Positive results for Gardasil trial in males

News came from Merck last week that results from its clinical trial of Gardasil in males showed the vaccine's efficacy in preventing HPV-related genital warts and other lesions. No serious safety concerns were found. Here's coverage from the Associated Press and the Merck press release detailing the (as yet unpublished) results which were presented at this European conference last week.

The trial included nearly 4,000 males between the ages of 16 and 26. The vaccine was 90% effective at preventing external genital lesions, the most common of which are genital warts.

Dr. Bernadine Healy, in the news earlier this year for comments seen as supporting a possible link between vaccines and autism, was pleased by these research results about Gardasil, writing about the many benefits of vaccinating males against HPV.

These findings will be part of Merck's eventual application to the FDA to license the vaccine for use in males in addition to females, a decision that has been widely expected for some time.

More interesting, however, will be the decision faced by the Advisory Committee on Immunization Practices regarding its recommendation for Gardasil in males. In particular, it remains to be seen if the direct protection provided against genital warts in males will be sufficient to recommend broad use of the vaccine, and/or what role the indirect benefits of male vaccination (i.e., aiding in the prevention of HPV-related disease in women) will play in the ACIP's recommendation.

No timetable has been set for these actions, but they are sure to be in the news in 2009.

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One other item related to HPV vaccines: The November 15 supplement to the journal Cancer is titled, "Assessing the Burden of HPV-Associated Cancers in the United States". It has a number of papers examining the burden of cervical cancer and other HPV-related conditions as well as several papers on the potential impact of HPV vaccination programs. Very interesting reading.

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.

Discussing HPV with teens; Overlooking genital warts; New data on South Asian HPV prevalence

A potpourri of recent publications on various aspects of HPV vaccination:

• "Genital warts: Mountains or molehills?" (Lancet Infectious Diseases, Vol. 8, No. 5, 277-278 -- free abstract) -- Co-authored by Sarah Hull and our own Art Caplan, this commentary focuses on genital warts, protection for which is included Merck's Gardasil but not in GSK's Cervarix. The authors discuss how the additional benefit provided by Gardasil may factor in to debates over pricing and the market battle between the two products sure to occur in the U.S. in the years ahead.

• "Informing adolescents about human papillomavirus vaccination: What will parents allow?" (Vaccine, Vol. 26, No. 18, 2203-2210) -- A study by British researchers Vallely, et al., this paper reports on a study using an informational film to improve adolescents' knowledge about HPV, cervical cancer, and HPV vaccinations. The key messages of the film were: 1) HPV causes cervical cancer, 2) HPV is sexually transmitted, 3) Condoms may not fully protect against HPV, and 4) HPV vaccination protects against cervical cancer. A post-screening test revealed improved knowledge regarding the information presented in the film. The adolescents' parents found the messages of the film acceptable.

• "A meta-analysis of human papillomavirus-type distribution in women from South Asia: Implications for vaccination" (Vaccine, Vol. 26, No. 23, 2811-2817) -- One of the unanswered questions regarding the use of HPV vaccines in the developing world is the extent of protection provided by the cervical cancer-causing HPV strains (16 and 18) included in the vaccine. In the U.S., these strains account for approximately 70% of cervical cancer cases. Studies examining the prevalence of these strains in other parts of the world have generally found them to be less common by as much as 10%. This paper, by Bhatla et al, examines nine previously published studies from India. The researchers conclude that HPV 16/18 vaccines could provide over 75% protection against invasive cervical cancer. While an encouraging finding, it is important to note that this data is largely the product of a mathematical estimate, and it does not speak to the challenges of implementing a large-scale vaccination program in India or elsewhere.
  

Lessons from the Failure of HPV Vaccine State Requirements

That's the title of a paper written by a group from the Penn Center for Bioethics -- including the editor of this site -- and the Johns Hopkins University Berman Institute of Bioethics. The article, a review of the events surrounding Gardasil state requirement proposals and their impact on long-term HPV vaccination efforts, will appear in the December issue of Clinical Pharmacology & Therapeutics but is already available on its website.

From a Penn news release on the paper:

“The arrival of Gardasil was a major achievement for cervical cancer prevention efforts worldwide,” says Jason Schwartz, MBE, Researcher, Penn’s Center for Bioethics and Department of History & Sociology of Science, and lead author. “Much of the initial enthusiasm for the vaccine was lost amid the controversy surrounding state proposals that would require teenage girls to be vaccinated in order to attend school. The events of the past year reveal important lessons regarding ways to introduce new vaccines successfully and in an ethically responsible manner."

In the months leading up to the June 2006 approval of Gardasil, there was unprecedented media coverage and support from even socially-conservative groups. However, this support for the vaccine began to slow in September 2006 following the introduction of a bill in the Michigan state legislature that would require the vaccination of girls attending public schools. Additional states also were quick to propose similar legislation. In response to the legislation, numerous groups expressed their opposition by arguing that it was either too soon to consider an HPV requirement, or that the sexual transmission of the virus did not warrant requiring the vaccine in schools.

The opposition grew when the governor of Texas issued an executive order requiring HPV vaccination for all girls entering the sixth grade. Critics of state HPV requirements called attention to how these policies violated obligations to respect parental autonomy. However, many critics often overlooked opt-out provisions, implying that the proposals made vaccination compulsory.

The authors note that, “Quite apart from whether it was prudent public health policy to implement state requirements for HPV vaccination so soon after the vaccine’s licensure, these attacks on the state initiatives may have exacted a very real ethical price in terms of the public’s understanding of the justifications for state vaccination requirements generally, as well as the public’s understanding of the merits of the HPV vaccine itself.” Additionally, they suggest that issues of price gouging, corporate profits, and political motives, may have also added to the opposition.

In order to move forward with cervical cancer prevention efforts, the authors suggest that attention be focused on assessing the long-term safety of the vaccine, while implementing effective patient and provider educational programs about HPV and the HPV vaccine, as this is the model that other successful vaccination programs have followed. "With a second HPV vaccine expected to be approved in early 2008, it is vital to understand the strategies that are most likely to lead to the long-term success of this remarkable weapon against cervical cancer," says Schwartz.

The authors also discuss the importance of designing and implementing HPV vaccination programs in developing countries. "Cervical cancer is a worldwide concern, but its impact is particularly severe in the developing world,” says Schwartz. “It would be tragic if the negative attention created by the debate over HPV vaccine ‘mandates’ in the U.S. hamper efforts to make the vaccine available to those internationally who could benefit most from it."

Only the abstract is available free. Those without access to the full text are welcome to contact us to receive an offprint.

More good news on Gardasil cross-protection?

An Associated Press story published last week began with what seemed to be remarkable news:

"New data show that a vaccine against the virus that causes cervical cancer partially blocks infection by 10 strains of the virus on top of the four types targeted. That boosts protection - at least partially - to 90 percent of strains causing the deadly cancer, according to data presented yesterday at a medical conference by Merck & Co., maker of Gardasil."

90% protection? Recalling that 70% had long been the number used to quantify the percentage of cervical cancer-causing HPV strains covered by the vaccine, this would be a major development.

As is often the case with unpublished data presented at medical conferences, specifics on the research results are difficult to come by. However, this WebMD story published at CBSNews.com adds more detail, explaining, "The new study, which involved about 11,000 young women aged 15 to 26, shows that the vaccine is also 38% effective against 10 additional HPV types, which are responsible for an additional 20% of cervical cancers."

The fact that the vaccine is only 38% effective against these additional strains is never clearly stated in the AP story. (Research has shown the vaccine to be 100% effective against the 70% of cancer-causing strains included in the vaccine.)

The findings are still good news, but readers of the AP story -- published in our hometown Philadelphia Inquirer and no doubt many other newspapers -- could be excused for thinking it was even more noteworthy.

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In other Gardasil news, Merck announced today plans to donate 3 million doses of the vaccine for use in the developing world. Here's coverage from the Associated Press and a Merck press release.

HPV: Is adolescent consent sufficient?; Data on vaccine effectiveness post-infection

The August issue of Pediatrics included a commentary related to HPV vaccine ethics and policy that is worth noting, even several weeks after its publication. Ruth Farrell and Ellen Rome from the Cleveland Clinic offer a well-reasoned argument in favor of adolescent consent being sufficient for HPV vaccination in their commentary, "Adolescents' Access and Consent to the Human Papillomavirus Vaccine: A Critical Aspect for Immunization Success." (free extract).

The authors argue that HPV vaccination could reasonably be given the same status as other reproductive health matters among teenagers, for which parental consent is not required. They outline some of the reasons why teenagers might seek the vaccine without parental involvement or knowledge and note the missed opportunity that would occur if physicians postpone discussion of the vaccine or vaccination itself until a future visit with a parent present. They write:

"Lack of parental authorization, whether because the adolescent's mother or father may not be reachable or the adolescent truly seeks confidentiality in immunization, should not overshadow the chance to initiate or continue immunization administration. By the time the adolescent returns for health care (with or without a parent), she may have initiated sexual activity, with the vaccine losing its maximum potential efficacy."

While these authors are not the first to suggest waiving parental consent for HPV vaccination, the publication of their argument in the nation's premier journal for pediatric medicine is likely to influence the policy discussion in the coming months.

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Data that could be seen as supporting Farrell and Rome's argument could be found in an August issue of JAMA. There, Allan Hildesheim and colleagues explore the "Effect of Human Papillomavirus 16/18 L1 Viruslike Particle Vaccine Among Young Women With Preexisting Infection" (In layman's terms, "Does Gardasil Help if a Woman Already Has HPV?") At the risk of oversimplifying a nuanced study, the answer is an unsurprising "NO!" This finding confirms what had long been known about the vaccine (and the reason why vaccination is recommended for 11-12 year old girls prior to first sexual contact).

An accompanying editorial "HPV Vaccines--Prophylactic, Not Therapeutic" reinforces this point and explains how the vaccine's lack of therapeutic action shaped the ACIP recommendations.

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Finally, a new issue of HPV Today was released earlier this summer. Included in it are status reports on HPV vaccination in the U.S. and worldwide and a short paper explaining why HPV subtype replacement is unlikely to occur as a result of widespread vaccination with Gardasil or Cervarix.

Merck report: $358m in Gardasil sales for Q2; $1 billion total for vaccines

While we don't typically highlight corporate earnings reports or similar news, the quarterly report released Monday by Merck for April-June 2007 provides some new information about the growing market for vaccines, and, in particular, Gardasil. Here's coverage from yesterday's New York Times, "Another Quarter of Strong Results by Merck," and a similar story from Reuters.

Since this news comes directly from the company, the Merck press release is particularly useful. Here's part of what it says about vaccines:

"Total vaccine sales, as recorded by Merck, were $1.0 billion for the quarter, compared to $349 million in the second quarter of 2006. The growth in vaccine sales was led by the performance of GARDASIL along with strong contributions from ROTATEQ and other pediatric vaccines. Vaccines in most major European markets are sold through the Company’s joint venture, Sanofi Pasteur MSD, and the results from its interest in the joint venture are recorded in equity income from affiliates.

Total sales as recorded by Merck for GARDASIL, the Company's cervical cancer vaccine, were $358 million for the second quarter. As of the second quarter, GARDASIL has been approved in 80 countries, many under fast-track or expedited review; and launched in 59 of those countries. The vaccine remains under review in approximately 40 other countries.

ROTATEQ, Merck's vaccine to help protect children against rotavirus gastroenteritis, achieved worldwide sales, as recorded by Merck, of $119 million for the quarter. As of the second quarter, ROTATEQ has been approved in 61 countries and it has launched in 22 of those countries."

The release goes on to note sales figures for Proquad ($89 million), Varivax ($147 million), and Zostavax ($47 million).

A companion document released by Merck breaks down sales between the U.S. market and internationally. Nearly 80% of Gardasil sales were in the U.S. ($286 million), as were an amazing 96% of RotaTeq sales ($114 million). There's little doubt from these data that the U.S. is leading the way in the uptake of these two fairly new vaccines, despite the far greater need for cervical cancer and rotavirus prevention internationally.

Overall, $1 billion in vaccine sales for a single company in a three-month period is perhaps the best evidence to date of the potential profitability of vaccines to an extent not previously seen. As for Gardasil, it is difficult to work backwards from the sales figures given ($358m) to ascertain the number of doses sold during the April-June period, since governments and insurance companies pay less than the well-known $120/dose 'sticker price'. This CDC price list shows a cost of $96.75/dose for Gardasil as part of the Vaccines for Children program. Using those figures as endpoints, a very rough estimate would suggest 3-4 million doses were sold, or enough doses to fully vaccinate slightly more than 1 million girls.

Given the size of the population for whom vaccination is recommended (all females 11-26), the potential growth of the Gardasil market is staggering, perhaps explaining, in part, the company's apparent enthusiasm to promote its vaccine in advance of the arrival of GSK's Cervarix.

Gardasil: CDC response on safety/efficacy; survey on parental support for mandates

The weekly news update from the Immunization Action Coalition alerted us to this CDC Q&A released last week titled "CDC Questions and Answers Concerning the Safety and Efficacy of Gardasil." The three-page document outlines the current status regarding safety monitoring, known safety concerns, the potential need for boosters, and the ongoing necessity of Pap screening.

It seems likely that the fact sheet was this breathless press release from JudicialWatch.org asserting (based on VAERS reports) that "three deaths were related to the vaccine." The CDC fact sheet clearly explains how and why this statement is a misinterpretation of VAERS data, reaching conclusions that are no possible from that information alone. Not surprisingly, a search of Google News suggests that the press release garnered virtually no attention from the print media. While safety concerns linked to Gardasil could still surface, there's no evidence at present to suggest such a connection.

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One other item related to Gardasil: The headline from a survey released by a group at the University of Michigan C.S. Mott Children's Hospital reads: "Majority of U.S. Parents Not in Favor of State HPV Vaccine Mandates." The report is available here, and here is coverage from CBS News and the Washington Times.

However, the headline -- while likely shrewdly written to generate the media coverage sampled above -- is very misleading. The report's own data (Table 1 in the report) lists 26% of parents disagreeing with an HPV mandate, 44% of parents agreeing, and a very significant 30% as 'neutral.'

Therefore, the same data could also carry the headline, "76% of parents not opposed to HPV mandate," which would actually more accurately capture the large percentage of respondents with no opinion for or against a mandate.

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).

HPV Roundup -- CQ Report, Texas Aftermath, N.H. Success, and More

Another look at recent news and perspectives on Gardasil and HPV vaccine policy appearing in print or online...

• The latest issue of CQ Researcher -- the issue-focused publication affiliated with Congressional Quarterly -- looks exclusively at HPV vaccines and the debate over mandates. The 24-page report is well researched, extensively cited, and offers an incredible range of information as to the scientific, political, public health, and economic considerations in play. It might be the single best source for non-scientists looking to understand 'what all the fuss is about.' Sadly, access requires a subscription to www.cqresearcher.com, but it's likely that readers with university affiliations can access it through their libraries.

• This story in the New Scientist -- US Conservatives Block Cancer Vaccine for Girls -- updates the US state mandate landscape, particularly this month's Texas law effectively overriding Gov. Rick Perry's executive order in February. (More on the Texas legislation can be found here and here. Also, here is the text of Gov. Perry's remarks upon the bill's passage with veto-proof majorities.)

• A major contrast to the Texas saga is what's been happening with Gardasil in New Hampshire, as described in this story from the New York Times: "In New Hampshire, Soft Sell Eases Vaccine Fears." Instead of mandates, the state's practice of voluntary, free vaccination has led to a surge in demand for Gardasil, the story explains.

• We're just about exhausted with op-eds on HPV mandates. At this point, all one hears are the same arguments (for or against) over and over. Here's one that does attempt to say something new, courtesy of The Hastings Center's "Bioethics Forum": In "Choosing Paternalism?", Karen Maschke explores lessons from the U.S. Gardasil experience thus far that might be useful when considering the vaccine's implementation in the developing world.

• Earlier this month, this story in the Washington Post -- "Who Gets Stuck? Doctors, Patients Want Insurers to Pay More for Vaccines" -- looks at some of the reimbursement issues being raised by physicians, particularly the (small) amounts provided for vaccine-related costs beyond the price of the dose itself.

HPV mandates and more in JAMA and NEJM

There is a lot of discussion on HPV vaccination and mandates in recent issues of the New England Journal of Medicine and the Journal of the American Medical Association.

In the May 2 JAMA, Lawrence Gostin -- a professor of health law at Georgetown -- and Catherine DeAngelis -- the editor of JAMA -- wrote an editorial titled "Mandatory HPV Vaccination: Public Health vs Private Wealth." Gostin and DeAngelis reject mandates for HPV at this time, referring to any use of state mandates as "a last resort." Specifically, they point to questions regarding cost/payment, long-term safety, injury compensation, and the fact that HPV is not "a highly infectious airborne disease" to support their argument against mandates.

The latest NEJM includes seven pieces on HPV vaccines, including two commentaries, two reports, two editorials, and a letter. All are available for free here. Of note is the commentary by Alta Charo -- professor of law and bioethics at the University of Wisconsin -- titled "Politics, Parents, and Prophylaxis -- Mandating HPV Vaccination in the United States." Charo argues in favor of state mandates, pointing to the easy-to-secure exemptions available in every state in which a mandate has been explored. With essentially any parent objecting the vaccine having the ability to receive such an exemption, the overall merits of a state mandate greatly outweigh the slight inconvenience the exemption process imposes on parents seeking it, she suggests.

Also of interest is "Introducting HPV Vaccine in Developing Countries -- Key Challenges and Issues" by Agosti and Goldie. The authors point to availability, access, and cost concerns related to the international implementation of HPV vaccination programs.

New Mexico HPV bill vetoed

Following up on an earlier post, New Mexico Gov. Bill Richardson vetoed a bill earlier this month that would have added a school entry requirement for HPV vaccination among all sixth grade girls. The decision was a reversal from his earlier public comments, from which his signature seemed all but certain. Here's the AP story from the Santa Fe New Mexican.

Gardasil: Recommendations published, views on industry role, male vaccination, N.M. mandate, and more

Some updates from the past 10 days or so on recent news about Gardasil and the ongoing discussions about mandates...

• Last Monday, the official ACIP recommendations on Gardasil were published online in MMWR. These are essentially the same recommendations that were announced in June 2006 (which we first wrote about here) -- there is an increasingly longer lag between such announcements and publication in MMWR. One important consequence of publication is that it typically pressures insurance companies who have not yet agreed to cover the cost of the vaccine to do so.

• A story in today's Detroit Free Press asks, "Why aren't more girls getting HPV vaccine?" The story relies more on anecdotal reports than any real data, however. The two million doses of Gardasil shipped in the 9 months since licensure is a not-insignificant number, particularly considering the delays in insurance coverage in many cases. Nevertheless, it may be a question worth asking. This AP story may be relevant to the discussion, examining continued public ignorance about HPV, despite the attention it's received in the past year.
  

• An interesting (and provocative) opinion from Adrian Fugh-Berman on "Bioethics Forum" (the blog of the Hastings Center, the bioethics think-tank) -- "Cervical Cancer Vaccines and Industry Influence". Fugh-Berman's conclusion: "Cervical cancer is uncommon in the United States. This is not an emergency; this is not SARS. Listen only to public health people without conflicts of interest. There’s time for a discussion – but ban industry from the room in which any decisions on public health are made." Worth reading, regardless of one's own opinion on the topic.
  

• Following up on our colleague James Colgrove's perspective on HPV mandates in NEJM last fall (which we noted then), several letters to the editor were published earlier this month in response. One letter highlights the potential value of vaccinating males, and another takes issue with the use of the word "compulsory" to describe vaccination requirements that allow for informed refusal. This point goes to the increasing use of the term "opt-out requirement" when discussing what have traditional been known as state mandates.

• Speaking of vaccinating males, yesterday's Los Angeles Times took a closer look at some of the unique issues regarding HPV infection in men and the potential value of vaccination.
  

• New Mexico appears to be the next state on the verge of an HPV school-entry requirement. Here's a story from last week about the passage of a bill in its state legislature. As best as we can tell, the bill is still awaiting Gov. Bill Richardson's signature, which could happen at any time. Many other states -- too many to count -- have bills at some stage of the legislative process.

• The Powerpoint slides from last month's ACIP meeting were recently posted here. Updated Gardasil efficacy data from Merck's Eliav Barr are available there, as is a general overview of the American HPV vaccine landscape by CDC's Lauri Markowitz. It's very interesting for those looking for somewhat less-filtered information than what appears in the popular media.

Gardasil round-up: Merck lobbying, ACIP chair comments, Virginia mandate, and more

There continues to be a steady trickle of news about Gardasil, largely centered on the ongoing debate regarding possible state mandates. Rather than attempt to keep up with each day's new op-eds, news stories, and the rest, we've decided to combine several of the most interesting items from the past 10-14 days into a single post. With that, here are some recent items making headlines:

• Perhaps the biggest news from the past few weeks was Merck's decision to stop participating in lobbying efforts for state mandates. Here's one account of the story from late February, courtesy of Reuters. It quotes Merck's Richard Haupt calling the company's activities a "potential distraction." Few would disagree with this assessment, and it is surprising, given the company's extensive and seemingly well orchestrated marketing and education efforts, that it would commit so significant a public relations blunder.

• Since that announcement, there has been no shortage of stories and op-eds more or less making the same point, namely, that the Texas political controversy and Merck's lobbying efforts have obscured the scientific and medical aspects of the vaccine and its potential benefits. That's the thesis of this New York Times editorial, "A Necessary Vaccine," (subscription required) which generated a number of letters in response. Also: a story in today's Times titled "A Vital Discussion, Clouded."

• Sunday's Washington Post also looked at these issues ("Parents Question HPV Vaccine: Push to Mandate Shots Rapidly Creates Backlash") Quoted in this story is ACIP chair Dr. Jon Abramson, who makes clear here and elsewhere that he is no supporter of current attempts to mandate vaccination. Abramson is also featured in this essay by Arthur Allen, "Why It's Too Soon for a Mandatory HPV Vaccine," published in the New Republic Online.

• Also mentioned in the Washington Post story above is the imminent action by Virginia Gov. Tim Kaine to sign legislation making his state the second to mandate HPV vaccination. The requirement would not take effect until 2008 or 2009 and would include the traditional types of exemptions (increasingly referred to in the media, accurately, as an 'opt-out provision'.) More information can be found in this story.
  

New data on HPV prevalence; conflicting thoughts on relevance to vaccine debate

Last week's JAMA paper by Dunne, et al., -- "Prevalence of HPV Infection Among Females in the United States" -- garnered a significant bit of media attention. An accompanying editorial, "Estimating the Population Prevalence of HPV," by Weller and Stanberry, makes a point of examining the implications of this data to HPV vaccination policy, specifically cost-effectiveness calculations. (Free abstracts; subscription required for full text).

Here's some of the coverage of the paper by the popular press: Associated Press, Dallas Morning News, Washington Times, and Washington Post.

The data has provided ammunition for both sides of the vaccine mandate debate. Proponents of vaccination (and mandates, specifically) are pointing to the surprisingly high prevalence of HPV, of all types, in women: 24.8%

Those on the other side note the study's findings that the specific HPV types included in Gardasil are present in only 3.4% of females. To critics of mandates, this suggests that it is unnecessary to vaccinate all young girls when only a small percentage of females have the specific strains included in the vaccine. However, these numbers do not change the overall facts regarding cervical cancer incidence and mortality.

If anything, the ways in which the Dunne, et al., paper's findings have been used and will continue to be used in the Gardasil debate offer a valuable lesson of the potential dangers of using statistics in isolation to advance a policy argument.

More on Texas HPV vaccine mandate backlash

There continues to be a tremendous amount of coverage of Gardasil in the media, most of it focused on reaction to Texas Gov. Rick Perry's nearly-three-week-old executive order rather than the vaccine itself, HPV, or cervical cancer.

Saturday's New York Times wrote about the "Furor on Rush to Require Cervical Cancer Vaccine." The story's premise:

"But a roaring backlash has some health experts worried that the proponents, including the vaccine's maker, Merck, have pushed too far too fast, potentially undermining eventual prospects for the broadest possible immunization."

Syndicated columnist Clarence Page writes, "Don't judge cancer vaccine by Austin political fallout," attempting to encourage the public to distinguish the political controversy created by Perry's actions from the merits and potential benefits of the vaccine itself. He argues,

"With emotions heated up, a lot of misinformation and unnecessary anxieties already are being stirred up over the new vaccine. The least grounded appears to be the fear that it will encourage more sexual activity outside marriage. Our society unfortunately has many larger reasons for that and it is a worthy debate for another time.

For now, Gardasil appears to be a very important and welcome life-saving step forward in the fight against cancer. Don't judge it by the political confusion it has caused."

For an example of emotions heated up, take a glance at this political cartoon at Newstarget.com.

A few more op-eds of note: In Newsday, Marc Siegel writes in favor of broad vaccination (though not explicitly addressing the question of mandates). In the Atlanta Journal-Constitution, Former Rep. Bob Barr writes against mandates, in part:

"None of these concerns will likely deter the legion of Big Government types out there who — allied with the many do-gooders populating state legislatures from California to New York, and prodded by companies willing to spend millions to make billions — will allow nothing to stand in the way of 'good government,' whether the people want it or not."

As far as news goes, the latest in Texas is an effort in the state legislature to effectively reverse Perry's executive order. According to this story, a hearing on the topic yesterday went well into the night. The Houston Chronicle has more.

Finally, the Arts and Leisure section of Sunday's New York Times took a closer look at the visual and creative elements of Merck's "One Less" television commercial.

Voices on HPV vaccination, Texas mandate

Of the many opinions expressed in the media over the past 10 days regarding the executive order by Texas Gov. Rick Perry, here are a few worth noting:

• Friday's USA Today included a point-counterpoint on the Texas mandate order. The USA Today editorial board questions the timing of the mandate. The headline and subhead of the story sums up their argument nicely: "Rush to require cancer shot threatens to promote backlash; HPV vaccine holds great promise, but Texas mandate is premature."

• On the same page, Gov. Perry (or more likely, a member of his staff) responded in a short commentary titled "My order protects life." It frames the decision less as a matter of instituting a 'mandate', but rather, implementing an 'opt-out' system of vaccination instead of an 'opt-in' system. Given the relative ease of obtaining exemptions (to the chagrin of vaccine advocates), that terminology is probably more precise than speaking about 'mandates', with its connotation of compulsion.

• Arthur Allen, author of Vaccine (which we noted previously and was reviewed this weekend in the Washington Post) wrote an op-ed that appeared in several papers last week. Titled "Idea behind the decision is sound, but Perry's timing is off," the piece makes an argument similar to that of the USA Today editorial. He writes, "By imposing the HPV vaccine in such a rushed, questionable way, Mr. Perry's action threatens to mobilize people who, under normal circumstances, would simply do what they were told, assuming it was best for them."

• In this AP story in the Seattle Post-Intelligencer, Washington Gov. Chris Gregoire voiced skepticism at Perry's decision. "'I told the medical association that I was reticent to dictate when I think there is a lot of public education that needs to go on,' Gregoire said. 'To go out and start just saying everybody mandatorily has to have this is a little bit troublesome for me.'"

• Finally, Art Caplan and James Colgrove appeared on "Radio Times," a Philadelphia-based NPR program, to discuss HPV vaccination, the Texas mandate, and related topics regarding the ethics of vaccines. You can listen to the one-hour program here.

Texas HPV vaccine mandate in the news

There has been a great deal in the news this week about Gardasil (and a corresponding spike in our traffic), much of which has been triggered by Texas Gov. Rick Perry's executive order on Friday requiring sixth-grade girls to be vaccinated against HPV. Here's the text of the executive order and an accompanying press release from the governor's office. Quoting Perry, "Requiring young girls to get vaccinated before they come into contact with HPV is responsible health and fiscal policy that has the potential to significantly reduce cases of cervical cancer and mitigate future medical costs."

Perry, a Republican, has received criticism for this decision from members of his own political party and conservative organizations, as this AP story and this Houston Chronicle story explain. Perry released a second statement over the weekend, saying, in part,

"Providing the HPV vaccine doesn’t promote sexual promiscuity anymore than providing the Hepatitis B vaccine promotes drug use. If the medical community developed a vaccine for lung cancer, would the same critics oppose it claiming it would encourage smoking?

"Finally, parents need to know that they have the final decision about whether or not their daughter is vaccinated. I am a strong believer in protecting parental rights, which is why this executive order allows them to opt out."

Indeed, likely lost in the headlines pointing to a "mandate" is the important point that the exemption policies already in place in Texas will apply to HPV vaccination in the same way, including parents having the ability to decline vaccination for 'philosophical reasons'. In fact, proponents of vaccine mandates will likely be disappointed to learn that the executive order also instructs state officials to make the exemption process easier by creating a system in which parents can decline vaccination online.

Today's New York Times includes an editorial praising Perry for the decision. In fairness, it argues far more convincingly for HPV vaccination generally than it does for a state mandate (though strong arguments can certainly be made for it.)

Independent of discussions about the appropriateness of philosophical exemptions from vaccination (such as Paul Offit's op-ed we noted here), the current state mandate system means that no parents will be forced to vaccinate their children against their will. However, years of experience have shown that state mandates provide the structures and encouragement necessary to maximize a vaccine's benefit across communities, particularly reaching those without regular access to medical care whom cervical cancer targets disproportionately.

When considering vaccine mandates, we should not focus our attention on those with strong beliefs opposing vaccination, as the exemption procedures provide, for better or worse, a relatively simple remedy. Instead, we must consider those silent in these debates, those not receiving even basic medical care, much less tracking the minute-by-minute developments regarding Gardasil. For them, state mandates have been shown repeatedly to provide the awareness and stimulus needed for the vaccine to reach all who could benefit from it.

Updates on HPV vaccination outside the U.S.

Those looking for information on the policy discussions and implementation of Gardasil worldwide will be very interested in the latest issue of HPV Today, an international newsletter on all things related to HPV research, policy, and practice.

Among the items in the issue: a short piece by Dr. Luisa Lina Villa, a Brazilian cancer researcher, updating the international regulatory landscape for Gardasil. She notes that more than 40 bodies around the world have approved the vaccine thus far. Australia, New Zealand, Peru, and Mexico are among the few to approve the vaccine for males as well as females. Dr. Villa also describes some of the implementation challenges faced by her native Brazil, among them cost and the absence of an adolescent vaccination infrastructure.

Also in the issue: a very helpful table outlining the different approvals (by age, gender, condition, etc.) that Gardasil has received by various regulatory bodies around the world and a brief report on the results of a survey in Australia exploring whether the vaccine could promote unprotected sex among Australian teens. (The short answer: no)

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 states introduce HPV mandate bills

A "wave of support" is how today's Washington Post describes the growing number of states in which bills to mandate HPV vaccination have been introduced in recent weeks. This story notes developments in Maryland, Virginia, and the District of Columbia, with many comments from politicians and physicians supporting the actions but nary a quote from opponents of the bills.

On Wednesday, a Washington Post columnist offered a very critical take on the D.C. measure and his views of the assumptions underlying the need for such a law in the city. Also of note is this counterpoint to the Post columnist's views in today's Washington Times, strongly supporting the proposed mandate.

Elsewhere, this story in Wednesday's Houston Chronicle discusses the debate likely to occur now that similar bills have been filed in both of Texas' state houses.

We're not generally in the business of forecasting the future, but it seems very likely that this momentum will lead to the passage of HPV vaccination mandates in at least some states in 2007. The fact that the exemptions (for medical, religious, and philosophical reasons) already available for other vaccine mandates are all but certain to apply to HPV requirements will likely play a significant role in how politicians react to the concerns of opponents of these bills. As a result, policy discussions of HPV mandates will be able to avoid entirely the difficult ethical questions raised by the exemption policies themselves, or, for that matter, the overall principle of mandating vaccination.

Michigan HPV mandate bill fails; similar bill introduced in Kentucky

This story from the Grand Rapids Press reports on the rejection of the bill in the Michigan legislature that would have mandated HPV vaccination for sixth-grade girls (while keeping the exemption system common to other vaccines). The bill, which passed the Michigan senate in September, was rejected by the state house during its last day in session prior to the holidays. The story above notes the intentions of two legislators to reintroduce the bill during the new session that has just begun.

Similar efforts are underway in Kentucky, according to this story from Friday's Lexington Herald-Leader. A bill that would require vaccination of girls prior to entering middle school was introduced by Rep. Kathy Stein and currently is being evaluated by the house's Health and Welfare Committee.

Gardasil: Profile of Merck Vaccines president; feature on early HPV-cancer link proponent

Two items worth reading for those interested in background content related to Gardasil's development and arrival:

• "Making her mark at Merck" (Business Week, 8 January) -- A profile of Margaret McGlynn, the president of Merck Vaccines. An interesting item in the story: "Analysts are counting on McGlynn to drive much of Merck's growth: Some predict revenues from her division will triple by 2010, to $6 billion." While the business of vaccines is not our area of expertise, this is point underscores the period of explosive growth for vaccines that we're just entering, one in which ethical considerations will demand that much more attention.

• "Cancer quest: How ex-Penn scientist's hunch led to cervical vaccine" (Philadelphia Inquirer, 24 December) -- A very lengthy feature (two pages in the print edition) on
  Dr. Harald zur Hausen, described in the story as a very early proponent (i.e., the 1960s) of a link between HPV and cervical cancer (the credit for proving such a link has gone to others in the early 1980s). A very interesting, seemingly well researched piece.
  

From NEJM: Ethics and Politics of HPV Mandates

This week's New England Journal of Medicine includes a commentary titled "The Ethics and Politics of Compulsory HPV Vaccination" by James Colgrove, an Associate Research Scientist at Columbia's Center for the History and Ethics of Public Health.

Colgrove -- a contributor to our Ethics of Vaccines Project -- does an excellent job outlining the many competing considerations that will influence states' decisions regarding possible mandates of HPV vaccination as a condition of school or day-care attendance. While there is not much new in the essay (particularly for regular visitors to this site), Colgrove's essay is, by far, the best available synopsis of the topic in print to date. Thanks to the folks at NEJM, its full text is available for free.

One problem (perhaps the only one) with the essay is Colgrove's simplistic characterization of the perspectives of bioethicists on the topic, a description that comes perilously close to caricature. He writes:

"Bioethicists, who generally hold the values of patient autonomy and informed consent to be preeminent, tend to be skeptical about compulsory vaccination laws. Not surprisingly, some have expressed wariness about or opposition to mandating HPV vaccination."

Colgrove surely must be aware that any attempt to describe how "bioethicists tend" to think about a specific policy issue is about as useful as trying to capture in one sentence what "politicians tend to think" about Iraq or what "judges tend to believe" about civil liberties, as though a single, dominant position exists on these topics. In fact, many bioethicists, particularly those coming from a public health background, are quite comfortable with state vaccine mandates, including those for HPV vaccination.

As for the "some" bioethicists expressing wariness, Colgrove cites only two papers on ethical aspects of HPV vaccination, one of which is written by Pitt's Richard Zimmerman (a paper we previously discussed here). While Zimmerman has written frequently on ethical topics in journals of the vaccinology community, it is a stretch to identify him as a bioethicist, let alone as one of two who represent how the discipline as a whole tends to think about vaccine mandates.

These criticisms aside, Colgrove's essay is well worth reading for anyone thinking seriously about the appropriateness of HPV mandates.

Survey of physician attitudes on HPV vaccination in Pediatrics

The December 6 issue of the journal Pediatrics includes an interesting paper titled, "A National Survey of Pediatrician Knowledge and Attitudes Regarding Human Papillomavirus Vaccination." (Vol. 118 No. 6 December 2006, pp. 2280-2289 -- free abstract, subscription required for full text. The survey was conducted by researchers at the University of Colorado at Denver, Children's Hospital in Denver, and the CDC.

A national sample of 431 physicians was surveyed "to determine physician characteristics, knowledge, and attitudes associated with an intention to recommend human papillomavirus vaccination," quoting from the abstract. Among the reported results:

"46% of respondents would recommend vaccination for 10- to 12-year-old females, 77% for 13- to 15-year-old females, and 89% for 16- to 18-year-old females. Corresponding rates for males were 37%, 67%, and 82%, respectively. Whereas 60% of respondents thought that parents would be concerned that human papillomavirus vaccination may encourage risky sexual behaviors, 11% reported that they themselves had this concern."

The main issue complicating attempts to assess the value of this data is that the survey in question occurred between August and October of 2005, long before HPV vaccines entered the public spotlight (and likely well before many practicing pediatricians gave the vaccine serious thought). There's no way to know what impact the events of the last six months (particularly the significant public support that seems to exist in favor of vaccination) has had on physician attitudes. Still, the paper is a helpful contribution to vaccine implementation efforts.

Penn research on HPV and vaccination willingness

We're generally more than a bit reluctant to post things based solely on press releases, but here's a very interesting item coming out of our own university about attitudes regarding HPV vaccination. The press release, "Likelihood of HPV Vaccination Affected by How Information Is Presented, Penn Study Reveals," describes a study presented last week at the American Association for Cancer Research's 5th Annual International Conference on Frontiers in Cancer Prevention Research.

A sample of 635 Americans was randomly assigned to read one of three different paragraphs explaining the purpose of HPV vaccination. Subjects were then asked about their willingness to receive the vaccine. The content of the paragraphs and corresponding results:

"One paragraph addressed how the vaccine protects against cervical cancer, another how the vaccine protects against cervical cancer and sexually transmitted infection and the third how the vaccine protects against cervical cancer, sexually transmitted infection and how it may or may not lead to increased sexual promiscuity among those vaccinated.... When women in the survey read that the vaccine protects only against cervical cancer, 63 percent indicated that they were very likely or somewhat likely to get the vaccine compared to 43 percent of women who read that the vaccine protects against cervical cancer and a sexually transmitted infection."

The survey was conducted by the Center for Excellence in Cancer Communication Research at Penn's Annenberg School for Communication. Without a published paper to consult, it's all but impossible at the moment to assess the strengths and weaknesses of the survey design and the overall value of these findings. (For example, the third paragraph about sexual promiscuity seems very peculiar, as does the absence of data regarding that portion of the survey.)

If confirmed, however, these would be very interesting insights regarding attitudes about sexually transmitted infections among potential recipients of HPV vaccines. We'll update you if and when the study appears in print.

Merck launches Gardasil ad campaign

Merck today announced the launch of a national advertising campaign for Gardasil. Information on the campaign, dubbed "One Less" (as in 'one less life affected by cervical cancer'), appears in this press release. The TV ads are available for viewing on the Gardasil website.

As the press release notes, this campaign follows earlier (and continuing) HPV education efforts supported by Merck, "Tell Someone" and "Make the Connection". Back in May, we wrote about some of the questions being raised by the company's "Tell Someone" campaign here (our most widely visited post in our 8-month history), particularly the omission of any reference to the then-still-unlicensed Gardasil. (Mentioning the vaccine in an ad before it was licensed would have violated FDA guidelines, but the ads still raised eyebrows among some.)

Regardless, the "One Less" campaign is unabashedly promoting Gardasil, as is entirely appropriate for Merck to do. From all appearances, if this isn't the first major national ad campaign for a vaccine, it will certainly be the largest by far, likely to supplement ads in medical journals (the traditional domain of vaccine advertisements) with those on television and other popular media. Yet another sign that the world of vaccines has entered a new, very different, and very promising phase in its history.

Speaking of Merck, there's a notable story in today's Times of Trenton from Dow Jones Newswires -- "Merck stakes its future on demand for vaccines." In yet another story explaining the growing importance of vaccine sales to pharmaceutical companies, there are some interesting facts about Gardasil's production facilities and plans. For example...

"In a plant that Merck expanded a few years ago while Gardasil was still being tested in clinical trials, three shifts of employees now work around the clock producing the vaccine. So far, at least 750,000 doses have been shipped since Gardasil's June launch, contributing to sales of more than $80 million so far."

HPV: favorable data for male vaccination; VFC action; CDC shift in research focus

A paper published in the November issue of the journal Pediatrics includes new data from Merck on some of their ongoing trials of Gardasil in different populations. It's a highly technical paper with an equally complex title: "Comparison of the Immunogenicity and Reactogenicity of a Prophylactic Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine in Male and Female Adolescents and Young Adult Women." (free abstract; subscription required for full-text).

To summarize, the paper reports the results of trials examining whether the vaccine's response in 10-15 year olds mirrors what's been shown in older females (16-23 year-olds). The short answer is that it does generate a comparable ('noninferior,' in scientific jargon) immune response in younger populations. Good news. The most interesting finding from the perspective of potential ethical issues is the comparison of data between 10-15 year old boys versus girls. Boys had a nearly identical response to the vaccine as their female counterparts did as well as a virtually identical safety profile between genders. As the paper's authors (all of whom are employees or consultants of Merck, critics might note, despite that being an obvious result of a Merck trial) note:

"Our findings in boys lend support for implementation of gender-neutral immunization using this vaccine for the purpose of preventing the widespread morbidity and mortality from anogenital cancer, as well as dysplastic cervical and external genital lesions, in the general population."

Speaking of Gardasil, news earlier this week that the vaccine has officially been added to the federal government's Vaccines for Children program, ensuring its availability to uninsured children age 18 or under. Here's a brief story from UPI.

One final related item: a story from Wednesday's Washington Post, "CDC Shifts Vaccine-Data Focus," reports on the decision to refocus intensive data-col