dal Financial Times:Merck’s Gardasil vaccine shows limited efficacy on precancerous grade 3 cervical lesions, physicians say
By Klara Czobor and Sasha Damouni
March 6 2008 13:49
This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
Merck’s Gardasil vaccine showed only a small efficacy margin on grade 3 cervical intraepithelial neoplasia in FUTURE II study, physicians told Pharmawire.
Cervical intraepithelial neoplasia (CIN) is an irregular growth of precancerous cells in the cervix. A large percentage of CIN’s are caused by high-risk types of human papillomavirus (HPV) infection.
Gardasil did not show efficacy for grade 3 CIN (CIN3) in the FUTURE II trial, according to an article published in the New England Journal of Medicine (NEJM) titled ‘More Answers, More Questions.’ However, the vaccine showed statistically significant results for grade 2 (CIN2) cervical intraepithelial neoplasia.
Dr Rick Haupt, head of biological clinical research and head of the HPV vaccine program at Merck commented, “We stand behind the clinical results.”
The company conducted the analyses in several different sub-populations in the FUTURE II study, which could tend to be “very confusing to a lot physicians,” Haupt emphasized.
He said the company demonstrated in the clinical trials, women who were negative to the vaccine HPV types 6, 11, 16, 18, who received Gardasil, the efficacy was virtually 100% against disease endpoints, Haupt said. “Another thing we showed is population analyses. We looked at women who entered the study and we looked at the impact of the vaccine, regardless of their baseline status,” he said.
The efficacy is high in women who are naïve, and the population efficacy benefit is lower in women who have HPV, he noted.
The company looked at several multiple disease endpoints, external lesion, vulvar and vaginal precancers. As a result the CIN2/3 endpoint was used as the regulatory authorities, such as the FDA and the World Health Organization (WHO) recognized CIN2 and CIN3 as a composite endpoint and as an appropriate surrogate of prevention of cervical cancer with Gardasil, said Haupt
In discussions with these authorities, it was recognized that it was not possible to use cancer itself as an endpoint, Haupt said. ”What was recognized to do was to use the next most important precursor endpoints which are immediate precursors to cancer and that would be the high grade precancers like CIN2 and CIN3 as appropriate endpoints,” Haupt reiterated.
“The question is would the CIN2 lesions in the study have resolved on their own, or was it due to Gardasil,” said Abby Lippman professor of epidemiology at McGill University said.
“I can understand the methodological reasons why researchers might want to combine CIN2 and CIN3,” said Lippman. “But doing so,” she continues, “is problematic insofar as the two have different prognoses and it may be that Gardasil’s effect on each is different. CIN2 lesions very often resolve on their own, whereas CIN3 is more likely to persist and progress to cancer if it is not picked up by PAP testing.
According to the NEJM study, 40% of CIN2 resolves on its own. On the other hand, grade CIN3 has the lowest chance of being cleared by the immune system.
Gynecologists are not united in how to treat CIN2 lesions, said Dr Howard Jones III, director of gynecologic oncology at Vanderbilt-Ingram Cancer Center. If a younger woman who has not yet given birth develops CIN2 lesions, most gynecologists would not treat them, he explained. However, CIN2 lesions are always treated in older women. But Jones added that physicians face a moral dilemma regarding where to draw the line since it is not precisely known who will develop cervical cancer.
The study results might be further confounded because CIN2 and CIN3 look so much alike, said Dr Warner Huh, a gynecological oncologist at the University of Alabama at Birmingham. CIN2 – which is between CIN1 and CIN3 not only in pathology but appearance – is almost impossible for pathologists to define on their own. They can very easily mistake CIN2 lesions for CIN3 lesions. If a CIN2 was defined as CIN3 in the study, it could have resolved on its own and affected the study results.
Dr Erick Suba, a physician who is affiliated with the Vietnam Cervical Cancer Association, who has written extensive research on cervical cancer, said that three pathologists are needed to confirm a CIN2 diagnosis in the lab. It cannot be called a CIN2 unless the majority of them agree.
Still, Dr Murali Duggirala, a physician who practices internal medicine in Rochester, Minnesota, said the vaccine efficacy against CIN2 or CIN3 is in the intention-to-treat analysis (women aged 15-26) is 17%. The number may be on the lower side because of HPV non-naïve patients in the study, he said, but added, “A vaccine that contains most (if not all) oncogenic HPV serotypes if administered before sexual activity has the potential for a big public health impact.”
The vaccine demonstrated an efficacy of 17% against CIN2 or CIN3 cervical lesions combined. “I believe a 17% reduction in the pre-cancerous lesions is significant,” said Duggirala. ”The total number of CIN that is actually reduced at a population level is actually quite high, even though the percentage reduction is lower than it appears,” said Haupt.
Combining CIN2 and CIN3 ”makes the study easier to conduct and increases power,” said Jones. The definitions of CIN2 and CIN3 are arbitrary and there might be some ”wishy-washiness” in the study as a result, he said.
Despite increasing the power of the study, Duggirala believes this is a reasonable surrogate because about 60% of the CIN2 lesions do not regress spontaneously and using CIN3 alone as a primary endpoint will increase the sample size needed.
Haupt explained that Gardasil’s 17% efficacy against CIN2 and CIN3 should not be interpreted at face value. The number represents the reduction of CIN caused by any type of HPV in the Gardasil arm compared to the placebo arm. It takes into account women in both groups who are already infected with the virus, not only with vaccine strains of HPV but HPV types which Gardasil has no impact on, he said.
For the time being, marketing enthusiasm about Gardasil has reached a peak, said Suba. “The manufacturers had an important role in promoting premature enthusiasm,” he added.
Suba mentioned that there are many unknowns in cervical cancer pathology and women need to know that it is possible that Gardasil may be ineffective. ”Suggestions for vaccination are premature, because there are unanswered questions about the vaccine for females,” he concluded.