February 22, 2008 4:11 pm

Merck’s Gardasil vaccine encounters skepticism from some physicians regarding wide-scale use, long-term safety and efficacy

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Merck’s human papillomavirus (HPV) vaccine Gardasil is seeing physician skepticism regarding its wide-scale use, as doubts of long-term safety and efficacy linger, Pharmawire has found. Recent reports have linked deaths and rare serious adverse events to the vaccine, doctors said.

Since Gardasil’s approval last year, there have been reports which have cited 11 deaths and adverse events which range from Guillan-Barre syndrome, Bells Palsy, seizures and fainting. The vaccine has also been linked to blood clotting and heart problems.

Also, out of 42 pregnant women who received the vaccine, 18 had complications that ranged from fetal abnormalities to miscarriages.

However, Dr Rick Haupt, head of biological clinical research and head of the HPV Vaccine program at Merck, explained that despite recent news on adverse events, there is the chance for discrepancies in the reporting of these events.

”Anyone that has adverse events or outcome after vaccination can report it to different databases that collect safety reports after vaccination,” said Haupt. “These are reports that are usually temporally related to the vaccine and there is no adjudication for casualty.”

Haupt also pointed out that deaths reported after vaccination have been based on hearsay.

”Many of the deaths reported in our database, are associated with known causes of deaths in this age group,” he said. “Things like there was a report of a woman who had acute influenza, for example, who died of influenza, and happened to have had the vaccine”.

Still, a pharmaceutical industry investor noted two recent deaths in Europe linked to Gardasil appear to have been dismissed. He added that considering an estimated 10 – 12 million girls and young women are being vaccinated for an illness that is not considered an epidemic is a dangerous premise. He said there are approximately 15,000 to 30,000 cases of cervical cancer in the US, and if caught early it’s almost always curable. He asked, ”It’s not a great vaccine and so all of a sudden you throw deaths in the mix, is the risk reward all that good?”

Haupt begged to differ regarding the term epidemic. ”I think HPV is an epidemic,” he said. “It is the most common sexually transmitted infection worldwide.”

The investor noted that Gardasil is Merck’s profit driver and the company is counting on the franchise for its continued growth. Any setbacks would severely hurt the company, he added. In 2007, Gardasil’s actual sales were USD 1.481bn, and its estimated 2013 peak sales are valued at USD 3,451bn.

Dr Abby Lippman, professor of epidemiology at McGill University, noted HPV is neither an emergency nor a crisis, and as a consequence advises against the ”mass vaccination” situation that has arisen.

She asked, ”Why can’t we take some time to realize its benefits and harms before we immunize school girls? Before we have a public health crisis, policies should be decided on harder data when we don’t have a crisis to deal with.”

An industry investment banker noted that there could be the possibility that young girls and women could be screened more diligently for Gardasil. Yet, none of the doctors had any specific comments towards screening or labeling changes prior to vaccination.

Considering Gardasil only prevents four types of HPV (Types 6, 11, 16, 18), and that trials were not lengthy, ”as far as risk benefit, you never know the long term safety concerns are going to be especially if you think about dosing young girls,” the investor said. Cervical cancer is a very curable cancer, he added.

Still, Kevin Ault, associate professor, department of gynecology and obstetrics at Emory University School of Medicine, defended Gardasil in relation to its side effects. There are two well documented cases of Guillain-Barre syndrome – a neurological disease characterized by reversible paralysis – which in relation to the size of the population that has been dosed has amounted to a ”rare event in a huge population.”

He added that blood clots have drawn attention, but that the rate of blood clots are the same as the rate of blood clots in birth control pills. ”It does not appear to be causally related to the vaccine,” he said.

Still, physicians are cautious about the effectiveness of Gardasil.

Dr William Bonnez, associate professor of medicine at the infectious diseases unit, University of Rochester Medical Center, said it is particularly important for Merck to find out if the rate of cervical cancer decreases after the administration of the vaccine. ”This is the final proof that is needed to affirm that the vaccine is effective,” said Bonnez, who also holds intellectual property rights on the HPV vaccine, and derives royalties from Gardasil, as well as GlaxoSmithKline’s Cervarix. ”The vaccine protects against the precursor lesions, we don’t have proof that it prevents the cancer from developing.”

Dr Abby Lippman added that there has been a huge amount of marketing, and that Gardasil is not a vaccine against cancer, as it only targets the prevention of HPV. ”We won’t know for 30 years if it makes a difference against cervical cancer,” she said.

Still, Merck’s Haupt said that the company’s clinical trials were specifically designed to demonstrate that Gardasil could prevent the highest grade precancers before the development of cervical cancer, and has therefore demonstrated that Gardasil prevented 99% of CIN (cervical intraepithelial neoplasia) grades II/III. These are the highest grade precancers and go on to develop cancer, he added.

Dr James Colgrove, assistant professor with the center for the history and ethics of public health at Columbia University’s Mailman School of Public Health, argued that there are still too many unanswered questions about safety and efficacy. Colgrove said he considers the Phase III trial that Merck sought for Gardasil’s approval, as ”a decent sized study,” but said that even with the largest trials, it is necessary to get post-market information.

Haupt noted that Merck is conducting a long-term study in the Scandinavian region with a group of women that the company has vaccinated in one of its largest Phase III trials. Merck is also enrolling in a long-term follow-up study that will assess the effectiveness of the vaccine over time and the safety of that population. The company is also seeking new medical conditions, such as pregnancies that occur in those women over a period of time.

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