The European Union will make review of clinical trials for drugs ” absolutely impossible “

2014-05-27

Just look, but don’t touch: EMA terms of use for clinical study data are impracticable

Data are only allowed to be viewed on screen / Pre-censorship by drug manufacturers

The European Medicines Agency (EMA) receives comprehensive clinical study data from drug manufacturers. These data form the basis for the decision on the approval of new drugs. To make this information available to researchers and decision-makers, EMA issued a draft policy in 2013 for the publication of clinical study data, in which extensive data transparency was planned. Continue reading “The European Union will make review of clinical trials for drugs ” absolutely impossible “”

Europe says No to drug data access ” arguing that this would undermine commercial interests and that there was no overriding public interest in disclosure”

Public release date: 10-May-2011 – Request Repost

Drug regulators are protecting profits over patients, warn researchers Analysis: Opening up data at the European Medicines Agency

Medicines regulators are protecting drug company profits rather than the lives and welfare of patients by withholding unpublished trial data, argue researchers on bmj.com today.

They call for full access to full trial reports (published and unpublished) to allow the true benefits and harms of treatments to be independently assessed by the scientific community. Continue reading “Europe says No to drug data access ” arguing that this would undermine commercial interests and that there was no overriding public interest in disclosure””

Current study shows: Important information on effects and side effects of drugs is missing in most publications

IQWiG: Reliable assessment of drugs is only possible on the basis of clinical study reports (CSRs)

In 2012 researchers from the German Institute for Quality and Efficiency in Health Care (IQWiG) presented a study in the BMJ analysing information sources used in 16 health technology assessment (HTA) reports of drugs (“benefit assessments”). This study clearly demonstrated that publicly available sources, such as scientific journals and entries posted in trial registries (“registry reports”), contained far less information on methods and outcomes of clinical trials than non-public CSRs prepared by pharmaceutical companies.

In a second article published today in PLOS Medicine, the IQWiG researchers now show that if, instead of only assessing selected outcomes as in the first study, all patient-relevant outcomes of the clinical trials are assessed, the information deficit in the publicly available sources is even greater.

Data analysed for more than 1000 outcomes

All HTA reports of drugs completed by IQWiG between 2006 and 2011 also formed the basis for the new study. The authors included those trials from the HTA reports for which the pharmaceutical companies had provided complete CSRs to IQWiG. Publicly available information in scientific journals and trial registries was available for 86 out of 101 of these trials, so that the information provided in all 3 sources could be compared. The trials contained data on more than 1000 patient-relevant outcomes such as mortality or disease symptoms.

Huge difference in the information provided

IQWiG assessed whether the results on the patient-relevant outcomes in the trials were “completely” or “incompletely” reported. The difference in the information provided was immense: Whereas 86% of all outcomes were fully reported in unpublished CSRs, the corresponding number was only 39% for combined publicly available sources. Likewise, negative effects on patients (“harm outcomes”) such as serious adverse events or treatment discontinuations were reported far less often in the publicly available sources (27 to 72% versus 84 to 92%, depending on the harm outcome investigated).

Make CSRs publicly accessible

Beate Wieseler, Head of the Drug Assessment Department, comments on this first comprehensive quantification of the information gain through full CSRs: “The publicly available journal articles and registry entries thus report less than half of outcomes of clinical trials comprehensively. At the same time, with CSRs documents are available that provide complete information on methods and outcomes. The consequence can only be: all CSRs must be made publicly accessible. One should note that IQWiG is already in a privileged position due to its legal remit to conduct benefit assessments. Other researchers and physicians wishing to be fully informed about the advantages and disadvantages of an intervention have even more difficulties in gaining access to data.

Although the proportion of clinical trials published as scientific articles or registry reports has increased in the past few years, this is unfortunately not accompanied by more complete reporting of patient-relevant outcomes. Large information gaps still remain and we cannot even guess how large these gaps are in other types of drug trials or in trials of non-drug interventions.”

Need for legislation

Beate Wieseler further points out: “The plan by the European Medicines Agency (EMA) to make all clinical trial data submitted for marketing authorization publicly available from January 2014 onwards can therefore only be a first step. A central repository is required, also including data from older trials, as such trials investigate drugs widely used in current medical practice. These data would probably shed a totally new light on several drugs and their position in their therapeutic area. However, a voluntary commitment by the pharmaceutical industry, which would like to decide on a case-by-case basis which data it discloses, is insufficient. We are hoping for legislation and continue to support the All Trials Campaign (see below) so that the problem stays on the agenda.”

Further information:

Article by IQWiG authors in PLOS Medicine

Investigation into safety of new diabetes drugs — will manufacturers release their data?

Contact: Emma Dickinson edickinson@bmj.com 44-207-383-6529 BMJ-British Medical Journal

Joint BMJ/Channel 4 Dispatches investigation

The BMJ and Channel 4 Dispatches investigated and found that evidence suggesting potential harm from the drugs in industry studies has not been published.

Some independent studies challenge the conclusions of the drugs manufacturers’ own research. Now some medical experts and patient groups are calling on the pharmaceutical companies to be more transparent in reporting of study data and to enter into dialogue about safety concerns.

As a result, millions of patients around the world have not been fully informed about some of the possible risks.

Some critics say the drug regulators in Europe and the US have been slow to pursue concerns about the potential adverse effects of these new diabetes drugs, despite the emerging warning signs in the medical literature, regulatory documents, and adverse event databases.

Full details will be published on bmj.com on Monday 10 June and broadcast in Diets, Drugs and Diabetes – Channel 4 Dispatches on Monday 10 June at 8pm on Channel 4.

GLP-1 based drugs are used to treat type 2 diabetes by regulating blood sugar. Some of these drugs also suppress appetite and are currently being tested as a possible treatment for obesity.

In the course of this investigation, the BMJ has reviewed thousands of pages of regulatory documents obtained under freedom of information and found unpublished data pointing to “unwanted proliferative or inflammatory pancreatic effects.”

The BMJ has also found that, despite published reports that indicated safety concerns, companies have not done certain critical safety studies; nor have regulators requested them yet. And access to raw data that might help resolve doubts about the safety of these drugs has been denied.

Dr Deborah Cohen, the BMJ‘s Investigation Editor, says: “On their own the individual pieces of unpublished evidence may seem inconclusive, but when considered alongside other emerging and long standing evidence, a worrying picture emerges, posing serious questions about the safety of this class of drug.”

Three publications this year have raised concerns long held by some experts about the potential side effects of GLP-1 based drugs, prompting both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to launch a review into whether the drugs may cause or contribute to the development of pancreatic cancer. And in America, hundreds of people are suing manufacturers alleging that the drugs caused pancreatitis and in some cases cancer.

Yet the evidence is fiercely contested amongst scientists and manufacturers stoutly defending the safety of their products.

Some argue that the published evidence against the drugs is weak, while others say we can’t yet be sure that these drugs are safe and are calling for all the study data to be made public for independent analysis.

Research by Professor Peter Butler at the University of California Los Angeles, for example, found worrying changes in the pancreases of animals that received a GLP-1 based drug. He has also found abnormal changes, including pre-cancerous lesions, in the pancreases of eight organ donors taking GLP-1 based drugs compared with patients taking other anti-diabetic drugs.

And studies of side effects reported to the regulators have also started turning up cases of pancreatic cancer among patients on GLP-1 based drugs. Both EMA and the FDA have confirmed to the BMJ that they have “signal” for pancreatic cancer – but this does not mean there is a causal link.

Together these findings raise important and troubling questions about a possible link between these diabetes drugs and pancreatic cancer, but no safety alert has yet been issued by the regulators.

More information is expected later this month, when the US National Institutes of Health hold a two-day meeting on possible links between diabetes, diabetes drugs and pancreatic cancer.

But some consumer groups are calling for the drugs to be withdrawn as a diabetes treatment to prevent potential harm to patients while we wait for this evidence – and they don’t want to see them licensed as an obesity treatment.

Writing in the BMJ, Dr Fiona Godlee, Editor in Chief said: “All drug licensing is about balancing benefits and risks. But instead of engaging in open debate about legitimate and important scientific questions, the manufacturers have been unwilling to share their data. Meanwhile patients and doctors have not been kept properly informed about the uncertainties surrounding these drugs.”

She adds: “The debate would be much easier to resolve if all the information was placed in the public domain so scientists, doctors and ultimately patients could make up their own minds.”

In an editorial in the BMJ, Edwin Gale, Professor of diabetic medicine, says this shows once again that current regulatory procedures are inadequate to deal with the challenge of drug treatments that have more than one biological target, which he calls “shotgun therapies.” He says: “Similar scenarios will be re-enacted while secrecy rules and the companies control access to the data.”

In statements to Channel 4 Dispatches airing tonight, the drug companies all maintain their commitment to patient safety. On monitoring, the companies all say they have regular, close and vigorous safety processes in place, including large scale, long term trials, and the results are routinely submitted to the regulatory authorities.

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The BMJ is campaigning for improved access to data from clinical trials – see bmj.com/opendata

If patients have any concerns about the diabetes drugs they are taking, they are asked to consult with a doctor before changing their medication.

Release all Tamiflu data as promised, argue researchers

Contact: Emma Dickinson edickinson@bmjgroup.com 44-020-738-36529 BMJ-British Medical Journal

Company plans to set up review board, but researchers want it to keep its promise

The latest correspondence is posted online today as part of the BMJ‘s open data campaign, aimed at persuading Roche to honour the promise it made almost three years ago to make key Tamiflu trial data available for independent scrutiny.

Last week, Donald MacLean, Life Cycle Leader for Tamiflu, wrote to Professor Chris Del Mar in his capacity as coordinating editor of the Cochrane Acute Respiratory Infections Group, concerning “our debate on Tamiflu data.”

The Cochrane researchers say they object to Roche’s suggestion that there is a debate on Tamiflu data. “There is no debate nor can there be any debate about the data whilst you do not honour your promise,” they say. “The only reason we keep asking Roche to keep its promise, rather than simply getting the data from the European Medicines Agency directly, is because Roche has not supplied all of the data to the European regulator.”

Roche’s letter also mentions “disagreements” over the type of analyses the Cochrane team wish to do, but the researchers point out that their methods and analyses have been public for nearly two years and “follow Cochrane procedure” and state that they are not aware of any specific concerns from Roche.

Roche’s letter goes on to say that, in order to reach “an amicable resolution” Roche plans to set up “a multi-party advisory board to review the totality of Tamiflu data” …. which they believe is “a sensible, fair and transparent way of addressing this public debate.”

But the Cochrane team argue that Roche’s offer is merely a belated attempt at turning the clock back, and call on the company to expand its data sharing pledges “to become compatible with current regulatory norms.”

They say: “The European Medicines Agency and the EU Ombudsman have made abundantly clear that there is no reason for anonymised clinical data to be withheld from public scrutiny once a marketing authorisation has been obtained for a pharmaceutical. Why should Roche not – at the minimum – meet this standard?”

In summary, they say, “we ask to you to honour your promise of three years ago and make public full clinical study reports in your possession.”

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BMJ editor urges Roche to fulfil promise to release Tamiflu trial data: Or anything that shows the drug does more good than harm.

Contact: Stephanie Burns
sburns@bmjgroup.com
44-020-738-36920
BMJ-British Medical Journal

BMJ editor urges Roche to fulfil promise to release Tamiflu trial data

Journal launches open data campaign to compel greater accountability in healthcare

In an open letter to company director, Professor Sir John Bell, she says: “Billions of pounds of public money have been spent on [Tamiflu] and yet the evidence on its effectiveness and safety remains hidden from appropriate and necessary independent scrutiny.”

The letter is published on the BMJ‘s website (bmj.com/tamiflu) alongside correspondence by the Cochrane team with Roche, the US Centres for Disease Control (CDC) and the World Health Organisation (WHO), as part of an open data campaign aimed at persuading Roche to give doctors and patients access to the full data on Tamiflu.

Dr Godlee’s letter follows recent reports that the European Medicines Agency (EMA) has initiated infringement proceedings against Roche to investigate deficiencies in safety reporting, including the processing of around 80,000 reports on suspected adverse drug reactions.

Dr Godlee is also one of 28 signaturies to a letter published in The Times today (thetimes.co.uk/letters) calling on drug companies to “come clean” and make clinical trial data for all drugs in current use available to healthcare professionals.

Pressure from politicians is also mounting. Last week, Sarah Wollaston, a GP and Conservative MP, raised the issue of missing data in Parliament, while Health Minister Norman Lamb has agreed to meet experts to discuss the issue of access to clinical trial data.

In December 2009, Roche made a public promise to release full clinical trial reports of its antiviral drug oseltamivir (Tamiflu) in response to a major investigation by the BMJ and researchers Peter Doshi and Tom Jefferson from the Cochrane Collaboration.

The investigation found no clear evidence that Tamiflu prevents complications like pneumonia in healthy people. It also raised serious concerns about access to drug data, the use of ghost writers in drug trials, and the drug approval process.

Since the investigation, some further data have been released to the Cochrane reviewers, but the full data set has still not been provided.

The Cochrane reviewers now know that there are at least 123 trials of Tamiflu and that the majority (60%) of patient data from Roche Phase 3 completed treatment trials remain unpublished. Their main concerns relate to “the likely overstating of effectiveness and the apparent under-reporting of potentially serious adverse effects.”

Meanwhile, Tamiflu has been a great commercial success for Roche and has been added to the World Health Organisation’s list of essential medicines.

In her letter, Dr Godlee appeals to Professor Bell “to bring your influence to bear on your colleagues on Roche’s board.” She adds: “In refusing to release these data of enormous public interest, you put Roche outside the circle of responsible pharmaceutical companies. Releasing the data would do a great deal to restore confidence in your company and its board of directors.”

In a response not for publication, Professor Bell said he has referred the matter to Roche and is awaiting a response.

“The open correspondence on bmj.com aims to hold specific individuals and organisations to account,” writes Dr Godlee in an accompanying editorial. “Their actions are preventing independent scrutiny of the results of clinical trials and putting patients’ lives at risk. We also hope it will contribute to a sea change in the public mood.”

A poll on bmj.com last week asked: “Who is mainly at fault for denying access to negative clinical trial results?” Of the 569 votes, 69% said pharma, 13.5% said regulators, and 9% said legislators.

The BMJ plans to launch other campaigns linked to its investigations in the future.

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France, Germany, Spain, Italy, and Switzerland now imposing partial ban on the Novartis Flu Vaccine

France halts sale of Novartis flu vaccine

Fri, 26 Oct 2012 14:18 GMT

Source: reuters

(Adds comment from European Medicines Agency)

PARIS, Oct 26 (Reuters) – France said it was halting sales of an influenza vaccine made by Swiss drugmaker Novartis as a precaution after potential impurities were found in batches of the product in Italy.

Health Minister Marisol Touraine said on Friday she had asked for all doses of Agrippal to be withdrawn from the market.

“At this stage no impurities have been found in France … There is no known risk for patients who have used this brand in France,” Touraine said in a statement.

France said it had taken the action pending a decision by the European Medicines Agency (EMA), although the London-based agency said it was not taking a lead in investigations since the flu vaccine was authorised by national governments.

The EMA is responsible for medicines that are authorised centrally, although it may be called on to help with issues concerning nationally approved products if requested by the European Commission or governments.

“At the moment there is no regulatory action from our side,” an EMA spokeswoman said.

The French decision follows the announcement by Swiss and Italian authorities on Wednesday that they were banning some flu vaccines produced by Novartis after small white particles were discovered in Italy in injections.

German and Spanish authorities also imposed a ban on certain Novartis flu vaccines on Thursday.

Agrippal is the only Novartis flu vaccine marketed in France. The ban in Switzerland concerns Novartis’ Fluad as well as Agrippal, while Italy has also withdrawn subunit Influpozzi and adjuvanted Influpozzi.

Novartis said on Thursday it believed its flu vaccines were safe, despite the discovery of aggregated protein in a batch of vaccine which was not released to the market. (Reporting By Vicky Buffery and Ben Hirschler; Editing by Keiron Henderson and Helen Massy-Beresford)

http://www.trust.org/alertnet/news/france-halts-sale-of-novartis-flu-vaccine/

Effects of Tamiflu still uncertain, warn experts, as Roche continues to withhold key trial data

2 years after pharmaceutical giant Roche promised the BMJ it would release key Tamiflu trial data for independent scrutiny, the safety and effectiveness of this anti-influenza drug remains uncertain, warn experts today

Two years after pharmaceutical giant Roche promised the BMJ it would release key Tamiflu trial data for independent scrutiny, the safety and effectiveness of this anti-influenza drug remains uncertain, warn experts today.

A new report by the Cochrane Collaboration says Roche’s refusal to provide full access to all its data leaves critical questions about how well the drug works unresolved.

A BMJ investigation, published to coincide with today’s report, also raises serious concerns about access to drug data, the use of ghost writers in drug trials, and the drug approval process.

Meanwhile, Tamiflu has become the mainstay of influenza treatment in the UK. It has also made it onto the World Health Organisation’s list of Essential Medicines and Roche’s claims continue to be supported by influential health agencies.

The Cochrane researchers set out to test Roche’s claim that Tamiflu prevented complications and reduced the number of people needing hospital treatment. But their investigation was hampered by Roche’s refusal to provide all of its trial data for analysis. The team obtained some clinical study reports from the European Medicines Agency (EMA), but found inconsistencies with published reports and possible under-reporting of side effects.

When previously questioned by the BMJ, Roche also admitted that some of the published papers had been ghost written.

The BMJ investigation reveals how different regulators took different approaches to the data submitted to them, leading to conflicting messages about it effectiveness.

For example, the EMA released a proportion of the clinical study reports relating to the Tamiflu trials to Cochrane, but it admits that it did not ask for the remainder from the manufacturer, although it was legally entitled to do so. The EMA has since told the BMJ that it plans to start publishing reports for all drugs submitted for approval in the next few years.

Dr Fiona Godlee, BMJ Editor-in-Chief says: “We hope very much that the EMA will indeed take this important step in making the full study reports available. But we are still a long way away from having a full trial history for all drugs in clinical use. Public safety and the proper use of public money demands that we should stop at nothing less than this.”

Meanwhile, the US Food and Drug Administration (FDA), which has reviewed the Tamiflu trial programme in perhaps more detail than anyone outside of Roche, chose not to review the largest ever trial of Tamiflu when considering the drug for approval. It states that “Tamiflu has not been shown to prevent such complications [serious bacterial infections].”

However, the US Centers for Disease Control and Prevention (CDC) continue to cite key published trials of Tamiflu, claiming a reduced risk of influenza complications, even after Roche admitted that some of these trials have been ghost written.

Dr Godlee says: “The discrepancies between the conclusions reached by different regulators around the world highlights the absurd situation we find ourselves in. In a globalised world, regulators should cooperate and pool their limited resources. Otherwise we will continue to waste money and risk people’s health on drugs that don’t work.”

The investigation also raises questions about Tamiflu’s clinical effects. After careful evaluation of trial data, the Cochrane group say that Tamiflu appears to affect antibody production – a claim that Roche refutes. This is important, say Cochrane, because influenza vaccination relies on an antibody response to be effective. But when asked by the BMJ, Roche refused to explain how the drug works.

As such, the Cochrane group say that “until more is known about the mode of action of neuraminidase inhibitors, health professionals, patients and other decision makers need to reflect on the findings of this review before making any decision about the use of the drug.”

Cochrane also argue that Tamiflu’s ability to prevent the spread of influenza has not been demonstrated in trials. Yet this is one of the main reasons governments around the world have spent billions of dollars stockpiling Tamiflu in case of a pandemic.

Roche maintain they provided the Cochrane team with enough information to conduct their evaluation, but the Cochrane team say this is not the case. Dr Peter Doshi from Johns Hopkins University School of Medicine says: “In the BMJ in December 2009, Roche promised full study reports to any legitimate investigators. They have not provided a single full study report to Cochrane, despite our repeated requests.”

Roche under investigation by UK watchdogs

Drug giant probed for not disclosing 15,000 patient death reports: Roche under investigation by UK watchdogs after 80,000 ‘adverse reactions‘

By Jo Macfarlane

PUBLISHED:16:48 EST, 7 July 2012 | UPDATED:08:20 EST, 8 July 2012

One of the world’s biggest drug companies is at the centre of an urgent investigation after failing to disclose reports that 15,000 people died while taking its medicines.

Swiss pharmaceutical giant Roche failed to pass on a further 65,000 reports of suspected side effects that were recorded by patients.

All of the reactions took place in the United States over the past 15 years with medicines used to treat breast cancer, bowel cancer, hepatitis B, and skin and eye conditions.

Roche, one of the world’s biggest drug companies, is at the centre of an urgent investigation after failing to report that people died while taking their medication

There is no evidence so far of any direct link between the problems and the drugs – but medicines watchdogs say they are taking Roche’s failure to disclose possible concerns ‘extremely seriously’.

The drugs involved include Herceptin, given to about 10,000 breast cancer patients in Britain, and Lucentis, which is used to treat about 20,000 UK patients a year with age-related vision loss. The NHS pays Roche millions of pounds for these treatments every year.

The extent of the failings were discovered when the UK medicines watchdog, the Medicines and Healthcare products Regulatory Agency (MHRA), carried out a routine inspection of Roche’s drug safety procedures at its headquarters in Welwyn Garden City, Hertfordshire.

The company has now been ordered by the MHRA and the EU-wide regulator, the European Medicines Agency, to investigate immediately each of the total 80,000 deaths and side effects reported. Both agencies said they were ‘taking action’ over Roche’s failures.

All of the deaths and possible adverse reactions were reported by patients who rang a call centre run by Roche’s US subsidiary Genentech. Staff there failed to pass on the reports to Roche’s drug safety team – but it is not known why

Professor Sir Kent Woods, chief executive of the MHRA, said: ‘Patients should continue to take their medicines because our investigation has currently found no evidence of a safety risk to patients.

‘Roche’s actions are unacceptable and our investigation has identified that its reporting systems are inadequate. We are taking urgent action to ensure that these are rectified by Roche as a matter of priority. We will take action to ensure that patients are protected now and in the future.’

Roche, which made profits of £6.3 billion in 2010, has a legal duty to examine every suspected side effect and report them to regulators around the world so that potential safety concerns can be investigated.

This means that each side effect reported to the patient support call centre should have been immediately sent to the safety team to be assessed.

These must then be sent to regulators – within 15 days for the most serious reactions – even if no link between the drug and the reaction be proved.

Some of the call centre’s records, which date back to 1997, are said to have been noted down on paper and kept in boxes.

The European Medicines Agency, which made the findings public, said: ‘There is at present no evidence of a negative impact for patients and while the investigations and being conducted there is no need for patients or healthcare professionals to take any action.’

A number of drugs are being investigated following the incident

However, a spokeswoman added: ‘It’s not often we make statements on such findings, so we do take this incredibly seriously. The numbers are huge but we’re not talking about confirmed reactions.

‘Some might not be related, and some may have already been reported to the regulators via other mechanisms – for example directly to us by doctors.’ But she added: ‘We cannot rule out that additional safety concerns could be discovered.’

When asked if legal action could be taken against Roche, she said: ‘We are looking at all options. There are penalty regulations and they could be fined.’

Other drugs being examined include Avastin, used for bowel and breast cancer; lung cancer medication Tarceva; Rituxan, which treats non-Hodgkin’s lymphoma; the stroke drug Alteplase; Actemra for rheumatoid arthritis; Pegasys for hepatitis B; and Raptiva for the skin condition psoriasis.

If any new safety concerns emerge after examining the data, regulators could decide to withdraw the drugs or change their guidance to doctors.

In a statement, Roche said: ‘Patient safety is of paramount importance to Roche. We acknowledge the concerns that can be caused by this issue for people using our medicines.

‘The non-assessment and non-reporting of these adverse events was not intentional and we are taking comprehensive steps necessary to address the findings of the MHRA inspection. We have provided initial estimates of missed adverse events and are in the process of confirming the final number.

‘We expect to complete all activities related to these programmes as soon as possible.’