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HPV Vaccines: Cervarix Approval and Gardasil Use in Boys/Men Recommended by FDA Advisory Committee

From Medscape Medical News by Zosia Chustecka
September 11, 2009 — A second vaccine against human papillomavirus (HPV) for the prevention of cervical cancer — GlaxoSmithKline's Cervarix — has been recommended for approval in the United States; the extended use of Merck & Co's Gardasil, the first vaccine, was recommended for boys and men for the prevention of genital warts.

The recommendations came from the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee. In both cases, the voting was almost unanimously in favor, with only 1 abstention or no vote, but the meeting heard concerns about the safety of the vaccines and questions about the public-health value of the extended indication.

The voting on Cervarix was carried out by 13 members of the committee. There were 12 votes in favor of and 1 vote against the data supporting its efficacy in preventing precancerous lesions and cervical cancer in females in the 15 to 25 year age group and, from immunobridging studies, the 10 to 14 year age group. One member left the meeting before the vote on safety, but 11 of the remaining members voted in favor of the data supporting the safety of Cervarix in this population; there was 1 vote against.

Eight members of the committee voted on Gardasil use in boys and men. The vote was 7 in favor of the efficacy data supporting the use of Gardasil in males 9 to 25 years of age for the indication of preventing genital warts; there was 1 abstention. The vote was also 7 in favor of the data supporting the safety of Gardasil in this population; there was 1 vote against.

The FDA usually — but not always — follows the recommendations of its advisory committees.

Second Vaccine for Cervical Cancer

If approved, Cervarix would be the second HPV vaccine available in the United States. It is already marketed in more than 100 countries worldwide, including the 27 member states of the European Union. This product has been used in nationwide vaccination programs in the United Kingdom and Australia since it was first approved in 2007. At the meeting, the manufacturer estimated that around 7 million doses have been distributed worldwide.

Ceravix is a bivalent vaccine, active against HPV types 16 and 18, which together are thought to be responsible for about 70% of all cervical cancer cases. However, data from clinical trials presented at the committee meeting suggested that the vaccine also offers protection against other virus types responsible for causing cervical cancer, including HPV types 31, 33, and 45, the next most common cancer-causing strains. In addition, the data presented showed a duration of immunity of 6.4 years.

In contrast, Gardasil is a quadrivalent vaccine with activity against 4 HPV types: HPV types 16 and 18, which cause cervical cancer, and HPV types 6 and 11, which cause genital warts. This extra activity means that this vaccine is also indicated for the prevention of genital warts in girls and women, and it has now been recommended for that same indication for boys and men. However, the current data on Gardasil in males extends only out 2 to 3 years, and in women extends only out 5 years.

Is Cervarix Better at Protecting Against Cervical Cancer?

The main purpose behind the development of these HPV vaccines was to prevent cervical cancer, and for this indication, Cervarix is the better of the 2 vaccines, said Diane Harper, MD, from the University of Missouri–Kansas City School of Medicine. She has been involved in clinical trials with both vaccines, and was approached by Medscape Oncology for comment.

Dr. Harper outlined the following reasons for her opinion:

  • Cervarix and Gardasil are equally effective for HPV types 16 and 18 in women with no previous HPV, but Cervarix has proven to have a longer duration than Gardasil (6.4 vs 5 years); there are still no data on how long the protection will ultimately last, and whether booster shots will be needed.
  • Cervarix offers cross protection for 5 cervical-cancer-causing types of HPV, whereas Gardasil offers cross protection for 3. In addition, Cervarix offers protection against the 3 most common types of HPV that cause adenocarcinoma, which is very difficult to detect with Pap testing; Gardasil is deficient in 1 of those types.
  • Cervarix prevents nearly twice the number of excisional therapies as does Gardasil (70% vs 40%), which is one of the harms that Pap screening can cause (excisional therapies lead to reproductive morbidity).
  • The antibody titers induced by Cervarix are superior to those for Gardasil, and are superior for women older than 25 years, should there come a time when the vaccines are approved for optional use by women in this age group. The antibody titers in the cervical mucous are also superior with Cervarix, and it is in the mucous on the epithelial surface that "half the action happens."

"I realize that this may sound like an advertisement for Cervarix, but these are the facts" Dr. Harper explained. "If you bother to vaccinate in countries with screening, then you want to vaccinate with the vaccine that will offer you the greatest cancer protection," she said.

Voting Against the Vaccines

The votes against both vaccines came from the consumer representative on the committee, Vicky Debold, PhD, RN, director of patient safety at the National Vaccine Information Center. She told Medscape Oncology that she has concerns about the safety of these vaccines, and acknowledged that her view is colored by listening to reports of adverse events from members of the public, in particular parents whose daughters who have suffered after vaccination with Gardasil.

"I'm not quite sure what is going on, but there have been too many patients with problems," she said. "There have been reports of demyelinating conditions and also deaths, and I wonder if there is a tendency toward a hyperstimulating of the immune system that results in such catastrophic outcomes." She suspects that there are individuals who might be particularly susceptible to adverse effects, maybe because of pre-existing conditions or genetic vulnerability.

It is very difficult to assess the safety of vaccines, Dr. Debold noted. At the meeting, she pointed out that, in many cases, the trials of both vaccines did not use a true placebo, such as a saline injection. The trials of Gardasil used an adjuvant control, and some of the Cervarix studies used hepatitis A vaccine as the control. "This makes the data very confusing," she said.

In addition, Dr. Debold had an issue with the way the question on the efficacy of Cervarix was worded. She felt the data showed that the vaccine did prevent precancerous lesions (and she would have voted yes for that), but the question also included wording about the prevention of cervical cancer, "and the data do not show this, not yet. The implication is that by preventing the earlier lesions, you prevent cervical cancer, but that is an implication, it has not been shown," she said.

At the meeting, specific questions about the safety of Cervarix focused on an "imbalance" of reports of spontaneous abortions and autoimmune adverse effects, but experts at the meeting were not convinced that these reports were related to the vaccine, with 1 commenting that "there are quirks in the collection of data."

Other Benefits From the Vaccines

Another potential benefit from a vaccine such as Gardasil that is active against HPV types 6 and 11 is that it might also offer protection against other "warty" diseases, including juvenile respiratory papillomatosis. Speaking during the open part of the meeting, Craig Derkay, MD, pediatric otolaryngologistat the Eastern Virginia Medical School in Norfolk, noted that there are about 1500 new cases each year of laryngeal papilloma caused by HPV 6 and 11, with the infection usually acquired from the mother during passage through the birth canal. There are no adjuvant therapies for this disease, and surgery is often not curative, he said. A vaccine that targets HPV 6 and 11 could "substantially reduce" this disease burden, and might also prevent HPV-associated head and neck cancer. If an HPV vaccine is to be used, it is preferable to use one with the broader spectrum so as to also prevent these types of diseases, he said.

Also speaking in the open part of the meeting was Dianne Zuckerman, PhD, president of the National Research Center for Women and Families. She expressed concern about the lack of long-term efficacy data for Gardasil in boys and men. The trial data that were presented were for 2 years, but some of the seroconversion data were for only 7 months, she pointed out.

The boys of America are not facing an epidemic of genital warts.

The whole point of vaccinating boys 9 to 11 years old is to protect them from genital warts once they become sexually active, but some of the data showed that the antibody titers dropped off during the 2 years of the trial, which raises the concern that any protection offered by the vaccine could have worn off by the time these boys become sexually active. "The boys of America are not facing an epidemic of genital warts and we have time to wait for efficacy data," she said.

In addition, she pointed out that genital warts are not life-threatening, and the male genital cancers that the vaccine offers protection against, such as penile and anal cancer, are very rare in heterosexual men.

One of the committee members highlighted the natural history of genital warts, which he felt was important for the discussion. "While they are ugly and a nuisance, they are also self-limiting and will go away on their own in individuals with a normal immune system," he said.

Approached for comment, Maurie Markman, MD, professor of gynecologic medical oncology at the University of Texas MD Anderson Cancer Center in Houston, who is an editorial advisor for Medscape Oncology, said: "I suspect evidence supporting the protection of males from genital warts will need to be very strong for the FDA to approve [this indication]. There is a very strong theoretical rationale to support vaccination of males to prevent cervix cancer in women, but considering the current cost of vaccination, I would seriously question the cost-effectiveness of this approach, at least in the United States. Further, there may be genuine protection of males against the risk of head and neck and other uncommon cancers, but again, this will need to be demonstrated in the clinical-trials setting."

Also during the open part of the meeting, there were testimonials from 2 mothers whose daughters had suffered adverse effects after vaccination with Gardasil, one of whom died shortly after her third dose. One of these mothers suggested that there was a link between niacin deficiency and adverse reactions to the HPV vaccine, and that individuals with pyruvate kinase deficiency might be particularly susceptible.

Paradigm-Shifting Prevention Strategy

Speaking out in favor of HPV vaccination — indeed, describing it as a "paradigm-shifting prevention strategy for cervical cancer" — was Mark Einstein, MD, MS, director of clinical research for women's health and gynecologic oncology at the Albert Einstein College of Medicine, in the Bronx, New York; he was representing the Society of Gynecologic Oncologists.

Cervical cancer remains a clinically relevant problem with in the United States, he told the meeting, with 11,000 new cases diagnosed annually, and about half a million women affected annually by precancerous lesions that could affect their reproductive health.

"The public-health value of the protection afforded by HPV vaccination overwhelmingly outweighs the self-limiting local side effects and even the rare but more serious effects that may or may not be vaccine-related," he told the meeting.