June 12, 2011
Dear Dr. Markowitz:
I am writing to you as a concerned physician and a former researcher at the National Institute of Health (NIH). As we all know, Gardasil is a vaccine approved for prevention of cervical cancer caused by two specific HPV genotypes under the Fast Track Drug Development Programs. The Guidance for Industry, Fast Track Drug Development Programs-Designation, Development, and Application Review stipulates:
“Where an accelerated approval is based upon a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity, postmarketing studies are ordinarily required “to verify and describe the drug’s clinical benefit and to resolve remaining uncertainty as to the relation of the surrogate endpoint upon which approval was based to clinical benefit, or the observed clinical benefit to ultimate outcome” (57 FR 58942, December 11, 1992).”
We wholeheartedly agree with your statement on HPV vaccines that, ”Post-licensure evaluation of vaccines plays an important role in monitoring the progress of immunization programs, demonstrating population impact of vaccines, and providing data for ongoing policy decisions.”  A vaccine without a science-based post-licensure monitoring system to evaluate its impact on the population should not be allowed to be marketed to the consumers.
The currently available HPV vaccines, Gardasil and Cervarix, are designed to prevent infection by two genotypes of HPV that may cause cell changes, which if persistent and not properly treated may lead to cervical cancer in 10-30 years. Therefore, we also agree with you that “ it will take decades before the impact of vaccine on cervical cancer is observed. More proximal measures of vaccine impact include outcomes such as prevalence of HPV vaccine types, incidence of cervical precancers and genital warts.” 
Monitoring the prevalence of HPV vaccine types is the most practical meaningful approach to analyze the impact of HPV vaccines, including Gardasil because cervical precancer CIN2 and CIN3 lesions are not irreversible morbidity even though these cellular changes were used as the surrogate endpoint in the clinical trials for evaluation of Gardasil as a vaccine for prevention of cervical cancer. Prevention of genital warts has never been the purpose for developing HPV vaccines.
However, we are disappointed to find no provision for implementation of an effective system to survey the prevalence of HPV vaccine types in your monitoring report . The only relevant statement in the report – “Some states, such as Florida and Connecticut have made some HPV-related outcomes reportable…” seems to be just a token gesture concealing the lack of CDC efforts to formulate a meaningful post-licensure surveying system.
One suspects the reason the CDC has delayed a genuine monitoring system is that it does not want to introduce a reliable DNA-sequencing-based HPV genotyping method for post-licensure monitoring. HPV DNA sequencing may reveal many post-vaccinated women are actually developing cervical precancerous lesions and cervical cancer caused by vaccine-relevant HPV genotypes which may include HPV-16, HPV-18, HPV-31 and HPV-45. This would be a fact the vaccine manufacturer, the CDC, the FDA and the NCI would not want to face.
On record, the CDC , FDA , NCI  and the standard textbooks [5, 6] all recognize that DNA sequencing is the gold standard for HPV genotyping beyond a reasonable doubt.
As an informed physician, I have learned that the DNA sequencing technology is not too complex or too expensive for HPV genotyping in order to ensure safe and effective vaccination. In the very CDC report authored by you and your associates , a quoted reference states:
“… HIV genotype DNA sequence has been made reportable as part of a Centers for Disease Control and Prevention-funded multistate surveillance system to monitor trends in HIV drug resistance.”
This document confirms that the CDC has made HIV genotype DNA sequence in electronic file reportable to monitor trends in HIV drug resistance.
Cervical cancer initiated by persistent infection of certain genotypes of HPV is at least as life-threatening as infection by drug resistant HIV. For this very reason, the FDA approved the HPV vaccines under the fast track drug programs and allows the vaccines to continue to be marketed in spite of its potential serious harmful side effects to the consumers.
According to Section 112 Expediting Study and Approval of Fast Track Drugs of the Food and Drug Administration Modernization Act of 1997 cited in Appendix 1 of the Guidance for Industry, Fast Track Drug Development Programs-Designation, Development, and Application Review, under the provision EXPEDITED WITHDRAWAL OF APPROVAL, The Secretary (of HHS) may withdraw approval of a fast track product when a post-approval study of the fast track product fails to verify clinical benefit of the product.
Therefore, the CDC post-licensure surveys on the prevalence of HPV genotypes which cause cervical precancer or cancer among women who have already been immunized with the HPV vaccines plays a pivotal role in determining if the benefit of the vaccine outweighs its potential risk to medical consumers.
Based on available science and law, we hereby request that the CDC issue a directive to the vaccine manufacturers, vaccine distributors, state health departments and health care providers as follows:
“Any female patient who has been vaccinated with HPV vaccines who subsequently is diagnosed with Pap cytology results positive for cervical precancer or cancer, the electronic file diagnostic of the HPV genotype DNA sequence derived from the cervicovaginal cell suspension in the cytology sample is now reportable to the CDC.”
We believe this format of post-licensure surveys will not need any special funds from the government and require little effort to implement. The cost of continued post-vaccination cervical cancer screening is already part of the routine health care expense for all women. In this manner, the CDC will have the data for analyses to determine if Gardasil has indeed reduced the percentage of cervical precancers and cancers caused by the vaccine-targeted HPV genotypes.
Gardasil is known to be associated with high frequencies of anaphylactic reactions. It is estimated the rate of anaphylaxis reaction after Gardasil vaccination is 5 to 20 times higher than those identified in comparable school-based vaccination programs . Gardasil may also play a role in triggering orthostatic hypotension . Anaphylactic reactions or orthostatic hypotension may be the cause of syncope (fainting) commonly reported after Gardasil injections, and may lead to serious permanent disabilities or deaths as listed on the CDC record.
Therefore, we urge the CDC to institute a reliable science-based post-licensure monitoring system nationwide immediately to determine if the benefits of mass vaccination of young women against HPV infection for cervical cancer prevention in fact outweigh the risks of the vaccine.
Recently, the fast-track cancer drug Mylotarg was withdrawn after post-marketing studies raised new safety concerns and failed to confirm its effectiveness. Medical consumers need post-licensure survey data on Gardasil to be reassured that they are not receiving the risk of HPV vaccination for no confirmed benefits. Any drug approved via Fast-Track procedures using surrogate endpoints must be adequately and accurately monitored post-licensure – or not be marketed.
We are looking forward to receiving your response to this request.
Sincerely,William Reichel Affiliated Scholar Center for Clinical Bioethics Georgetown University School of Medicine
cc.Director of CDC- Thomas R. Frieden – email@example.com FDA commissioner – Margaret Hamburg – Margaret.Hamburg@fda.hhs.gov Secretary of HHS – Kathleen Sebelius – Kathleen.Sebelius@hhs.gov
 Markowitz LE, Hariri S, Unger ER, Saraiya M, Datta SD, Dunne EF. Post-licensure monitoring of HPV vaccine in the United States. Vaccine. 2010; 28:4731-7.
 Vernon SD, Unger ER, Williams D. Comparison of human papillomavirus detection and typing by cycle sequencing, line blotting, and hybrid capture. J Clin Microbiol 2000; 38:651-5.
 Reference Book
 Brotherton JM, Gold MS, Kemp AS, McIntyre PB, Burgess MA, Campbell-Lloyd S; New South Wales Health HPV Adverse Events Panel. Anaphylaxis following quadrivalent human papillomavirus vaccination. CMAJ. 2008;179:525-33.
 Mosnaim A, Abiola R, Wolf M, Perlmutter L. Etiology and risk factors for developing orthostatic hypotension. American Journal of Therapeutics. 2010; 17: 86-91.