Too fast or not too fast: the FDA's approval of Merck's HPV vaccine Gardasil

ArticleinThe Journal of Law Medicine & Ethics 40(3):673-81 · September 2012with 1,889 Reads
Cite this publication
Abstract
There are not many public health issues where views are as extremely polarized as those concerning vaccines, and Merck's HPV vaccine Gardasil is a case in point. Ever since gaining the FDA's approval in 2006, Merck has been heavily criticized for their overly aggressive marketing strategies and lobbying campaigns aimed at promoting Gardasil as a mandatory vaccine. Subsequently, questions have been raised as to whether it was appropriate for vaccine manufacturers to partake in public health policies when their conflicts of interests are so obvious. Some of their advertising campaign slogans, such as "cervical cancer kills x women per year" and "your daughter could become one less life affected by cervical cancer," seemed more designed to promote fear rather than evidence-based decision making about the potential benefits of the vaccine. Although, conflicts of interests do not necessarily mean that the product itself is faulty, marketing claims should be carefully examined against factual science data. Currently Gardasil vaccination is strongly recommended by the U.S. and other health authorities while public concerns about safety and efficacy of the vaccine appear to be increasing. This discrepancy leads to some important questions that need to be resolved. The current review examines key issues of this debate in light of currently available research evidence.

Do you want to read the rest of this article?

Request full-text
Request Full-text Paper PDF
  • Article
    Full-text available
    The rationale behind current worldwide human papilloma virus (HPV) vaccination programs starts from two basic premises, 1) that HPV vaccines will prevent cervical cancers and save lives and, 2) have no risk of serious side effects. Therefore, efforts should be made to get as many pre-adolescent girls vaccinated in order to decrease the burden of cervical cancer. Careful analysis of HPV vaccine pre- and post-licensure data shows however that both of these premises are at odds with factual evidence and are largely derived from significant misinterpretation of available data.
  • Article
    Full-text available
    Pap screening combined with loop electrosurgical excision procedures (LEEP) is almost 100% effective in preventing cervical cancer mortality yet many countries with these procedures have now implemented broad HPV vaccination programs. HPV vaccines have not been demonstrated to be more effective or safer than Pap screening in the prevention of cervical cancer and Pap screening will still be required even in vaccinated women. The HPV vaccine costs Au$450 per person and it does not protect against ~30% of cancer. This investigation analyses the cost-effectiveness of using the HPV vaccine in countries where Pap screening and surgical procedures have already reduced cervical cancer mortality to very low rates. Cost-effectiveness of vaccination programs is being determined by mathematical models which are founded on many assumptions. It is necessary to examine the rigor of these assumptions to be certain of the health benefits that are predicted. In 2002 scientists concluded that HPV 16 and 18 were the central and independent cause of most cervical cancer. This conclusion was based on molecular technology. If HPV 16 and 18 infections are the central and independent cause of most cervical cancer then the incidence of HPV 16 and 18 should vary with the incidence and mortality of cervical cancer worldwide. This correlation does not exist. It is also observed that the majority of HPV 16/18 infections do not lead to cervical cancer. This indicates that other etiological or 'risk' factors are necessary for persistent HPV infection to progress to cancer. The benefits of HPV vaccines have been determined by using pre-cancerous lesions in young women as a surrogate for cervical cancer. This surrogate is found to be inadequate as an end-point for cervical cancer. Clinical trials have only provided speculative benefits for the efficacy of HPV vaccines against cancer and the long-term risks of the vaccine have not been established. Pap screening will still be required in vaccinated women hence HPV vaccination programs are not cost-effective, and may do more harm than good, in countries where regular Pap screening and surgery has already reduced the burden of this disease.
  • Article
    Full-text available
    We carried out a systematic review of HPV vaccine pre- and post-licensure trials to assess the evidence of their effectiveness and safety. We find that HPV vaccine clinical trials design, and data interpretation of both efficacy and safety outcomes, were largely inadequate. Additionally, we note evidence of selective reporting of results from clinical trials (i.e., exclusion of vaccine efficacy figures related to study subgroups in which efficacy might be lower or even negative from peer-reviewed publications). Given this, the widespread optimism regarding HPV vaccines long-term benefits appears to rest on a number of unproven assumptions (or such which are at odd with factual evidence) and significant misinterpretation of available data. For example, the claim that HPV vaccination will result in approximately 70% reduction of cervical cancers is made despite the fact that the clinical trials data have not demonstrated to date that the vaccines have actually prevented a single case of cervical cancer (let alone cervical cancer death), nor that the current overly optimistic surrogate marker-based extrapolations are justified. Likewise, the notion that HPV vaccines have an impressive safety profile is only supported by highly flawed design of safety trials and is contrary to accumulating evidence from vaccine safety surveillance databases and case reports which continue to link HPV vaccination to serious adverse outcomes (including death and permanent disabilities). We thus conclude that further reduction of cervical cancers might be best achieved by optimizing cervical screening (which carries no such risks) and targeting other factors of the disease rather than by the reliance on vaccines with questionable efficacy and safety profiles.
  • Article
    Full-text available
    Purpose – The purpose of this paper is to present a three-part framework of information engagement for situated gynecological cancers. These particular cancers intertwine with medicalization of sexuality and gender power dynamics, situating information behaviors and interactions in women’s socio-health perceptions. Using Kavanagh and Broom’s feminist risk framework, the framework establishes functional and temporal parameters for sense-making and information engagement. Design/methodology/approach – This paper employs a structured, reiterative literature review with emergent thematic analysis. Nine indices from medicine, information studies, and sociology were searched using combinations of five terms on cervical cancer (CC) and 14 terms on information engagement in the title, abstract, and subject fields. Results were examined on a reiterative basis to identify emergent themes pertaining to knowledge development and information interactions. Findings – Environmentally, social stigma and gender roles inhibit information seeking; normalizing CC helps integrate medical, moral, and sexual information. Internally, living with the dichotomy between “having” a body and “being” a body requires high-trust information resources that are presented gradually. Actively, choosing to make or cede medical decision-making requires personally relevant information delivered in the form of concrete facts and explanations. Research limitations/implications – The study covers only one country. Originality/value – This study’s information framework and suggestions for future research encourage consideration of gender power dynamics, medicalization of sexuality, and autonomy in women’s health information interactions.
  • Article
    There is strong evidence for causal association between human papillomavirus (HPV) and cervical cancer, evidence of association of HPV and oropharyngeal cancer is beginning to mount. To review the HPV-oral cancer literature for a comprehensive assessment of the issues involved. Literature search conducted using PubMed, Google Scholar and Google search engine. Both available HPV vaccines are efficacious and safe although expensive. Policy for mandatory HPV vaccination for cervical prevention is mired in political issues stemming from negative cost-effectiveness balance. Dental professionals are not ready to discuss the role of HPV vaccine in cancer prevention. This review discusses the impact of HPV on cervical cancer, transmission of HPV among humans, impact of HPV in oral health, and its plausible role in oral and oropharyngeal cancer, prevention of HPV transmission, available vaccines against HPV, testing, cost, policy and use of HPV vaccines internationally and dentists readiness related to HPV associated health communication. Given the mounting literature on the association between HPV and oropharyngeal cancer, the dental community must be prepared to answer patients' HPV-related questions and to educate patients about the role of HPV as a risk factor for oral and oropharyngeal cancers.
  • Article
    Los problemas éticos de las investigaciones sobre vacunas han crecido en las últimas décadas en frecuencia y magnitud debido a la posición dominante de la industria farmacéutica en el desarrollo de esos estudios. Las tradicionales cuestiones de seguridad y eficacia se han visto agravadas por el conflicto de intereses introducido por la competencia comercial en un mercado a escala global de miles de millones de dólares. La integridad profesional de los investigadores, la responsabilidad moral de los patrocinadores, y la regulación y control por parte de los Estados nacionales, se muestra cuestionada en varios ejemplos. Los resultados de estos cambios son las amenazas a la protección de los derechos de las personas incluidas en estas investigaciones y el discutible progreso que resulta para la salud pública.
  • Article
    To investigate the association between human papillomavirus (HPV) vaccination and autoimmune manifestations compatible with systemic lupus erythematosus (SLE) or SLE-like disease, the medical history of six women who presented with SLE or SLE-like disease following HPV immunization was collected. Data regarding type of vaccine, number of immunization, family and personal, clinical and serological features, as well as response to treatments were analyzed. In the reported cases, several common features were observed, such as personal or familial susceptibility to autoimmunity or adverse response to a prior dose of the vaccine, both of which may be associated with a higher risk of post-vaccination autoimmunity. Favorable response to immunosuppressant was observed in all patients. In the current study, a temporal association between immunization with HPV vaccine and the appearance of a spectrum of SLE-like conditions is reported. Additionally, among the patients described, several common features were observed that may enable better identification of subjects at risk. Further studies are required to assess the safety of immunization with the HPV vaccine in patients with autoimmune-rheumatic diseases or in subject at risk of autoimmunity as well as the potential beneficial effect of preventive immunosuppressants.
  • Post-vaccination autoimmune phenomena are a major facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and different vaccines, including HPV, have been identified as possible causes. The medical history of three young women who presented with secondary amenorrhea following HPV vaccination was collected. Data regarding type of vaccine, number of vaccination, personal, clinical and serological features, as well as response to treatments were analyzed. All three patients developed secondary amenorrhea following HPV vaccinations, which did not resolve upon treatment with hormone replacement therapies. In all three cases sexual development was normal and genetic screen revealed no pertinent abnormalities (i.e., Turner's syndrome, Fragile X test were all negative). Serological evaluations showed low levels of estradiol and increased FSH and LH and in two cases, specific auto-antibodies were detected (antiovarian and anti thyroid), suggesting that the HPV vaccine triggered an autoimmune response. Pelvic ultrasound did not reveal any abnormalities in any of the three cases. All three patients experienced a range of common non-specific post-vaccine symptoms including nausea, headache, sleep disturbances, arthralgia and a range of cognitive and psychiatric disturbances. According to these clinical features, a diagnosis of primary ovarian failure (POF) was determined which also fulfilled the required criteria for the ASIA syndrome. We documented here the evidence of the potential of the HPV vaccine to trigger a life-disabling autoimmune condition. The increasing number of similar reports of post HPV vaccine-linked autoimmunity and the uncertainty of long-term clinical benefits of HPV vaccination are a matter of public health that warrants further rigorous inquiry.
  • Article
    In 2011 a new syndrome termed 'ASIA Autoimmune/Inflammatory Syndrome Induced by Adjuvants' was defined pointing to summarize for the first time the spectrum of immune-mediated diseases triggered by an adjuvant stimulus such as chronic exposure to silicone, tetramethylpentadecane, pristane, aluminum and other adjuvants, as well as infectious components, that also may have an adjuvant effect. All these environmental factors have been found to induce autoimmunity by themselves both in animal models and in humans: for instance, silicone was associated with siliconosis, aluminum hydroxide with post-vaccination phenomena and macrophagic myofasciitis syndrome. Several mechanisms have been hypothesized to be involved in the onset of adjuvant-induced autoimmunity; a genetic favorable background plays a key role in the appearance on such vaccine-related diseases and also justifies the rarity of these phenomena. This paper will focus on protean facets which are part of ASIA, focusing on the roles and mechanisms of action of different adjuvants which lead to the autoimmune/inflammatory response. The data herein illustrate the critical role of environmental factors in the induction of autoimmunity. Indeed, it is the interplay of genetic susceptibility and environment that is the major player for the initiation of breach of tolerance.
  • Article
    Counseling messages for tobacco cessation, condom use, circumcision, and selective choice in the number of sexual partners can help reduce the risk of cervical cancer. Other sexual behavioral and reproductive risk factors for cervical cancer are a younger age at first intercourse and at first full-term pregnancy as well as increasing duration of combined hormonal oral contraceptive use. Micronutrients and supplements can reduce the risk of human papillomavirus infection, persistence, progression, and regression. Some human papillomavirus infections can be prevented by vaccination. Cervical cancer is best prevented by screening.
  • Article
    Quadrivalent human papillomavirus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil(®); Silgard(®)) is composed of virus-like particles formed by self-assembly of recombinant L1 capsid protein from each of HPV types 6, 11, 16 and 18. It is indicated for use from the age of 9 years as a two- or three-dose vaccination course over 6 months for the prevention of premalignant anogenital lesions, cervical and anal cancers, and genital warts caused by the vaccine HPV types. In placebo-controlled trials, quadrivalent HPV vaccine provided high-level protection against infection or disease caused by the vaccine HPV types over 2-4 years in females aged 15-45 years who were negative for the vaccine HPV types, and provided a degree of cross-protection against certain non-vaccine HPV types. The vaccine also provided high-level protection against persistent infection, anogenital precancerous lesions and genital warts caused by the vaccine HPV types over 3 years in susceptible males aged 16-26 years. Protection has been demonstrated for up to 8 years. In subjects who were negative for the vaccine HPV types, high seroconversion rates and high levels of anti-HPV antibodies were observed in females of all age ranges from 9 to 45 years and in males aged 9-26 years. The vaccine was generally well tolerated and was usually predicted to be cost effective in girls and young women. Therefore, quadrivalent HPV vaccine offers an effective means to substantially reduce the burden of HPV-related anogenital disease in females and males, particularly cervical cancer and genital warts.
  • Article
    Full-text available
    We report the case of a 14-year-old girl who developed postural orthostatic tachycardia syndrome (POTS) with chronic fatigue 2 months following Gardasil vaccination. The patient suffered from persistent headaches, dizziness, recurrent syncope, poor motor coordination, weakness, fatigue, myalgias, numbness, tachycardia, dyspnea, visual disturbances, phonophobia, cognitive impairment, insomnia, gastrointestinal disturbances, and a weight loss of 20 pounds. The psychiatric evaluation ruled out the possibility that her symptoms were psychogenic or related to anxiety disorders. Furthermore, the patient tested positive for ANA (1:1280), lupus anticoagulant, and antiphospholipid. On clinical examination she presented livedo reticularis and was diagnosed with Raynaud’s syndrome. This case fulfills the criteria for the autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA). Because human papillomavirus vaccination is universally recommended to teenagers and because POTS frequently results in long-term disabilities (as was the case in our patient), a thorough follow-up of patients who present with relevant complaints after vaccination is strongly recommended.
  • Article
    The ethical problems in vaccine research have grown in frequency and magnitude in last decades, due to the dominant place of the pharmaceutical industry in the development of such studies. Traditional issues of security and efficacy have been aggravated by the conflicts of interests introduced by commercial competition in a global market worth billions of dollars. We present here a few examples in which the professional integrity of researchers, the moral responsibility of sponsors, and the public regulation and control by national States are put into question. The consequences of these changes represent serious threats to the rights of people included in these studies as well as disputable progress for public health.
  • Article
    Full-text available
    Plant molecular pharming has emerged as a reliable platform for recombinant protein expression providing a safe and low-cost alternative to bacterial and mammalian cells-based systems. Simultaneously, plant viruses have evolved from pathogens to molecular tools for recombinant protein expression, chimaeric viral vaccine production, and lately, as nanoagents for drug delivery. This review summarizes the genesis of viral vectors and agroinfection, the development of non-enveloped viruses for various biotechnological applications, and the on-going research on enveloped plant viruses.
  • Article
    Full-text available
    It was disconcerting, not to say frightening, to see that at the time of writing, only weeks after the launch of the national campaign of human papillomavirus (HPV) vaccination of grade 4 girls in South African (SA) public schools, a number of countries had put a moratorium on HPV vaccines. The Japanese government has done so more recently. Austria has rejected the inclusion of HPV in its vaccination schedule. The Green Party MPs at the European Parliament are preparing to call for a moratorium in France.
  • Article
    Discussions of drugs in international political economy tend to focus on the relative advantages and disadvantages of particular regulatory regimes and governmental policy approaches. While the particular regulation(s) and social context(s) differ, the drug literature is in this sense repetitive and neglectful of significant features of the global drug economy. Drawing on social economics, we argue that the neglect of broad and holistic, synthetic, integrative and comparative drug research in IPE stems in part from a research program in which the state is “essentialized”, resulting in drug research that is too narrowly cast. Borrowing from social economics, poststructuralist Marxism, and new materialism, we develop an anti-essentialist approach for thinking about the global drug economy in an effort to reveal aspects of global drug production, distribution and consumption, and the power relations entailed therein, that are currently obscured.
  • Book
    Global Issues in Pharmaceutical Marketing presents a balanced, research-based perspective combined with a practical outlook on the current issues faced by the ethical, biotech, and generic segments of the pharmaceutical industry. It integrates an analytical approach with a global view to examine such issues as market access, digital marketing, emerging markets, branding, and more. The book covers not only the North American and Western European markets, but on non-Western markets, such as Latin America and Asia. Each chapter is written as an individual essay about a given issue, and where relevant, original cases are provided to illustrate how these issues are currently managed by the global industry. This book offers a thoughtful and thorough description of the industry’s current situation and integrates the latest scholarly and industry research from different disciplines for convenient researcher reference.
  • Article
    Current popular accounts of sexual morality for adolescents based simply on purity or self-determination cannot adequately anchor a Christian sexual ethic, although positions based on both notions hope to facilitate sexual health among young females. Here I critique both popular Christian purity movements and a popular feminist critique of these purity movements (based upon self-determination) and suggest the virtue of prudence as a corrective. Situated within the Catholic theological tradition, prudence (practical wisdom) acknowledges the process of human moral and sexual development and is robust enough to negotiate the concrete complexities of sexual activity and the social realities in which such activity takes place. Further, it honours an embodied sense of female sexual self-determination: females as moral agents directed towards sexual flourishing.
  • Background Immunization rates for human papillomavirus (HPV) infections remain low among teenagers despite strong evidence of the effectiveness of vaccines. Physician recommendations of the vaccine are far from universal. Several states have enacted policies that mandate HPV vaccination or distribute educational materials. Objectives To provide policy makers, physicians, and researchers information on the relative importance of physician recommendations and early state-level policies to promote HPV vaccinations among targeted age groups. Methods We first use probit models to determine the strongest correlates of immunization in a nationally representative US sample of teenagers. We then use instrumental variable probit models to determine the direct role that physician recommendations play in vaccination using plausibly exogenous physician encounters that are likely not the result of more health-conscious parents seeking out information on the vaccine. Results We show that children in the targeted age range who are more likely to encounter physicians for reasons other than seeking out the vaccine, such as through mandatory wellness exams or previous asthma diagnoses, are significantly more likely to get the vaccine. There is no consistent evidence that the state policies we analyze have been effective. Conclusion Encouraging recommendations by physicians may be the most effective path toward increasing HPV vaccination. State-level mandates and policies are yet to exhibit effectiveness.
  • Article
    The primary healthcare approach advanced at Alma Ata to address social determinants of health was replaced by selective healthcare a year later at Bellagio. Subsequently, immunization was endorsed as a cost-effective technical intervention to combat targeted infectious diseases. Multilateral efforts to collaborate on immunization as a universal public health good ambiguously capture the interests of the world's governments as well as private, public, and not for profit institutions. Global assemblages of scientists, governments, industry and non-governmental organizations now work in public-private partnerships to develop and make essential vaccines accessible, with vaccines marketed as single fix solutions for global health. Drawing from ethnographic fieldwork in France and Burkina Faso that followed the development, regulation and implementation of the group A meningococcal conjugate vaccine for sub-Saharan Africa, in this article I describe events during and after the development of MenAfriVac. A technological success narrative steeped in collaborative capitalist rhetoric disguises neglected healthcare systems.
  • Chapter
    Full-text available
    This chapter reviews the data from numerous reports substantiating the link between adverse immune reactions and human papillomavirus (HPV) vaccines. It discusses the results from safety clinical trials on HPV vaccines. In their 2008 pre-licensure analysis of ADRs of potential autoimmune etiology in a large integrated safety database of ASO4 adjuvanted vaccines (including Cervarix), Verstraeten et al. pointed out that “It is important to note that none of these studies were set up primarily to study autoimmune disorders.” Large post-licensure epidemiological studies assessing the safety of Gardasil likewise failed to identify any significant autoimmune safety concerns. Post-vaccination adverse immune phenomena can have long latency periods. The human clinical trial data for the two HPV vaccines currently on the market reveal a troubling safety profile that requires an accurate reevaluation of the risks and benefits.
  • Article
    Mass immunisation is a central aspiration of global health programmes, such as in the 2000 Millennium Development Goals (MDG), as a means of addressing the glaring inequalities in life expectancy that separate the Global North and South. A recent initiative, the Human Papillomaviruses (HPV) vaccine, is being rolled out in so-called developing countries to prevent a number of sexually transmitted diseases, including one of the rarer forms of cervical cancer. Despite its apparent good intentions, resistance to the vaccine has occurred, in developed as well as in developing countries, not least because it constitutes a largely gendered form of medical intervention which is promoted according to Western concepts of risk, biomedical knowledge and normative understandings of female sexual behaviour. As a major component of the MDG health strategy aimed at developing countries, the HPV vaccine initiative carries implicit tendencies towards ‘medical colonialism’ underpinned as it is by hegemonic scientific masculinity, in which gendered forms of structural violence are legitimised through the discursive affiliations of progress and global health. This paper will examine the intersecting themes of political economy, gendered structural violence and hegemonic medical masculinity underpinning HPV immunisation programmes within the context of development. It interrogates how masculine scientific narratives of disease prevention, which legitimises the state-endorsed (and increasingly mandated) pharmaceuticalised protection of young women as objects of patriarchal care and control, have become the new missionary voices, saving bodies rather than souls.
  • Article
    Full-text available
    This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of aluminium adjuvants used in vaccines versus placebo or no intervention, taking into consideration the type of the vaccine, and the type, size and concentration of aluminium adjuvant. © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  • Chapter
    A large body of evidence supports the prevailing scientific opinion that human papillomavirus (HPV) vaccines are efficacious, safe, and cost-effective. Since first licensure in 2006, however, HPV vaccines have sparked unjustified controversy over their effectiveness, safety and risks, utility, and ethical implementation. We discuss various public criticisms relating to HPV vaccination and the weight of the evidence and counterarguments concerning each. These criticisms can be classified as follows: (1) effectiveness (lack of demonstrated efficacy against cervical cancer, lack of vaccine clinical trial data in targeted age groups, and limited HPV type protection of first-generation vaccines), (2) safety and risk (concerns regarding potential serious adverse health events linked with vaccination, effect of vaccines on prevalent infections, and potential sexual disinhibition caused by vaccination), (3) utility (disputing the added value of vaccination on the grounds of financial conflicts of interests, the low risk of cervical cancer consequent to screening, and the cost-effectiveness of vaccination), and (4) ethics (concerns regarding informed consent and self-determination in vaccination programs, the social justice of vaccine distribution, and gender equity). Most HPV vaccine controversies stem from misinformation and distrust of institutions. Public health institutions must deploy effective communication strategies to address ill-founded criticisms, enable informed consent, and foster public confidence in HPV vaccines.
  • Article
    This article examines the rise of the anti-vaccination movement, the proliferation of laws allowing parental exemptions to mandatory school vaccines, and the impact of the movement on immunization rates for all vaccines. It uses the ongoing debate about the Human Papillomavirus (HPV) vaccine as an example to highlight the ripple effect and consequences of the anti-vaccine movement despite robust evidence of the vaccine's safety and efficacy. The article scrutinizes how state legislatures ironically promote vaccination while simultaneously deferring to the opposition by promulgating broad opt-outs from mandatory vaccine laws. This article concludes by offering an alternative legislative approach to specifically combat the anti-vaccine movement's impact on HPV vaccination rates. Lowering the age of consent has not been widely attempted or proposed and provides an alternative statutory mechanism to push back against vaccine resistance.
  • Article
    This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of aluminium adjuvants used in a vaccine or an excipient versus the same vaccine or excipient, but having a different type of aluminium adjuvant formulation, or a different concentration, or with a different particle size.
  • The cause of primary ovarian insufficiency (POI) is multifactorial. Known causes include external factors such as chemotherapy, radiotherapy, exposure to endocrine-disrupting chemicals, infections that lead to a permanent insult to the ovary, autoimmune conditions, and genetic causes. An association between the quadrivalent antihuman papilloma vaccine (HPV4) and POI was recently suggested. An increasing number of cases of POI post-HPV4 are being reported. Possible mechanisms for the suspected effect of HPV on female reproductive function are a toxic effect or an autoimmune response. The trigger could be the vaccine immunogen contents or the adjuvants, the latter are used to increase the immune reaction. The adjuvant in HPV4 contains aluminum. Animal models have shown aluminum exposure to inhibit expression of female reproductive hormones and to induce histologic changes in the ovaries. Specific genetic compositions may be more susceptible to developing an autoinflammatory syndrome after exposure to an environmental factor. The mechanisms responsible for POI are not yet fully understood. Although case reports cannot establish causation, awareness of a possible link between HPV4 and POI will help to identify and manage future cases that may arise.
  • “Flogging Gardasil,”
    • See Tomljenovic
    See Tomljenovic and Shaw, supra note 22. 66. Centers for Disease Control (CDC), CDC WONDER VAERS Request, available at <http://wonder.cdc.gov/vaers.html> (last visited September 11, 2012).
  • Michele Bachmann HPV Row Prompts Fears for Vaccine Programme in US The Guardian, available at <http://www.guardian.co.uk/world
    • C Mcgreal
    • I Sample
    C. Mcgreal and I. Sample, " Michele Bachmann HPV Row Prompts Fears for Vaccine Programme in US, " The Guardian, available at <http://www.guardian.co.uk/world/2011/sep/14/ michele-bachmann-hpv-vaccine> (last visited September 6, 2012).
  • Gardasil (Human Papillomavirus Vaccine) Questions and Answers
    • Drug Food
    • Administration
    Food and Drug Administration (FDA), " Gardasil (Human Papillomavirus Vaccine) Questions and Answers, " available at <http://www.fda.gov/BiologicsBloodVaccines/Vaccines/Ques- tionsaboutVaccines/ucm096052.htm> (last visited September 6, 2012).
  • Workshop on Nonclinical Safety Evaluation of Preventative Vaccines: Recent Advances and Regulatory Considerations
    • Drug Food
    • Administration
    Food and Drug Administration (FDA), Workshop on Nonclinical Safety Evaluation of Preventative Vaccines: Recent Advances and Regulatory Considerations, December 2, 2002, available at <http://www.fda.gov/downloads/biologicsblood- vaccines/newsevents/workshopsmeetingsconferences/tran- scriptsminutes/ucm054459.pdf> (last visited September 6, 2012).
  • FDA Science and Mission at Risk, Report of the Subcommittee on Science and Technology
    • Drug Food
    • Administration
    Food and Drug Administration (FDA), FDA Science and Mission at Risk, Report of the Subcommittee on Science and Technology, 2007, available at <http://www.fda.gov/ohrms/dock- ets/ac/07/briefing/2007-4329b_02_01_FDA%20Report%20 on%20Science%20and%20Technology.pdf> (last visited September 6, 2012).
  • Merck Launches National Advertising Campaign for Gardasil, Merck's New Cervical Cancer Vaccine
    • News Medical
    • Today
    Medical News Today, " Merck Launches National Advertising Campaign for Gardasil, Merck's New Cervical Cancer Vaccine, " available at <http://www.medicalnewstoday.com/ releases/57419.php> (last visited September 18, 2011).
  • Michele Bachmann Correct to Criticize Gardasil Mandate, Doctors Say, available at <http://www.prnewswire. com/news-releases/michele-bachmann-correct-to-criticize- gardasil-mandate-doctors-say-129824558.html> (last visited
    • Usnewswire
    USNewswire, " Michele Bachmann Correct to Criticize Gardasil Mandate, Doctors Say, available at <http://www.prnewswire. com/news-releases/michele-bachmann-correct-to-criticize- gardasil-mandate-doctors-say-129824558.html> (last visited September 6, 2012).
  • Natural History of Cervical Intraepithelial Neoplasia: A Critical Review
    • A G Ostor
    A. G. Ostor, " Natural History of Cervical Intraepithelial Neoplasia: A Critical Review, " International Journal of Gynecological Pathology 12, no. 2 (1993): 186-92.
  • Statement on HPV Vaccine, Press Release
    American Academy of Pediatrics (AAP), Statement on HPV Vaccine, Press Release, September 11, 2011, available at <http://www.aap.org/advocacy/releases/hpv2011.pdf> (last visited September 6, 2012).
    • L Villa
    • R L Costa
    • C A Petta
    • R P Andrade
    • J Paavonen
    • O E Iversen
    • S E Olsson
    • J Hoye
    • M Steinwall
    • G Riis-Johannessen
    • A Andersson-Ellstrom
    • K Elfgren
    • G Krogh
    • M Lehtinen
    • C Malm
    • G M Tamms
    • K Giacoletti
    • L Lupinacci
    • R Railkar
    • F J Taddeo
    • J Bryan
    • M T Esser
    • H L Sings
    • A J Saah
    • E Barr
    L. Villa, R. L. Costa, C. A. Petta, R. P. Andrade, J. Paavonen, O. E. Iversen, S. E. Olsson, J. Hoye, M. Steinwall, G. Riis- Johannessen, A. Andersson-Ellstrom, K. Elfgren, G. Krogh, M. Lehtinen, C. Malm, G. M. Tamms, K. Giacoletti, L. Lupinacci, R. Railkar, F. J. Taddeo, J. Bryan, M. T. Esser, H. L. Sings, A. J. Saah, and E. Barr, " High Sustained Efficacy of a Prophylactic Quadrivalent Human Papillomavirus Types 6/11/16/18 l1 Virus-Like Particle Vaccine through 5 Years of Follow-Up, " British Journal of Cancer 95, no. 11 (2006): 1459-1466.
  • Article
    Full-text available
    We read with great interest the analysis by Mello et al.(1) on how Merck & Co., Inc. (Merck) influenced state human papillomavirus (HPV) vaccination policymaking. The exclusive reliance on Merck for scientific information on behalf of the legislators is unfortunate, especially in the light of independent research which has repeatedly warned that drug companies may manipulate clinical trial designs and subsequent data analysis and reporting to make their drugs look better and safer.(2-4) Indeed, careful scrutiny of Gardasil clinical trials shows that their design, as well as data reporting and interpretation, were largely inadequate.(4-6) (Am J Public Health. Published online ahead of print July 19, 2012: e1-e2. doi:10.2105/AJPH.2012.300837).
  • Article
    Gulf War Syndrome is a multi-system disorder afflicting many veterans of Western armies in the 1990–1991 Gulf War. A number of those afflicted may show neurological deficits including various cognitive dysfunctions and motor neuron disease, the latter expression virtually indistinguishable from classical amyotrophic lateral sclerosis (ALS) except for the age of onset. This ALS “cluster” represents the second such ALS cluster described in the literature to date. Possible causes of GWS include several of the adjuvants in the anthrax vaccine and others. The most likely culprit appears to be aluminum hydroxide. In an initial series of experiments, we examined the potential toxicity of aluminum hydroxide in male, outbred CD-1 mice injected subcutaneously in two equivalent-to-human doses. After sacrifice, spinal cord and motor cortex samples were examined by immunohistochemistry. Aluminum-treated mice showed significantly increased apoptosis of motor neurons and increases in reactive astrocytes and microglial proliferation within the spinal cord and cortex. Morin stain detected the presence of aluminum in the cytoplasm of motor neurons with some neurons also testing positive for the presence of hyper-phosphorylated tau protein, a pathological hallmark of various neurological diseases, including Alzheimer’s disease and frontotemporal dementia. A second series of experiments was conducted on mice injected with six doses of aluminum hydroxide. Behavioural analyses in these mice revealed significant impairments in a number of motor functions as well as diminished spatial memory capacity. The demonstrated neurotoxicity of aluminum hydroxide and its relative ubiquity as an adjuvant suggest that greater scrutiny by the scientific community is warranted.
  • Article
    Full-text available
    To the Editor: Mr Gostin made an important point in his Commentary on mandatory HPV vaccination: “Above all, health policy must be driven by science.”1 However, the author's recommendation that “if voluntary vaccination proves unsuccessful, states should seriously consider compulsory vaccination laws without generous exemptions” appears premature. As Gostin noted, clinical trial evidence has not demonstrated that HPV vaccines can actually prevent invasive cervical cancer, let alone cervical cancer deaths.2,3 Because HPV vaccines were specifically developed to protect against cervical cancer, we conclude that in the absence of long-term data, their true benefits remain speculative. The Food and Drug Administration acknowledges that “It is believed that prevention of cervical precancerous lesions is highly likely to result in the prevention of those cancers.”4
  • Article
    Physicians are often puzzled by enigmatic medical conditions or the abrupt appearance of an immune-mediated disease. Such a story was recently presented to us by a young Sheikh. A Saudi Sheikh, who suffered at the age of 27 from joints pains, rash and serological evidence of antiRo antibodies, was diagnosed with probable systemic lupus erythematosus (SLE) at that time. He was treated with Plaquenil for a year, but as no signs of SLE were apparent, treatment was stopped and he remained disease free for the next 12 years. At the age of 39 years, 2 weeks after immunization with the flu vaccine, his disease reemerged. This time he presented with severe arthritis and pericarditis, which required treatment with high doses of
  • Article
    Full-text available
    All drugs are associated with some risks of adverse reactions. Because vaccines represent a special category of drugs, generally given to healthy individuals, uncertain benefits mean that only a small level of risk for adverse reactions is acceptable. Furthermore, medical ethics demand that vaccination should be carried out with the participant's full and informed consent. This necessitates an objective disclosure of the known or foreseeable vaccination benefits and risks. The way in which HPV vaccines are often promoted to women indicates that such disclosure is not always given from the basis of the best available knowledge. For example, while the world's leading medical authorities state that HPV vaccines are an important cervical cancer prevention tool, clinical trials show no evidence that HPV vaccination can protect against cervical cancer. Similarly, contrary to claims that cervical cancer is the second most common cancer in women worldwide, existing data show that this only applies to developing countries. In the Western world cervical cancer is a rare disease with mortality rates that are several times lower than the rate of reported serious adverse reactions (including deaths) from HPV vaccination. Future vaccination policies should adhere more rigorously to evidence-based medicine and ethical guidelines for informed consent.
  • Article
    Full-text available
    Nearly a half a million women throughout the world develop cervical cancer every year Parkin and Bray ("Chapter 2. The burden of HPVrelated cancers," Vaccine, vol. 24, no. 3, pp. S11-S25, 2006); 80% of these women are in countries without a quality-assured cytology screening program. It is in this setting that Cervarix could reduce the incidence of cervical cancer to about 9.5/100,000 women. New evidence indicates that this might be able to be accomplished with a single dose of Cervarix, a great advantage to public health implementation programs Kreimer et al. ("Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine, The Journal of the National Cancer Institute, vol. 103, no. 19, pp. 1444-1451, 2011). In countries with screening programs, adenocarcinoma is the most difficult to detect and treat with later-stage presentation and higher mortality Smith et al. ("The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States-a 24-year population-based study," Gynecologic Oncology, vol. 78, no. 2, pp. 97-105, 2000) and Gunnell et al. ("A longitudinal Swedish study on screening for squamous cell carcinoma and adenocarcinoma: evidence of effectiveness and overtreatment," Cancer Epidemiology Biomarkers and Prevention, vol. 16, no. 12, pp. 2641-2648, 2007). With additional cross-protection to HPV 31, 33, and 45 and protection against HPV 16 and 18 lasting at least 9.4 years, Cervarix may reduce adenocarcinomas in screened populations by more than 90%. This paper will detail the evidence about the efficacy, immunogenicity, and safety of Cervarix in the studied populations contrasting public health goals with individual health options.
  • Article
    Macrophagic myofasciitis (MMF) is characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and cognitive dysfunction. Representative features of MMF-associated cognitive dysfunction (MACD) include (i) dysexecutive syndrome; (i) visual memory; (iii) left ear extinction at dichotic listening test. In present study we retrospectively evaluated the progression of MACD in 30 MMF patients. Most patients fulfilled criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits seemed unusually severe. MACD remained stable over time, although dysexecutive syndrome tended to worsen. Long-term follow-up of a subset of patients with 3 or 4 consecutive neuropsychological evaluations confirmed the stability of MACD with time, despite marked fluctuations.
  • Article
    Vaccinations are among the most cost-effective and widely used public health interventions, but have provoked popular resistance, with compulsion framed as an unwarranted state interference. When the FDA approved a human papillomavirus (HPV) vaccine in 2006, conservative religious groups strongly opposed a mandate, arguing it would condone pre-marital sex, undermine parental rights, and violate bodily integrity. Yet, Governor Rick Perry signed an executive order in 2007 making Texas the first state to enact a mandate — later revoked by the legislature.Mandatory HPV vaccination reached the heights of presidential politics in a recent Republican debate. Calling the vaccine a "very dangerous drug" that could lead to "mental retardation," Michele Bachmann asserted, "To have innocent little 12-year-old girls be forced to have a government injection through an executive order is just wrong." Rick Santorum added, "There is no government purpose served for having little girls inoculated at the force and compulsion of the government." Governor Perry almost immediately disavowed his action, saying first that the vehicle of an executive order was wrong and then vaccination should be "opt-in."This political theater could frighten parents from vaccinating their children, causing preventable suffering and death. The scientific evidence demonstrates that population-based HPV vaccination is highly safe and effective, justifying widespread adoption of the vaccine. The only question is whether a state mandate would increase vaccination rates or result in a backlash against HPV and wider childhood vaccinations. Given the political divisiveness, states should launch health education campaigns before resorting to compulsion.
  • Acute Disseminated Encephalomyelitis Following Vaccination against Human Papilloma Virus A 16-Year-Old Girl with Bilateral Visual Loss and Left Hemiparesis Following an Immunization against Human Papilloma Virus Opsoclonus Myoclonus after Human Papilloma Virus Vaccine in a Pediatric Patient
    • B Wildemann
    • S Jarius
    • M Hartmann
    • J U Regula
    • C Hametner
    • F J Dimario
    • M Hajjar
    • T Ciesielski
    • J E Mccarthy
    • J Filiano
    B. Wildemann, S. Jarius, M. Hartmann, J. U. Regula, and C. Hametner, " Acute Disseminated Encephalomyelitis Following Vaccination against Human Papilloma Virus, " Neurology 72, no. 24 (2009): 2132-2133; F. J. DiMario, Jr., M. Hajjar, and T. Ciesielski, " A 16-Year-Old Girl with Bilateral Visual Loss and Left Hemiparesis Following an Immunization against Human Papilloma Virus, " Journal of Child Neurology 25, no. 3 (2010): 321-327; J. E. McCarthy and J. Filiano, " Opsoclonus Myoclonus after Human Papilloma Virus Vaccine in a Pediatric Patient, " Parkinsonism & Related Disorders 15, no. 10 (2009): 792-794; I. Sutton, R. Lahoria, I. L. Tan, P. Clouston, and M. H. Barnett, " CNS Demyelination and Quadrivalent HPV Vaccination, " Multiple Sclerosis 15, no. 1 (2009): 116-119.
  • Article
    The role of various environmental factors in the pathogenesis of immune mediated diseases is well established. Of which, factors entailing an immune adjuvant activity such as infectious agents, silicone, aluminium salts and others were associated with defined and non-defined immune mediated diseases both in animal models and in humans. In recent years, four conditions: siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena were linked with previous exposure to an adjuvant. Furthermore, these four diseases share a similar complex of signs and symptoms which further support a common denominator.Thus, we review herein the current data regarding the role of adjuvants in the pathogenesis of immune mediated diseases as well as the amassed data regarding each of these four conditions. Relating to the current knowledge we would like to suggest to include these comparable conditions under a common syndrome entitled ASIA, "Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants".
  • Article
    Full-text available
    Approaches for cervical cancer prevention are changing. Screening still remains the most effective method for cervical cancer prevention. Guidelines are moving to an older group of women to be screened less frequently with combinations of technologies that include biomarkers and cytology. HPV vaccination is an appropriate option for this older group of women as well, should the woman not wish to make her decision about vaccination until 21 years of age, the age of screening. Parents making decisions about HPV vaccination for their young adolescent daughters need to be fully informed that only continued screening prevents cervical cancer. HPV vaccination reduces the possibility of their daughter having an abnormal Pap test by 10% if the vaccines have not waned by the time the young adolescent becomes sexually active. HPV vaccine efficacy must last at least 15 years to contribute to the prevention of cervical cancers. At this time, protection against cervical intraepithelial neoplasia grade 2/3 (CIN 2/3) is 5 years for Gardasil and 8.4 years for Cervarix. The value of the current protection HPV vaccines offer will be viewed differently by different women. Physicians' ethical duties are to provide full explanation of the risks and benefits of adding HPV vaccination to the ongoing screening programs, and to support women in their personal choice for cervical cancer prevention.
  • Article
    Full-text available
    The story of epidemiologists and surrogate variables is one of a classic love–hate relationship. Epidemiologists love surrogates because many studies would not be possible without them. When events are rare or the time between an intervention and the outcome is long, surrogate variables are used to fill the gap. Epidemiologists hate surrogate variables because they introduce an additional step in the chain between intervention (or exposure) and outcome, and thus an additional source of error. To introduce surrogates means to increase uncertainty — and, perhaps, an error. A recent “collection of misleading surrogate end points” reminds us that caution is warranted: examples from this collection include the Cardiac Arrhythmia Suppression Trial in which a group of patients with asymptomatic or mildly symptomatic ventricular arrhythmia after myocardial infarction were treated with encainide or flecainide. Both drugs are used to suppress ventricular arrhythmia (the surrogate end point), but they were actually associated with excess mortality (the relevant outcome). In another case, patients treated with fluoride developed the desired increase in bone mineral density at the lumbar spine (the surrogate end point) but suffered from a higher rate of vertebral fractures than the control group.1 Assessing whether surrogate variables actually measure what they purport to measure (ie, for their validity) is therefore required. Available instruments, however, can only test if a surrogate correctly indicates the direction of an effect — that …
  • Article
    Full-text available
    We report the course of a 16-year-old girl who presented with near complete visual loss associated with chiasmal neuritis and a biopsy proven tumefactive demyelinating lesion on magnetic resonance imaging (MRI) in association with a recent immunization against human papilloma virus.
  • Article
    Some adjuvants may exert adverse effects upon injection or, on the other hand, may not trigger a full immunological reaction. The mechanisms underlying adjuvant adverse effects are under renewed scrutiny because of the enormous implications for vaccine development. In the search for new and safer adjuvants, several new adjuvants were developed by pharmaceutical companies utilizing new immunological and chemical innovations. The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of special immune receptors called toll-like receptors (TLRs) that are expressed on leukocyte membranes. The very fact that TLR activation leads to adaptive immune responses to foreign entities explains why so many adjuvants used today in vaccinations are developed to mimic TLR ligands. Alongside their supportive role, adjuvants were found to inflict by themselves an illness of autoimmune nature, defined as 'the adjuvant diseases'. The debatable question of silicone as an adjuvant and connective tissue diseases, as well as the Gulf War syndrome and macrophagic myofaciitis which followed multiple injections of aluminium-based vaccines, are presented here. Owing to the adverse effects exerted by adjuvants, there is no doubt that safer adjuvants need to be developed and incorporated into future vaccines. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. More adjuvants were approved to date besides alum for human vaccines, including MF59 in some viral vaccines, MPL, AS04, AS01B and AS02A against viral and parasitic infections, virosomes for HBV, HPV and HAV, and cholera toxin for cholera. Perhaps future adjuvants occupying other putative receptors will be employed to bypass the TLR signaling pathway completely in order to circumvent common side effects of adjuvant-activated TLRs such as local inflammation and the general malaise felt because of the costly whole-body immune response to antigen.
  • Article
    Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.
  • Article
    Full-text available
    HEN DO PHYSICIANS KNOW ENOUGH ABOUT THE beneficial effects of a new medical interven- tiontostartrecommendingorusingit?When istheavailableinformationaboutharmfulad- verse effects sufficient to conclude that the risks outweigh the potential benefits? If in doubt, should physicians err on the side of caution or on the side of hope? These questions are at the core of all medical decision making. It is a com- plicated process because medical knowledge is typically in- complete and ambiguous. It is especially complex to make decisions about whether to use drugs that may prevent dis- ease in the future, particularly when these drugs are given to otherwise healthy individuals. Vaccines are examples of such drugs, and the human papillomavirus (HPV) vaccine is a case in point. zur Hausen, winner of the Nobel Prize in Physiology or Medicine in 2008, discovered that oncogenic HPV causes cervical cancer. 1-4 His discovery led to characterization of the natural history of HPV infection, an understanding of mechanisms of HPV-induced carcinogenesis, and eventu- allytothedevelopmentofprophylacticvaccinesagainstHPV infection.
  • Article
    The new vaccine against 4 types of human papillomavirus (HPV), Gardasil, like other immunizations appears to be a cost-effective intervention with the potential to enhance both adolescent health and the quality of their adult lives. However, the messages and the methods by which the vaccine was marketed present important challenges to physician practice and medical professionalism. By making the vaccine's target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to adolescents was maximized, and the subpopulations most at risk practically ignored. The vaccine manufacturer also provided educational grants to professional medical associations (PMAs) concerned with adolescent and women's health and oncology. The funding encouraged many PMAs to create educational programs and product-specific speakers' bureaus to promote vaccine use. However, much of the material did not address the full complexity of the issues surrounding the vaccine and did not provide balanced recommendations on risks and benefits. As important and appropriate as it is for PMAs to advocate for vaccination as a public good, their recommendations must be consistent with appropriate and cost-effective use.
  • Article
    Vaccination is generally considered safe in patients with multiple sclerosis (MS). We report five patients who presented with multifocal or atypical demyelinating syndromes within 21 days of immunization with the quadrivalent human papilloma virus (HPV) vaccine, Gardasil. Although the target population for vaccination, young females, has an inherently high risk for MS, the temporal association with demyelinating events in these cases may be explained by the potent immuno-stimulatory properties of HPV virus-like particles which comprise the vaccine. A prospective case-control study of patients with MS or clinically isolated demyelinating syndromes receiving the Gardasil vaccine may provide relevant safety data in this population.
  • Article
    Over the past 2 decades, the pharmaceutical industry has gained unprecedented control over the evaluation of its own products. Drug companies now finance most clinical research on prescription drugs, and there is mounting evidence that they often skew the research they sponsor to make their drugs look better and safer. Two recent articles underscore the problem: one showed that many publications concerning Merck's rofecoxib that were attributed primarily or solely to academic investigators were actually written by Merck employees or medical publishing companies hired by Merck1; the other showed that the company manipulated the data analysis in 2 clinical trials to minimize the increased mortality associated with rofecoxib.2 Bias in the way industry-sponsored research is conducted and reported is not unusual and by no means limited to Merck.3
  • Article
    The literature dealing with the natural history of cervical intraepithelial neoplasia (CIN) since 1950 is reviewed, in particular from the viewpoint of regression, persistence, and progression. When stratified into the various grades of severity, the composite data indicate the approximate likelihood of regression of CIN 1 is 60%, persistence 30%, progression to CIN 3 10%, and progression to invasion 1%. The corresponding approximations for CIN 2 are 40%, 40%, 20%, and 5%, respectively. The likelihood of CIN 3 regressing is 33% and progressing to invasion greater than 12%. It is obvious from the above figures that the probability of an atypical epithelium becoming invasive increases with the severity of the atypia, but does not occur in every case. Even the higher degrees of atypia may regress in a significant proportion of cases. As morphology by itself does not predict which lesion will progress or regress, future efforts should seek factors other than morphological to determine the prognosis in individual patients.
  • Article
    The approval of rofecoxib (Vioxx) by the US Food and Drug Administration has led to the “single greatest drug safety catastrophe in the history of this country or the history of the world,” charged one of the agency's own experts, Dr David Graham, in US Senate hearings last Thursday. Dr Graham, associate director in the FDA's Office of Drug Safety, said an estimated 88 000 to 139 000 Americans had heart attacks and strokes as a result of taking rofecoxib. The number, he said, far exceeds earlier disasters such as the 100 children killed in the United States by an elixir of sulfanilamide in the 1930s and the 5000 to 10 000 children born in the 1960s with birth defects related to thalidomide. Both events led to sweeping regulatory changes in the United States. Senator Charles Grassley, chairman of the Senate's finance committee, opened the hearings on the FDA and rofecoxib and its manufacturer, Merck, saying he hoped Congressional investigation would help shed “disinfecting sunlight” on the approval …
  • Article
    An Australian newspaper recently bestowed Ian Frazer the title of "God's gift to women" for his research team's part in developing a vaccine to help control cervical cancer. Here Frazer discusses this work and the science behind the vaccine.
  • Article
    Full-text available
    Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16-23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrollment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy = 100%; 95% CI:12-100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.
  • Article
    Full-text available
    In October UK patients who had cardiovascular events while taking rofecoxib lost the right to fight Merck in the US for compensation. But researchers and journals can still benefit from this case if they learn from the mistakes, write Harlan Krumholz and colleagues
  • Article
    Full-text available
    These recommendations represent the first statement by the Advisory Committee on Immunization Practices (ACIP) on the use of a quadrivalent human papillomavirus (HPV) vaccine licensed by the U.S. Food and Drug Administration on June 8, 2006. This report summarizes the epidemiology of HPV and associated diseases, describes the licensed HPV vaccine, and provides recommendations for its use for vaccination among females aged 9-26 years in the United States. Genital HPV is the most common sexually transmitted infection in the United States; an estimated 6.2 million persons are newly infected every year. Although the majority of infections cause no clinical symptoms and are self-limited, persistent infection with oncogenic types can cause cervical cancer in women. HPV infection also is the cause of genital warts and is associated with other anogenital cancers. Cervical cancer rates have decreased in the United States because of widespread use of Papanicolaou testing, which can detect precancerous lesions of the cervix before they develop into cancer; nevertheless, during 2007, an estimated 11,100 new cases will be diagnosed and approximately 3,700 women will die from cervical cancer. In certain countries where cervical cancer screening is not routine, cervical cancer is a common cancer in women. The licensed HPV vaccine is composed of the HPV L1 protein, the major capsid protein of HPV. Expression of the L1 protein in yeast using recombinant DNA technology produces noninfectious virus-like particles (VLP) that resemble HPV virions. The quadrivalent HPV vaccine is a mixture of four HPV type-specific VLPs prepared from the L1 proteins of HPV 6, 11, 16, and 18 combined with an aluminum adjuvant. Clinical trials indicate that the vaccine has high efficacy in preventing persistent HPV infection, cervical cancer precursor lesions, vaginal and vulvar cancer precursor lesions, and genital warts caused by HPV types 6, 11, 16, or 18 among females who have not already been infected with the respective HPV type. No evidence exists of protection against disease caused by HPV types with which females are infected at the time of vaccination. However, females infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types. The vaccine is administered by intramuscular injection, and the recommended schedule is a 3-dose series with the second and third doses administered 2 and 6 months after the first dose. The recommended age for vaccination of females is 11-12 years. Vaccine can be administered as young as age 9 years. Catch-up vaccination is recommended for females aged 13--26 years who have not been previously vaccinated. Vaccination is not a substitute for routine cervical cancer screening, and vaccinated females should have cervical cancer screening as recommended.