OBOS is committed to expanding our audience and in this spirit we’ve asked former board member Moises Russo to translate into Spanish several of our blog entries. We hope to translate more entries in the coming year.

En OBOS estamos comprometidos a expandir nuestra audiencia de lector@s  y en este espíritu le hemos solicitado a Moisés Russo, ex-miembro de la Junta de OBOS, que traduzca al español varios de los blogs que tenemos en la página electrónica. Esperamos continuar con dichas traducciones durante este año.

Una segunda vacuna diseñada para proteger contra el cáncer cervicouterino estará disponible pronto en Estados Unidos.

La semana pasada, un panel de la de Food and Drug Administración (FDA) dio su aprobación a la vacuna Cervarix de GlaxoSmithKline PLC*, esencialmente recomendando que la FDA apruebe la vacuna para el uso en mujeres de 10 a 25 años de edad. La recomendación no es obligatoria; la FDA puede rechazar la decisión, pero ésta generalmente acepta la opinión de paneles externos de expertos.

La vacuna protege contra dos tipos de virus papiloma humano (VPH), asociados al 70% de los cánceres cervicouterinos.

Escribiendo en el Wall Street Journal, Jennifer Corbett Dooren resumió las preocupaciones con respecto a la seguridad que la FDA levantó acerca de Cervarix, incluyendo “una mayor tasa de abortos entre las mujeres que recibieron Cervarix”. La FDA refirió además “no se puede excluir un ‘pequeño efecto’ sobre los embarazos”. (La vacuna no está aprobada para su uso en mujeres embarazadas).

GlaxoSmithKline intentó por primera vez conseguir la aprobación el año 2007, pero la FDA solicitó más información luego de que algunos reportes sugirieron una tasa más alta de abortos en mujeres embarazadas. Dooren escribe:

La agencia dijo que se requeriría de un estudio de seguridad post- marketing para monitorizar los resultados de embarazos en mujeres que pudiesen recibir Cervarix, junto con otras potenciales preocupaciones sobre su seguridad incluyendo el desarrollo de enfermedades autoinmunes como Artritis Reumatoide y Esclerosis Múltiple. En su revisión del año 2007 de Cervarix, la FDA indicó que tenía preocupaciones sobre un “desequilibrio” en posibles desordenes autoinmunes visto en algunos estudios clínicos. Sin embargo, la agencia ha dicho que revisiones adicionales de los datos realizadas por sus propios equipos y por un reumatólogo externo concluyeron que las diferencias no eran estadísticamente significativas.

Oficiales de Glaxo dijeron que estaban planeando un estudio de post-marketing que enrolaría a 100.000 mujeres en los EEUU, el cual incluiría un registro de embarazos. La compañía también se encuentra realizando otro estudio de post-marketing de grandes proporciones en Finlandia.

Gardasil, la popular vacuna contra el VPH fabricada por Merck y & CO. Fue aprobada por la FDA el 2006. Uno de los principales investigadores para la vacuna recientemente ha comenzado a denunciar preocupaciones con respecto a sus riesgos, beneficios y agresivas estrategias de marketing – principalmente que la protección puede no durar más allá de los 5 años, por lo que las niñas que sean vacunadas a una edad temprana pudiesen en el futuro aún encontrarse en riesgo.

El mes pasado, Rachel apuntó a una editorial del Journal de la Asociación Médica Americana sobre los riesgos y beneficios de la vacunación contra el VPH y analizó un comentario en la misma edición de JAMA (sólo resumen) sobre el marketing de Gardasil. Describiendo los hallazgos de los autores, Rachel escribió: “ La táctica de la compañía fue fomentar que todas las mujeres dentro de un cierto grupo de edad se vacunaran como una medida para evitar el cáncer, en vez de trabajar con oficiales de la salud pública para enfocarse en aquellas niñas que tienen un riesgo más elevado”.

Los Centros para el Control y Prevención de las Enfermedades (CDC por sus siglas en inglés) recomienda la vacuna para niñas de 11 y 12 años, y niñas y mujeres entre las edades de 13 y 26 años que aún no hayan sido vacunadas. Esa recomendación sin embargo se convierte en un mandato para las mujeres inmigrantes entre 11 y 26 años que buscan la ciudadanía Estadounidense. Gardasil fue agregada a la lista de vacunas requeridas el año 2008.

Simona Davis, una niña de 17 años en Florida que nació en el Reino Unido está buscando la ciudadanía Estadounidense pero se rehúsa a vacunarse. El noticiario ABC News tiene un reportaje completo sobre su rechazo a la vacuna. Davis, que es una cristiana devota que dice no tener intención de iniciar relaciones sexuales en el futuro cercano (menciona su promesa de virginidad como una prueba), está buscando una exención por razones morales y religiosas. Los Servicios de Ciudadanía e Inmigración de los EEUU han rechazado su solicitud.

“La decisión de incluir el VPH como una vacuna requerida fue hecha por el CDC”, ha dicho la vocera de los Servicios de Ciudadanía e Inmigración de los EEUU Chris Rhatigan a ABC News. “Nosotros seguimos la ley….La objeción a una exención debiese ser a todas las vacunas, no solamente a Gardasil”.

Un vocero del CDC ha dicho que se espera que el CDC publique nuevos criterios dentro de aproximadamente un mes para determinar que vacunas debiesen ser recomendadas a inmigrantes a los EEUU.

In explaining the need for such research funding and initiatives, the agency states:

About two-thirds of women who deliver a baby have taken at least one prescription medication during pregnancy according to a journal article published in the American Journal of Obstetrics and Gynecology. There are very few clinical trials that test the safety of medications in pregnancy due to concerns about the health of the mother and child.

In order to gather such information, the FDA will collaborate with researchers to analyze data on prescription drug use and pregnancy outcomes from 11 sites of the HMO Research Network Center for Education and Research in Therapeutics, Kaiser Permanente’s multiple research centers, and Vanderbilt University (this blogger’s larger workplace).

The National Women’s Health Information Center provides further information on the use of prescription and OTC medications in pregnancy, including the current labeling categories applied to prescription drugs to indicate what is known about using them during pregnancy.

In 2008, the FDA proposed a rule change that would eliminate these somewhat unhelpful letter categories (A, B, C, D, and X) in favor of adding a “Pregnancy” section to drug labels with a risk summary and more clear information about available data on use of the drug during pregnancy and breastfeeding. A public comment period was held on the proposed rule, but it does not appear to have been finalized yet.

See also: Strollerderby post on the announced drug studies; the FDA’s info for consumers on the proposed labeling change; LactMed (search for information on specific drugs and breastfeeding); fact sheets on drug exposures during pregnancy and lactation from the Organization of Teratology Information Specialists; and Motherisk’s publications on drugs in pregnancy.

The current study compared women who used DMPA for at least 24 months and had less than 5% vs. at least 5% bone loss to attempt to identify any characteristics that might be associated with a higher risk of bone loss.

The authors report that being a current smoker was associated with higher bone loss, while higher calcium intake (at least 600 mg/day) and having ever delivered a child were associated with lower levels of bone loss. Age, race or ethnicity, previous contraceptive use, and body mass index did not appear to be associated with higher bone mineral density loss.

Although only the abstract of the article is freely available, ScienceDaily provides an additional summary.

In other bone-related news, NPR published a piece this week, “How A Bone Disease Grew To Fit The Prescription,” which describes Merck’s approach to marketing the drug Fosamax, including its efforts to push smaller, cheaper machines to perform bone density scans (and for Medicare payment for the scans) and to expand the “osteopenia” diagnosis.

However, as the piece notes, “There are no long-term studies that look at what happens to women with osteopenia who start Fosamax in their 50s and continue treatment long-term in the hopes of preventing old-age fractures. And none are planned.”

The story and accompanying transcript provide a fascinating look at the marketing of a drug, from the perspective of a former Merck rep who believed he was helping save women from fractures through his marketing efforts, to criticisms of that work as “a plot to misdiagnose American women,” and the debate over whether women with slightly decreased bone density should be medicated at all.

As Roth explains:

When a generic drug is approved to come to market, the maker of the more expensive name-brand drug sues the generic for patent infringement. But instead of a conventional settlement, in which the generic pays the patent-holder to settle the claim that it infringed the patent, the payment goes the other way: the patent-holder pays the maker of the generic, in exchange for a pledge to delay bringing the generic to market.

As a result of these “pay-for-delay” deals, cheaper generic drugs are often kept off the market for a longer period than they otherwise would be.

While the TPM story doesn’t mention any drugs specific only to women’s health, Prescription Access Litigation provides at least one relevant example — a patent litigation/generic case from the late 1990s over the breast cancer drug Tamoxifen. The Centers for Disease Control and Prevention estimates that 46 percent of Americans used at least one prescription drug in the past month, so many consumers (male and female) are affected by drug prices on a regular basis.

There’s been little action in recent years on proposed legislation to prevent such deals. The “Protecting Consumer Access to Generic Drugs Act of 2009″ — HR 1706 — was introduced earlier this year by Rep. Bobby Rush (D-Ill.), and so far, like similar bills introduced the past, it has not made it past the committee stage.

The House Subcommittee on Commerce, Trade and Consumer Protection held a hearing on the proposed legislation in March and apparently referred the bill on to the full Committee on Energy and Commerce, which does not seem to have considered it.

The Federal Trade Commission has also come out against the practice. FTC Chairman Jon Leibowitz said during a talk at the Center for American Progress in June that ”American consumers would save $35 billion dollars over the next decade if these deals were banned.”

This past summer, the Department of Justice weighed in on one such case and concluded: “a settlement involving a payment to the alleged drug patent infringer in exchange for its agreement to withdraw its challenge to the patent and delay bringing its generic drug to market is presumptively unlawful and requires the defendant to offer justifications in order to avoid antitrust liability.”

More than $100 million was awarded by juries between those two cases, although news reports indicate that Pfizer will appeal and damages awarded are likely to be reduced; a Pfizer spokesperson said the company does not believe the verdicts “were supported by the evidence or the law.” About 10,000 similar cases are apparently pending at this time.

In 2002, the Women’s Health Initiative study was released results indicating that women taking estrogen plus progestin hormone replacement (such as Prempro) were more likely to develop breast cancer than women taking placebo, and their cancers were more likely to be more advanced. The trial was stopped early that year after it became clear to investigators that the risks of combination hormone therapy outweighed the reported benefits.

As a result of WHI findings, in 2003 the FDA required the addition of a black box warning to the drug’s label to state that estrogen and estrogen plus progestin therapies should not be used for the prevention of cardiovascular disease, and to warn of increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women taking the estrogen/progestin combo.

Our own Judy Norsigian is quoted in Time, expressing caution:

Certainly, there may be women who will do better after taking flibanserin, says Judy Norsigian, executive director of the women’s health advocacy Our Bodies Ourselves, based in Cambridge, Mass. But she thinks the diagnosis of HSDD unnecessarily medicalizes women’s sexual lives. Attempting to treat low libido with a pill ignores the fact that many women’s level of desire is deeply affected by everyday life stress and interpersonal relationships. Add to that a cultural milieu that at once promotes shame and ignorance about women’s sexuality while wildly inflating their expectations for sex.

In many cases, says Norsigian, the proper solution to a lack of sexual desire would involve a number of non-drug approaches, such as therapy, mind-body techniques and getting partners involved in the solution. “That could be equally successful while at the same time not exposing women to the [potential] long-term adverse effects of drugs,” says Norsigian, who suggests testing drugs like flibanserin against drug-free therapies. “Moreover, the non-medication approaches often address root causes for lack of libido and thus reflect a prevention approach that is usually much wiser.”

During a recent event hosted by the Vanderbilt University School of Nursing’s Midwifery Program, Norsigian raised similar questions about whether women are receiving the best and safest treatments. She also discussed examples of how mixed, inaccurate or incomplete media coverage can make it difficult for women to navigate their health options and to understand the risks involved with some procedures. The Reporter, Vanderbilt Medical Center’s weekly newspaper, covered Norsigian’s talk.

The authors used sales data from the U.S. distributor of mifepristone and abortion surveillance data from the CDC and Guttmacher’s own surveys of abortion providers. Using this data, they attempted to calculate the estimated numbers of mifepristone abortions and providers by year, provider type, and physician specialty, the proportion of all abortions and of eligible (i.e., early enough for the medication option) abortions that used mifepristone, and the number of mifepristone-only providers who were more than 50 miles away from a known surgical provider. [The researchers detail this process and their related assumptions in the methods; statistics geeks will want to get a full copy of the paper for that info and their notes on the limitations.]

Among the findings:

• Not surprisingly, the estimated number of medication abortions increased sharply in the years immediately after the drug became available, from about 55,000 in 2001 (the first full year of availability) to about 158,000 by 2007.
• Based on existing trends, they estimate that mifepristone would represent 7% of eligible abortions performed in 2000, and about 21% in 2007 (an increase in percentage of all abortions from about 4% in 2001 to 10% in 2007).
• Provision of medication abortion tends to follow trends for provision of all abortion, with clinics providing the most, followed by physicians and hospitals. More ob/gyns provide the drug than other physicians (such as family practice or internal medicine) by a wide margin.
• Clinics, which typically provided surgical abortions as well, accounted for 88% of mifepristone abortions, and 96% were in metropolitan areas – “Only 14 mifepristone-only providers were located more than 50 miles away from any surgical provider. Only five mifepristone-only providers of 10 or more abortions were located farther than 50 miles from any surgical provider of 400 or more abortions.” Fewer counties had a mifepristone provider than had any abortion provider generally, and more total abortion providers were estimated than mifepristone providers (meaning that some providers may offer surgical abortion only).

The authors conclude, therefore, that “The large geographic overlap between facilities that provide surgical abortion and those that offer mifepristone means that, in many cases, women are able to choose the type of early abortion procedure they prefer,” but that “mifepristone has not brought a major improvement in the geographic availability of abortion.”

The study did not survey providers as to why they might not offer medication abortion when surgical abortion is offered, why more providers such as family practice physicians don’t seem to provide the drug, or why more providers in areas with few or no surgical providers nearby do not offer the drug as a matter of accessibility. The authors speculate that “One limiting factor may be liability coverage, which has been identified as a barrier to provision of abortion services generally, and mifepristone specifically, in family medicine.” Another unexamined issue is that a small percentage of women (5-8% according to the drug label) using Mifeprex  need a follow-up surgical procedure to complete the abortion or control bleeding; it is not clear what impact this might have on providers who do not provide surgical abortions or in areas where those services are not easily located.

But according to a new study by the editors of the Journal of the American Medical Association, some of the top medical journals have published a significant number of articles written by ghostwriters without notifying readers about any potential conflict of interest.

“In the scientific literature, ghostwriting usually refers to medical writers, often sponsored by a drug or medical device company, who make major research or writing contributions to articles published under the names of academic authors,” write Duff Wilson and Natasha Singer in The New York Times, which covered the study last week.

The Times has published several other articles on this topic recently, including news that Wyeth pharmaceutical company paid ghostwriters to produce 26 scientific papers promoting the benefits and downplaying the risks of hormone replacement therapy. (Read our coverage, including Stephen Colbert’s take.)

Considering what’s at stake — treatment decisions and patient care — it’s remarkable that articles in well-respected, peer-reviewed journals are not fully transparent.

The JAMA editors created an anonymous, online questionnaire for authors of journal articles. The authors were asked to self-report their own behavior. Authors of 630 articles responded; of them, 7.8 percent acknowledged other people worked on the articles and the contributions were substantial enough that they should have been listed as authors.

The New England Journal of Medicine had the highest rate of ghostwriting at 10.9 percent. The rate was 7.9 percent in JAMA; 7.6 percent in The Lancet; 7.6 percent in PLoS Medicine; 4.9 percent in The Annals of Internal Medicine; and 2 percent in Nature Medicine.

“It was very compelling, and I find it quite shocking, to be honest,” Ginny Barbour, chief editor of PLoS Medicine, the journal of the Public Library of Science, said after the findings were unveiled at an international meeting of journal editors in Vancouver. “We are a journal that has very tough policies, very explicit policies on ghostwriting and contributorship, and I feel that we’ve basically been lied to by authors.”

Read more from PLoS here.

The news comes just weeks after the National Institutes of Health (NIH), a federal agency that invests more than $30 billion in medical research each year, most of which is awarded through competitive grants to researchers at universities, medical schools and other research institutions, came under fire for not promoting a clear policy on ghostwriting with regards to NIH-funded researchers and institutions.

In a letter to the NIH, which was obtained by The New York Times, Sen. Charles Grassley (R-Iowa) identified researchers at Columbia University and University of Maryland who were recipients of NIH grants and who have signed on to ghostwritten publications. Academic institutions traditionally have also taken a hands-off approach.

A Food and Drug Administration panel last week gave its approval to GlaxoSmithKline PLC’s Cervarix vaccine, essentially recommending that the FDA approve the vaccine for use in females 10 to 25 years old. The recommendation is not binding; the FDA can reject the decision, but it generally accepts the opinions made by an outside panel of experts.

The vaccine protects against two strains of human papilloma virus (HPV) that are associated with 70 percent of cervical cancers.

Writing in the Wall Street Journal, Jennifer Corbett Dooren summarized the safety concerns the FDA raised about Cervarix, including “a higher rate of miscarriages among females who received Cervarix.” The FDA also “couldn’t rule out a ’small effect’ on pregnancies.” (The vaccine is not approved for use in pregnant women.)

GlaxoSmithKline first sought approval in 2007, but the FDA asked for more information after reports suggested a higher miscarriage rate in pregnant women. Dooren writes:

The agency said it would require a post-marketing safety study to monitor the outcome of pregnancies in women who might receive Cervarix along with other potential safety concerns including the development of autoimmune diseases like rheumatoid arthritis and multiple sclerosis. In its 2007 review of Cervarix, the FDA said that it was concerned about an “imbalance” of possible autoimmune disorders seen in clinical trials. However, the agency said an additional review of the data by its own staff and an outside rheumatologist concluded the differences weren’t statistically significant.

Officials from Glaxo said they were planning a post-marketing study that would involve 100,000 women in the U.S., which would include a pregnancy registry. The company is also conducting another large post-marketing study in Finland.

Gardasil, the popular HPV vaccine manufactured by Merck & Co., was approved in 2006. One of the lead researchers for the drug recently started speaking out with concerns about its risks, benefits and aggressive marketing — namely that the protection may not last beyond five years, so girls who are vaccinated at an early age may still be at risk.

Last month, Rachel pointed to a Journal of the American Medical Association editorial on the risks and benefits of HPV vaccination and discussed a commentary in the same JAMA issue (abstract only) about  the marketing of Gardasil. Describing the authors’ findings, Rachel wrote: “The company’s tactic was to encourage all girls within a certain age group to be vaccinated as a cancer avoidance measure, rather than to work with public health officials to target those girls at the highest risk.”

The Centers for Disease Control and Prevention recommends the vaccine for 11- and 12-year-old girls, and girls and women age 13 through 26 who have not yet been vaccinated. That recommendation becomes a mandate, however, for  female immigrants between the ages of 11 and 26 seeking U.S. citizenship. Gardasil was added to the list of required vaccines in 2008.

Simone Davis, a 17-year-old girl in Florida who was born in Britain is seeking citizenship but she refuses to get the vaccine. ABC News has a comprehensive story about her refusal. A devout Christian who says she has no intention of having sex anytime soon (she mentions her virginity pledge as proof), Davis is seeking a waiver for moral and religious reasons. U.S. Citizenship and Immigration Services has rejected her claim.

“The decision to include HPV as a required vaccine was made by the CDC,” Citizenship and Immigration Services spokeswoman Chris Rhatigan told ABC News. ”We follow the law … The objection to a waiver would have to be to all vaccines, not just Gardasil.”

A CDC spokesperson said the CDC is expected to publish new criteria to determine which vaccines should be recommended for U.S. immigrants in about a month.

The authors observe that the vaccine was “promoted primarily to ‘guard’ not against HPV viruses or sexually transmitted diseases but against cervical cancer,” and provides an interesting critique of the broad approach vaccine-maker Merck used. The company’s tactic was to encourage all girls within a certain age group to be vaccinated as a cancer avoidance measure, rather than to work with public health officials to target those girls at the highest risk:

Marketing this HPV vaccine as an anticancer vaccine appears to have enabled its manufacturer to circumvent possible parental and public unease with an antidote to sexually transmitted diseases. But in doing so, the company bypassed public health officials who would have spearheaded a risk-sensitive vaccination campaign. So too, this manufacturer understandably wanted as many adolescents as possible to be vaccinated. But the pursuit of this goal was neither cost-effective nor equitable. It meant rather than concentrating on populations in geographic areas with excess cervical cancer mortality, including African Americans in the South, Latinos along the Texas-Mexico border, and whites in Appalachia, the marketing campaign posited that every girl was at equal risk: “Your daughter could become 1 less life affected by cervical cancer.”

The authors also explain how, in order to “avoid limiting the vaccine to high-risk populations, promote it for all women, and secure government reimbursement and mandates,” Merck approached professional medical associations (PMAs), and funded them to promote the vaccine. These included the American College of Obstetricians and Gynecologists, American Society for Colposcopy and Cervical Pathology, the Society of Gynecologic Oncologists , and the American College Health Association, according to the authors.

Funding to at least one of these organizations was used to develop a kit to guide speakers in promoting the vaccine, including the directive to encourage the audience to ask for state mandates and funding for the vaccine. Speakers were also instructed to play down sexual transmission of HPV, and the organizations were asked to report back to Merck on their promotional talks.

The authors of the commentary describe the ethical problem with this approach, and provide guidance to medical organizations:

Professional medical associations are obligated to provide members with evidence-based data so they can present relevant risks and benefits to their patients. To this end, PMAs must become more transparent about their relationships with industry, disclosing both the precise funding and technical assistance they have received to develop and disseminate the promotional products. Under no circumstances should PMAs administer product-specific speakers’ bureaus, nor should they accept funding that requires them to report activity to the donor.

A related editorial on the risks and benefits of HPV vaccination is freely available in the same issue of JAMA. In it, the author explains that while “the theory behind the vaccine is sound,” long-term follow-up is needed to determine whether there is an effect on cervical cancer incidence 20-40 years from now. The author also notes that the net benefit of the vaccine to an individual woman is currently unknown.