[Note from SaneVax: On April 23 an open letter was sent to the European Medicines Authority (EMA) containing multiple questions regarding their recent assessment of HPV vaccine safety. True to their word, the EMA responded within 30 days. Their response was sent to signatories for perusal. Below is the original letter, complete with the EMA responses and the follow-up response from various individuals who signed the original letter.]
3rd June 2016
Questions to EMA & comments to answers from EMA
There is a growing number of adolescents becoming seriously ill after HPV vaccinations. Consequently many parents, general physicians, medical specialists (including cardiologists, gynecologists, immunologists, neurologists, rheumatologists, pathologists, etc.) and scientists (biochemists, neuroscientists, etc.) around the globe strongly disagree with your conclusions that the benefits outweigh the risks of HPV vaccines (Cervarix/Gardasil) currently offered to young girls to prevent cervical cancer.
It is a commonly accepted rule that the risks of any preventive interventions offered to healthy people should be close to zero. An emerging amount of peer-reviewed literature suggests this is not the case with Gardasil and Cervarix, both of which contain aluminum as an adjuvant.
On the other hand, it is well known that health authorities have more raw data for risk/benefit evaluation than what can be found from the published literature. Consequently, the continuously expanding group of laity and academic professionals wish to ask you the following questions divided into major and other concerns:
Major points of concern
I. Pharmaceutical Questions
a) HPV vaccine (Gardasil) has been shown to contain viral DNA impurities that have been related to fatal adverse events (SAEs, Refs.: e.g. Lee SH, 2012a Advances Biosc Biotech, 3: 1214-24; Lee SH, 2012b J Inorg Chem, 112: 85-92, Lee SH 2013, Advances Biol Chem, 3:76-85). What is the impact of these pertinent findings on the benefit/risk ratio? Shouldn’t the marketing authorization be reconsidered (see recent open letter of complaint to the Director-General of the WHO, Dr Margaret Chan).
RESPONSE FROM EMA: “Vaccines may contain residual amounts of viral or cellular DNA fragments (depending on the manufacturing process) that originate from the processes used for their manufacture and this is not considered a contaminant but a residual substance. During the evaluation of the manufacturing process for any medicinal product, including vaccines, the possibility of impurities and endogenous viral contaminants is always investigated.
Although the manufacturing process of vaccines is strictly controlled and designed to minimise residual DNA to within acceptable limits, the presence of trace amounts of such residues is inevitable. This is not considered to pose a risk for recipients of the vaccines and there has been no identified link between its presence and any adverse events.
Regarding host related impurities for Gardasil, the clearance and estimated amount of DNA and RNA was evaluated at the time of the marketing authorisation application (MAA) and it was within the acceptable limits. The DNA assay validation was described in the dossier and assessed by the CHMP. The results confirmed the sensitivity of the residual DNA method for samples from the manufacturing process.
The findings of residual amounts of viral DNA fragments referred to in the question are an expected finding and data in the literature supports that the residuals are rapidly eliminated and do not result in any expression of protein. The findings do not support that Gardasil is contaminated with HPV DNA and have no impact on its benefit risk balance.
We would like to inform you that for vaccines, as for any other medicinal product, a thorough evaluation of its quality, safety and efficacy is undertaken prior to approval. In addition, the EMA takes very seriously its role in protecting public health by monitoring medicines already on the market, and as such, the quality, safety and efficacy of all medicines, including all vaccines, are continuously monitored.
See also responses to questions under the section ‘other concerns, preclinical questions I.a/b. ”
Signatories’ comment: The clinical significance of the published data referred to in the question has not been addressed in the response. The issue remains unsolved.
II. Preclinical questions
a) What is the LD50 of aluminum? How does it compare to the amount of aluminum in HPV vaccines?
b) Has aluminum been shown to be safe in animal models when applied parenterally (i.e. sc, im, ip or iv) at doses equivalent to human exposure? If not, what toxic reactions have been found?
EMA RESPONSE: “For aluminium hydroxide, published data have shown a LD50 following an injection into the abdomen in rats of 1100 mg/kg bw [Joint FAO/WHO Expert Committee on Food Additives; WHO Food Additives Ser 24: Aluminum (1989). Available from, as of June 4, 2004: http://www.inchem.org/documents/jecfa/jecmono/v024je07.htm] and a LD50 of >5000 mg/kg bw when given orally (through the mouth) in rats [European Chemicals Bureau; IUCLID Dataset, Aluminum hydroxide (21645-51-2) (2000 CD-ROM edition). Available from, as of June 15, 2004: https://ec.europa.eu/jrc/]
Similar values have been reported for oral LD50 values for aluminium phosphate (https://www.fishersci.ca/viewmsds.do?catNo=AC344445000).
The use of aluminium hydroxide and aluminium phosphate as adjuvants in products for specific immunotherapy is established for several decades and the substances are defined in the European Pharmacopoeia. It has been proven that aluminium adjuvants in some vaccines enhance the capability of mounting an adequate immune response that is able to confer protection from specific infectious diseases such as pneumococcal pneumonia, tetanus or diphtheria. Vaccines that are authorised to be placed on the market in the European Union are manufactured in accordance to strict standards of quality. Moreover, any potential risk has to be balanced against the important benefits of the use of these substances, as aluminium adjuvants are known to play an important role in enhancing the efficacy of certain vaccines.
Concerning aluminium, according to the European Pharmacopoeia the upper limit for the amount of aluminium for allergens and vaccines is 1.25 mg per dose. Most authorised vaccines in the EU contain less than this maximum amount. The content of aluminium for Gardasil and Cervarix is, for example, 0.225 mg and 0.5 mg per dose, respectively. For a person who weighs 25 kg, this corresponds to 0.009 mg / kg, and 0.02 mg/kg, respectively.
On the basis of the scientific assessments performed over the years by EMA1 and other experts such as from EFSA2, FDA3 and WHO4,5, the scientific evidence available to date continue to support the safe and effective use of aluminium adjuvants in vaccines.
Notwithstanding this, in the context of its routine on-going pharmacovigilance activities, EMA will review any new safety signal related to aluminium-containing vaccines, should they arise from the EudraVigilance database of suspected adverse reactions or from any other source of information.
Non-clinical studies (i.e. studies in animal models) for HPV vaccines, such as conventional studies of safety pharmacology, acute and repeated dose toxicity, local tolerance, fertility, embryo-foetal and postnatal toxicity, reveal no potential risk for humans. For details we would recommend consulting the EPARs, which are available on our website:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Scientific_Discussion/human/000721/WC500024636.pdf ”
Signatories’ comment: The scientific conclusion adopted by EMA (and other experts) on the safe and effective use of aluminium adjuvants in vaccines is not in line with the available published literature. The issue remains unresolved.
c) Based on the literature, aluminum is involved with ’autoimmune/autoinflammatory syndrome induced by adjuvants’ (ASIA) syndrome (refs. e.g. Shoenfeld Y & Aron-Maor A, 2000, J Autoimmun 14: 1-10; Shoenfeld Y & Agmon-Levin N, 2011, J Autoimmun, 36: 4-8). This syndrome has been described in several animal models (Refs. in textbook ’Vaccines & Autoimmunity’ 2015, edited by Shoenfeld, Y, Agmon-Levin N & Tomljenovic L, pp. 35-41). Has the possibility of aluminium induced ASIA syndrome been acknowledged before approval of marketing authorization for Cervarix or Gardasil, or at some point afterwards? Do these findings have any implications for human safety? If yes, what?
EMA RESPONSE: “As indicated above, there is no evidence linking aluminium contained in HPV vaccines, nor any other vaccine, to the development of an autoimmune syndrome. However, any adverse effects that may develop following vaccination including autoimmune diseases are continuously monitored as part of routine pharmacovigilance. ”
Signatories’ comment: The published literature on ASIA-syndrome has not been acknowledged in the response – nor presumably in the assessment of risk/benefit profile of HPV-vaccines. Thus, the issue remains unsolved.
III. Clinical Questions
Safety: POTS, CRPS and co-exsisting symptoms
a) Why have health officials evaluated only a few distinct symptoms (POTS, CRPS) in spite of the fact that in most cases there are usually a number of other co-existing symptoms?
It was not surprising to learn from EMA’s report that the criteria of POTS/CRPS were not met in all cases. In clinical realm, there is a vast number of those who have become seriously ill after being vaccinated regardless of whether the diagnostic criteria for POTS/CRPS are fullfilled or not. A wide variety of SAEs reported to the health officials has been published in peer-reviewed journals (refs. e.g. Chang J et al., 2011, J Neurol Neurosurg Psychiatry, 82(11): 1296-304; Chao C et al., 2011, J Intern Med, 271: 193-203; Colafrancesco S et al., 2013, Am J Reprod Immunol, 70: 309-16; Das A et al., 2008, Med J Aust, 189: 178; Di Mario FJ et al., 2010, J Child Neurol., 25: 321-7).
Therefore, shouldn’t different SAEs (experienced by previously healthy adolescents) be assessed as a group of post-vaccination symptoms (instead of focusing only on a single symptom at a time) when estimating the overall benefit/risk ratio?
EMA RESPONSE: As mentioned in the beginning of this letter, the scope of the scientific assessment conducted in the framework of a referral is defined by the Notification letter received by the EMA (http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/HPV_vaccines_20/Pro cedure_started/WC500189479.pdf). In this specific case, the scope focused on POTS and CRPS, and therefore they were the subject of the review.
However, the continuous monitoring of HPV vaccines is not restricted to these two symptoms and all SAEs of the HPV vaccines, as with all medicines, are regularly assessed within the periodic safety assessment reports (PSURs). General information on the PSURs submission and assessment can be found here: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC50014246 8.pdf, and here http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000620.js p&mid=WC0b01ac0580902b8d. Access-to-documents requests can assist in the retrieval of documents of interest, as it is elaborated below.
In addition to the PSURs, as part of active signal management procedures, SAEs reported in Eudravigilance, the European pharmacovigilance database, are also assessed regularly. This assessment identifies changes in reporting rate and severity of known adverse effects, as well as new and unexpected events, and allows action to be taken where the evidence warrants it. More information on signal detection and management can be found here: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC50012913 8.pdf
Signatories’ comment: The scope of the scientific assessment has to be the overall safety of the HPV-vaccines taking into account what is being published in peer reviewed literature. Therefore, the multifaceted SAEs experienced by the adolescents should be assessed as post-vaccination symptoms (see e.g. *). The issue remains unresolved.
(*) Martinez-Lavin M, Martinez-Martinez LA, Reyes-Loyola P. HPV vaccination syndrome. A questionnaire-based study. Clin Rheumatol. 2015; 34 (11): 1981-83.
b) Since the diagnostic criteria for CRPS was not established until 2010 (refs. 1,2 in EMA report for POTS, CRPS), how was a backround rate for this condition determined?
c) Presumably the data for the referred backround rate at EMA report was collected in the Netherlands by de Mos and colleagues (ref, 5 in EMA report); can this be considered to give a reliable estimate of the backround rate for any other country?
Do health authorities have some relevant statistics available from other member states or other countries (e.g. US, Japan) for comparison? In other words, shouldn’t the possible variation in the incidences of CRPS in various regions / countries be known in general population before any definite conclusions can be drawn of the CRPS risks related to HPV-vaccines?
EMA RESPONSE: b. and c. ”The syndromes are recognised to occur in the general population, including adolescents, regardless of vaccination. Proposed diagnostic criteria were discussed already in 20076 and have been defined more recently. As noted in the assessment report of the review procedure, published here (http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/HPV_vaccines_20/Opinion_provided_by_Committee_for_Medicinal_Products_for_Human_Use/WC500197129.pdf), the background incident rates for CRPS were calculated in reference to de Mos and colleagues (de Mos et al, (2007) The incidence of complex regional pain syndrome: A population-based study, Pain; 129, 12- 20.).
The PRAC used all the available scientific data to reach its conclusions in a fact-based approach. At the same time, PRAC also acknowledged that given the complexity of the syndrome and likely differential practice in approaches to diagnosis and management across countries and centres, reported background incidence may differ between countries. ”
Signatories’ comment: Data for variability in backround rate of CRPS seems to be missing. Thus, no definite conclusions can be drawn of the CRPS risks related to HPV-vaccines. Issue is resolved, but the conclusion drawn by the PRAC may be questioned.
– Safety: reproductive toxicity
a) Could there a be a real causality between HPV vaccination and premature ovarian failure as suggested in series of published case reports (e.g.. Colafrancesco S et al., 2013, Am J Reprod Immunol, 70: 309-16; Little DT & Ward HR, 2014, J Investig Med High Impact Case Report, 28(2):1-12, http://www.ncbi.nlm.nih.gov/pubmed/26425627, http://hic.sagepub.com/content/2/4/2324709614556129.full,
Are there any preclinical (unpublished) studies, where enduring ovarian capacity and duration of function have been researched in vaccinated female rats or other animals?
EMA RESPONSE: ”Concerning a possible causality link between premature ovarian failure (POF) and Cervarix, please note that suspected cases of primary ovarian failure are continuously monitored by routine pharmacovigilance activities, which includes systematic review of the literature.
Based on the latest PSUR concluded for Cervarix (dated June 2015, reporting period 17.11.2014/17.11.2015), the cases included in the publications by Colafrancesco and colleagues (2014) are under evaluation. Searches on safety databases are also performed for events that could be indicative of possible POF, and 7 cases were identified for assessment. No cases of ovarian failure were reported in the clinical trials with Cervarix up to the 31 August 2014. No difference in the occurrence of amenorrhea was found between Cervarix and the control group in the analysis of pooled clinical trial data up to 30 April 2011. The PRAC overall was of the opinion that the available data are not sufficient to characterise a potential link between HPV vaccination and premature ovarian failure. The PRAC will re-assess ovarian failure following Cervarix vaccination in the next PSURs, and during this time the company will continue to monitor this event through routine pharmacovigilance.
The most recent PSUR assessment for Cervarix is currently ongoing.
Concerning Gardasil, premature ovarian failure has also been evaluated in the context of its PSURs. The most recent PSUR concluded in January 2016. Premature ovarian failure for Gardasil/Silgard was identified as a signal by PRAC in October 2013 and was thereafter closed in January 2014, due to lack of evidence supporting any causal link to the quadrivalent human papillomavirus (qHPV) vaccine. The PRAC recommended review of relevant data/publications in the PSUR as part of ongoing routine pharmacovigilance. The issue has thereafter been evaluated in subsequent PSURs, including reviews of non-clinical and clinical studies, post-marketing data and discussions on possible mechanisms. Overall, these data did not suggest a causal association between POF and Gardasil/Silgard vaccination. Within the latest PSUR covering period, a total of nine new cases of ovarian failure were presented and are being assessed. Since the background age-specific incidence of idiopathic premature ovarian failure in early to mid-adolescence is so rare [the annual incidence reported is 10/100 000 person-years up to age 30 years Coulam, C.B., Adamson, S.C., Annegers, J.F. 1986. Incidence of premature ovarian failure. Obstet Gynecol. 67:604-606)], it is difficult to make precise estimates about observed vs expected rates of the condition. However, considering the large number of patients estimated to have been vaccinated since market introduction (i.e. approximately 63 millions), the rate of POF (35 cases received in total from post-marketing sources worldwide since market introduction) is estimated to fall within the expected range of cases in the general (non-vaccinated) population.
Concerning non-clinical data:
As Cervarix is intended for administration to women of childbearing potential, the potential toxicity on the reproductive functions was investigated at the time of the initial MA for Cervarix. For this purpose, the influence of the HPV-16/18 L1 AS04 vaccine and of AS04 on fertility, embryo-foetal, peri-natal and post-natal survival and development was examined in sexually mature female rats. The pre-pairing injection with HPV-16/18 L1 AS04 or AS04 alone had no adverse effect on female fertility, as indicated by the numbers of pregnant females or the number of implantation counts in pregnant animals. There was no evidence that vaccination or AS04 administration impacted on the pattern of oestrous cycles in the rat. Within each group, the pre-coital intervals were conforming to the expected values for rats. The numbers of copulation plugs, as an index of the receptivity of the female to the male, and the estimates of sperm numbers in the vaginal washings were similar in all groups and showed no evidence that prior vaccination of the female had any effect on mating.
Overall, the reproductive toxicity study in rats did not show any effects of vaccination or AS04 administration on fertility and pre- and post-natal development.
The effect of Gardasil on embryo-foetal development was tested in a study in female rats at time of the initial marketing authorisation application. The objective of this study was to evaluate the potential effects of Gardasil on development, growth, behaviour, reproductive performance, and fertility of F1 generation. There were no treatment-related effects on developmental signs, behaviour, reproductive performance, or fertility of the offspring.
Signatories’ comment: Case reports published by highly qualified clinicians in peer-reviewed medical literature are considered a more reliable safety monitoring method than routine pharmacovigilance activities, which are based on spontaneous reporting and which have been estimated to reveal only 1-10% of all adverse events. A well recognized problem related to spontaneous reports is that the backround medical information (available for single cases) is usually too limited for any definite conclusions on potential causality. Therefore, the summaries of product information and product leaflets should be updated right away when serious safety concerns come from clinical experts instead of relying on arbitrary spontaneous reports and sales figures. The issue remains unsolved.
b) In the case of possible causality between HPV vaccination and premature ovarian failure, one would expect to see an increase in congenital abnormalities and miscarriage rate. Prematurely ageing ovaries would have an increased chance of producing eggs with defects such as trisomies i.e. chromosome abnormalities. Increased chromosomal abnormalities would also be expected to be associated with an increased miscarriage rate. Has such trend been observed in any preclinical/clinical studies or during post-marketing surveillance? Is there any clinical data available for public review (see also QVa)? “
EMA REPONSE: “See answer a. above.”
Signatories’ comment: The clinical data for congenital abnormalities and miscarriage rate have not been addressed by the PRAC in the answer a above. Thus, the issue is only partly resolved.
Safety: causality and reliability of safety data
a) There are several cases where the symptoms have increased after each booster (see e.g. Cervarix: Will my life ever be normal again?, My daughter’s life altering changes after Gardasil, Gardasil Injuries: No more excuses, we need answers). Shouldn’t such cases with a clear dose-response between symptoms and number of vaccinations be considered as a direct proof of true causality? Shouldn’t additional boosters be contraindicated whenever the vaccinated has experienced unexpected adverse eactions as advised in the medical literature (http://www.ncbi.nlm.nih.gov/pubmed/20541691)?
RESPONSE FROM EMA: ”All adverse events reported following vaccination are fully considered as part of regular monitoring of medicines and the possibility of causality is always investigated. The presence of adverse events after re-challenge does not equate to a dose-response relationship. Temporal association, although an important element, is only one component of the causality assessment. If it were the sole determinant, the fact that far more vaccinees who experience some adverse event after the first administration do not do so after subsequent doses could be used to support the absence of any causal relationship. Additional boosters are contraindicated in case of individuals who develop symptoms indicative of hypersensitivity after receiving a dose of Gardasil. ”
Signatories’ comment:The commonly accepted medical standards need to be followed; a positive re-challenge must be considered as a definite proof of true causality. The issue remains unsolved.
b) Has the safety of HPV vaccines been studied in any of the conducted trials in a reliable way – i.e. by using an inert saline as a placebo and by carrying an active (not just passive) safety follow-up?
As far as we know the placebo vaccines (that have been used in most of the clinical trials) have contained aluminium and other excipients, which may induce harmful effects without the vaccine’s active (antigen) components (see also QIIc above). Thus, comparisons beween such active and placebo groups cannot be expected to prove anything about the safety of HPV-vaccines. Thus, the quality of safety data is not convincing. The poor reliability of safety data is further emhasized by the notion that the safety data of clinical trials is based on a passive follow-up, which is commonly believed to reveal only 1-10% of all adverse reactions. For further details related to biased study designs see e.g. the following published papers: Busch FX & deSanjose S, 2003, J Natl Cancer Inst Monogr, 31: 296-304;Tomljenovic L & Shaw CA, 2012a, J Intern Med, 272: 514-15; Tomljenovic L & Shaw CA, 2012b, J Law Med Ethics, 40: 673-81; Tomljenovic L & Shaw CA, 2012c, Am J Public Health, 102: e13-14, Tomljenovic L & Shaw CA, 2013, Ann Med, 45: 182-93.
Based on personal correspondence between Dr Deidre Little and Dr John Skerritt from Australian Government Department of Health (31 August 2015, R15/554600) the vaccine constituents have formed a placebo in all safety trials of Gardasil.
Afterwards, upon this clinician’s request, the national regulatory authority requested the sponsor to correct their product information stating erroneously that saline had been used in one controlled safety trial for under 16-year olds (protocol 018) as explained in the original letter:
EMA RESPONSE: ”Safety of the different Gardasil formulations has been evaluated in a total of 16,041 subjects. Of these 11,813 received Gardasil and the remaining received monovalent vaccine formulations. All studies were placebo controlled and the total population that received placebo included 9,701 subjects.
Placebo consisted in most studies of aluminium-containing solution (225 or 450mcg aluminium adjuvant) except for study 018, where a non-aluminium containing placebo was given (see below). In two studies hepatitis B vaccine (Recombivax HB) or a hepatitis B vaccine-matched placebo was given concomitantly with Gardasil.
Study 018 investigated almost 700 subjects. The study’s primary objective was to evaluate the safety of Gardasil among 9- to 15- year-old boys and girls. The study allowed the comparison of Gardasil with a non-aluminium-containing placebo (all other studies compared the vaccine with aluminium containing placebo). Finally subjects were also evaluated for new medical conditions 1 year post vaccination. The data from 018 was compared with the safety of the antigens and adjuvant as evaluated in the rest of the clinical trials.
Overall there was no major increase in the reactogenicity following Gardasil vaccination as compared to the non-aluminium containing placebo administration. Local pain, headache, nausea and pyrexia were the most common symptoms observed in both groups. The only major difference noted between aluminium containing placebo and placebo without aluminium was the rate of local pain which was less frequent after non-aluminium-containing placebo administration [(45.4%) vs. Gardasil (81.3%) and placebo (aluminium containing) (75.4%)].
Concerning Cervarix, in efficacy studies HPV-001 and HPV-007, the control group received Al(OH). In study HPV-013, the control group received Havrix, a Hepatitis A vaccine containing 360 EL.U. hepatitis A antigen and 250 μg Al(OH)per 0.5 mL dose. Concerning the safety dataset at the time of Cervarix authorisation, of the 29,953 healthy girls and women included in the overall clinical development program of Cervarix, 16,142 subjects have received at least one dose of Cervarix and 13,811 subjects have received one of the control vaccines (Havrix 720, Havrix 360 or Al(OH)).
The use of Al(OH)3 (500μg) rather than a true placebo (inactive control was found acceptable in order to maintain the double blinding of the studies and consequently the validity of data. Indeed an inactive placebo would have induced little local reactogenicity and may have allowed the subjects and/or study site personnel to identify which vaccine had been administered. As the control product contained the same amount of Al(OH)3 as the study vaccine, it induced some level of local reactions that would have not allowed subjects or study personnel to readily distinguish whether Cervarix or control was administered.
Havrix was used in the control group of study HPV-013 since the vaccine is widely used in this age group, since it is administered according to a 0, 1, 6-month schedule as the candidate vaccine and since it confers benefit to subjects randomised to the control group.
The approach taken for both vaccines was found by the CHMP as a reliable way to establish the safety profile of the vaccines at the time of authorisation.
Clinical trial adverse events reporting do not rely on passive reporting, but clinical trial pharmacovigilance requirements apply, which means that there is an active elicitation of adverse events from vaccinees. ”
Signatories’ comment: As anticipated placebo has consisted aluminium in most studies and, therefore, comparative safety data (with an inert saline as a control vaccine) is nonexisting. Furthermore, the constituents of placebo in study 018 remains obscure; According to the PRAC a non-aluminium placebo was used whereas Australian health officials have stated in their letter to Dr Deidre Little (as shown in a letter attached to the question above) that saline was not used in the study 018 for Gardasil as erroneously written (before being asked to be corrected) in the summary of product information. Whom should be believed – EMA or Australian Goverment Health Department? The issue remains unsolved.
c) Is it possible that rather similar, multiple symptoms experienced by HPV vaccinated girls around the world are coincidental?
EMA RESPONSE: ”The symptoms of CRPS and POTS are not experienced by the vast majority of vaccinated girls, and also occur in non-vaccinated teenage girls. The PRAC concluded that these symptoms were not seen more often in vaccinated girls than in girls in the general population.
In addition most symptoms of CRPS and POTS are unspecific, making them difficult to diagnose both in the general population and in vaccinated individuals and some symptoms may overlap with chronic fatigue syndrome (CFS). Many of the reports considered in the referral review have features of chronic fatigue syndrome and some patients have been diagnosed with both POTS and chronic fatigue syndrome, an observation which was also supported by recent publications (Brinth et al, 2015).
For this analysis, reports that did not fully meet the diagnostic criteria for these syndromes, and broad underreporting scenarios were also taken into account. One element that emerged clearly form this assessment is that individual cases analysed did not show a consistent pattern regarding time-to-onset following vaccination or clinical characteristics.
The question which PRAC asked was whether the total number of cases reported would be similar or higher than the total number of cases expected in a comparable population, i.e. an observed versus expected analysis. This careful review concluded that the occurrence of CRPS and POTS in vaccinated girls is no higher than would be expected in girls in the general population. ”
Signatories’ comment: The position of PRAC to the original question (if a post-vaccination syndrome (*) experienced by previously healthy adolescents is coincidential or not) has not been specified. The issue remains unsolved. (*) Martinez-Lavin M et al. Clin Rheumatol. 2015; 34(11):1981-83.
d) So far there has been only indirect evidence of the efficacy. Are there perhaps already by now some direct data demonstrating that either Cervarix or Gardasil can prevent cervical cancer and/or deaths from cervical cancer? If yes, what?
EMA response: ”The interval between the acquisition of HPV infection and progression to invasive carcinoma is usually about 10 years or longer. Therefore in order to demonstrate prevention of cervical cancer, regulatory authorities rely on a recognised surrogate for cervical cancer, which is Cervical Intraepithelial Neoplasia (CIN 2/3), and on prevention of persistent viral infection. CIN 3 is universally recognised as an immediate precursor to cervical cancer (a precancerous lesion). Based on this, there is robust data to conclude that HPV vaccines are expected to prevent cervical cancer. Studies to show the precise magnitude of risk reduction for cervical cancer or death are planned but study results have not been yet submitted for regulatory review. See also response to question II.a Clinical questions (listed under other concerns). ”
Signatories’ comment: As anticipated there has been so far no direct clinical evidence of the efficacy. The issue is solved.
IV Questions on overall benefit/risk ratio of HPV vaccines
a) Based on the accumulating scientific proof (obtainable from the published literature) the benefit/risk ratio of HPV vaccines (Cervarix/Gardasil) appears negative. Does EMA have some extra data suggesting otherwise? If yes, what?
EMA RESPONSE: ”The information contained in the Product Information is the result of analysis of the totality of the data made available to regulators from use of these vaccines in millions of patients around the world. The reactions included in the Product Information are adverse events where a causal relationship between the vaccine and the adverse event was considered to be at least a reasonable possibility. The rates of adverse effects described have been found by the PRAC and CHMP to be acceptable, leading to the conclusion that the benefits of the vaccines outweigh their risks. In addition, all products are subject to continuous monitoring, and any noted concerns or changes are assessed immediately via pharmacovigilance procedures (e.g. PSURs or Signal detection).
Moreover note that the WHO Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body, has also reviewed the safety of HPV vaccines in December 2015 and the conclusions can be found here: http://www.who.int/vaccine_safety/committee/topics/hpv/en/ ”
Signatories’ comment: The present conclusions of the overall benefit/risk ratio of HPV-vacines cannot be endorsed until the previous issues have been solved.
b) What is the critical threshold rate of SAE’s for HPV vaccines that would result in withdrawal of marketing authorization?
EMA RESPONSE: ”There is no predefined threshold for reporting rates of SAEs for any vaccine or any other medicinal product that would lead to an automatic suspension. The risks of any products are judged in the context of their benefits i.e. benefit-risk balance assessment. The benefit-risk balance of authorised medicinal products is constantly assessed by EMA through the various pharmacovigilance mechanisms discussed in this letter. Should there be doubts that the risks associated with an administration of a medicinal product outweigh the associated benefits, the EU Member States, EMA and the European Commission would take actions. These actions may include suspension or a withdrawal of the marketing authorisation. ”
Signatories’ comment: The PRAC does not specify what would be the sufficient safety ’doubt’ for suspension or withdrawal of marketing authorisation. Thus, the issue remains unsolved.
V. Regulatory questions
a) Are all safety and clinical studies conducted for HPV vaccines available for public review or are some of those still considered confidential (as were in 2014)? Is EMA still facing a legal procedure over the release of certain documents? (http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/04/news_detail_001779.jsp&mid=WC0b01ac058004d5c1)
To our knowledge some academic individuals have had difficulties in receiving the data that they have asked the EMA to provide for their review in relation to the suspected reproductive toxicity of HPV-vaccines (see ’Safety/reproductive toxicity’ questions above).
EMA RESPONSE: ”The EMA has developed a policy on the publication of clinical data for human medicines (Policy 0070)7. The policy is the result of extensive discussions with a broad range of stakeholders and institutional partners, and, we believe, accommodates their needs and concerns. The policy complements other policies and mechanisms established by the EMA in order to ensure transparency. A key goal in this process is the publication of clinical-trial data for medicines once the decision-making process on an application for a European Union (EU)-wide marketing authorisation is complete. It is the belief of the EMA that the release of data is essential in establishing trust and confidence in the system, because it will allow the public to better understand the Agency’s scientific assessment. The policy has taken effect as of 1st January 2015, and it is currently being implemented. The policy applies to clinical reports, including clinical study reports, contained in all initial marketing-authorisation applications submitted on or after 1 July 2015 to vary a marketing authorisation foran extension of indication or a line extension. The first clinical reports are foreseen to be published in September 2016. For more information please see the link:
In addition, in accordance with Regulation (EC) No 1049/2001 of 30 May 2001 regarding public access to European Parliament, Council and Commission documents and the Rules for the implementation of Regulation (EC) No 1049/2001 of 19 December 2006 on access to European Medicines Agency documents, the Agency is releasing clinical-trial reports on request. This policy enables third parties to request the release of documents held by the Agency, including documents submitted as part of marketing-authorisation applications. It is acknowledged that in 2013, EMA decided to temporarily halt the release of non-clinical and clinical reports. This was due to ongoing litigations at the level of the General Court of the European Union. Two pharmaceutical companies challenged EMA decisions to release of clinical and non-clinical study reports and, applying a precautionary approach, EMA decided to await the Court rulings in this matter before releasing further non-clinical and clinical reports. This temporary halt was relatively brief and EMA resumed, in 2014, the release of clinical and non-clinical study reports in response to requests for access to documents.
For more information in EMA’s access to documents policy, see this link:
The Agency is also involved in making summaries of the results of clinical trials publicly available through the EudraCT Register (https://www.clinicaltrialsregister.eu/). As of 21 July 2014, with the launch of a final iteration of EudraCT, it is mandatory for sponsors to post results on a systematic basis, and the summary results will be made publicly available. ”
Signatories’ comment: It is not understood why the requested information was not provided after the legal procedure had been solved. Thus, the issue remains unsolved.
Other points of concern
I. Preclinical questions
a) Are the potential long-term health consequences of injected foreign DNA known?
EMA RESPONSE: ”Potential safety concerns due to intake of foreign DNA would depend on the origin, type, quality, quantity and route of administration of the DNA.
For example DNA derived from continuous cell lines might have the potential to confer the capacity of uncontrolled growth if inserted in the genome (insertional mutagenesis, i.e. by insertion of an intact oncogene or by inactivation of tumour-suppression genes). This would apply only to vaccines which use such cell lines for manufacturing purposes, which is not the case for HPV vaccines. ”
Signatories’ comment: According to peer reviewed literature Gardasil does contain viral DNA impurities that have been associated with fatalities (Refs.: e.g. Lee SH, 2012a Advances Biosc Biotech, 3: 1214-24; Lee SH, 2012b J Inorg Chem, 112: 85-92, Lee SH 2013, Advances Biol Chem, 3:76-85). The risk related to foreign DNA found in Gardasil has not been addressed. The issue remains unsolved.
b) The weight limit for DNA contamination is 10 nanograms for a single vaccine and children are commonly exposed to several vaccines and to their varying amounts of impurities. Has the safety limit for accumulative exposure of humans to different types of foreign DNA been estimated or has it been just considered an irrelevant concern?
EMA RESPONSE: ”The CHMP has previously looked at these aspects in detail, following similar questions from the public, and came to the following conclusions regarding the Gardasil vaccine:
“The Committee noted that the presence of recombinant DNA fragments does not represent a case of contamination and is not a risk to vaccine recipients. All vaccines manufactured using recombinant technology may contain small fragments of residual DNA from the cells producing the proteins included as active ingredients. These fragments cannot cause infection. Their presence in minute quantities is inevitable in vaccine production using recombinant technology. All recombinant protein products are therefore likely to contain measurable residues of DNA and it can be expected that DNA coding for the recombinant protein will be detected by sufficiently sensitive testing methods.
Gardasil does not contain DNA from other HPV genes or any full-length infectious HPV genomes.
Since the early development of Gardasil it has been well known and documented that small quantities of residual recombinant HPV L1-specific DNA fragments remain in the vaccine following purification. The manufacturing process of Gardasil has been shown to reduce the amount of host cell DNA to a defined and acceptable level in line with international guidelines. The presence of a small amount of residual host cell DNA was known and accepted at the time of licensure.”
A maximum of 10 ng of DNA (host-cell and vector-derived) in a quantity of purified antigen equivalent to a single vaccine dose is allowed as per the European pharmacopeia (Ph. Eur.) monograph on recombinant HPV vaccines. Gardasil’s manufacturing process has been validated to reduce residual DNA to a much lower level.
Given the current knowledge and based on the currently recommended vaccination schedules, it is not expected that co-administration of vaccines is linked to safety issues due to cumulative exposure to DNA residues. ”
Signatories’ comment: The safety of DNA impurities may be questioned based on peer-reviewed literature (Refs.: e.g. Lee SH, 2012a Advances Biosc Biotech, 3: 1214-24; Lee SH, 2012b J Inorg Chem, 112: 85-92, Lee SH 2013, Advances Biol Chem, 3:76-85). It is unclear if these studies have been assessed by the PRAC during safety evaluations of Gardasil. This issue remains, thus, unresolved.
c) Are there any long-term carcinogenicity studies for HPV vaccines and/or their ingredients?
EMA RESPONSE: ”Except for Cervarix (see below), in vitro/in vivo genotoxicity studies and carcinogenicity studies were not performed for these products because they were not deemed scientifically relevant. That is because vaccine antigens, in general, are not considered to have genotoxicity potential or carcinogenic effects based on their chemical structure, mechanism of action and lack of repeated chronic administration.
Concerning the Merck Aluminium Adjuvant contained in Gardasil (aluminium hydroxyphosphate sulphate), this is not a novel adjuvant. This adjuvant is used in other vaccines, which are authorised in the European Union. Consequently, no further studies on the adjuvant were considered necessary for Gardasil. Please note that this information may be found in the EPAR for Gardasil, which is published on the EMA website.
Concerning Cervarix, genotoxicity studies were performed in vitro for the monophosphoryl lipid A (MPL) component of the AS04 adjuvant, and did not reveal any MPL-related mutagenic activity or genotoxic effect. In vivo studies did not show any evidence of increased frequency of micronucleated immature erythrocytes or bone marrow cell toxicity linked to MPL. This information is reflected in the EPAR for Cervarix that is also published on the EMA website. ”
Signatories’ comment: The fact that Aluminium Adjuvant is used commonly in many vaccines does not prove that it is safe. Since the PRAC does not present any safety data for this claim, the issue remains partly unsolved.
II Clinical questions
a) As far as we know health professionals have not been warned to look for the risk of leukaemia among vaccinated adolescents as suggested in the assessment report referred to below (*). What actions (if any) have been undertaken to determine whether or not HPV vaccines could cause or trigger this condition in certain pre-disposed individuals?
(*) Reference: Info 26 March 2015 EMA/CHMP/76591/2015
Page 117: ”Five cases (4 with 9vHPV vaccine and 1 with qHPV vaccine) of acute leukaemia have been reported, three of which occurred in subjects younger than 20 years of age at diagnosis. While the observed number of cases of leukaemia exceeded the expected number of cases, this observation is based on a few cases in relation to a very low background risk for leukaemia in this age group. Such a comparison will inevitably be sensitive to random occurrences of single cases and it is not considered sufficient to implicate a causal relation at this stage. There is no sufficient evidence to support a biological plausibility for a causal relation. While it is considered that the finding is most likely a random occurrence, further reassurance can be gained from the ongoing study program, which will add substantially to the total exposed person-time. Occurrence of any further cases of leukaemia, with a main focus on the ongoing/planned studies, should be reported as a part of close monitoring of leukaemia in PSURs.”
Conclusions on page 118: ”There was one case of pulmonary vasculitis and few cases of leukaemia, which upon assessment do not constitute sufficient evidence to raise a specific safety concern at the moment.
EMA RESPONSE: As mentioned in the EPAR for Gardasil 9, the currently available evidence does not support a causal link between the above mentioned events and HPV vaccination. Hence, specific recommendations for healthcare professionals are not required at this stage.
The safety of all medicines, including vaccines, is continuously monitored by EMA, as already mentioned. The actions currently in place to monitor the safety of HPV vaccines include:
- routine pharmacovigilance activities in the form of signal detection, which is able to evaluate post- marketing reports and raise a signal if a disproportionate number of such events are reported;
- – additional pharmacovigilance activities in the form of long term follow-up studies, which include endpoints on health outcomes such as death, cancer, and hospitalisation (e.g. studies V503-021 and V503-002-20 for Gardasil 9).
Monitoring for leukaemia is part of these routine pharmacovigilance activities in the PSURs for Gardasil 9, with a main focus on the ongoing/planned studies. The latest PSUR assessment is currently ongoing.
Signatories’ comment: The issue is solved.
b) Has a possible genetic predisposition (resulting in an increased sensitivity to aluminium toxicity (http://www.ncbi.nlm.nih.gov/pubmed/24238833) been acknowledged when assessing the benefit/risk profile of HPV-vaccines all of which contain aluminium? If yes, how?
EMA RESPONSE: ”As already mentioned in responses to II.a/b Major Points of concerns, Aluminium adjuvants have been used in vaccines for several decades and their safety profile can be considered as adequately characterised. The scientific evidence available to date continues to support the safe and effective use of aluminium adjuvants in vaccines, which is a position agreed by regulatory authorities worldwide. Genetic factors are considered when known for a specific disease. The article mentioned is referring to genetic susceptibility in the context of ASIA syndrome. Relevant scientific findings from the literature are assessed in the context of PSURs assessments, and are considered in the benefit/risk assessments. Please see also response to question II.c Major Points of concerns.”
Signatories’ comment: There is a discrepancy between the recent scientific literature on aluminium toxicity and the common position agreed by regulatory authorities. The issue remains unsolved.
c) What do health officials consider as the acceptaple precentage of SAEs for HPV vaccines?
Given that there has been so far only indirect proof of the benefits (i.e. the capability of HPV-vaccines to prevent cervical cancer) the percentages of SAEs observed in clinical trials do appear alarming:
– Serious adverse events representing 2.3% (Gardasil 9) of the population and 2.5% (Gardasil)
– 4.5% of the participants in a trial for Gardasil 9 in India reported new medical conditions potentially indicative of systemic autoimmune disorders.
EMA RESPONSE: ”See also response IV.b above. The rates of SAEs quoted in the first paragraph for Gardasil and Gardasil 9, presumed to be quoted from the products European Public Assessment Reports (EPAR), represent the percentage of subjects in clinical trials that have reported such an event. The benefit/risk evaluation also considered the causality assessment. e.g. for Gardasil 9, the EPAR states that “only 5 SAEs were assessed as related” to Gardasil 9, out of 15,776 subjects receiving at least 1 dose of Gardasil 9.
The adverse reactions rates described in the Product Information are based on the information made available to regulators from use of these vaccines in clinical trials and in millions of patients post-approval. The reactions included in the Product Information are adverse events where a causal relationship between the medicinal product and the adverse event was considered to be at least a reasonable possibility. The rates described have been found by the PRAC and CHMP to be acceptable, leading to the conclusion that the benefits of the vaccines outweigh their risks.
The rate presented in the second paragraph does not include a reference and could not be verified. ”
Signatories’ comment: Presumably, due to the complexity of safety data collection there is no answer to the question of acceptable rate of SAEs for HPV-vaccines. The issue remains unsolved.
lll Regulatory questions
a) Is testing for adventitious agents in HPV vaccines obligatory, or based on nonbinding recommendations?
EMA RESPONSE: The four centrally approved HPV vaccines (Gardasil, Gardasil-9, Silgard and Cervarix) comply with the requirements of the Ph. Eur. monograph (Human papillomavirus vaccine (rDNA)). The Ph. Eur monographs are legally binding technical specifications. Of the four vaccines mentioned, three are from the same manufacturer and are prepared in yeast cells and one manufactured using insect cells (Cervarix). In addition, the Ph. Eur. mentioned above also describes those tests for extraneous agents (Ph. Eur. 2.6.16), which are required for a HPV vaccine. It should be noted that regardless of legally binding provisions in the Ph. Eur. monographs, the CHMP conducts a thorough evaluation of the risk of extraneous agent contamination for all vaccines during the assessment of the marketing authorisation application in accordance with relevant EU / international guidance e.g. for products manufactured using cells of human or animal origin9 and approves testing regimes in accordance with this assessment. The conclusions of the adventitious agent risk assessment for individual vaccines can be found in the respective EPARs on the Agency’s website.
Signatories’ comment: Appropriate requirements for testing the adventitious agents in HPV vaccines could not be found from the documents referred to in the response. The scientific literature (referred to in the first pharmaceutical major concern above) suggests that the testing should be obligatory. Thus, the issue remains unsolved.
b) Did the rapporteurs have all raw data available for the assessment of marketing authorization application? Was it considered sufficient and reliable?
Based on the published literature (outlined above) and the other unpublished information available for international independent clinicians and scientists, the reliability of study results should be seriously questioned.
EMA RESPONSE: ”Results of studies are one of the main sources of information which is used by the regulatory agencies globally in the assessment of any medicinal product. In addition data from the published literature and from pharmacovigilance databases can provide significant information. In addition raw data from clinical trials are available and can be requested if issues are identified during the evaluation of the marketing authorisation application. In the case of the HPV vaccines, study results were considered sufficient and reliable to obtain marketing authorisation approval.
During the recent review of CRPS and POTS for HPV vaccines, the rapporteurs had access to all the available data as per any other referral procedure, i.e. responses from the companies on the List of Questions, data from the published literature, reports from Eudravigilance database, reports available from member states, notably Denmark and the Netherlands and information from the public. ”
Signatories’ comment: The issue is resolved.
c) Did the clinical assessors of the EMA report (on CRPS & POTS) consult specialists in autonomic disorders? If they did, had those specialists declared any conflict of interests?
EMA RESPONSE: ”The PRAC requested the input of leading scientists in autonomic disorders, through a consultation with a scientific advisory group. All scientists with whom EMA collaborates are required to complete a declaration of interests, which is made available on the EMA website in this link:
Signatories’ comment: The problem may not be in the lack of signed declaration of conflict of interests but in the tendency of EMA to rely on opinions of experts with conflict of interests as recently outlined in a complaint from Nordic Cochrane Centre to EMA