More abut Tamiflu


Cochrane CollaborationImage via Wikipedia

By Michael Smith, North American Correspondent, MedPage Today
Published: January 17, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
A new review of the influenza drug oseltamivir (Tamiflu) has raised questions about both the efficacy of the medication and the commitment of its maker to supply enough data for claims about the drug to be evaluated by independent experts.

It also raises questions about the entire process of systematic review.

Researchers led by Tom Jefferson, MD, of the Cochrane Collaboration, pored over 15 published studies and nearly 30,000 pages of “clinical study reports.”

But, they reported, the clinical study information – data previously shared only with regulators – was only a part of what internal evidence suggested was available.

And many published studies had to be excluded because of missing or contradictory data, Jefferson and colleagues reported.

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Action Points  


  • Explain that a new review of an important flu drug has raised questions about the medication and the entire process of systematic review.
  • Point out that the review of oseltamivir showed that there was no evidence of effect on hospital admissions.
The drug’s maker, Switzerland-based Roche, had promised after a previous Cochrane review to make all of its data available for “legitimate analyses.” After a request for the data, Jefferson and colleagues reported, the company sent them 3,195 pages covering 10 treatment trials of the drug.
But, three of the reviewers noted in a parallel report in BMJ, the tables of contents suggested that the data were incomplete.
“What we’re seeing is largely Chapter One and Chapter Two of reports that usually have four or five chapters,” according to theBMJ article’s lead author, Peter Doshi, PhD, of Johns Hopkins University.
Roche did not immediately respond to a telephoned request for comment.
Requests for More Data
The researchers then asked the European Medicines Agency (EMA) for the data, under a Freedom of Information request, and obtained a further 25,453 pages, covering 19 trials.
But that data, too, was incomplete, they said, although the agency said it was all that was available.
The FDA is thought to have the complete reports, but has not yet responded to requests for them, the researchers reported.
Regulatory agencies such as the EMA and FDA routinely see the large clinical study reports, Jefferson and colleagues said in BMJ, but systematic reviewers and the general medical public do not.
“While regulators and systematic reviewers may assess the same clinical trials, the data they look at differs substantially,” they said.
The Cochrane group has been trying for several years to put together a clear-cut systematic review of the evidence on antivirals aimed at flu.
In 2006, the group concluded that the evidence showed that oseltamivir reduced the complications of the flu. But that conclusion was challenged on the basis that a key piece of data was flawed.
An updated review in 2009 – throwing out the flawed study — concluded there wasn’t enough evidence to show that the drug had any effect on complications.
For this analysis, the Cochrane reviewers had originally intended to perform a systematic review on both of the approved neuraminidase inhibitors – oseltamivir and zanamivir (Relenza), using the clinical study reports to supplement published trials.
In the end, they decided that for oseltamivir, they needed more detail in order to perform the review in its entirety. But, they reported, some conclusions could be drawn from published data on the 15 trials and from 16,000 pages of clinical study reports that were available before their deadline.
They also decided to postpone analysis of zanamivir (for which they had 10 trials) because the drug’s maker, GlaxoSmithKline, offered individual patient data which they wanted time to analyze.
The oseltamivir analysis showed:
  • The time to first alleviation of symptoms in people with influenza-like illness was a median of 160 hours in the placebo groups and about 21 hours shorter in those treated with oseltamivir. The difference, evaluated in five studies, was significant at P<0.001.
  • There was no evidence of effect on hospital admissions: In seven studies, the odds ratio was 0.95, with a 95% confidence interval from 0.57 to 1.61, which was nonsignificant atP=0.86.
  • A post-protocol analysis of eight studies showed that oseltamivir patients were less likely to be diagnosed with influenza.
  • The data “lacked sufficient detail to credibly assess” any effect on influenza complications and viral transmission.
Data Discrepancies Found
But discrepancies between the published trial data and the clinical study reports “led us to lose confidence in the journal reports,” Doshi and colleagues wrote in BMJ.
For example, they noted that one journal report clearly said there were no drug-related serious adverse events, but the clinical study report listed three that were possibly related to oseltamivir.
As well, the sheer scope of the clinical study reports meant that much was left out of journal reports. One 2010 study, on safety and pharmacokinetics of oseltamivir at standard and high dosages, took up seven journal pages and 8,545 pages of the clinical study report.
But the researchers were also shaken, they said, by the “fragility” of some of their assumptions.
For instance, they found that the clinical study reports showed that in many trials, the placebo contained two chemicals not found in the oseltamivir capsules.
“We could find no explanation for why these ingredients were only in the placebo,” they wrote in BMJ, “and Roche did not answer our request for more information on the placebo content.”
Jefferson and colleagues also reported they found disparities in the numbers of influenza-infected people reported to be present in the treatment versus control groups of oseltamivir trials.
One possible explanation, they noted, is that oseltamivir affects antibody production – even though the manufacturer says it does not.
Gaps in Knowledge Remain
That question is profoundly important, Doshi told MedPage Today, because it may offer clues to how the drug works – one of the gaps in knowledge about oseltamivir.
“You can’t make good therapeutic decisions if you don’t know how the drugs works,” he said – information that he and his colleagues suspect may be buried in the mass of missing data.
It’s also important, he said, because public health agencies have been making decisions to stockpile oseltamivir without a clear understanding of the facts.
Essentially, he said, those decisions have been based on the flawed study – a Roche-supported meta-analysis – that was thrown out of the 2009 Cochrane review.
“They’re taking the drug manufacturer’s word at face value,” he said.
The results seem unlikely to resolve conflicts over the medical value of the drug, which is a major cash cow for Roche, adding some $3.4 billion to the company’s bottom line in 2009 alone, according to Deborah Cohen, investigations editor of BMJ.
In an accompanying article, Cohen said that “clinicians can be forgiven for being confused about what the evidence on oseltamivir says.”
She noted that the European Centre for Disease Prevention and Control, the CDC, and the World Health Organization “differ in their conclusions about what the drug does.”
As well, those conclusions are often contradicted by claims on the drug labels – themselves allowed by regulators, Cohen argued.
The Cochrane reviewers reported grant support from the U.K. National Institute for Health Research and Jefferson and Doshi reported they had no recent financial links with industry.
Cohen is employed by BMJ.

Roche Refuses To Disclose Tamiflu Data: Scientists


Roche Refuses To Disclose Tamiflu Data: Scientists


confidential.jpgAn influential review that is due out tomorrow will not contain up-to-date efficacy information about Tamiflu, the widely used influenza drug sold by Roche, because researchers at the Cochrane Collaboration say they were stymied by the drugmaker in their efforts to fully assess the medication, according to reports.
Iain Chalmers, one of the founders of the Cochrane Collaboration, a non-profit group dedicated to analyzing medical evidence, last week told a conference on research integrity in London that a review of influenza treatments will state that Roche would not comply with requests to provide additional dataNature writes.
“We have invested millions of pounds on stockpiling Tamiflu on the basis of a paper that presented the results of 12 trials, only two of which have been published. The investigation… shows Roche refused to provide data to evaluate these trials. Investigators got some data through the European Medicines Agency, but this doesn’t answer all of the questions they have,” he tells The Independent. “It is a disgrace that Roche have not provided this data.”
This is not the first time that the Cochrane scientists have tangled with Roche. An earlier review about Tamiflu and the Relenza drug made by GlaxoSmithKline was withdrawn in 2010, as the researchers made clear in two different pieces in BMJ in which they complained about unpublished studies the drugmaker would not release (see this and this).
Tom Jefferson, the lead author of the study, tells The Independent he was concerned that the European Medicines Agency, which approved Tamiflu, only saw some trial results and the FDA is believed not to have reviewed the largest ever trial of Tamiflu when the med was being considered for approval.
A Roche spokesperson tells the newspaper that full clinical study data was made available to regulators for review as part of the approval process, and that all completed Roche-sponsored studies on safety and efficacy were available as peer-reviewed publications or in summary form. The Cochrane researchers were also given access to 3,200 pages of detailed information. “Roche stands behind the robustness and integrity of our data supporting the efficacy and safety of Tamiflu,” Roche says.
We will see what tomorrow brings, yes?

Una empresa comprometida con la salud………un de-Roche


La multinacional Roche admitió que no entregará algunos   antitumorales a hospitales de Grecia, medida que tomaría en lo pronto en   España. Es por el retraso de los pagos, que alcanza los varios meses. En el   país helénico, otros laboratorios ya retiraron algunos fármacos del mercado.  

El fantasma de la crisis financiera se extienda   en Europa a cada vez más países y cada vez más sectores. Durante el fin de   semana, el anuncio del laboratorio Roche –que advirtió que dejará de   suministrar algunos medicamentos a varios hospitales de Grecia y España   –despertó la alarma en materia sanitaria. Especialistas aseguran que esta   situación puede extenderse a otras partes del mundo.  
   
  En un artículo publicado por el diario El País, el director general de Roche   Severin Schwan aseguró que su empresa “ya no entrega medicamentos destinados   a curar el cáncer y otras enfermedades” a los hospitales de Grecia, medida   que se extendería en lo inmediato a España y otros países. Por esto, los   pacientes tienen que comprar el tratamiento antitumoral en la farmacia y pagarlo   de su bolsillo.
   
  En el país ibérico, la situación causa alarma. La filial española de Roche   afirma que “al igual que sucede en otros países, la situación de crisis   y deuda en España es significativa y, en el caso de algunas comunidades   autónomas se encuentra al límite”. La compañía destaca que la mayoría de   sus operaciones se centran en los hospitales, por lo que es   “especialmente vulnerable a la morosidad” de las administraciones y   por eso “su impacto en la compañía es más grave y más rápida que para   otros laboratorios”.  
   
  Según El País, a 31 de marzo, la deuda de los hospitales públicos españoles   con el sector ascendía a 5.191 millones pero ya ha superado los 5.400   millones, según la patronal del sector, Farmaindustria. La demora media en el   pago es ya de un año y dos meses. Hay comunidades, como Castilla y León, que   pagan con casi dos años de retraso de media. Roche destaca que   “determinados hospitales de Castilla y León” acumulan   “retrasos superiores a los 900 días”, casi dos años y medio,   mientras que en Andalucía, Valencia y Castilla-La Mancha el periodo medio de   pago supera los 600 días.
   
  Roche insiste en que esto “supera ampliamente los plazos de demora en el   pago que marca la ley” y que a pesar de ello lleva meses negociando con   las comunidades para evitar el desabastecimiento.
   
  Humberto Arnés, director general de Farmaindustria, huye de la comparación   con Grecia: “En España hay problemas porque las empresas farmacéuticas   están financiando el déficit de las comunidades y hay una gran deuda. Pero   está reconocida, contabilizada y se va a cobrar. El problema es que quien ha   prestado a Grecia ya se arriesga a no ver el dinero”. “Hay un   problema y el pago del sistema sanitario debería ser prioritario, porque   además así lo piden los ciudadanos, pero no hay riesgo de   desabastecimiento”, añade Arnés.
   
  Una portavoz del Ministerio de Sanidad coincide en distanciarse de Grecia:   “La situación de los proveedores no tiene nada que ver. Ni contemplamos   que ocurra algo parecido a lo de Grecia y hay incluso garantías legales para   recibir el tratamiento. El sistema sanitario es sostenible”.
Si la situación de   España preocupa, en Grecia se está al borde del colapso. En el país helénico,   además de Roche otras empresas como la danesa Novo Nordisk cortó el   suministro de ciertos tipos de insulina con el argumento de que se había   reducido los precios más de un 25 por ciento. En junio pasado Leo Pharma se   sumó a Novo y dejó de vender dos de sus medicamentos (un anticoagulante y   otro para la soriasis) en el país. El Gobierno de Papandreu finalmente cedió   y aceptó no rebajar tanto el precio. La Asociación Helénica de Farmacéuticas   calcula que los hospitales públicos han pagado tan solo un 37 por ciento de   los 1.900 millones de euros que gastaron en medicinas desde enero de 2010 a   junio de 2011.
   
Kaitanibi replica que la mayor parte de la deuda   del sector es de hace años, ya que el Gobierno está haciendo ahora un   esfuerzo por pagar más rápido. La deuda total que arrastran los hospitales   con todos sus proveedores ronda los 8.000 millones de euros.
   
“Hace seis meses tuvimos un problema con la   recepción de medicamentos, pero ahora no he notado nada”, afirma el   cirujano Antonis Doumoulakis, que asegura que uno de los problemas del   sistema es la corrupción del sistema público, que hace que muchas farmacéuticas   ofrezcan dinero o regalos a los médicos que receten sus productos. “Por   eso el Gobierno quiere hacer un experimento con los tres mayores hospitales   del país: que solo podamos elegir una marca para cada fármaco”, explica.   La idea es ejercer un control más estricto sobre la gestión de los centros   para controlar unos costes que se han disparado.
   
Ante esta amenaza, el ministerio de Sanidad   explicó que los pacientes de España “pueden estar tranquilísimos”   respecto al suministro de medicamentos. Sin embargo, hay preocupación en   varios aspectos.

BUENOS AIRES: La multinacional Roche admitió que no entregará algunos   antitumorales a hospitales de Grecia, medida que tomaría en lo pronto en   España. Es por el retraso de los pagos, que alcanza los varios meses. En el   país helénico, otros laboratorios ya retiraron algunos fármacos del mercado.  

El fantasma de la crisis financiera se extienda   en Europa a cada vez más países y cada vez más sectores. Durante el fin de   semana, el anuncio del laboratorio Roche –que advirtió que dejará de   suministrar algunos medicamentos a varios hospitales de Grecia y España   –despertó la alarma en materia sanitaria. Especialistas aseguran que esta   situación puede extenderse a otras partes del mundo.  
   
  En un artículo publicado por el diario El País, el director general de Roche   Severin Schwan aseguró que su empresa “ya no entrega medicamentos destinados   a curar el cáncer y otras enfermedades” a los hospitales de Grecia, medida   que se extendería en lo inmediato a España y otros países. Por esto, los   pacientes tienen que comprar el tratamiento antitumoral en la farmacia y pagarlo   de su bolsillo.
   
  En el país ibérico, la situación causa alarma. La filial española de Roche   afirma que “al igual que sucede en otros países, la situación de crisis   y deuda en España es significativa y, en el caso de algunas comunidades   autónomas se encuentra al límite”. La compañía destaca que la mayoría de   sus operaciones se centran en los hospitales, por lo que es   “especialmente vulnerable a la morosidad” de las administraciones y   por eso “su impacto en la compañía es más grave y más rápida que para   otros laboratorios”.  
   
  Según El País, a 31 de marzo, la deuda de los hospitales públicos españoles   con el sector ascendía a 5.191 millones pero ya ha superado los 5.400   millones, según la patronal del sector, Farmaindustria. La demora media en el   pago es ya de un año y dos meses. Hay comunidades, como Castilla y León, que   pagan con casi dos años de retraso de media. Roche destaca que   “determinados hospitales de Castilla y León” acumulan   “retrasos superiores a los 900 días”, casi dos años y medio,   mientras que en Andalucía, Valencia y Castilla-La Mancha el periodo medio de   pago supera los 600 días.
   
  Roche insiste en que esto “supera ampliamente los plazos de demora en el   pago que marca la ley” y que a pesar de ello lleva meses negociando con   las comunidades para evitar el desabastecimiento.
   
  Humberto Arnés, director general de Farmaindustria, huye de la comparación   con Grecia: “En España hay problemas porque las empresas farmacéuticas   están financiando el déficit de las comunidades y hay una gran deuda. Pero   está reconocida, contabilizada y se va a cobrar. El problema es que quien ha   prestado a Grecia ya se arriesga a no ver el dinero”. “Hay un   problema y el pago del sistema sanitario debería ser prioritario, porque   además así lo piden los ciudadanos, pero no hay riesgo de   desabastecimiento”, añade Arnés.
   
  Una portavoz del Ministerio de Sanidad coincide en distanciarse de Grecia:   “La situación de los proveedores no tiene nada que ver. Ni contemplamos   que ocurra algo parecido a lo de Grecia y hay incluso garantías legales para   recibir el tratamiento. El sistema sanitario es sostenible”.
Si la situación de   España preocupa, en Grecia se está al borde del colapso. En el país helénico,   además de Roche otras empresas como la danesa Novo Nordisk cortó el   suministro de ciertos tipos de insulina con el argumento de que se había   reducido los precios más de un 25 por ciento. En junio pasado Leo Pharma se   sumó a Novo y dejó de vender dos de sus medicamentos (un anticoagulante y   otro para la soriasis) en el país. El Gobierno de Papandreu finalmente cedió   y aceptó no rebajar tanto el precio. La Asociación Helénica de Farmacéuticas   calcula que los hospitales públicos han pagado tan solo un 37 por ciento de   los 1.900 millones de euros que gastaron en medicinas desde enero de 2010 a   junio de 2011.
   
Kaitanibi replica que la mayor parte de la deuda   del sector es de hace años, ya que el Gobierno está haciendo ahora un   esfuerzo por pagar más rápido. La deuda total que arrastran los hospitales   con todos sus proveedores ronda los 8.000 millones de euros.
   
“Hace seis meses tuvimos un problema con la   recepción de medicamentos, pero ahora no he notado nada”, afirma el   cirujano Antonis Doumoulakis, que asegura que uno de los problemas del   sistema es la corrupción del sistema público, que hace que muchas farmacéuticas   ofrezcan dinero o regalos a los médicos que receten sus productos. “Por   eso el Gobierno quiere hacer un experimento con los tres mayores hospitales   del país: que solo podamos elegir una marca para cada fármaco”, explica.   La idea es ejercer un control más estricto sobre la gestión de los centros   para controlar unos costes que se han disparado.
   
Ante esta amenaza, el ministerio de Sanidad   explicó que los pacientes de España “pueden estar tranquilísimos”   respecto al suministro de medicamentos. Sin embargo, hay preocupación en   varios aspectos.

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An Avastin Recommendation & Conflicts Of Interest


Earlier this month, the National Comprehensive Cancer Network, a non-profit group of oncologists whose guidance is closely followed by leading treatment centers, voted overwhelmingly in favor of maintaining its recommendation that Avastin should be used to treat breast cancer. The vote came shortly after an FDA panel voted 6-to-0 to revoke the breast cancer indication for Avastin.
The endorsement is important because oncologists will likely continue to use Avastin even if FDA commish Margaret Hamburg rescinds the breast cancer indication. Roche and its Genentech unit had appealed a decision last December by the agency to pull the indication for their best-selling med after new studies showed the med does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh significant risks. This prompted the unusual two-day hearing last month (back stories here and here).
However, 10 of the 33 members of the NCCN breast cancer panel members have ties to Roche or Genentech, either as advisory board members, speakers, consultants, expert witnesses or having received clinical research support. These connections are disclosed on the NCCN web site (look here). And 25 members of the panel participated in the recent vote to maintain the recommendation.
Specifically, the NCCN panel voted 24 in favor, 0 against and 1 abstention. The simple math suggests that at least one panel member – and possibly two – with ties to Roche voted to support the metastatic breast cancer recommendation. Perhaps more panel members with connections voted, although there is now way to know ascertain this since the NCCN press release does not specify who participated in the voting.
As we have noted previously, the NCCN endorsement is likely to be a boon for Roche, since treatment for breast cancer has typically generated about $1 billion or more in annual sales. Avastin rings registers – worldwide sales last year totaled about $6.8 billion and rose 9 percent, which meant this one drug accounted for 14 percent of total Roche sales. In other words, much is at stake.
Meanwhile, the stated NCCN policy conflicts of interest requires “disclosure of external relationships and recusal of NCCN Guidelines Panel Members with conflicting interests so that the integrity of the NCCN Guidelines is not compromised or diminished by conflicts or by the perception of conflicts,” according to the NCCN web site.
The policy also states that a panel member with a significant and direct or indirect relationship with “an external entity” that constitutes a conflict shall not participate in NCCN Guidelines Panel discussions, when the panel’s action on the topic under discussion “may advantage or disadvantage an external entity.” An exception is granted when requested by the panel chair “to participate for the purpose of providing or presenting information to the NCCN Guidelines Panel.”
More specifically, certain “direct relationships,” such as a panel member who is a beneficial owner of stock in an “external” entity or a director of such an organization” would be considered to have a de facto conflict. The policy also defines “direct relationships” as anyone “who receives compensation for services including, but not limited to, management or consulting services to the organization” (here is the policy).
So we asked NCCN whether this policy was followed for the recent breast cancer panel, given that the vote tally suggested otherwise. The spokeswoman repeatedly declined to discuss specifics and referred us back to the recent press release which, again, offers no information on the topic. In fact, she refused to answer whether NCCN has a recusal policy, even though this exists on the web site. “I’m only allowed to discuss what is in the press release,” she told us over and over.
We also reached out to the 10 panel members who have ties to Roche and Genentech. One responded. Antonio Wolff wrote us to confirm that “Genentech provides funding to Johns Hopkins University (where I am employed as School of Medicine faculty) to support research costs associated with an ongoing early phase clinical trial, and I am the site PI for that study. As for your specific question regarding my activities within NCCN, I will ask (you) to contact it directly as NCCN requires all panel members to adhere to its confidentiality policy.”
And so, an influential panel with ties to a drugmaker – which has a lot of sales on the line – voted to maintain a key recommendation. In this instance, NCCN panel members fully disclosed their ties to Roche, but is this sufficient? Supposedly, there is a reason NCCN has a disclosure and recusal policy, but in this instance, there would appear to have been a breach. If none occurred, the organization should be willing to discuss specifics and defend its policy. Yet NCCN refused to do so. What do you think?
Source: Pharmalot