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.
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:
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.
Primary source: Cochrane Database of Systematic Reviews
Jefferson T, et al “Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children” Cochrane Database of Systematic Reviews 2011; 12. Art. No.: CD008965.
Additional source: BMJ
Cohen D “Flu drugs: search for evidence goes on” BMJ 2012; 344: e458.
Additional source: BMJ
OBJECIONES EN RELACION CON AMBAS VACUNAS DISPONIBLES CONTRA EL VIRUS DEL PAPILOMA HUMANO
(especial para SIIC © Derechos reservados)
|Se presenta un análisis del diseño, evaluación, aplicación y seguimiento de las 2 vacunas disponibles contra el HPV llevado a cabo por ambos laboratorios fabricantes para comentar sobre su aplicación. Se incluye una breve revisión bibliográfica sobre la historia natural del HPV, el comportamiento del sistema inmune y otros factores en el desarrollo del cáncer cervical uterino.|
Columnista Experto de SIIC
Hospital Materno-Neonatal Artículos publicados por Teresita Audisio
Vainer Osvaldo*** Ramallo Rogelio* Vásquez Federico** Ringelheim Claudia**** Pelliza Palmes Maria Nuria****
Doctor, Clínica del Niño, Córdoba, Argentina*
Doctor, Clínica del Noreste, Córdoba, Argentina**
Doctor, Hospital Materno-Neonatal, Córdoba, Argentina***
Doctora, Hospital Materno-Neonatal, Córdoba, Argentina****
|Recepción del artículo
10 de marzo, 2010
26 de junio, 2010
26 de agosto, 2011
|Segunda edición, ampliada y corregida
21 de septiembre, 2011
Las infecciones genitales por el virus papiloma humano (HPV) son altamente frecuentes tanto en adultos como en niños; varios estudios demuestran la relativa frecuencia en esta población de los serotipos oncogénicos del HPV (16 y 18), como sus proteínas tempranas (early proteins); por lo que se objeta que la vía de transmisión sexual sea la única. El comportamiento biológico de las neoplasias intraepiteliales cervicales (CIN) I y II en las adolescentes y adultos jóvenes es similar y presenta una alta tasa de regresión espontánea. Por lo tanto, la indicación de las dos vacunas para el HPV disponibles actualmente en el comercio no condice con la historia natural del HPV y las CIN. Los estudios realizados con ambas vacunas han demostrado la baja efectividad y el efecto contraproducente cuando los sujetos eran ADN-HPV positivos a los tipos de HPV que contiene la vacuna, por lo que sería peligroso vacunar si no está asegurado el control de los sitios donde se ubican los tipos de HPV, como el aparato genital. Además, el corto seguimiento de los estudios realizados con ambas vacunas no permitió observar la repercusión en el estado inmunitario, como también el remplazo por los serotipos de HPV que no contiene la vacuna. La rápida autorización de la US Food and Drug Administration (FDA) y de la European Medicines Agency (EMEA) llevó a la introducción de la vacuna en muchos países, sin tener en cuenta las indicaciones y las repercusiones mencionadas.
Clasificación en siicsalud
Artículos originales > Expertos de Iberoamérica >
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Genitals infection through human papilloma-virus (HPV) is frequently found in both adults and children, and several studies show the relative frequency of oncogenic HPV (16 and 18) in this population as well as their early proteins. This is why we object to the claim that this virus is exclusively sexually transmitted. The biological behavior of cervical intraepithelial neoplasia (CIN) I and II in teenagers and young adults is similar, presenting high spontaneous regression. Therefore, the indications for the two HPV vaccines do not match the natural history of HPV and CIN. The studies performed with both these vaccines have shown their low rate of efficacy and their counterproductive effect when the vaccinated subjects were HPV DNA positive to the HPV types in the vaccine, on account of this, vaccination without control of possible HPV type locations such as the genital apparatus would be dangerous. Besides, the short follow-up that has been made of the studies carried out with both vaccines has not allowed us to see their effects on immune system status nor on possible replacement by other types of HPV not contained in the vaccine. The fact of its rapid authorization by the U S Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) led to the introduction of the vaccine in many countries without considering its indications and the repercussions mentioned above.
Bibliografía del artículo 1. VRBPAC. VRBPAC background document. Gardasil HPV quadrivalent vaccine. Vaccine and Related Biological Products Advisory Committee Meeting. Washington, DC, USA; May 18, 2006 http://www.fda.gov/ohrms/dockets/ac/06/briefi ng/2006-4222B3.pdf (accessed may 20, 2008).
Delayed FDA Removal of Painkiller Propoxyphene (Darvon, Darvocet) From U.S. Market Has Cost More Than 1,000 U.S. Lives
Statement by Dr. Sidney Wolfe, Director, Public Citizen’s Health Research Group
Note: Public Citizen petitioned the FDA in 1978 and 2006 to ban propoxyphene.
The announcement by the U.S. Food and Drug Administration (FDA) that propoxyphene-containing products are finally going to be taken off the market * because of dangers previously known and acted upon, with bans announced in the UK almost six years ago, and in Europe, almost 1½ years ago * is a serious indictment of the FDA’s long-lasting unwillingness to protect people in this country from a deadly but barely effective painkiller. In announcing the ban in 2005, the UK stated that the efficacy of propoxyphene (sold generically and under the brand name Darvon) “is poorly established and the risk of toxicity in overdose, both accidental and deliberate, is unacceptable” and that “[I]n relation to safety, there is evidence that fatal toxicity may occur with a small multiple of the normal therapeutic dose and a proportion of fatalities are caused by inadvertent overdose.” The FDA’s claim that this is the first evidence that the drug is dangerous at the “standard therapeutic dose” thus rings dangerously hollow.
The FDA’s deadly delay in this case starkly illustrates how one of the most important public health concepts, the precautionary principle, was embraced by the UK and Europe, but was for too long recklessly rejected by the FDA.
Evidence going back more than 30 years indicates that propoxyphene is not very effective, is toxic at doses not much higher than the recommend dose because a heart-toxic metabolite accumulates in the body, and is somewhat addictive. It has been linked to many thousands of U.S. deaths since 1981, a large proportion of which were likely caused by cardiac toxicity, including the interruption of electrical conduction in the heart.
Since the time of the UK announcement in January 2005 of a phased, two-year withdrawal of this drug (which was followed by an immediate steep decline in use), approximately 120 million retail prescriptions have been filled in the U.S. for propoxyphene-containing drugs. These include Darvocet, which contains propoxyphene and acetaminophen and, primarily, the generic versions of the drug.
Due to FDA negligence, at least 1,000 to 2,000 or more people in the U.S. have died from using propoxyphene since time the UK ban was announced. The best forensic data, the kind relied upon in those countries for the UK and European bans, come from Florida where, because of routine drug testing required by the state medical examiner as part of many autopsies, deaths are categorized as being “caused” by certain drugs if the levels found are to be above a certain level. From 2005 through 2009, in Florida alone, 395 deaths were “caused” by propoxyphene. If data from 2007 are representative, in that year, 78 percent of the Florida deaths caused by propoxyphene were ruled accidental.
Our February 2006 petition to the FDA to ban the drug, following the UK ban announcement, did not even result in an FDA advisory committee hearing until we had sued the agency in 2008 to force them to respond to our petition. The subsequent January 2009 FDA advisory committee hearing resulted in a 14-12 vote in favour of banning propoxyphene, despite some FDA efforts to sway the committee against voting for a ban. In July 2009, several weeks after the European Medicines Agency announced its ban, the FDA denied our petition to ban the drug.
The FDA’s pitiful excuse that it needed to order a human study to find that “the drug puts patients at risk of potentially serious or even fatal heart rhythm abnormalities” before deciding whether to ban propoxyphene only emphasizes how out-of-step the agency is with the rest of the world * which already had enough human evidence of death and near-death in tens of thousands of people to act accordingly.
In a study on dogs published 31 years ago, researchers at Lilly, the discoverer of propoxyphene, stated that “cardiac conduction depression may be a factor in some of the [human] cardiac toxicities associated with propoxyphene overdose.” This study examined the same kind of function measured in the human study now being put forth by the FDA as a justification for belatedly banning propoxyphene.
We will ask for and support a congressional investigation into whom in the FDA, specifically in the Centre for Drug Evaluation and Research, was responsible for the loss of so many lives in this country. It is clear that long before today, many drug safety experts in the Office of Surveillance and Epidemiology had decided the drug should be removed from the market.
Note: For a chronology of events related to Darvon and Darvocet, go to
Public Citizen is a national, non-profit consumer advocacy organization based in Washington, D.C. For more information, please visit www.citizen.org.