ABSTRACT
Clinical trials remain the gold standard for evaluating the effectiveness and safety of health interventions. Every clinical trial is mandated to be registered prospectively in a publicly accessible trial registry before the enrollment of the first participant. The aim of the current study was to provide a cross-sectional analysis of registered HPV vaccine clinical trials listed in the International Clinical Trials Registry Platform (ICTRP). On 05 March 2023, we searched the ICTRP for registered HPV vaccine clinical trials using the term “human papillomavirus vaccine.” Two authors independently extracted data including the name of the clinical trial registry, location, recruitment status, gender of participants, phase, primary outcome, and type of sponsor. Our search of the ICTRP resulted in 437 HPV vaccine clinical trials registered between 1999 and 2022. Most of the trials were: registered retrospectively (61.3%, n = 268), registered in ClinicalTrials.gov registry (66.8%, n = 292), conducted in Europe (26.0%, n = 112), not recruiting (80.5%, n = 352), in phase 3 (37.3%, n = 163), conducted among female participants (64.3%, n = 281), studying immune responses (46.7%, n = 204), and sponsored by pharmaceutical companies (50.3%, n = 220). To increase research transparency, prevent duplication of research, and prevent publication bias, there is an urgent need for all primary registries to make prospective registration mandatory and remain the only type of registration available to trial sponsors. All clinical trial primary registries should also make the completion of all fields compulsory when registering a trial to improve transparency.
KEYWORDS: Human papillomavirus, vaccines, clinical trials, clinical trial registries, International Clinical Trials Registry Platform
Introduction
Human papillomavirus (HPV) is the most common sexually transmitted infection in the world.1,2 It is estimated that approximately 75% of sexually active men and women are infected with HPV during their lifetime.3 There are over 200 HPV types that are classified into high-risk (carcinogenic) and low-risk (non-carcinogenic) categories.4–6 While most HPV infections are transient and asymptomatic, persistent infection with high-risk HPV types may result in various cancers, including anal, cervical, oropharyngeal, penile, vaginal, and vulvar cancer.3–5,7,8 Cervical cancer is the most common HPV associated cancer, with an estimated 604,127 cases and 341,831 deaths in 2020.3 The burden of this disease is most severe in sub-Saharan Africa,4,9 accounting for 20% of cases and 25% of deaths worldwide.10 HPV infection is also associated with an estimated 90%, 60%, and 70% of anal, penile and oropharyngeal cancers in men, respectively, with men who have sex with men at increased risk of infection.2 In contrast to cervical cancer, the burden of anal, penile and oropharyngeal cancers is severe in high income countries (HICs). The incidence of these cancers in men is estimated to be similar to that of cervical cancer in women.2
HPV vaccination is one of the most effective biomedical interventions used for preventing and controlling HPV infection and its associated diseases.11 Several HPV vaccines have been developed and licensed. The first vaccine was licensed in 2006.1,5,11–13 Currently, there are six prophylactic HPV vaccines that are licensed for use across the world: Cervarix, Cecolin, and Walrinvax, the bivalent vaccines; Gardasil and Cervavac, the quadrivalent vaccines; and Gardasil 9, the nonavalent vaccine.12,14 All vaccines have proven to be safe, highly immunogenic, and effective in preventing HPV infection and its associated diseases.14 Although they are effective, HPV vaccines are most effective when administered before sexual exposure to HPV.15 The World Health Organization (WHO) currently recommends HPV vaccination for adolescent males and females aged 9–14 years in a one- or two-dose series and as a three-dose series for young men and women aged 15 years or older and immunocompromised individuals, including people living with HIV.12 HPV vaccines have been introduced in the national immunization programs of many countries across the world.4,16–18 As of December 2022, 172 of the 194 WHO Member States were considered to have partially or fully introduced national HPV vaccination programs, with 24% (n = 47) of them targeting both males and females.12
Although there are several HPV vaccines, the development of new, effective, and safe vaccines to control and prevent HPV infection and its associated diseases is ongoing. Clinical trials remain the gold standard for evaluating the effectiveness and safety of health interventions.19 They are the central means by which diagnostic, preventive, and therapeutic strategies are evaluated.20 Clinical trial results are used by clinicians and other decision-makers to make informed choices about the benefits and safety of healthcare interventions.21,22 In 2005, the International Committee of Medical Journal Editors (ICMJE) mandated the registration of each clinical trial in a public trial registry before the enrollment of the first participant.23,24 Registration of clinical trials is both an ethical and legal obligation in the conduct of clinical trials.25 Prospective registration of clinical trials helps to prevent unethical research conduct,26 wasteful duplication of research,19,25 and increases research transparency.23,25–27 Registering clinical trials gives the public, clinicians, and researchers access to information on all conducted clinical trials.25,28 It reveals the types of research being conducted, their location, methods, and the researchers involved.23
The clinical trial registry is defined as a publicly available online database that contains information about planned, ongoing and completed clinical studies.24,29 It contains information on study design, conduct, administration, results reporting, and investigators’ data sharing plans.24 Clinical trial registries have been around for many years, especially in the field of cancer, but their numbers have increased in the past ten years.29 In 2006, the WHO established the International Clinical Trials Registry Platform (ICTRP) to bring together clinical trials data from different clinical trial registries around the world, thus providing one single point of access to all registered clinical trials in the world.23,26,30,31 The WHO-ICTRP registry network is comprised of primary and partner clinical trial registries.23,25 Primary clinical trial registries are those that meet specific criteria for content, quality and validity, accessibility, unique identification, technical capacity, and administration.23–25,32 Although they meet some of the criteria as primary registries, partner registries are not required to have a regional or national mandate, be managed by a nonprofit organization, or accept prospective registration.25 At present, the ICTRP receives data on registered clinical trials from 17 primary registries and 1 partner registry, ClinicalTrials.gov.23–25,31 As of 2021, ICTRP was recognized as the largest clinical trial platform worldwide, with more than 700 000 records of registered clinical trials.24
To the best of our knowledge, there is no study that has evaluated registered HPV vaccine clinical trials. The objective of this study was therefore to identify and analyze all planned, ongoing, and completed HPV vaccine clinical trials registered in the ICTRP.
Methods
This study used secondary data obtained from the ICTRP, a one-stop search portal for all registered clinical in the primary clinical trial registries of the WHO registry network. We searched the ICTRP database on 5 March 2023 for all registered HPV vaccine clinical trials using the term “human papillomavirus vaccine.” The search output was downloaded to a Microsoft Excel spreadsheet for deduplication and analysis. Two researchers (EJM and TMM) independently screened the titles of the records to identify eligible trials and resolved discrepancies through discussion and consensus. We included all HPV vaccine clinical trials. We used Microsoft Excel to perform descriptive analysis of the name of the clinical trial registry, location of the trial, recruitment status of the trial, gender of participants, phase of the trial, primary outcome of the trial, and type of trial sponsor. We considered “not recruiting” clinical trials as those that are done with the recruitment of participants, and “recruiting” clinical trials as those that are actively recruiting participants. We used tables and graphs to present our findings. Ethical approval was not required for this study since the data used was publicly available.
Results
Results of the search
Our search of the ICTRP database for HPV vaccine trials resulted in 1211 records. After removing duplicates and ineligible trials, we included 437 eligible trials in our analysis. These trials were registered between 1999 and 2022, with many of them (n = 33) registered in 2007 (Figure 1). Of these 437 HPV vaccine trials, most of them (61.3%, n = 268) were registered retrospectively, while the remaining 38.7% (n = 169) were registered prospectively. Majority of the clinical trials (66.8%, n = 292) were registered in ClinicalTrials.gov registry, followed by EU-CTR (16.9%, n = 74) and REPEC (3.7%, n = 16) registries (Table 1).
Figure 1.
Registered HPV vaccine clinical trials by year.
Table 1.
Number of clinical trials per registry.
| Registry | N | % |
|---|---|---|
| ANZCTR | 9 | 2.1 |
| ChiCTR | 3 | 0.7 |
| ClinicalTrials.gov | 292 | 66.8 |
| CRIS | 5 | 1.1 |
| CTRI | 9 | 2.1 |
| EU-CTR | 74 | 16.9 |
| IRCT | 3 | 0.7 |
| ISRCTN | 7 | 1.6 |
| JPRN | 5 | 1.1 |
| NTR | 6 | 1.4 |
| PACTR | 4 | 0.9 |
| ReBec | 3 | 0.7 |
| REPEC | 16 | 3.7 |
| TCTR | 1 | 0.2 |
| Total | 437 | 100 |
Australian New Zealand Clinical Trials Registry (ANZCTR), Brazilian Clinical Trials Registry (ReBec), Chinese Clinical Trial Registry (ChiCTR), Clinical Research Information Service (CRIS), Clinical Trials Registry – India (CTRI), EU Clinical Trials Register (EU-CTR), Iranian Registry of Clinical Trials (IRCT), International Standard Randomised Controlled Trial Number (ISRCTN), Japan Primary Registries Network (JPRN), Netherlands Trial Register (NTR), Pan African Clinical Trial Registry (PACTR), Peruvian Clinical Trial Registry (REPEC), Thai Clinical Trials Registry (TCTR).
Location of the trials
Figure 2 is showing the geographical distribution of HPV vaccine clinical trials around the world. Our study found that most of the HPV vaccine clinical trials were conducted in Europe (26.0%, n = 112), followed by Asia (25.0%, n = 111), and North America (20.0%, n = 88). We also found that 13.0% (n = 59) of the trials were conducted in multi continent.
Figure 2.
Geographic distribution of HPV vaccine clinical trials.
Recruitment status of the trials and gender of participants
Of the 437 identified HPV vaccine clinical trials, 80.5% (n = 352) of them had “not recruiting” recruitment status, followed by 12.8% (n = 56), and 4.6% (n = 20), with “recruiting” and “authorized” status, respectively. The remaining 2.1% (n = 9) clinical trials did not indicate their recruitment status (Table 2). With regards to the gender of the participants, majority of the trials (64.3%, n = 281) were conducted among females, followed by both males and females (25.9%, n = 113), males (5.7%, n = 25), while the remaining 18 (4.1%) did not indicate the gender of the participants.
Table 2.
Recruitment status of the HPV vaccine clinical trials.
| Recruitment tatus | N | % |
|---|---|---|
| Authorized | 20 | 4.6 |
| Not recruiting | 352 | 80.5 |
| Recruiting | 56 | 12.8 |
| Not indicated | 9 | 2.1 |
| Total | 437 | 100 |
Phase of the trials
The phase of the registered HPV vaccine clinical trials is shown in Table 3. Majority of the trials (37.3%, n = 163) were in phase 3, followed by phase 4 (14.2%, n = 62), and phase 2 (14.0%, n = 61). Seventeen percent (n = 76) of the trials did not indicate phase of the trial.
Table 3.
Phase of the registered HPV vaccine clinical trials.
| Phase | N | % |
|---|---|---|
| Phase 0 | 3 | 0.7 |
| Phase 1 | 47 | 10.8 |
| Phase 1/2 | 24 | 5.5 |
| Phase 2 | 61 | 14.0 |
| Phase 2/3 | 1 | 0.2 |
| Phase 3 | 163 | 37.3 |
| Phase 4 | 62 | 14.2 |
| Not indicated | 76 | 17.4 |
| Total | 437 | 100 |
Primary outcome of trials
Our study found that most of the clinical trials were studying the immune responses to HPV vaccines (46.7%, n = 204), followed by efficacy (19.9%, n = 87), and safety (17.8%, n = 78) of the HPV vaccines. Five percent (n = 22) of the clinical trials were investigating safety and immunogenicity, while 3.9% (n = 17) had a primary outcome that was unclear (Table 4).
Table 4.
Primary outcome of the HPV vaccine clinical trials.
| Primary outcome | N | % |
|---|---|---|
| Safety and immunogenicity | 22 | 5.0 |
| Safety and efficacy | 9 | 2.1 |
| Immune response | 205 | 46.7 |
| Safety | 78 | 17.8 |
| Not indicated | 3 | 0.7 |
| Unclear | 17 | 3.9 |
| Other | 17 | 3.9 |
| Total | 437 | 100 |
Sponsor of the trials
Table 5 is showing the type of sponsor of the HPV vaccine clinical trials. Our study found that most of the HPV vaccine clinical trials were sponsored by pharmaceutical companies (50.3%, n = 220), followed by universities (17.8%, n = 78), and hospitals (13.5%, n = 59).
Table 5.
Sponsor of the registered HPV vaccine clinical trials.
| Sponsor | N | % |
|---|---|---|
| Government | 24 | 5.5 |
| Hospital | 59 | 13.5 |
| Pharmaceutical company | 220 | 50.3 |
| Research institute | 26 | 5.9 |
| Self-funding | 21 | 4.8 |
| University | 78 | 17.8 |
| Non-profit organization | 7 | 1.6 |
| No funding | 1 | 0.2 |
| Not indicated | 1 | 0.2 |
| Total | 437 | 100 |
Discussion
In this paper, we conducted a descriptive analysis of the HPV vaccine clinical trials registered in the ICTRP. We found that there were 437 HPV vaccine trials in the ICTRP registered between 1999 and year 2022. Most of the trials were registered in 2007. Our findings were not surprising at all, since the licensing of the first HPV vaccine took place in 2006. Therefore, the rise in the studies and investigation of HPV vaccines was expected. Of the 18 clinical trial registries that provide data to ICTRP, HPV vaccine clinical trials were registered in 14 registries, with most of them registered in ClinicalTrials.gov. According to Hunter 2022,24 ClinicalTrials.gov is the largest clinical trial registry in the world, with 391 704 records as of 11 October 2021. The registry was established in 2000 by the US National Institutes of Health (NIH) Library of Medicine.24,30 Instead of prospective registration as mandated,23,27,32 majority of the HPV vaccine clinical trials were registered retrospectively. Prospective registration of clinical trials helps to prevent selective reporting of trial outcomes.19,23,26 Despite the ethical obligation to accurately report the findings of any research conducted among humans, some clinical trial sponsors conceal negative findings when they report the results of the clinical trials.26 Although it is mandatory to register clinical trials prospectively, some clinical trial sponsors register their trials only retrospectively.23,25 In 2005, the WHO and ICMJE mandated the registration of all clinical trials as a prerequisite of publishing their findings.25,27 In addition, clinical trial sponsors are mandated to publish their trial findings in peer reviewed publications to improve transparency.25 Therefore, the need to publish clinical trial findings might be the main reason behind the retrospective registration of most HPV vaccine clinical trials.
Despite Africa bearing the severe burden of HPV and its associated diseases, very few clinical trials (4%, n = 17) were conducted on the continent. According to Edem and colleagues,25 although there is an increase in the number of clinical trials conducted in Africa, they remain less when compared to the rest of the world. Due to the majority of African countries being LMICs, the low number of clinical trials being conducted may be due to the inadequate resources on the continent, particularly the funding needed to finance them. The majority of African countries are experiencing challenging economic conditions and are marked by severe poverty.33 Therefore, funding of research in the African continent is a challenge.34 Furthermore, out of the 17 HPV vaccine clinical trials carried out in Africa, only 4 clinical trials were registered in PACTR, which is the sole WHO primary registry in Africa.
The stage at which the clinical trial is at is indicated by the recruitment status.35 We found that most of the HPV vaccine clinical trials were not recruiting, meaning many of these trials were planned. Our study also found that most of the trials were conducted among females. Our findings were not surprising at all, since sexually active young women are at the highest risk of HPV infection and its associated complications, with studies documenting rates as high as 68–71%.36 In addition, cervical cancer, the most common HPV-associated cancer, is the fourth most common cancer among women worldwide.3 When exploring the phase of the registered clinical trials, we found that most of the HPV vaccine clinical trials were in Phase 3. This means most of registered clinical trials were evaluating the safety and efficacy of HPV vaccines. With regards to the primary outcome of the registered trials, our findings showed that immune responses were the most primary outcome studied by HPV vaccine clinical trials. Our study also found that most of the trials were funded by pharmaceutical companies.
Our findings have both commonalities and dissimilarities with the findings of other similar studies. Similar to our findings, two studies analyzing Cholera37 and Rotavirus35 vaccine clinical trials also found that most of the trials were registered in ClinicalTrials.gov registry and they were not recruiting. Edem and colleagues,25 studying the trends in clinical trials registered in Sub-Saharan Africa between 2010 and 2020, also reported that most of the trials were registered in ClinicalTrials.gov. Like our findings on HPV vaccine clinical trials, majority of Rotavirus vaccine clinical trials were also registered retrospectively, in the phase 3 clinical trial phase, and sponsored by the pharmaceutical companies.35 A study by Edem 202125 also found that most of the clinical trials registered in sub-Saharan Africa were registered retrospectively. Similar to our findings regarding primary outcome evaluated by registered HPV vaccine clinical trials, Mathebula and colleagues37 also found that immune response was the most studied primary outcome by Cholera vaccine clinical trials. Different to our findings, Mathebula and colleagues37 reported that most of the Cholera vaccine clinical trials were in the phase 2 clinical trial phase and they were sponsored by research organizations. Unlike our study that found that most of the HPV vaccine clinical trials were conducted in Europe, studies on Cholera37 and Rotavirus35 vaccine clinical trials found that most of the trials were conducted in Asia.
Our study has some limitations; therefore, our findings should be interpreted with caution. Firstly, we only searched the ICTRP for all registered HPV vaccine clinical trials in the world. This means that we may have missed other registered HPV vaccine clinical trials from the registries that do not provide data to the ICTRP. Secondly, we found that many clinical trials from different registries had incomplete fields. This may also have influenced our findings in this study. According to Edem 2021,25 the problem of incomplete fields in registered clinical trials remains a challenge across different registries.
Conclusion
There are several HPV vaccine clinical trials conducted in different parts of the world and registered in different clinical trial registries that are providing data to the ICTRP. To increase research transparency, prevent the duplication of research, and prevent publication bias, there is an urgent need for all primary registries to make prospective registration mandatory and remains the only type of registration available to trial sponsors. All clinical trial primary registries should also make the completion of all fields compulsory when registering a trial, to improve transparency. Therefore, more research is needed on the registration processes of the clinical trials by various registries. In addition, there is also an urgent need for sponsors to fund more HPV vaccine clinical trials in LMICs, as they bear the highest burden of the HPV and its associated diseases. Furthermore, most LMICs are facing difficult economic situations.
Biography
Edison Mavundza is a Senior Scientist at Cochrane South Africa (CSA), an intramural unit of South African Medical Research Council (SAMRC). His research interests include human papillomavirus and vaccine hesitancy. He holds a PhD degree in Ethnobotany from the university of KwaZulu-Natal. He has published over 20 peer-reviewed articles. Dr Mavundza has also presented his research findings at national and international conferences.
Funding Statement
This study was supported by the South African Medical Research Council.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author’s contributions
DN conceived the study. EJM and TM conducted data analysis. EJM wrote the first draft of the manuscript. All authors have read, amended and approved the final version of the manuscript prior to submission.
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