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Failure of regulators Yolande Lucire PhD, MBBS, DPM, (FRANZCP has been withdrawn by RANZCP) Forensic Psychiatrist and pharmacogeneticist Edgecliff NSW.

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Presentation on theme: "Failure of regulators Yolande Lucire PhD, MBBS, DPM, (FRANZCP has been withdrawn by RANZCP) Forensic Psychiatrist and pharmacogeneticist Edgecliff NSW."— Presentation transcript:

1 Failure of regulators Yolande Lucire PhD, MBBS, DPM, (FRANZCP has been withdrawn by RANZCP) Forensic Psychiatrist and pharmacogeneticist Edgecliff NSW ANZAPPL Conference 2012

2 In the time available, I will look at: 1. The United States Food and Drug Administration (US FDA). 2. The Therapeutic Goods Administration (TGA). 3. The New South Wales Medical Council and Health Care Complaints Commission. I will use 2 drugs as examples of such frauds currently being perpetrated in Australia. Zyprexa (olanzapine), an “antipsychotic.” Efexor (venlafaxine), an “antidepressant.” All new generation psychiatric drugs are similarly misrepresented, as are many other medical drugs.

3 Ronald Kavanagh, Safety Expert blew the whistle on the US regulator the Food and Drug Administration (US FDA)... I reported irregularities in an antipsychotic drug review and FDA financial collusion with outsiders to Senator Grassley’s office..... a company clearly stated in a meeting that they had "paid for an approval.”... I was threatened with prison if I should release trade secret information to Congress.... Managers have placed the nation at risk by corrupting the evaluation of drugs and by interfering with our ability to ensure the safety and efficacy of drugs.... Drug reviewers were clearly told not to question drug companies, and that our job was to approve drugs.... We were prevented from presenting findings at advisory committees. of-safety

4 Ronald Kavanagh continued:... if we asked questions that could delay or prevent a drug's approval - which was our job as drug reviewers - management would reprimand us, reassign us, hold secret meetings about us, and worse.... sometimes we were instructed to read a 100-150 page summary and to accept drug company claims, without examining the actual data, which on multiple occasions I found directly contradicted the summary document.... other times I was ordered not to review certain sections of the submission, but invariably that's where the safety issues would be.

5 Fraud in relation to antidepressants, was documented by Professor David Healy in ‘Let Them Eat Prozac.’ He summarised literature about antidepressant suicide, and examined the selected trials that got the drugs licensed by US FDA.* FDA’s criterion for licensing: that a drug beats placebo in some way in two trials. 373 antidepressant trials had been done and had failed to demonstrate efficacy or safety. Safety is not our concern” said FDA. “We licence drugs.” *Healy D, Whitaker C. Antidepressants and suicide: risk-benefit conundrums. J Psychiatry Neurosci 2003;28:331-7

6 Healy reported on trials and follow up studies which all showed the same outcomes: New generation antidepressants induce suicide 2.5 to 3 fold over placebo. Old antidepressants (TCAs) increase suicide rates when given to large populations. (But save lives when carefully given to a biologically depressed at high risk of suicide) Antipsychotics have a RR of 3-6 of suicide over untreated/placebo. Asbestos is considered causal for cancer with a Relative Risk of 1.2. WHO funded ecological study of 100 countries. It is of concern that most mental health initiatives are associated with an increase in suicide rates.* *Burgess P, Pirkis J, Jolley D, Whiteford H, Saxena S. Do nations' mental health policies, programs and legislation influence their suicide rates? An ecological study of 100 countries. Aust N Z J Psychiatry. 2004Nov-Dec;38(11-12):933-9. PubMed PMID: 15555028.

7 Investigational DrugPatient NoSuicide NoSuicide Attempt No Suicides & Attempts as a % of Patient No sertraline (Zoloft) Active comparator Placebo Placebo Washout 2,053 595 786 20002000 71237123 0.44% 0.17% 0.25% paroxetine (Aropax) Active comparator Placebo Placebo Washout 2,963 1151 554 53025302 40 12 3 2 1.52% 1.30% 0.54% nefazodone (Serzone) Active comparator Placebo 3,496 958 875 900900 12 6 1 0.60% 0.63% 0.11% mirtazapine (Avanza) Active comparator Placebo 2,425 977 494 820820 29 5 3 1.53% 0.72% 0.61% Bupropion (Zyban) Placebo 1,942 370 3030 ---- citalopram (Cipramil) Placebo 4,168 691 8181 91 10 2.38% 1.59% fluoxetine (Prozac) Placebo Placebo Washout 1,427 370 101101 12 0 0.91% 0.00% venlafaxine (Efexor) Placebo 3082 739 7171 36 2 1.40% 0.41% All New Drugs All SSRIs Total Placebo 21,556 13,693 4,879 43 23 2 232 186 21 1.28% 1.53% 0.47%

8 After these publications: US FDA issued a Public Health Advisory, March 22, 2004 Worsening Depression and Suicidality in Patients Being Treated With Antidepressant. Heath care providers should carefully evaluate patients in whom depression persistently worsens, or emergent suicidality is severe, abrupt in onset, or was not part of the presenting symptoms, to determine what intervention, including discontinuing or modifying the current drug therapy, is indicated. Anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Suicidality, therefore, has no relationship, to psychiatric diagnosis.

9 The Therapeutic Goods Administration (TGA) follows the FDA in licensing and then produces no decent Product Information or Public Health Advisories. TGA takes advice from “The College,” (which is not an expert body), and from Key Opinion Leaders, remunerated and educated by Big PharMA. “We are not convinced,” says RANZCP. No suicide warning was issued by TGA or RANZCP clinical practice guidelines. RANZCP does not accept Product Information or Public Health Advisories. RANZCP does not want a Black Box warning for persons under 23, (where the side effects are even more common, for developmental reasons) No Black Box warning was issued for young people. Not one of these new drugs has ever been approved for kids, as safety and efficacy have never been established. So prescribing them is “off label,” and can be dangerous.. Useful drugs for children” says the College of Psychiatrists. Whatever happened to the Precautionary Principle?

10 Suicidality with SSRIs: Adults and Children In 2004, ADRAC (TGA) published a statement on the use of SSRI antidepressants* in children and adolescents, in view of evidence that in these age groups SSRIs were associated with an increased risk of suicidality, including suicidal ideation, suicide attempts and self-harm events. conducted a review of the evidence of suicidal thoughts and behaviour associated with the use of SSRIs in adults. concluded that, in most adult patients, SSRIs in the treatment of depression are beneficial or cause no harm. Were advised by a Key Opinion Leader but Literature and science contradict this.

11 2003–2004. I reported 192 admissions to a rural ward serving 150,000 people to The Adverse Drug Reactions Advisory Committee. Admitted for suicidal and homicidal behaviours on these new drugs. Prescribed by general practitioners. They accounted for half the admissions and bed numbers had been increased by a third. These were a small proportion of the 12,000 similar reports made reported by other doctors from around Australia Psychiatrists working in this area hospital and community mental health centre produced eight SSRI suicides, a bleeding death from Efexor and a Prozac homicide in 2003–2004. None was ever investigated by area director or HCCC. The area director is the chief advisor to the Medical Board and HCCC. A Victorian psychiatric unit and a Queensland unit each had 13 suicides in a year. My colleagues will not countenance these well recognised causes. Coroners will not take this evidence as Crown Solicitor resists it. All relevant authorities have it. It is an inconvenient truth.

12 SSRIs and atypical antipsychotics have never been approved for the treatment of depression or any other condition in those less than 18 years of age, and neither have any other antidepressants. GSK experts advised staff to withhold data about SSRI use in children to in 1998, that indicated the antidepressant paroxetine (Paxil in North America and Seroxat in the UK) had no beneficial effect in treating adolescents. Paroxetine is 1 of 6 drugs in the class of selective serotonin reuptake inhibitors (SSRIs) that Britain has banned for pediatric use because of increased risk of suicide. GSK paid a $3 billion fine to the Department of Justice for fraud, and paid $1 million in 2004 to the State of New York for fraudulent promotion to children. No one does anything in Australia.

13 TGA The ‘Report Of The Psychiatric Drug Safety Expert Advisory Panel,’ 2009, looked at: 90 of my Workers Compensation reports of working persons who were fully functional until;  They were prescribed antidepressants for stress or physical injuries, and who had developed;  Akathisia with suicidal and or homicidal behaviours. Experts looked at gene based drug-drug interactions and confirmed my findings. This report was never circulated. Non feasance No regulator here has done anything other than dive for cover

14 The atypicals were touted as wonder drugs for which the Commonwealth paid 30 times the cost of older comparator drugs. From Whistleblower Allan Jones False Claims Act litigation in USA 2003:... the Atypicals entered the market... a side effect profile that includes serious and life threatening conditions in an alarming number of patients. Food and Drug Administration (FDA) data established that: One of every 145 persons enrolled in clinical trials for Zyprexa, Risperdal and Seroquel died as a result of adverse reactions. Suicide, Diabetes Type 1 and Type 2, Diabetes Mellitus, Convulsions, Necrotic pancreas, Stroke, Hypertension, Cardio Arrhythmia, Obesity.. The FDA is far behind its European counterparts in issuing strong warnings for Atypicals, but has recently issued warnings regarding suicide, stroke and diabetes. Alan Jones received hundreds of millions in a whistle blower False Claims Act lawsuit reward and will still get more. And in Australia? No warnings, no advisories, no response from regulators. Fraud on The Commonwealth remains unprosecuted.

15 Risperdal trials presented to US FDA for licensing Safety Review on FDA website: 231 eliminated in Stage 1, 12 lost to follow up, 2067 subjects remained, 37% failed to complete 6 week trials, 24 died, of which 9 were suicides. (One on comparator and none on placebo). Death rate in these (best) clinical trials was: 1 in 86 clinical trial subjects. The Commonwealth, prescribers and patients were never told of trial drop- outs or deaths.

16 Zyprexa trials presented to US FDA for licensing Of 7,500 starters, 5,000 did not complete stage 1. (No reasons given for dropping out of trials). Stage 2: Of 2607 subjects, 22 died, of which 12 were suicides, (One on comparator and none on placebo). Death rate in these (best) clinical trials was: 1 in 118 clinical trial subjects. Zyprexa remains the most poorly tolerated and suicidogenic drug in the history of clinical trials......and it is given out like sweets, for work stress.

17  At the very least, Zyprexa was associated with a four-fold rate of suicide in patients, relative to older neuroleptics.  Risperdal was not far behind.  Was fraud committed on the Commonwealth as it was in USA?  Do we need a False Claims Act with whistleblower rewards?

18 American Product Information for Zyprexa Note: There were five schizophrenia trials at this time but only two short six week trials are cited in the document as “establishing efficacy,” (line numbers 112 & 113). Line numbers as in APPROVED AGREED-UPON LABELLING 1997 2003. 261 Neuroleptic Malignant Syndrome. 264 altered mental status 282 Tardive dyskinesia 321 Seizures occurring in 0.9% 358 Potential for motor an cognitive impairment 378 suicide 416 Interference with motor and cognitive function Adverse Reactions 628-personality disorder Akathisia 630 somnolence, dizziness, tremor 638 akathisia, articulation impairment 639 Events reported by at least 2%: agitation, anxiety, apathy, confusion, depression, hallucinations, hostility, nervousness, paranoid reaction, personality disorder, thinking abnormal, 644 COSTART (Non aggressive objectionable behaviour) 650 at more the twice the placebo rate: speech disorder, amnesia, 625 apathy confusion euphoria 659 at least 2%: emotional lability, abnormal dreams, agitation, hostility, insomnia, akathisia, anxiety, insomnia, libido up or down, nervousness, paranoid reaction, personality disorder, sleep disorder, thinking abnormal (what can this mean here given results for akathisia?)

19 American Product Information for Zyprexa continued 676 akathisia rates are given as percentages: 23% on placebo! 16%, 19% and 27% on Zyprexa, increasing with dose. Using Barnes Akathisia Scale. Note akathisia is a medication-induced condition. 685 akathisia events (different from the simple observable movement disorder (DESCRIBED ABOVE). On placebo 1,on Zyprexa 5% 11% and 10%. 286 11% and 10% statistically different from placebo. 691 COSTART counted akathisia and hyperkinesia. 693 choreoathetosis 746 Body as a Whole — Frequent: dental pain and flu syndrome; Infrequent: abdomen enlarged, 747 chills, face edema, intentional injury, malaise, moniliasis, neck pain, neck rigidity, pelvic pain, 748 photosensitivity reaction, and suicide attempt ; Rare: chills and fever, hangover effect, and sudden death 770 Nervous System — 770 Frequent: abnormal dreams, amnesia, delusions, emotional lability, 771 euphoria, manic reaction, paresthesia, and schizophrenic reaction; Infrequent: akinesia, alcohol 772 misuse, antisocial reaction, ataxia, CNS stimulation, cogwheel rigidity, delirium, dementia, 773 depersonalization, dysarthria, facial paralysis, hypesthesia, hypokinesia, hypotonia, 774 incoordination,, obsessive compulsive symptoms, phobias,

20 American Product information for Zyprexa continued 824 In post marketing reports of overdose with olanzapine alone, symptoms have been reported in the 825 majority of cases. In symptomatic patients, symptoms with ©¯10% incidence included 826 agitation/aggressiveness, dysarthria, tachycardia, various extra pyramidal symptoms, and reduced 827 level of consciousness ranging from sedation to coma. Among less commonly reported symptoms 828 were the following potentially medically serious events: aspiration, cardiopulmonary arrest, 829 cardiac arrhythmias (such as supra ventricular tachycardia and one patient experiencing sinus pause 830 with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant 831 syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension 67 out of 3100 patients and/or normal subjects, took accidental or intentional acute over dosage of of Zyprexa, Overdose rate of Zyprexa alone us 2161/100,000 Suicide rate in population is 12-16/100,000. Suicide attempt rate is 20-40 times that 640/100,000 vs. >2161?100,000 So they say Zyprexa is safe in overdose. Were these uncounted suicide attempts Taxpayers pay cost of overdoses Socialised costs and privatised profits?

21 AUTRALIAN Product Information for Zyprexa 2003 UPDATED 2005 ADVERSE REACTIONS Nervous system – _Very common (≥ _10%): somnolence. Common (≥ _1% and < 10%): dizziness; akathisia. Australian Product information says it has lower rates of akathisia. 27% is a lot higher than old drugs. that’s all folks. We get only 3 psychiatric side effects but USA prescribers are warned of hundreds of psychiatric side effects. that’s all folks. We get only 3 psychiatric side effects but USA prescribers are warned of hundreds of psychiatric side effects.

22 American Product Information Effexor 1996 et sequi USA 106 “psychiatric” side effects Body as a whole - Frequent: suicide attempt, withdrawal syndrome; Nervous system - Frequent: amnesia,, confusion, depersonalization hypesthesia, thinking abnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia, in coordination, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormal speech, stupor, suicidal ideation; Rare: abnormal/changed behavior, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hypokinesia, hysteria, impulse control difficulties, libido increased, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis

23 Australian product information for Efexor 2005 MIMS Annual: We are informed of 39 “psychiatric” side effects. Nervous. Common: abnormal dreams, decreased libido, dizziness, dry mouth, increased muscle tonus, insomnia, nervousness, paresthesia, sedation, tremor; uncommon: apathy, hallucinations, myoclonus, agitation; rare: convulsion, manic reaction, neuroleptic malignant syndrome (NMS), serotonergic syndrome; very rare: delirium, extra pyramidal reactions (including dystonia and dyskinesia), tardive dyskinesia.

24 These words appear in US, but not in Australian Product Information: Suicidal ideation; Suicide attempt, akathisia, Psychosis, Seizure, Abnormal speech, stupor, abnormal/changed behaviour, Loss of consciousness, Delusions, Dementia, homicidal ideation, impulse control difficulties, paranoid reaction psychotic depression, If someone I cared about were getting Efexor I would want to know it was the drug not the disease.

25 Neuroleptic and SSRI induced Akathisia DSM 333.99 states The subjective distress is significant and can lead to noncompliance with neuroleptic treatment. Akathisia may be associated with dysphoria, (feeling awful) irritability, aggression or suicide attempts. Worsening of psychotic symptoms or behavioural dyscontrol (out of control criminal behaviours) may lead to an increase in neuroleptic medication dose, which may exacerbate the problem. (That is make it worse). Acute akathisia tends to persist for as long as neuroleptic medications are continued, although the intensity may fluctuate over time. The reported prevalence of akathisia varied widely (20%-75%). So it is not rare! Search Google Scholar for ‘akathisia suicide’ and ‘akathisia homicide.’ There are thousands of papers, Law Reports and judgements. 609 results for ‘akathisia suicide’ and ‘akathisia homicide.’ 24 legal documents and judgments. Scores more on World Law.

26 RANZCP Summary of guideline for the treatment of depression Pete M. Ellis, Ian B. Hickie and Don A. R. Smith for the RANZCP Clinical Practice Guideline Team for Depression. States: Depression is common, serious and treatable. It affects 1 in 25 people in any 1 month. An “evidence-based” guideline. Second line of treatment: If TCA or Efexor, review and increase dose. If SSRI or Nefazadone switch to TCA or Efexor (mild/mod add CBT) If TCA or Efexor consider adding CBT/IPT. If CBT/IPT then add TCA or Efexor (mild/mod add SSRI). Note Efexor was found in clinical trials to be associated with the highest suicide risk, 12 times that of placebo.* Nefazadone had been withdrawn three months before the publication of this guidelines. The graphics came from the fraudulent Texas Medication Algorithm Project, a consortium like the PharMA collaboration, formed to promote use of these drugs. * Geddes JR, Barbui C, Cipriani A. Risk of suicidal behaviours in adults taking antidepressants. BMJ. 2009 Aug 11;339:.

27 Almost $6.4 billion, or $287 per person, was spent on mental health-related services in Australia during 2009–10, an increase from $241 per Australian in 2005–06 (an average annual increase of 4.5%). And is mental health improving? Not if you look at demand and rates of suicide and homicide under mental health care. The conditions that lead to suicide and violence fill psychiatric hospitals and prisons.

28 From Tracking Tragedy Biennial reports in NSW Emeritus Professor the Hon Peter Baume AO and Bill Barclay: “We looked at everything but medication” They still will not look at medication”

29 The incidence of mental illness is well known Research criteria for schizophrenia or bipolar. Schizophrenia rates have remained constant across cultures and across time, at 1%. Bipolar is rare 0.5% of the population, but in USA, 10% of children are so diagnosed and medicated. Biological depression is even more rare. Outcomes worse than 100 years ago for number of episodes and suicide. Most are misdiagnosed So why are 5% of Australians on antidepressants and 9% on psychiatric drugs, which cause “psychiatric” side effects for at least 27% of them?

30 10218—PSYCHIATRIC DRUGS Mr Daryl Maguire to the Deputy Premier, and Minister for Health— 2010 Has the Minister and her predecessors been warned by individuals that suicides committed by patients and clients under mental health care could be caused by psychiatric drugs: – that affect persons who have a genetically determined inability to metabolize them; – that such persons should be recognized by their adverse medication responses? How many persons have committed suicide whilst under mental health care in the years 2003 to 2008? How many have committed homicide? Do these figures represent a deterioration or improvement in the numbers of suicides under mental health care: – before 1990; – before 2002?

31 Answer—: The Chief Psychiatrist in consultation with the NSW Mental Health Clinical Advisory Council is currently (2010) considering these issues. According to the Mental Health Client Incident Information System, there were: 937 notifications of suspected suicides of persons under mental health care that were reported to the NSW Health Department between 1 Jan 2003 and 31 Dec 2008. 43 notifications of suspected homicides by persons under mental health care that were reported to the NSW Health Department between 1 Jan 2003 and 31 Dec 2008. It is not possible to compare the data over this time period due to the fact that different methodology was used to collate this data. That is 3 suicides a week and a homicide every two months under Mental Health care in NSW. Pro rata in other states makes >500 such suicides each year.

32 Why are these suicide and homicide statistics relevant and important? Because the sub lethal side effects fill hospitals and prisons with persons experiencing suicidal and homicidal ideation, displaying aggression caused by medication, most commonly antidepressants prescribed for stress to which antipsychotics have been added. Each suicide is underpinned by 40 attempts and more suicidal ideations. As well, hallucinations, delusions and delirium are listed side effects here and in the USA but no one here takes any notice. Not even the regulators. Who pays? Qui bono?

33 Expert Evidence Issues That antidepressants cause akathisia and thereby suicide and homicide has passed 6 Daubert Hearings in USA. Daubert determines that evidence is reliable and is (kind of) incorporated into the Expert Code of Conduct when we promise to give evidence in accord to the scientific literature.

34 Properly defended homicide cases in Australia R vs. Hawkins, SCNSW, 2001. A 72 year old man kills his beloved wife after taking Zoloft. “...wholly likely that but for taking 250 mg Zoloft that he would have killed his beloved wife.” R vs. B, SCWA, 2004. Woman makes multiple attempts to kill herself and her children on Efexor. (She has three defective metabolising genes). At least 43 medication-induced homicides in 7 years in NSW have been attributed to mental illness, which was not there before the patient took psychiatric or illicit drugs.

35 So back to the FDA and other whistleblowers and litigation for fraud in USA Look at these judgements and settlements!

36 During the 20 months to July 2012, drug makers settled 74 fraud cases with the federal government or states for a combined $10.2 billion.74 fraud cases The $6.6 billion in settlements through July is the most ever in a single year, Public Citizen reports. Half, $3 billion, came from GlaxoSmithKline and the U.S. Justice Department. While the dollar amounts may seem staggering, they're meagre relative to pharmaceutical company profits. GlaxoSmithKline paid out $7.5 billion to resolve 20 fraud accusations since 1991, representing almost one-quarter of the total amount recouped by the government. But GSK made $8.4 billion in profit in 2011 alone, or nearly $1 billion more than it paid the federal and state governments over a 21-year period. More than two decades' worth of payouts by drug makers were worthless than two-thirds of the profits earned by the 10 biggest drug makers in 2010, Public Citizen noted in a release.less than two-thirds of the profits "Financial penalties still continue to pale in comparison to company profits and a parent company is only rarely excluded from participation in Medicare and Medicaid for the illegal activities," according to the report.pale in comparison to company profits



39 Public Citizen Pharmaceutical Industry Criminal and Civil Penalties: An Update September 2012 Table 6. Ten Largest Settlements and Judgments, Nov. 2, 2010 – July 18, 2012


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