Prophylactic HPV vaccines: the Finnish perspective

Abstract

Finland is a country with a dual role in the human papillomavirus (HPV) field. Finnish scientists have pioneered in HPV research and participated in international HPV vaccine trials, but officially Finland is reluctant to implement HPV vaccines into its national vaccination program owing to the reasons discussed in this article. In contrast to other European countries, Finnish authorities were reluctant to initiate the evaluation process for HPV vaccines after licensure. Instead of prompt implementation, it was decided that a long-term prospective (Phase IV effectiveness) study to evaluate the bivalent HPV vaccine in a randomized community trial should be started. In addition, the Finnish authorities refuse to accept the compelling scientific evidence on the efficacy and safety of HPV vaccines. They report that cervical cancer (CC) is effectively controlled by the national screening program, despite the fact that CC in Finland has increased very rapidly since 1992. The Finnish perspective on HPV vaccines appears to postpone all critical decisions until the second half of the 2010s. This will have two direct consequences: 1) every year of delay means that an entire birth cohort (>60,000 girls and boys) will lose the opportunity of being offered the state-of-art cancer prevention provided by prophylactic HPV vaccines; and 2) given the declining trends of CC elsewhere, within a few years Finland will fall among the countries with a high incidence of CC. It is the personal conviction of this author that there are no sustainable arguments remaining that advocate continuing this Finnish perspective on HPV vaccines any further.

Keywords::

• Cervarix™
• cervical cancer
• cost–effectiveness
• efficacy
• Finland
• Gardasil^®
• HPV disease burden
• HPV vaccines
• implementation
• national program
• organized screening
• perspective
• Phase IV trial

Figure 1. Age-adjusted annual incidence and mortality rates of cervical cancer in Finland (1953–2005).

Figure 2. Age-adjusted annual incidence rates of cervical cancer among young women (25–39 years old) in Finland (1953–2005).

Scientists in Finland pioneered in human papillomavirus research

In both human papillomavirus (HPV) research and in translation of its most outstanding recent results into clinical practice, Finland has played a dual and conflicting role: scientists from Finland have pioneered in several important fields of HPV research [1,2], while at the same time Finland remains among the last few countries in Europe that have not implemented prophylactic HPV vaccines in their national vaccination program [101]. Starting in the early 1970s, Finnish scientists were the first to demonstrate the presence of HPV antibodies in up to 90% of young adults (at 20 years of age) [3]. This same group went on to present an idea that more than one HPV type must exist to explain the plurality of their clinical manifestations [4]. Finland was the country where the link between HPV and cervical intraepithelial neoplasia (CIN) was first disclosed when Purola et al. described koilocytes in CIN lesions in 1976 [5]. Prompted by these keystone observations, other Finnish researchers were the first to suggest the potential causal link between HPV and esophageal [6], sino-nasal [7], oral [8], laryngeal [9] and bronchial cancers [10]. Soon after the characterization of HPV-16 and HPV-18 in 1983 and 1984, respectively [1,2], the same Finnish group working with the 2008 Nobel laureate in Medicine, Harald zur Hausen, provided the first direct evidence (in 1985) to implicate that HPV-16/18 are highly oncogenic viruses with a significant risk for progression to invasive cervical cancer (CC), thus creating the concept of high-risk (HR) and low-risk (LR) HPV genotypes [11]. These pioneering studies, as well as several other lines of innovative research conducted in Finland since the early 1970s, made Finland a fruitful soil upon which the two companies could solicit clinical partners for their international HPV vaccine efficacy trials [12,13].

Considering this background, it is difficult to understand why the authorities in Finland have adopted a clearly backward pathway of development; rigidly refusing to accept one of the most innovative achievements of modern medicine – cancer prevention through prophylactic HPV vaccines – as a part of their national healthcare program. Equally hard to understand is their persistent refusal to even include HPV vaccines among the remedies reimbursable by the national health insurance (KELA) for those who choose to purchase the vaccines voluntarily.

With good reason, one might ask what the causes are of this abnormal Finnish perspective on HPV vaccines. This review was solicited from the author to start a discourse on the developments that led to this official policy and to critically explore whether there are any sustainable arguments that could advocate continuing this uncharacteristic perspective on HPV vaccines adopted by the authorities in Finland.

Standard policy for evaluating candidate vaccines for the national vaccination program in Finland

Before entering into a detailed discussion on the Finnish perspective on HPV vaccines, one must be familiar with the different steps that must be followed before any new vaccine can be implemented in the national vaccination program in Finland. This policy consists of two separate procedures: 1) the protocol for the vaccine licensure in Finland, and 2) the regular policy of evaluation for the national vaccination program. The former is rather straightforward and harmonized in all EU countries (Table 1). Only after successful completion of all clinical studies can one proceed with an application for licensure. In the case of HPV vaccines, a centralized procedure was used, with the applications for licensure being submitted by companies to the EMEA. As far as the author is aware, the National Agency of Medicines in Finland [102] played an active role in this process, working in close contact with the two HPV vaccine companies and also at the level of the EMEA to ensure that the clearance of licensure for the two HPV vaccines in Finland was a smooth process.

Clearing the licensure in Finland does not mean that any new vaccine will automatically be included in the national vaccination program. This requires another procedure, which in contrast to the harmonized and transparent policy for licensure, is a domestic affair, with several contributors at different stages (Table 2). On several occasions with other vaccines, this complex domestic policy has been the subject of criticism, most notably owing to the lack of transparency and several documented autocratic interventions, as discussed later.

In Finland, the evaluation and acceptance of new vaccines into the national program has been allocated to the National Institute of Health and Welfare (subsequently called THL) [103]. Orchestrated by one Department (Department of Vaccination and Immune Protection [DVIP]) and subordinated to the Division of Health Protection of the THL [103], there is a potential danger that this protocol leaves far too much supremacy to too few people. In the extreme scenario, this protocol allows cessation of the whole evaluation process, independent of the recommendations of both the Expert Panel (PE) and the National Panel of Vaccine Experts (NPVE), as the DVIP is not bound to the opinion of these two expert panels (Table 2). This worst-case scenario is exactly what has happened in this unfortunate case of HPV vaccines.

Since the licensure of the two HPV vaccines, the THL has adopted an inherently negative attitude against the idea of implementing HPV vaccines into the national vaccine program in Finland [103]. This position is based on arguments that remain incomprehensible to this author in an era when compelling evidence based on high-profile international research [12–27] and the opinions of leading international experts [28–37], including the 2008 Nobel laureate [1,38] and also the WHO [104], advocate the prompt implementation of prophylactic HPV vaccines worldwide.

The arguments of the THL [103] are well known in this country from several public presentations, interviews and solicited articles against HPV vaccines in daily newspapers and weekly magazines during the past 3–4 years when this subject has emerged as a public issue. As will be seen, the position taken by the THL has resulted in multiple deviations from the regular policy for vaccine evaluation in the national program, which is the very essence of the Finnish perspective on HPV vaccines.

Multiple deviations of the regular evaluation policy: major delays & further research instead of HPV vaccine implementation

The two available HPV vaccines (Cervarix™ [Merck, MA, USA] and Gardasil^® [GlaxoSmithKline, Belgium]) were granted licensure in 2007 and 2006, respectively. Given that these two vaccines represent a major breakthrough in modern medicine [1,38], one would have expected their evaluation for implementation to be started immediately by the THL. However, as late as November 2007 (more than 1 year after the licensure of Gardasil), DVIP expressed their official position by stating that there is no need to start the evaluation process for HPV vaccines.

This perplexing statement did not remain unnoticed by the informed circles who brought the issue to the attention of the Finnish Ministry of Social Affairs and Welfare [105] who control the THL, emphasizing the urgent need for HPV vaccine implementation. However, it still took over half a year until the THL finally (13 May 2008) agreed to set up “a national committee for control of papillomavirus diseases”, intended to be an equivalent to the PE in the regular vaccine evaluation protocol (Table 2). Interestingly, few of the committee members have any personal research experience on HPV-related diseases, and none of the few international HPV experts in Finland were invited.

In line with the adopted THL policy, this ‘national committee’ was assigned goals that are far too diverse to cope with, extend beyond the expertise of its members and are, in part, unrelated to the main subject: the evaluation of HPV vaccines. These goals are to evaluate: 1) the overall HPV disease burden in Finland; 2) all potential measures to prevent HPV-associated disease, including organized CC screening programs, and 3) the cost–effectiveness of these optional control measures.

In addition, the fixed deadline to finish their work (August 2010) is felt by many to be far too late to enable prompt implementation of HPV vaccination in this country. On the other hand, this deadline is also too soon for the committee to complete all of its assigned work. However, it well serves the purpose of the THL to postpone the difficult decisions to come. Even after a positive recommendation by the committee, opponents still have several means of postponing the final entry of HPV vaccines into the national vaccine program by several more years (Table 2). Given the complexity of the official procedure, HPV vaccines would not be implemented before 2012. This would have an additional adverse impact on CC prevention in Finland, a country which was so admired for its excellent achievements in the field of HPV not so long ago [39].

Interestingly enough, these authorities went on to further extend this delay by several more years, by creating another deviation from the regular vaccine evaluation policy in Finland. In 2006–2007, they designed a new long-term trial involving one of the two vaccines (called the Phase IV effectiveness trial) and, at the same time, decided to postpone all decisions on implementation until this project concludes in December 2014. In other words, all the compelling evidence provided by the carefully controlled international multicenter trials [14–27], which has been convincing enough for leading experts [28–38], has convinced the regulatory agencies (the US FDA and EMEA) to clear the licensures and the WHO to recommend global implementation [104], was not convincing enough for this national organization (THL) controlling vaccine implementation in Finland. There is no such option as additional research in the official vaccine evaluation protocol in Finland (Table 2), and this novel innovation of the THL results in several more years of delay in making the inevitable decisions.

Reiterating all the details of these recent developments is not appropriate in this context. It is sufficient to describe in brief the goals of this trial at the level of detail that appears on the project websites (no reports have been published as yet). Being a key point of the Finnish perspective on HPV vaccines, the author will also shortly review the main criticisms presented by domestic and international experts against this new trial that has not been considered necessary in the evaluation of HPV vaccines in any other European country [101]. One should emphasize that it is not this Phase IV study itself that is criticized, as experts are unanimous in suggesting that additional research is needed on HPV vaccines [40], but the adopted policy of the THL to use this ongoing study as an excuse for not seriously evaluating HPV vaccines for implementation until the results of the trial are available in December 2014.

The Phase IV HPV vaccine effectiveness trial in Finland (2007–2014)

Study design & aims

The official name of the study is: “A Phase III/IV, community-randomized, controlled study to evaluate the effectiveness of two vaccination strategies using GlaxoSmithKline Biologicals’ HPV-16/18 L1 VLP AS04 vaccine in reducing the prevalence of HPV-16/18 infection when administered intramuscularly according to a 0, 1, 6-month schedule in healthy female and male study participants aged 12–15 years. 106636” [106,107]. This community randomized trial [41] was designed to find answers to several open questions related to the optimal implementation of HPV vaccines. These two key questions are: whether both genders (adolescent boys and girls) must be vaccinated to obtain the most optimal eradication of HPV, and what the optimal age for the vaccination is. Overall, 33 different municipalities in Finland are involved in this trial [106,107]. The study was initiated in 2007 and will extend until the end of 2014. It is entirely sponsored by the manufacturer of the HPV vaccine (GlaxoSmithKline).

The original aim was to enroll a cohort of 70,000 adolescents born between 1992 and 1995 [107]. However, this cohort size has not been reached and the true sample size might currently level off at approximately 25,000 [106]. Invitations are being sent to the mothers of 12–15-year-old children to ask for their written informed consent. These 33 participating communities are randomized into three categories: A, B and C [106]. The boys and girls to be vaccinated will receive both the HPV-16/18 vaccine (Cervarix) and the hepatitis B (HBV) vaccine (Engerix-B), and will therefore recieve three injections each. In communities randomized into arm A, both the boys and girls obtain first the HPV-16/18 vaccine, whereas in communities in arm B, only the girls receive the HPV-16/18 vaccine and the boys are vaccinated with the HBV vaccine. In arm C, both boys and girls first obtain only the HBV vaccine [106]. In the crossover vaccination phase at the age of 18 years, all participants will be offered the vaccine that was not introduced in the first phase.

The study is also partly blinded in that every tenth subject of the HPV arm will receive (blindly) the HBV vaccine instead. Starting from 2010, this study also incorporates an extra arm, which monitors the benefits of screening for Chlamydia trachomatis, offered at the age of 18–19 years for those who were vaccinated against HPV. The end points of the study will be the incident HPV infections in the participating communities during 2010–2014, to be compared across the three arms to assess whether the boys should also be vaccinated to eradicate these infections [106].

Criticism against the Finnish HPV vaccine trial

First of all, the researchers can be criticized for the lack of transparency, for deciding not to make their study a public domain, by publishing information such as the study design and baseline data, which has been a common practice for major vaccine trials [12–27]. Given this lack of published reports, the criticism aroused by the experts stating their concern is necessarily unofficial and has been collected from different sources for this review. The criticisms will be described without reference to the specific sources, which is justified by the fact that there is no published report on the trial which the specific concerns could be targeted to.

It has been argued that in the letter sent to mothers of the boys and girls invited to participate in the trial, the description of the study setting is superficially presented and does not mention, for example, the fact that the participants allocated into the control vaccine (HBV) group will not gain any protection against HPV infection. Similarly, there is no clearly stated caution that if the non-HPV-vaccinated participant initiates sexual activity and contracts HPV infection during the study, the HPV vaccine given at the end of the study will not provide any protection against HPV infection. In other words, the participants allocated to the HBV vaccination arm will remain unprotected against the causal agent of CC during the 3-year period, coinciding with the probable onset of their sexual activity.

Furthermore, there is no clear statement in the invitation letter that this test vaccine will not confer any protection against genital warts (condylomata). This is felt to be important because of the possibility that adolescents have adopted misinformation (from the ongoing public discussion about HPV and genital warts) that all HPV vaccines will also protect against condylomata. In the same documents, there is only a superficial narrative of the second (effectiveness) phase of the trial, with no clear description of how the members in the different arms will be handled in this second phase. The same is true with the failure to find a clear statement regarding at which age the adolescent will obtain the crossover vaccine.

There are also sceptics stating that this ongoing trial will not be capable of providing any such data that would be essential or indispensable to justify postponing the implementation of HPV vaccines until the end of 2014. According to these experts, the accumulated evidence from international studies [14–38,104] should have been convincing enough to prompt a rapid conduct of the regular evaluation process in Finland, similar to, for example, all other Nordic countries [101]. Many of these same experts strongly advocate that in the light of existing compelling evidence, it is completely unethical to initiate any randomized Phase IV trial like this; the undeniable fact is that many of the subjects in the placebo arm will inevitably develop incident HPV-16/18 infections and high-grade precursor lesions (CIN and adenocarcinoma in situ) that would be preventable by the HPV-16/18 vaccine [14–27].

Some concern has also been expressed about the study design of this community randomized trial, better known as cluster randomization. It is well known that standard statistical procedures become invalidated when applied to cluster randomized trials in which the unit of inference is the individual [42]. As a consequence, researchers conducting such trials are faced with a multitude of design choices, including 1) selection of the primary unit of inference; 2) the degree to which clusters should be matched or stratified by prognostic factors at baseline; and 3) decisions related to cluster subsampling. Moreover, application of ethical principles developed for trials randomizing individuals rather than clusters may also need to be modified [42]. However, the lack of transparency of this ongoing trial precludes a detailed listing of the potential pitfalls in this particular setting and all subsequent comments are necessarily only at a general level.

In addition to the measures of the variability between the clusters, known as coefficient of variation (CV), there are several important issues related to the variability within the clusters (communities), called intracluster correlation (ICC) [43]. In their report describing the background of their community randomized trial [41], the authors focus exclusively on scenarios based on different values of CV and neglect the major impact of ICC in such study designs [42]. In fact, cluster randomized trials may have substantially reduced statistical efficiency compared with trials that randomize the same number of individuals. This reduction in efficiency is a function of the variance inflation due to clustering, known as the ‘design effect’ [42].

The variation between the clusters for a given exposure is assumed to be 50% – that is, a CV of 0.5. In exposure to HPV, one must assume that, within a small country like Finland, this CV must be much less, depending on the topographic distance between the clusters. However, indirect data on past exposure to HPV are only available from young women, based on serological samples collected during the 1980s and early 1990s [41]. No similar nationwide data are available for adolescent males and no direct data on recent exposure to HPV-16/18 based on DNA detection are available for either gender. To reliably estimate the CV between the clusters, a pilot study on HPV prevalence would have been beneficial. In the study protocol [41,106,107] however, there is no mention that the participants in the three study arms are tested for HPV DNA before vaccination, which is a definite pitfall, because some of these 12–15-year-old subjects are certainly not HPV-16/18-naive upon vaccination.

Aside from giving a more reliable estimation of CV in HPV exposure than that provided by the historical serology data [41], HPV DNA testing would also provide invaluable information for calculating ICC. This in turn has a major impact on estimation of the sample size because it is used for calculating the design effect [42,43]. Actually, the design effect is the ratio of the total number of subjects needed using cluster randomization to the number required using individual randomization [43]; the larger the ICC, the bigger the design effect is, and the more subjects are needed to achieve the same statistical power as in an individual randomized study. Thus, having reliably established ICC data would help decide whether cluster randomization or individual randomization would be a more feasible approach.

In recent reviews, considerable attention has been paid to the issues related to the informed consent in cluster randomized studies [42]. In addition to having an important ethical impact, the mode of obtaining informed consent also has a profound influence on the sampling and subsampling bias. Most probably, one of the major reasons for the low participation rate (40–50% of those invited) complained of by the researchers [106] is the mode of the administration of the informed consent. In addition to violating the national and EU legislation (see below), their approach potentially builds up the first barrier to unbiased sampling of their subjects into this cohort. There is a good reason to suspect that these nonparticipants are the same women who do not participate in other CC prevention programs (i.e., organized mass screening by Pap test) a few years later.

Related to this administration of the informed consent, a most serious negative incident took place on August 14 2009, when the Deputy Ombudsman (DO) issued an official reminder (DNo 2983/4/07) to the coordinators of this trial (the THL and Tampere University)[108]. There is no need to reiterate the broad range of laws, statutes, bylaws and EU directives not appropriately followed in this trial. According to the reminder from the DO, the most serious incriminations are related to the following two issues: 1) written consent should be obtained from both parents, and 2) the information given in the invitation letter and its annexes was insufficient to ensure an objective judgment by the parents (or the legal representatives of the children) to decide whether or not to give their informed consent [108].

In contrast to the applicable legislation, the invitation letter was sent to, and informed consent was asked from, the mothers exclusively, rather than from both parents. The second point in this public reminder highlights the confusing information given by the researchers in different public media [108]. Importantly, this discordant public information even includes the title of the study (Phase III and/or Phase IV study), as well as the description of the randomization protocol into the three study arms. On the basis of this confusing information, it was not clear to the parents and the test subjects how they were randomized into the HPV-16/18 and HBV vaccine groups in those three study arms [106].

Although it did not lead to direct legal consequences for the researchers, this public interference by the highest-ranking officer supervising the national legislation potentially contributes towards a declining interest in this trial among those 33 cluster communities. In the worst-case scenario, such a low participation rate will inevitably decrease the power of the study and might even lead to its termination before the planned end point in 2014.

Official arguments against HPV vaccines in Finland

As a part of their policy of postponing the implementation of HPV vaccines in Finland, the THL has continued campaigns in different media, presenting the public with an ever-growing list of arguments against this implementation. Together with the intentional delay in the vaccine evaluation protocol and this extraordinary Phase IV trial, this THL policy has been effective – Finland is one of the last remaining countries in Europe that has not implemented HPV vaccination. Unsustainable as these arguments are from the scientific standpoint, some of the most perplexing ones deserve to be discussed here as essential elements of this Finnish perspective on HPV vaccines.

Organized mass screening for CC is highly effective in Finland

One of the most frequently used arguments of the THL authorities opposing HPV vaccines states that in Finland, organized mass-screening for CC has an outstanding performance, which makes any further preventive measures unnecessary. The argument includes the fact that in this country, only 150–160 cases of CC are diagnosed each year (Figure 1), which is a very small number as compared with the neighboring countries of Sweden and Denmark, for example, where the incidence rates are more that two- and three-times higher, respectively.

Unfortunately, however, this statement has little to do with the current reality in Finland. It is true that the organized CC screening program in Finland was probably the most effective of all national screening programs worldwide during the first three decades of its implementation [39]. Accordingly, the age-adjusted incidence of CC in Finland was the lowest in the world (3.2 per 100,000), when it reached the lowest ever level in 1992 (Figure 1). Until that time point, the program had an excellent performance and progressively reduced the incidence and mortally of CC year after year since the early 1960s [39,44,45]. However, CC has started making a rapid and steady increase in this country, as clearly demonstrated in Figure 1. The undeniable fact is that since 1992, CC has increased by 25–30% (from 120 to 160 cases), which makes Finland a country with one of the most rapidly rising incidence rates of CC. The other unfortunate fact is that this increase is almost exclusively confined to the youngest age groups – women between 25 and 39 years of age – as clearly evident from Figure 2.

The basic reasons for this untoward development have not been fully elucidated, albeit discussed to some extent in the recent communications from the Finnish Cancer Registry [46]. More detailed discussion of the topic falls outside the scope of this communication. It suffices to state that referring to a “current excellence of organized CC screening in Finland” is not a valid argument to refute the necessity of HPV vaccine implementation in this country.

HPV vaccines have not been demonstrated to be effective in the prevention of CC

The second argument constantly repeated by THL states that there is no evidence as yet to demonstrate that HPV vaccines can prevent CC. Literally speaking, this is true; we do not yet have that formal evidence [14–38]. However, this argument is strictly contradictory to the reasoning discussed previously because it would deny the time-honored concept that prevention of CC precursors (by whatever means) is sufficient evidence that CC can be prevented. In this respect, there is no difference whether this prevention of high-grade CIN will be achieved by organized screening (which the THL believes to be highly effective), or by prophylactic HPV vaccines. We have the evidence that both approaches are highly effective, as shown by the dramatic (80%) decline of CC incidence in Finland since the early 1960s until 1992 (Figure 1)[39,44,45], and by the compelling evidence that currently available HPV vaccines can prevent incident (vaccine-HPV type-associated) high-grade CIN in practically 100% of patients [14–27]. This evidence has been sufficient for both the FDA and the EMEA to clear the global licensure for both vaccines, and for the WHO to recommend their global implementation [104].

Another unanimously agreed fact is that one cannot use (or request using) invasive CC as a valid end point in any prospective cohort studies [45] or in vaccine efficacy studies [14–27], because of the simple fact that it is completely unethical to follow-up any woman until the development of invasive CC. Accordingly, both the FDA and EMEA have accepted the incidence of high-grade CIN (CIN2/3) as the only valid end points of these vaccine efficacy trials, which is clearly stated in all these studies [14–27]. Importantly, both agencies are currently considering whether it would be feasible to relax these requirements of histological (CIN2/3) end point in the future vaccine trials testing the second-generation (non-HPV-16/18) vaccines. Work is currently in progress to evaluate other intermediate end points, most notably the 6- or 12-month persistent HR-HPV infections, as valid end points for demonstrating HPV vaccine efficacy [47]. This will most probably be the reality in the near future, if the author correctly interprets the ambiance in the recent joint meeting of the FDA and EMEA held in London.

Accordingly, there should no longer be a place for such requests as immediate demonstration of HPV vaccine efficacy against CC. It is needless to reiterate that such an evidence is impossible to obtain in any short-term trial; enough time is required to demonstrate how the effective prevention of CIN2/3 will translate to progressively declining incidence and mortality rates of CC. This will be achieved first in those countries where high-coverage HPV vaccinations have already been implemented. This author is very much afraid that with its constantly increasing trends of CC incidence and with its current national perspective on HPV vaccines, Finland will unfortunately not be among the first countries to demonstrate this.

Lack of cost–effectiveness data from Finland

The last two in the long list of THL arguments that deserve to be addressed here are related to: 1) the expressed concern about the cost–effectiveness of these vaccines and 2) the burden of residual disease that remains after implementation of these first-generation HPV vaccines. The first of these concerns is reasonable as no such cost–effectiveness calculations are available from Finland as yet. Such work is underway, however, as a part of the assignments of the appointed national evaluation committee. On the other hand, there is a constant flow of these cost–effectiveness reports on HPV vaccines in different countries, many of which are very comparable to Finland. According to almost all such reports [48,49], there is little doubt that implementation of HPV vaccines is cost effective, although the details are subject to local variations in the infrastructure of the national healthcare systems in different countries.

There is no way to deny that such cost–effectiveness calculations are also needed in Finland. To bring these cost–effectiveness issues to the right context, however, one should keep clearly in mind what the basic principles (also agreed by the THL) of the national healthcare are; its ultimate goal is to reach optimal healthcare and ensure its equality-based maintenance among the entire population. According to this same reasoning, the principal goal of the national healthcare system is not to make maximal savings of costs and other resources, but to promote general health and welfare at the population level [103]. Thus, it is not only the cost–effectiveness issues that should dictate the implementation of these vaccines; one should also consider several other issues, many of which are examined in the ongoing Phase IV trial.

Vaccine effect on total HPV disease burden not estimated

With regard to the residual disease burden, one needs to consider the total disease burden due to HPV infections first, followed by judging the magnitude potentially preventable by the current HPV vaccines. Owing to the different design of the two vaccines (bivalent vs quadrivalent), it is clear that this vaccine-preventable fraction of the total HPV disease burden is also markedly different for these two vaccines. Until now, no systematic data on the total and/or genotype specific disease burden were available. Prompted by this obvious gap in our knowledge, this author recently completed such systematic surveys separately for the HPV-6/11 [50] and for the HPV-16/18 [51] disease burdens in Finland.

According to these data, the total annual disease burden due to HPV-6/11 in this country would be between 12,666 and 13,066 new cases, covering all HPV-6/11-related pathology, corresponding to age-adjusted incidence rates of 221 per 100,000 and 228 per 100,000 [50]. Similarly, between 7859 and 8316 new cases of HPV-16/18-associated clinical lesions are detected each year in Finland [51], translating to respective age-adjusted incidence rates of 137 per 100,000 and 145 per 100,000. Aside from this difference in magnitude, another major difference between HPV-6/11 and HPV-16/18 is that the disease burden due to the former is much more evenly distributed among the genders [50], in contrast to the HPV-16/18 disease burden, of which the major proportion is contributed by females [51]. Noteworthy is the fact that the clinical lesions counted in these two reports only represent a small minority of the total viral burden due to infections by these four HPV genotypes. This is because the vast majority of all HPV infections are transient and spontaneously resolve within a few months, without ever developing into clinical disease. However, this spontaneous clearance does not make these latent infections less important, because as long as the virus reservoir exists it serves as a potential source of viral transmission to susceptible individuals, with a multitude of HPV-6/11/16/18-associated pathologies as a potential outcome [50,51].

Most importantly, there cannot be any doubt that with the existing bivalent and quadrivalent HPV vaccine, one can achieve a significant reduction in the total HPV disease burden if the vaccine is implemented in the national vaccination program.

Specific arguments targeted to minor details in clinical trials

The rest of the presented arguments are targeted to several minor details of vaccine efficacy data in certain subgroups described in the international trials. Typically, these arguments cite the lowest efficacy rates reported in some marginal subgroups of these studies. This is not the right context in which to go into any further detail about these artificially raised concerns which are not of any value in evaluating the overall efficacy of both HPV vaccines [14–37]. As such, however, they clearly illustrate the Finnish perspective and the negative attitude against the concept that HPV vaccines might be of some benefit in this country.

Advocates of prompt implementation

Professional societies

To avoid communicating an entirely gloomy impression of this Finnish perspective on HPV vaccines, one must admit that there are some parties that have expressed their public opinion advocating the prompt implementation of HPV vaccines. In addition to the few individual HPV experts who have expressed their opinion in public, the role of two professional societies deserves to be acknowledged in this context. The two organizations that have firmly expressed their position advocating the vaccine implementation are: the Finnish Society of Gynaecologists [109] and the Finnish Cancer Society [110], who expressed their opinions in early 2008 and late 2007, respectively. Both issued documents are available in Finnish only and are almost identical in format, as they were mostly created by the same experts.

These two reports are slightly different only in the details of their recommendations [109,110]. According to the Finnish Society of Gynaecologists, one should initiate the evaluation of HPV vaccines for the national program without delay; the national vaccination program should be targeted to 10–13-year-old girls; opportunistic vaccinations should also be recommended for 14–25-year-old girls; the inclusion of prophylactic HPV vaccines among the items reimbursable by the health insurance (KELA) should be seriously considered; organized mass-screening program for CC must be continued with possible modifications to the screening methods; and the future vaccination program should be integrated as a part of the organized healthcare in schools, linked with counseling on sexual health in general. The recommendations of the Finnish Cancer Society [110] follow these same outlines and raise the same topics with only slightly different weights.

Together, these two public statements represent an important position taken by the professional societies engaged in diagnosing and treating HPV infections, CIN and cancer, as well as in conducting cancer registration and organized screening in this country. However, until now, these documents have had little (if any) impact on the persistently negative position of the THL against the implementation of HPV vaccines in Finland.

Women’s organizations

Different women’s organizations in Finland have also expressed their position on HPV vaccines, which they recognize as an important contribution to female health. The two most visible position papers are quite recent: one from the Finnish Association of Midwives (January 2009) [111] and the other from the National Council of Women of Finland (April 2008) [112]. These two statements are quite similar in content, both clearly expressing a recommendation for prompt national implementation and making HPV vaccines reimbursable from the national health insurance. In 2009, the Finnish Association of Midwives celebrated its 90 years of existence and issued a news release in January, reminding women of two important topics (self-examination of breasts and participation in organized Pap smear screening), as well as giving a recommendation to the authorities for prompt acceptance of HPV vaccines in the national vaccination program [111].

Even more influential is the proclamation of the National Council of Women of Finland issued in April 2008 by this cover organization of more than 50 independent women’s organizations [112]. This public statement received considerable visibility in the media and was warmly welcomed by those numerous individual families who have acquired HPV vaccines for their children opportunistically, without any chance for reimbursement. This position paper gives an informed account on HPV infections as a major disease burden, summarizing the untoward recent developments in the organized CC screening program in Finland, emphasizing the major health impact of HPV vaccines and ending by pinpointing the fact that Finland is among the last few countries in Europe to implement these vaccines into their national health program [112]. This public statement concludes by sending a firm memorandum to health authorities, advocating prompt actions for initiating the evaluation of HPV vaccines for their national implementation. At the same time, it makes a concrete initiative to amend the current legislation so as to permit the reimbursement of opportunistic HPV vaccines from the national health insurance. Incidentally, 1 month later, the THL finally decided to set up its “national committee for control of papillomavirus diseases”, as discussed in previous sections.

Scientific evidence advocating implementation is compelling

In this context, there is no need to make a detailed discourse about the different lines of evidence provided by the randomized international efficacy trials, which indisputably confirms the efficacy of Cervarix and Gardasil against the various study end points accepted by the FDA and EMEA for these two vaccines [14–27]. To bring this evidence into the Finnish context, however, it is interesting to reiterate the specific requirements set forth by THL for any new candidate vaccine to be accepted into the national vaccination program [103]. Accordingly, the following criteria must be met by any such vaccine:

• • The vaccine must be targeted to and capable of eradicating (or significantly reducing) the disease that is a major public-health problem in the country;

• • The vaccine must be safe at the level of vaccinated individuals;

• • The vaccination must be safe at the level of public health (i.e., national implementation gives more benefits than adverse effects);

• • The vaccination must be cost effective at the public-health level.

Needless to say, both currently available HPV vaccines meet all these predetermined criteria of THL. Accordingly, there cannot be any doubt that HPV infections in general represent a major public-health burden [1,2,52]. In fact, Finland is the first country where a systematic information about the annual disease burden was provided specifically for those four HPV types (HPV-6/11/16/18) covered by these two vaccines [50,51]. It is hard to deny that any disease with annual age-adjusted incidence rates exceeding 140 per 100,000 (HPV-16/18) and 220 per 100,000 (HPV-6/11) would not represent a major public-health burden [50,51]. Similarly, the evidence is compelling enough to indicate that the current HPV vaccines are highly effective against the high-grade disease end points caused by the HPV types included in these vaccines [14–27]. The most recent evidence also imdicates that significant cross-protection is achievable against the closely related nonvaccine HPV types [25–38], which significantly increases their impact in reducing the disease burden [1,2,52] due to both LR- and HR-HPV types.

The published data are also unanimous in that the two current HPV vaccines are well tolerated and safe to the individuals who have received the full dosage [14–27,30–36]. This applies equally well to individuals and whole vaccinated cohorts, indicating that the benefits to be obtained from these vaccines far outnumber the expected (extremely rare) adverse effects even when implemented at the population level. This should also be easy to appreciate in Finland by weighting all the expected gains in reducing the substantial annual disease burden due to these four HPV types only (HPV-6, -11, -16 and 18) [50,51], against the extremely rare (and not always convincingly documented) adverse effects reported in association with the use of these vaccines in large international trials [14–27].

As to the cost–effectiveness of HPV vaccines, it is true that such formal data are still missing in Finland. However, there are an ever-increasing number of reports from other European countries, including Finland’s closest neighbors, which could be easily used as a solid basis for such an assessment. Indeed, the number of published cost–effectiveness studies is far too extensive to be cited here, with only a couple of recent ones being referred to for orientation [34,48,49]. Importantly, in almost every country, such cost–effectiveness data have been published only after the decisions of implementation have already been made. This gives an advantage of using real data instead of computer modeling, which improves the accuracy of these calculations. It is the conviction of this author that the lack of these formal cost–effectiveness data should never form a permanent obstacle against the national implementation of any vaccines that otherwise fulfill all the predetermined criteria. Even less should this lead to delays in the initiation of the vaccine evaluation process, which has now happened for HPV vaccines in Finland. Once again, we should remember that the principal goal of the national healthcare is not to make maximal savings of costs, but to promote the general health and welfare of the citizens [103].

Prospects for the future: each year of delay in implementation will bring inequity to an additional birth cohort

Not too long ago, Finland enjoyed the glory of being a country with the most effectively organized mass screening for CC, with a dramatic impact (i.e., an 80% reduction) in incidence and mortality since the early 1960s, reaching the lowest figures worldwide in 1992 [39,44,45]. After the current deeply increasing CC incidence rates that began in 1992 (Figures 1 & 2)[46], Finland has seen the most acutely rising CC incidence rates of all countries, the developing world included. One might ask the painful question: what else has gone fundamentally wrong since 1992?

In the above, we already discussed the problems associated with the organized CC screening program that fails to attract the women in this country as it did during the preceding three decades [39,44–46]. This recent development has resulted in a remarkable (over 10%) drop in the annual coverage of the program, down to around 70% (and just above 50% among the youngest age groups) [113]. Frightening as this should be for this single country, at the same time, this is an excellent demonstration of the validity of the leading concept of organized screening, that is, the high coverage [39,46]. As shown by theoretical calculations dating back to the 1980s [39], organized screening programs perform effectively only as long as the coverage exceeds the minimum of 80%, as the Finnish program did year after year, proving this concept in practice [44,47]. Any further discussion of these alarming issues falls outside the scope of this communication; it suffices it say that those currently running the national CC screening program in Finland should take some time for a serious self-inspection to critically revisit what has actually gone wrong since 1992.

Highly unfortunately, this failing control of CC by the national screening program coincides with the decision of the authorities to postpone the formal evaluation of HPV vaccines. This in turn inevitably leads to a substantial delay in their eventual implementation in the national program, which violates one of the leading principles of public healthcare in this country – that is, equity between the citizens. In practical terms, every year of delay in the national implementation of HPV vaccines means that an entire birth cohort (>60,000 boys and girls of vaccination age) will lose their constitutional right of being offered a community-supported state-of-art healthcare – in this case, prevention of cancer (and other pathologies) by prophylactic HPV vaccines [50,51].

Paradoxically enough, one of the leading arguments of these same authorities against the acceptance of HPV vaccines among health insurance-reimbursable remedies continues to be the statement that such a practice would create inequity between the citizens. This is difficult to understand; by contrast, it sounds feasible that the citizens with lower incomes could much better afford the vaccines if properly reimbursed compared with the current situation with no such compensation. Needless to repeat in this context, it is usually these low-income people who are the high-risk groups for contracting the most severe HPV-associated pathologies, for example, high-grade CIN and CC [1,2,50–52]. In addition, against this background, it is impossible to find any sustainable arguments for why this Finnish perspective on HPV vaccines should be continued any further.

Expert commentary & five-year view

Having actively conducted HPV research since the late 1970s, this author has witnessed the remarkable progress made in this field during the past three decades [2–11,101]. There is no doubt whatsoever that CC and its precursor (CIN) lesions, together with all other HPV-related pathologies, constitute a substantial annual disease burden both worldwide and in individual countries [1,2,50,51]. Undeniably, the development of prophylactic HPV vaccines and their prompt licensure for global distribution represents one of the most innovative breakthroughs of modern medicine [1]. For the first time, these vaccines offer effective tools for realistic intervention to reduce the disease burden due to a multitude of HPV-related pathologies (most notably CC and its precursors) at a global scale.

As a scientist, this author is as equally convinced as the regulatory agencies (the EMEA/FDA), the WHO and the majority of the leading world authorities by the compelling evidence provided by all published randomized controlled trials that these first-generation HPV vaccines are highly effective in preventing the conditions (CIN, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia and adenocarcinoma in situ) accepted as valid end points in these studies. Similarly, there is no evidence that these HPV vaccines are different from any other vaccines in general use in their safety profile, both for vaccinated individuals and from the public health standpoint. Furthermore, modeling studies from an increasing number of countries confirm that the implementation of the currently available HPV vaccines is cost effective. However, owing to the significant country-to-country differences in the national healthcare systems and their cost structure, it is justified to repeat these calculations in each country.

According to the policy adopted by most of those countries where HPV vaccines have been already implemented in the national vaccination programs [101], the temporary lack of these cost–effectiveness calculations should not constitute a permanent obstacle for this implementation. Similarly, there is unanimous agreement that a substantial amount of additional research is needed to fully elucidate the optimal uses of these vaccines and their integration into the existing and planned CC screening programs [1,14–36,41,107]. However, the vast majority of European countries and several other countries have given official recommendations for adopting HPV vaccines as part of their public healthcare [101]. Finland, beyond all expectations, has adopted a different policy and postponed all decisions of implementation of these vaccines to the non-foreseeable future, as discussed in this review. To this author, the reasoning behind these decisions is not acceptable.

The next 5 years will certainly witness an ever-increasing speed of progress in the field of prophylactic HPV vaccines. The ongoing postlicensure studies will contribute to the elucidation of the optimal target groups of these vaccines, as well as the conditions for their optimal implementation, as stand-alone measures or as an integral part of organized national CC prevention (screening) programs [27–38,53–56]. Studies on second-generation HPV vaccines containing multiple HPV types are currently in progress and, once available, will increase the coverage of HPV genotypes involved, for example in CC and CIN, further reducing the disease burden due to these non-HPV16/18 genotypes. It is also anticipated that instead of requesting the use of the histological (CIN2/3) end points, the regulatory agencies will relax their requirements so that the future trials with non-HPV-16/18 vaccines can rely on other end points (e.g. 6- and 12-month persistent HR-HPV infections [47]) as intermediate surrogate end points. This seems necessary to make the future studies feasible, as otherwise a huge cohort size (100,000) and long follow-up times (10 years) would be needed to make the studies adequately powered to demonstrate the vaccine efficacy in preventing CIN2/3 lesions due to non-HPV-16/18 genotypes [47,55,56].

However, apart from these expected scientific breakthroughs, there are a multitude of other issues that most certainly constitute a major obstacle for the global implementation of these vaccines during the coming 5 years. Such issues are not in the hands of the scientists, and despite the above deciphered scientific progress, this author is afraid that we still need to wait for decades to witness the impact of HPV vaccines in reducing the incidence and mortality of CC at a global scale. The prospects for individual countries can be significantly different and vary from one country to another. This of course depends on the farsightedness of the national authorities in their decisions to implement the available HPV vaccines, as already done by those privileged European countries [101].

In 5 years time from the pojnt at which this paper was published, December 2014 will have passed and the results of the Finnish national Phase IV trial are expected to be available [41,106,107]. As firmly stated by the national policy makers [103], no decisions can be made (or even considered) until they have convincingly witnessed with their own eyes that HPV vaccines are also effective in Finland, and not only in all other countries. While waiting for this to happen, it might be useful to spend some time considering that during this coming 5-year period of silence in this front, over 300,000 young adolescents (both girls and boys) at vaccination age in Finland will lose their opportunity to obtain the state-of-art cancer prophylaxis offered by the other European countries to their citizens. Furthermore, using very conservative estimates, it can be predicted that by 2015 there will be over 220 new cases of CC in this country, which translates to a greater than 80% increase since 1992, when the national screening program still had an adequate coverage.

Table 1. The procedures for licensure of human papillomavirus vaccines^* in Finland.

Step	Procedure or outcome
1	Synthesis (design) of the molecule: virus-like particles produced in yeast
2	Assessment of biological activity
3	Early administration, distribution, metabolizing and excretion assessment
4	In silico screening (computer modeling)
5	In vitro studies
6	Preclinical phase
7	Phase I–III clinical studies
8	Application for the licensure (two optional procedures) from the EMEA

^*Specific for Gardasil^®.

Table 2. Official protocol for the evaluation of new vaccines for inclusion in the national vaccination program in Finland.

Step	Procedure, action or outcome	Person/authority in charge
1	Recognition of the need for evaluation of any new vaccine for potential inclusion into the program, e.g., a newly licensed vaccine	Head of DVIP at the THL
2	Founding a PE and invitation of its members	Head of DHP (upon advice by Head of DVIP)
3	Evaluation of the candidate vaccine by the expert panel using predefined criteria^*	PE
4	Recommendation for acceptance or rejection into the national program	PE
5	Decision to continue the process. This is independent of the PE’s position, i.e., to discontinue even if recommended acceptance by PE	Head of DVIP at the THL
6	NPVE^‡ can be invited to express its opinion for the recommendation to the THL	THL: DHP, DVIP
7	Decision to recommend or reject. This is independent of the NPVE’s position	THL: DHP, DVIP
8	In positive case, recommendation to the Finnish Ministry of Social Affairs and Health (STM)	THL
9	Critical consideration and taking position	STM
10	In positive case, inclusion in the budget framework of STM; recommendation for Ministry of Finance (MF)	STM
11	Inclusion in the annual national budget	MF, Parliament of Finland

^*Predefined criteria for evaluation of any new vaccines by PE are as follows:

a) Impact on public health

b) Safety of the vaccine to vaccinated individuals

c) Advantages and disadvantages at population level

d) Cost–effectiveness

^‡National Panel of Vaccine Experts: 50% of members from THL, 50% of members from outside.

DHP: Division of Health Protection; DVIP: Department of Vaccination and Immune Protection; MF: Ministry of finance; NPVE: National Panel of Vaccine Experts; PE: Panel of Experts; STM: The Finnish Ministry of Social Affairs and Health; THL: National Institute for Health and Welfare.

Key issues

• • Two commercial human papillomavirus (HPV) vaccines (Cervarix™ and Gardasil^®) have been accepted into the national vaccination programs in most European countries, except for Finland.

• • Finland is a country with a dual role in the HPV field: Finnish scientists have pioneered in several fields of HPV research but officially Finland is reluctant to implement HPV vaccines in the national program.

• • This Finnish perspective on HPV vaccines contains several perplexing elements that are critically discussed in this review.

• • Authorities responsible for the official evaluation of vaccines for the national program postponed the start of regular evaluation of HPV vaccines, resulting in a significant delay compared with most other European countries.

• • Instead of national implementation, a long-term (Phase IV effectiveness) trial was stared to evaluate one of the vaccines in a community-randomized cohort to be continued until December 2014.

• • Criticized by domestic and international experts for its design and conduction, this Finnish trial recently received an official reminder from the supervising officer of the national legislation, due to multiple violations of national and EU legislation, most notably the way in which they administered the written informed consents.

• • The official arguments by the authorities opposing the implementation demonstrate a complete refusal to accept the compelling scientific evidence on the undeniable efficacy and safety of both HPV vaccines.

• • Another key argument is based on the unfortunate misconception emphasizing the effective control of cervical cancer by the national screening program; however, since 1992, cervical cancer in Finland has increased more rapidly than in any other country owing to the dramatic drop in the program coverage.

• • Apart from a few experts within the country, two professional societies and a number of women’s organizations have expressed their concern in public position papers, recommending prompt implementation of HPV vaccines in the national program and making them reimbursable by the national health insurance (for opportunistic users).

• • In the worst-case scenario, this Finnish perspective on HPV vaccines seems to postpone all the critical decisions on the national implementation of HPV vaccines until the second half of the 2010s, when the results of the Phase IV trial are expected to be available.

• • This unfortunate development will have two direct consequences: 1) every year of delay in the national implementation means that an entire birth cohort (>60,000 adolescents) will lose the opportunity of being offered the state-of-art cancer prevention by prophylactic HPV vaccines; 2) given the expected declining trends elsewhere, Finland (a country with the most effective cervical cancer control a few years ago) will fall among the category of high-incidence countries in the coming years.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.