The use of accelerated approval for human papilloma virus vaccines could compromise adequate collection of safety data, members of FDA's Vaccines & Related Biological Products Advisory Committee asserted at a Nov. 29 meeting in Bethesda, Md.

"I am concerned about an accelerated approval process for licensure," committee member Barbara Fisher, National Vaccine Information Center, said, "because the majority of women clear HPV infection, and a very small number go on to develop persistent infection and an even smaller number go on to develop cervical cancer."

Fisher pointed out that the target population could include all healthy adolescent girls and adult women and, potentially, male and female children.

In light of the potential widespread use of an HPV vaccine, "long-term studies need to be done to measure for all morbidity and mortality outcomes...such as multiple sclerosis-like symptoms, arthritis, thyroid disease, etc. as well as exacerbation of pre-existing autoimmune conditions," Fisher said.

FDA asked the committee to discuss the use of accelerated approval regulations for licensure of HPV vaccines for the prevention of cervical cancer.

The committee expressed concern that an accelerated review would not allow for the sufficient collection of safety data prior to approval.

"If we don't ask for these kinds of studies pre-licensure...young women who may indeed avoid infection with HPV and cervical cancer by using HPV vaccine could be left with other vaccine-induced chronic health problems, simply because the vaccine was licensed too quickly," Fisher explained.

Committee members also cited the problem of keeping participants in a confirmatory trial on placebo after approval.

"Let's say all the issues were resolved a year after...BLA submission," CBER Division of Vaccines & Related Products Applications Director Karen Goldenthal, MD, proposed, "I would think that the confirmatory [trial], at least in the U.S., would basically have to be finished about the time of approval, because I think it would be untenable to have that trial ongoing."

If the trial was not completed prior to approval, the institutional review broad could halt the placebo arm, complicating the goal of long-term studies asked for by most committee members.

Goldenthal pointed out, however, "that accelerated approval might buy you a year in terms of [being] out on the market."

In light of data showing that exposure to HPV occurs in 75% of the population, and that in a worldwide survey of invasive cervical cancers, 99.7% were HPV-positive, "some may argue that year would be valuable," Goldenthal added.

Some committee members were persuaded by Goldenthal's comments on earlier marketing of HPV vaccines with accelerated approval.

"I favor an accelerated approval strategy, but only if things can be put into place....What swayed me to be in favor of it is Goldenthal's notion that we might be able to get an [effective] vaccine to the public a year early and I am sort of shooting for that," Committee Chair Robert Daum, MD, said.

"Cervical cancer appears to be almost 100% associated with infection by HPV. So if you have a vaccine which basically prevents infection...as a virologist, I feel that [if] there is no virus, then there is no disease," committee member Peter Palese, PhD, Mount Sinai School of Medicine said.

FDA asked the committee to help identify the most appropriate endpoints for both traditional and accelerated HPV vaccine approval. The endpoints discussed included incident and persistent HPV infection, low-grade squamous intraepithelial lesions, cervical intraepithelial neoplasia (levels 1, 2 and 3) and cervical cancer.

Early cervical dysplasias such as LSIL and CIN 1 could be too distal to cervical cancer to show a vaccine's efficacy in prevention, the committee concurred. Both tend to regress and do not have as strong a correlation to cervical cancer as CIN 2 or 3.

The use of HPV infection as an endpoint was also identified as having the potential to overstate a vaccine's ability to prevent cervical cancer.

Committee member Diane Griffin, MD/PhD, Johns Hopkins University, noted that "becoming infected with one of these [oncogenic] HPV types is a precursor to developing cervical carcinoma...therefore it seems to be a priori that if we prevent that infection we're going to prevent that cervical carcinoma."

However, Griffin added, if efficacy based on prevention of HPV infection were used, "what you've overestimated perhaps, or likely, is the efficacy for preventing cervical carcinoma," she explained.

Another problem with using persistent infection as an endpoint is the lack of a time interval between two positive tests for HPV to define the infection as persistent versus incident. The American College of Gynecologists is currently working on a definition for persistent HPV infection.

"I don't know what the exact definition is...for lack of a better one, I think I would accept a one year cut-off as a definition for viral persistence," Daum said.

Cervical cancer as an endpoint could be problematic because physicians would likely want to intervene to prevent cervical dysplasia from reaching that point.

Many committee members disagreed with FDA's proposal that the most informative surrogate endpoint would be CIN 1 associated with oncogenic HPV. Instead, the committee suggested that CIN 2/3 could serve as an endpoint for both traditional and accelerated approval trials.

"There's enough evidence to indicate that persistent papilloma virus infection is associated with CIN," committee guest Dennis O'Conner, MD, said.

"I think there is excellent evidence to indicate CIN 3 is associated with cervical cancer and, although the information regarding CIN 2 is not as clear because criteria for diagnosis are not reproducible, I think there's enough here to say that CIN 2 should be lumped into CIN 3. CIN 1 doesn't work...the diagnosis is extremely irreproducible," O'Conner noted.

Those who favored accelerated approval for HPV vaccines asked for a single large trial with persistent HPV infection as the interim endpoint and CIN 2/3 as the surrogate endpoint for the confirmatory trial.

"I agree with everybody else that CIN 2/3 is a reasonable surrogate endpoint....I think if viral persistence were to be shown, it could be the interim endpoint," Daum said, adding: "I would not favor interim approval if it compromised gathering appropriate safety data."

Committee guest Juan Felix, MD, University of Southern California Medical Center, pointed to an issue that troubled many committee members about HPV vaccines: researchers do not know what the duration of effect will be.

"We have to remember that if you protect a woman very early on, that may be in itself...an extraordinarily important protection agent because age at first coitus is an extremely important risk factor for the development of cervical cancer," Felix noted.

"If we protect these women at [an early] age, even if immunity wanes, there is at least theoretical benefit of even those first two or three [years] of protection, it lowers the relative risk of the population for acquiring invasive carcinoma," Felix said.

Committee Chair Daum ended the advisory committee saying, "I would encourage anybody working on [a preventative HPV vaccine] to go forward as [quickly] as possible." He added: "if we have a potential preventive strategy to stop a disease like cancer, we have to do everything in our power to ensure, and I think everyone in the room would agree with this, that it be developed."

Merck is one of the companies currently working on a prophylactic HPV vaccine for the prevention of genital warts and cervical cancer. The Merck vaccine is a virus-like particle that targets HPV related to cervical cancer, types 16 and 18, and two types related to genital warts, 6 and 11.

The company has completed a Phase II program and will present the analyzed data at its Dec. 11 annual business briefing. Although a Phase III program is in the works, the trials will not be initiated until 2002, Merck said.

MedImmune is also working on a prophylactic HPV vaccine based on virus-like particle biotechnology. The company had expected to finalize a Phase III trial endpoint following the advisory committee meeting. (Also see "Synagis Re-Treatment Patients Represent 21% Of Use, MedImmune Says" - Pink Sheet, 15 October, 2001., p. 24).

HPV Vaccine Accelerated Approval May Affect Safety Data Collection

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