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SaneVax Open Letter to Kathleen Sebelius, Secretary of Health and Human Services

January 31, 2012 By 12 Comments

31 January 2012, Open Letter

To:  Kathleen Sebelius, Secretary of Health and Human Services – Kathleen.Sebelius@hhs.gov

Subject: Rescind approval of Gardasil® due to lack of efficacy during post-licensure monitoring

Dear Ms. Sebelius:

The quadrivalent human papillomavirus (HPV) vaccine, Gardasil® was approved for marketing as a drug to prevent cervical cancer under the fast track drug development program despite the fact the proposed vaccine did not qualify to use this program under FDA regulations. Since it was ‘fast-tracked,’ the manufacturer was allowed to use self-reversible precancerous lesions as surrogate endpoints for the evaluation of its efficacy to potentially prevent cervical cancer 30-40 years down the road. As you know, Fast Track Drug Development Programs are governed by the following stipulation:

“Where an accelerated approval is based upon a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity, post-marketing 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).”

In compliance with the required post-marketing monitoring surveys, the CDC published the following guideline:

“While there are well established cancer registries in the United States, 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 pre-cancers and genital warts.” [1]

According to a recently published, industry-sponsored study conducted on 12,852 young women, HPV vaccination was found to reduce 0.6% of HPV-16 infections, while increasing the rate of other high-risk (carcinogenic) HPV infections among the vaccinated women by 2.6-6.2% compared to the non-vaccinated women. The latter increased rate of infections caused by carcinogenic HPVs other than HPV-16 and HPV-18 in vaccinated women is 4 to 10 times higher than the reduced rate in HPV-16 infection. [2]

In the interest of public health and safety, due to this demonstrated lack of efficacy among consumers during post-licensure monitoring that used CDC recommended ‘more proximal’ measures to monitor vaccine impact, we hereby request the Secretary take immediate action to rescind the approval of Gardasil® for marketing in the United States until additional post-licensure data is available to support the efficacy of this new drug.

Thank you for your kind attention to this matter.

Respectfully,
Norma Erickson, President
SANE Vax Inc.
 
Signed on behalf of the Board of Directors, SANE Vax, Inc.
Leslie Carol Botha, Vice President of Public Relations
Janny Stokvis, Vice President of Research
Rosemary Mathis, Vice President of Victim Support
Freda Birrell, Secretary
Linda Thompson, Treasurer

References

  1. 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.
  2. Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206:46.e1-46.e11. (See Table 3)
  3. Human papillomavirus (HPV) vaccine policy and evidence-based medicine:
    Are they at odds? Lucija Tomljenovic, Ph.D., Christopher A. Shaw,
    Ph.D., Annals of Medicine, Jan. 2011
Cc: Dr. Margaret Hamburg, FDA Director – margaret.hamburg@fda.hhs.gov
Dr. Lauri Markowitz, CDC Epidemiologist – lauri.markowitz@cdc.hhs.gov 
 
 
Filed Under: United States Concerns Tagged With: , , , ,

SANE Vax to FDA: Recombinant HPV DNA found in multiple samples of Gardasil

September 2, 2011 By 109 Comments

 
 
 
 
 The Honorable Margaret A. Hamburg, M.D., Commissioner
U. S. Food and Drug Administration (FDA)
10903 New Hampshire Ave.
Silver Spring MD 20993-0002August 29, 2011

Dear Dr. Hamburg:

At the request of medical consumers concerned about HPV vaccine safety and efficacy, SANE Vax Inc. has retained a private laboratory to test a number of samples of HPV 4 Gardasil™ (Merck) for possible contamination by human papillomavirus (HPV) DNA in the vaccine lots distributed to physicians.

The laboratory has informed SANE Vax Inc. that one hundred percent of thirteen (13) samples of Gardasil™ taken from lots  #1437Z, #1511Z, # 0553AA, #NL35360, #NP23400, #NN33070, #NL01490, #NM25110, #NL39620, #NK16180, #NK00140, #NM08120 and #NL13560, currently being  marketed in the U.S.A., Australia, New Zealand, Spain, France, and Poland have been found to be positive for HPV DNA.

One of the HPV DNA fragments detected in the vaccine is part of a synthetic construct (GenBank Locus SCU55993) for HPV11 major capsid protein L1 gene, a recombinant DNA genetically engineered specifically for manufacturing of the Gardasil vaccine. Its unique sequence is copied below for your reference.

Because one hundred percent of the samples tested were positive for HPV DNA contamination, SANE Vax Inc. requests the FDA investigate the extent of the HPV DNA contamination in the Gardasil HPV4 vaccine currently on the market and take appropriate actions to ensure public safety regarding future shipments.

The SANE Vax Inc. data, including the electropherograms of short target sequencing used to validate the HPV DNA detected in the thirteen (13) Gardasil samples, each with a different lot number, are available for your review, provided appropriate safeguards are in place to protect the proprietary processes and information utilized by our laboratory to test the samples.

Thank you for your immediate attention to this matter.

Respectfully, 
Norma Erickson, President SANE Vax Inc.
154 Cecil Drive
Troy MT 59935
 
Signed on behalf of the Board of Directors, SANE Vax, Inc.
Leslie Carol Botha, Vice President of Public Relations
Janny Stokvis, Vice President of Research
Rosemary Mathis, Vice President, Victim Support
Freda Birrell, Secretary
Linda Thompson, Treasurer
 

Read the response from the FDA here.

SANE Vax Inc. issued the following rebuttal to the FDA response:

 

 

 
 
To:  Mr. Walter J. Gardner (walter.gardner@fda.hhs.gov)
Re: Rebuttal to FDA response dated September 23, 2011 
14 October 2011 

Dear Mr. Gardner:

Thank you for taking time to respond to our September 2, 2011 letter addressed to Commissioner Hamburg, informing the FDA of our discovery of recombinant HPV DNA in Merck & Co.’s HPV 4 vaccine, Gardasil currently marketed worldwide.

Your response dated September 22, 2011 seems to indicate that the FDA is unaware of, or indifferent to the harms HPV vaccines have brought to medical consumers;  primarily adolescent girls, as documented in the VAERS reports. Do you know how many parents have lost their perfectly healthy young daughters and how many parents still have to deal with the hardship of caring for their physically disabled or mentally impaired daughters as a result of Gardasil vaccinations?

There are at least seven reports published in the peer-reviewed medical journals containing documented links between HPV vaccination and a class of newly recognized, probably immune-mediated inflammatory neurodegenerative disorders, also described under the name of acute disseminated encephalomyelitis (ADEM).[1-7] These inflammatory pathologies in the central nervous system may constitute a highly likely cause for the commonly reported seizures, physical and mental impairments or even deaths following Gardasil vaccinations.

Your response appears to show the FDA has definitively dismissed the aforementioned peer-reviewed articles and the possible link of the confirmed cases of ADEM to HPV vaccinations, a link that has been universally suggested by the authors of the science-based articles.

Contrary to your assertion, recombinant HPV DNA does not have to be able to infect cells, or to self-reproduce to cause or to trigger a disease. When adsorbed to cationic particles, [8, 9] including aluminum adjuvant, [10] the DNA molecules can be inserted into human cells via mechanisms only recently recognized as nonviral gene delivery to their targets.[11]

Chromosomal integration of foreign DNA may occur through poorly understood mechanisms [12, 13] with uncertain consequences.[14] Recombinant DNA molecules have long been recognized as potential biohazards.[15] Retention of residual recombinant DNA in protein-based vaccines has been a concern in the virology industry since the induction of cancer as a single-cell phenomenon.  It is well documented that a single functional unit of foreign DNA integrated into the host cell genome might serve to induce cell transformation as a single event or part of a series of multifactorial events. [16]

SANE Vax Inc. believes it is the FDA’s responsibility to conduct an investigation based on the new scientific information to protect public safety. We believe it is irresponsible of the FDA to simply declare ‘…the presence of residual DNA is not a safety factor’ without ‘due diligence’ and supportive data.

Unlike other vaccines against contagious childhood infectious diseases, and even if proven effective as claimed, HPV vaccination is targeting 9-12 year old children to prevent 70% of cervical cancers which may develop at an average age of 54 at the death rate of <3 to 6.7 per 100,000 women in various population groups in the United States[17]. Cervical cancer deaths are primarily the result of a lack of adequate gynecologic care.

For a vaccine to prevent a disease that may occur 40 years later, at a death rate of 3-6.7/100,000 – which may be further decreased by adequate and affordable gynecologic care, the risk to the vaccinated children should be zero to reap any benefits from said vaccination. As you are aware, all other childhood vaccines are used for public safety in the prevention of infectious diseases, not for a disease that may occur 40 years down the road in a finite demographic who have limited access to adequate gynecological care.

The members of SANE Vax and the thousands of parents whose daughters have suffered injuries or died after receiving Gardasil injections were shocked to learn for the first time that “Gardasil does contain recombinant HPV L1-specific DNA fragments,” as stated in your response on behalf of the FDA to our report of September 2, 2011.

Your statements, “The presence of these expected DNA fragments, which are inevitable in vaccine production; this DNA is not a contaminant; after purification of the vaccine, small quantities of residual recombinant HPV L1-specific DNA fragments remain in the vaccine; and Information concerning the presence of HPV DNA has never been in the U.S. labeling for Gardasil” seemed to play a semantics game when compared to the information data released to the consumers in public by the vaccine manufacturer with collaboration of the FDA and equivalent regulatory agencies in other countries.

Following are samples of some of the documents with relevant statements still available in the public domain:

1)      A briefing document submitted to the FDA for the Gardasil™ Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting held on May 18, 2006 attached to a letter signed by Patrick Brill-Edwards, MD, Director Worldwide Regulatory Affairs Vaccines/Biologics of Merck Research Laboratories dated April 19, 2006, made public and posted on the FDA website, clearly stated that the vaccine (sic) “…contains no viral DNA”.

2)      In another Gardasil® Supplemental Biologics Licensing Application for Use in Anal Cancer Prevention submitted as Briefing Document presented to the FDA VRBPAC on 17-Novemner-2010, it is again stated under 3.2 GARDASIL®- “The Quadrivalent HPV (Types 6, 11, 16, 18) Vaccine GARDASIL®is not a live virus vaccine; it contains no viral DNA, and is therefore incapable of causing infection.”

3)      In Submission Control No. 102682 to Health Canada by Merck Frosst Canada Ltd. GARDASIL™ – Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18), Recombinant Vaccine, Date 2007/03/16, it is stated “Gardasil™ contains HPV 6, 11, 16, and 18 L1 proteins in addition to the following excipients: amorphous aluminium hydroxyphosphate sulphate adjuvant, sodium chloride, L-histidine, polysorbate 80 (PS-80), sodium borate, and water for injection (WFI). The product contains no preservative or antibiotics. Gardasil™ is not a live virus vaccine. It contains no viral DNA and is not capable of causing infection. All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.”

4)      In United Kingdom, Sanofi Pasteur MSD Limited Summary of Product Characteristics last updated on the eMC: 26/08/2011 states that Gardasil is an adjuvanted non-infectious recombinant quadrivalent vaccine prepared from the highly purified virus-like particles (VLPs) of the major capsid L1 protein of HPV types 6, 11, 16 and 18. “The VLPs contain no viral DNA, they cannot infect cells, reproduce or cause disease.” http://www.medicines.org.uk/emc/document.aspx?documentid=19016

5)      In an Australian Public Assessment Report for Gardasil submitted by Merck Sharp & Dohme (Australia) Pty Ltd February 2011, it states that GARDASIL contains HPV 6, 11, 16 and 18 L1 VLPs. Each VLP is composed of a unique recombinant L1 major capsid protein for the respective HPV type. Because the virus-like particles contain no viral DNA, they cannot infect cells or reproduce. http://www.tga.gov.au/pdf/auspar/auspar-gardasil.pdf

6)      In New Zealand Ministry of Health Information for Health Professionals Data Sheet submitted by Merck Sharp & Dohme (NZ) Limited  on 29 April 2009, it states that GARDASIL contains HPV 6, 11, 16 and 18 L1 VLPs. Each VLP is composed of a unique recombinant L1 major capsid protein for the respective HPV type. Because the virus-like particles contain no viral DNA, they cannot infect cells or reproduce. …Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of borax, and water for injection.

7)      In the document issued April 2011 and titled as USPPI 9883616 Patient Information about GARDASIL®, the medical consumers are informed “The ingredients are proteins of HPV Types 6, 11, 16, and 18, amorphous aluminum hydroxyphosphate sulfate, yeast protein, sodium chloride, L-histidine, polysorbate 80, sodium borate, and water for injection.” There is no reference to DNA in the vaccine although yeast protein which is an adventitious substance is disclosed.

8)      In HIGHLIGHTS OF PRESCRIBING INFORMATION 9883616, April 2011. GARDASIL is described as a “sterile suspension for intramuscular administration. Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, <7 mcg yeast protein/dose, and water for injection.” There is no reference to DNA in the vaccine although yeast protein which is an adventitious substance is disclosed and listed the amount present to be <7 mcg/dose.

The above documents clearly indicate that all documents #1- #6 issued prior to April 2011 contained the words ‘no viral DNA.’ However, the same reference has not been on the last two documents, #7 and #8 issued in April 2011. Comparing your statements with the history of records, it is highly disturbing to find out now that the FDA and vaccine manufacturer knew from the very beginning and withheld such an important material fact from consumers; namely that  Gardasil has always been contaminated by residual recombinant HPV DNA.

Your statement ‘this DNA is not a contaminant’ is a simply another semantics game designed to evade inconvenient information. It grossly contradicts what the manufacturer has acknowledged and presented to the public.

For your information, the US patent #6,602,697 granted to Merck states:

“Specifically, it has been found that most contaminating biomolecules, including DNA, lipids and proteins are removed from the lysate.”

“Quantitation of L1 was made using a 2.5 mg load and yeast contaminants were quantitated at 20.0 mg loading.”

Therefore, again the record shows that the vaccine manufacturer has considered both residual DNA and yeast protein to be contaminants in the final product and as such must be removed. If not completely removed, it must be disclosed when it was detected. For example, the contaminant yeast protein was detected and listed as <7mcg/dose in April 2011 (See document above #8). Why was the contaminant HPV DNA not disclosed if known to exist?

To help medical consumers understand these very disturbing statements in your response, please provide answers to the following questions:

1)      How large, in number of base pairs, are these recombinant HPV DNA fragments that are known to exist in the vaccine Gardasil?

2)      Are these DNA fragments in the vaccine still spliced into plasmids?  If not, please show data.

3)      Can you provide a copy of the document in which the vaccine manufacturer reported that Gardasil does contain these DNA fragments, along with the date of the report made to the FDA?

4)      What was the decision of the FDA issued on the above report? Why not make public the information about the existence of HPV DNA in the vaccine products? Who signed off the decision?

Your categorical denial that ‘there is no scientific evidence linking juvenile rheumatoid arthritis and vaccination with Gardasil’ grossly contradicts the safety data observed in the clinical trial which showed  rheumatoid arthritis, including juvenile rheumatoid arthritis, occurred 3 times more frequently in the Gardasil®-vaccinated subjects than in the placebo control subject receiving aluminum placebo.[18] Complexes of anti-DNA antibodies with microbial or self DNA may play a role in the activation of B cells by Toll-like receptors and surface IgM rheumatoid factor.[19, 20]  The immunotoxic reactions may be further augmented by the aluminum adjuvant in the vaccine.[21]

Your response and this letter of rebuttal will be posted on the SANE Vax website so medical consumers will be properly informed of the contradicting evidence on the risks and benefits of Gardasil vaccination. This will preserve their right to make an informed choice regarding the use of Gardasil for their families.

SANE Vax Inc. and the injured patients along with their families urge the FDA to immediately appoint a committee composed of unbiased scientists to review the safety impact of the newly discovered residual recombinant HPV DNA in Gardasil. All cases of unexplained deaths of young women following Gardasil immunizations must be reviewed and the brains obtained at autopsies re-examined by qualified neuropathologists to determine if an immune-based acute disseminated encephalomyelitis might be the cause of death. Research must be conducted to determine if residual HPV DNA might have played a role in triggering the inflammatory lesions of the brain as a cause of death.

If you need more scientific evidence which will contradict your evaluation of the risks and benefits of Gardasil for adolescents age 9-26; especially those 9-12 years old, in the United States, please contact SANE Vax Inc. at your earliest convenience.

Thank you for your cooperation in performing your due diligence to reduce the unnecessary risks to future generations in this country.

Sincerely,

Norma Erickson, President SANE Vax Inc.
154 Cecil Drive
Troy MT 59935
 
Signed on behalf of the Board of Directors, SANE Vax, Inc.
Leslie Carol Botha, Vice President of Public Relations
Janny Stokvis, Vice President of Research
Rosemary Mathis, Vice President, Victim Support
Freda Birrell, Secretary
Linda Thompson, Treasurer

 

References

  1. Sutton I, Lahoria R, Tan I, Clouston P, Barnett M. CNS demyelination and quadrivalent HPV vaccination. Mult Scler. 2009; 15:116-9.
  2. Wildemann B, Jarius S, Hartmann M, Regula JU, Hametner C. Acute disseminated encephalomyelitis following vaccination against human papilloma virus.  Neurology. 2009;72:2132-3.
  3. Mendoza Plasencia Z, González López M, Fernández Sanfiel ML, Muñiz Montes JR. Acute disseminated encephalomyelitis with tumefactive lesions after vaccination against human papillomavirus. Neurologia. 2010; 25:58-9.
  4. Chang J, Campagnolo D, Vollmer TL, Bomprezzi R. Demyelinating disease and polyvalent human papilloma virus vaccination. J Neurol Neurosurg Psychiatry. 2010 Oct 9. doi:10.1136/jnnp.2010.214924
  5. DiMario FJ Jr, Hajjar M, Ciesielski T. A 16-year-old girl with bilateral visual loss and left hemiparesis following an immunization against human papilloma virus. J Child Neurol. 2010; 25:321-7.
  6. Balamoutsos G, Bouktsi M, Paschalidou M, Tascos N, Milonas I.  A report of five cases of CNS demyelination after quadrivalent human papilloma virus vaccination: could there be any relationship?  (Abstract No. P297)- Poster Access : www.guthyjacksonfoundation.org/services/download.php?2297.pdf+374
  7. Rossi M, Bettini C, Pagano C. Bilateral papilledema following human papillomavirus vaccination. J Med Cases. 2011; 2:222-4.
  8. van der Aa MA, Huth US, Häfele SY, Schubert R, Oosting RS, Mastrobattista E, Hennink WE, Peschka-Süss R, Koning GA, Crommelin DJ. Cellular uptake of cationic polymer-DNA complexes via caveolae plays a pivotal role in gene transfection in COS-7 cells. Pharm Res. 2007 Aug;24(8):1590-8. Epub 2007 Mar 24.
  9. Lechardeur D, Verkman AS, Lukacs GL. Intracellular routing of plasmid DNA during non-viral gene transfer. Adv Drug Deliv Rev. 2005 Apr 5;57(5):755-67.
  10. Matzuzawa Y, Emi N, Kanbe T. Calcium phosphate and aluminum hydroxide as non-virus gene carrier: the morphology of DNA-salt complex and the effects it has on DNA transfection. Kagaku Kogaku Ronbunshu. 2003; 29:680-684. In Japanese (English Abstract)
  11. Bergen JM, Park IK, Horner PJ, Pun SH. Nonviral approaches for neuronal delivery of nucleic acids. Pharm Res. 2008 May;25(5):983-98. Epub 2007 Oct 12.
  12. Berg P, Baltimore D, Boyer HW, Cohen SN, Davis RW, Hogness DS, Nathans D, Roblin R, Watson JD, Weissman S, Zinder ND. Potential biohazards of recombinant DNA molecules. Proc Natl Acad Sci U S A. 1974; 71: 2593–4.
  13. Würtele H, Little KC, Chartrand P. Illegitimate DNA integration in mammalian cells. Gene Ther. 2003 Oct;10(21):1791-9. Review.
  14. Milot E, Belmaaza A, Wallenburg JC, Gusew N, Bradley WE, Chartrand P. Chromosomal illegitimate recombination in mammalian cells is associated with intrinsically bent DNA elements. EMBO J. 1992 Dec;11(13):5063-70.
  15. Doerfler W, Schubbert R, Heller H, Kämmer C, Hilger-Eversheim K, Knoblauch M, Remus R. Integration of foreign DNA and its consequences in mammalian systems. Trends Biotechnol. 1997 Aug;15(8):297-301.
  16. Hilleman MR. History, precedent, and progress in the development of mammalian cell culture systems for preparing vaccines: safety considerations revisited. J Med Virol 1990 May;31(1):5-12.
  17. Testimony on Cervical Cancer by Nancy C. Lee, M.D. Before the House Committee on Commerce, Subcommittee on Health and Environment  March 16, 1999 http://www.hhs.gov/asl/testify/t990316b.html
  18. Merck & Co., Inc. 2006. Gardasil [Quadrivalent Human Papillomavirus Types 6,11,16,18) Recombinant Vaccine] product insert. Table 9.  Merck 9883616
  19. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002;416(6881):603-7.
  20. Zhong XY, von Mühlenen I, Li Y, Kang A, Gupta AK, Tyndall A, Holzgreve W, Hahn S, Hasler P. Increased concentrations of antibody-bound circulatory cell-free DNA in rheumatoid arthritis. Clin Chem. 2007;53:1609-14.
  21. Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, Lekeux P, Coban C, Akira S, Ishii KJ, Bureau F, Desmet CJ. DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med. 2011;17:996-1002.

 

 

Filed Under: United States Concerns Tagged With: , , ,

SANE Vax to CDC: Request for additional data on HPV vaccine post-marketing monitoring

August 31, 2011 By Leave a Comment

Lauri Markowitz, M.D.
Centers for Disease Control and Prevention
MS E05, 1600 Clifton Road
Atlanta, GA 30333
lem2@cdc.govAugust 31, 2011

Dear Dr. Markowitz:

Thank you for your August 29, 2011 response to my letter requesting additional information about post licensure monitoring for Gardasil™ from the CDC. Before relaying your response to medical consumers, I would like to ask you to clarify the following two points.

1)       Your letter stated: ‘In Australia…some decreases in HPV associated outcomes have been observed already.’ May I ask you to provide a published reference to support this statement? The only paper I have read from Australia on this issue is an article by Brotherton et al. [1] in which the authors stated ‘we recorded a decrease in the incidence of HGAs by 0.38%.’ According to the authors, HCAs were lesions coded as CIN2 or worse. Since CIN2 is not a true biologic entity [2] and 25-50% of the CIN2 lesions are self-resolving [3] a 0.38% decrease of CIN2 lesions with a self-resolving rate of up to 50% can hardly be used as convincing evidence for demonstrating the efficacy of a vaccine approved to prevent cervical cancer in the decades to come.
Furthermore, there appeared to be no HPV genotyping data in the Brotherton paper. [1] As a result, there were no HPV associated outcomes in their study. I assume you must have another Australian reference to support your statement. If you do, please provide the reference.

2)      The HPV genotype distribution in the table attached to your letter seems to show highly contradictory results between the states. For example, the numbers of HPV-16 and HPV-18 infections in 2009 may well exceed the numbers infected by these two genotypes in 2008 in Oregon and Tennessee while the data in California, Connecticut and New York may show a decrease in HPV-16 and HPV-18 infections. I am wondering if the discrepancy in efficacy results in different states might be due to a lack of a common denominator or varying method being used for HPV genotyping.

 According to a group of experts on HPV testing, ‘To meet currently achievable standards, the test should have a clinical sensitivity to detect at least 92% ± 3% of CIN 3+ …and the test should have clinical specificity of at least 85% such that adequate positive predictive value for CIN 3…’ [4]

Therefore, I would like to have elaboration on:

  • Whether the CDC requires all states to use CIN3 lesions as the common denominator in tabulating the numbers of infections by various individual HPV genotypes?
  • Does the CDC require all the methods used for HPV testing by these states to meet the clinical sensitivity to detect at least 92% of CIN3 lesions and the clinical specificity of at least 85% for CIN 3?

I am looking forward to receiving your kind clarification.

Norma Erickson, President

SANE Vax Inc.
154 Cecil Drive
Troy Montana, 59935

References:

[1] Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet. 2011; 377:2085-92.

[2] Castle PE, Stoler MH, Solomon D, Schiffman M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2007;127:805-815.

[3] Castle PE, Schiffman M, Wheeler CM, Wentzensen N, Gravitt PE. Impact of improved classification on the association of human papillomavirus with cervical precancer. Am J Epidemiol. 2010;171:155-63.

[4] Stoler MH, Castle PE, Solomon D, Schiffman M. The Expanded Use of HPV Testing in Gynecologic Practice per ASCCP-Guided Management Requires the Use of Well-Validated Assays. Am J Clin Pathol. 2007;127:1-3.

The following response was received from Dr. Lauri Markowitz via email on 21 Sept 2011:

Ms. Erickson,

Data from Australia on decreases in HPV-associated outcomes include mainly ecologic data on declines in genital warts. From Donovan et al. Lancet Infect Dis 2011:  “After vaccination began, a decline in number of diagnoses of genital warts was noted for young female residents (59%, p(trend)<0·0001). No significant decline was noted in female non-residents, women older than 26 years in July, 2007, or in men who have sex with men. However, proportionally fewer heterosexual men were diagnosed with genital warts during the vaccine period (28%, p(trend)<0·0001).”  The data on trends in cervical precancer lesions from Australia show minimal declines, as you stated, and there are no genotyping data.

Concerning the genotyping data we shared with you from the U.S, these are preliminary data. We do not have complete data from the states yet and it is not possible to compare between states.  We eventually will be able to do so.  All genotyping is done by the same method at CDC.  The methods were shared with you in a previous letter.

Sincerely,
Lauri Markowitz, M.D.
 
 
 
 
 
 
Filed Under: United States Concerns Tagged With: , , , , ,

SANE Vax to CDC: Request for post-HPV vaccination monitoring data

August 31, 2011 By Leave a Comment

Lauri Markowitz, M.D. 
Centers for Disease Control and Prevention
MS E05, 1600 Clifton Road
Atlanta, GA 30333
lem2@cdc.gov

July 26, 2011

Dear Dr. Markowitz:

Thank you for your letter dated July 14, 2011in response to the SaneVax Inc. letter of  28 May 2011, concerning the post-licensure monitoring project on Gardasil™, which was approved for marketing under the Fast Track Drug Development Programs in 2006.

Your letter stated, “Beginning in 2003, cervicovaginal swabs have been collected from women participating in the National Health and Nutrition Evaluation Survey (NHANES).  These swabs are tested to determine individual HPV types. Types will continue to be monitored to evaluate changes after vaccine introduction.”

We are now eight (8) years past the inception of said program and five (5) years since Gardasil™ was first approved for marketing in the United States. Therefore, on behalf of concerned medical consumers, S.A.N.E. Vax, Inc. respectfully requests a copy of the monitoring data over the past 8 years. We would like to know specifically if mass vaccination of young women has indeed reduced the prevalence of the vaccine-relevant HPV genotypes as compared to other HPV genotypes in theU.S. population.

Your letter also stated, “CDC is participating in two ongoing special projects to evaluate HPV types in women who have cervical precancer lesions.   Sites in five states (California,Connecticut,New York,OregonandTennessee) have developed a population-based system for monitoring cervical intraepithelial neoplasia (CIN) grade 2 or 3 and adenocarcinoma in situ and associated HPV types.  In addition to collecting standard basic surveillance data on all reported cases, this project is determining HPV types in the precancers.”

In order to be able to assure medical consumers that these “ongoing special projects” are effectively implemented, we would like to ask you to fill in the numbers of HPV genotypes as supplied by these five states in the past 5 years in the Table attached so that we can post the results on our website to inform the public. The purpose of the Table is to present the number ofCIN2/3 and AIS associated with HPV type in each case from 2006 to 2011 to determine if the prevalence of the vaccine-relevant HPV genotypes is indeed decreasing in the precancer lesions among the vaccinated population, as compared to the non-vaccinated population.

In this era of government budget crisis, we would like to know the cost for the CDC’s ongoing special projects to evaluate HPV types in women who have cervical precancerous lesions in those five states mentioned above. Taxpaying medical consumers need some assurance that their money is being wisely spent. If these projects have not generated any meaningful data in the past five years, perhaps they should be abolished and replaced by some other more cost-effective means of post-licensure monitoring.

The SaneVax Team finds your statement “Since HPV genotyping is not done in clinical practice, it is not feasible to have HPV genotypes from all patients with Pap test results indicating cervical precancer or cancer reported to CDC” to be quite disturbing for two reasons. First, the CDC should have known that HPV genotyping has been done in clinical practice for years in the U.S., and there are two FDA-approved commercial test kits for HPV genotyping on the market now.  Second, if the CDC believes HPV genotyping is not done in clinical practice, then the CDC should have known that “determining HPV types in the precancers” for post-licensure monitoring in clinical practice is not possible. However, the CDC felt quite comfortable to endorsing the vaccine Gardasil™, whose approval requires post-licensure monitoring based on using HPV genotyping, for use in clinical practice. The CDC should recommend that since HPV genotyping is not done in clinical practice, Gardasil™ should not be endorsed for use in clinical practice.

We are looking forward to your further comments on behalf of the CDC.

Sincerely,
Norma Erickson, President
SaneVax Inc. 

cc.

Director of CDC- Thomas R. Frieden – txf2@cdc.gov
FDA commissioner – Margaret Hamburg – Margaret.Hamburg@fda.hhs.gov
Secretary of HHS – Kathleen Sebelius – Kathleen.Sebelius@hhs.gov 
 

View the CDC’s response here.   

View the data provided by the CDC, complete with independent analysis here.

 

 

Filed Under: United States Concerns Tagged With: , , , ,

SANE Vax to Dr. Mark Schiffman: HPV Vaccine Accountability

August 31, 2011 By Leave a Comment

 
Mark Schiffman, M.D., M.P.H.
Senior Investigator, National Cancer Institute
Executive Plaza South, Room 5026
6120 Executive Boulevard
Bethesda, Maryland 20892-7335 
301-435-3983
301-402-0916
schiffmm@mail.nih.gov 

Dear Dr. Schiffman:

Since you are the first scientific officer to promote mass HPV vaccination of women as a means to prevent cervical cancer [1], and have been working with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) as the Medical Monitor of the human papillomavirus (HPV) vaccine trial [2], you must know that the HPV vaccines currently being marketed were approved by the FDA under the Fast Track Drug Development Programs. You must also be aware of the fact that approval of the HPV vaccine was based on using “CIN 2/3, AIS, or worse by histology – with virology to determine the associated HPV type” as the surrogate endpoint in the evaluation of the efficacy of the vaccine to prevent cervical cancer.

According to the Guidance for Industry, Fast Track Drug Development Programs-Designation, Development, and Application Review, “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).”

Since the clinical endpoint used in the clinical trial for Gardasil and Cervarix approval was not an “irreversible morbidity”, post-licensure studies are required to verify and describe the vaccine’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, according to the FDA drug law.

This letter is to request you, the official medical monitor of the HPV vaccine trial leading to its final FDA approval under the Fast Track Drug Development Programs, to publish the HPV genotypes which are causing precancerous and cancerous cytologic changes in the women who have been immunized by the HPV vaccines, under the brand names of Gardasil and Cervarix. Based on the VAERS Reports, a significant number of post-vaccinated women are now developing cervical precancer and cancer lesions. It is extremely important for the public to be informed if these cervical precancer or cancer lesions are being caused by vaccine-relevant HPV genotypes or by HPV genotypes not targeted by the HPV vaccines. Since both the FDA [3] and the NCI [4] have acknowledged that the only reliable HPV genotyping is by DNA sequencing, the consumers who have paid a great price to this controversial vaccine want to have the data based on HPV genotype determination by DNA sequencing.

As the official Medical Monitor of the HPV vaccine clinical trial, you are held accountable for supplying the post-licensure monitoring survey results as requested. If no reliable data are forthcoming, you should recommend rescinding its approval until a reliable post-licensure monitoring system is instituted.

I am looking forward to receiving your reply.

Sincerely yours,

Norma Erickson, President

Cc:

Director FDA, Margaret Hamburg
Director HHS, Kathleen Sebelius
Director CDC, Thomas Frieden 

References:

[1] http://jnci.oxfordjournals.org/content/93/4/260.full

[2] Schiffman M, Wentzensen N. From human papillomavirus to cervical cancer. In Reply.  Obstet Gynecol 2010; 116:1221-1222.

[3] http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM181511.pdf

[4]https://www.fbo.gov/index?s=opportunity&mode=form&id=da396b97ad6eb7ec4f7d511f85d9e325&tab=core&_cview=0

 

Filed Under: United States Concerns Tagged With: , , , , ,

SANE Vax to Senator Grassley: Congratulations, keep on investigating

August 30, 2011 By 2 Comments

Dear Senator Grassley:

The SaneVax Team read your October 22, 2010 letter to Dr. Harold E. Varmus, director of the National Cancer Institute (NCI), with great interest. We would like to congratulate you on your efforts to examine the ethical questions raised by NCI employees accepting extensive travel sponsored by private companies. NCI is the nation’s top institute in cancer science. Publications and opinions from its intramural scientists have great impact on national health care policies affecting American consumers. Because their influence carries so much weight in the medical community, their reputation should be beyond reproach. We appreciate your office initiating this investigation into the ethics of those NCI employees who are apparently accepting excessive travel funds from private companies.

Along the same line, the SaneVax Team would like to bring to your attention another even more disturbing issue involving two senior NCI scientists who knowingly promote an unreliable human papillomavirus (HPV) test for patient care, and the development and monitoring of genotype-specific HPV vaccines in promoting a virology-based business agenda.

In a recently published financial disclosure[1] Dr. Mark Schiffman, a NCI senior investigator, stated that he “works with the U.S. Food and Drug Administration (FDA) as well as the National Cancer Institute (NCI). He is the medical monitor of the independent human papillomavirus (HPV) vaccine trial of Cervarix being conducted by the NCI, for which he does not receive compensation. GlaxoSmithKline pays costs related to regulatory use of the data. He also works on the development of HPV tests for low-resource public health settings and is collaborating with Qiagen on this effort. Qiagen is providing free test supplies for this research effort but has no role in the evaluation of performance.”

In this disclosure, Dr. Schiffman did not mention that a similar Qiagen test has also been used in the U.S. as the only FDA-approved HPV test for American women for the past 20 years. Digene Corporation with its HC2 HPV test kit was sold to Qiagen, a Dutch company for $1.6 billion in 2007[2], with a 5-times value appreciation over less than 5 years.

During the past 20 years, Dr. Mark Schiffman and Dr. Philip Castle, the two senior NCI officials promoting the virology-based agenda, have co-authored numerous articles with Dr. A. Lorincz, the chief scientist employed by Digene Corporation[3] as scientific literature endorsing the Digene HC2 test. A PubMed search revealed that Dr. Schiffman and Dr. Lorincz coauthored 34 such articles from 1988 to 2005[4], and that Dr. Castle and Dr. Lorincz coauthored 15 similar articles from 2001 to 2007[5]. The NCI endorsement has undoubtedly boosted the sales value of Digene Corporation.

However, the Digene HC2 HPV test is not a reliable HPV genotyping test, as well known in the NCI. A public document titled “HPV genotyping”, identified as Solicitation Number: NCI-100143-MM, reveals the NCI acknowledges that a reliable genotyping of HPV is a method based on “PCR system with short target sequences,” a methodology the NCI and the FDA do not encourage companies to develop in this country. They prefer to pay $13.5 million to contract a foreign laboratory to test 230 biopsy samples, an exorbitant amount of our tax money for a small number of tests.

The obvious conclusion is that these two NCI scientists have been promoting a test kit which the NCI knows is not as reliable as “a PCR system with short target sequences” for patient care. The NCI scientists responsible for the HPV project have apparently maintained a double standard, a reliable HPV test for good science and another unreliable HPV test for patient care. The unreliable Digene HC2 HPV test has sent numerous American women to harmful cervical biopsies, 95% of which are unnecessary, at a great cost to individuals and society.[6]

We believe that the NCI-promoted virology-based program, which depends on massive HPV vaccination of young American girls, HPV screening and colposcopic biopsies, to replace the traditional Papanicolaou test for cervical cancer prevention[7] is highly speculative for the following reasons:

  • The currently marketed HPV vaccines lack proven efficacy in cervical cancer prevention and are associated with potentially serious side effects.
  • They can only protect against a fraction of high-risk HPV genotypes, provided there is no prior vaccine-related HPV infection.
  • Cervical cancer is not a contagious disease.
  • There is no epidemic of cervical cancer in the United States.
  • The perceived cervical cancer crisis in the United States is obviously man-made news.
  • Cervical cancer can be prevented with good gynecological care. This is a proven fact.
  • Progression from persistent HPV infection to cervical cancer is a complicated pathological process which is not well understood, even among scientists.
  • Clinical trials for efficacy of HPV vaccines used the wrong endpoint to prove their value to medical consumers.
  • Reliable HPV genotyping methods were not used in the development of HPV vaccines.
  • Reliable HPV genotyping methods are not currently available to American medical practitioners, or consumers for post-marketing monitoring.
  • At least two National Cancer Institute employees have co-authored promotional articles with a senior employee of a private company to promote an unproven virology-based cervical cancer prevention program to the American public while knowing the device being promoted is unreliable.
  • The NCI virology-based program is apparently being advanced by individuals with a personal agenda, rather than any interest in national health.

Therefore, the SaneVax Team believes medically and scientifically the currently marketed HPV vaccines’ benefits do not justify the costs and the potential side effects for medical consumers in the United States.

The SaneVax Team has expressed our concerns to the FDA Commissioner, Dr. Margaret Hamburg and the NCI director, Dr. Harold Varmus, respectively [see attached letters in references #8 and #9]. We have not received a response from either of these two government agencies.

We respectfully request that the ethics investigation of your Senate Committee extend to examine the appropriateness of the two senior NCI officials named above and their efforts to promote an HPV test kit the NCI knows to be not a reliable genotyping method and the circumstances surrounding the FDA approval of two currently approved HPV vaccines, Gardasil and Cervarix.

I am looking forward to receiving your response to this request on behalf of American medical consumers.

Yours respectfully,

Norma Erickson, President
S.A.N.E. Vax, Inc.
154 Cecil Drive
Troy MT 59935
 
Signed on behalf of the Board of Directors, S.A.N.E. Vax, Inc.
Leslie Carol Botha, Vice President of Public Relations
Janny Stokvis, Vice President of Research
Rosemary Mathis, Vice President, Victim Support
Freda Birrell, Secretary
Linda Thompson, Treasurer

References:

  1. Schiffman M, Wentzensen N.  From human papillomavirus to cervical cancer. In Reply to a Letter to the Editor. Obstet Gynecol 2010;116:1221-2.
  2. Qiagen bought Digene-SAN FRANCISCO (MarketWatch) News attached.
  3. Lorincz and Digene-News report attached.
  4. Lorincz Schiffman coauthored, attached PubMed search.
  5. Lorincz Castle coauthored, attached PubMed Search.
  6. Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks. Arch Intern Med 2008;168:1881-9.
  7. Schiffman M, Wentzensen N. From human papillomavirus to cervical cancer. Obstet Gynecol 2010;116:177-85.
  8. Sane Vax Inc. Letter requests FDA Commissioner to rescind Gardasil.
  9. Sane Vax Inc. Letter urges NCI and FDA to establish reliable HPV genotyping for better patient care.
Filed Under: United States Concerns Tagged With: , , , , , ,

Congressman Charlie A. Wilson to FDA: Gardasil Concerns

August 30, 2011 By Leave a Comment

Dear Ms. Stephens,

Thank you for your response to my recent inquiry into the safety and effectiveness of the HPV vaccine, Gardasil. I have studied your letter thoroughly and frankly, am somewhat disturbed by the fact that your response gives rise to more questions than answers.

The following quotes from your letter raise these questions:

“The Vaccine Adverse Event Reporting System (VAERS) is subject to many limitations…..”

If these ‘limitations’ are known, why are they not being addressed and remedied?

“There is a lack of a direct, concurrent, and unbiased comparison group.”

Is this not the purpose of conducting clinical trials, to establish and monitor a proposed vaccine under a ‘direct, concurrent, and unbiased comparison group’ situation? If clinical trials are designed to test the safety and efficacy of proposed vaccines, why was Merck not made to use a true placebo while conducting their clinical trials on Gardasil?

“FDA and the Centers for Disease Control and Prevention (CDC) use VAERS to identify potential safety signals…..”

Is not over 100 reports of adverse events per week a ‘potential’ safety signal? Is 28 deaths within 30 days of HPV vaccination not a ‘potential’ safety signal?

“To evaluate whether or not the vaccine causes an adverse effect, various types of epidemiologic studies are conducted.”

In addition to epidemiology, are any tests or medical evaluations done in an attempt to determine whether the vaccine did cause the adverse events?

“The rate at which adverse events are reported to VAERS is often described by the number of adverse event reports received, divided by the number of vaccine doses distributed.”

Even the most uneducated can see this calculation skews information in favor of the vaccine manufacturer. This is particularly true in the case of a vaccine, such as Gardasil, where three doses are recommended. How many of these ‘distributed’ doses are in storage awaiting administration at any given time?

In order to provide a more accurate picture, why are adverse events not calculated by the number of doses actually administered? In the case of HPV vaccines, why are they not calculated by the number of girls who received one, two, or all three doses?

“In addition, some of the Phase 4 post-marketing studies are conducted in other countries. Many small countries do not have the infrastructure to conduct safety surveillance.”

Why does the FDA accept the results from post-marketing studies which have been conducted in countries that cannot conduct adequate safety surveillance?

“To date, we do not have scientific evidence that the vaccine caused these events.”

I would respectfully submit that neither do you have scientific evidence that the vaccine did not cause these events.

“We continue to review all serious reports daily, and we do analyses to evaluate potential safety signals.”

Exactly what type of ‘analyses’ does the FDA conduct to evaluate potential safety issues? Your letter provided no evidence of such analyses.

According to an article published in ‘The Journal of the American Medical Association (Aug 2009), “From June 1, 2006, through December 1, 2008, VAERS received 12,424 reports of adverse AEFI’s following receipt of qHPV (TABLE 1), an overall reporting rate of 53.9 reports per 100,000 vaccine doses distributed. The majority of reports (8471/12,424, or 68%) were submitted by the manufacturer, compared with an overall rate of 40% for VAERS reports on other vaccines.

During the same time period, manufacturer reports accounted for 14.5% of the meningococcal conjugate vaccine reports and 7.5% of the reports for tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine submitted to VAERS. Of the 8471 manufacturer reports for qHPV AEFI’s, 7561 (89%) had insufficient identifying information to permit clinical follow-up or review.”

Has the FDA taken any steps to require the manufacturer to provide adequate information on future VAERS reports?

Does the FDA examine other countries’ databases regarding serious adverse events and death reports? For example, The Paul Ehrilich Institute in Germany reported 5 fatalities following HPV vaccination. Are these reports included in VAERS?

Does the FDA examine reports from the World Health Organization adverse events database?

In reference to study 013, your letter said, “These underlying risk factors can skew the results.”

Do these underlying risk factors not exist in the general population also? Do they not ‘skew’ the effectiveness of the vaccine? Should people with these ‘underlying’ risk factors not be excluded from vaccination as a safety precaution?

Also in reference to study 013, you stated, “Other large trials have not replicated the results of the aforementioned analysis.”

Is it not true that these results have not been replicated because other large trials have not examined those cohorts of the population?

When questioned about reports linking HPV infections to other types of cancer, you responded with the statement, “HPV 16 and HPV 18 and other oncogenic HPV types are recognized as carcinogenic biologic agents by internationally recognized experts……..”

Are not many of the ingredients in Gardasil also recognized as either carcinogenic, neurogenic, or hazardous waste by internationally recognized experts, including other regulatory agencies such as the EPA?

When asked why the FDA believes HPV vaccines are safe for administration to adolescents and how the FDA justifies a vaccination program for all adolescent girls based on low cervical cancer incidence rates, your response completely sidestepped the safety issue and went on to indicate other government agencies responsible for making advice regarding vaccination schedules.

Since it is the FDA’s responsibility to approve vaccines based on effectiveness and safety, the question remains… Why does the FDA believe HPV vaccines are safe for administration to adolescents?

In view of the fact the FDA is a science-based, science-driven regulatory agency whose stated mission is to promote and protect the health of the public, Congress and the American public has a right to know the organization is doing that job. Please provide science-based answers to the questions in this letter.

In closing, my recommendation for an independent study analyzing the safety and efficacy of HPV vaccines be performed still stands.

Respectfully,

Congressman Charlie A. Wilson

Filed Under: United States Concerns Tagged With: , , , , ,

SANE Vax to NCI/FDA: Request for reliable HPV genotyping test for medical consumers

August 30, 2011 By Leave a Comment

November 2, 2010

The Honorable Margaret Hamburg, M.D., Commissioner, FDA
The Honorable Harold E. Varmus, M.D., Director,NCI 

Subject: Request recommending a reliable human papillomavirus (HPV) genotyping test to support the national virology-based cervical cancer prevention program for patient care

Dear Dr. Hamburg and Dr. Varmus:

A recently published letter to the editor of ‘Obstetrics and Gynecology,’ authored by two senior officials from the National Cancer Institute (NCI), has confirmed it is on the NCI’s agenda to replace the traditional Papanicolaou (Pap) cytology with a virology-based program to prevent cervical cancer in the United States.[1]

As we all know, regular Pap cytological screening has successfully reduced the U.S. cervical cancer prevalence rate to one of the lowest in the world in the past 60 years. Now, cervical cancer in the U.S. is primarily a disease among women who have not received regular Pap screenings, or whose Pap tests have not been properly performed.

The proposed virology-based program by the NCIconsists of prophylactic vaccination of adolescents against carcinogenic HPV infections and HPV testing followed by colposcopic biopsies.[2]

The SaneVax team is very concerned about instituting a virology approach for cervical cancer prevention because the current HPV vaccines have not been proven to be effective in preventing cervical cancer among the highly heterogeneous female populations in the U.S., as elaborated in our previous letter addressed to the FDA commissioner on October 19, 2010.

Based on a recent NCI document [3], the currently FDA approved HPV tests on the market may not be reliable in generating HPV genotyping information for patient care. The results of two FDA-approved HPV tests often contradict each other. The NCI officials now “agreed that the increased detection of HPV by Hologic Cervista in the data submitted to the FDA is a concern that must be addressed in the mandated postmarketing studies.” [1]

The SaneVax team finds this disclosure highly disturbing. If the data submitted to the FDA in support of a Class III medical device premarket approval application (PMA) raised a concern about its safety and efficacy, why did the governmental regulatory agency approve the device to be marketed to the general consumers without resolving the concern at the reviewing stage?

Knowing there was a concern that must be addressed and relying on mandated postmarketing studies to address the concern should not be the right way for the FDA to approve a PMA diagnostic device. Common sense tells us that the damage to the public will be extensive if the FDA waits for a known safety or efficacy issue of a drug or a medical device to become obvious during postmarketing monitoring before addressing the issue.

Since the Cervista™ HPV HR test was approved by the FDA “to screen patients with atypical squamous cells of undetermined significance (ASC-US) cervical cytology results to determine the need for referral to colposcopy,” a positive test result is used by gynecologists as a triage tool to channel women into harmful 4-quadrant cervical biopsies. More false positive HPV test results will lead to more unnecessary biopsies on women at a greater cost to society.

Our research further revealed that the Cervista™ HPV HR test kit was approved in March 2009 without conducting an FDA advisory committee public meeting. Approval of a ClassIIImedical device without an open session advisory meeting is highly unusual.

As a result of this non-transparent approval process, the public does not know what the positive predictive value (ppv) is for the Cervista™ HPV test for CIN3 detection.[4]

Since theNCIhas now disclosed this concern, we are respectfully requesting the FDA to conduct an advisory committee public meeting to review the original data submitted for the PMA application of Cervista™ to determine if the device was properly reviewed and approved for marketing.

Since the senior NCIofficial in charge of the HPV project also works with the FDA, the vaccine manufacturer, and the HPV test device manufacturer[1] in developing the virology-based cervical cancer prevention program, and acknowledges the fact that “increased detection of HPV by Hologic Cervista in the data submitted to the FDA is a concern,” SaneVax believes both the FDA and NCI have a responsibility to address the concern over why one FDA-approved HPV test generates two to four times more positive results than the other.[5]     

Since reliable HPV genotyping is a valuable tool for pre-vaccination and post-vaccination monitoring of type-specific HPV infections, S.A.N.E. Vax, Inc. hereby requests permission to attend any future advisory committee public meetings for HPV test applications to convey the desire of the consumers to the committee members for consideration.

A copy of this letter is being sent to Shanika Craig, the designated federal official of the microbiology devices panel, as a formal request for notification whenever meetings are scheduled to discuss HPV PMA applications.

Thank you,

Norma Erickson, President
S.A.N.E. Vax, Inc.
154 Cecil Drive
Troy MT 59935
 
Signed on behalf of the Board of Directors, S.A.N.E. Vax, Inc.
Leslie Carol Botha, Vice President of Public Relations
Janny Stokvis, Vice President of Research
Rosemary Mathis, Vice President, Victim Support
Freda Birrell, Secretary
Linda Thompson, Treasurer

 References:

  1. Schiffman M, Wentzensen N.  From human papillomavirus to cervical cancer. In Reply to a Letter to the Editor. Obstet Gynecol 2010;116:1221-2.
  2. Schiffman M, Wentzensen N. From human papillomavirus to cervical cancer. Obstet Gynecol 2010;116:177-85.
  3. National Cancer Institute. HPV Genotyping. Solicitation Number:NCI-100143-MM. August 2, 2010.  https://www.fbo.gov/index?s=opportunity&mode=form&id=da396b97ad6eb7ec4f7d511f85d9e325&tab=core&_cview=0
  4. Stoler MH, Castle PE, Solomon D, Schiffman M. The expanded use of HPV testing in gynecologic practice per ASCCP-guided management requires the use of well-validated assays. Am J Clin Pathol 2007;127:1-3.
  5. Kinney W, Stoler MH, Castle PE. Special commentary: patient safety and the next generation of HPVDNAtests. Am J Clin Path 2010;134:193-9.

 cc.

Microbiology Devices Panel:

Shanika Craig, Designated Federal Official

Filed Under: United States Concerns Tagged With: , , , , , , , ,

SANE Vax to Margaret Hamburg: request the FDA rescind Gardasil approval

August 30, 2011 By Leave a Comment

 

 
 
 
 
 
The Honorable Margaret A. Hamburg, M.D., Commissioner                                                       October 19, 2010
U. S. Food and Drug Administration (FDA)
10903 New Hampshire Ave.
Silver Spring MD 20993-0002

Subject:    Request that the FDA rescind its approval for Gardasil™ as a vaccine to prevent cervical cancer or to prevent genotype-specific human papillomavirus (HPV) infection due to use of an inappropriate primary endpoint and unreliable HPV genotyping methods for efficacy evaluation 

Dear Dr. Hamburg:

S.A.N.E. Vax, Inc. is a non-profit organization established to promote safe, affordable, necessary and effective vaccines and vaccination practices. In response to inquiries from families of girls around the world suffering mysterious illnesses and death after HPV vaccination, our team began researching the mechanisms of action of HPV vaccines in general and Gardasil™ in particular.

This research revealed the fact that in November 2001 the VRBPAC committee allowed the vaccine manufacturer, Merck & Co., Inc., to use:

CIN 2/3, AIS, or cervical cancer; i.e. CIN 2/3 or worse by histology- with virology to determine the associated HPV type- as the primary endpoint in the evaluation of a vaccine to prevent cervical cancer. [1] 

Using this primary endpoint for statistical calculation in the clinical trials invalidates the claimed efficacy of Gardasil™ as a vaccine to prevent cervical cancer. The reason is as follows:

It is well known in the natural history of cervical cancer development only a small fraction of the CIN 2 lesions will progress to CIN 3 lesions; and only a small fraction of CIN 3 lesions will progress to cervical cancer. Therefore, there are many more CIN 2 lesions than CIN3 lesions and cervical cancers combined in any female population, including the subjects enrolled in the Gardasil™ clinical trials. As a result, the overwhelming majority of the “CIN 2/3 or worse” cases used for evaluation of efficacy, and listed in the VRBPAC Background Document on Gardasil™ HPV Quadrivalent Vaccine presented at the May 18, 2006 VRBPAC Meeting [1] must have been CIN 2 lesions.

A scientific report published by the National Cancer Institute (NCI) concludes:

CIN 2 is not a true biologic entity but an equivocal diagnosis of pre-cancer, representing an admixture of HPV infection and pre-cancer. The existence of CIN 2 biopsy results as a clinical entity may be the consequence of the inaccuracies of colposcopy and colposcopically directed biopsy, which could result in less-than-perfect representation of the underlying disease state. That CIN 2 is the least reproducible of all histopathologic diagnoses may in part reflect sampling error; i.e., the biopsy procedure could make a CIN 1 or HPV infection appear worse by sampling the lesional area diagonally and, thereby, make the lesion appear thicker and could make a CIN 3 lesion appear less severe by only partially sampling the precancerous lesion. [2] 

Two additional NCI reports further confirmed that approximately 40% of undiagnosed CIN 2 will regress over two years [3] and that even the CIN 3 lesions are heterogeneous. [4]

Based on the above NCI findings, the data presented in the VRBPAC Background Document on Gardasil™ HPV Quadrivalent Vaccine only supports the claim that Gardasil™ can prevent “an equivocal diagnosis of pre-cancer, representing an admixture of HPV infection and pre-cancer” –about half of which are self-reversing to normal - not cervical cancer which is a malignant lesion at a point of no return to normalcy.

Furthermore, based on a recent NCI document, the only reliable HPV genotyping method is a “PCR system with short target sequences.”[5] However, such a reliable HPV genotyping method was never used to ‘determine the associated HPV type’ in the clinical trials for evaluation of the efficacy of Gardasil™ to prevent type-specific HPV infections. Obviously, any data collected using unreliable methods cannot be used to reliably evaluate the efficacy of any drugs or vaccines.

The FDA has approved a vaccine which is being marketed as a cancer vaccine, when in fact it has only been proven to prevent ‘not a true biologic entity,’ in the words of the NCI, the inventor of the current HPV vaccine technology and the co-developer of Gardasil™.

The situation is exacerbated because the FDA and the NCI have not attempted to encourage development of a reliable HPV genotyping method for post-license monitoring of the effects of Gardasil™ vaccination on the epidemiology of HPV infections in the American population. One of the two FDA-approved HPV tests generates two to four times more positive results than the other. [6] The doctors do not know which test to use for patient management, which may lead to more unnecessary harmful colposcopic biopsies on women at a great cost to society. [7]

In view of the fact the FDA is a science-based, science-driven regulatory agency whose stated mission is to ‘promote and protect the health of the public,’ S.A.N.E. Vax, Inc. respectfully requests a temporary suspension of the sales and marketing of Gardasil™ as a cervical cancer preventive, until such time as the efficacy of the vaccine is properly re-evaluated using the true endpoint for cervical cancer prevention, and a reliable HPV genotyping method for detection of type-specific HPV infections.

I am looking forward to receiving your response to this reasonable request on behalf of medical consumers around the world.

Yours respectfully,
Norma Erickson, President 
S.A.N.E. Vax, Inc. 
154 Cecil Drive 
Troy MT 59935  
 
Signed on behalf of the Board of Directors, S.A.N.E. Vax, Inc.
Leslie Carol Botha, Vice President of Public Relations
Janny Stokvis, Vice President of Research
Rosemary Mathis, Vice President, Victim Support
Freda Birrell, Secretary
Linda Thompson, Treasurer 

References

1. VRBPAC Background Document: Gardasil™ HPV Quadrivalent Vaccine. May 18, 2006 VRBPAC Meeting  www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4222B3.pdf

2. Castle PE, Stoler MH, Solomon D, Schiffman M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2007;127:805-815.

3. Castle PE, Schiffman M, Wheeler CM, Solomon D. Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol. 2009;113:18-25.

4. Schiffman M, Rodríguez AC. Heterogeneity in CIN3 diagnosis. Lancet Oncol. 2008;9:404-406. A comment on the article – McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, Skegg DC.   Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9:425-434.

5. National Cancer Institute. HPV Genotyping. Solicitation Number: NCI-100143-MM. August 2, 2010. https://www.fbo.gov/index?s=opportunity&mode=form&id=da396b97ad6eb7ec4f7d511f85d9e325&tab=core&_cview=0

6. Kinney W, Stoler MH, Castle PE. Special commentary: patient safety and the next generation of HPV DNA tests. Am J Clin Pathol. 2010;134:193-199.

7. Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks. Arch Intern Med. 2008; 168: 1881-1889.

CC:   Vaccines and Related Biological Products Advisory Committee:

Jack Stapleton, M.D., Chair
Donald Jehn, M.S., Designated Federal Officer
Denise Royster, Committee Management Specialist
Ambrose Cheung, M.D.,
Vicky Debold, Ph.D., R.N.
Frank DeStefano, M.D., M.P.H.
Anna Durbin, M.D.
Peter Gilbert, Ph.D.
Gregory Gray, M.D., M.P.H.
Margaret Rennels, M.D.
Jose Romero, M.D.
Pablo Sanchez, M.D.
Gary Schoolnik, M.D.
Carol Tacket, M.D. 

Microbiology Devices Panel: 

Shanika Craig, Designated Federal Official
Michael  L.Towns, M.D.
Filed Under: United States Concerns Tagged With: , , , ,

SANE Vax to Jack Stapleton, Chairman VRBPAC (vaccines and related biological products advisory committee)

August 30, 2011 By Leave a Comment

 

October 19, 2010

Jack Stapleton, M.D., Chair 
Vaccines and Related Biological Products Advisory Committee 
University of Iowa Hospital Clinic 
200 Hawkins Drive 
Iowa City, Iowa 52242

SUBJECT:  Valid endpoint and reliable HPV genotyping for expanded use   proposal of GardasilTM vaccine

Dear Dr. Stapleton:

S.A.N.E. Vax, Inc. is a non-profit organization established to promote safe, affordable, necessary and effective vaccines and vaccination practices. We have been informed by the news media that the Vaccines and Related Biological Products Advisory Committee will meet on Nov. 17 to discuss the effectiveness of GardasilTM vaccination of males and females to prevent anal dysplasia and anal cancer, in fact to initiate a regulatory process which may lead to FDA expanded use approval allowing GardasilTM to be marketed as a cancer vaccine to the general American population, including both men and women.

Although detailed information has not been provided, the vaccine manufacturer seems to propose using ‘anal dysplasia and anal cancer’ as a single primary endpoint for evaluating the effectiveness of this virus vaccine.

The SaneVax team believes this primary endpoint is inappropriate for the following reasons:

  1. Anal dysplasia, also known as anal intraepithelial neoplasia (AIN),1 is a term representing collectively various grades of precancerous changes, also referred to as epithelial dysplasia, grades I, II and III. There is considerable inter-observer variation in the reporting of this condition even by experienced histopathologists.1 If anal dysplasia is used as an endpoint for evaluation in the clinical trials, the grades of dysplasia must be stratified in the vaccinated group and in the placebo group so that the percentage of a particular grade of anal dysplasia can be compared between the vaccinated and the placebo-receiving subjects for efficacy calculation. The vaccine manufacturer must present data to show the percentage of spontaneous regression of each grade of anal dysplasia in the trial human population so that the self-reversing lesions in a low grade of dysplasia will not introduce bias in the calculation of the effectiveness of the vaccine.
  2. A number of risk factors have been implicated in the development of anal dysplasia, with the most significant being anal HPV infection, receptive anal intercourse, HIV infection, and lower CD4+ levels. The subjects enrolled into the clinical trial programs for the evaluation of the efficacy of GardasilTM to prevent anal dysplasia must have similar risk factors. Only when all risk factors have been equalized, a reduced rate of anal dysplasia observed in the vaccinated group, if any, compared to the placebo-receiving group, can be attributed to the effects of Gardasil vaccination. It is well known that different HPV genotypes pose different levels of cancer risk. Reliable HPV genotyping is essential in stratification of risk factors to anal dysplasia among enrolled trial subjects. Since PCR/short target DNA sequencing is the only reliable method for HPV detection and genotyping, 2 all pre-vaccination and post-vaccination HPV infections in these trial subjects must be ruled out by PCR or confirmed by short target sequencing genotyping. It is obvious that trial subjects infected by different genotypes of HPV will have different risks in developing anal dysplasia independent of the effects of GardasilTM vaccination.
  3. The vaccine manufacturer must demonstrate the effectiveness of GardasilTM in preventing each grade of anal dysplasia. The criteria of diagnosis for each grade of anal dysplasia must be clearly defined and the diagnosis must be consistently reproducible among at least three board-certified pathologists.
  4. It is well known that anal dysplasia is largely a pathology found in patients who have a history of practicing receptive anal intercourse.3 The clinical trial data derived from study subjects practicing anal sex should not be extrapolated to  populations which do not practice anal sex. If the vaccine manufacturer claims that GardasilTM is also effective in preventing anal dysplasia in the populations which do not practice anal sex and intends to market GardasilTM to the latter group, then trial subjects who do not practice anal sex must be recruited for the clinical studies, independent of those studies in which the trial subjects are practitioners of anal sex.
  5. If the vaccine manufacturer intends to claim that GardasilTM can prevent the development of anal cancer, then anal cancer must be used as the primary endpoint to determine the efficacy of the vaccine. Precancerous changes, such as anal dysplasia grade I, grade II or gradeIII, should not be used as a surrogate endpoint for anal cancer in the clinical trials.
  6. If the vaccine manufacturer intends to claim that GardasilTM can prevent anal infection by vaccine-relevant HPV genotypes, then a reliable method, namely a PCR system with short target DNA sequencing2 must be used to detect HPVDNA in the anal specimens and for HPV genotyping.

Our research also revealed that an inappropriate primary endpoint was used in the evaluation of GardasilTM to prevent cervical cancer, and that no reliable HPV genotyping methods were used to validate the efficacy of GardasilTM to prevent genotype-specific HPV infections in women. A letter to the FDA commissioner, requesting that the FDA rescind approval of GardasilTM as a vaccine for prevention of cervical cancer, is enclosed herewith for your reference.

In the interest of promoting and protecting the public health, S.A.N.E. Vax, Inc. respectfully requests that expanded use for GardasilTM as an anal cancer preventive vaccine be delayed, until such time as the efficacy of the vaccine is properly evaluated using the true endpoint for anal cancer prevention, and a reliable HPV genotyping method for detection of type-specific HPV infections.

I am looking forward to receiving your response to this reasonable request on behalf of medical consumers around the world.

Yours respectfully,

Norma Erickson, President 
S.A.N.E. Vax, Inc. 
154 Cecil Drive 
Troy MT 59935
 
Signed on behalf of the Board of Directors, S.A.N.E. Vax, Inc. 
Leslie Carol Botha, Vice President of Public Relations 
Janny Stokvis, Vice President of Research 
Rosemary Mathis, Vice President, Victim Support 
Freda Birrell, Secretary 
Linda Thompson, Treasurer 

References

  1. Carter PS, Sheffield JP, Shepherd N, Melcher DH, Jenkins D, Ewings P, Talbot I, Northover JM. Interobserver variation in the reporting of the histopathological grading of anal intraepithelial neoplasia. J Clin Pathol. 1994;47:1032-1034.
  2. National Cancer Institute. HPV Genotyping. Solicitation Number: NCI-100143-MM. August 2, 2010. https://www.fbo.gov/index?s=opportunity&mode=form&id=da396b97ad6eb7ec4f7d511f85d9e325&tab=core&_cview=0
  3. Moscicki AB, Hills NK, Shiboski S, Darragh TM, Jay N, Powell K, Hanson E, Miller SB, Farhat S, Palefsky J. Risk factors for abnormal anal cytology in young heterosexual women. Cancer Epidemiol Biomarkers Prev. 1999;8:173-178. 

CC:   Vaccines and Related Biological Products Advisory Committee:

Donald Jehn, M.S., Designated Federal Officer 
Denise Royster, Committee Management Specialist 
Ambrose Cheung, M.D., 
Vicky Debold, Ph.D., R.N. 
Frank DeStefano, M.D., M.P.H.
Anna Durbin, M.D. 
Peter Gilbert, Ph.D. 
Gregory Gray, M.D., M.P.H. 
Margaret Rennels, M.D. 
Jose Romero, M.D. 
Pablo Sanchez, M.D. 
Gary Schoolnik, M.D. 
Carol Tacket, M.D. 
 
Dr. Margaret Hamburg, M.D., Commissioner 
U. S. Food and Drug Administration (FDA)
Filed Under: United States Concerns Tagged With: , , , ,
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