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.

More Benefits of Gardasil?

With GSK's HPV vaccine -- Cervarix -- about to enter the final stages of FDA review prior to its all but certain licensure in the coming months, the marketing battle between GSK and Merck is about to begin in earnest.

One precursor of what's to come has been the occasional announcements and published papers noting protection against additional HPV strains beyond those specifically included in the vaccine. We've linked to many of those items previously.

Another sign is this headline: "Gardasil Guards Against Vaginal, Vulval Cancers: Researchers found cervical cancer vaccine reduced risk of lesions by 49%". The story is based on a paper in the latest issue of The Lancet by Joura and colleagues (abstract available here with free registration).

GSK planning head-to-head comparison of HPV vaccines

Earlier this month, GSK announced its plans to conduct a head-to-head clinical trial comparing its HPV vaccine, the still-unlicensed Cervarix, with Merck's Gardasil. Here's the GSK press release and a provocatively-headlined story from the Philadelphia Inquirer, "Area drug firms go to war over vaccine."

As the story notes, such a trial design is rare in medicine and all but unheard of for a vaccine. There's little doubt that this move by GSK is an attempt to frame an argument for the superiority of its HPV vaccine, despite the numerous advantages of Merck's Gardasil at present, among them, an increasingly longer head start in the market, immense media coverage over the past year, data showing 100% effectiveness (with respect to the HPV strains included in the vaccine), and the additional protection it provides against genital warts. Whatever their motives, head-to-head comparisons are helpful to patients and physicians, and it would by no means be a bad thing for other manufacturers of pharmaceuticals and vaccines alike to follow this lead, despite the high risks.

A sidebar piece in the same issue of the Inquirer looked at cost and access issues related to Gardasil. One interesting item: According to Merck's Richard Haupt, about $80 million worth of Gardasil had been sold through October, which he describes as "an extraordinary uptake." At Merck's listed price of $120/dose, that works out to roughly 660,000 doses, or enough to fully vaccinate 220,000 girls and women. (That number is likely higher, given the discounts offered to government programs and other groups).

More on HPV vaccine criticisms, collaboration, and competition

As predicted, a slew of stories are appearing about HPV vaccines, with Gardasil's expected licensure later this week. A sampling of the best:

• Merck's $4 billion PR problem (Fortune) -- A look ahead at the (possible) battles that await Gardasil, particularly regarding opposition to state mandates. Includes quotes from Barbara Loe Fisher, perhaps the most prominent critic of vaccines, vaccine safety, and U.S. vaccination regulation and policy.

• Vaccine helps show value of partnerships (Boston Globe) -- Examines the collaboration between researchers at the National Cancer Institute, particularly Dr. Douglas Lowy, and subsequent commercial partners Merck and GSK in bringing HPV vaccines from the earliest stages of research through licensure. A great example of a successful public-private partnership, but one all but certain to add to the uneasiness of those who think the relationship between government and the pharmaceutical industry are too cozy.

• Cancer vaccine shows promise for older women (Reuters) -- Realizing the massive attention Merck's Gardasil will receive this month while its vaccine is months behind, GSK chose a conference this weekend to release new trial data on Cervarix. A 666-subject study of women age 15-55 showed that the vaccine generated antibody levels equal to those seen in younger women in earlier trials. What isn't answered in this or other stories is how beneficial it would be to launch HPV vaccination campaigns for older women, as many will have already been infected with the HPV types included in the vaccine.
  

GSK submits cervical cancer vaccine for EU approval

We haven't yet posted about Merck's and GSK's vaccines against human papillomavirus (HPV), a sexually transmitted infection best known as the cause of cervical cancer (among other effects). By June, however, this will be the biggest vaccine ethics issue getting public attention.

A quick summary of where we stand today for those not following the developments closely... Both Merck (Gardasil) and GSK (Cervarix) have HPV vaccines nearing licensure. There are over 100 subtypes of the virus, but 2 are responsible for about 70% of cervical cancers. Both vaccines provide protection against these HPV subtypes. The Merck product also includes 2 additional subtypes that are the leading causes of genital warts in both males and females. As a result, both genders could directly benefit from Merck's vaccine, while the GSK product will target only females.

In the race to be the first on the market, Merck is in the lead, having submitted licensure applications in the U.S. and EU in December '05. Today's news courtesy of Reuters is that GSK submitted for EU approval of Cervarix. A decision is not expected for about a year. Their U.S. application is even farther behind; it's not expected until late 2006.

The reason why June is important is that two events scheduled for that month will determine the fate of Merck's Gardasil -- likely FDA approval early in the month followed by a recommendation from the CDC's Advisory Committee on Immunization Practices a few weeks later.

Why the likelihood of controversy? Several groups -- notably the Family Research Council -- have already expressed concerns about mandating HPV vaccination as a requirement for school entry. Why? 1) HPV is sexually transmitted. 2) To be maximally effective, the vaccine should be administered to pre-teen girls (age 11-13, perhaps as young as 9). 3) A key concern among some of these groups is that vaccinating girls of this age will encourage sexual activity -- a phenomenon known as 'behavioral disinhibition'. (It should be noted that there's no evidence that human papilloma virus is much of a factor at all in teens' sexual behavior -- factors such as pregnancy, religion, and risk of HIV dominate.) 4) These decisions should be left to families, they argue.

The FRC has tempered their position compared to comments made in this Fortune piece last October previewing the debate. Rather than broad opposition to the vaccine in principle, their key objection at this point is mandating vaccination for school attendance rather than leaving it a parental decision. The battleground is set for the June ACIP meeting and subsequent decisions by state departments of health.

The topic is more complex than this short preview allows. While it isn't on many people's radars just yet, the Fortune piece was right in dubbing it "the coming storm". We'll stay on top of it.