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Gardasil - The Mercky World of Anti-Cancer Vaccines

By Cathy van Miert

President Nixon declared the "war on cancer" in 1971 by passing the National Cancer Act. A bounty of US$100 million was provided for research in the hope that a cure could be found for what was then the second-leading cause of death in the United States. At this time it was believed that many viruses played a role in cancer causation, so the race was on to identify, and develop vaccines against, the offending pathogens.

What followed was more of a one-legged limp to a distant finish line with precious little of therapeutic benefit arising from this research despite immense strides in technology and billions of dollars spent.
In June 2006 however, Merck Pharmaceuticals finally hopped over the finish line with Gardasil - the "first anti-cancer vaccine".

So is Gardasil really the Holy Grail of cancer prevention - or is it just media hype?

Following US Food and Drug Administration (FDA) approval, Gardasil received the biggest hard sell of any recently introduced new medicines. Merck staged a dual campaign of intense lobbying of congress to have the vaccine made mandatory for all 11- and 12-year old girls, in tandem with an equally intense media campaign.

While a "life-saving vaccine" would be logically expected to sell itself, the campaign suffered some serious setbacks. Far from being perceived as a miracle, some sections of the public are regarding the vaccine with scepticism and suspicion. A vociferous backlash has put many of these state mandates on hold, and those state governors who initially backed the mandates have justified fears for re-election.

It isn't all doom and gloom for Merck however; the vaccine is predicted to achieve blockbuster status of over $1 billion in sales by the end of 2007. The media campaign is reaping pretty good returns.

The Hard Sell

The "One Less" Gardasil TV commercial is a prime example of slick marketing and corporate spin. In an attempt to resonate with its intended recipients, Merck has effectively 'branded' Gardasil much like Coca Cola or MacDonalds.

Pretty girls with 'attitude' display the words "One Less" written on skateboards, running shoes and clothing, while performing cool but wholesome activities like skateboarding, basketball and playing drums. They look deadpan at the camera; repeatedly stating they would like to be the "one less" (death from cervical cancer) statistic. Then an attractive mom introduces a note of caution delivered in loving, dulcet tones that the vaccine has potential adverse effects (required by US advertising law).

The overall message is that Gardasil is "cool" and lifesaving, even when mum has a few concerns (a note of teen rebellion). Furthermore, it's the only vaccine available, so who could possibly say no?

Watching the commercial more carefully demonstrates just how clever Merck has been with this approach - "one less" negates the need to state actual numbers of lives they expect Gardasil to 'save'. And the words in the voice-over expose a subtle but important difference between the commercial's overall feel and the necessity of insuring themselves against future litigation or charges of fraudulent claims.

"Gardasil - the only vaccination that may protect you against 4 types of human papilloma that may cause 70% of cervical cancer".

The voice is inflected on the word 'only' while 'may' almost slips past unnoticed. Semantics surely? But the use of the word may rather than will provides this insurance nicely; Merck cannot categorically state that Gardasil prevents cervical cancer for the simple reason that it has not been proven to do so in properly conducted clinical trials. This omission has not deterred the US Centers for Disease Control from recommending that all women between ages 11 to 26 years should be vaccinated.

In New Zealand, Merck seem rather more brazen than their US counterparts in the claims being made for Gardasil. On their website - gardasil.co.nz - information is provided for both patients and health professionals. Both are informed that HPV causes all cervical cancer. It appears that our cervixes (or our litigation laws) are different to those of the rest of the world! The information provided for doctors makes even more bizarre claims; "Gardasil is 100% effective in protecting your patients from diseases caused by HPV 16, 18, 6 and 11" including cervical cancer!" Were Ministry of Health officials asleep when this one snuck under the radar?

What you should know about this vaccine

Rather than rely the emotive (but no less important) anti-vaccine arguments this writer would like to bring a little logical perspective to the debate by looking at the evidence for the vaccine's effectiveness.

Human Papilloma Virus (HPV) infection is mild and self-limiting in the majority of cases; indeed many people have no symptoms at all. The virus is generally cleared from the system within a few weeks to months.

HPV is not a single virus entity - over 200 sub-types have been identified, 30 of which are known to infect the genital tract. HPV 6, 11, 42, 43 and 44 are classified as low-risk (for cancer), while 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 70 are considered to be the "high-risk" subtypes depending on the population studied. Viral particles of subtypes 6, 11, 16 and 18 are used in the Gardasil vaccine. Although HPV DNA has been found in ~ 80% of cervical squamous carcinoma, many researchers feel that HPV alone "is neither necessary nor sufficient" for the development of cervical carcinoma, and have found evidence that additional genetic predispositions must be present. A US study published in Clinical Microbiology Reviews in 2003 stated:

"A genetic predisposition to colorectal cancer, lung cancer, and melanoma has long been recognized and is widely accepted. Genetic predisposition was found to be even a greater component in cervical cancer when the same method of analysis was used. Genetic heritability was found to account for 27% of the effect of underlying factors for tumor development. Heritability could affect many factors contributing to the development of cervical cancer, including susceptibility to HPV infection, ability to clear HPV infection, and time to development of disease."

And yet Merck state repeatedly on their promotional material that cervical cancer is not heritable.

Far from being the much-touted epidemic, the incidence of cervical cancer has been declining steadily for the last 50 years largely thanks to effective screening programmes. Mortality from cervical cancer has also decreased - between 1980 the rate dropped from 12 to 5 per 100,000 people per year; so while HPV infection is on the increase, the rate of cervical cancer is not.

Cervical cancer falls into two types; squamous carcinoma and adenocarcinoma - the former is associated with the human papilloma virus (HPV). Squamous carcinoma is more easily detected by Pap smear, and comprises about 70% of all cervical cancers. The remaining 30% adenomcarcinomas are not easily detected with current cervical screening because it develops further up the cervical canal in areas that are not accessed by the traditional Pap smear.

How much does "One Less" cost?

The current incidence (new cases per year) of cervical cancer in NZ is 14 per 100,000 women - and one in three will die from the disease.

The cost of the 3 vaccinations required is $450.00. Once the GP fees are included (around $50.00 per visit) the total cost is roughly $600.00.

GSK's rival cervical cancer vaccine was shown to have "efficacy [antibodies in the blood] for up to 4.5 years". If we assume Merck's vaccine to be slightly superior, and generously allow up to 5 years protection (and it is a big if) and then calculate the number of HPV 16 and 18 associated cancer incidence:

14 X 70% (HPV-associated cervical cancer) = 9.8 cases per 100,000

9.8 X 30% (non HPV 16, 18-associated cervical cancer = 2.94 per 100,000

9.8 - 2.94 = 6.9 per 100,000 women per year with an HPV16,18-associated cervical cancer

6.9 per 100,000 equates to a 1 in 14,492 chance per year of getting the type of cancer associated with the strains of HPV in the Gardasil vaccine. Put another way, 14,492 females would have to be vaccinated to prevent one case of cervical cancer:

14,492 X $600 = $1,739,040
5 years

To possibly prevent one case of cervical cancer

$1,739,040 X 3 = $5,217,120

To possibly prevent one death from cervical cancer

There will always be the argument that every life is priceless, but the price tag of over 5 million dollars to possibly prevent one death from cervical cancer makes the Herceptin (breast cancer drug) funding issue look like the contents of the tips jar at a kleptomaniacs' convention.

So what evidence is there that Gardasil prevents HPV, and by inference, cervical cancer? A Medline search with the limit "randomised clinical trial" and the key word "Gardasil" returns nothing.

Forgive my cynicism, but surely the peer-reviewed medical publishing world would fight over publication of studies proving an anti-cancer vaccine was "effective and safe" if they were written in green crayon on plastic bubble-wrap by a dyslexic 2-year old chimpanzee. This should be earth-shattering news after all. Don't the researchers want any glory? They are not usually such reticent beings.

Evidence-Based Medicine?

There have been a few published HPV vaccine trials however; a repeat search using the key words "HPV vaccine" instead of "Gardasil" yielded 4 results. Reading these studies was a Goldilocks-type experience. One was too small, one was irrelevant, and two used a different vaccine. So where was the evidence of testing in over 20,000 women in clinical trials?

The only evidence of these trials is the Merck data itself (remember these are the chaps who "forgot" to submit the data on the deadly cardiovascular effects of Vioxx to the FDA or New England Journal of Medicine).

The trial results have not been published in the peer-reviewed literature, but were submitted for the FDA approval requirement. This is very common, and it may surprise many to learn that the FDA does not require publication of the data either prior to, or following approval. This means that new drugs, vaccines and devices are not independently reviewed before coming to the market. How 'independent' these FDA officials are is a valid point; new rules announced in March 2007 will bar medical professionals from serving on their advisory committees if they receive less than US$50,000 from the company whose product is being evaluated (or a competitor)! $49,999.99 wouldn't influence anyone - would it? How much were they receiving under the old rules?

A summary of their data is available in an FDA Vaccines and Related Biological Products Assessment Committee (VRBPAC) background document. It combines the results of some (but not all) of the Merck trials of Gardasil. The document is a veritable morass of anomalies and contradictions.

1) In its promotional material Merck claims that women aged 16-23 years are at highest risk of HPV infection; presumably due to the high level of sexual activity in this demographic.

The largest phase III study was the FUTURE (Females United To Unilaterally Reduce Endo/ectocervical disease) II study. Described as "a randomised, worldwide, placebo controlled, double blind study" which enrolled 12,167 women aged 16-23 years of age. Women were excluded if they were deemed high-risk (more than 4 lifetime sexual partners or other conditions deemed by the investigator to possibly interfere with the trial).

So Merck apparently excluded exactly the "high-risk" demographic the vaccine was intended for!

What the conditions were that investigators deemed to be possible interfering factors were not described. This is scientifically unusual; exclusion criteria are generally listed.
Of over 12,000 women screened, only 540 (4.5%) were deemed "high risk".

Only 4.5% of women screened by Merck were "high-risk" - how did they tap into such a virginal or abstentious population?

2) The results of study 015 are decidedly self-contradictory. External growth lesions (EGL or warts) were measured and the offending HPV subtype identified:

Table 1: EGL caused by HPV 6/11/16/18

Endpoint Gardasil
(n = 6082) Placebo
(n = 6075)
HPV 6/11/16/18 EGL (cases) 1 70

Table 2: EGL caused by all HPV infection (including HPV 6/11/16/18)

Endpoint Gardasil
(n = 6082) Placebo
(n = 6075)
HPV any type EGL (cases) 96 177

Merck has claimed repeatedly that "strains 6 and 11 cause 90% of genital warts". If this were the case then why so many extra cases of "all" HPV once the HPV 6/11/16/18 are subtracted. Using the 90% figure, one would expect 7 extra HPV infections caused by other strains rather than the 107 reported in the placebo group, and there should have been only 7 rather than 96 in the Gardasil group. According to Merck's own results, strains 6 and 11 contribute less than 40% to all genital warts.

3) In study 013 when they compared "HPV 6/11/16/18 and CIN 1" (pre-cancerous cells) and all "HPV and CIN 1 or worse" and the same phenomenon occurred - only 32% of the EGLs were caused by HPV 6/11/16/18. In the placebo group it was reported that there were 39 cases of CIN related to the HPV strains in the vaccine and 107 related to strains not covered by the vaccine, putting the oft-claimed 70% figure under the spotlight again; it now looks more like 27%.

4) The prevalence of women who were positive to HPV infection (using PCR) at the start of the study was 568/9075 in the Gardasil group and 580/9075 in the placebo group.
This puts HPV prevalence of Merck's participants at just over 6%, and yet most prevalence studies put (PCR) HPV prevalence at 30%.

5) The placebo recipients received one of two preparations. This type of protocol is unheard of in 'placebo controlled' studies.

Of all "placebo" recipients, 3470 received a preparation containing aluminium and 594 received saline - only 17% received a true placebo.

Aluminium is not an inert substance when it is injected into the human body. It is added as an adjuvant to enhance the immune response to a viral vaccine that on its own produces only a weak (and ineffective) response.

Why use this atypical protocol? Because it skews the safety data considerably; it effectively ensures that the adverse effects between placebo and Gardasil recipients did not differ significantly so they could claim it was 'safe and well tolerated'. In only one table the saline recipients are listed separately but in all the others they were not. This is nothing but scientific sophistry.

6) In one of the studies, in the group that had asymptomatic HPV infection confirmed at the start of the study, Gardasil vaccine resulted in a 33% greater number of external genital lesions. How did Merck explain this result?

"Differences in baseline characteristics". The package insert has conveniently left this information out.

7) When Merck combined the efficacy analyses for studies 007, 013 and 015 they used a "composite endpoint" to compare the efficacy of the vaccine with placebo. Researchers often use this somewhat sneaky contrivance when they know their product will not achieve any significant benefit in any single endpoint such as the 'actual' numbers of cervical cancers in each group. CIN 2/3 does not always progress to carcinoma. Lumping them in together does not allow any meaningful comparison.

8) Merck lobbied congress hard to have the vaccine made mandatory for all girls aged 11-12 years. Their trials had such a short duration of follow-up that nobody knows how long the antibodies will hang around (GSK's vaccine was 4.5 years).

The antibodies will be long gone from the bloodstream when an 11-year old vaccinee becomes sexually active 7-8 years later. Repeated vaccines would be necessary to confer ongoing protection (if it works) throughout her lifetime of sexual activity of over 40 years.

The Merck study results are inconsistent and self-contradictory at the very least; what they might be at worst could be the basis of litigation. They should be seriously called into question and thoroughly examined by independent (if there are any) epidemiological peer-reviewers.

To be fair to Merck, it is very difficult to prove an intervention works (or not) in healthy individuals. Usually 200 or so people have actually contract a disease in each group for the data to have any statistical power. If cervical cancer only has an incidence of 14 in 100,000 women/year they would need to follow over 2 million women for 1 year, or 1 million women for two years- and so on. Far more convenient and profitable for Merck that we offer up our daughters as the guinea pigs whilst paying through the cervix for the privilege - it's called "Post-Marketing Surveillance (and Merck have a woeful track record on that too).

Summary

• Gardasil is a vaccine that may protect against a virus that may cause some but certainly not the majority of cases of cervical cancer


• Gardasil is a vaccine that may only confer protection for less than 5 years


• Gardasil is a vaccine that will require the spending of over five million dollars to possibly prevent one death


• Merck are laughing all the way to the bank

ENDS

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