March 12, 2014
by Dr. Anna E. Mazzucco
My name is Dr. Anna Mazzucco, and I thank you for the opportunity to speak today on behalf of the Cancer Prevention and Treatment Fund. After completing my Ph.D. in Cell Biology at HarvardMedicalSchool, I conducted research at the National Cancer Institute. Those are the perspectives I bring today. Our organization does not accept funding from medical device companies, and therefore I have no conflicts of interest.
The question today is whether HPV tests should be the first-line screening tool for cervical cancer. This would be a significant departure from current recommendations of the CDC and US Preventive Services Task Force as well as ACOG, ACS and AAFP.
Currently, HPV tests are recommended ONLY for co-testing with a Pap smear and only for patients 30 and older. Those recommendations are based on clear evidence as well as common sense because we all know that HPV usually goes away by itself, and encouraging colposcopies for young women based on HPV tests, if those women are sexually active with multiple partners, would result in a lot of unnecessary, invasive treatment with no real benefit.
What is the sponsor’s proposal based on? In their study, the comparator arm triaged ALL abnormal cytology ASC-US or higher with immediate colposcopy. That does NOT reflect current practice. 6% of all women in the trial had abnormal cytology at baseline, so this strange clinical trial design resulted in an artificially high colposcopy rate in the comparator arms.
Manipulating the control arms in that way made it seem that the proposed indication didn’t increase the percentage of colposcopies. But, we can’t trust that result because of the FLAW in the research design.
We have other concerns as well:
- Current, the Roche cobas test is approved to use the same sample vial as the Pap test. As FDA points out, this cytology is also used to diagnose candida and trichomonas infections, herpes viral changes, atypical repair, and abnormal endometrial cells. The HPV test can’t identify ANY of those. Therefore, eliminating the Pap smear every 3 years would result in losing that important information which is currently easily obtained from the same Pap smear sample at little additional cost. This will put women at risk.
- Most cervical cancers occur in women who have never been screened or were not screened in the last five years. What is needed is to increase patient compliance with screening. The sponsor does not provide any evidence that HPV testing will increase patient compliance. On the contrary, the sponsor’s plan, based on the trial population, would result in 7% of women ages 25 to 29 undergoing immediate colposcopy, which is more expensive AND more unpleasant than a Pap smear. This is likely to reduce the chances of patients undergoing screening. In this trial, for example, 14% of the patients were lost from the baseline colposcopy.
- Colposcopy often results in biopsy, which can result in subfertility, pre-term labor, and perinatal death. These are risks that are unnecessary but directly result from the sponsor’s plan.
- The sponsor states that “Current U.S. screening guidelines already consider both cytology and HPV 16/18 genotyping to be established approaches to determining which HPV positive women require colposcopy”. That is very misleading. In fact, the US Preventive Services Task Force gives a “D” rating for HPV testing in women under age 30 because the risks outweigh the benefits, as shown in previous clinical trials.
- The sponsor compares their proposed indication to other algorithms, but only relative to detection of CIN2 orCIN3. Per10,000 women, the Candidate arm only detected 15 more cases >= CIN3, and 3 more cases of CIN2. The vast majority of women will never develop CIN2 or CIN3, and CIN2 usually spontaneously goes away within 2 years. These small benefits do not outweigh the risks of less screening compliance, pre-term labor, compromised fertility, and perinatal death.
- The Comparator arm triages all cytology of ASC-US or greater with immediate colposcopy. As the FDA noted, this is no longer current clinical practice. The 2012 ASCCP guidelines recommend either repeat cytology in one year, or HPV testing, with only a positive result leading to colposcopy. Similar observations can be made about the alternative comparator arms. 2012 ASCCP guidelines support a 1 year repeat of co-testing ONLY for women 30 or older who are cytology negative but HPV positive before recommending colposcopy. USPSTF currently only sanctions co-testing for women over 30 who wish to lengthen the screening interval from 3 to 5 years, it does not explicitly prefer co-testing. In order to accurately weight risks and benefits, we must have a comparator arm which represents current clinical practice and guidelines.
- Of the patients in this clinical trial, 99% had not received the HPV vaccine, and the median age was 41, with one-third post-menopausal. Only 6,654 women were between the ages of 25 and 29. The proposed new indication would pose the greatest risks to young women who hope to have children, so they would need to be studied MUCH more carefully than the sponsor has done.
One last point: the sponsors identify economic and clinical complexities of performing two tests instead of one to justify elimination of cytology. Economic considerations are outside of today’s considerations, but even if they were, HPV tests cost much more than cytology. The clinical challenge of dealing with more information, rather than less, is also irrelevant, since the sponsor’s proposal would still often rely in colposcopy and cytology results as well as HPV results for clinical decision-making.
Moreover, to prevent cervical cancer while preserving young women’s ability to have children, we should not be seeking less information, we should be seeking more information.
The data presented today are too discordant with current clinical practice and cannot be used to justify such sweeping change. This proposed indication represents a radical shift in clinical practice which would affect millions of women for most of their adult lives. These proposed indications also encroach on clinical practice, and FDA cannot “establish or recommend guidelines for medical practice.”
We urge the committee to consider the risks to young women and reject the proposed indication.