July 15th 2017


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Articles from this issue:

COVER STORIES Liberal discontents take internal struggle to Shakespearean heights

NATIONAL AFFAIRS Cardinal Pell charged: the process is the punishment

EUTHANASIA What Boudewijn Chabot can teach Victoria

INTERNATIONAL AFFAIRS Taiwan's 'friends' make the Beijing cut

FREEDOM OF CONSCIENCE NT abortion law oppressive towards health professionals

HEALTH Gardasil(R) and the man upon the stair, Part I

AFRICAN AFFAIRS Special force deals with scourge of poaching

MUSIC Andrea Keller: transpositions of death and grief

CINEMA Cars 3: On ageing without rusting

BOOK REVIEW Biggest democracy makes big strides

BOOK REVIEW A refinement of the Industrial Revolution

LETTERS

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HEALTH
Gardasil(R) and the man upon the stair, Part I


by Dr Deirdre Little

News Weekly, July 15, 2017

Yesterday upon the stair
I met a man who wasn’t there.
He wasn’t there again today ...

 

Dr Deirdre Little is a general practitioner in Bellingen, NSW, where she has worked in private practice and in the district hospital since 1985. Her qualifications include MBBS (Syd), DRANZCOG, FACRRM and a Graduate Certificate in Bioethics. In this first part of a two-part series, Dr Little writes about her experience as a general practitioner with young girls turning up at her surgery presenting with menopause-like symptoms. She outlines the investigations she has made and the research she has had published in which she raises questions about the trialling and safety of the Gardasil® vaccine. In part II, she reviews the resistance she has come up against within the drug research community to her findings, although, as she says, her findings have not been refuted.

 

Vaccines are wonderful. Can’t live without them. Love them. Thank you, Edward Jenner, gratefully named the “father of vaccines”. We can never know the total number of tragic deaths that have been, are being and will be prevented by the birth of this science.

Doctors are rightly committed to vaccinations. We know their benefits. We also know the importance of being able to trust and rely responsibly on their product information (PI). We are assured of licensed vaccines’ successful journey through well-designed “double-blind, placebo-controlled randomised trials” with sound internal validity and generalisable outcomes.

We have confidence that these pillars of the scientific method have sifted the benefits and sieved the risks of the final vaccine product to a knowable tally. Patient questions – and our own – will lean on this accounting.

We know, too, rarer vaccine-adverse events may slip between these tall pillars and into the family GP’s office. Our job is to flag such possible adverse events. The accompanying science of pharmacovigilance begins at the visit to the doctor. The World Health Organisation stresses the importance of this after-sales service for “the detection and prevention of adverse effects or any other possible drug-related problems”.[1]

The trustworthiness of each step in this process – from the tested rat to the GP’s desk – is not only a condition for informed consent, it protects those for whom a vaccine may be harmful or “contra-indicated” and, just as importantly, it is the bulwark of public vaccine confidence.

Thus, the presentation of three young teenagers with disintegrated menstrual cycles and formal diagnoses of early menopause after receiving Gardasil® vaccination is going to raise the antennae of any non-comatose GP. Case reports cannot establish causality and correlation is not causation, but correlation is the basic ingredient of pharmacovigilance. GPs notify and researchers research. This notifying GP has lately found a few holes in the system.

 The first young teenager had noticed her cycle pattern change after vaccination. She rightly queried any possible association. I rightly replied I did not think so, but would “look into it”. She had been diagnosed as having premature menopause, also known as premature ovarian failure, in high school. It is now known by the more benign-sounding but no less harmful name of “premature ovarian insufficiency”.

Product information gave the most common side effects. She needed more. After a “Freedom of information” (FOI) request to see the rat ovary histology (microscopy) report after trialling of Gardasil®, I found there was none. Histology was only presented for the male rat testis. Curious. My FOI request was not displayed on the government website as legislatively required because it was commercially sensitive. Curiouser. This first case was published in the British Medical Journal Case Reports, 2012.[2] Peer reviewed. In 2013 a similar series of cases of teen premature ovarian failure was published in the American Journal of Reproductive Immunology 2013.[3] Peer reviewed.

My earliest Gardasil® safety research review findings were presented to the 18th World Congress of Controversies in Obstetrics, Gynaecology and Infertility (COGI) in 2013.[4] Peer reviewed. My subsequent cases were also published, after peer review, in the Journal of Investigative Medicine High Impact Case Reports, 2014.[5]

I was invited to present my literature search review of Gardasil® safety research to the 10th International Autoimmune Congress Leipzig 2016 and I also presented to the 23rd World Congress COGI in Melbourne 2016. The former was peer reviewed and published in 2017.[6]

There has been no formal refutation. I have earned the right to comment on this vaccine’s ovarian safety profile and respectfully to request more research into this phenomenon, which is so rare that there are no figures for its occurrence in young teens.

This great grandbaby of vaccine science well deserves such scrutiny. Gardasil® protects against four types of human papillomavirus (HPV), of which two types cause 70 to 80 per cent of cancer of the cervix in Australia.[7] It can cross-protect against a third cancer-causing viral HPV type, known as type “31”.[8]

Previously, Australian women had relied on our pap-smear screening program, which could prevent up to 90 per cent of cancer of the cervix but is about to be axed. Pap smears are less successful at finding the much less common cervical adenocarcinomas, of which 80 per cent contain vaccine-protected types, not including type 31.

The pap-smear screening take-up in Australia has recently declined, with a concomitant plateauing decline[8] in cancer reduction and now an increase in cervical cancer – expected to rise to 7.1 cases per 100,000 women in 2017,[9] up from 6.8 cases in 2013.

The new five-year viral screening and vaccination plan could reduce these cases by 70 to 80 per cent if we can reverse the “alarming” decline in screening by vaccinated women[10] and if vaccine protection is long lived. Its lifespan is not yet known. Due to the nature of the disease process, a measured effect of this vaccine on actual cancer (cervical, anal, oropharyngeal) may not be seen for 10 years.

My review of Gardasil’s® safety research regarding the adolescent ovary has just been published.[6] Rat fertility studies were not generalisable to the standard three-dose young teen course because rats were all tested for their ability to conceive after two vaccine doses, not three.[11, 12] There is still no ovary histology report. Rats were killed after their first and only litter – so fertility longevity and ongoing egg-bearing capacity is unknowable.

In a separate study of tested mice (not referenced at licensing) only weights of testes were published after vaccination,[13] not ovary weights. No girls in the vaccine’s target age group of 12 to 13 years participated in Gardasil’s® huge phase III safety studies.[14, 15] Moreover, up to 83 per cent of phase III trial participants were on hormone-masking contraception.[16] Contraception was permitted to cease at month seven, but new medical conditions occurring after month seven were not to be reported.[17]

Only two phase II studies enrolled young teens. One had no control group and lost more than half its participants to follow-up at 12 months.[18] (How is that a safety study?) The other gave three Gardasil® doses to 587 young girls of average age 11.9 years.[19] How many had reached puberty is not known as menstrual cycles are not recorded or reported on in published trials.

 

Dr Deirdre Little

Our reference: R15/554600                                                                  31 August 2015

Dear Dr Little

Subject: Gardasil Product Information Safety Trial Data

Thank you for your correspondence of 20 June 2015 regarding the representation of Gardasil’s safety trial information in its Product Information (PI).

Following a review of the PI, I have been advised that your observation about the composition of the placebo in study 018 is valid and that the current information is a misrepresentation of the situation. That is, that the current reference to the placebo being “saline” misrepresents the actual placebo used in protocol 018.

As a result of this review, the sponsor, Merck, Sharpe and Dohme Australia Pty Ltd, have been requested to amend the relevant headings in Table 11 and Table 12 of the PI from “Saline Placebo” to “Placebo” and under each table include an additional footnote stating the composition of the (non-aluminium containing) placebo. Merck have been asked to undertake this amendment when they next revise the Product Information.

Thank you for bringing this matter to my attention.

Yours sincerely

(Signed) Dr John Skerritt
Therapeutic Goods Administration
Department of Health

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Product Information[20] and licensing documentation[21] state a saline placebo was used in safety trials. A saline placebo was never used in any safety trials. The published trial abstract misrepresents the placebo.[19] In 2015 I informed the Therapeutic Goods Administration (TGA) that Gardasil® PI falsely claimed use of a saline placebo to establish vaccine safety. Dr John Skerritt,[22, see accompanying text] national manager of the Therapeutic Goods Administration, verified my observation and PI was, partly, corrected by Merck Sharp and Dohme in Australian PI in 2016, 10 years after vaccine introduction.

Furthermore, no controlled adolescent safety studies done since marketing began have ever reported on menstrual cycle patterns.[5] Only one study that included teenagers, a mere observational study, has reported on menstrual cycles. This study in a syncope (“fainting”) unit incidentally found 48 per cent of young women recorded irregular periods after Gardasil®.[23] No research is able to attest to ongoing ovarian safety after this vaccine.

It has now been presented, published, and peer reviewed and remains unrefuted: no scientific sieve has yet been applied to this tragic young teen safety signal.

Responses from health authorities are breathtakingly void. The TGA/Department of Health and Ageing 2013 directive to vaccine providers claimed that “high doses of HPV vaccine in female and male rats showed no evidence of infertility”.[25] But high doses were not used. Two-thirds of the total dose was used. Their directive states that there is “no biologically plausible” link, ignoring the known ovarian toxicity of injected polysorbate 80[26] present in both the vaccine and all placebos, unidentified,[6, 14, 15, 23, 26, 27] and ignoring the postulated autoimmune ovarian effects of aluminium.[3, 28, 29]

Thanks to the use of improper placebo principles (a placebo should lack the substance being tested and be correctly identified), if such substances did cause cycle demise, it wouldn’t show up in safety trials. Orally ingested polysorbate 80 doesn’t affect rat ovaries until a much higher dose is given, but this is said to demonstrate ovarian safety in injected forms.[24]

References

1. Uppsala Monitoring Centre: A global culture of patient safety, sighted May 24, 2017.

2. D.T. Little and H.R. Ward, Premature ovarian failure 3 years after menarche in a 16-year-old girl following human papillomavirus vaccination, BMJ Case Reports, 2012.

3. S. Colofrancesco et al, Human papilloma virus vaccine and primary ovarian failure: another facet of the autoimmune/inflammatory syndrome induced by adjuvants, Am J Reprod Immunol, 2013.

4. D.T. Little, Human papillomavirus vaccine and the ovary: The need for research, in Proceedings of the 18th World Congress on Controversies in Obstetrics, Gynecology and Infertility, 2013.

5. D.T. Little and H.R.G. Ward, Adolescent premature ovarian insufficiency following human papillomavirus vaccination: A case series seen in general practice, Journal of Investigative Medicine High Impact Case Reports, 2014.

6. D.T. Little, Quadrivalent human papillomavirus vaccine and the young ovary: Review of safety research following two case series of premature ovarian insufficiency, Journal of Immunology and Infectious Diseases, 2017.

7. J. Brotherton, How much cervical cancer in Australia is vaccine preventable? A meta-analysis, Vaccine, January 10, 2008.

8. M. Smith and K. Canfell, Impact of Australian National Cervical Screening program in women of different ages, Med J of Aust, 2016.

9. Cervical cancer statistics, 2017, Australian Government.

10. A. Budd et al, Cervical screening rates for women vaccinated against human papillomavirus, Med J of Aust, 2014.

11. L.D. Wise et al, Lack of effects on fertility and developmental toxicity of a quadrivalent HPV vaccine in Sprague-Dawley rats, Birth Defects Research (Part B), 2008.

12. L.D. Wise et al, Lack of effects on male fertility from a quadrivalent HPV vaccine in Sprague-Dawley rats, Birth Defects Research (Part B), 2010.

13. EMEA Scientific Discussion, [0]. 2006, p39.

14. S.M. Garland et al, Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases, N Engl J Med, 2007.

15. Future II Study Group, Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions, N Engl J Med, 2007.

16. N.B. Miller, Clinical review of Biologics License Application for human papillomavirus 6, 11, 16, 18 L1 virus-like particle vaccine. (S. cerevisiae) (STN 125126 Gardasil), Center for Biologics Evaluation and Research Food and Drug Administration, 2006, p143.

17. S. Block et al, Clinical trial and post licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine, Pediatr Infect Dis J, 2010.

18. S. Block et al, Comparison of the immunogenicity and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16 and 18) virus-like particle vaccine in male and female adolescents and young adult women, Pediatrics, 2006.

19. K.S. Reisinger et al, Safety and persistent immunogenicity of quadrivalent human papillomavirus Types 6, 11, 16 and 18 L1 virus-like particle vaccine in preadolescents and adolescents: A randomised controlled trial, The Pediatr Infect Dis J, 2007.

20. Product Information Gardasil®WPC-V501-I-022011, 2010.

21. Miller, op cit, p330.

22. J. Skerritt, TGA formal communication re Gardasil Product Information safety trial data, August 31, 2015, Therapeutic Goods Administration of Autralia.

23. L. Brinth, A. Theibel, and K. Pors, Suspected side effects to the quadrivalent human papilloma vaccine, Danish Medical Journal, 2015.

24. Myths and Realities: Responding to arguments against vaccination. A Guide for Providers, TGA Aust Gov Dept of Health and Ageing, 2013.

25. M. Gajdova, J. Jakubovsky, and J. Valky, Delayed effects of neonatal exposure to Tween 80 on female reproductive organs in rats, Food Chem Toxic, 1993.

26. Product Information Gardasil®WPC-V501-I-022011.

27. L.L. Villa, R.L. Costa, and C.A. Petta, Prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial, Lancet Oncol, 2005.

28. C. Perricone et al, Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects, Journal of Autoimmunity, 2013.

29. Y. Fu et al, Effects of sub-chronic aluminium exposure on rat ovaries, Life Sciences, 2014.




























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