FDA Panel: HPV DNA Test Before Pap for Cervical Cancer Screening

Troy Brown, RN

March 13, 2014

A US Food and Drug Administration (FDA) advisory committee unanimously recommended March 12 premarketing approval for the cobas human papillomavirus (HPV) test (Roche) for primary cervical cancer screening of women aged 25 years or older.

The Microbiology Devices Panel of the Medical Devices Advisory Committee voted 13 to 0 that the DNA test is safe and effective and that the benefits outweigh the risks for this indication.

The recommended indication is for first-line primary cervical screening to detect high-risk HPV, including genotyping for genotypes 16 and 18, according to an FDA briefing. "Women who test negative for high-risk HPV types...should be followed-up in accordance with the physician's assessment of screening and medical history, other risk factors, and professional guidelines. Women who test positive for HPV genotypes 16 and/or 18 by the cobas HPV Test should be referred to colposcopy. Women who test high risk HPV positive and 16/18 negative by the cobas HPV Test (12 Other [high-risk] HPV positive) should be evaluated by cervical cytology to determine the need for referral to colposcopy."

The cobas HPV test is currently FDA-approved for use along with cervical cytology in women aged 30 years and older to screen for the presence or absence of high-risk HPV types, including genotypes 16 and 18. It is also used as a follow-up test in patients aged 21 years and older with abnormal cytology results. This information, together with the physician's assessment of cytology history, other risk factors, and professional guidelines, may be used to guide patient management.

The cobas HPV test is a qualitative in vitro test that amplifies target DNA by polymerase chain reaction and nucleic acid hybridization to specifically detect and identify HPV types 16 and 18 while concurrently detecting the 12 high-risk types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).

Cervical cytology (Papanicolaou test, or pap) has traditionally been the primary screening method for cervical cancer, but because HPV causes most cervical cancers, cytology testing is now done on all women, and HPV testing is done on some of those women according to their age and cytology results.

"This gives us the opportunity to use what we've learned in the science over the last 2 decades, and improve it, and hopefully there will be further improvements to the technology to molecular diagnoses," voting committee member Robert Burk, MD, professor of obstetrics and gynecology and women's health (gynecological oncology) at Albert Einstein College of Medicine, Bronx, New York, said.

More Sensitive Than Cytology

The committee's vote followed a discussion of data from a prospective cohort study of 47,208 women in which both the cobas HPV test (candidate) and cytology (comparator) were performed at baseline. A cervical sample from each participant was tested with the cobas HPV test, as well as an investigational-use-only high-risk HPV test and an investigational-use-only HPV genotyping test. Thereafter, disease evaluation was conducted in the same manner for all those who had either abnormal cytology or positive cobas HPV test results and for a randomly assigned subset of patients with high-risk HPV negative and normal cytology results.

The candidate was also tested against the currently recommended cervical cancer screening algorithm, which includes cytology testing on all women and HPV testing on a subset of women according to their age and cytology results.

The sensitivity for cervical intraepithelial neoplasia grade 3 or higher (≥CIN3) was 58.26% (95% confidence interval [CI], 44.02% - 74.37%) for the candidate and 42.63% (95% CI, 31.75% - 55.41%) for the comparator.

The risk for ≥CIN3 (positive predictive value) in women referred to colposcopy in the candidate group was 12.25% (95% CI, 10.69% - 13.91%) compared with 6.47% (95% CI, 5.54% - 7.50%) for those referred in the comparator group.

The risk for ≥CIN3 in those who were not referred to colposcopy by the candidate algorithm (1-negative predictive value) was 0.42% (95% CI, 0.20% - 0.74%), and the risk was 0.59% (95% CI, 0.36% - 0.92%) among those not referred by the comparator.

The false-positive rate (1-specificity) for ≥CIN3 for the candidate was 4.09% (95% CI, 3.89% - 4.28%), and the rate was 6.04% (95% CI, 5.81% - 6.27%) for the comparator.

Education of Providers, Patients Important

Some members were concerned that the test may not be used as intended and may lead to unnecessary colposcopies.

"I'm concerned that potentially, all of those women with the other high-risk positivities will not go to having pap next but...will go to colposcopy, and that will magnify the potential morbidities of colposcopy," voting committee member Paula Hillard, MD, from the Department of Obstetrics and Gynecology at Stanford University School of Medicine in California, said.

"The clinicians of the United States, and probably the rest of the world, now have 3 options for screening women — 3 very different options that have very potentially different intervals, different triage trees," temporary voting member Alan G. Waxman, MD, MPH, professor of obstetrics and gynecology at the University of New Mexico School of Medicine in Albuquerque, said. "The challenge is now there for professional societies...to put together data-driven evidence-based algorithms to the extent that there is data, and then go forward with robust education for providers and for patients."

The voting advisory committee members have disclosed no relevant financial relationships.


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