Anne Milton MP 20 Greenacre Court
Minister for Public Health Lancaster
Department of Health LA1 4LE
London SW1A 2NS
9th March 2011
Subject: The licensing of the tranquilliser Ativan/Lorazepam
I am writing regarding the granting of a licence for Ativan/lorazepam to John Wyeth and Brother Ltd as it is the view of many experts, MPs and addicted patients that it should never have received a market authorisation.
I would ask the Public Health Minister to respond to this letter personally and not the MHRA on her behalf as I am requesting a full investigation into what went wrong with the regulatory procedure.
John Wyeth and Brother had begun to compete with Roche and in 1972 launched Ativan which was promoted for anxiety. Ativan was ten times stronger than Valium and was shorter-acting (shorter-acting compounds have significantly more severe withdrawal symptoms); this alone should have alerted the regulatory authority.
1. Clinical Trials
Wyeth ignored a serious problem with Ativan exposed in the form of a trial it sponsored in 1972 carried out by Dr Rene De Buck, a consultant psychiatrist in Belgium. Dr De Buck’s trial revealed that 2 out of 30 patients on therapeutic doses of Ativan for less than one month suffered epileptic seizures on withdrawal. This indicated the highly addictive nature of Ativan in the form of a major withdrawal reaction after only three weeks on therapeutic doses. The appropriate warning for a specific Adverse Drug Reaction (epileptic seizure) that the De Buck trial should have generated does not appear in the UK Ativan Data Sheet; neither did an appropriate high level addiction warning.
Dr Raine, Director, Vigilance and Risk Management of Medicines informed me that “Two cases from clinical trials, particularly if these included a confounded case, are unlikely to have roused suspicion. However, it is not possible to be certain what was queried, as the records are no longer available.”
Dr Raine is stating that convulsions are an acceptable risk when withdrawing from a minor tranquilliser or sleeping tablet and also that she does not know what information Wyeth sent because the MHRA have destroyed the records.
Also, convulsions were not added to the Data sheet until 1990, 18 years after the De Buck trials and the licence application. Dr Raine can give no explanation for this catastrophic delay and during this period a large population became addicted. When questioned as to whether Wyeth sent details of the De Buck study with the original licence application Dr Raine informed me that the MHRA (then MCA) had to contact Wyeth in 2002 and that Wyeth confirmed that details of the study had been sent with the licence application.
This is surreal because Wyeth has plenty of form when it comes to non-compliance with regulatory authorities and it should be Dr Raine’s remit to ensure patient safety by checking important details like this, not accepting Wyeth’s word that they sent details of the De Buck study. This is not regulation or enforcement, it is negligence and naivety. Either Wyeth sent details, in which case the regulatory authority is guilty of negligence, or Wyeth withheld details and should be prosecuted.
Dr Raine expects me to accept that Wyeth sent details of the De Buck study yet cannot prove it because the MHRA records have been destroyed including the original licence application.
Wyeth will have copies of these and should be asked to produce them.
It is the belief of damaged patients that Ativan received its licence with little more than promotional literature and that all subsequent lorazepam licences have been granted on this information alone using Directive 65/65/EC which is a method of “rubber stamping” drug licences without reference to clinical trial data.
The relevant safety requirement at the time of licensing was that Ativan should be no less safe than other drugs indicated for the same condition (i.e. Valium and Librium). This was not an objective standard, it was a comparative standard and it was a comparison to Roche’s benzodiazepine products; these had not yet been assessed for safety either. As Ativan had secured a full Product Licence it was not even subject to the future CRM review. Ativan was never fully assessed for safety by the licensing authority.
Other Wyeth Ativan clinical trials were poor quality and also short term; none provided reliable evidence that Ativan was safe. The earliest Ativan trial sponsored by Wyeth was conducted in a US prison in 1970 and is by HW Elliot. This was a one-tablet only, one day trial. Cross-referencing this trial with the 1974 UK Ativan Data Sheet shows Wyeth withheld vital safety information from the Data Sheet.
2. Dr Thomas Harry
One of Wyeth’s medical directors Dr Thomas Harry was responsible for the development of Ativan and the crucial clinical trials for the drug at the company’s research centre in Taplow, Bucks. The UK was the launch pad for licensing Ativan around the world.
In a statement he said he was never asked by Wyeth to undertake trials to find out whether Ativan was safe to prescribe for several months or more. He further stated that one reason why long-term trials were not carried out “was that there was nothing to be gained by them, but everything to lose in the sense we could be courting disaster”.
Dr Harry, a former psychiatrist, further stated that the drugs were designed to be taken for only a few weeks, and if he had been told it was to be used long term, he would have queried the instructions over the trials.
“I would have to advise a company that it would not be proper to market the product for a long-term,” he said. But he says that for years after they went on sale, the company failed to make it clear that the drugs were not to be taken over a prolonged period.
“The company did not tell doctors, either in data sheets or elsewhere, that Ativan should only be prescribed short-term,” he said.
Dr Harry says the company could have foreseen this potential danger if they had done more research before Ativan was launched.
He said: “The view of most people in the industry at the time was that there was a high probability that a patient would have difficulties in withdrawing from any drug that acts on the central nervous system.
“The trials were carried out for too short a period of time to reveal the side-effects which, we now know result from prolonged administration of this drug.”
He says no proper long-term research work was done on dependency until after 1986 – 14 years after the drug had gone on sale – despite the fact, he says, that “there was a growing awareness of the dependency problem from, at the latest, the late 1970s”.
He also alleges that Wyeth failed to pursue research which had earlier indicated that the drug could cause seizures, memory loss and tremors.
3. MP’s concerns in Parliamentary Questions
Several MPs were expressing concerns about Ativan in the early eighties and asking whether it should be banned. Some of these are as follows from Hansard and all these concerns were ignored as well:
HC Deb 06 November 1986 vol 103 c601W
Mr. Coombs asked the Secretary of State for Social Services what representations he has received about the drug lorazepam; whether he is conducting inquiries into its use and effects; and if he will make a statement.
HC Deb 03 February 1987 vol 109 cc585-6W
Mr. Greg Knight asked the Secretary of State for Social Services (1) what information he as concerning the addictive qualities of the drug Ativan; and if he will make a statement;
(2) what representations he has received concerning the banning of the drug Ativan;
(3) whether he has any plans to seek to ban or restrict the sale or use of the drug Ativan.
HC Deb 27 October 1987 vol 121 cc251-3W
Mr. Wareing asked the Secretary of State for Social Services what efforts he is making to assist patients 252Wsuffering from the withdrawal effects of taking lorazepam; how this assistance is being given; at what cost; and if he will make a statement.
Mr. Wareing asked the Secretary of State for Social Services (1) if he has any plans to ban the prescribing of lorazepam to new patients; and if he will make a statement;
(2) whether he has set up or plans to set up a study of the problems associated with the prescribing and represcribing of lorazepam; and if he will make a statement;
(3) if he has now received a copy of the report of the Committee on safety of Medicines concerning the prescribing and represcribing of lorazepam; and when it is likely to be published.
HC Deb 14 June 1988 vol 135 cc170-1W
Mr. Atkinson To ask the Secretary of State for Social Services if he has received any recent representations regarding the side-effect of the drug Ativan; and if he will make a statement.
HC Deb 23 May 1991 vol 191 cc587-8W
Mr. David Nicholson To ask the Secretary of State for Health when his Department first received evidence of the harmful side effects, including addictiveness, from the drug Ativan; and what action was taken to end its availability on prescription.
None of these questions were ever returned to by the Health Minister and remain ignored.
4. Data sheet
It took until 1990 to add convulsions as a withdrawal reaction, eighteen years after the licence was granted? Dr Raine can offer no explanation as to why patients were put at risk by this omission.
Wyeth consistently issued a lower level of information on Ativan in the UK Data Sheet, lower than the information provided in the equivalent year Data Sheet for Ativan in the USA, Canada or Australia.
Ativan is ten times stronger than Valium yet the maximum dose of 10mg in the UK was double that of North America and elsewhere; this was a catastrophic difference. Dr Raine cannot explain the discrepancy between UK data sheets and other countries either.
5. Expert advice
The regulatory authority (then CSM) was also advised by benzodiazepine experts that Ativan should be banned. This advice was also ignored and after recent re-emergence remains ignored.
Professor Peter Tyrer, who was a consultant psychiatrist at Mapperley Hospital in Nottingham at the time, and a recognised authority on benzodiazepine dependency, wrote to the CSM in 1987. He clearly stated in his letter to the CSM that problems with dependency and withdrawal symptoms from Ativan/lorazepam were sufficient for him not to prescribe it at all, except to those patients who were already addicted or unable to changeover to another longer-acting benzodiazepine such as Valium (letter attached).
Professor Ashton advised the CSM that Ativan should be phased out over a five year period. This advice was also ignored (letter attached).
Professor Malcolm Lader wrote to the CSM as well advising that addiction to Ativan could occur in a short period on low doses and that additional warnings were required (letter attached).
He also provided evidence from scientific studies linking brain damage to use of benzodiazepines; this was also ignored and no further studies commissioned.
The MHRA are aware of all the above yet still have taken no action.
Wyeth has plenty of form when it comes to avoiding regulatory control and manipulating information on safety and efficacy. Dr Rheinstein of the FDA in the United States wrote a regulatory letter to Wyeth-Ayerst in 1989 telling them they had an “intolerable record of compliance with the law” (on drug promotion).
Wyeth-Ayerst had “in case after case…disseminated promotional materials that are clearly false and misleading” indicating a “general and wilful disregard for legal and regulatory limitations upon drug promotion”. Dr Rheinstein told Wyeth-Ayerst that a 1989 advertisement for the heart drug Cordarone was “clearly intended to minimise the hazards of the drug and emphasise the drugs efficacy”. Dr Rheinstein’s Office of Drug Standards issued 18 notices of violation to Wyeth-Ayerst concerning drug advertising and labelling in 1988/89.
In 1999, AHP had to pay $4.85 billion compensation in the ‘Fen-Phen’ litigation to 5.8 million ex-users who suffered heart-valve damage. The drug was marketed through Wyeth-Ayerst, it was linked to serious lung disease and leaky heart valves. Wyeth-Ayerst were found to have concealed this information. Settlements included medical care and monitoring for the victims, paid for by the manufacturers. (11)
Wyeth paid a fine and received a deferred prosecution by the Security Exchange Commission to stop investigation into worldwide corruption and admitted paying bribes worldwide.
Also in 1999, Wyeth Laboratories were convicted by the Supreme Court of New Jersey of failing to warn adequately of side-effects associated with the contraceptive device Norplant.
Wyeth-Ayerst failed to disclose withdrawal information about Effexor until 8 years after it was licensed.
Dr Raine expects damaged patients, in the light of the above, to accept Wyeth’s word regarding Ativan.
7. Conflict of interest
At the time of the UK litigation in 1996, when the CSM/MCA were co-defendants along with Wyeth and Roche, ten members of the CSM/MCA declared financial links with John Wyeth and Brother.
During my correspondence with Dr Raine I visited the MHRA website and saw a Pfizer logo; this provided a link to Pfizer’s website providing a good news story about Wyeth’s recent merger with Pfizer.
I thought that the MHRA’s function was to ensure the safety of our drugs; not to provide links to companies the agency is supposed to be regulating with “vigilance”?
8. MHRA misinformation
Since May 2010 the following wrong or misleading information has been provided to me and my MP, Eric Ollerenshaw:
Dr Raine stated that: ‘The original guidance to use benzodiazepines for no longer than 2-4 weeks was issued by the Committee on the Review of Medicines (CRM) in 1980.’ In fact the 2-4 week guideline was not issued until 1988 by the CSM, not CRM.
Dr Raine stated that generic lorazepam licences were authorised by Directive 2001/83/EC whereas they were in fact authorised by Directive 65/65/EC.
Sue Jones (complaints) informed me that the MHRA were not directly involved in the 1986-96 litigation whereas the agency was a co-defendant along with Wyeth and Roche.
In Parliamentary Questions every time the MHRA is asked how many generic lorazepam licences have been issued a different answer has been provided.
In Parliamentary Questions the answer provided to the legislative procedure most of these generic lorazepam licences were granted was “not confirmed”.
At a meeting with you the MHRA official gave assurances that companies have been prosecuted in the past for withholding safety data yet no such prosecution has ever occurred.
At the same meeting the MHRA official further gave assurances that all safety data is on the Summary of Product Characteristics yet this is not the case; the SPC is only 12 or so pages long and only contains prescribing information.
The MHRA record keeping is chaotic, safety evidence, if any ever existed, has been destroyed and I would not expect Dr Raine and her officials to provide me with so much incorrect information regarding one drug. I am then expected to accept Dr Raine’s word that Ativan has been robustly monitored for safety.
Regarding assessment of long-term and permanent damage caused by these drugs Dr Raine informs me that “the Agency’s remit does not include regulation of clinical practice and we cannot enforce prescription for short term use of these medicines.”
This is the same excuse used by the Department of Health to avoid responsibility. I accept that it must be an embarrassment for the Public Health Minister that the Department of Health and the MHRA have between them been responsible for prolonged mass prescription drug addiction and both pass the blame with ease, firstly to the doctors who in turn blame the patients.
In summary this is not drug regulation; it is drug registration. Safety does not seem to be an important issue to the MHRA and licences are issued with alarming ease with no supporting safety evidence. All expert advice and concerns expressed by academics, MPs and damaged patients has been ignored for over thirty years and many patients have been damaged permanently; it is a disgrace.
I and other campaigners request an immediate investigation into what went wrong with regard to the licensing and regulation of Ativan/lorazepam and we also request withdrawal of this product in the interest of public safety.
All Members of the All Party Parliamentary Group for Involuntary Tranquilliser Addiction
(Attachment: Expert comments – withdrawal reactions 1987)