FDA Reply Letter - and Further Questions Raised on Gardasil Reply questions are highlighted and in parentheses
Dear Dr. XXXXXX
Thank you for your inquiry to Ms. Mary Malarkey, Director of the Office of Compliance and Biologics Quality (OCBQ) concerning Gardasil. Your inquiry was forwarded to the Office of Communications, Outreach, and Development (OCOD) within the Center for Biologics Evaluation and Research (CBER) for reply. CBER, one of seven centers within the United States Food and Drug Administration (FDA), is responsible for the regulation of biologically-derived products, including vaccines, blood intended for transfusion, blood components and derivatives, allergenic extracts, and cell, tissue and gene therapy products.
In your email, you express concerns regarding the effectiveness and safety of Gardasil to prevent cervical cancer and whether there is potential increased risk for HPV infections with non-vaccine HPV types. These concerns are addressed below.
Determination of Safety and Effectiveness from Clinical Trials
FDA evaluated the safety and efficacy of Gardasil, which was studied in approximately 21,000 girls and women. Approximately half of the study participants received the vaccine, and the other half received a control product for comparison. (This ‘control’ solution was AAHS, a proprietary adjuvant created by Merck which has not been independently evaluated for safety. The only thing demonstrated by using this as a control solution is that the vaccine is no more dangerous, or safe, than the adjuvant. The only trial that used saline as a control, was not independently evaluated – the results were added into the other trials, thereby masking any potential safety difference that could have appeared. (See VRBPAC document submitted prior to approval.)These studies showed that in women with no evidence of prior infection with HPV types 6, 11, 16 or 18, the vaccine is highly effective in preventing precancerous lesions of the cervix, vagina, and vulva, as well as genital warts caused by the HPV types contained in the vaccine.
The clinical endpoints used to assess efficacy in the pre-licensure studies were discussed at the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) in November 2001. The committee, which included experts in infectious diseases, gynecologic cancer, and gynecologic pathology, considered a range of possible endpoints for clinical trials of HPV vaccines. The committee advised FDA that a primary endpoint that included cervical intraepithelial neoplasia of grade 2 or worse (CIN 2/3), adenocarcinoma in situ (AIS), or cervical cancer by histology (and virology studies to "type" the HPV virus) was appropriate to demonstrate efficacy of the HPV vaccine, and that prevention of these conditions would support an indication of cervical cancer prevention.
CIN2 is an identification of cervical dysplasia, which is a necessary precursor for cervical cancer. In current clinical practice in the United States, treatment is required for all CIN2 lesions to prevent progression to cancer. Since this is the standard of care for this lesion, it is not ethical to delay treatment until a person develops CIN3. (Incident infection with HPV does not carry the same risk of leading to cervical cancer as does development of CIN 3. Since progression to cervical carcinoma in situ (CIS) only occurs in approximately 22% of CIN2 cases, and progression to invasive cancer occurs in approximately 5% in CIN2 cases and at about 12% in CIN3 cases, using CIN2/3 as clinical endpoints artificially inflates the supposed efficacy of the vaccine – because 78% of the CIN2 as well as many CIN3 diagnoses would never have progressed to cancer in the first place. (See http://www.lwwoncology.com/Textbook/Content.aspx?aid=8258935 – Principles and Practice of Gynecologic Oncology; Chapter 19: Pathogenesis and Diagnosis of Invasive Lesions of the Lower Enital Tract.)
By preventing the most common HPV types (Where are the studies proving that HPV 16/18 are the most prevalent high-risk types prevalent in the general population of the United States?) causing CIN2/3 cervical lesions, an effective HPV vaccine would substantially reduce health care utilization for follow-up of abnormal PAP screening and surgical treatment to remove abnormal and precancerous cervical tissue. For these reasons, prevention of CIN2/3 provides a rigorous demonstration of vaccine efficacy and clear benefit to the individual and to public health. Evaluation of more advanced cervical disease would be extremely difficult in clinical studies for ethical reasons and because current screening and treatment practices are generally effective in preventing cancer. (If current practices are ‘generally effective’ how is a vaccine cost-justified when it does not eliminate the need for those current practices that are already in place and functioning well? (See the package insert) Detailed analyses of efficacy endpoints were conducted in the clinical review of Gardasil. This information is available on FDA’s website at: http://www.facebook.com/l/NAQFTcx6QAQE0Y015snwUEFLZWjiMmAcV0zNGvYq1oLMPbw/www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm216352.htm.
Studies since the approval to further assess the efficacy of Gardasil are either underway or completed by the manufacturer, Merck and Co., Inc. One such completed study report submitted to FDA for evaluation has shown that the efficacy of Gardasil persists for at least five years following vaccination. In combined analyses of two end-of-study reports, prevention of HPV 16 and HPV 18 related VIN2/3 and VaIN 2/3. (Same inflated efficacy as stated above for the same reasons. In addition, the Athena study provided some evidence of HPV type replacement in subjects after vaccination, not to mention an extremely low efficacy rate. See Athena study, table 3 here - http://www.ncbi.nlm.nih.gov/pubmed/21944226. This table shows HPV vaccination was found to reduce HPV-16 infections a mere 0.6% in vaccinated women versus unvaccinated women. At the same time, other high-risk (carcinogenic) HPV infections were diagnosed in vaccinated women 2.6% to 6.2% more frequently than in the unvaccinated women. The increased rate of infections caused by carcinogenic HPV types other than those targeted by Gardasil® in vaccinated women is 4 to 10 times higher than the reduction in HPV 16/18 infections. A 0.6% reduction in HPV 16 infections is NOT a ‘statistically significant’ outcome in anyone’s book.) In analyses of subjects regardless of prior HPV exposure, efficacy was positive (statistically significant) for prevention of CIN2/3 regardless of HPV type. These data demonstrate that non-vaccine HPV-related CIN2/3 does not outweigh the benefit from prevention of HPV 16 and HPV 18 CIN2/3.
FDA-approved vaccines are held to the highest safety standards; however, there is the potential for side effects associated with medical products. (Every medication ever pulled from the market was first approved as safe and effective by the FDA. This does not lend a lot of confidence in your so-called ‘highest safety standards’ – perhaps the bar needs to be raised.) FDA weighs recognized risks against anticipated benefits when licensing (approving) vaccines; this assessment then continues after licensure as more data become available about less common possible side effects that could not be detected in the clinical trials before licensure. (Is it a faulty analysis of risks versus benefits that allows HPV vaccines to remain on the market when the incidence of severe adverse reactions is higher than the risk of cervical cancer? This is particularly disturbing when the only public accessible denominator for judging reactions against HPV vaccine doses is the number of distributed doses – NOT – administered doses. Who knows how many of these ‘distributed doses’ are in storage at any given moment?)
Many adverse events will occur coincidentally after receipt of a vaccine, so when evaluating whether an adverse event might be caused by a vaccine, FDA uses several approaches. In clinical trials that are conducted in people to collect safety and effectiveness information before approval, FDA looks for differences that cannot be explained by chance in the number of people who experience an adverse event in the group receiving a vaccine compared to the group not receiving the vaccine. (Considering the fact that prior to Gardasil approval there was not an HPV vaccine on the market to compare against – there is no excuse for not using a real placebo to test safety and efficacy. Why did the FDA not demand such a test for medical consumer protection?) After a vaccine is approved for use in the United States, FDA and the Centers for Disease Control and Prevention (CDC) use the Vaccine Adverse Event Reporting System (VAERS) to look for new safety concerns which may emerge as many more individuals receive the vaccine. (One has to wonder why the high percentage of adverse event reports after HPV vaccines has not indicated a need for a ‘more in-depth analysis, particularly when one considers reporting to VAERS is voluntary and so under-utilized. The FDA can check their own VAERS percentages here – or SaneVax can certainly provide ours.)When patterns or clusters of reports are detected, more in-depth analyses are performed using the FDA’s Post-licensure Rapid Immunization Safety Monitoring (PRISM) program and the CDC’s Vaccine Safety Datalink (VSD). The FDA’s Post-licensure Rapid Immunization Safety Monitoring (PRISM) program is part of the Agency’s Sentinel Initiative which has expanded the use of large health care databases to evaluate medical product safety. Information about PRISM can be found on FDA’s website at http://www.facebook.com/l/cAQHSwyGeAQFHpP-tkKiiW3iY5eQI_kiPgnof0MSZCQKuZQ/www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Post-MarketActivities/ucm196251.htm
VAERS, which is jointly managed by FDA and CDC, receives reports from vaccine manufacturers, private practitioners, state and local public health clinics, and vaccine patients themselves (or their parents or guardians). Spontaneous report-based surveillance programs, such as VAERS, perform a critical function by generating signals of potential problems that may warrant further investigation. Reports of adverse events are routinely reviewed by physicians and vaccine safety staff at FDA and CDC. VAERS is especially valuable in assessing the safety of new vaccines as post-licensure use begins. Careful review of reports (One has to wonder about this supposed ‘careful review’ when said reviews do not include talking to the parents of those whose children were included in the unexplained deaths statistic. Reference news video – here -http://www.youtube.com/watch?v=mqZNhOclixc&feature=youtu.be&t=2s– also referenced in this article - http://sanevax.org/how-to-create-a-vaccine-safety-advocate/ ) during the initial months following licensure can help to uncover previously unexpected risks which only come to light when a vaccine is used in a larger and more diverse population than had been studied in clinical trials.
An important limitation of VAERS is that most reports only describe suspected side effects that followed vaccinations. These anecdotal case reports usually cannot support a conclusion that the vaccine actually caused the adverse event. No "control group" exists in VAERS, because the same kinds of adverse events occur in unvaccinated individuals but are not reported to VAERS. Without an unvaccinated comparison group it is usually not possible to assess whether the number of reported events is different from the number that would have been observed in the absence of vaccination. Therefore, VAERS is an important warning system, but usually safety concerns from VAERS remain hypotheses until further study can evaluate how often the adverse events occur in vaccinated compared to unvaccinated people.
Response to your questions regarding the ATHENA Trial and specific VAERS data
We have reviewed the publication cited in your email by Wright et al., The ATHENA human papillomavirus study: design, methods, and baseline results, published in the American Journal of Obstetrics and Gynecology in January 2012. The purpose of this study was to provide a baseline dataset from a group of 46,887 eligible women to inform the development of HPV diagnostics. It did not have the objective of determining the effectiveness of Gardasil. Notably, only 10% of women 21 to 29 years of age (comprising 2.6% of the overall population) had previously been vaccinated against human papillomavirus. It is therefore inappropriate to draw conclusions about the effectiveness of Gardasil from this study.
In your email, you also highlighted a table describing counts of VAERS reports about abnormal Pap smears, cervical dysplasia, and cervical cancer. As noted above, VAERS is a passive reporting system, so the rate of reporting of a particular outcome can be affected by a host of factors (e.g., media reports, general awareness about HPV, etc.). Because of these factors, the rate of reporting on a specific outcome frequently varies from year to year without any link to the true incidence of the outcome. Therefore, it is not possible to link the changes in reporting of cervical dysplasia to vaccination with Gardasil.
HPV is the most common sexually transmitted infection in the US with 6 million new infections each year, 74% of which occur among persons aged 15 – 24 years. Cervical dysplasia and abnormal pap smears are potential outcomes from HPV infection, although many infections result in no symptoms at all. HPV is acquired through sexual activity, which can begin in early adolescence: 24% of 15 year olds are sexually active, and this increases to 40% of 16 year olds and 70% of 18 year olds. Although Gardasil vaccination is effective at preventing new infections by multiple HPV types associated with cervical dysplasia and cervical cancer, Gardasil cannot cure pre-existing infections. (Then explain why there is no required HPV testing prior to vaccination so that those who will not benefit are eliminated from vaccination?) Many of the VAERS reports with cervical dysplasia describe girls and women who were vaccinated late in adolescence and early adulthood and most likely represent clinical outcomes of prior infection, acquired before vaccination. (Even though it normally takes 15-20 years for said progression from infection to occur? Come on, who are you kidding?) For this reason, the CDC recommends routine administration at age 11 to 12 years to maximize the effectiveness of the HPV vaccination.
Finally, some of these reports might represent infection with serotypes not covered by the vaccine. (Particularly since no studies were conducted prior to approval to determine the most prevalent serotypeds in the general US population.) Gardasil covers sertoypes 16 and 18, which account for 68% of squamous cell cervical cancers in the US, but other high risk serotypes can also infect patients. (Please provide documentation for this statement.) Gardasil’s label emphasizes that all women vaccinated with Gardasil should continue to undergo routine cervical cancer screening as vaccination does not protect against all forms of cervical cancer. (So, where is the benefit? Routine gynecological care has virtually eliminated the threat of invasive cervical cancer in most developed countries. The public health funds spent on Gardasil would have been much better utilized reaching those subsets of the population who do not currently have good OB/GYN care.) In the absence of systematically obtained data, it is impossible to make any inference about the prevalence of these other high risk serotypes from this passive reporting system. (What is being done to ‘systematically’ obtain this necessary data? Has not the emergence of MRSA been enough of a lesson for those in charge of the public health and safety at the FDA?)
In summary, the scientific data available to the FDA support the continued use of Gardasil as a safe and effective vaccine and we continue to find that its benefits outweigh its risks. (If you truly believe this to be true, you are simply not looking at the facts.) Additional information regarding the safety of Gardasil can be found on both the FDA and CDC websites at