taken part in many trials, it would only have been for the money, which would amount to an inducement according to national and international ethical guidelines for research – an inducement that might have made him overlook the risks of the trials. And, in any case, why did the company let him take part in the felodipine trial when it was aware that he had taken part in many others? The answer to this question lies in the compulsions of the global pharmaceutical industry. The GVK trials are among the increasing number of international clinical trials that are taking place in India – and the concerns that they raise will come up increasingly frequently in the future. The reports of various government and private bodies put the potential of the clinical-trial industry into billions of dollars, though the method of calculating these numbers is not available. One market-research company, Frost and Sullivan, reportedly estimates a USD two billion turnover by 2010.

Marcin Bondarowicz
The growth of the outsourced clinical-trial industry in India followed changes in the law in January 2005 that encourage clinical research in India. The most important of these was an amendment to the Drugs and Cosmetics Rules, permitting clinical trials in India to be carried out at the same time that they are done in other countries, rather than waiting until the results of drug trials in other countries were made public. Previously, this ‘phase lag’ had ensured that India was of no interest to big pharmaceutical companies to test their drugs. At that time, Phase II trials were permitted in India only after the results of a Phase III trial abroad were declared. And Phase I trials of foreign drugs were simply not permitted. (Phase I or safety trials are done on healthy ‘volunteers’, Phase II trials look at the drug’s safety and effectiveness on patients, and Phase III trials also look at safety and effectiveness, but in large numbers of patients.) It should be noted, though, that an exception was made for drugs deemed of importance to India. While the Drugs and Cosmetics Rules do not specify, such drugs would probably include the HIV vaccine.

This changed in January 2005, and India is now prominently on the radar screen of the international pharmaceutical industry in terms of clinical trials, given its vast population of potential trial subjects. As of today, the bulk of clinical trials are still located in rich countries. To illustrate, as of 19 July 2009, the US government clinical-trial database lists a total of 76,018 trials, of which 44,758 have sites in North America and 17,878 have sites in Europe – accounting for the bulk of trials. In contrast, only 1021 clinical trials have sites in India, in addition to 122 in Pakistan, 61 in Bangladesh and 12 each in Nepal and Sri Lanka.

However, the number of trials in India is growing fast. Figures given by the DCGI’s office show that the number of newly approved trials every year went from 100 in 2005, when the new rules kicked in, to about 500 in 2008. What is of concern here is that many of the trials that come to countries such as India are likely to be those rejected as unethical in Western countries. As trials shift to countries such as India, there has been an international debate on ethical concerns of the outsourcing boom. This debate has been partly responsible for amendments in the World Medical Association’s Declaration of Helsinki, “Ethical Principles for Medical Research Involving Human Subjects” in 1996, 2000 and in October 2008. Drug regulators in Europe and the US require that clinical trials submitted to them adhere to the Declaration.

Some of these changes have dealt with placebos or ‘sugar pills’. The October 2008 revision took a strong stance against the use of a placebo in a trial when a treatment exists. Clinical trials compare the effect of an experimental drug to an existing drug. If there is no drug for the condition, the experimental drug may be compared to a placebo. Using a placebo when a treatment exists deprives the trial participant of effective treatment. The ethical guidelines of the Indian Council of Medical Research and the World Medical Association’s Declaration of Helsinki both forbid the use of a placebo when an effective treatment exists, with certain specific exceptions. While both of these documents have been a bit ambiguous in the past, the 2008 revision of the Helsinki Declaration is clear: placebos can be used only when absolutely methodologically necessary, and when the risk to the participant is low. This revision was reportedly preceded by behind-the-scenes lobbying by the drug industry to permit greater use of placebo controls.

In the same month that the revised Declaration was announced, the US Food and Drug Administration (FDA) amended its own requirements for clinical trials. While placebos are rarely necessary, regulatory bodies such as the FDA require placebo-controlled trials to give marketing approval to new drugs. Yet as of October 2008, trials conducted for FDA approval no longer had to adhere to the Declaration of Helsinki – an internationally accepted document, but not binding unless incorporated into national regulations. The FDA would continue to require placebo controls, and no one was going to tell them otherwise.

Concerns about the ethics of clinical trials do not exist merely in the realm of speculation. The GVK exposés are not unusual. An increasing number of reports are coming to light of unethical and illegal practices that exploit people’s social and economic vulnerability, subject them to serious risks without their knowledge and consent, and do not even assure them of access to the drugs developed from the trials. Certain types of trials depend on paid volunteers who desperately need money. In Gujarat, unemployed diamond workers and migrants from Uttar Pradesh and Bihar get paid between INR 5000 and INR 20,000 to take part in bioequivalence trials – sums large enough for them to put money over personal safety. Indeed, trial participants may be both financially and socially vulnerable. It is reported that Surender, who died in the Hyderabad felodipine trial, was one of a number of Dalit students being recruited for clinical trials in that city. Likewise, some years ago, a 22-year-old Adivasi youth died in a bioequivalence trial of the antidepressant citalopram by the Sun Pharma Advanced Research Centre in Vadodara.

Certain types of trials are more likely to be conducted in India and other countries where regulatory and monitoring mechanisms are weak, or regulators are too willing to please drug companies. The use of placebos is a good example, as it is not difficult to conduct placebo trials in India. In 2005-06, Indian patients with schizophrenia were taken off their regular medication and given either a new, ‘extended-release’ formulation of an approved drug (quetiapine, marketed by AstraZeneca) or a placebo, to compare the time it took for people in each group to have a relapse attack of schizophrenia. The trial was conducted by a Contract Research Organisation (CRO) called Quintiles, in India as well as a number of countries in Eastern Europe. One patient (not in India) who was on the placebo committed suicide. Experts are unanimous in their view that a placebo was methodologically unnecessary in that trial, as the new formulation could have been compared to the existing ‘immediate-release’ drug. But the European regulators required a placebo-controlled trial, noted Irene Schipper and Francis Weyzig of the Dutch research organisation Centre for Research on Multinational Corporations, in a 2008 report. They also argued that placebo-controlled trials for severe conditions, which put the participants at greater risk, are more likely to be conducted in developing countries.

Trials in government hospitals in India can also be of special concern. In one trial, 290 people who had been hospitalised because they were having a severe attack of acute mania were given either a drug (risperidone, marketed by Johnson & Johnson) or a placebo. The idea, of course, was to examine how many people recovered with the drug, and how many with the placebo. This subjected seriously ill people to harm. The majority of patients in this India-only trial, also conducted by Quintiles, were recruited from government hospitals where, according to the principal investigator of the trial, the most seriously ill patients could be found. It is also where patients can be recruited easily, because trial participation ensures a hospital bed and free, quality treatment.

Another concern about trials in government hospitals is that they are conducted on poor people who may have no access to the drugs tested on them after the trial is over. In August 2008, the media reported that 49 children died in 42 clinical trials that were conducted over two and a half years in the Department of Paediatrics at the All India Institute of Medical Sciences (AIIMS) in Delhi. An investigation ordered by the National Human Rights Commission concluded that the trials were conducted properly: the children in the trials were seriously ill, and all the deaths occurred because of the serious illnesses, not the treatments. However, the committee’s report left many questions unanswered. What, for instance, was the purpose of these trials? Would they help other poor children in India?

One of these trials tested the blood-pressure drug valsartan, supplied by its manufacturer Novartis. Paediatric hypertension is indeed a serious condition, but companies conduct paediatric trials for various reasons, including to get information for the benefit of doctors who prescribe the drug to children. Another reason is because the US FDA extends a drug’s exclusive marketing rights when it is tested on children; this provision is meant to encourage research on children who are otherwise prescribed drugs based on the results of research on adults. However, companies also use this clause to maximise their profits. Another trial was linked to gene-activated human glucocerebrosidase, a treatment for Gaucher’s disease, a serious genetic condition in which a fatty substance (lipid) gets deposited in cells and specific organs. The drug for this trial was provided by the US-based Shire Human Genetic Therapies. Will the drug be made available in India once it is proved effective? Both the Helsinki Declaration and the ICMR’s guidelines emphasise that a community on which a drug is tested should have access to the drugs, if proven effective, once the trial is over. Unfortunately, this is rarely the case. Although all of the new drugs being tested in India will indeed be available in India, this will be at prices unaffordable to the very people who agree to have them tested on their bodies.

More generally, but of no less concern, AIIMS has stated that the trials did not “target” children from poor backgrounds. But there is no need to target poor people at AIIMS – they constitute the majority of patients at this government referral hospital. The simple fact is that the vast majority of people seeking care at the AIIMS centre would be there because they cannot afford treatment elsewhere.

Body market
The pharmaceutical industry depends on constantly getting new drugs into the market. New drugs include new uses for old drugs (a cancer drug that can also be used for infertility?) or ‘improved’ or ‘me-too’ versions of older drugs (all those antacids, blood-pressure and cholesterol-lowering drugs, anti-depressants or antibiotics). These drugs must be tested on human beings before they can go into the market. Permission has to be obtained, patients have to be recruited, trials carried out and the results filed – all at top speed, because time is money.

This is where the Contract Research Organisation – the CRO, such as GVK Biotech referred to earlier – steps in. The CRO undertakes all aspects of the process involved in getting regulatory clearance: getting the necessary permissions, tying up with doctors and hospitals to recruit patients on whom the drugs are to be tested, analysing the data that emerges from the trials, monitoring the trial to make sure that the information collected meets standards, putting together reports and even ghostwriting articles for publication in medical journals. Of course, the most important aspects of all this is the recruitment of patients. The best place to recruit patients for, say, a diabetes-drug trial, is a country with a large diabetic population. And diabetics who have not received treatment make better trial subjects, as the results of drugs tested on them will not be ‘contaminated’ with the results of drugs that they have already used.

Clinical trials in developing countries depend not only on physical infrastructure – hospitals and laboratories – and trained human power. They also depend on drug companies getting access to bodies on which they can test their drugs. So, CROs in India market Indian bodies. In a 2006 advertisement on their website (which has since been removed), a CRO named Igate advertised the ‘India advantage’ as “40 million asthmatics, about 34 million diabetics, 8-10 million people HIV positive, 8 million epileptic patients, 3 million cancer patients.”

CROs in India all claim to have ‘access’ to patients with various health problems for which drugs can be tested. For instance, a research group called Veeda claims to have “access to vast patient populations and has specific expertise in recruiting patients with cardiovascular disease, oncology, diabetes, renal disease”. The CRO Quintiles India once boasted that, for a paediatric-flu-vaccine trial, it recruited 201 one- to three-year-olds from three sites in India in just six days. What kind of network does Quintiles have, and what kind of influence does it have with the medical profession, that it can round up 200 children and convince their parents to let them get an experimental flu shot – all in just six days flat?

It seems that at least some of this is able to take place through wilful misinformation. Spectrum Clinical Research specialises in recruiting patients, collecting patients through networks of private clinics, hospitals, specialists and family physicians. It also runs ‘awareness campaigns’ – for instance, a “white ribbon initiative” on osteoporosis, co-organised with the women’s magazine Femina of the Times of India stable, collected data on 2000 patients with osteoporosis. Another campaign, this time to “defeat diabetes”, collected data on 1000 patients with diabetes. In these ways, people who think they are joining patient-support groups are actually being tracked so they can potentially be put on a trial.

Behind a veil
Other than the boasts of CROs, there is little information available on the hundreds of clinical trials being conducted in India. This is despite the evidence that many of these trials are conducted for the benefit of international drug companies, at unacceptable cost to the local population; that trial subjects could be put at risk; that subjects often have not given their informed consent to participate; that they might be provided care that is of lower quality than if they had been recruited for a trial in the West; that injuries during a trial might not be investigated thoroughly, and that those injured may not receive treatment of the highest standard, or even compensation; and that drugs that are tested are often too expensive for people who need them in India.

The only institution to have direct power over the conduct of a trial is the ethics committee (EC). Research institutions appoint their own institutional ethics committee to conduct an ethics review of all research proposals from within the institution. Independent or freelance ethics committees undertake ethics review for a fee, from anyone who applies – usually the CRO or drug company who coordinates the trial at a number of small nursing homes or private clinics, which don’t have their own ethics committee. The EC is a collection of specialists from various fields who review trial documents, including the trial design, the manner in which subjects are recruited, the patient information sheet and the informed-consent form, and approve or reject the application. These committees also have the authority to investigate a trial, and even to stop it if they feel that something is not right.

Ethicist Amar Jesani points out that ethics committees have a lot of power, as the DCGI requires that all trials be passed by such an appointed group. In fact, the DCGI only requires approval by an ethics committee, since it does not monitor the actual conduct of the trial – it does not check that informed consent is taken, that the investigators do their job correctly, that subjects are not harmed, and so on. Thus, says Jesani, it is the ethics committee, not the DCGI, that is the real regulator of clinical trials.

Yet the effectiveness of an ethics committee depends entirely on the setting in which it functions. Important factors, for instance, include the institution that funds the committee’s work or that determines its level of independence, the training of its members, and their competence in terms of doing a proper ethics review. Likewise ‘independent’ or freelance ethics committees are more accountable to the companies that pay for their services. Even the patient information sheet and informed-consent document are treated as confidential documents by the ethics committee – and, of course, the trial’s sponsor. These contain the information on the purpose of the trial, its risks and benefits, and an assurance that a patient’s treatment will not be jeopardised by refusal to participate, or withdrawal from a trial. There is nothing here of proprietary value – on the contrary, everything in these documents is of public interest, and they should be available to the public. Ethics committees are also often poorly educated in their responsibilities.

The reports of people dying in trials are likely to be merely the tip of the proverbial iceberg. And many more are likely to suffer an injury related to the trial drug, injuries that require treatment and that could result in temporary or permanent disability. Indian guidelines require that trial participants be compensated for injuries suffered during research. However, a study by Urmila Thatte and others in a 2009 issue of the UK-based Journal of Medical Ethics found that many trial investigators as well as ethics committee members are not even aware of this requirement. The guidelines of trial sponsors – such as drug companies – provide for medical treatment of any participant who suffers a trial-related injury, or reimbursement of their medical costs. However, Thatte and her colleagues found that none of the companies sponsoring trials, or ethics committees reviewing their trials, had a policy of compensation for trial-related disability or death. Yet for ethics committees to be a law unto themselves is hardly surprising, given the overall environment of lax regulation and monitoring.

Now, the FDA’s decision to do away with the Declaration of Helsinki will create a dilemma for the DCGI. If CROs in India are to follow the FDA requirements – such as using a placebo even when it is not absolutely necessary, and when it might put subjects at risk – they will be violating Indian regulations, which require that the Declaration of Helsinki be followed. The latest revision of the Declaration is quite clear that the placebo may be used in very few circumstances. At the moment, however, the DCGI’s record – permitting a number of unethical trials – suggests that his office places greater value on the potential financial returns of clinical trial outsourcing than on protecting the people who take part in drug trials in India.

Sandhya Srinivasan is a Bombay-based journalist specialising in public health and development issues. She is executive editor of the Indian Journal of Medical Ethics.

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PROZAC: Man Hallucinates for Two Weeks: U.S.A.

Paragraphs 2 and 3 read: “I had a bout of hallucinations about 10 years ago. I was suffering quite badly with depression and had been on anti-depressants for years. Then came along Prozac®. The doc thought they would be good so off I went!

The three stages of my hallucinations always happened at night and in bed. I had always been asleep for a while and was awakened by the goings on. They happened in quite quick succession, perhaps over the space of two weeks, then stopped.

http://www.clusterflock.org/2009/08/dear-clusterflock-have-you-ever-hallucinated.html

August 1, 2009

Dear Clusterflock: Have you ever hallucinated?

I had a bout of hallucinations about 10 years ago. I was suffering quite badly with depression and had been on anti-depressants for years. Then came along Prozac®. The doc thought they would be good so off I went!

The three stages of my hallucinations always happened at night and in bed. I had always been asleep for a while and was awakened by the goings on. They happened in quite quick succession, perhaps over the space of two weeks, then stopped.

1. I woke violently as a tiger jumped from sitting above the bedroom door, onto my pillow and then jumped up onto a shelf (which didn’t exist in reality) above the bed. I woke my wife, quite calmly pointed out said tiger, but was told to return to sleep as there wasn’t one. He only appeared once.

2. I woke to see a man standing in the doorway of the bedroom — that would have been about 4 feet from me. He didn’t scare me. I came around slowly to see him standing there. I don’t remember colour — I do remember him being an Abe Lincoln type ­ stovepipe hat, and a beard. He wasn’t moving. I woke my wife and asked her quite calmly if she could see the man stood in the corner ­ she could not. I lay there for a while looking at him, closing my eyes and opening them. He stayed for a while and then left.

He returned for quite a few nights. He was always in the same place, always in monochrome and he never spoke. Unfortunately, I never spoke to him.

3. I woke one night. I was lying on my back, and as I looked up at the ceiling it was alive with a sea of frogs ­ all moving as one. I again woke my wife ­ just for the reality check. They stayed until I closed my eyes, say 20 minutes, then disappeared.

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DEPRESSION MED: Violence: Man Beats Up Frail Neighbor: England

Fourth paragraph from the end reads: “Rod Hunt, in mitigation, said his client had been mixing alcohol with anti-depressant tablets, which had made him turn violent.”

Paragraphs four & five read: “In a letter to the court, Mr Hodgson described Summersgill as a decent man and said the brutal assault was out-of-character.”

“The pair were friends at the time, and Summersgill and his partner, Heather Barnett, acted as carers for their neighbour.”

Paragraphs seven & eight read: “Paul Newcombe, prosecuting, said that without warning, Summersgill turned to his housebound friend and said he would kill him.”

“He then grabbed him by the throat and squeezed tightly as he pushed him onto a bed in his front room.”

SSRI Stories Note: The Physicians Desk Reference states that antidepressants can cause a craving for alcohol and alcohol abuse. Also, the liver cannot metabolize the antidepressant and the alcohol simultaneously, thus leading to higher levels of both alcohol and the antidepressant in the human body.

http://www.thenorthernecho.co.uk/news/4515923.Man_jailed_for_threats_to_kill_frail_neighbour/

Man jailed for threats to kill frail neighbour
1:06pm Tuesday 28th July 2009

By Neil Hunter »

A DRUNK who throttled a wheelchair- bound neighbour after threatening to kill him was yesterday jailed for four years.

Paul Summersgill left the frail pensioner on the floor of his home and stole his mobile phone and spectacles before fleeing.

Teesside Crown Court heard that Bernard Hodgson, 65, blacked out during the attack, which left him covered in wounds and bruises.

In a letter to the court, Mr Hodgson described Summersgill as a decent man and said the brutal assault was out-of-character.

The pair were friends at the time, and Summersgill and his partner, Heather Barnett, acted as carers for their neighbour.

On the day of the attack, April 9, Summersgill had been at Mr Hodgson’s home watching television and drinking his beer.

Paul Newcombe, prosecuting, said that without warning, Summersgill turned to his housebound friend and said he would kill him.

He then grabbed him by the throat and squeezed tightly as he pushed him onto a bed in his front room.

On the brink of consciousness, Mr Hodgson then had his face pushed into a pillow.

Summersgill then loosened his grip and took the phone and glasses.

After a short time, Summersgill threw a chair at Mr Hodgson, knocking him to the floor.

Mr Newcombe said: “He then straddled him, using his knees on the victim’s shoulders to pin him to the floor. He again put his hands around the victim’s throat, strangling him and striking him repeatedly across the face.”

Rod Hunt, in mitigation, said his client had been mixing alcohol with anti-depressant tablets, which had made him turn violent.

Summersgill, 34, of The Bungalows, Grangetown, Middlesbrough, admitted wounding with intent to cause grievous bodily harm.

The court heard that last year he throttled his girlfriend, now pregnant, until she lost consciousness.

Judge Tony Briggs, who described Mr Hodgson’s supportive letter as “unusual and extremely generous”, said: “It was a nasty, vicious attack and custody is inevitable.”

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DEPRESSION MED: Talk Radio Show Host Fired for “Wacky” Personality Change…

Paragraph two reads: “The Hammer, sacked by ESPN Radio in May partly because of a couple of wacky nights he blamed on a change in depression medication, will sit in with Big Dick the next couple of afternoons 4-6 p.m. – today, Friday, Monday and Tuesday, to be exact – on Rational Radio KMNY 1360 AM’s and see where this thing goes.”

http://blogs.dallasobserver.com/sportatorium/2009/07/breaking_news_greg_williams_ta.php

BREAKING NEWS: Greg Williams, Take III
By Richie Whitt in Radio, TV and that Damned Media
Thursday, Jul. 2 2009 @ 7:00AM

Welcome back.

If you were surprised by Greg Williams’ cameo on with Richard Hunter yesterday afternoon, you haven’t been paying attention.

The Hammer, sacked by ESPN Radio in May partly because of a couple of wacky nights he blamed on a change in depression medication, will sit in with Big Dick the next couple of afternoons 4-6 p.m. – today, Friday, Monday and Tuesday, to be exact – on Rational Radio KMNY 1360 AM’s and see where this thing goes.

No defined role, and the gig is somewhere comfortably between a tryout and full-time. It’s the Wild Ass Circus, so who knows?

“It’s the talk radio equivalent of a jam session,” Hunter told me last night. “We wanted to do it before he went to ESPN, but he had a contractual conflict.”

I know this: Williams should be – and is – thankful to have a friend like Richard Hunter.

First, BDH invited him to be a groomsman in his wedding at this jumpin’ joint in Las Vegas. And now – you listening, Ticket boys? – when Williams needs a friend in the business Hunter is doing the opposite of turning his back on an old buddy.

I know, what a concept.

“There are two guys that I owe for my break in radio, and I will always have a place for either one of them to join me on air,” says Hunter. “Hammer’s one of them, and the other one is his former partner. I owe both those guys big time.”

No, I don’t think he’s referring to RJ Choppy.
Tags: Big Dick Hunter, Greg Williams, radio

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Strattera Deaths (German TV Request) False Reports from Eli Lilly

Wed Nov 12, 2008

We have received a request from a German TV crew who is doing a special on Lilly’s newer ADHD medication, Stratera. These investigative reporters from Germany are doing a 45 minute piece and looking for experiences of tragedy /suicide or severe adverse reactions in children treated for ADHD with this drug. I know we have had reports, but I do not keep close track anymore of which drug is involved after so many cases because all these drugs work basically the same way. An antidepressant is an antidepressant no matter what you callmit or what you prescribe it for or how you explain its supposed uniqueness. So if you or someone you know has been through a Strattera-induced nightmareand would be willing to help get some exposure of this in the press, please get in touch with me so that I can put you in touch the reporters.

O nce you read the following article on Strattera deaths you will see how very important it is to get information about this drug out to the public –

especially throughout the UK and Europe. What is going on here IS CRIMINAL!!
And here is just one example out of the article below that is full of data on how
the government agency in the UK who oversees these drugs is ignoring
critical information – even fatalities, and doing NOTHING but making excuses
for their own behavior:

MHRA has for almost three years been in possession of data showing that
Strattera in many cases actually can cause or worsen the œcondition it is
claimed to alleviate. More than 700 reports were submitted to the manufacturer,
Eli Lilly, about Strattera inducing “œpsychomotor hyperactivity. Lilly called
this an exacerbation of the “œunderlying ADHD”. If we would apply this to
the area of real medicine and to diabetes we could say that the patient got a
diabetes medication with resulting heavy increase in blood sugar level. Such a
medication would probably be withdrawn very fast from the market. But the
MHRA has not yet, after three years, succeeded to get even a bad quality review
of these cases done not even from the manufacturer.

Do read the rest of the information because it is clearly eye opening!! This
newer ADHD drug, Strattera, which is really an SSRI antidepressant, is
getting away with murder right under everyone’s noses. So definitely if you
know someone who is willing to talk to this news crew about their experience with
this drug, please do let me know ASAP.

Thank you,

Ann Blake-Tracy, Executive Director,
International Coalition for Drug Awareness
_www.drugawareness.org_ (http://www.drugawareness.org/) &
_www.ssristories.org_ (http://www.ssristories.org/)
Author of Prozac: Panacea or Pandora? – Our
Serotonin Nightmare & the audio, Help! I Can’t
Get Off My Antidepressant!!! ()

_atracyphd1@…_ (mailto:atracyphd1@…)

_http://www.newmediaexplorer.org/sepp/2008/10/20/strattera_adverse_effects_uk_
medicines_agency_refuses_to_act.htm#_
(http://www.newmediaexplorer.org/sepp/2008/10/20/strattera_adverse_effects_uk_me\
dicines_agency_refuses_to_act.htm#
)

October 20, 2008
_Print this article_
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Strattera adverse effects: UK Medicines Agency refuses to act
By Sepp Hasslberger

Categories
_Pharma_ (http://www.newmediaexplorer.org/sepp/pharma.htm)

Janne Larsson, an investigator and reporter in Sweden, has obtained
information about adverse event reports on Eli Lilly’s ADHD drug Strattera,
using the Swedish freedom of information laws. The data, coming from both the FDA’s
adverse reaction database and from reports to the UK’s Medicines agency, shows
numerous adverse effects and scores of deaths by suicide.

Yet the agency, even after repeated prodding by Larsson to initiate action,
has refused to budge or even acknowledge that there is a problem. MHRA
apparently accepts the drug’s producer Eli Lilly’s data rather than its own and
the
FDA’s adverse event reports.

Image credit: _Monheit Law_
(http://www.monheit.com/strattera/contact_lawyer.asp)

Larsson says: An investigation of MHRA™s handling of the harmful effects of
the ADHD drug Strattera has proven the following:

MHRA has ignored data about instances of death among children in connection
with Strattera treatment. At least 41 children have died. The agency has not
investigated the reported cases and does not even have a compiled summary of
cases with fatal outcome. Further the agency has allowed the manufacturer Eli
Lilly to give false information about the number of fatal cases and has
taken no action against the company once the false information was revealed.

MHRA has for almost three years been in possession of data proving that
Strattera can cause agitation, mania and psychotic reactions with hallucinations
among children. Yet no warning has been issued to doctors and parents. The
agency has withheld these disastrous consequences despite clear evidence. Due
to bureaucratic procedures no warnings have been issued even if Eli Lilly reluc
tanly conceded to include these harmful reactions in its information to the
public almost a year ago.

MHRA has for almost three years been in possession of data showing that
Strattera in many cases actually can cause or worsen the œcondition it is
claimed to alleviate. More than 700 reports were submitted to the manufacturer,
Eli Lilly, about Strattera inducing œpsychomotor hyperactivity. Lilly called
this an exacerbation of the œunderlying ADHD. If we would apply this to
the area of real medicine and to diabetes we could say that the patient got a
diabetes medication with resulting heavy increase in blood sugar level. Such a
medication would probably be withdrawn very fast from the market. But the
MHRA has not yet, after three years, succeeded to get even a bad quality review
of these cases done“ not even from the manufacturer.
The background data for these conclusions can be found in the following text
and in the linked documents. When reading the data below please remember the
promise from the MHRA: we take any necessary action to protect the public
promptly if there is a problem._MHRA, About us_
(http://www.mhra.gov.uk/Aboutus/index.htm) [1]

Note that the linked documents (within letters described below) in most
cases could not be obtained in UK where the issuance of them would be deemed as
prejudicing œthe ability of the Assessory body to offer impartial advice and
where the MHRA wants to allow marketing authorisation holders the chance to
respond to regulatory action and make commercial decisions before data are
in the public domain. (MHRA, e-mail about FOIA-request, 29th September,
2006). However the documents could be obtained in Sweden, even if the MHRA has
tried to stop the issuance of them by implying that publication could threaten
the relations between Sweden and UK.
Deaths among children in connection with Strattera treatment

In May I submitted detailed data about cases of Strattera death to the MHRA.
1st October I finally got an answer from the Scientific Assessor of the
Vigilance and Risk Management of Medicines (VRMM). 7th October I got an answer
from Professor Kent Woods, CEO of the MHRA, referring to the letter sent by the
Scientific Assessor.

My data about Strattera deaths can be found _in the letter_
(http://jannel.se/Strattera.death2.pdf) Strattera: Eli Lilly gave false
information about
deaths from Strattera treatment “ a request for full investigation from 15th
May. [2]
The answer from the Scientific Assessor shows that MHRA is continuing to
ignore data about instances of death among children and adults in connection
with Strattera treatment. Despite limited resources and having to rely on data
released by reluctant medical agencies I had been able to produce a summary of
reported cases of Strattera death. Thats much more than the MHRA, with its
immense resources, had been able to do.

The agency was provided with specific data about instances of death forming
an excellent starting point for a full investigation. But instead of using
the data the MHRA used its energy to explain why it is impossible to
investigate these cases further, and in doing so presents some remarkable
comments.

The Scientific Assessor states _in the letter 1st October_
(http://jannel.se/Reply.from%20MHRA.Assessor.October.pdf) [3]:

in order to calculate the total number of reports with a fatal outcome
it is not simply a case of adding up reports with a fatal outcome mentioned
in our assessment reports of the PSURs [Periodic Safety Update Reports] and
those available on the FDA website as these different sources may contain
duplicate information. [Emphasis added.]

I fully agree and it takes only a casual reading of my letter from 15th May
to find out that much care has been taken to exclude possible duplicates. It
is quite easy to see that the data presented about fatal cases in my letter
is NOT simply a case of adding up reports with a fatal outcome. The only
way to come to another conclusion would be not to look in the first place and
it is a condemnation of the effectiveness of the agency to state the following
in the letter:

We have looked at the data you have sent us to see if they can add insight
to the statutory sources of data we have received and do not think that they
are of benefit as we cannot verify their source or accuracy. (p. 3)
[Emphasis added.]

I must add to all the data provided in my letter 15th May that the our

of the information about fatal cases is FDA™s Medwatch system and the PSURs
(submitted directly to the MHRA). I must make it clear that is very easy for
a lay person to find out that almost all reports about fatal outcome from
Strattera treatment submitted to the FDA came from Eli Lilly!

Thus the our of the information about fatal cases was in most of the
cases the manufacturer itself“ Eli Lilly. And yet the MHRA has not been able
to verify the source or accuracy of the information. The MHRA Scientific
Assessor states in the letter:The sources of data that regulators use such
as company data, spontaneous adverse reaction reports and literature are set
out in European and national law.
My FOIA request earlier this year to get a compilation of fatal cases in
connection with Strattera treatment was answered 12th August:

Thats very good and now we know that the data I submitted to the MHRA about
all fatal cases from Strattera treatment “ in the absolute majority of cases
were known by and reported via the manufacturer Eli Lilly.
The MHRA holds no data other than that previously released to you [the
misleading data from Eli Lilly in November 2007, see my letter from 15th May
for
more data] which was the data provided by the company. If you have any
questions about FDA data or the data provided by the company, you should
contact those organisations.

In other words the MHRA didn’t have a compiled summary of cases with fatal
outcome in August and the agency has not to this point been able to compile
such a summary.

As the agency has not been capable of getting the data or not even been
capable of using the specific data submitted for its use in a full
investigation NO action is taken despite the many verified deaths among
children in connection with Strattera treatment. This disregard for the safety of children is a scandal which should lead to a full formal investigation by the
Department of Health.

Drug induced agitation, mania and psychosis with hallucinations

Ive been contacted by parents asking if Strattera can induce mania and
psychosis with hallucinations. Their children have had such symptoms. The
parents have not found any warnings about it and their childrens doctors don’t
think that the symptoms are caused by the drug. The parents were desperate.

However the MHRA has known for almost three years that Strattera can cause
agitation, mania and psychotic reactions with hallucinations among children,
but has refused to issue warnings about it.

The Scientific Assessor from the MHRA _in the letter of 1st October_
(http://jannel.se/Reply.from%20MHRA.Assessor.October.pdf) [3] now confirms my
earlier arguments that the agency had knowledge about these effects a long time ago:

following an initial request in the assessment report for the Periodic
Safety Update for the period (dates 27-05-2005 to 26-11-2005) we asked Eli
Lilly for more information to enable us to review this issue in more detail. (p. 2)

This means that in the period ending 26th November, 2005 at the time when
Strattera was approved only in UK and four other European countries, but not
in the 22 additional European countries where it is now approved Eli Lilly
and the MHRA had knowledge about these disastrous effects in children taking
Strattera. But neither the MHRA nor Eli Lilly told anything about it and
Strattera was approved in 20 additional European countries in April 2006.
Image credit: _Wikimedia Commons_
(http://commons.wikimedia.org/wiki/Image:Strattera_atomoxetin.jpg)

Professor Kent Woods, CEO of the MHRA seems to be very misinformed by his
staff when answering about Strattera in a recent _letter of 7th October, 2008_
(http://jannel.se/answer.kent.woods.pdf) . In the letter Professor Woods
states [4]:

The MHRA is committed to ensuring that all safety concerns are subject to
robust scientific assessment and the best possible regulatory action is taken
in a timely manner. We strive to maintain the highest standards of work and
review our practices to ensure these standards are maintained or improved
upon where necessary. (p. 1)

In their 3rd March, 2006 report Psychiatric Adverse Events Associated with
Drug Treatment of ADHD: Review of Postmarketing Safety Data [5], the FDA
stated that there was compelling evidence for a likely causal association
between [Strattera/amphetamine drugs] and treatment emergent onset of signs and/or
symptoms of psychosis or mania, notably hallucinations, in some patients.

(p. 17) 360 reports about the drug inducing these effects had been received
up to June 2005.

From this FDA report the MHRA had knowledge about the œcompelling evidence for Strattera causing these effects on or about 3rd March, 2006 but did nothing.

In August the same year (2006) the MHRA requested the same data set from Eli
Lilly that was submitted to the FDA and which formed the basis of the FDA
report for Strattera. The data was sent to the MHRA some days later. But the
agency then decided not to do anything with the information. Instead it was
decided that Eli Lilly the manufacturer should do an analysis of the data
and submit its conclusions to the agency.

Professor Kent Woods says in his letter: An important aspect to this [ robust scientific assessment, highest standards] is ensuring that data from all available sources have been consider This may be true in some other area but it is definitely not true for the
safety work around Strattera. A very good example of this is the complete
rejection of the robust scientific assessment of Strattera in the FDA report.
Answering the question why the agency did not use the compelling evidence for harm in the FDA report _an official at the MHRA declared in a letter_
(http://jannel.se/mhraanswer.pdf) [6]:

Changes to European product information are based on assessment by EU
regulators, agreement between member states and in line with legal requirements
about product information, not on conclusions of FDA assessors. (25th May,
2007) [Emphasis added.]

Responsible officials at the MHRA had instead decided to rely completely on
the analysis of the manufacturer of the drug Eli Lilly. (In an article in
the Daily Mail this summer, Andrew Herxheimer, editor of the Drug and
Therapeutics Bulletin, and emeritus fellow of the Cochrane Centre commented:
Asking a drug company to review its own product is crazy, but it goes on quite a lot.
) [7]

At the end of 2007/beginning 2008 Eli Lilly submitted its review of
Strattera induced agitation, mania and psychosis with hallucinations to the
MHRA. It was a complete whitewash.

In summary: FDA was very clear about the psychosis-inducing effects of
Strattera; the MHRA did not listen. Instead the MHRA turned to the
manufacturer. Eli Lilly tried to explain away all the bad results found in its review. For
the full history about MHRA’s failure in this area and for a comparison of
the FDA report with the Lilly report, please see the following letter: _The
ADHD drug Strattera“ actions needed now_
(http://jannel.se/letter.mhra.strattera.jan08.pdf) [8] from January 2008, and
the letter _The ADHD drug Strattera“
an analysis of reports of drug induced mania, psychosis and hallucinations_
(http://jannel.se/strattera.mhra.March.08.pdf) [9] from March 2008.

In the letter from March [9] Eli Lilly’s whitewash report for the period up
to November 2007 is presented. At the end of that report Lilly says [10]:

Nevertheless, Lilly will consider adding language regarding psychotic symptoms
including hallucinations to its product information sheet. (p. 1279)

Larsson – _Suicides & Psychiatric Drugs_
(http://www.newmediaexplorer.org/sepp/suicide.psychiatricdrugs.pdf)

And so we come to October 2008 and the letters from Professor Kent Woods and
from the Scientific Assessor for Strattera. We are reassured that the MHRA
is acting to ensure that Strattera is used as safely as possible that

all safety concerns are subject to robust scientific assessment and the best
possible regulatory action, that any new safety signals are evaluated in
an independent, scientifically robust manner (Woods); we are told that

discussions between European Member States and Eli Lilly are ongoing to agree
on the most appropriate information to be included in the product information
for patients and prescribers; we are told to be patient, to understand that
it takes time from the point where œupdates have been agreed for inclusion in
the product information to the point where these will appear in the packs
in the market place due to movement of stock in the supply chain, and that
the appearances are estimated to be within the next 6 months (Scientific
Assessor).

It is probably hard to find a more obvious violation of the promise¦ we
take any necessary action to protect the public promptly if there is a
problem than the case described above. The worried parents still have no answers if
Strattera can induce the symptoms they find in their children. And the MHRA
knew about it three years ago but withheld the data. This should be
included in the investigation of the agency by the Department of Health.

Strattera causing hyperactivity“ the condition it was supposed to alleviate In my earlier letter to the Department of Health (29th August) I took up the data about the 700 forgotten cases of hyperactivity. I referred to my _letter 2nd January to the MHRA_
(http://jannel.se/letter.mhra.strattera.jan08.pdf) [8] and gave data about the
fact that Eli Lilly had withheld sensitive information and classified harmful effects as an exacerbation of the underlying ADHD.

The logical solution would have been for the MHRA to request all data about
this security risk, followed by an independent review of the data. But this
was not done and as expected nothing is still done. MHRA asked Lilly for an
explanation about this signal stemming from Periodic Safety Update Report
5 (dates 27-05-2005 to 26-11-2005) but got no answer. Three years later the
Scientific Assessor from the MHRA writes in the letter from 1st October:

The information submitted by the MAH [Market Authorization Holder] has been
evaluated and the MAH will be requested to provide further detailed
information within the next 2 months to ensure the issue has been investigated
in a thorough and scientific manner. (p. 2) [3]

The MHRA got this safety signal almost three years ago and is still in
the process of getting some sensible answers from Eli Lilly.

————

I again request the Department of Health to take action. This does not
concern only the children in UK; it concerns the children in the whole of
Europe, indeed it concerns all the children of the world.

The failure of the agency will also mean that psychiatrists within The
Guideline Development Group in NICE can push through more treatment with
Strattera and other ADHD drugs. The MHRA is withholding the clear evidence for
harmful effects and the psychiatrists with close relations to the manufacturers
of the drugs can unimpeded recommend these medicines to unsuspecting
doctors and parents.

The answers given by Professor Kent Woods and the Scientific Assessor did
not in any way handle my concerns. On the contrary, they finally proved that a
full formal investigation of the matters raised above is needed.

Yours sincerely,

Janne Larsson

Reporter – investigating psychiatry
Sweden
_janne.olov.larsson@…_ (mailto:janne.olov.larsson@…)

[1] MHRA, About us, _http://www.mhra.gov.uk_ (http://www.mhra.gov.uk/)
[2] Larsson, Strattera: Eli Lilly gave false information about deaths from
Strattera treatment“ a request for full investigation, May 15, 2008,
_http://jannel.se/Strattera.death2.pdf_ (http://jannel.se/Strattera.death2.pdf)
[3] MHRA, Re: letter of 9th September 2008 to “Assessor responsible for
Strattera, October 1, 2008,
_http://jannel.se/Reply.from%20MHRA.Assessor.October.pdf_
(http://jannel.se/Reply.from%20MHRA.Assessor.October.pdf)
[4] MHRA, Re: Open letter to Pr. Kent Woods (10th August 2008), October 7,
2008
_http://jannel.se/answer.kent.woods.pdf_
(http://jannel.se/answer.kent.woods.pdf)
[5] FDA, Psychiatric Adverse Events Associated with Drug Treatment of ADHD:
Review of Postmarketing Safety Data, released March 3, 2006.
_http://www.fda.gov/ohrms/dockets_
(http://www.fda.gov/ohrms/dockets/AC/06/briefing/2006-4210b_11_01_AdverseEvents.\
pdf
)
[6] MHRA, answer FOI request, May 25, 2007,
_http://jannel.se/mhraanswer.pdf_ (http://jannel.se/mhraanswer.pdf)
[7] Daily Mail, Heart attacks and suicides… yet the dangers were all kept
so quiet. So how CAN you trust your medicine? July 7, 2008,
_http://www.dailymail.co.uk/_
(http://www.dailymail.co.uk/health/article-1033132/Side-effects-include-suicide-\
heart-attacks-So-prescribed-drugs.html
)
[8] Larsson, The ADHD drug Strattera – actions needed now, January 2, 2008,
_http://jannel.se/letter.mhra.strattera.jan08.pdf_
(http://jannel.se/letter.mhra.strattera.jan08.pdf)
[9] Larsson, The ADHD drug Strattera – an analysis of reports of drug
induced mania, psychosis and hallucinations, March 9, 2008,
_http://jannel.se/strattera.mhra.March.08.pdf_
(http://jannel.se/strattera.mhra.March.08.pdf)
[10] Eli Lilly, Cumulative review of Spontaneous Case Reports of Mania,
Psychotic Disorders, Hallucinations, and Agitation, Appendix 16 to Periodic
Safety Report 9 for Strattera, 2008,
_http://jannel.se/Lilly_psychosis_strattera.pdf_
(http://jannel.se/Lilly_psychosis_strattera.pdf)

See also:

_Doctors told to curb use of Ritalin in hyperactive children_
(http://www.timesonline.co.uk/tol/news/uk/science/article4813727.ece)
_Children’s suicide attempts raise concerns about ADHD medication_
(http://www.theglobeandmail.com/servlet/story/RTGAM.20080703.wadhd03/BNStory/spe\
cialScie

nceandHealth/home)
_The ADHD drug Strattera: Lilly to issue warnings about psychosis,
hallucinations, mania and agitation_ (http://jannel.se/strattera.psychosis.doc)
_Strattera side effects_ (http://www.bonkersinstitute.org/stratteraffex.html)

_Strattera – 10,988 adverse “psychiatric reactions” reported in less than
three years_ (http://www.24-7pressrelease.com/view_press_release.php?rID=16662)
_Attention Deficit Hyperactivity Disorder? No, they’re just naughty, say
experts_
(http://www.dailymail.co.uk/news/article-1031436/Attention-Deficit-Hyperactivity\
-Disorder-No-theyre-just-naughty-say-experts.html#
)

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Withdrawing from a Decade of Drugs

“I have a few shopping bags full of drugs given to my son.”

Dear Ann Blake Tracy,

I don’t really know where to begin but I will try. Your website is incredible and anyone thinking of letting the psychiatric system help a loved one or any human for that matter should read your books, listen to your tapes and fine comb your website.

Our horror story began in 1995 and hasn’t stopped as of today Jan. 04, 2004. Our son (only child) is still withdrawing from the treacherous side effects of all the drugs given to him mostly by force throughout the last 10 years.

He is now 29 years old and having missed 10 years of living and learning is just starting to show signs of life.

Watching him almost die in front of me has taken a toll of my body and brain and we are recovering from this ordeal. Unlike many others who have lost their loved ones to these pretentious rehabs and treatment centers has endlessly aged and stolen time from our families happiness and our lives.

I have a few shopping bags full of drugs given to my son. There are hundreds of containers of Luvox, Prozac, Buspar, Ativan, Paxil, Celexa, Thorazine, Mellaril, Serentil, Prolixin, Haldol, Risperdal, Zyprexa, Stool Softeners and many others I cannot remember. In fact I had to take a breather remembering all these poisons.

The suicide attempts and induced anger created by these cocktails of poisons is unspeakable. People who do not understand the routine drugging regime of humans who get caught up in this system need to be informed before we have nothing but drugged humans living on this earth.

There are no quick fixes for human feelings and no drug will prevent anyone from feelings we are born to feel.

We know what Tardive Dyskinesia looks like and we know what acute Akathisia is all about and Tardive Dystonia. We have spent endless nights in emergency rooms and hospitals only to see our son drugged and misunderstood like the others who happen to be locked up at the same time. We have met hundreds who have been warehoused, committed, Conserved, etc. This system is nothing more than a pharmaceutical/psychiatric money making industry damaging humans and their families. We have spent thousands of dollars seeking help with little or no help to be found just more drugging and irreversible damages.

My friends Marilyn, Delores, Cathy, Felicia, Dorothy, Anne and many others know the truths about neuroleptics and SSRI’s. We live with poisoned humans and some of us lived together as we tried everything to help our loved ones withdraw from Mind Altering Chemicals.

Linda Valentine
lindaraps97@yahoo.com

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Losing a Sense of Being on Luvox

“I have felt ‘dead’ ‘doped’ and ‘stunned’ on the various medications I have been prescribed.”

 

I was prescribed Luvox in May this year (2002) as I suffer from O.C.D. (for 28 years), chronic insomnia and depression. I also cope with life to a great degree, by employing magical thinking.

I had the Luvox in my possession for a few weeks before I finally decided to take it one night, as I couldn’t cope with waking up again knowing I hadn’t done anything (medication wise) to improve my situation. (In principal, I am against medication as, since I was first diagnosed with O.C.D. and depression (about 13 years ago), I have felt ‘dead’ ‘doped’ and ‘stunned’ on the various medications I have been prescribed).

In short, the Luvox kept me awake all night, (and has continued to do so (it is now December).

My doctor prescribed co-medications (Mogadon and Alprazolam). Mogadon to knock me out to sleep, and Alprazolam to calm me down, as I was awake all night due to extremely fast palpitations, confused & abstract thinking, exceptional alertness, and a total inability to ‘switch off’. I also experienced occasional auditory hallucinations, which had only been previously present on two occasions in my life, when I was medicated.

In general, I am not prone to hallucinations. The Mogadon knocked me out so that I couldn’t get up to drive children to school. I have recently (a week and a half ago) gone off the Luvox. In the meantime I have become addicted to Temazepan, as my insomnia has continued.

My choice now has been to work with a dedicated professional, who is willing to work without medication via hypnosis and psychotherapy and to attempt to reduce the sleeping medication myself and eventually deal with the insomnia in any way possible whilst my children are on school holidays.

Although I most certainly recognize the need and value of medication, my experience has always been that the side effects are so complex, and in the end, the co-medications make the situation so much worse, and one totally loses any sense of ‘being’.

Australia

 

12/27/2002

This is Survivor Story number 3.
Total number of stories in current database is 48

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