FDA sets draft rules for biotech drug copies

Biogen Idec
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Thu Feb 9, 2012 4:46pm EST

(Reuters) – The Food and Drug Administration’s long-awaited guidelines for the sale of lower-cost versions of biotechnology drugs leave open the possibility that some products might not need to be tested in humans.

The proposed rules, issued on Thursday, require studies showing that the generic copies are “highly similar” to the originals, but there are several ways that might be proven.

Because of their complexity, generic copies of biotech drugs – first introduced in the 1980s – are known as “biosimilars.”

“We’re trying to send the signal that it’s not one-size-fits-all. It’s product-by-product,” Rachel Sherman, director of the FDA’s office of medical policy, said during a conference call with reporters.

The worldwide market for copies of biotech medicines will grow to $3.7 billion by 2015, from just $243 million in 2010, as more than 30 branded biologics with sales of $51 billion lose patent exclusivity, according to market analysis firm Datamonitor.

The FDA rules would set “an abbreviated pathway” to approval that would consider factors including a product’s complexity, formulation and stability, the agency said.

The proposal “reads largely as we expected, although a few points read as slightly more friendly to the generics industry,” ISI Group analyst Mark Schoenebaum said in a note to clients.

The FDA said it would decide on the “extent and scope of animal and clinical studies” needed for approval once it has considered other analytical data. The agency said it has yet to receive an application for a biosimilar drug, but nine applications have been filed for clinical trials.

Manufacturers will have the option of asking the FDA to deem their copies “interchangeable” with a brand-name drug, but the `agency said that would require additional clinical studies.

Makers of branded biotech drugs have argued that full-scale human trials need to be conducted before a rival version of an existing biologic drug should be allowed on the market.

Despite such qualms, biotech drug makers including Amgen Inc, Merck & Co and Biogen Idec are working to produce rival versions of biotech drugs made by competitors.

“While the documents provide a roadmap, they are sufficiently vague as to give FDA leeway for case by case assessments of each proposed biosimilar along their respective development paths,” said Wells Fargo analyst Brian Abrahams.

The Congressional Budget Office has estimated that the United States could save $25 billion from the use of biosimilars over 10 years.

European regulators have already approved cheaper versions of some biotech drugs.

The FDA said advances in science and manufacturing may facilitate fingerprint-like analysis of therapeutic protein products, which may allow for a more selective approach to any animal or human studies.

Unlike conventional, easy-to-replicate, chemical-based drug compounds, biotech drugs are derived from living organisms, such as proteins, and are often produced using recombinant DNA technologies.

Once a traditional pill loses patent protection, there is a quick regulatory pathway for generic drugmakers to sell much cheaper versions of the branded medicine. Similar U.S. guidelines for biotech drugs have been under negotiation for several years.

Biosimilar drugs are expected to sell at discounts of 25 to 45 percent to branded rivals, compared with generic versions of traditional pills that often sell for one-tenth the price of the branded product.

Under the U.S. healthcare reform law passed in 2010, brand-name biotech drugs – ranging from relatively simple molecules like insulin to complex antibodies used to treat cancer – were granted a 12-year period of market exclusivity, after which generic versions can be sold.

Opposing trade groups – the Biotechnology Industry Organization and the Generic Pharmaceutical Association – said they are reviewing the proposed rules.

The generic drugs group said it was pleased with the FDA’s action, which it called “an important step in getting these affordable, lifesaving medicines into the hands of doctors and patients.”

The FDA will require that biosimilar manufacturers provide a post-marketing safety monitoring program, which in some cases may include long-term clinical studies.

The agency is accepting public comment on the draft guidance documents for the next 60 days.

(Reporting by Deena Beasley in Los Angeles, Additional reporting by Bill Berkrot in New York and Anna Yukhananov in Washington; Editing by Gerald E. McCormick, John Wallace and Matthew Lewis)

Caffeine to inhale hits market

Source: Newsmap

CAMBRIDGE —  Move over, coffee and Red Bull. A Harvard professor thinks the next big thing will be people inhaling their caffeine from a lipstick-sized tube. Critics say the novel product is not without its risks. 

The product, called AeroShot, went on the market late last month in Massachusetts and New York, and is also available in France. A single unit costs $2.99 at convenience, mom-and-pop, liquor and online stores. 

Biomedical engineering professor David Edwards said AeroShot is safe and does not contain common additives, like taurine, used to amplify the caffeine effect in common energy drinks. Each grey-and-yellow plastic canister contains 100 milligrams of caffeine powder, about the amount in a large cup of coffee, plus B vitamins. 

But Democratic U.S. Sen. Charles Schumer of New York wants the U.S. Food and Drug Administration to review AeroShot, saying he fears it will be used as a club drug so that young people can drink until they drop. Schumer’s national press secretary did not immediately respond to calls for comment. 

FDA spokeswoman Siobhan DeLancey declined to comment, saying the agency will respond directly to Schumer on the matter. 

Edwards said Schumer’s comments are understandable in the context of developments over the last few years, when students looking for a quick and cheap buzz began consuming caffeine-packed alcoholic drinks they dubbed “blackout in a can” because of their potency. But he said AeroShot is not targeting anyone under 18 and it safely delivers caffeine into the mouth, just like coffee. 

“Even with coffee — if you look at the reaction in Europe to coffee when it first appeared — there was quite a bit of hysteria,” he said. “So anything new, there’s always some knee-jerk reaction that makes us believe ‘Well, maybe it’s not safe.’ ” 

Once a user shoots a puff of calorie-free AeroShot into his or her mouth, the lemon-lime powder begins dissolving almost instantly. Each single-use container has up to six puffs. 

“The act of putting it in your mouth is the act of breathing — so it’s sort of surprising and often people the first time they take the AeroShot, they laugh … that it’s kind of a funny way of putting food in your mouth,” said Edwards, who also came up with a breathable chocolate product a few years back. 

Dr. Lisa Ganjhu, a gastroenterologist and internal medicine doctor at New York-based St. Luke‘s-Roosevelt Hospital, said people need to be aware of how much caffeine they are ingesting. 

“You want those 10 cups of coffee, it will probably take you a couple hours to get through all that coffee with all that volume that you are drinking,” Ganjhu said. “With these inhale caffeine canisters you can get that in 10 of those little canisters — so you just puff away and you could be getting all of that within the hour.” 

Even the product packaging warns people not to consume more than three AeroShots per day. 

Northeastern University students who sampled the product recently gave it mixed reviews. 

“This tastes really good and I think it rocks,” student Zack Huang said after puffing onto a free sample before rushing to join a group of friends who were walking away from campus. 

Still, one student was not happy with the taste, echoing sentiment expressed online by some consumers. 

People elsewhere vowed they would never give up their morning coffee. 
“I want to brew it, I want to stir it and I want to drink it slowly as I absorb the caffeine,” said longtime coffee fan Mark Alexander. 

The makers of AeroShot appear to be aware of that sentiment, declaring that the product isn’t about switching away from coffee, but rather making it easier for people with active lifestyles to get their caffeine fix. 

“AeroShot can be used in a variety of settings inconvenient for liquids, such as when you study in the library, board an airplane or get into the car for a long drive,” they say in the section dedicated to frequently asked questions on their website. “It’s easy to take AeroShot with you when you go biking, skiing, curling, or any other activity that consumes energy.” 

AeroShot, manufactured in France and the flagship product of Cambridge-based Breathable Foods Inc., is the product of a conversation that Edwards had with celebrity French chef Thierry Marks over lunch in the summer of 2007. 

“We were discussing what interesting culinary art experiments we might do together and I had the idea that we might breathe foods since I’ve done a lot of work over the last 10 or 15 years on medical aerosols,” Edwards said. 

The first venture Edwards worked on with Harvard students was the breathable chocolate, called Le Whif. Now he’s preparing to promote a product called Le Whaf, which involves putting food and drinks in futuristic-looking glass bowls and turning them into low-calorie clouds of flavor. 

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La FDA, acusada de ‘espiar’ a sus empleados | Noticias | elmundo.es

Economic and clinical evaluation of a catch-up dose of 13-valent pneumococcal conjugate vaccine in children already immunized with three doses of the 7-valent vaccine in Italy

Boccalini S, Azzari C, Resti M, Valleriani C, Cortimiglia M, Tiscione E et al. Economic and clinical evaluation of a catch-up dose of 13-valent pneumococcal conjugate vaccine in children already immunized with three doses of the 7-valent vaccine in Italy.Vaccine.2011;28;29:9521-8. D.O.I.: 10.1016/j.vaccine.2011.10.013.

Revisores: Ochoa Sangrador C1, Andrés de Llano JM2

1Servicio de Pediatría. Hospital Virgen de la Concha. Zamora (España).
2Servicio de Pediatría. Hospital General del Río Carrión. Palencia (España). 

Correspondencia: Carlos Ochoa Sangrador. Correo electrónico: cochoas@meditex.es
Fecha de recepción: 23/01/2012   Fecha de aceptación: 24/01/2012   Fecha de publicación: 26/01/2012   

Resumen Estructurado

Objetivo: realizar una evaluación clínica y económica de la administración de una dosis
adicional de puesta al día de la vacuna 13-valente en niños de hasta cinco años.
Diseño: análisis de coste-efectividad y coste-utilidad.
Emplazamiento: el entorno del estudio fue tanto hospitalario como en Atención Primaria
 desde la perspectiva del sistema de salud.
Población de estudio: población residente en la provincia de , a 1 de enero de 2010, agrupada por tramos de edad, previamente inmunizada con vacuna 7-valente. Se utilizaron registros del Instituto Nacional de Estadística y registros de un hospital pediátrico de Florencia. Las tasas de hospitalización, costes y mortalidad fueron extraídas de estudios italianos. Los parámetros clínicos y epidemiológicos usados en el modelo principal incluían la eficacia de la vacuna frente a hospitalización por meningitis/sepsis, neumonías hospitalarias y ambulatorias.
Intervención: se evaluaron cuatro posibles estrategias para ponerse al día con la vacuna 13-valente (menores de 24, 36, 48 y 60 meses). Se utilizó un modelo matemático de simulación ya desarrollado para estimar el impacto de la transición de los programas de inmunización.
Medición del resultado: se estimó el impacto en un periodo de 5,5 años tras la inmunización, considerando como resultados de infección por S. pneumoniae:hospitalización por meningitis/sepsis, neumonías bacteriémicas hospitalizadas (complicadas y no complicadas), neumonías no bacteriémicas ingresadas y neumonías ambulatorias. Se asumió la eficacia de ensayos clínicos con vacuna 7-valente (94% para meningitis neumocócica, 87,5% para neumonías hospitalizadas y 20,5% para neumonías ambulatorias). Se calculó el número de casos evitados por tipo de enfermedad neumocócica, el número de muertes evitadas y años de vida ganados, los costes para el tratamiento de la casos prevenidos, el coste de la vacunación, el coste promedio por caso evitado y el coste por año de vida ganado. El análisis no tuvo en cuenta los costes directos no médicos ni los indirectos asociados a la pérdida de productividad. Se realizó un análisis de sensibilidad para coberturas de vacunación, coste de la vacuna, incidencia de las enfermedades neumocócicas, tasas de letalidad y cobertura de serotipos.
Resultados principales: las muertes evitadas con el rescate hasta los 24 meses de edad serían 2,5 por 100 000 niños, que ascenderían, con la ampliación hasta los 60 meses de edad, a 6,6 por 100 000. Los años de vida ganados en este programa hasta los 24, 36, 48 y 60 meses de edad serían 191, 322, 423 y 483 por cada 100 000 niños. El coste medio por caso evitado hasta los 24 meses de edad fue 1674 euros, aumentando a 2522 euros al ampliar hasta los 60 meses. El coste por año de vida ganado fue de 12 250 euros para los niños hasta 24 meses de edad y de 22 093 euros para los niños hasta 60 meses.
Conclusión: vacunar a los niños de hasta 24 meses de edad con un programa de rescate con vacuna neumocócica 13-valente está justificado desde el punto de vista económico. Extenderlo a menores de 60 meses de edad, también está justificado tanto desde el punto de vista económico como clínico.
Conflicto de intereses: los autores declaran la ayuda del laboratorio Pfizer Italia S.r.l.
Fuente de financiación: El trabajo ha sido financiado por Pfizer Italia S.r.l.

Comentario Crítico

Justificación: la generalización de la vacuna neumocócica conjugada en la primera infancia ha permitido reducir el riesgo de infección neumocócica grave. Existe suficiente evidencia sobre la eficacia de la vacuna 7-valente para prevenir infecciones graves, fundamentalmente sepsis y meningitis, aunque la efectividad a medio-largo plazo podría verse reducida por cambios espontáneos o inducidos en el perfil de serotipos. La disponibilidad de nuevas vacunas con mayor cobertura de serotipos ofrece una oportunidad para mejorar la prevención. Para plantear la conveniencia de realizar una campaña de rescate con estas vacunas en población previamente vacunada interesa establecer su coste-efectividad y su coste-utilidad.
Validez o rigor científico: el planteamiento del estudio está bien formulado en cuanto a la intervención evaluada, las medidas de resultado consideradas (coste por episodio evitado, coste por año de vida ganado) y la perspectiva (sistema sanitario). Las estimaciones de costes no se detallan, aunque se refieren a trabajos del mismo entorno que se citan. Sin embargo, las estimaciones de efectividad no están correctamente justificadas. Se ha asumido la eficacia observada en ensayos clínicos de la vacuna 7-valente en población menor de dos años1,2, para un programa de rescate, del que solo se disponen estudios de inmunogenicidad y seguridad, sin justificarse la aplicabilidad de las cifras de efectividad elegidas. Por ejemplo, no se ha valorado la menor eficacia a partir del primer año de vida o las diferencias de eficacia según serotipos2. Esta asunción puede resultar especialmente crítica en cuanto a la eficacia asumida para neumonías ambulatorias (que influirá en el coste por episodio evitado) y para la reducción de mortalidad (no detallada y que influirá en el coste por año de vida ganado). Se ha realizado un ajuste temporal y un análisis de sensibilidad, en el que se explora el efecto de variaciones en varias asunciones del modelo, pero no en las de efectividad.
Importancia clínica: se ha estimado que una campaña de rescate con vacuna antineumocócica 13-valente en niños menores de 60 meses previamente inmunizados frente a siete serotipos permitiría evitar un episodio de infección neumocócica a un coste de 2522 euros. Para juzgar la importancia clínica de esta estimación debería haberse especificado el coste para evitar episodios graves (sepsis/meningitis y neumonías bacteriémicas), presumiblemente mayor. En cuanto al coste por año de vida ganado (22 093 euros), si aceptamos las asunciones de eficacia planteadas en el estudio, estaría bajo el umbral de los 30 000 euros (aceptado para otras intervenciones). No obstante, creemos que las asunciones realizas en cuanto a la reducción de la mortalidad de la campaña de rescate (no demostrada) podrían verse comprometidas por variaciones en la efectividad o cambios en el perfil epidemiológico de serotipos. Un estudio referido a Estados Unidos, que consideraba la prevención de otitis (no contemplada en este estudio) ha estimado un coste de la campaña hasta 60 meses por año de vida ajustado por calidad de 73 564 dólares (solo resultaban rentables las estimaciones en las que se asumía la existencia de protección indirecta sobre población no vacunada)3.
Aplicabilidad en la práctica clínica: las estimaciones aquí referidas al sistema sanitario italiano podrían ser adaptables a nuestro entorno, ajustándolas con datos epidemiológicos propios. Si las estimaciones fueran similares en nuestro entorno parece lógico plantearse la oportunidad de realizar una campaña de rescate, aunque, a falta de estudios de eficacia (no previsibles), deberá supeditarse a su competencia con la financiación de otras intervenciones en función de su coste-utilidad. En este sentido, interesaría saber, mediante la realización de nuevos estudios, si variaciones en las asunciones de eficacia de la intervención o en el perfil de serotipos podrían comprometer su utilidad.
Conflicto de intereses de los autores del comentario: no existe.

Cómo citar este artículo


  1. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J. 2000;19:187-95.
  2. Black SB, Shinefield HR, Ling S, Hansen J, Fireman B, Spring D et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J. 2002;21:810-5.
  3. Rubin JL, McGarry LJ, Strutton DR, Klugman KP, Pelton SI, Gilmore KE et al. Public health and economic impact of the 13-valent pneumococcal conjugate vaccine (PCV13) in the United States.Vaccine. 2010;28:7634-43.

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Nicotine replacement therapies may not be effective in helping people quit smoking

Public release date: 9-Jan-2012

Contact: Marge Dwyer
Harvard School of Public Health 

Nicotine replacement therapies may not be effective in helping people quit smoking

Boston, MA – Nicotine replacement therapies (NRTs) designed to help people stop smoking, specifically nicotine patches and nicotine gum, do not appear to be effective in helping smokers quit long-term, even when combined with smoking cessation counseling, according to a new study by researchers at Harvard School of Public Health (HSPH) and the University of Massachusetts Boston.
The study appears January 9, 2012 in an advance online edition of Tobacco Control and will appear in a later print issue.
“What this study shows is the need for the Food and Drug Administration, which oversees regulation of both medications to help smokers quit and tobacco products, to approve only medications that have been proven to be effective in helping smokers quit in the long-term and to lower nicotine in order to reduce the addictiveness of cigarettes,” said co-author Gregory Connolly, director of the Center for Global Tobacco Control at HSPH.
In the prospective cohort study the researchers, including lead author Hillel Alpert, research scientist at HSPH, and co-author Lois Biener of the University of Massachusetts Boston’s Center for Survey Research, followed 787 adult smokers in Massachusetts who had recently quit smoking. The participants were surveyed over three time periods: 2001-2002, 2003-2004, and 2005-2006. Participants were asked whether they had used a nicotine replacement therapy in the form of the nicotine patch (placed on the skin), nicotine gum, nicotine inhaler, or nasal spray to help them quit, and if so, what was the longest period of time they had used the product continuously. They also were asked if they had joined a quit-smoking program or received help from a doctor, counselor, or other professional.
The results showed that, for each time period, almost one-third of recent quitters reported to have relapsed. The researchers found no difference in relapse rate among those who used NRT for more than six weeks, with or without professional counseling. No difference in quitting success with use of NRT was found for either heavy or light smokers.
“This study shows that using NRT is no more effective in helping people stop smoking cigarettes in the long-term than trying to quit on one’s own,” Alpert said. He added that even though clinical trials (studies) have found NRT to be effective, the new findings demonstrate the importance of empirical studies regarding effectiveness when used in the general population.
Biener said that using public funds to provide NRT to the population at large is of questionable value, particularly when it reduces the amount of money available for smoking interventions shown in previous studies to be effective, such as media campaigns, promotion of no smoking policies, and tobacco price increases.
Smoking cessation medications have been available over the counter since 1996, yet U.S. Centers for Disease Control and Prevention statistics show that the previous adult smoking rate decline and quitting rates have stalled in the past five years.
Funding for the study was provided by the National Cancer Institute, State and Community Tobacco Control Interventions Research Grant Program.
“A Prospective Cohort Study Challenging the Effectiveness of Population-based Medical Intervention for Smoking Cessation,” Hillel R. Alpert, Gregory N. Connolly, Lois Biener. Tobacco Control, doi:10.1136/tobaccocontrol-2011-050129, online January 9, 2012.
Visit the HSPH website for the latest news, press releases and multimedia offerings.
Harvard School of Public Health (http://www.hsph.harvard.edu) is dedicated to advancing the public’s health through learning, discovery, and communication. More than 400 faculty members are engaged in teaching and training the 1,000-plus student body in a broad spectrum of disciplines crucial to the health and well being of individuals and populations around the world. Programs and projects range from the molecular biology of AIDS vaccines to the epidemiology of cancer; from risk analysis to violence prevention; from maternal and children’s health to quality of care measurement; from health care management to international health and human rights. For more information on the school visit:http://www.hsph.harvard.edu


After months of hard, collaborative work, Webicina.com just published the first version of the open access guide for pharma about using social media. While drug companies, healthcare professionals and e-patients wait for FDA guidelines on social media, with an expert crowd we created our own guidelines to serve as a basis for more detailed, extended guides.

You can download the PDF (14 pages) here!

Please feel free to download it, share it with your colleagues and join us to create an even more sophisticated second version which we can submit to the FDA. Give us feedback on Twitter through#pharmaSMguide!

The original Google Docs document contains more details, negative and positive social media-related pharma case studies as well.

Best regards,

Dr. Bertalan Mesko

Managing director and founder
Webicina LLC
Twitter: Berci

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FDA Says Chantix Benefits Outweigh The Risks or were you expeting another end ?

Ed Silverman in Pharmalot

cigarette-smoke-flickrAfter reviewing the results of two epidemiological studies that compared the controversial Chantix smoking-cessation pill with NicoDerm patches, the FDA has decided that the benefits of the Pfizer pill continue to outweigh the risks. The decision comes three years after the drugmaker added warnings its anti-smoking drug is connected to suicidal thoughts and behavior (back story).
Due to the myriad reports linking Chantix to psychiatric side effects, the FDA had sponsored two observational studies of neuropsychiatric adverse events with Chantix. One was conducted by the Department of Veterans Affairs’ Center for Medication Safety and the other by the Department of Defense’s US Army Medical Command’s Pharmacovigilance Center.
The VA study population included 14,131 Chantix users and an equal number of NRT users. The DoD study was also a retrospective cohort study comparing 30-day rates of hospitalizations for neuropsychiatric adverse events among 19,933 new Chantix users and 15,867 NRT patch users who started therapy from August 1, 2006 to August 31, 2007 in the Military Health System. Patients were drawn from active duty military personnel, military retirees and their dependents.
“Neither study found a difference in risk of neuropsychiatric hospitalizations between Chantix and nicotine replacement therapy,” the FDA says in a statement. “However, both studies had a number of study design limitations, including only assessing neuropsychiatric events that resulted in hospitalization, and not having a large enough sample size to detect rare adverse events.
“Although these two studies did not suggest an increased risk of neuropsychiatric events that result in hospitalization, they do not rule out an increased risk of other neuropsychiatric events with Chantix…(But) based on FDA’s assessment of currently available data, the agency continues to believe that the drug’s benefits outweigh the risks and the current warnings in the Chantix drug label are appropriate.”
The verdict is a big win for Pfizer, which has struggled to promote Chantix against a rising mound of studies that its pill is more trouble than it’s worth. In addition to concerns about suicide, studies have suggested Chantix can be responsible for violent behavior and cause serious cardiovascular risks (see herehere and here). The European Medicines Agency, however, recently ruled that Chantix benefits outweigh any heart risks (see this).

Eficacia y seguridad del ibuprofeno y del paracetamol en niños y adultos: metaanálisis y revisión cualitativa

Traductores: Esparza Olcina MJ1
1Centro de Salud Barcelona. Móstoles. Madrid (España). 
Correspondencia: María Jesús Esparza Olcina. Correo electrónico: mjesparza8@gmail.com
Fecha de publicación: 13/10/2011   

Procedencia del artículo

Los autores del documento original no se hacen responsables de los posibles errores que hayan podido cometerse en la traducción del mismo.

Autores de la revisión sistemática

Pierce CA, Voss B1.

Autores del resumen estructurado

Revisores del CRD. Fecha de la evaluación: 2011. Última actualización: 2011. URL del original en inglés disponible en:http://www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?AccessionNumber=12010003052&UserID=0

Artículo Traducido

Título: Eficacia y seguridad del ibuprofeno y del paracetamol en niños y adultos: metaanálisis y revisión cualitativa.
Resumen del CRD: la revisión concluyó que el ibuprofeno era igual o más eficaz que el paracetamol para el tratamiento del dolor y la fiebre en adultos y niños y que era igual de seguro. Las prudentes conclusiones de los autores reflejan la evidencia presentada, pero algunas deficiencias en el proceso de revisión, la falta de valoración de la calidad y una heterogeneidad clínica importante hacen dudosa la fiabilidad de las conclusiones.
Objetivos de los autores: estimar la eficacia y seguridad analgésica y antipirética del ibuprofeno comparado con paracetamol en niños y adultos.
Búsqueda: se consultaron PubMed (hasta agosto de 2009) y EMBASE (hasta enero de 2008). La búsqueda se restringió a estudios en inglés. Se aportaron los términos de búsqueda. Se buscaron en las listas de referencias de los artículos obtenidos.
Selección de los estudios: se consideraron seleccionables para la revisión ensayos clínicos prospectivos o retrospectivos que incluyeran datos sobre la eficacia y/o seguridad (efectos adversos) en comparación directa de ibuprofeno con paracetamol para el tratamiento del dolor o de la fiebre. Se excluyeron los estudios que incluían medicación concomitante.
En los estudios incluidos, la dosis unitaria de ibuprofeno osciló entre 200 y 600 mg. Varios estudios utilizaron al menos una dosis o más de 600 mg para la reducción del dolor y la temperatura en adultos. Las dosis de ibuprofeno en niños dependían sobre todo del peso; y oscilaban entre 5 y 20 mg/kg (algunos estudios administraban dosis fijas). Las dosis de paracetamol oscilaban entre 500 y 1300 mg por dosis en adultos y entre 10 y 40 mg/kg en niños. Para la reducción del dolor en adultos, los participantes habían sufrido una variedad de procedimientos quirúrgicos o tenían dolor menstrual, articular, cefalea, dolor de garganta, dolor oncológico o dolor inducido experimentalmente. El tratamiento antipirético en adultos se utilizó sobre todo para disminuir la fiebre y cefalea producida por interferón en participantes con esclerosis múltiple; también se utilizó en participantes con ataque isquémico agudo y malaria. Otras patologías en niños incluían traumatismos musculoesqueléticos, dolor por vacunación y malestar por fiebre. La mayoría de los estudios consideraban niños a los menores de 18 años y adultos a los mayores de 18 años. El dolor, la fiebre y los efectos adversos se definieron de acuerdo con los autores de los estudios individuales.
Los autores no especificaron cómo se hizo la selección de los estudios para la revisión.
Evaluación de la validez: los autores no dejan constancia de que evaluasen la calidad de los estudios incluidos en la revisión.
Extracción de los datos: los datos de los estudios se extrajeron y separaron en estudios pediátricos y de adultos. Para incluir en el metaanálisis las medidas continuas de temperatura o las puntuaciones de un simulador visual del dolor, se calcularon las diferencias de medias estandarizadas (DME) con su intervalo de confianza del 95% (IC 95%). Esto se calculó para todas las medidas relacionadas con tiempo tal como la media del paracetamol menos la media del ibuprofeno (en los estudios en los que constaba). Para estudios sobre dolor se hizo la medición a las dos horas tras la primera dosis (en los estudios en los que constaba) o en el punto más próximo a las dos horas en que cambiaba la línea basal. Para estudios de fiebre, se midió a las cuatro horas (en los estudios en los que constaba). Se calcularon las odds ratios (OR) y sus IC 95% para la proporción de participantes que experimentaron al menos un efecto adverso y al menos un efecto adverso grave. Si no se observaban efectos adversos en la rama de tratamiento, se añadió 0,5 a cada celda de la tabla de contingencia para posibilitar el cálculo de las OR. En todos los otros estudios no incluidos en el metaanálisis se extrajeron los resultados.
Los autores no explicaron cómo llevaron a cabo la extracción de los datos.
Métodos de síntesis: los ensayos clínicos aleatorizados (ECA) se combinaron en metaanálisis. Los ECA cuyos datos estaban resumidos gráficamente no se incluyeron en el metaanálisis. Las OR totales se calcularon utilizando el estimador de Mantel Haenszel solo si el test estadístico de heterogeneidad no era significativo. Las DME ponderadas globales se calcularon de acuerdo con la medida gde Hedge. Las conclusiones de los demás estudios se combinaron cualitativamente en formato narrativo. Las conclusiones que indicaban diferencias entre tratamientos en los estudios individuales tenían que aportar valores significativos de p o de los IC 95%; en caso contrario los dos tratamientos se consideraron igual de eficaces y/o seguros.
Se fabricaron gráficos de embudo para valorar el sesgo de publicación y la heterogeneidad.
Resultados de la revisión: en la revisión se incluyeron 85 estudios. Cincuenta y cuatro (n  = 7603 participantes) valoraban los efectos del tratamiento sobre el dolor (36 en adultos y 18 en niños). Treinta y cinco estudios (n = 3985) valoraban los efectos del tratamiento sobre la fiebre (cinco en adultos y 30 en niños). Sesenta y seis estudios (no se informó la n) valoraban los efectos adversos de los tratamientos, 35 en adultos y 31 en niños.
Dolor en adultos: 26 estudios concluían que el ibuprofeno era mejor que el paracetamol y 10 no encontraron diferencias significativas. En el metaanálisis de ECA, el ibuprofeno se asoció con una puntuación en la escala de puntuación clínica de dolor significativamente más baja dos horas tras la dosis (DME: 0,69; IC 95%: 0,57-0,81; nueve estudios), que se correspondía con un tamaño medio del efecto obtenido utilizando la regla general del tamaño del efecto de Cohen (Cohen’s rule of thumb).
Dolor en niños: seis estudios concluyeron que el ibuprofeno era superior al paracetamol, once no encontraron diferencias significativas entre los tratamientos y uno encontró diferencia significativa a favor del ibuprofeno solo el día de la intervención quirúrgica y no posteriormente. En el metaanálisis de los ECA el ibuprofeno se asoció a una puntuación significativamente menor que el paracetamol en escala de puntuación para dolor a las dos horas tras la dosis (DME: 0,28; IC 95%: 0,10-0,46; seis estudios), que coincide con un tamaño del efecto pequeño según la regla de Cohen.
Fiebre en adultos: tres estudios concluyeron que el ibuprofeno era superior al paracetamol y dos estudios no encontraron diferencias significativas entre los tratamientos. No se realizó metaanálisis.
Fiebre en niños: quince estudios concluyeron que el ibuprofeno era superior al paracetamol y 15 estudios no encontraron diferencias significativas entre los tratamientos. En el metaanálisis de los ECA el ibuprofeno se asoció a una puntuación significativamente menor en las escalas clínicas de puntuación para fiebre a las cuatro horas tras la dosis (DME: 0,26; IC 95%: 0,10-0,41; siete estudios), consistente con tamaño del efecto pequeño utilizando la regla de Cohen.
Efectos adversos en adultos: ningún estudio encontró diferencias significativas entre el ibuprofeno y el paracetamol en la incidencia de uno o más efectos adversos (35 estudios). En el metaanálisis de ECA, el ibuprofeno se asoció con una menor (pero no estadísticamente significativa) incidencia de efectos adversos que paracetamol (OR: 1,12; IC 95%: 1,00-1,25; 25 estudios), consistente con un tamaño del efecto pequeño según Cohen. Un estudio no encontró diferencias en la tasa de efectos adversos graves entre los tratamientos.
Efectos adversos en niños: veintinueve estudios no encontraron evidencia o ésta no fue estadísticamente significativa entre ibuprofeno y paracetamol en la incidencia de uno o más efectos adversos. Un estudio concluyó que el paracetamol era más seguro o mejor tolerado que el ibuprofeno. En el metaanálisis no se evidenció diferencias en la tasa de efectos adversos entre ibuprofeno y paracetamol (OR: 0,82; IC 95%: 0,60-1,12; 19 estudios). Dos estudios refirieron que no encontraron diferencias significativas en los efectos adversos graves entre los tratamientos.
Conclusiones de los autores: el ibuprofeno fue similar o más eficaz que el paracetamol para el tratamiento del dolor y la fiebre en adultos y niños y fue igualmente seguro.


La revisión aborda una pregunta de investigación bien definida. Los criterios de inclusión fueron amplios y se consideran adecuados. La búsqueda realizada incluyó consultas en una serie importante de fuentes con términos de búsqueda adecuados para estudios publicados en inglés; no se puede descartar el sesgo de idioma. Los autores afirman que se realizaron gráficos de embudo para valorar el sesgo de publicación, pero no informan los resultados de estos análisis, y los investigadores no contactaron con los autores para buscar la información no escrita en los estudios individuales; no se puede descartar el sesgo de publicación. No se aportaron los métodos utilizados para la selección de los estudios, para la valoración de la calidad y para la extracción de los datos; no se puede descartar error y sesgo del revisor. No se realizó valoración de la calidad, lo que hace difícil determinar la fiabilidad de las conclusiones. Los participantes padecían una amplia variedad de situaciones que justificaban el tratamiento. Había una amplia variedad de dosis y de pautas de dosificación en el tiempo. No se hicieron análisis de subgrupos para determinar los efectos diferenciales. Los efectos adversos se definieron e informaron de distinta manera en los estudios, lo cual se añadió a la dificultad de valoración cuantitativa de la proporción con uno o más efectos adversos. Los estudios incluidos utilizaron puntos de tiempo variables para la valoración del efecto de los tratamientos; los autores eligieron puntos de tiempo precoces (dos horas tras la dosis para efectos sobre el dolor y cuatro horas para efectos sobre la fiebre) basándose en la inclusión del máximo número posible de estudios en el análisis.
Los autores realizaron metaanálisis con los ECA encontrados y presentaron tanto los resultados del metaanálisis como la síntesis narrativa de todos los estudios, informando sobre la proporción de todos los estudios con diferencias significativas entre los tratamientos y sobre la proporción de los que no encontraron evidencia estadística de diferencia. La valoración cuantitativa con el metaanálisis estaba basada sobre todo en estudios de corta duración, que hacen difícil aportar conclusiones fiables sobre la seguridad a más largo plazo. Los autores informaron que se valoró la heterogeneidad estadística para el metaanálisis, pero no se informó sobre el testque utilizaron ni sobre el resultado. Uno de los autores trabajaba para Cumberland Pharmaceuticals en Nashville, Tennessee.
Las prudentes conclusiones de los autores reflejan la evidencia presentada, pero las deficiencias del proceso de revisión, la falta de evaluación de la calidad y la importante heterogeneidad clínica hacen que sea dudosa la fiabilidad de las conclusiones.
Implicaciones de la revisión: los autores no establecieron implicaciones ni para la práctica clínica ni para la investigación.
Financiación: no especificada.
Asignación de descriptores: asignación por la NLM.
Descriptores: Acetaminophen/Adverse effects/therapeutic use; Adult; Age Factors; Analgesics, Non-Narcotic/adverse effects/therapeutic use; Child; Female; Fever/drug therapy; Humans; Ibuprofen/adverse effects/therapeutic use; Male; Odds Ratio; Pain/drug therapy; Randomized Controlled Trials as Topic.
Número del registro de entrada: 12010003052.
Fecha de inclusión en la base de datos: 20 de julio de 2011.

Cómo citar este artículo

Esparza Olcina MJ. Eficacia y seguridad del ibuprofeno y del paracetamol en niños y adultos: metaanálisis y revisión cualitativa. Evid Pediatr. 2011;7:98.
Traducción autorizada de: Centre of Reviews and Dissemination (CRD). Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review.Universityof York. Database of Abstracts of Review of Effects web site (DARE) Documento número: 12010003052 [en línea] [fecha de actualización: 2011; fecha de consulta: 27-9-2011]. Disponible en: 


  1. Pierce CA, Voss B. Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review. Annals of Pharmacotherapy. 2010;44(3):489-506.

Tipo de Documento

Este informe es un abstract estructurado producido por el CRD. El artículo original cumplió una serie de criterios de calidad exigidos. Desde septiembre de 1996 se procede enviando los abstracts a los autores del artículo original para ser comentados. Si se aporta alguna información adicional, esta se incorpora dentro del informe bajo el siguiente encabezamiento: (A:….).

All Trial Data Must Be Disclosed: Rogawski Explains

National Institutes of HealthImage via Wikipedia

michael-rogawskiOver the past few years, there has been controversy over clinical trial results that remain unreported. This has stoked concern, for instance, when data may provide information about side effects. At the same time, other researchers may be precluded from learning clues needed to proceed on related drug development. However, these issues pertain to studies on drugs that are not commercialized as well. In a recent paper in Science Translational Medicine, a pair of academics argue that “translational medicine cannot approach its full potential if negative drug developments are unpublished” (here is the abstract). And they cite an ethical duty for insisting on disclosure. We spoke with Michael Rogawski, one of the co-authors and chair of the Department of Neurology at the UC Davis School of Medicine, about the need to disclose trial data. This is an excerpt…
Pharmalot: So why raise this issue and why now?
Rogawski: When I participated in a translational working group of the International League Against Epilepsy on how to encourage the development of more effective epilepsy therapies, I realized that negative clinical data was critically important in assessing the predictiveness of animal models. Then, sometime later when I was writing a review article I asked a company for the clinical trial results on a product they had abandoned. I let them know that I hoped they would publish their trial results as even negative studies provide important scientific information and the patients who participated in the trials expect that the information derived from their participation will benefit mankind. The terse answer was that the company “does not intend to publish the results of the epilepsy trial.
So, this is a problem that has concerned me for some time, but we’re now at a critical moment where the NIH has the opportunity to require sponsors to post the results of clinical trials on the ClinicalTrials.gov web site. A new law that many people may not be aware of requires the results for most drug and device trials to be posted on ClinicalTrials.gov. However, there is a loophole that exempts trials of products that are still in development and if they are never approved, the results don’t need to be posted. A provision in FDAAA (the Food and Drug Administration Amendments Act of 2007) Section 801 allows HHS to require results reporting for clinical trials for drugs and devices not approved by the FDA. In the law, Congress gave the NIH the ability to formulate regulations that require sponsors to do this, to post results on this web site, even for drugs and devices not approved by the FDA. They’re going to publish draft regulations by the end of the year and then there will be a public comment period.
As I dug into this, I began to realize that there were quite a lot of changes going on in this area. The FDAMA (the FDA Modernization Act of 1997) required anyone doing a clinical trial to post an announcement posting on ClinicalTrials.gov. The original intent was to help patients find relevant clinical trials. Then, when concerns were raised about selective reporting, ClinicalTrials.gov was seen as a way to keep track of all the trials that have been done. More recently, they have made a requirement to post basic results. I don’t think a lot of people realize that. But if you go to the web site, there are few clinical trials with results actually there, as this is all so new. Even drug companies seem to be confused about the requirements.
Going into the future, the results from all clinical trials for approved products will have to be up there. But that raises the question about publication. I guess some people thought this would be sufficient. But it’s not. Our position is it’s still necessary to publish results of clinical trials in the peer-reviewed literature.

Pharmalot: Why is that?
Rogawski: The results data in ClinicalTrials.gov is simply presented in tables. There’s no presentation of detailed analysis or an interpretation as in a journal publication. And there’s minimal review. ClinicalTrials.gov could become the primary repository for the results of clinical trials of drugs and devices. And some people may feel that publication in a peer-reviewed article is no longer needed.
We’re arguing that you still need to write up the results.
Pharmalot: So you’re saying some results are located on ClinicalTrials.gov, but not all?
Rogawski: There’s a whole separate tab on every entry for results. If no study results are available, it will indicate that. For terminated products, you may never see the results published. There’s a loophole in the law that allows them (sponsors) to be exempt from posting the basic results when the product hasn’t been approved.
Pharmalot: What are these exemptions?
Rogawski: There are a couple of ways a study can be exempt. One way is to study the drug for another indication. Delayed submission is permitted when sponsor is seeking a new use. The other way is if a drug or device is never approved. In principle, although it’s not stated this way, if the sponsor never submits the particular product for FDA approval, then they don’t have to post the basic results. The current law only applies to agents approved by the FDA. Let’s say the sponsor submits an NDA and the agency gives a complete response letter saying they have to do X, Y and Z, and the sponsor never does that. They decide it would be too expensive to do further clinical trials and they decide to abandon the product. Then they also don’t have to put data on ClinicalTrials.gov.
What we maintain is that it’s unethical to do that. It’s a basic principle of clinical research – it’s espoused in the fundamental ethics of clinical trials, such as in the Declaration of Helsinki, which states that “authors have duty to make publicly available results of research on humans and are accountable for the completeness and accuracy of their reports….Negative and inconclusive, as well as positive results should be published or otherwise made publicly available.”
Pharmalot: And so you’re hoping the HHS will close this loophole, as you call it.
Rogawski: We’re hoping HHSs will use its authority under FDAAA 801 to require sponsors to report results with any trial registered with ClinicalTrials.gov, even for any product that is abandoned… There’s potentially useful information in any clinical trial and if it’s not available, it diminishes public knowledge. It may even place patients in later trials at risk. There could be some data showing this particular product causes green spots. It would be important to know this the next some time somebody considers developing a drug that acts by a similar molecular mechanism.
Pharmalot: But a drug maker may argue that intellectual property is at stake, whether or not they choose to continue development, because disclosure may somehow give a rival an edge, right?
Rogawski: HHS may decide to balance with the interests of pharmaceutical companies with the public interest. They may decide it’s commercially damaging to require companies to publish the results of trials with abandoned products. We think it’s a fallacious argument. We understand that many sponsors consider data proprietary… They put all this money into it and may want to continue work on the product later on or try for a different indication, and they may perceive that negative trial data would impair that. And they may consider it a waste of time and money to write stuff up when it isn’t going to go anywhere…We think it’s incorrect, but I guess companies may think that way.
Pharmalot: You mentioned you also believe all trial results should be published as well? How does this tie in?
Rogawski: I’ve noticed that it’s often the case that sponsors do not publish results when they’re abandoning the product. In my own area, which is the development of anti-epileptic drugs, we have a problem. We use animal screening models to identify drugs, but we don’t know how valid the models are because we don’t know much about the cases where a drug was effective in the models, but not in clinical trials because very little information about failed drugs is available publicly.
That’s what stimulated my concern. We make the assumption that these animal models are highly predictive, but it could be a flawed assumption because we don’t have the full set of data. There could be situations where drugs don’t work in the clinical trials. I do know of situations like that, being in this field for as long as I have, but we don’t know why there was a failure – lack of efficacy, the sponsor ran out of money, or perhaps there were idiosyncratic reactions?
So I also believe the companies should voluntarily publish negative results in the peer-reviewed literature. I believe they have an ethical responsibility to do that, but ethics is not the same as the law. In my view, many companies are not acting ethically by not reporting trial results.
Source: Pharmalot



Notable HPV types and associated diseasesImage via Wikipedia

(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.
audisio9_o0510.jpg Autor:
Teresita Audisio
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
Primera edición
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 >
página  www.siicsalud.com/des/expertocompleto.php/

 Principal: Infectología,  Obstetricia y Ginecología 
  Relacionadas: Atención Primaria,  Educación Médica,  Epidemiología,  Farmacología,  Medicina Farmacéutica,  Inmunología,  Medicina FamiliarMedicina Interna,  Medicina Reproductiva,  Pediatría 

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Teresita Audisio, 5000, Córdoba, Argentina

Artículo completo

Extensión:  +/-4.8 páginas impresas en papel A4
Exclusivo para suscriptores/assinantes
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.

 Key words
HPV, vaccine, pre-teenage

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15. Cason J , Rice P , Best J.Transmission of Cervical Cancer-Associated Human
Papilloma Viruses from Mother to Child. Intervirology.1998; 41:213-18
16. De Palo Bergeron C., Ferenczy A., Richart R.: Underwear: contamination by human papillomavirus. Am. J. Obstet. Gynecol. 1990;162: 25.
17. Müller M, Viscidi R, Ulken V, et al .Antibodies to the E4, E6 and E7 proteins of Human Papillomavirus (HPV) type 16 in patients with HPV-associated diseases and the normal population.J Invest Dermatol.1995;104:138-41.
18. Hildesheim A, Herrero R, Wacholder S, et al. for the Costa Rican HPV Vaccine.Effect of Human Papillomavirus 16/18 L1Viruslike Particle Vaccine Among Young Women With Preexisting Infection- A Randomized Trial. JAMA. 2007; 298(7):743-53.
19. Pasqualini C.D. La etiología del cáncer .Vigencia de cinco paradigmas sucesivos. Medicina. 2003;63:757-60.
20. Pasqualini CD.Papel bivalente del sistema inmune en el crecimiento tumoral. Medicina. 2004; 64:277-80.
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Why Do Americans Take So Many Prescription Drugs?

Logo of the United States National Cancer Inst...Image via Wikipedia
Why Do Americans Take So Many Prescription Drugs?
J. Douglas Bremner, MD
Scope of the Problem
“Today we are faced with what may be the single greatest drug safety catastrophe in the history of this country or the history of the world… In my opinion, the FDA has let the American people down, and sadly, betrayed a public trust.”Those ominous words, spoken by David J. Graham, M.D., M.P.H., Associate Director of Drug Safety for the Food and Drug Administration (FDA), on November 18, 2004, were part of Congressional testimony concerning the dangers of Vioxx. The drug had just been taken off the market because of evidence that the arthritis medication increased the risk of heart attacks. Yet he could have been talking about the prescription drug industry in general, especially since he noted that Vioxx was not the only medication that posed serious health threats. It was only the tip of the iceberg. Graham identified five widely-prescribed drugs still on the market that are particularly dangerous, including Accutane, Bextra, Crestor, Meridia, and Serevent (in 2005 Bextra was taken off the market).
While it’s true that many drugs help people live longer and better lives, myriad others may hurt you in other ways that you don’t know about. Dr. Graham’s testimony provided the public a fleeting glimpse at that knowledge, normally hidden from view or frustratingly difficult for the average person to access. Pharmaceutical and supplement manufacturers have to increase sales and profits, as all businesses must, and they do so in part by developing drugs to treat disease and also by convincing people they need meds to prevent disease or lessen the perceived risk of future illness. The result is that nondisclosure of potentially harmful side effects of the drugs they make has become routine.
How We Got HereThe latest drive to get new pills on the shelves and into people’s mouths began when government deregulation and an earnest attempt to help AIDS-HIV patients access important life-extending drugs collided. In the 1980s there was a strong movement to decrease the role of government regulation in all businesses, and budgets of regulatory agencies like the FDA were slashed as part of that effort. The Reagan Administration painted the FDA as a bloated bureaucracy that was slowing down the approval of drugs and getting in the way of business.
There was some truth to that claim. At that time it could take up to two years to gain drug approval, two years too long if you were suffering from HIV-AIDS. Throughout the 1980s, AIDS activists and patients echoed the drug companies’ sentiments, complaining that it took too long to bring disease-fighting drugs to market. The pharmaceutical industry lent a sympathetic ear and a loud voice to calls for speed in approvals of AIDS drugs such as Agenerase (amprenavir). Since drugs are on patent for a limited number of years, every year spent waiting for approval from the FDA meant losing a year of profits.
Couple that with the fact that the FDA could now honestly say that, because of cuts, it was understaffed. The answer was essentially legislation allowing pharmaceutical companies to pay the salaries of the staff at the FDA. In 1992, the Prescription Drug User Fee Act (PDUFA) stipulated that a fee (now $576,000) be paid to the FDA by the pharmaceutical companies for each new drug application. The number of staff at the Center for Drug Evaluation and Research (CDER) doubled overnight. Today, the FDA receives about $260 million a year from these fees. Part of the bill stipulated that funding by Congress for new drug evaluations had to increase by 3% per year. Since the overall funding for the FDA did not increase at 3% per year, the FDA had to actually cut funding for surveillance and research of approved drugs.
Another interesting phenomenon resulted from the change in law: the boundaries between the drug companies, FDA, and doctors became increasingly blurred. FDA officials sometimes move to jobs in the pharmaceutical industry, which means they may not want to burn their bridges with industry. The same FDA officials who approve the drugs are responsible for monitoring them after they are on the market, which gives them an obvious disincentive to say that the drugs they earlier certified as safe were now unsafe. Finally, the FDA gets input from outside advisory panels made up of doctors who are experts in their fields. Most of these doctors receive payments as consultants, research grants and support for travel to conferences from drug companies. In some cases, the doctors are working as paid consultants to the same companies whose drugs are coming up for approval by their advisory committees.
For instance, as reported by USA Today on October 16, 2004 (“Cholesterol Guidelines Become a Morality Play”) eight of the nine doctors who formed a committee in 2001 to advise the government on cholesterol guidelines for the public were making money from the very same companies that made the cholesterol lowering drugs that they were urging millions of Americans to take. For example, one of the committee members, Dr. H. Bryan Brewer, was the Chief of the Molecular Disease Branch at the National Institute of Health. He worked as a consultant or speaker for 10 different pharmaceutical companies, making over $100,000 over three years while he was on the committee, and sat on one of their boards (Los Angeles Times, December 22, 2004, “The National Institutes of Health: Public Servant or Private Marketer?”). Dr. Brewer left the NIH in 2005 in the midst of adverse publicity about potential conflicts of interest. Nassir Ghaemi, MD, a psychiatrist at Emory University, was quoted in the Emory Academic Exchange (February, 2007) as saying, “Critics say we are being influenced and don’t realize it—that drug companies are smarter than we are and know a lot more about human psychology than we think, and they’re probably right about that to some extent.”
Expert consensus guidelines have a potent effect on doctors; they can be held liable if they do not adhere to accepted standards of care. Dr. Curt D. Furberg, a former head of clinical trials at the National Heart, Lung, and Blood Institute and now a professor at Wake Forest University in North Carolina, explained how such information reached physicians: “The [company] reps tell the doctors, ‘You should follow these guidelines,’ implying that you’re not a good doctor if you don’t follow these guidelines.” (Los Angeles Times, December 22, 2004, “The National Institutes of Health: Public Servant or Private Marketer?”)”
The result of this co-mingling was a boon for drug makers, approval time of their products decreased from 20 months to six months right after the law changed. However, the number of drugs that had to be later withdrawn also increased from 2% of drugs to 5% of drugs.
There is another troubling dichotomy that could have terrible repercussions for our health: while the number of people with disease is not growing, the number of adult Americans taking medication is increasing – half of us take prescription drugs and 81% of us take at least one kind of pill everyday – and that percentage is expected to rise in the coming years. To gain the most market share, companies have to invent drugs for diseases that previously had no treatment (or treat problems that may not necessarily require drug treatment, such as “restless leg syndrome”), or create prevention medications for alleged risks (like the risk of fracture in the elderly) by expanding the potential pool of medication takers. That meant moving from the realm of giving medications to sick people, to giving medications to people who looked well, but might be at an increased risk based on the result of a blood test or some other hidden marker of disease. Thus the era of disease prevention and risk factor modification was born.
To promote this shift, for the past two decades the pharmaceutical industry has pushed educational programs, which they claim are designed to identify people in need of treatment or prevention with medication. This is usually done by donating money to organizations who advocate on behalf of a specific disease who will in turn “get the word out,” increasing public awareness and screening, and expanding the number of individuals who will potentially take the medication. This is fine for identifying individuals with undiagnosed high blood pressure or to detect the early stages of colon cancer. But awareness campaigns are not always meant to be purely, altruistically educational. Most are linked to a drug company’s marketing campaign.
There are a number of conditions for which we are now urged to obtain screening and potential treatment, including high cholesterol, osteoporosis, hypertension, diabetes, and undetected heart disease. However, the potential benefit of medications to treat these conditions is often exaggerated, side effects are minimized, and in some cases recommendations are applied to people based on evidence from different groups of people (e.g. women with risk factors for heart disease are urged to take cholesterol lowering medications based on studies in men). In addition, doctors who work as paid consultants to the pharmaceutical industry often write the guidelines about who should take the drugs, so it is unclear how unbiased their recommendations really are.
Another factor that has expanded use of prescription medications happened in 1997, when the FDA lifted the ban on direct to consumer advertising along with the law that required ads to list every possible side effect. Soon after, Americans were bombarded daily with commercials for prescription drugs. The US is the only country in the world where you can turn on the TV and have an announcer tell you to go ‘ask your doctor’ for a drug. Doctors often will give medications to patients even if they don’t think they need it. For example, one study showed that 54% of the time doctors will prescribe a specific brand and type of medication if patients ask for it.
A Bleak DiagnosisWith so many of us popping pills or gulping down spoonfuls of medicine, it’s not surprising that more of us report related adverse effects. One hundred thousand Americans die every year from the effects of prescription medications. Over a million Americans a year are admitted to the hospital because they have had a bad reaction to a medication. About a quarter of the prescriptions that doctors write for the elderly have a potentially life threatening error. Many of these people are getting medications that they don’t need, or for problems that can be appropriately and safely addressed without drugs. For example, most cases of adult onset diabetes can be prevented and possibly cured with a change in diet alone – and with considerably fewer negative side effects and numerous healthy ones, like weight loss, and lower blood pressure and cholesterol.
In 2005 in the aftermath of the Vioxx debacle and withdrawal from the market, the Institute of Medicine was asked to provide recommendations for ways to improve drug safety. As part of this process they interviewed Janet Woodcock, Deputy Commissioner of Operations at the FDA. As reported by The New York Times on June 9, 2005 (“Drug Safety System is Broken, Top FDA Official Says”), she told them that the nation’s drug safety system had, “pretty much broken down.” She went on to say that “the keystone of the current system is the prescriber, and that person is the one who decides if the benefits of a drug outweigh the risks for that patient. This system has obviously broken down to some extent as far as the fully informed provider and the fully informed patients.” She charged that neither doctors nor patients had enough information about the side effects of drugs to make informed decisions about taking them. Dr. Woodcock went on to say that, “the bottom line is that a lot of drug safety problems are actually preventable, [because] most adverse events are from known side effects.”
Unfortunately, your doctor may not be able to provide you with all the details on side effects. They aren’t hiding anything; they just can’t keep up with new information. There are over 5,000 medical journals; each publishes 20 articles a month, meaning there a million articles published each year. It’s impossible for anyone to read all of this, let alone a busy general practitioner or internist, or even a specialist, who are often buried by insurance forms and HMO paperwork. Most of the information doctors receive is distilled versions of research results that are assembled by the pharmaceutical industry and distributed through promotional materials and the product representatives that visit doctors’ offices. Legitimate publications are distributed, but papers that are not favorable are ignored, and favorable data within papers are highlighted to the exclusion of less favorable data.
In addition drug companies hire academic physicians to give lectures, but require them to show only the slides that have been approved by the company. The companies support “grand rounds” lectures (the traditional lectures given by outside speakers to the entire department) at universities, but retain the option of approving or disapproving the speakers. I know about this first hand because I have personally been affected by these policies. I fought to not use company-approved slides and was dropped as a speaker, and I was not approved as a grand rounds speaker, and the university where I was lecturing had to find funds from other sources to pay for me to give grand rounds.
Marcia Angell wrote about other ways drug companies distort the flow of information to doctors about the risks and benefits of medications in her excellent book, The Truth About the Drug Companies. She contends that doctors get most of their information about drugs during the weekly visits from drug company product representatives who are typically young, attractive women with no background in health or science; in fact, as reported by The New York Times on November 28, 2005, drug companies often recruit former college cheerleaders for this job (“Gimme an Rx! Cheerleaders Pump Up Drug Sales”).
Reps are sent into the field with a list of talking points to help them answer questions, as well as packets of product-favorable articles and other material such as copies of expert consensus guidelines (created by their paid consultants) to leave with doctors. These articles often have critical information buried in tables without comment, or assert conclusions that are not supported by the data in the paper.
Drug companies also buy information about the medications that doctors prescribe from major chain drug stores like CVS, and then use this information to reward doctors who prescribe their drugs frequently, with trips to resorts and other perks. Drug companies also lavish dinners, gifts, and paid trips to conferences on doctors. Research studies show that, although doctors deny that the perks have any effect on their prescribing practices, there are changes in objective measures, like how often a doctor will try to have a drug from that particular company put on his hospital’s formulary.
Do We Get Our Money’s Worth?I’m not saying that some drugs don’t ever successfully prevent disease, or that newly described diseases and syndromes are necessarily invalid. But the fact is that no matter how you look at it, the US (and to a lesser extent other countries) has a prescription drug problem. The US spends two times more on drugs, and takes twice as many drugs, as other countries, and has worse health. That means we are paying money for drugs that are not working for us.
Despite the fact that Americans spend twice as much on health care as any other country in the world, we have some of the worst healthcare outcomes in the industrialized world, including total life expectancy, and survival of children to their 5th birthday. In a survey of 13 industrialized nations, the US was found to be last in many health-related measures, and overall was 2nd to the last. Countries with the best health care included Japan, Sweden, and Canada, in that order. Factors that were thought to explain worse healthcare outcomes in the US included the lack of a developed and effective primary care system and higher rates of poverty. Even England, which has higher rates of smoking and drinking and a fattier diet, has better health than the US.
It is no accident that we are paying the most money and getting the worst healthcare. In Overdosed America: The Broken Promise of American Medicine, author John Abramson, M.D. says we are pouring money into expensive drugs and medical devices that have marginal value over more economical alternatives. Meanwhile we neglect the development of things like primary care that can have a real impact on health. Forty-three million Americans go without insurance, and that number is growing. We are paying a lot of money for health care we may never even receive, through the rising costs of individual health insurance, health care benefits that drive companies into the ground, expensive Medicare Drug Benefits, and Medicaid costs that cannot be controlled.
Many of the aforementioned expenses are related to expensive drugs that we often don’t need, that are no more effective than older alternatives, or that are simply not as valuable as drug companies make them out to be. For example, studies have shown that peasants in Indian villages with the diagnosis of schizophrenia who get intermittent doses of chlorpromazine, the original antipsychotic that is dirt cheap, together with support from their family, actually dobetter in terms of having fewer psychotic symptoms than Americans who get expensive new generation anti-psychotics and traditional Western psychiatric care. Another example is Nexium, “the purple pill,” which works no better for gastric reflux than the older medications like Prilosec, even though it costs much more.
Drugs cost twice as much in the US as in Canada or Europe. A year of treatment with many medications can cost up to $3000. Billy Tauzin, President of the Pharmaceutical Research and Manufacturer’s Association (PhaRMA), the lobbying organization for the drug companies, in response to efforts to regulate the content of TV ads for drugs, was quoted by The New York Times (May 17, 2005) as saying, “We don’t make ice cream or handbags or automobiles, we make products that save lives.”(Drug Industry is Said to Work on Ad Code”).
The argument drug manufacturers make for the high cost of their products, which has become an old saw by now, is that the money supports research and development of new life-saving meds. And they also say that expensive advertising is needed not to sell drugs, but to educate doctors and patients. Indeed, a whopping 80% of their budgets is used for marketing.
The major drug companies don’t develop a lot of new drugs. The truth is, most new drugs are developed through basic science research performed in universities, and not in drug company laboratories. University scientists receive research grants from the National Institute of Health (NIH). The NIH is supported by money from taxes. Take the case of the Cox-2 inhibitors, like Vioxx. The mechanisms of Cox-2 inhibition that led to the development of the Cox-2 inhibitors were discovered at a university by researchers supported by taxpayer’s dollars.
In order to keep making money, companies are under enormous pressure to create new drugs they can patent and sell without competition for 20 years, after which patents run out and generic (cheaper) versions go to market. In fact, there really aren’t a lot of truly new drugs being developed these days. Most pharmaceuticals touted as new are essentially the same as other drugs in their class, with a slight chemical modification that allows the company to have a unique patent; these are called “me too” drugs.
Once the drug companies have developed a new drug, they patent it and begin clinical trials in the hopes of gaining FDA approval for its use. In order to get approval, they must perform two multi-center randomized placebo or sugar pill controlled studies demonstrating that their drug is better than nothing. This means that patients get randomly assigned to either the drug or placebo for, say, three months, and neither the doctors nor the patients know what they are on. This is the gold standard for evaluating risks and benefits of drugs, and is required to definitively evaluate drugs, as well as alternative treatments.
The placebo response is essentially how much better you do if you take a pill that you believe helps you, even if it really does nothing in terms of its actual effect on your body. At the end of the study the “blind” is removed and the doctors look to see if the drug was better than the placebo in improving the symptoms of the disease, or preventing some pre-defined event, like a heart attack. The company must do at least two studies showing the drug is better than placebo. If they did eight studies and only two showed that the drug was better than placebo that is good enough.
Because the drug companies are only required to show that the drugs are better than nothing we usually never know whether they are better than older drugs the new versions seek to replace. It is usually left to the marketing people to generate enthusiasm, through TV ads, product representative visits to doctor’s offices, and sponsored lectures, that the new drugs are safer or better than the old drug. They do this by picking some aspect of the drug’s properties that theoretically makes it better.
For example, when tricyclic antidepressants went off patent, the new generation of drugs was selective serotonin reuptake inhibitors, or SSRIs. Even though SSRIs were never shown to be better at treating depression than the old drugs, it was argued that because the SSRIs were more specific in blocking serotonin uptake, instead of a non-specific blockage of serotonin, norepinephrine, and other chemicals, that they would be more effective with fewer side effects. The same argument was made for the COX-2 inhibitors, like Vioxx, which were said to more specifically inhibit the COX receptor involved in pain, unlike the non-specific Non-steroidal Anti Inflammatory Drugs (NSAIDs).
The head of the American Psychiatric Association recently bemoaned the fact that psychiatrists had gone from the “bio-psycho-social” model to the “bio-bio-bio” model. Us doctors have become mesmerized with the idea that all depressions are caused by imbalances of serotonin that can be fixed only with a drug that acts on serotonin. However most cases of depression are caused by life traumas, spiritual upheavals, and other jolts along the road of life. That isn’t to say that these changes aren’t accompanied by changes in brain chemistry: it is both. But I think it is time that we acknowledge the role of emotion and spirituality in mental disorders. It only makes sense.
Merrill Goozner, M.D.’s book The $800 Million Pill: The Truth Behind the Cost of New Drugs, says that charging a lot for patented medications is unnecessary to pay for developing future drugs. The second generation of drugs for a particular disorder often will cost as much as ten times as much as the old drugs that have gone off patent. The few studies that did do direct comparisons usually did not show any improvement in efficacy over the old drugs. For example, the newer antidepressant drugs like Prozac have never been shown to work better than the older tricyclic antidepressant drugs.
Sometimes new drugs are found to have consequences much worse than older alternatives; when negative consequences come up, the companies typically resist admitting it for as long as possible. For instance, the painkiller Vioxx was a second-generation drug that was never shown to be better for pain relief than the old painkiller, Advil, which could be bought for a fraction of the cost, and over the counter. However Vioxx was marketed as having a lower risk of gastrointestinal bleeding. After the drug had been on the market for many years it was discovered that it increased the risk of heart attack by several fold (see Chapter Two). Tens of thousands of people died unnecessarily taking Vioxx, and to make matters worse, they had to pay a lot more money for the privilege. What this shows is that the FDA should require companies to test new drugs against old ones, and compare both efficacy and side effects.
Given medical scares like Vioxx it’s not surprising that Americans have become wary of the FDA and drug companies, and both of their public images are beginning to suffer. The Economist reported November 24, 2004 (“Lessons For Pharma From Tobacco”) that less than 50% of us perceive drug companies as “favorable.” That’s only slightly above the low favorable ratings we give oil and tobacco companies.
Another reason why our confidence has been shaken is because of the common defense against charges of drug toxicity that drug companies use: “it was approved by the FDA.” There has even been proposed legislation to make a law that drug companies cannot be liable for drug safety problems if the FDA has approved the drug. The FDA is so paralyzed by politics, and the balance they want to achieve between scientific advancement, commerce, and safety, that it could be letting down its guard. For instance, Daniel Troy, the Chief Counsel for the FDA under George W. Bush in 2004 was a political appointee who formerly worked in a Washington law firm defending the interests of pharmaceutical companies. As reported by Drug Store News (December 22, 2004 “FDA Chief Counsel Resigns”) he worked as a “friend of the court” on cases where pharmaceutical companies had been sued for drug safety problems. The logic was that the FDA approved the drug and therefore had an interest in the outcome.
Finding AnswersIf you are like many Americans who is prescribed a drug or who loves someone who has been, you hop online to research and read about it (and the circumstances that warranted the prescription in the first place), and spend many frustrating hours coming up with little useful information. Worse, you may unwittingly be accessing information on the Internet that is not medically sound or is just anecdotal reports from individual consumers. In fact, research studies show that one out of four medical information web sites offer information that is inaccurate or misleading, and only one out of five are authored by identifiable medical experts.
The book on every doctor’s shelf, the Physicians Desk Reference (PDR), provides detailed information about drug side effects and drug interactions, but is based on product inserts that go into packages of drugs the FDA has approved. New information obtained on the millions of patients treated with drugs after they come onto the market is not incorporated into annual versions of the PDR. Since most of the consumer reference books on drugs are simply over the counter versions of the PDR, these books also do not include data on the millions of people who receive the drug after it comes on the market.
Many Americans have become disgusted with prescription drugs and the American medical establishment, who seem to be conspiring with what I call the Gang of Four (hospitals, insurance companies, the AMA and drug companies) to keep Americans sick and poor. And so they turn to alternative medicine, who frequently promote vitamins, herbs and supplements. And yet these promoters of alternative remedies are not always the peaceful, benign, and well intended people they make themselves out to be. In fact research has shown that some of the vitamins and supplements pose serious safety hazards, hazards that you may be unaware of. We have over indulgently endorsed the makers of vitamins and supplements. Those companies promote themselves as healthy alternatives to prescription medications. Many doctors take a hands-off approach to vitamins, or have the attitude that if they don’t do any harm it’s okay to take them.
However vitamins and supplements can and do indeed cause harm. And unfortunately the government has contributed to misinformation about vitamins and supplements. The US Department of Agriculture (USDA), whose job it is to promote the interests of agriculture (i.e., makers of meat and milk) and not health, regulate foods and beverages. Vitamins and supplements are classified as foods, not drugs. Lobbyists for the vitamin and supplements industry have blocked efforts by the Department of Health and Human Services (DHHS), the federal agency responsible for health, to get involved.
The USDA’s Recommended Daily Allowance (RDA) of vitamins and minerals has been great for the vitamin and supplement industry, as well as cereal makers who supercharge sales by adding vitamins, and minerals to breakfast foods, and then convince customers they need to eat these fortified products to get their minimal daily requirements of vitamins and minerals. This is despite the fact that there is no way to get enough of the recommended vitamins and minerals in normal food without overeating. Government recommendations are actually four times higher than what you really need. The fact is that youdon’t need extra vitamins, and that if you stick with fresh vegetables and fruit and other whole foods, you will stay healthy. Those making big money on vitamins and supplements are often doing so at the expense of your pocket book, and sometimes your life.
All this is not to say that many medications have not changed life for the better, particularly those that treat infections. However, ironically most recent health gains have come through increased knowledge of health risks and better health practices (or prevention). We smoke less, have better access to nutritious fruits and vegetables year round, pay more attention to cleanliness and hygiene, and have improved safety in general. For instance, in the 19th century it was not known that dirty water and shared cups could spread disease. Hand washing is still the single most powerful way to prevent the spread of communicable disease, but this was not discovered until 1847, when Ignaz Semmelweis, a young Viennese doctor in an obstetrics ward, observed that midwives who washed their hands had lower mortality rates among their patients than doctors, who often went from autopsy room to delivery ward without so much as a hand wipe.
Future advances in health will likely come more from changes in lifestyle, diet and exercise, than from medications. Almost all of the chronic conditions for which pills are prescribed are preventable through such changes. Other conditions like cancer are partially preventable.
It is time for Americans to rethink the role of medications and other pills in their lives in relation to other actions that can be taken to maximize health, such as making changes in diet; incorporating exercise into one’s daily routine; learning and using stress reduction techniques; and changing other behaviors like quitting smoking. The most common disorders, like diabetes and heart disease, are always better treated and prevented through changes in diet, exercise, and lifestyle that they are with medication. Pharmaceuticals can be life saving for some conditions, such as insulin for Type I diabetes, thyroid hormone for hypothyroidism, or antibiotics for life threatening infections. All of this has been shown through several scientific studies. Before you take that pill, consider taking charge of your health by making informed decisions and smart changes in your lifestyle. In some cases, however, you may need medications for prevention or treatment of disease, or to help you with troubling symptoms or disabilities. In those cases you should know as much as you can about the risks and benefits, so that when it is time to talk to your doctor you can make an informed decision that both of you are happy with.
J. Douglas Bremner MD is a physician and researcher and author of ‘Before You Take That Pill: Why the Drug Industry May be Bad for Your Health: Risks and Side Effects You Won’t Find on the Label of Commonly Prescribed Drugs, Vitamins and Supplements,’

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FDA Is Petitioned To Add Black Boxes For PPIs

Diagram depicting the major determinants of ga...Image via Wikipedia

nexium-flickrThe widely used class of drug known as proton pump inhibitors that are used to treat acid reflux can cause dependency and, therefore, are likely to increase various serious risks, some of which are not specified in product labeling, according to Public Citizen. And so the consumer watchdog is petitioning the FDA to upgrade labeling for these meds with Black Box warnings.
In making its case, Public Citizen notes that patients who use PPIs for at least a month, but then stop taking the med can have even more stomach acid, which is called rebound acid secretion. As a result, patients may return to the meds, creating what the watchdog group calls a “long-term dependence.” Yet some patients may not need the meds in the first place, Public Citizen argues.
“PPIs are often prescribed outside of their approved uses, for purposes such as stress ulcer prophylaxis in noncritical hospitalized patients and long-term treatment of conditions such as GERD past the approved time frame. It has been estimated that up to two-thirds of all people on PPIs do not have a verified indication for the drug. In addition, even in many people with presumed GERD on PPI therapy, less intense acid-suppressive therapies are effective in relieving symptoms, and in other cases, the medical problem does not even involve acid reflux,” the group writes in its petition.
“Compounding the problem of massive inappropriate use, recent evidence has documented several serious new safety problems with long-term PPI use. For some of these risks, current FDA-approved PPI labels do not mention the adverse effect at all, including the potential for developing dependence on the drugs, which results in rebound hypersecretion of stomach acid and recurrence of symptoms after stopping PPI use. For other risks, even if mentioned, the label does not adequately explain or emphasize them. There are currently no black box warnings in the label of any PPI” (you can read the petition here).
To bolster its cause, Public Citizen enlisted Helge Waldum, who heads of the Department of Digestive and Liver Diseases at Trondheim University Hospital in Norway and has authored dozens of medical journal articles on PPIs, including what is said to be the first trial to show patients could become dependent on the meds through the so-called rebound effect. He signed on as a co-petitioner (and you can read his statement here).
In response, a spokeswoman for AstraZeneca, which sells Nexium, Prilosec and Vimovo, wrote us this: “We work with the FDA to ensure the benefit/risk profile of our products are reflected appropriately in the prescribing information so that health care professionals can weigh the risk and benefit of medicines when making treatment decisions. PPIs have been available in the US for over 20 years and are among the most widely-studied class of medicines.
“The data referred to by Public Citizen is in the public domain and available to regulators and physicians across the world. Ultimately, it’s up to doctors to prescribe these medicines based on individual patient need. We encourage ongoing communication between physicians and patients concerning individual medical needs. AstraZeneca is confident in the positive benefit-riskand safety profiles of NEXIUM, PRILOSEC and VIMOVO.”

Investigate Gardasil Vaccine Risks NOW!

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Giant Cell Arteritis

The latest article in our Clinical-Problem Solving series, A Sleeping Giant, presents this case: A 71-year-old woman presented with abdominal pain and night sweats. Four weeks earlier, headache, sinus pressure, and night sweats had developed, and amoxicillin was prescribed for presumed sinusitis. Her symptoms improved, but after 1 week, new abdominal pain developed.
GCA, the most common form of systemic vasculitis in patients over age 50, preferentially involves large- and medium-sized arteries.

Clinical Pearls

 What are the classic manifestations of GCA?
The classic manifestations are headache, jaw claudication, PMR, and visual symptoms. However, 40% of patients present with less typical manifestations, such as breast or ovarian masses, peripheral neuropathy, SIADH, or mesenteric ischemia.
 What laboratory findings are typical among patients with GCA?
In a large case series of patients with GCA, over 95% had an ESR above 50 mm/h, and over 40% had an ESR over 100mm/h. Elevation of CRP and hepatic enzymes, particularly alkaline phosphatase, a normocytic anemia, hypoalbuminemia, reactive thrombocytosis, and increased immunoglobulin levels are also commonly associated with GCA.

Morning Report Questions

Q: How is uncomplicated GCA generally managed?
A: Uncomplicated GCA can generally be controlled in the acute setting with 40 to 60 mg prednisone daily; this dose is typically tapered slowly over 9 to 12 months. For patients with visual loss, aortitis, or other widespread involvement, higher dose therapy is recommended (e.g., 1000 mg methylprednisolone intravenously each day for three days, followed by oral therapy of 1 mg/kg daily).
Q: Is the use of glucocorticoid-sparing agents recommended for patients with GCA?
A: Randomized, placebo-controlled trials have evaluated the use of methotrexate, infliximab, and etanercept as glucocorticoid sparing agents; however, the data are conflicting and further investigation is needed.

Smoked Pfizers Chantix heart problems

Logo of Pfizer Incorporated.Image via Wikipedia

Source: Pharmalot


Yet another red flag is being raised about the Chantix smoking-cessation drug and the likelihood of cardiovascular problems. A new meta-analysis found that the Pfizer pill was associated with a 72 percent increased risk of serious adverse cardiovascular risks in smokers without a history of heart disease, and two authors suggest the FDA should consider having the drug removed from the market.
Just three weeks ago, the FDA added a warning on the product labeling about an association with a small, but increased risk of cardiovascular adverse events in patients with cardiovascular disease. The agency had reviewed a study in which 700 such patients received either Chantix or placebo, although results showed the pill was effective in helping them quit smoking and remain abstinent for up to year (back story).
In the latest analysis, which was published today in the Canadian Medical Association Journal, the researchers analyzed 14 double-blind, randomized controlled trials that involved 8,216 patients and ranged in duration from 7 to 52 weeks. They found a significantly increased risk of serious cardviovascular adverse events – 1.06 percent in Chantix versus 0.82 percent in placebo – including myocardial infarction, stroke and cardiovascular-related death. Only five trials, though, reported death (read the study here).
The findings are likely to add to the controversy over the drug, which has been associated with suicidal behavior and vivid dreams (see here and here). The government later banned Chantix for pilots and licenses wouldn’t be issued to truck drivers taking the med (see this and this). The FDA subsequently imposed a risk management program and Pfizer added warnings. Last year, a study in The Annals of Pharmacotherapy finds Chantix is not only associated with violent and agressive thoughts and acts (read here). Another in PLoS One found an association with serious acts of violence, such as physical abuse, physical assault and homicide (lookhere).
“Ours is the first study to show that Chantix increases cardiac risk substantially among smokers free of cardiac disease at baseline (13 out of 14 trials did not have heart disease at baseline) – important information that is missing from the Chantix label, despite the recent FDA warning on a small increased risk of cardiac events with Chantix among smokers with heart disease based on a single study of 700 patients (we included this study),” Sonal Singh, one of the authors and an assistant professor at the Johns Hopkins University School of Medicine, writes us.
“Since information that Chantix increases cardiac risks was available and noted by FDA safety reviewers at the time of speedy approval in May 2006 priority review, but never made it to the label, there should be no further delay in disseminating these findings to clinicians and patients. Given that there are other substantial risks with Chantix (neuropsychiatric effects) with only modest benefits compared to other therapies (such as Nicotine replacement therapy), this study shifts the risk-benefit profile of Chantix in an unfavorable direction,” he continues. “The FDA should deliberate, but also act with deliberate speed and consider all regulatory options, including removal from the market or further boxed warnings among smokers without heart disease.”
The lead author on the study, Curt Furberg, a professor of medicine at Wake Forest University, wrote us that the FDA should “clearly add the CV risk to the boxed warning (that already appears in the Chantix labeling) and seriously consider removing the drug from the maket due to the sum of serious adverse effects.”
In a statement, Pfizer says it “disagrees with the interpretation of the data” in the meta-analysis, which the drugmakers notes contains several limitations – notably, a small number of events, “which raises concerns about the reliability of the authors’ conclusions. The authors acknowledge that their risk ‘estimates are imprecise owing to the low event rates.’ The actual difference in cardiovascular event rates seen in the Singh analysis was less than one quarter of one percent – 1.06 percent with varenicline versus 0.82 percent with placebo.
“Pfizer works with regulators, like the FDA, on a continual basis to review and monitor data for Chantix. In particular, we are working with FDA to conduct a combined analysis of clinical trial data (meta-analysis), which will help further evaluate the cardiovascular safety of Chantix.” The drugmaker adds that it believes Chantix remains an important treatment option.
The meta-analysis did note that Chantix increases the chances of successfully quitting smoking by twofold compared with unassisted efforts. And there were limitations: the trials analyzed had enrolled different populations, evaluated different doses and had different lengths of follow-up and proportions lost to follow-up. “Our estimates are imprecise owing to the low event rates. None of the trials was adequately powered to detect individual differences in cardiovascular events,” the authors wrote. Furberg, by the way, is a paid expert for plaintiffs who are suing Pfizer over its Cox-2 painkillers.
“Despite the limitations of our analysis,” the authors wrote, “our findings have potential regulatory and clinical implications. Drugs that receive priority review have limited safety data at the time of approval. The initial safety signal regarding cardiovascular events in people using varenicline was not followed up by an adequately powered safety trial. Until such trials are conducted, clinicians should carefully balance the risk of serious cardiovascular events and serious neuropsychiatric adverse events asociated with varenicline use against the known benefits of the drug on smoking cessation.”
One noted cardiologist had this to say: “I continue to be perplexed by the resistance of companies to putting their subject-level data, published and unpublished, in the public domain and allowing independent investigators to evaluate the safety and efficacy of their products,” Harlan Krunholz, a professor of medicine and epidemiology and public health at Yale University School of Medicine, wrote us. “This article raises concerns but the authors are limited by the summary data that are in the public domain. We need companies to take these concerns seriously enough to support inquires by independent investigators who have unfettered access to all the data.”
In an accompanying editorial, J. Taylor Hays of the Department of Medicine at the Mayo Clinic, who has received grant funding from Pfizer to conduct a Chantix trial, wrote that the adverse events were rare; the rate of participants lost to follow-up was greater in the placebo arm than in the treatment arm in most of the studies included in the analysis, which “introduces bias in determining serious adverse events;” cardiac events were adjudicated in only one study and no significant differences were seen in the number of cardiovascular events or in deaths between those taking Chantix or a placebo.
Finally, he added that the “degree of uncertainty for the number needed to treat for harm is considerably greater than it is for the number needed to treat.” The meta-analysis found that the number needed to treat with Chantix for one additional person to successfully quit smoking was estimated to be 10, while the number needed to cause one additional serious cardiovascular event was estimated to be 28.
“These results represent a significant degree of uncertainty about the relative good or harm from Chantix, leaving the issue unsettled,” writes Hays, who acknowledges the pill is not free of risks. “The best outcome from this analysis would be more rigorous and adequately powered studies evaluating the safety of using (Chantix) among smokers who have known cardiovascular disease. The worst outcome would be for health care providers to abandon (Chantix), which has proven to be among the most efficacious pharmacotherapies used for the treatment of tobacco dependence.”
One of the researchers who explored the association between Chantix and violent behavior responded with this: “The more we learn about the safety profile of Chantix, the more unsuitable it looks as an alternative to low-risk nicotine replacement products. Chantix is linked to acts of serious violence, suicidal behavior, depression, psychosis and now increased cardiovascular risks. Canadian health authorities are examining a link to diabetes, a biologically plausible because of dopamine involvement, but not yet proven. Its effects on vision and motor control have led to it being banned for pilots, air controllers and military missile crews. Chantix is emerging as one of the biggest regulatory breakdowns in recent memory,” says Thomas Moore, a senior scientist with the Institute for Safe Medication Practices and who serves as a consulting expert in the civil litigation regarding Chantix.

Victoza (liraglutide [rDNA origin]) Injection: REMS – Risk of Thyroid C-cell Tumors, Acute Pancreatitis

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Victoza (liraglutide [rDNA origin]) Injection: REMS – Risk of Thyroid C-cell Tumors, Acute Pancreatitis

AUDIENCE: Endocrinology, Family Practice
ISSUE: Novo Nordisk reminded healthcare professionals of important safety information about Victoza (liraglutide [rDNA origin]) injection required in a Risk Evaluation and Mitigation Strategy (REMS). The letter is being sent because a recent assessment of healthcare providers showed that some primary care providers are not fully aware of the serious risks associated with the use of Victoza.
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Additionally, in clinical trials studying Victoza, there were more cases of pancreatitis in patients treated with Victoza than in patients treated with comparators.
BACKGROUND: FDA may require a REMS for newly or already approved prescription drug product when FDA determines that a REMS is necessary to ensure the benefits of a drug outweigh the risks of the drug. Victoza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
RECOMMENDATION: Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation.
After initiation of Victoza, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, and which may or may not be accompanied by vomiting).
Healthcare professionals and patients are encouraged to report adverse events, side effects, or product quality problems related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:
  • Complete and submit the report Online:www.fda.gov/MedWatch/report.htm
  • Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
Read the MedWatch safety alert, including a link to the Dear Healthcare Professional Letter, at:

“Revisión prioritaria” para el “superfármaco” contra la E. coli

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Publicado por Miguel Jara el 8 de junio de 2011

La “crisis del pepino” o de la bacteria Escherichia coli, para ser más exactos, comenzó el pasado 26 de mayo a raíz de las declaraciones de la senadora regional alemana Cornelia Prüfer-Storcks en las que achacaba el origen del brote infeccioso provocado por la bacteria a los pepinos españoles. Alexion, como saben las personas que siguen este blog, es una compañía farmacéutica que sólo tiene un producto, y que lo rentabiliza muy bien por lo visto, llamado Soliris (eculizumab), que hasta ahora sólo está autorizado para tratar una enfermedad de las consideradas “raras“, aquellas que afectan a menos de cinco personas de cada 10.000, la Hemoglobinuria Paroxística Nocturna (HPH) y que el año pasado fue el fármaco más caro del mundo.
El 1 junio, sólo seis días después de aparecer las bacterias recombinantes de E. Coli que nadie parece saber de dónde proceden ni controlar, la agencia estadounidense del medicamento, la todopoderosa y controvertida -por estar en buena medida financiada por la industria farmacéutica-, la FDA, otorga a Alexion una “revisión prioritaria” para desarrollar Soliris para el tratamiento del Síndrome Hemolítico Urémico(SHU), que están padeciendo parte de las personas afectadas por los alimentos contaminados con las nuevas cepas de E. coli. Deben saber que en Estados Unidos los laboratorios pueden pagar unas tasas extras a la FDA para que esta acelere el proceso de revisión y autorización de un nuevo medicamento, por ello la industria es cliente de quien está encargada de vigilarla.
Fuente: Miguel Jara.
La designación de revisión prioritaria se da a los medicamentos que pueden ofrecer importantes avances en el tratamiento o cuando no existe una terapia adecuada. Si la aprobación se concede, Alexion prevé que Soliris estará disponible para los pacientes de EE.UU. con SHU en el cuarto trimestre de 2011. La Agencia Europea del Medicamento(EMA) también está examinando una solicitud de comercialización de eculizumab como tratamiento para pacientes europeos de la enfermedad.
Según un comunicado de la propia empresa, ésta ha recabado datos estadísticos positivos en dos ensayos de 26 semanas, realizados con Solaris, que han superado la Fase II (la de establecer mediciones preliminares de la relación eficacia terapéutica/toxicidad) como tratamiento para pacientes adultos y adolescentes de SHU. Los datos finales de estos estudios se presentarán en el congreso de la Asociación Europea de Hematología (EHA) que comienza mañana día 9 de junio y durará hasta el próximo día 12.

5-alpha reductase inhibitors (5-ARIs): Label Change – Increased Risk of Prostate Cancer

MedWatch logoMedWatch - The FDA Safety Information and Adverse Event Reporting Program
5-alpha reductase inhibitors (5-ARIs): Label Change – Increased Risk of Prostate Cancer
Drugs in the 5-ARI class include finasteride and dutasteride. These drugs are marketed under the brand-names Proscar, Propecia, Avodart, and Jalyn
ISSUE: FDA notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).
BACKGROUND: The new safety information is based on FDA’s review of two large, randomized controlled trials––the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. Proscar, Avodart, and Jalyn are approved to improve symptoms of an enlarged prostate gland (benign prostatic hyperplasia or BPH). Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate. Propecia is approved to treat male pattern hair loss.
RECOMMENDATION: Prior to initiating therapy with 5-ARIs, perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH). See Drug Safety Communication for a Data Summary and additional information.
Healthcare professionals and patients are encouraged to report adverse events, side effects, or product quality problems related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:
  • Complete and submit the report Online:www.fda.gov/MedWatch/report.htm1
  • Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
Read the MedWatch safety alert, including a link to the FDA Drug Safety Communication, at:

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Delayed FDA Removal of Painkiller Propoxyphene

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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.


Sidney M. Wolfe MD
Director, Health Research Group at Public Citizen
1600 20th St. NW
Washington, DC 20009
Phone: +1 202 588-7735