SaneVax Letter to Dr. Margaret Hamburg, FDA Commissioner

April 22, 2011

Dear Dr. Hamburg:

I have just read a press release issued by Roche announcing the FDA approval of its cobas HPV Test. The press release states “The cobas HPV Test is the only FDA-approved cervical cancer screening test that allows HPV 16 and 18 genotyping concurrently with high-risk HPV testing.”

It is disturbing that the FDA has approved this class III cancer screening test without an open Advisory committee meeting. As a result, the public does not know what safety and efficacy data was submitted to the FDA in Roche’s PMA application. I assume the pivotal data for the application are contained in the following publication by Stoler et al.

Stoler MH, Wright TC Jr, Sharma A, Apple R, Gutekunst K, Wright TL; ATHENA (Addressing THE Need for Advanced HPV Diagnostics) HPV Study Group. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol. 2011 Mar;135(3):468-75.

If my assumption is correct, the approval of the cobas HPV Test for HPV 16 and 18 genotyping is contrary to the FDA Draft Guidance for Industry and FDA Staff – Establishing the Performance Characteristics of In Vitro Diagnostic Devices for the Detection or Detection and Differentiation of Human Papillomaviruses, a document issued on, September 9, 2009. This document contains the following important statements:

(1) HPV vaccination and study populations 

Due to the likelihood of an increase in the number of HPV vaccinated individuals in the United States over the coming years, the most clinically relevant HPV genotypes are expected to shift over time. For this reason, you should consider including in your analytical evaluations (precision, carryover, stability, etc.), one of the most clinically relevant non-vaccine targeted HPV genotypes (such as HPV 45 or 31) in addition to HPV genotypes targeted by any current FDA licensed vaccine(s).

(2)Evaluation of HPV detection in clinical dataset 

We recommend that you provide an evaluation of your device’s ability to detect the targeted HPV genotypes in your clinical dataset. One way to do this is to perform an FDA-approved HPV test that detects the same genotypes as your test, or you may perform PCR plus sequencing (PCR/Sequencing) on your clinical specimens and compare these results to the results of your device. Use of a composite HPV comparator that incorporates both FDA-approved HPV test(s) and/or PCR/Sequencing is also an option…….A comparison against PCR followed by sequencing of the amplicon is especially important for HPV genotyping assays to establish that the correct HPV genotype has been identified by your device.

Since the cobas HPV Test for HPV 16 and 18 genotyping has not been validated by an FDA-approved genotyping HPV test, or by PCR plus sequencing, this test will be potentially misused as a valid HPV genotyping method for vaccination monitoring.

Therefore, the SaneVax Team hereby respectfully requests that the FDA rescind its approval of the cobas HPV Test for HPV 16 and 18 genotyping for safe and effective HPV vaccination, until such time as validation occurs.

We also object to the approval of this HPV Test as a cervical cancer screening device because the published data do not support such a claim. The data only deal with the presence or absence of HPV in ASCUS patients and their correlation with CIN2 and CIN3 lesions.

The positive predictive value (ppv) of this cancer test for CIN3 (8.4%) was reported to be lower than the ppv for CIN2 lesions (14.0%). We all know a CIN3 lesion is more cancer-like than a CIN2 lesion. It is highly disturbing to learn that a ‘cancer test’ approved by the FDA appears to lose its positive predictive value as a precancerous lesion progresses to a more severe stage closer to cancer.

With all due respect, according to the information above, this test appears to be nothing more than an HPV detection test for use in precancerous lesions, which quite frequently reverse on their own without proceeding to the development of cancer. The declining positive predictive value hardly inspires confidence in a ‘cancer screening’ test.