Am J Perinatol 2019; 36(S 02): S41-S47
DOI: 10.1055/s-0039-1691799
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Post-trial Access in Maternal Vaccine Trials

I. M. A. A. Van Roessel
1  Division of Paediatric Immunology and Infectious Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands
,
N. I. Mazur
1  Division of Paediatric Immunology and Infectious Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands
2  Lurie Children’s Hospital, Smith Child Health Research and Advocacy Center, Chicago, United States
3  Department of Pediatrics, Northwestern University Medical School, Chicago, United States
,
S. K. Shah
2  Lurie Children’s Hospital, Smith Child Health Research and Advocacy Center, Chicago, United States
3  Department of Pediatrics, Northwestern University Medical School, Chicago, United States
,
L. Bont
1  Division of Paediatric Immunology and Infectious Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands
,
R. Van Der Graaf
4  Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands
› Author Affiliations
Further Information

Address for correspondence

L. Bont, MD, PhD
Division of Paediatric Immunology and Infectious Diseases
University Medical Centre Utrecht, Utrecht
The Netherlands   

Publication History

Publication Date:
25 June 2019 (online)

 

Abstract

Provisions for post-trial access (PTA) of the experimental intervention are required before the start of a clinical trial. Although there has been ample attention for PTA in the context of preventive vaccine research, discussions on PTA barely include maternal vaccine trials in which mother–infant pairs are exposed to the intervention. In maternal vaccination trials, specific PTA arrangements are required because pregnancy is transient and PTA may apply to the next pregnancy or the child. In this article, we examine the application and adherence to PTA in the context of maternal vaccine trials. We focused on differences between publications before and after 2000 when international ethical guidance documents formalized PTA requirements. Randomized maternal vaccine trials were included after a systematic search for clinical trials in phases II and III with a maternal vaccine as intervention. We used PTA as defined at the time of publication in the World Medical Association's Declaration of Helsinki (DoH) or in the ethical guidelines of the Council for International Organizations of Medical Sciences (CIOMS). In addition, we investigated whether PTA was included in the trial design. Therefore, we contacted principal investigators (PI’s) of the publications found in the review to fill out a questionnaire regarding provisions for PTA. Before and after 2000, no trial articles examined in the systematic review described PTA in their trial publication (0/7, 0% and 0/17, 0%, respectively). In addition, more than half of the PI’s of the trials found were not familiar with PTA recommendations in international ethical guidelines. Most cases of PTA included making knowledge available by publishing the results of the trial. The revision of the DoH in 2002 and the CIOMS ethical guidelines in 2002 has not resulted in increased PTA provisions for maternal vaccination trials. PTA is a shared responsibility of various stakeholders including sponsors, Institutional Review Boards, regulators, political entities, and researchers. Inclusion of PTA provisions in trial protocols and publications on maternal vaccination trials is essential to increase transparency on the form and content of these provisions.


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Maternal vaccination is an intervention to protect newborns from life-threatening infectious disease in the first month of life. Maternal immunization can protect newborns via an immunoglobulin G (IgG) antibody response to an (in)activated micro-organism. IgG antibodies are transported actively across the placenta to the fetus and thereby provide passive immunity in the newborn which lasts for the first 6 months of life. After this period, the immune system of the child can generate active antibody responses via infant vaccination.[1] Maternal vaccines for several pathogens are already approved and recommended for pregnant women in various countries: influenza, tetanus, and pertussis, while meningo-/pneumococcus, group B Streptococcus, and Haemophilus influenzae type B are still in clinical development and not yet recommended. More vaccines are in the pipeline: cytomegalovirus, herpes simplex virus, and respiratory syncytial virus (RSV).[2] [3] Despite maternal vaccination as a rapidly growing field, there is still hesitancy to vaccinate pregnant women.[4] However, various RSV trials are now moving forward from early to late phase clinical trials.[5] This development requires reflection on post-trial access (PTA) provisions.

International ethical guidelines for research involving human subjects support the value of PTA requirement for clinical trials. In 2000, PTA was added to the Declaration of Helsinki (DoH) paragraph 20. The DoH stated that “At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.” Various other international ethical frameworks, including the National Bioethics Advisory Commission, the Nuffield Council on Bioethics, and the Council for International Organizations of Medical Sciences (CIOMS) have adopted PTA requirements in their guidance documents ([Fig. 1]).[6] [7] [8] [9] Despite agreement about the importance of the requirement, there is extensive discussion about the underlying rationales for PTA, about its content, the length, and to whom it applies. In general, according to small interpretations fulfilling the PTA requirement implies making provisions for continued access to interventions identified as beneficial, but broader interpretations also include provisions for transitioning participants who continue to need care or preventive measures to appropriate health services when the study has ended. The responsibility to fulfill PTA requirements is typically shared among several stakeholders including sponsors, regulators, political entities, and researchers. The shared responsibility makes providing PTA a complex issue. Investigators of a study cannot provide PTA alone and are dependent on the government, pharmaceuticals, and sponsors.[10]

Zoom Image
Fig. 1 Overview posttrial access in various ethical guidelines.[8] [9] [10] [11]

Although there is ample literature on PTA in the context of human immunodeficiency virus (HIV) prevention research, scholars have barely reported on PTA for maternal vaccination studies. Poor attention is remarkable since it is reasonable to assume that in the case of maternal vaccination, PTA could be conceived as access to the vaccine in future pregnancies not only for women receiving placebo.

To understand why PTA requirements receive limited attention in discussions about maternal vaccination studies, we performed an in-depth study whether and how PTA requirements as formulated in the CIOMS guidelines and the DoH are included in publications on late phase maternal vaccine trials and contacted principle investigators of these publications about provisions made. We compared PTA provisions made before and after 2000, when the guidelines were not in place yet. Furthermore, this study identifies best practices for implementation of PTA provisions.

Materials and Methods

Systematic Review

Randomized maternal vaccine trials were included after a systematic search ([Supplementary Appendix A], available in the online version) in PubMed for clinical trials in phases II and III with a maternal vaccine or prophylaxis as intervention. All articles were screened for eligibility by two people independently, using Rayyan.[11] The World Health Organization (WHO) clinical trial registry and ClinicalTrials.gov were searched for phase II/III maternal vaccine trials, using the same in- and exclusion criteria as for PubMed. Relevant completed or ongoing trials were included, and withdrawn trials were excluded. Trials with no article available were also excluded for the systematic review ([Table 1]). Trials before 2000 and after 2000 were compared since PTA was first included in the ethical guidelines in 2000.

Table 1

In- and exclusion criteria systematic review

Inclusion

Exclusion

Pregnant women

Women of childbearing age/nonpregnant women

Animals

Passive or active immunization

No vaccination

Maternal vaccine trials

HPV 16/18 trials (because goal of vaccination is not child protection)

HIV PMTCT trials

Phases I/II, II, and III trials

Phases I and IV trials

Positive and negative outcomes

Prospective randomized controlled trials

Editorial

Secondary analysis (NB: if duplicate, only primary article was included)

Review

No PDF available

No author information provided

Language barrier

Duplicates or secondary analysis while primary article was already included

Abbreviations: HIV, human immunodeficiency virus; HPV, human papillomavirus; PMTCT, prevention of mother-to-child transmission.



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Definitions

A vaccine was defined according to the WHO's definition: an intervention that augments immunity to a particular disease, which contains an agent that resembles a disease-causing microorganism.[12] Human intravenous immunoglobulin (HIVIG) and intravenous immunoglobulin (IVIG) trials were included as relevant interventions. HIV prevention of mother-to-child transmission trials, HBV tenofovir trials, and antibiotic prophylaxis were not included since they do not enhance immunity or contain a part of a microbe, but only prevent mother-to-child transmission by reducing the viral load. Full-text articles were screened for description of PTA as defined at the time of publication in the DoH or CIOMS ([Fig. 1]).


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Data Collection

The principal investigator (PI) of each trial was contacted and asked to fill out a short questionnaire regarding provisions for PTA in the trial design. Contact with the PI was still attempted for trials that were excluded from the systematic review if there was no article available. All ongoing and completed trials from the WHO clinical trial registry and ClinicalTrials.gov were included. PI’s were contacted first by telephone, then e-mail for a maximum of three times of follow-up. They were also asked to inform us if they were not willing to participate. The questionnaire was shared using Qualtrics software, version 2017. Where questionnaire data are factual, facts were verified against other sources such as trial protocols. The methods were modeled after the methodology of Haire and Jordens, Developing World Bioethics, 2015 in which PI’s of phase IIB/III HIV efficacy trials were contacted in an empirical study of PTA.[12]


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Results

Systematic Review

Twenty-four maternal vaccine trials were identified for this systematic review ([Fig. 2], [Table 2]). Before and after 2000, no trial articles examined in this systematic review described PTA in their trial report (0/7, 0% and 0/17, 0%, respectively); 6/17 (35.3%) trials mentioned that they were conducted in accordance with the DoH in their trial report but did not specify PTA provisions.

Table 2

Maternal vaccine trials overview systematic review

Pathogen

Article

Year

Country

Study size

Before 2000

Pneumococcal

Quiambao et al[14]

1994–1995

Philippines

160

Munoz et al[15]

1995–1996

United States

60

Meningococcal

Shahid et al[16]

1995–1998

Bangladesh

157

Hib

Mulholland et al[17]

1993–1995

The Gambia

451

Tetanus

Newell et al[18]

1961–1966

Colombia

1,618

Varicella zoster

Koren et al[19]

1999–2000

United States

60

RSV

Munoz et al[20]

1999–2002

United States

35

After 2000[b]

Influenza

Jackson et al[21]

2009

United States

120

Tielsch et al[22]

2010–2018

Nepal

3,000[a]

Omer et al[23]

2011–2013

Nepal

3,700

2011–2013

Mali

4,193

2012

South Africa

2,108

Tsatsaris et al[24]

2009

France

107

Abzug et al[25]

2009

United States

127

Madhi et al[26]

2011–2012

South Africa

2,310

Zaman et al[27]

2004–2005

Bangladesh

340

Tetanus

Salama et al[28]

2002–2003

Egypt

131

GBS

Donders et al[29]

2011–2013

Belgium

Canada

86

Madhi et al[30]

2010–2011

South Africa

417

Heyderman et al[31]

2011–2012

Malawi

South Africa

270

Pneumococcal

Binks et al[32]

2006–2011

Australia

227

Daly et al[33]

2000–2003

United States

153

Lopes et al

[34]

2005–2006

Brazil

139

Tdap

Hoang et al[35]

2012–2014

Vietnam

103

Villarreal Perez et al[36]

2011–2014

Mexico

204

Munoz et al[37]

2009–2012

United States

80

Abbreviations: GBS, group B Streptococcus; Hib, Haemophilus influenzae type b; RSV, respiratory syncytial virus; Tdap, tetanus, diphtheria, pertussis.


a Ongoing trial.


b All trials after 2000 were included for contact with PI’s.


Zoom Image
Fig. 2 Flow chart systematic review maternal vaccine trials.[13]

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Questionnaires

Thirty trials were identified as the PI was contacted to collect data on PTA ([Tables 2] and [3]). Thirty trials were eligible for the qualitative analyses. Out of 30 PI’s, 17 responded to the questionnaire. One PI was not willing to participate, and 12 investigators did not respond after follow-up. Eighty-two per cent (14/17) of PI’s from trials conducted after 2000 described provisions regarding PTA.

Table 3

Additional trials contact PI’s

Pathogen

NCT

Year

Country

Study size

Phase

Influenza

NCT00992719[38]

2009–2011

United States

84

II

NCT01173211[39]

2010–2011

United States

183

II

NCT00905125[40]

2009–2010

United States

102

II

NCT01577316[41]

2012–2013

Mexico

240

II/III

NCT01527825[42]

2012–2014

South Africa

800

III

GBS

NCT02046148[43]

2014–2016

United States

75

II

Pneumococcal

NCT02628886[44]

2016–2019[a]

Gambia

600

III

NCT02717494[45]

2016–2019[a]

Brazil

345

II

RSV

NCT02624947[46]

2015–2020[a]

United States

8,618

III

NCT02247726[47]

2014–2016

United States

50

II

Pertussis

NCT00553228[48]

2007–2016

Canada

440

II/III

Tdap

NCT02301702[49]

2016–2018[a]

Guatemala

376

II

HIV

NCT00000751[50]

2001–2007

United States

1,600

III

Abbreviations: GBS, group B Streptococcus; HIV, human immunodeficiency virus; PI, principal investigator; RSV, respiratory syncytial virus; Tdap, tetanus, diphtheria, pertussis.


a Ongoing trial.



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Awareness

The majority (59%, 10/17) of the PI’s for maternal vaccine trials were not aware of post-trial recommendations in international ethical guidelines. In several cases, the PI was not aware of PTA, but the PI indicated that he or she had made provisions for PTA. Half of the PI’s who were aware of posttrial provisions still did not describe them for their trial.


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Best Practice

From the PTA provisions that have been made by investigators in phase II/III maternal vaccine trials, most of them included making knowledge available for the population and transition to care when the research is concluded (79% [11/14] and 64% [9/14]). Researchers who described PTA provisions shared their protocol. Some only described making knowledge available through publication of the article as PTA provision in their protocol. Researchers indicated that the best way to incorporate obligation of PTA in the future would be to state intentions to local Institutional Review Board and Research Ethics Committee. Several PI’s indicated incorporating obligations in trial protocols and informed consent to be a best practice to conform to PTA obligations.


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Challenges

Researchers reported different reasons to not address PTA. One reason was that PTA was felt to be the responsibility of the local government rather than that of the researcher. Other challenges included the lack of proven benefit, awaiting WHO recommendation or national approval, a delay caused by lack of funding, consulting with other relevant stakeholders, and determining the responsibilities of different stakeholders. Finally, the PI’s indicated that there was no practical guidance available, or at least none that the investigators were aware of.


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Discussion

No trial article, before and after 2000, examined in this systematic review described specifically PTA in their publication. However, 82% of the trials after 2000 described provisions regarding PTA elsewhere, for example, in trial protocols. Most of them included making knowledge available for the population. The percentage of 82% may be relatively high but should be critically examined. Several researchers published the article and did not address other aspects of PTA that are important for the community, such as providing continued access for study participants and making the vaccine available for the population.

The majority of the PI’s was not aware of the concept of PTA. Remarkably, there were several cases in which the PI was not aware of PTA, but still indicated that he or she had made provisions for PTA. Lack of awareness of the concept PTA despite inclusion of provisions may indicate that provisions were included in the research without knowledge of the underlying concept of PTA such as publication of results without awareness of PTA obligations. Half of the PI’s who were aware of posttrial provisions still did not describe them for their trial. This finding demonstrates a gap in implementation of PTA guidelines and not only awareness.

Best practices and obstacles in the process of PTA were identified. According to researchers, the best way to incorporate PTA obligations for trial planning in the future would be including PTA provisions in the protocol submitted to the ethical committees. Obstacles to including PTA in the trial planning were shared responsibilities, lack of funding, and awaiting proven benefit and recommendation. Lack of practical guidance available for PTA provisions in prevention trials remains an important obstacle and the creation of such guidance may also enhance awareness.

This study provides the first data on whether researchers implement provisions in the planning of published maternal vaccine trials. Thorough methodology was used including a systematic search with an extensive search term and careful examination of trials by two independent researchers. Furthermore, PI’s of the trial were contacted to verify whether PTA provisions were included in the trial planning process. Where possible, facts have been verified against other sources, such as trial protocols. A limitation of this study is the small group of maternal vaccine trials. Unfortunately, 12/30 investigators did not respond to our questionnaire. There may be selection bias. PI’s who were aware of PTA and made provisions for PTA may have been more likely to respond to our questionnaire than PI’s who did not make them. PI’s with PTA provisions in place could be more likely to respond to our questionnaire, and therefore, the proportion of PTA provisions may be an overestimation of the actual provisions implemented.

In conclusion, the publication of international ethical guidelines in 2000 has not resulted in increased publication of ethical provisions in maternal vaccine trial literature. PTA provisions were described in trial protocols, but often the only PTA provision described was publication of the article to make knowledge available instead of providing continued access to interventions that have been proven significant benefit. Future studies should include PTA in their trial protocols, which will increase transparency on the form and content of these provisions. In theory, it can be stated that trials adhere to ethical guidelines and have PTA provisions in place, but in reality, studies do not incorporate all important aspects of PTA provisions into trial planning.


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Conflict of Interest

None declared.

Acknowledgment

We acknowledge Sharon Nachman (maternal child HIV network, IMPAACT) for providing us data.

Supplementary Material


Address for correspondence

L. Bont, MD, PhD
Division of Paediatric Immunology and Infectious Diseases
University Medical Centre Utrecht, Utrecht
The Netherlands   


Zoom Image
Fig. 1 Overview posttrial access in various ethical guidelines.[8] [9] [10] [11]
Zoom Image
Fig. 2 Flow chart systematic review maternal vaccine trials.[13]