# FDA Briefing Document #1

## Preventive Human Papillomavirus (HPV) Vaccines-

## Regulatory Briefing Document on Endpoints

**Vaccines and Related Biological Products Advisory Committee Meeting**

**November 28 and 29, 2001**

## 

## Discussion of Possible Endpoints for Licensure of Human Papillomavirus (HPV) Vaccines[^1]^,2,3^

**Douglas Pratt, M.D., M.P.H.**

**Karen Goldenthal, M.D.**

**Antonia Geber, M.D.**

The purpose of this document is to discuss the merits and drawbacks of
endpoints proposed for clinical efficacy trials to evaluate preventive
HPV vaccines containing "oncogenic" HPV types. The ultimate goal for
these vaccines is the prevention of cervical cancer. Since infection
with an oncogenic HPV type is thought to be a necessary step in the
pathogenesis of most cervical cancer, a number of potential endpoints
proceeding from the initial infection are considered.

Endpoints in clinical studies may be defined as measurable outcome
variables following an experimental intervention. Primary efficacy
endpoints are usually selected to provide an outcome measure of the
greatest clinical relevance. In efficacy trials of vaccines, prevention
of a disease is commonly used as the primary outcome variable. However,
the severity and stages of disease can vary considerably, and endpoints
based on preventing disease of greater or lesser severity may be
appropriate for vaccine efficacy trials.

Certain federal regulations relate to selection of efficacy endpoints.
Under 21 CFR 314.125, FDA may refuse to approve a drug application if
there is a lack of substantial evidence of efficacy from adequate and
well-controlled investigations demonstrating that the drug product will
have the effect it purports or is represented to have in its proposed
labeling. Thus, the approved product indication will reflect the
endpoint selection in definitive efficacy studies.

Characteristics of adequate and well-controlled studies are described
under 21 CFR 314.126. Relevant parts of this regulation state that the
purpose of conducting clinical investigations of a drug is to
distinguish the effect of a drug from other influences, such as
spontaneous change in the course of the disease, placebo effect, or
biased observation. Studies are to use a design that permits valid
comparison with a control to provide a quantitative assessment of drug
effect. The methods of assessment of subjects' responses are to be well
defined and reliable.

**Potential endpoints for traditional approval**

The choice of endpoints in clinical efficacy trials of prophylactic
human papillomavirus (HPV) vaccines will affect the sample sizes, trial
designs, duration, resources needed, choice of study populations, and
the indication in the vaccine label. In the discussion that follows,
endpoints based on virologic, cytologic, and histopathologic outcomes
are presented, and arguments both favoring and against those endpoint
selections are described. Only endpoints for oncogenic HPV types in the
context of cervical abnormalities are considered here.

### Virologic endpoints

The presence of an HPV infection in a clinical trial would not be
established using classical *in vitro* cell culture methods.
Identification and typing of HPV infections rely on detection of viral
DNA using tools of molecular virology, such as polymerase chain reaction
(PCR) or DNA hybridization. Serology appears to be less sensitive than
molecular techniques in establishing that a new, or incident, infection
has occurred, and would likely not be able to distinguish a persistent
infection from an infection that has resolved. Both incident and
persistent infections (starting during the trial) have been proposed as
endpoints in HPV vaccine trials.

**Incident HPV infection due to vaccine HPV types**

Based on abundant epidemiologic data, infection by an oncogenic HPV type
appears to be a necessary step in the pathogenesis of the vast majority
of cervical cancers. Specifically, it appears likely that incident HPV
infection begins the process of malignant transformation and invasion of
cervical tissue. Therefore, prevention of HPV infection may be expected
to preclude all subsequent steps in the pathogenesis of cervical cancer.

Studies assessing incident HPV infection as the primary efficacy
endpoint may be easier to conduct than studies using other outcome
measures. Cases could accrue relatively quickly and be completed within
a relatively short period of time, a few years from study initiation.
Sample sizes adequate to demonstrate a treatment effect would likely be
relatively small (e.g., a few thousand subjects), and may not require
the length of follow-up to ascertain endpoints as would be required for
endpoints assessing more advanced disease in the pathogenesis of
cervical cancer. Definitive efficacy trials for incident HPV infection
could be completed within a relatively short time frame, e.g., a few
years from study initiation. Monitoring would need to be fairly
extensive, e.g., regular Pap smears and HPV testing on all trial
participants, plus other interventions such as colposcopy and biopsy,
based on a protocol specified algorithm.

From a population perspective, prevention of infection among vaccinated
individuals may be expected to result in a decrease in circulating HPV
within the larger population. However, this effect is difficult to
quantify in the context of an efficacy study.

Prevention of infection can be a difficult endpoint to meet. Typically,
the efficacy of vaccines is demonstrated by prevention of disease, as
symptomatic disease (or its sequelae) is of greater clinical relevance
than is infection, which may be transient and asymptomatic. It is
usually symptomatic disease that brings patients to clinicians and trial
participants to the attention of clinical investigators. In general, it
can be quite difficult to determine whether a vaccine prevents the
infection of interest, or whether the vaccine induces an immune response
that contains and clears an incipient infection, before disease becomes
apparent.

Most incident HPV infections are thought to be asymptomatic and
transient without intervention and, therefore, lack clinical relevance
for the individual. Thus, a vaccine efficacy estimate for prevention of
incident infection could substantially overestimate the protective
efficacy for the endpoint of greatest clinical relevance, cervical
cancer.

Also, hypothetically, women who develop a poor immune response to an HPV
vaccine may be those who are less likely to clear infections
spontaneously, and more likely to develop high-grade cervical lesions
and cervical cancer. For example, a vaccine that is 90-95% effective in
preventing incident infection could be much less effective in preventing
high-grade cervical lesions and cancer, if those at greatest risk of
progression are over-represented among the 5-10% who would not be
protected from infection by the vaccine. If an HPV vaccine proves highly
efficacious (\>95%) in preventing infection across populations, such a
scenario may be less likely.

Another consideration in using incident (or persistent) infection as an
efficacy endpoint is the reliability of detection of type-specific HPV
infection, both at study entry and throughout the trial. Detection of
incident or persistent HPV infection relies on detection of DNA from
cervical samples or smears. These samples obtain superficial cervical
cells more so than basal layer cells. (This type of HPV testing should
be distinguished from testing of biopsy samples, e.g., with *in situ*
hybridization of actual lesions). Thus, it may not always be possible to
distinguish a new infection from a recurrence or reactivation of a
previously latent infection. Assuming a sensitive assay, productive HPV
infections (i.e., infection resulting in shedding of infectious viral
particles) may be detected readily, but there is uncertainty about
detecting "latent" infections, which would be expected to exist
predominantly in basal layer cells of the cervical epithelium.

In a randomized study design, inability to detect the presence of HPV
infection at study entry would likely be evenly distributed among
groups. While this type of uncertainty about the case definition would
not result in systematic bias of measures of efficacy, it would result
in less case specificity and may result in a less precise estimate of
efficacy. Moreover, if an incident infection in a previously uninfected
person achieves latency and integration prior to the next scheduled
visit, it might be falsely concluded that no infection occurred.
Additionally, it is plausible that a vaccine induced immune response
might impair detection of HPV DNA, possibly by facilitating clearance of
virus from the more superficial epithelium, while infection and
integration of cells in the deeper epithelial layers, especially the
basal layer, persists.

The benefits of vaccination to prevent asymptomatic HPV infections may
not be viewed favorably when compared to risks of adverse events related
to vaccination. This risk-to-benefit assessment would more likely favor
vaccination if clear evidence for prevention of high-grade cervical
lesions were demonstrated.

Finally, although virologic endpoint studies may allow for demonstration
of efficacy using relatively small sample sizes, large randomized
datasets are preferred to evaluate safety of HPV vaccines. The bulk of
safety data supporting licensure of vaccines is usually obtained in
trials designed to demonstrate efficacy. If virologic endpoints are
chosen based largely on feasibility considerations, it may be necessary
to conduct additional randomized trials in order to closely monitor a
large cohort of individuals for safety outcomes.

# Persistent HPV infection by oncogenic HPV types

Persistent HPV infection can be defined by the presence of type-specific
HPV DNA on repeated visits over some period of time. In one large study,
detection of HPV type 16 DNA in the last 2 Pap smears before a diagnosis
of carcinoma *in situ* (CIS) excluding smears taken less than 1 year
before diagnosis, was found to have a higher odds ratio for association
with CIS than was a single finding of HPV DNA (Ylitalo N et al., [Cancer
Res]{.underline}, 2000). In another study, the relative risk for
developing squamous intraepithelial lesions (29 of 31 were low grade)
was 37 (95% CI: 14.6-95) for women with the same high-risk type HPV
detected at two consecutive visits (6 months apart) compared to women
who were HPV negative at one or both visits (Ho GYF et al., 1998).

The optimal interval after which an HPV infection would be considered
persistent is not readily apparent. Estimates of the median duration of
HPV type 16 infection vary from 8 to 12 months (Ho GYF et al., 1998,
Franco EL et al., 1999, Woodman CB, et al., 2001). Thus, study designs
in which HPV testing is performed every 4-6 months could conclude that
an infection is persistent in cases where viral clearance proceeds
normally within a typical duration of infection.

# Reservations regarding use of incident HPV infection as an endpoint, as discussed above, also apply to persistent infection. Like incident infection, most persistent infections are thought to be asymptomatic, and, therefore, lack clear clinical relevance for the individual. Clinical trials using only virologic endpoints, ignoring cervical pathology, could significantly overestimate the benefit from vaccination for prevention of cervical cancer. Until an efficacy study using clinical endpoints is conducted that clearly validates virologic endpoints as quantitatively predictive of clinical outcomes of interest with HPV vaccine use, the value of virologic endpoints used without cervical pathology will remain uncertain.

If virologic endpoints are not judged to be adequate for demonstrating
efficacy in preventing cervical cancer, it is possible that incident or
persistent infection might be suitable surrogate endpoints to support
accelerated approval, as described in the FDA regulations. Accelerated
approval is discussed later in this document.

# [Endpoints based on cytology]{.underline}

# 

# LSIL and/or ASC, or worse, in association with oncogenic HPV types

Low-grade squamous intraepithelial lesion (LSIL) as discussed in this
section, and atypical squamous cells (ASC) are cytologic terms used in
the interpretation of Pap smear results. Management of such cytology
findings may vary. Workup by immediate colposcopy may occur. However,
depending on clinical factors such as availability for follow-up and
immune status, clinicians may elect to follow-up such cytologic findings
with another Pap smear without immediate colposcopy. When incident or
persistent LSIL leads to colposcopy and biopsy, abnormal findings could
be reflected in a pathologic diagnosis, such as cervical intraepithelial
neoplasia (CIN), as discussed in several sections below.

It may be argued that prevention of LSIL or ASC, or prevention of
persistent LSIL would translate into fewer repeat Pap smears,
colposcopies and biopsies, and thus would provide evidence of clinical
benefit. However, there must be histologic evidence (e.g., CIN 1 on
biopsy) in order to initiate treatment. In the US, a finding of LSIL
cytology by itself is an insufficient basis to treat. Thus, prevention
of the pathologic diagnosis (by histology) would more clearly indicate
clinical benefit.

# 

# [Endpoints based on histology]{.underline}

# 

# CIN 1 histology, adenocarcinoma *in situ* (AIS) of the cervix, or worse, in association with oncogenic HPV types

Cervical intraepithelial neoplasia (CIN) is a pathologic diagnosis based
on tissue obtained at biopsy, e.g., after a Pap screening test finding
of ASC or LSIL. CIN 1 histology is considered a low-grade lesion. The
histology is characterized by a finding of undifferentiated cells in the
lower third of the cervical epithelium. A pathologic diagnosis of CIN I,
or worse, by biopsy is considered more definitive than a cytologic
finding of LSIL with regard to therapeutic decisions. Biopsy specimens
would include the basal epithelium, thus possibly enabling
identification of latent or otherwise inapparent HPV infection. The
actual lesions can be evaluated for HPV type by *in situ* hybridization.

Because a diagnosis of CIN 1 is based on tissue samples, prevention of
CIN 1 or worse would directly reflect prevention of a procedure
(biopsy).

In a recent study (ALTS), 26% (298/1149) of subjects with ASC (at entry)
who were randomized to immediate colposcopy had CIN (majority are CIN
1), or worse, at biopsy (Solomon D et al., 2001). In addition, studies
have found that 52 to 85% of women with LSIL cytology have CIN (majority
are CIN 1) or worse on biopsy \[Lonky NM e al., 1999; Jones BA, 2000\].

Similar to LSIL, about 50% of CIN 1 regressed to normal (Östör AG,
1993). (See Natural History section of the FDA HPV Vaccine Background
document for more details.) The risk of CIN 1 progressing to cancer over
a period of months or even a few years is thought to be low, at least in
those subjects with adequate follow-up \[ASCCP (1), 2001; Östör AG,
1993\]. Thus, an efficacy estimate for prevention of CIN 1 could
substantially overestimate the efficacy in preventing cervical cancer,
although the magnitude of an overestimate may be diminished if the
efficacy in preventing CIN 1 is high.

Also of interest here, in at least 2 longitudinal studies, some women
with normal cytology at baseline had a diagnosis of CIN2/3 (histology)
identified on initial workup for an abnormal Pap smear during the study
(Koutsky LA et al., 1992; Woodman CD et al., 2001).

If licensure of HPV vaccines were to be based on prevention of
predominantly CIN 1, the vaccine indication in the label would reflect
that the vaccine prevents CIN 1, not cervical cancer. Additional
efficacy studies would be required post-licensure to justify extending
the labeled indication to include prevention of cervical cancer.

# CIN 2/3 histology, adenocarcinoma *in situ* (AIS) of the cervix, or worse, in association with oncogenic HPV types

Most of the endpoints in this category would be CIN 2 or 3. CIN 2 is
defined by moderate dysplasia. CIN 3 includes both severe dysplasia and
carcinoma *in situ*. Both CIN 2 and 3 are considered high-grade cervical
lesions. In the US, little distinction is made between CIN 2 and CIN 3
in terms of medical management. Thus, it is reasonable to consider CIN
2/3, AIS, or worse as a single entity for the purpose of selection of
efficacy endpoints for HPV vaccine trials. If efficacy trials using
cervical cancer as the endpoint cannot be conducted, prevention of CIN
2/3, AIS, or worse will most closely approximate the preventive efficacy
of HPV vaccines for cervical cancer.

As discussed under the CIN 1 or worse endpoint section, a pathologic
diagnosis based on tissue is needed for therapeutic decisions.
Prevention of CIN 2/3 would translate into prevention of both the
diagnostic biopsy, and a subsequent therapy (excisional or ablative
procedure, as appropriate). Thus, in preventing CIN 2/3, substantial
clinical benefit will have been realized.

It has been argued that studies examining CIN 2/3 as the primary
efficacy endpoint could be prohibitively resource intensive, and of long
duration. Concerns expressed regarding use of CIN 2/3 as a primary
efficacy endpoint have focused on the following areas:

1.  The length of trial considerations as well as sample size
    projections have been cited as a problem, although little specific
    information has been presented or published in this regard (WHO
    meeting, Geneva, Switzerland 1999).

2.  Large preventive vaccine efficacy trials, e.g., 10,000 to 40,000
    enrollees, are not unusual. However, the type of follow-up (i.e.,
    multiple clinical examinations and laboratory testing) makes this
    sort of trial more resource intensive and complex than typical
    preventive vaccine efficacy trials, although similar to virologic
    endpoint trials with regard to resources per subject per year.

3.  In a trial of subjects being followed, e.g., at 4, 6, or 12-month
    intervals, a certain percentage of [incident]{.underline} cervical
    dysplasia would need to be CIN 2/3 at initial work-up, in order to
    accrue sufficient cases of CIN 2/3 to demonstrate efficacy. This may
    be the case whether or not CIN 1 is treated during a trial.

It should be noted that a certain proportion of women with ASC, LSIL and
atypical glandular cells (AGC) cytology will have HSIL/CIN 2/3 upon
initial work-up. In fact, work-up of such low-grade lesions with
colposcopy and biopsy could generate most of the CIN 2/3, AIS, or worse
diagnoses in an efficacy trial (Kinney WK et al., 1998; Lonky NM et al.,
1999; Woodman CB et al., 2001). Across studies, the proportion of women
with CIN 2/3 or worse following the work-up for ASCUS (ASC) has ranged
from about 6% to 11% (Solomon D et al., 2001). For LSIL, the proportion
with CIN 2/3 or worse at work-up has usually ranged from about 16% to
28% \[ASCCP (1) 2001\]. However, several European studies have reported
rates as high as 50-70%. For AGUS (AGC), the proportion with CIN 2/3 or
worse at work-up has usually ranged from about 9-13%, with a special
concern about the percent of frank cancer (as discussed in the other FDA
document).

The estimate of the size/duration of a preventive HPV vaccine efficacy
trial with a CIN 2/3, AIS, or worse endpoint would come from a
prospective cohort of closely monitored subjects who have normal
cytology and negative HPV testing results at baseline. Data from one
such longitudinal study was recently published (Woodman C et al., 2001,
included with FDA briefing materials). In this prospective study
conducted in the UK, 1075 women with normal Pap smears and who were
negative for HPV at study entry, were followed for a median of 26
months. A diagnosis of CIN 2 or 3 was established for 28 women, 20 of
whom were diagnosed with CIN 2 or 3 during work-up of the first episode
of abnormal cytology. Median time to diagnosis of CIN 2/3 was 36 months
from study entry.

If one assumes the following parameters, *approximately* 12,000 women
would need to be enrolled:

> A trial with 1:1 randomization, HPV 16 and 18 infection rate similar
> to the Woodman et al., article, a vaccine efficacy of ≥ 80%, trial
> duration of 3 1/2 years (mean follow-up 3 years), 80% power, 20% loss
> to follow-up, and about 50% of incident CIN 2/3 cases attributed to
> vaccine types (HPV type 16 or 18).

If preventive efficacy trials using cervical cancer as the outcome are
deemed not feasible or not appropriate, then endpoints based on
high-grade CIN pathologic criteria, in the context of HPV infection,
appear to be the most clinically relevant and most accurate in
predicting and quantifying the preventive efficacy of HPV vaccines for
cervical cancer. Should efficacy of an HPV vaccine in preventing
high-grade cervical lesions be demonstrated, a labeled indication for
prevention of cervical cancer may be considered.

# Cervical cancer (invasive)

Prevention of cervical cancer would be the most clinically relevant
endpoint for a preventive HPV vaccine comprising oncogenic types.
However, there appears to be significant feasibility issues for
conducting a vaccine study using cervical cancer as the endpoint.
Standard of care in the US dictates that women enrolled in HPV vaccine
trials would be followed closely by means of Pap screening and other
interventions, as appropriate. Given the relatively protracted duration
of carcinogenesis following HPV infection ([median]{.underline} time
from HPV infection to carcinoma *in situ* has been estimated to be 7-12
years) (Ylitalo N et al., [Cancer Res]{.underline} 2000), and the
relatively low frequency of cervical cancer in the US due to screening
and early treatment, clinical studies using cervical cancer as an
endpoint could require a prolonged duration of follow-up to identify
sufficient cases to establish efficacy.

The possibility of conducting a long-term, e.g., up to 20 year,
population based trial to evaluate the impact of vaccination on ICC
(invasive cervical cancer) \[with or without CIN 3\] in Nordic countries
and Estonia has been discussed in the literature. The proposal involved
use of cancer registry follow-up. For example, Finland has a
country-wide cancer program where practically all invasive cancer cases
(\>95% histologically confirmed diagnoses) are captured; in addition,
CIN 3 and adenocarcinoma *in situ* are captured (Lehtinen M et al.,
2000).

It might be considered feasible to conduct HPV vaccine studies using
cervical cancer as an endpoint in areas of the world where cervical
cancer rates are high, and screening and treatment are not effectively
employed. However, in the context of a clinical trial, some would
consider it unethical not to provide effective screening and treatment
to all participants, even if that level of medical care would not
otherwise be available. If effective screening and treatment were made
available, then the rates of cervical cancer would be expected to fall,
and advantages of conducting trials in those high incidence areas might
no longer exist.

Another complex issue for a cervical cancer trial, given the size of
such a trial, could be screening for HPV and exclusion at baseline.
Without screening and exclusion at baseline, pre-existing HPV infection
may substantially dilute vaccine efficacy estimates, as well as increase
sample size. The same consideration (although logistically more
feasible) applies to the decision of whether or not to HPV test/type the
cervical cancer specimens.

# Other considerations affecting the selection of endpoints

It should not be assumed that efficacy trials with endpoints such as CIN
2/3 must be conducted in developing countries. HPV infection annual
incidence rates that equal or exceed \~ 3% for HPV Type 16 and \~2% for
HPV Type 18 have been documented in cohorts in developed countries
(Woodman CB et al., 2001; Ho GYF et al., 1998; Thomas KK et al., 2000).
If HPV infection is linked to the subsequent development of CIN 2/3 (or
worse), then these cohorts would appear to be relatively high-risk
populations for the development of high-grade cervical lesions.

The public health community may have difficulty assessing the value of
wide implementation (for the US and elsewhere) of an HPV vaccine if the
approval is based on endpoints associated with asymptomatic infections,
when the effect on the medical conditions of interest, high-grade
dysplasia and/or cervical cancer, has not been demonstrated in a
well-controlled trial.

When multiple serotypes, etc., of an infectious agent cause disease, the
primary endpoint in vaccine efficacy trials has been prevention of
disease caused specifically by the ones represented in the vaccine
(e.g., pneumococcal conjugate vaccine comprising 7 of the most common
serotypes). Cervical cancer has been associated with multiple oncogenic
HPV types, of which HPV type 16 is the most common, found in
approximately 50% of cervical cancers. Limiting the primary endpoint to
HPV types represented in the vaccine will likely result in a higher
vaccine efficacy estimate than if the endpoint reflected disease caused
by all HPV types. However, prevention of all cervical cancer associated
with HPV is the ultimate goal of an HPV vaccine. Therefore, it will also
be important in HPV vaccine trials to conduct pre-specified secondary
analyses to assess efficacy of the vaccine for the chosen endpoints
(e.g., all CIN 2/3), regardless of the HPV type implicated. Such
secondary analyses have the potential to address questions that can be
important to the overall risk-benefit assessment, such as "replacement"
disease caused by non-vaccine types or other infectious diseases.

Another consideration is that adenocarcinoma accounts for an increasing
proportion of cervical cancer in developed countries. HPV Type 18 is the
type most commonly associated with cervical adenocarcinoma (Smith HO et
al., 2000). Type 18 infections may be fundamentally different from Type
16 infections. Trials using an endpoint other than cervical cancer may
not provide sufficient data to make conclusions about the protective
efficacy of HPV Type 18 vaccines.

It may not be possible to conduct additional placebo-controlled clinical
endpoint studies after licensure of an HPV vaccine, regardless of the
efficacy endpoint that provided the basis of licensure. Furthermore,
non-inferiority studies comparing a licensed HPV vaccine to another
candidate HPV vaccine, using clinical endpoints would need to be larger
and even more resource intensive than placebo-controlled studies. Thus,
the opportunity to conduct and complete a vaccine study using prevention
of high-grade cervical lesions as the primary efficacy outcome, as
compared to placebo, may be lost with the licensure of the first HPV
vaccine.

**Accelerated Approval**

**\[21 CFR 601 Subpart E:** **Accelerated** **Approval of New Biologic
Products for Serious or Life-Threatening Illnesses\].** This subpart of
the regulations applies to certain biological products that have been
studied for the treatment of serious or life-threatening illnesses, and
that provide meaningful therapeutic benefit to patients over existing
treatments (e.g., ability to treat patients unresponsive to, or
intolerant of, available therapy, or improved patient response over
available therapy). "FDA may grant marketing approval for a biological
product on the basis of adequate and well-controlled clinical trials
establishing that a biological product has an effect on a surrogate
endpoint that is reasonably likely, based on epidemiologic, therapeutic,
pathophysiologic, or other evidence, to predict clinical benefit, or on
the basis of an effect on a clinical endpoint other than survival or
irreversible morbidity" (Sec. 601.41).

The accelerated approval regulations were intended to make available
promising therapies while the definitive confirmatory efficacy studies
were completed. Products approved under the accelerated approval
regulations must be studied further, to verify and describe clinical
benefit of the product, where there is uncertainty as to the relation of
the surrogate endpoint to clinical benefit, or of the observed clinical
benefit to ultimate outcome.

Confirmatory post-marketing studies would usually be studies already
well underway at the time of accelerated approval; these studies must be
carried out with due diligence. Safety of the product will have been
demonstrated at the time of accelerated approval. Should the
confirmatory studies fail to demonstrate efficacy for clinical
endpoints, the product may be withdrawn from the market.

The accelerated approval regulations originated in the setting of rising
mortality due to acquired immunodeficiency syndrome (AIDS), prior to
availability of highly active antiretroviral agents. The original, and
current, intent of accelerated approval regulations is to serve the best
interests of the public. Drugs for treatment of HIV infections, drugs
and biologics for the treatment of cancer, and other therapeutic
products have been approved under accelerated approval. However, the
accelerated approval provisions have not previously been invoked for
licensure of a prophylactic vaccine.

# Accelerated approval and HPV vaccines

Cervical cancer is clearly a serious and life-threatening medical
condition. The time from incident infection by oncogenic HPV types to
high-grade neoplasia or cancer may be years, and the event rate in a
population that has normal cytology and negative HPV status at baseline
could be quite low. It has been suggested that studies using CIN 2 and
CIN 3 as primary efficacy endpoints could also be resource intensive.
Nevertheless, such trials may be feasible, as discussed earlier.

Interest in surrogate endpoints and accelerated approval for HPV
vaccines is understandable given the duration of trials that may be
required to document unequivocal histologic evidence of high-grade
cervical dysplasia or cancer. However, the appropriateness of
accelerated approval regulations to prophylactic HPV vaccines is open to
interpretation. Available options for preventing cervical cancer include
cytologic screening with appropriate interventions, e.g., colposcopy,
biopsies, and excisional or ablative procedures as indicated. It may be
argued that these prevention modalities are both effective and widely
available in the US. It is also expected that continued screening will
be necessary, even if HPV vaccines are effective and become available,
in order to prevent cervical lesions caused by HPV types not included in
the vaccines. On the other hand, a reduction in the number of surgical
interventions could be considered a meaningful therapeutic benefit to
patients over existing treatments. Of note, cost-effectiveness cannot be
used as the basis for FDA regulatory decisions.

To date, the intended populations for products approved under
accelerated approval have been limited to those groups of individuals
affected by the severe or life-threatening condition in question. In the
case of HPV vaccines, all healthy adolescents and adults could comprise
the intended target population. Public health decisions regarding such
wide implementation of an HPV vaccine following accelerated approval
based on a surrogate endpoint rather than the medical conditions of
interest, high-grade dysplasia and/or cervical cancer could be
particularly difficult, as was discussed above in the context of
traditional approvals based on virologic endpoints or low grade lesions

Should accelerated approval regulations be judged an acceptable pathway
for the licensure of HPV vaccines, surrogate and confirmatory endpoints
will need to be identified.

# 

# Surrogate Endpoints for Accelerated Approvals

FDA regulations state that the surrogate must be "reasonably likely",
based on epidemiologic, therapeutic, pathophysiologic, or other
evidence, to predict benefit for the serious or life-threatening
condition of interest. Thus, the strength of evidence demonstrating that
a surrogate predicts benefit in life-threatening conditions can be
broadly interpreted. Arguments can be made that incident HPV infection,
persistent HPV infection, LSIL cytology associated with HPV infection,
and CIN 1 associated with HPV infection are reasonably likely to predict
benefit.

For reasons discussed above, the most informative of these candidate
surrogates may be CIN 1 associated with oncogenic HPV.

# Confirmatory Trials for Accelerated Approvals

One of the necessary conditions for accelerated approval is that the
indication be for treatment or prevention of a serious or
life-threatening illness. The confirmatory trial should
[validate]{.underline} that the surrogate endpoint predicts the outcome
of interest. However, because the current practice of screening and
treatment of pre-cancerous cervical lesions is largely effective in
preventing cervical cancer in the US, the most appropriate confirmatory
endpoints would be those most proximal to the endpoint of cervical
cancer. It appears that an endpoint combining all cases of CIN 2, CIN 3,
AIS, and those cases of cervical cancer not detected through screening
and treatment combined is the most appropriate confirmatory endpoint, if
the accelerated approval path is followed.

Once a product becomes available through accelerated approval, it may be
quite difficult to conduct confirmatory studies because of widespread
availability of the product. Sponsors might propose conducting
confirmatory studies in countries where the product is not yet approved
or available. However, as would be the case following a traditional
approval, it may be problematic in the post-licensure setting to conduct
trials in which subjects would be randomized to a placebo, even if the
product is not otherwise available. Therefore, if a path to accelerated
approval is pursued, the confirmatory trials should be fully accrued and
well underway at the time of an accelerated approval in order to assure
that the confirmatory trials would yield a definitive result. An
efficient approach to past accelerated approvals has been to embed the
surrogate endpoint study within a confirmatory endpoint study. Given the
long duration of follow-up that may be required to accrue sufficient
cases of high-grade lesions, it is also unclear whether completion of
the confirmatory trials would be feasible.

Advantages and disadvantages of potential efficacy endpoints for
clinical trials of preventive HPV vaccines (cervix)

+--------+---------------+-------------------------+-------------------+
| **Endp | *             | **Disadvantages**       | **Other           |
| oint** | *Advantages** |                         | Comments**        |
+--------+---------------+-------------------------+-------------------+
| In     | -Likely to    | -Traditional endpoints  | -Could be         |
| cident | accrue cases  | usually for prevention  | difficult to      |
| HPV    | quickly.      | of infectious disease.  | demonstrate       |
| Inf    |               |                         | treatment effect  |
| ection | -May predict  | -Most HPV infections    | for incident      |
|        | epidemiologic | resolve.                | endpoint if       |
|        | benefit.      |                         | vaccine promotes  |
|        |               | -Benefit of preventing  | viral clearance   |
|        |               | asymptomatic infection  | from superficial  |
|        |               | uncertain and difficult | cervical cells.   |
|        |               | to weigh against        |                   |
|        |               | potential risks         | -Transient        |
|        |               | (adverse events related | infection may not |
|        |               | to vaccination).        | have consequences |
|        |               |                         | for host. Latent  |
|        |               | -Potential for          | infection might   |
|        |               | vaccine-induced immune  | have              |
|        |               | response to make HPV    | consequences,     |
|        |               | detection more          | e.g., if host is  |
|        |               | difficult.              | subsequently      |
|        |               |                         | immunosuppressed. |
|        |               | -Uncertainty in         |                   |
|        |               | distinguishing          |                   |
|        |               | re-infection from new   |                   |
|        |               | infection.              |                   |
|        |               |                         |                   |
|        |               | -Uncertainty in         |                   |
|        |               | existence of, or        |                   |
|        |               | detection of latent HPV |                   |
|        |               | infection.              |                   |
|        |               |                         |                   |
|        |               | -Non-responders to      |                   |
|        |               | vaccine may be same as  |                   |
|        |               | those with greatest     |                   |
|        |               | risk for high-grade     |                   |
|        |               | lesions/lesion          |                   |
|        |               | progression.            |                   |
+--------+---------------+-------------------------+-------------------+
| Pers   | -             | -No common definition   | -HPV type 18 is   |
| istent | Epidemiologic | of persistent.          | type most often   |
| HPV    | data may      |                         | associated with   |
| Inf    | indicate that | -Appropriate time       | cervical          |
| ection | persistent    | interval between        | adenocarcinoma.   |
|        | HPV infection | positive HPV DNA test   |                   |
|        | is a better   | results not defined.    | -Type 18          |
|        | predictor of  |                         | infections may be |
|        | high-grade    | -See bullets in above   | fundamentally     |
|        | lesions than  | grid.                   | different from    |
|        | a single      |                         | Type 16           |
|        | positive      |                         | infections.       |
|        | finding.      |                         |                   |
|        |               |                         | -May be           |
|        |               |                         | insufficient data |
|        |               |                         | to conclude       |
|        |               |                         | anything about    |
|        |               |                         | HPV 18.           |
+--------+---------------+-------------------------+-------------------+
| LSIL   |               | -Most LSIL resolves.    | -LSIL cytology    |
| cy     |               |                         | (or ASC) is not   |
| tology |               | -See above regarding    | sufficient for    |
|        |               | non-responders to       | therapy.          |
| with   |               | vaccine.                |                   |
| H      |               |                         | -Need biopsy      |
| PV^\*^ |               |                         | result for        |
|        |               |                         | therapy in US.    |
+--------+---------------+-------------------------+-------------------+
| CIN 1  | -Pathologic   | -About half of CIN 1    | -C                |
| (b     | diagnosis,    | regresses.              | ost-effectiveness |
| iopsy) | based on      |                         | cannot be used as |
| with   | tissue,       | -Risk of progression to | basis for FDA     |
| H      | needed for    | invasive cancer is low, | regulatory        |
| PV^\*^ | therapy.      | at least over the       | decisions.        |
|        |               | short-term.             |                   |
|        | -Prevention   |                         |                   |
|        | of CIN        |                         |                   |
|        | implies       |                         |                   |
|        | prevention of |                         |                   |
|        | a procedure   |                         |                   |
|        | (biopsy).     |                         |                   |
+--------+---------------+-------------------------+-------------------+
| HSIL   | -High         | -HSIL cytology would be |                   |
| cy     | predictive    | worked up by colposcopy |                   |
| tology | value for a   | and biopsy, so          |                   |
| with   | high-grade    | definitive pathologic   |                   |
| H      | histology     | diagnosis expected      |                   |
| PV^\*^ | lesion.       | anyway.                 |                   |
+--------+---------------+-------------------------+-------------------+
| CIN2/3 | -Most         | -Studies could take     | -Would probably   |
| (b     | proximal      | several years to        | address any       |
| iopsy) | endpoint to   | conduct and would be    | issues about      |
| with   | cervical      | resource intensive.     | vaccine           |
| H      | cancer.       |                         | alteration of HPV |
| PV^\*^ |               |                         | natural history.  |
|        | -Always       |                         |                   |
|        | merits        |                         |                   |
|        | treatment in  |                         |                   |
|        | US.           |                         |                   |
+--------+---------------+-------------------------+-------------------+
| Ce     | -Definitive   | -View of conducting     | -Would give best  |
| rvical | endpoint.     | studies in less         | understanding of  |
|        |               | developed countries     | impact on         |
| cancer |               | without screening       | adenocarcinoma,   |
| with   |               | programs is unclear.    | an increasing     |
| H      |               |                         | proportion of     |
| PV^\*^ |               | -Feasibility unclear    | cervical cancer   |
|        |               | for both developed and  | in developed      |
|        |               | developing countries.   | countries.        |
+--------+---------------+-------------------------+-------------------+

**\*** HPV testing would be used to assign the finding as vaccine
serotype or not.

**References**

ALTS Group. Human papillomavirus testing for triage of women with
cytologic evidence of low-grade squamous intraepithelial lesions:
baseline data from a randomized trial. The Atypical Squamous Cells of
Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions
Triage Study (ALTS) Group.

[J Natl Cancer Inst]{.underline} 2000;92:397-402.

ASCCP (1) Clinical Management of LSIL (draft). Consensus Conference on
Cytological Abnormalities and Cervical Cancer Precursors. September 6-9,
2001, Bethesda, MD.
[http://consensus.asccp.org/guidelines.asp]{.underline}

Franco EL, Villa LL, Sobrinho JP, Prado JM, Rousseau MC, Desy M, Rohan
TE. Epidemiology of acquisition and clearance of cervical human
papillomavirus infection in women from a high-risk area for cervical
cancer. [J Infect Dis]{.underline} 1999;180:1415-23.

Ho GYF, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural History of
Cervicovaginal Papillomavirus Infection in Young Women.

[N Engl J Med]{.underline} 1998;338:423-8.

Jones BA, Davey DD. Quality management in gynecologic cytology using
interlaboratory comparison. [Arch Pathol Lab Med]{.underline}
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Kinney WK, Manos MM, Hurley LB, Ransley JE. Where's the high-grade
cervical neoplasia? The importance of minimally abnormal Papanicolaou
diagnoses.

[Obstet Gynecol]{.underline} 1998;91:973--976.

Koutsky LA, Holmes KK, Critchlow CW, Stevens CE, Paavonen J, Beckmann
AM, DeRouen TA, Galloway DA, Vernon D, Kiviat NB. A cohort study of the
risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to
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Lehtinen M, Kibur M, Luostarinen T, Anttila A, Pukkala E. Prospects for
phase III-IV HPV vaccination trials in the Nordic countries and in
Estonia.

[J Clin Virol]{.underline} 2000;19:113-22.

Lonky NM, Sadeghi M, Tsadik GW, Petitti D. The clinical significance of
the poor correlation of cervical dysplasia and cervical malignancy with
referral cytologic results. [Am J Obstet Gynecol]{.underline}
1999;181:560-6.

Östör AG. Natural history of cervical intraepithelial neoplasia: a
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Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of
adenocarcinoma relative to squamous cell carcinoma of the uterine cervix
in the United States\--a 24-year population-based study. [Gynecol
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management strategies for patients with atypical squamous cells of
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[J Natl Cancer Inst]{.underline} 2001;93:293-9.

Stubenrauch F, Laimins LA. Human papillomavirus life cycle: active and
latent phases. [Semin Cancer Biol]{.underline} 1999;9:379-86.

Thomas KK, Hughes JP, Kuypers JM, Kiviat NB, Lee SK, Adam DE, Koutsky
LA. Concurrent and sequential acquisition of different genital human
papillomavirus types. [Journal of Infectious Diseases]{.underline}
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Woodman CB, Collins S, Winter H, Bailey A, Ellis J, Prior P, Yates M,
Rollason TP, Young LS. Natural history of cervical human papillomavirus
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Ylitalo N, Sorensen P, Josefsson AM, Magnusson PK, Andersen PK, Ponten
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human papilloma virus 16 and risk of cervical carcinoma *in situ*: A
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Ylitalo N, Josefsson A, Melbye M, Sorensen P, Frisch M, Andersen PK,
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[^1]: **This is one of two FDA documents. Please refer to the other FDA
    document (#2) for more background information on HPV, cervical
    intraepithelial neoplasia (CIN) and cervical cancer.**

    **^2^ The meeting is only addressing preventive HPV vaccines.**

    **^3^ Summary table in this document, located immediately before
    references, may help to orient the reader.**