HPV Roundup: Gardasil safety worries, Cervarix FDA delays, more on mandates

There's been a flurry of media coverage this week about possible safety issues related to Gardasil. It appears that the attention was initiated by this report released by Judicial Watch, the conservative watchdog group. Like its previous reports alleging numerous deaths and illnesses caused by vaccine, this Judicial Watch report is based on unconfirmed submissions to VAERS, the government's clearinghouse for reports of possible vaccine-related adverse events. Reports to VAERS -- widely described as a 'hypothesis-generating mechanism' -- are later examined by government officials to determine what, if any, role a vaccine may have had in the reported condition.

Numerous other outlets have raised questions about Gardasil's safety in the past few days, most notably this CBS News story by Sharyl Attkinson, the media member who is increasingly at the forefront of reporting on alleged vaccine risks. Other media outlets examining the topic include CNN and WebMD.

In the meantime, officials from CDC and FDA have assured the public that the vaccine remains safe and effective and that reports of possible adverse events will continue to be investigated. Merck responded similarly yesterday, noting the limitations of reports made to VAERS.

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Meanwhile, it appears that the U.S. head-to-head battle between Gardasil and GSK's Cervarix will most likely be delayed until late 2009. Last week, the Wall Street Journal and Reuters, among others, reported the GSK announcement of its timetable for submitting additional trial data requested by FDA. Here is the GSK press release. It notes that Cervarix is already approved in 67 countries, including the E.U., but it's no secret that the U.S. market is by far the most lucrative, as Merck's sales figures from earlier this year illustrated.

From a business standpoint, this is decidedly good news for Merck, as it extends its head start in the U.S. (The news has not all been good, however, as it was announced late last month that Merck's application to expand the indication for Gardasil for women through age 45 will face additional scrutiny and delays. Here's a story from Reuters and the Merck press release.)

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In other news, two papers have recently been published in academic journals on HPV mandates (joining a growing literature on this topic -- including papers by Schwartz, et al., Colgrove, and Zimmerman.) One paper, "Assessing Mandatory HPV Vaccination: Who Should Call the Shots?" (Javitt, et al.) appears in the Summer 2008 issue of the Journal of Law, Medicine & Ethics (subscription required). In short, the authors conclude, "...Mandating HPV vaccination at the present time would be premature and ill-advised."

Also, the May 2008 Harvard Law Review published a paper titled "Toward a 21st Century Jacobson v. Massachusetts (pdf), alluding to the 1905 case that is widely seen as the foundation for state public health powers. The authors argue that a distinction should be drawn between vaccines that are 'medically necessary' (such as smallpox) and those that are 'practically necessary' (such as hepatitis B and HPV, for which other preventive measures are available but not widely used). The paper suggests that current law and policy fail to acknowledge the implications of this distinction.

Flu vaccine recommendation expanded through age 18

News out of this week's ACIP meeting in Atlanta that the committee voted today to expand its influenza vaccine recommendation to include all children and teenagers up to age 18. Previously, the recommended pediatric population only included children between 6 months and 5 years of age. Here's the CDC announcement about the expanded recommendation; it notes that approximately 30 million children are affected.

Here's coverage from the New York Times, CIDRAP News, and the Associated Press. The AP story reports that of the 36,000 annual influenza deaths in the U.S., only 25-50 occur in the 5-18 population. (Of course, preventing deaths is only one goal of expanded vaccination efforts.)

With some in the medical and public health communities advocating a universal recommendation, i.e., that all Americans receive the vaccine annually, the new recommendations (once fully implemented) will include essentially all Americans under age 18 and over age 50, in addition to a host of specific groups at higher risk of influenza morbidity or mortality.

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Today's announcement follows several weeks of bad news about the severity of the current flu season and issues with this year's vaccine failing to match a significant percentage of the circulating strains. Earlier this month, WHO recommended a wholesale redesign of the composition of the 2008-9 influenza vaccine -- replacing all three strains in the current season's vaccine. Here's the WHO report (pdf) and a CDC Q&A explaining the process by which the annual composition of the vaccine is determined. As is standard practice, the identical three strains were also recommended by the relevant FDA advisory committee at their meeting last week. Here's a related CIDRAP News story.

This link includes the most recent weekly report from CDC on influenza activity in the U.S., just part of the vast amount of information and resources available at its seasonal flu website.

FDA: GSK rotavirus vaccine appears safe and effective

Rotarix, the rotavirus vaccine developed by GSK, moved closer to U.S. licensure on Friday, as an FDA staff report stated that clinical trial results suggest that the vaccine is safe and effective.

Here is coverage of the news from The Wall Street Journal, Associated Press and Dow Jones. Rates of intussusception -- the gastrointestinal condition that doomed the first rotavirus vaccine, Rotashield, in 1999 -- were not significantly different in those receiving Rotarix versus control groups receiving a placebo.

A positive recommendation from government advisors at next week's meeting of FDA's Vaccines and Related Biological Products Advisory Committee would likely be the final step prior to licensure in the U.S. Rotarix is already approved in over 90 countries, according to GSK.

Merck's rotavirus vaccine, RotaTeq, was approved in February 2006 and is currently recommended for all infants at 2, 4, and 6 months of age

ACIP: FluMist OK for children 2+; 6th seasonal flu vaccine approved

There's news from this week's meeting of the ACIP that the committee's influenza vaccine recommendation for children age 2-5 now includes FluMist. Here's a story from the Associated Press and another from the Wall Street Journal. This is hardly a surprise, in light of the decision by FDA to approve the vaccine for use in the 2-5 age group. (FluMist had previously been approved for 5-49 years olds only.)

In unrelated seasonal influenza vaccine news, we haven't yet noted the FDA approval late last month of Afluria, an injectable vaccine made by the Australian company CSL Biotherapies. The vaccine, licensed for use in adults 18 and older, is now the 6th different influenza vaccine available in the U.S. Here's coverage from CIDRAP News and Forbes.com and a media release from FDA.

Info on Kawasaki disease added to RotaTeq label

A colleague from CDC alerted us to this announcement regarding a change to the label of RotaTeq, Merck's rotavirus vaccine recommended to all infants at 2, 4, and 6 months. Here's the first paragraph of the CDC statement:

"The Food and Drug Administration (FDA) approved today a revised label for RotaTeq, a rotavirus vaccine manufactured by Merck and Co., Inc., to include information on reports of Kawasaki disease occurring before and after the vaccine’s licensure in February 2006. FDA has not made any changes to its indications for use of RotaTeq nor has it issued new or revised warnings or precautions. Likewise, the Centers for Disease Control and Prevention (CDC) has not made any changes in its recommendations regarding the use of RotaTeq. Healthcare providers and parents should remain confident in using RotaTeq in infants."

Here's the FDA release and a related story from Reuters (the only media outlet to have reported on this item as of now.)

General info on Kawasaki disease can be found here and here. It's a rare and poorly understood inflammatory condition that affects 4,000 American children annually.

The "label" referred to in the announcements above is actually this document, an 11-page, single-spaced, data-laden product insert unlikely to top the reading lists of most parents (or pediatricians, for that matter).

The FDA statement notes, "The cases reported to date are not more frequent than what could be expected to occur by coincidence," a statement that could also describe its announcement in February regarding intussusception reports among recipients of RotaTeq.

Similar to that earlier occasion, this announcement was seemingly made so that providers and parents may be vigilant in looking for symptoms of Kawasaki disease, in case a connection to the vaccine does exist. However, calling attention to severe conditions for which no evidence suggests a vaccine link may create undue confusion and worry among parents still told to vaccinate their children with RotaTeq. Admittedly, it is a difficult balance that must be weighed by policy-makers, but one that merits further study.

Renewed attention to possible rotavirus vaccine link to intussusception

A fairly significant amount of alarm was raised by an FDA statement last week titled "Information on RotaTeq and Intussusception". The statement reports 28 cases of intussusception -- the significant intestinal complication that led to the removal of the first rotavirus vaccine, RotaShield, in 1998 -- in children following administration of RotaTeq.

But what may have seemed at first glance to be a major announcement about the vaccine's safety was clarified later in the statement...

"Intussusception can occur spontaneously in the absence of vaccination. Of the reported 28 cases of intussusception, the number that may have been caused by the vaccine, or occurred by coincidence, is unknown."

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"The number of intussusception cases reported to date after RotaTeq administration does not exceed the number expected based on background rates of 18-43 per 100,000 per year for an unvaccinated population of children ages 6 to 35 weeks (CDC, unpublished data)."

In other words, there's no reason to be alarmed about the number of cases reported to date, but the statement, not unsurprisingly, did just that. This AP story by Andrew Bridges originally did not include any information about the background rate, likely contributing to the Alliance for Human Research Protection (and others, no doubt) misinterpreting the FDA item. "Merck rotavirus vaccine linked to 28 reports of life-threatening effect," is how the AHRP item describes the announcement, not at all what the FDA said.

CDC promptly released a statement attempting to clear up confusion. Among the 'key facts' they list:

• "We are not surprised by the number of reported intussusception cases following RotaTeq vaccination."
• "Intussusception, a form of bowel obstruction, occurs spontaneously in the absence of vaccination."
  
• "This notice does not mean there is a problem with the RotaTeq vaccine."

There's been no detectable coverage of this topic in the media since the initial FDA statement last week. It will, however, be discussed at this week's meeting of the ACIP, the agenda for which can be viewed here.

Even more bad news for VaxGen anthrax vaccine development

Back in March, we wrote about the Washington Post's reporting on setback for VaxGen in their development of a next generation anthrax vaccine as part of a $1 billion contract through Project Bioshield. (The New York Times chimed in back in October, as we noted then as well.)

Today, this story, also from the Washington Post:

"The Food and Drug Administration has postponed advanced testing of a proposed anthrax vaccine that was supposed to be stockpiled this year because of concerns it could lose its potency too fast to be useful, the company developing the drug announced today.

The announcement by VaxGen Inc. was yet another setback to the U.S. government's $1 billion effort to develop a new anthrax vaccine. It followed predictions on Capitol Hill two-and-a-half years ago that a small company like VaxGen wouldn't be able to meet the government's aggressive schedule for stockpiling 25 million doses of the new vaccine by this month."

As this VaxGen press release explains...

"The FDA's Center for Biologics Evaluation and Research (CBER) said the hold notice was issued because data submitted to date by the company are insufficient to determine that the product is stable enough to resume clinical testing. In the notification, the agency expressed concerns that the vaccine's potency could decline during the immunization phase of the trial, potentially resulting in an uninterpretable outcome."

Fifth vaccine approved for upcoming flu season

Yesterday, the FDA approved FluLaval, a seasonal flu vaccine developed by ID Biomedical, a subsidiary of GSK. Here are the FDA press release and news items from Time and CIDRAP News.

FluLaval joins the four vaccines approved by the FDA in early August for the upcoming flu season, as we wrote about here. It's an injected vaccine (like three of the other four -- the exception being the nasally-administered FluMist) and is licensed for use in adults 18 and older. Among the five products, this year's supply is expected to set a record, with estimates of 115 doses being available in the U.S. Today's New York Times has a related story about the surge in flu vaccine supply.

The challenge for health care providers and public health officials will be to see that most or all of these doses are administered to patients, as the current record for vaccinations in a single flu season is 83 million, as we wrote last month. However, compared to the much-publicized shortages of years past, this is a far better 'problem' to face.

FDA approves 2006-2007 flu vaccines

News from Washington yesterday that the FDA approved the vaccines to be used for the upcoming flu season. Here's the FDA press release and AP story regarding the announcement.

These approvals are an annual occurrence, as manufacturers produce flu vaccines including the specific strains of the virus recommended by WHO and FDA. There are four vaccines available:

• Fluvirin (Novartis Vaccines, formerly Chiron)
• Fluarix (GSK)
• Fluzone (Sanofi Pasteur)
• FluMist (Medimmune)

FluMist is the increasingly popular nasally-administered vaccine, the other three are injected (and few patients know which of the three they receive). In total, the FDA estimates a supply of approximately 100 million doses in the U.S. for the season.

Should Gardasil be called a 'cancer vaccine'?

A few weeks back, we were asked by a reporter whether it was misleading to refer to Gardasil as a 'cancer vaccine'. The phrase has been widely used of late -- and not only by the media. Both the FDA and Merck refer to Gardasil as a 'cervical cancer vaccine' in their press releases this month announcing the product's licensure.

We hadn't thought much about the issue at the time, but it didn't (and still doesn't) strike us as dishonest. There's no dispute regarding the link between HPV and cervical cancer, and the data show that Gardasil prevents infection from HPV strains responsible for 70% of such cancers. The fact that the vaccine is less than 100% protective against cervical cancer has no impact on whether it can rightly be called a 'cervical cancer vaccine,' since no vaccine available provides complete protection.

Gardasil is beneficial for multiple reasons, but cervical cancer is clearly the most prominent of the group. From a medical perspective, referring to it as a cervical cancer vaccine is prudent, as public awareness of HPV (and, in particular, its close link to cancer) is lacking. A vaccine against cervical cancer is much more likely to attract patient interest than one against 'human papillomavirus,' meaning that more people who should receive the vaccine actually will. Meanwhile, there's no denying that the branding of Gardasil as a cervical cancer vaccine is a shrewd (but appropriate) marketing decision by Merck.

A story in today's Charleston (W.V.) Gazette is the first we've seen that discusses this topic. Most of those interviewed in the story appear to share our view, with the chief reservation being that the branding ignores the other benefits of vaccination. True, but the additional attention Gardasil receives as a 'cervical cancer vaccine' will likely put it in a better position to accomplish its full range of benefits for a greater number of people.

HPV vaccines: "Everything's been said, but..."

There's a quote that often surfaces in Congress during confirmation hearings or at other times when a long list of senators wish to speak on the same topic. The last in line, having nothing new to add to the debate, will say almost apologetically, "There's a famous quote about times like this. 'Everything's been said, but not everyone has said it.'"

That's about where we are with respect to the public discussion about HPV vaccines. With virtually no developments for months (last week's favorable FDA recommendation was long-expected) but several approaching, we're left with hundreds of stories in papers large and small presenting the same overview of the vaccine, the same potential obstacles the vaccine faces, etc.

So while we won't link to the vast majority of these types of stories until there's news to report, this first-person commentary in today's New York Times caught our eye. Some excerpts:

"There have been only a few times in my life as a physician when I've been able to say (at least to myself), "This is truly big news." My colleagues are saying the same thing. But they are also asking how this promising new treatment will be made available to women and girls worldwide."

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"...and we can now see the opening act of another sophisticated "ask your doctor" advertising campaign on the evening news. This one begins with a well-dressed, hip young woman who reflects, while contemplating the middle distance: "There's a common virus that can cause cancer? I didn't know that!"

We've been meaning to mention the ad campaign referred to above. Sponsored by Merck and linked to www.tell-someone.com, the television and print ads mention no products but only stress the link between HPV and cervical cancer. The television ad briefly features a small Merck logo at its end, but the website (which can also be reached via hpv.com and cervicalcancer.com) prominently features the Merck branding and layout.

Notably, nowhere in any of the advertisements or in the website content are HPV vaccines so much as mentioned. It's safe to say this is part of a strategy to build awareness and acceptance incrementally over the coming months, thereby reducing the impact of objections to the vaccine before they're given substantial attention.

FDA nominee von Eschenbach on HPV vaccines

Dr. Andrew von Eschenbach, recently nominated to serve as director of the Food and Drug Administration, delivered the keynote address at the national conference of the Association of Health Care Journalists yesterday in Houston. Von Eschenbach is currently the acting director of the FDA (following Lester Crawford's abrupt resignation last September) as well as director of the National Cancer Institute.

As the Houston Chronicle reports, von Eschenbach declined to offer specifics of his vision for the FDA because of his pending confirmation hearing in the Senate. (The FDA has generated considerable criticism and controversy due to its handling of the contraceptive Plan B, which will almost certainly receive more attention from the Senate than anything vaccine-related).

Von Eschenbach did respond (generally) to questions regarding the status of HPV vaccines as well as the broader topic of the Bush administration's positions on science. On HPV vaccines...

"Von Eschenbach...would not talk about where the vaccine is headed in the approval process. But he hailed its 'great promise for the prevention of one of the most significant killers of women' and said it 'fits very well' into his anti-cancer agenda."

On science vs. ideology:

"Asked about the criticism that the Bush administration makes health care policy based on ideology rather than science, von Eschenbach said medical progress can't be removed from 'an ongoing societal discussion.' But he added that he has never felt constrained by the administration from following the scientific path."