EU a major source of ASPRE funding
Dr Hamutal Meiri* answers questions on how funding was arranged through the EU’s Seventh Framework Programme. Click on any of the questions to see the corresponding answer.
What were the reasons for initiating the ASPRE trial?
ASPRE was set up to find out whether screening for pre-eclampsia (PE) combined with prevention by aspirin provides a means for effective prenatal care. PE is a major cause of short- and long-term death and damage for the mother and her baby. Effective identification of pregnancies at high risk of development of PE and treatment of such pregnancies with aspirin could potentially prevent the development of PE. If this proves to be the case there would be major health and social benefits for pregnant women and their babies.
The major objective of the EU-funded project ASPRE was to build on the results from an earlier EC funded (FP6 framework) research project (PREGENESYS). This project involved developments by several partners of the ASPRE project, who had introduced novel biomarkers and kits for the early prediction of PE . These biomarkers were combined with multi-marker algorithms for first trimester prediction of the risk for a later development of PE, particularly preterm PE, associated with premature delivery and affecting both the mother and her newborn baby. However, although the project yielded >80 scientific publications in major journals, there was a reluctance by professionals to adopt this approach to prediction. The main reason was the shortage of means to prevent PE. Prediction is associated with elevated anxiety. As a counterbalance against the negative impact of anxiety, increased surveillance, which reflects the standard of care to manage high risk of PE, was not perceived as sufficient benefit to justify the introduction of early prediction.
PREGENESYS involved in vitro studies that demonstrated that aspirin is the most promising agent for PE prevention . In addition, several small-size clinical studies have indicated that prophylactic use of low-dose aspirin starting before 16 weeks of gestation can decrease the prevalence of PE by 50% .
In ASPRE, biomarkers already verified in PREGENESYS are used to combine screening for high risk for developing PE with a randomized drug and placebo clinical trial for reducing the frequency of PE, especially preterm PE, by 50%.
In what ways can the ASPRE project be seen as a European project and how will it benefit the peoples of Europe?
The Pan-European aspects are reflected in both the partners and the studied population. ASPRE involves partners from five countries from across Europe: the Fetal Medicine Foundation (FMF) from London, UK, Wallac-PerkinElmer from Turku, Finland, Astraia from Munich, Germany, Hylabs from Rehovot, Israel and Hananja from Reykjavik, Iceland. The FMF is the academic partner responsible for the medical aspects and the clinical trial. Wallac, the genetic screening division of PerkinElmer specializes in developing diagnosis means and tools to predict PE. Astraia is a leader in developing computerized software and algorithms for online data acquisition, and determination of the risk for various pregnancy disorders based on maternal demographic and medical information combined with biomarkers. Hylabs specializes in molecular diagnosis of markers for various women’s health disorders using protein, DNA and RNA technologies. Hananja is a small pharmacological company that develops various drugs and delivery methods for pregnant women.
The multi-center clinical study enrolls patients from six countries: The UK, Spain, Belgium, Italy, Greece and Israel, representing several sub-population groups in Europe. Accordingly, this study forms pan-European dimensions in prediction and prevention of the disorder. PE is now affecting at least 2-5% of all European pregnant women. If the study demonstrates effective reduction in the prevalence of PE, it is estimated that within 5 years about 2-3 million women in Europe will be screened using the ASPRE protocol. Among them, the use of aspirin will allow at least 11,000 cases of PE to be avoided. This would translate into a reduction of many maternal and perinatal deaths. The cost saving is estimated to be at least 803 million EUR for immediate health care expenditures and much higher for long-term treatments.
Funding for ASPRE has been supplied through the EU’s Seventh Framework Programme (FP7). What kind of projects does the EU fund, and what were the key criteria of the ASPRE trial that led to it being chosen?
The EU 7th Research and Development Framework supports research and development of all research topics. ASPRE was funded under the Health Section of FP7.
The criteria for approving the project were innovative excellence, the impact it could have on the European people and on economic growth and the quality of the research plan to accomplish the above.
Reduction in the rate of PE and its associated complications requires firstly, a method of early and effective identification of pregnancies at high-risk for subsequent development of PE and secondly, treatment of these high-risk pregnancies, and the demonstration that such treatment can reduce the rate of PE. We proposed to enroll 33,680 pregnant women in the first trimester, and evaluate their risk to develop PE by a method we have developed that combines information from maternal characteristics and medical history with the measurement of biophysical and biochemical markers. Women identified by this method as being at high risk of developing PE will be invited to participate in a randomized study comparing aspirin (150 mg per day) with placebo taken at between 11-13 weeks to 36 weeks. It is anticipated that 1,684 high risk pregnancies will agree to participate in the randomized study. This is the largest ever clinical study conducted to predict and prevent PE, thereby maintaining the European leadership in a global dimension in the field of prenatal care and management. The study meets the global need to reduce pregnancy mortality and morbidity by early prevention, before complications develop. Prof. Nicolaides, ASPRE Coordinator, introduces the project as one example of the benefit of the inverted pyramid of prenatal care in revolutionizing prenatal care by early identification of those at risk and prevention of later complications. This emphasis provides a broader prospective of the entire prenatal system of care beyond the disorder of PE. We had also to show the project potential to create economic growth through sales of diagnostic kits, software for prenatal risk assessment, and prenatal aspirin. We had to calculate the anticipated number of lives saved and long term health and cost savings associated with PE prevention .
What was the process by which the FP7 funding was applied for and granted?
We had the idea for ASPRE some time before we applied. Prof. Nicolaides, the Director of FMF, who is ASPRE coordinator, had already outlined a clinical study protocol and on a visit he made to Israel in March 2012 we discussed this idea. Subsequently we contacted the former Officer of the PREGENESYS project and inquired whether there might be an open call for a project like ASPRE. In April the EC first published the last call of FP7 in Health where all topics, scopes, criteria and time lines were listed. A topic that addressed the potential benefit of exploitation of former FP^ and FP7 projects was included in the list, with a large budget allocated, indicating the emphasis the EC placed on this aspect (and also indicating the likelihood for project approval). It seemed to be a reasonable framework. We were limited to 5 partners and a maximum EC contribution of 6 million EUR of which at least 51% should be dedicated to small-to-medium enterprises (SMEs). We contacted the five partners and everyone agreed to the program outline and we prepared the proposal.
In September 2012 we uploaded the ASPRE proposal onto the EC electronic upload system. The preliminary, short (7 page) application that was evaluated and selected to be among the top proposals. In November 2012 we were invited to submit the full proposal.
All partners got together in December 2012 around the Winter FMF course to agree on the comprehensive work plan, the parties’ responsibilities in the project and their respective share in the budget. We split writing responsibilities and prepared the proposal that was submitted in February 2013.
By the end of March 2013 we were informed that the project was approved for funding and invited for negotiation in Brussels that was held in April 2013. We were asked to make a few minor changes to the plan and budget, as per the reviewer comments. The EC had allocated a Project Officer and an Administrator to be the EC management personnel of our project.
Accordingly, ASPRE was uploaded to the EC electronic website along with an agreement between the parties on the way the project is managed and conducted, including IP management issues. In early June we got the signed agreement and the first advance funding was transferred to our account and distributed to the partners. The kickoff meeting was held during the World Congress in Fetal Medicine in Marbella, Spain.
While these processes were going on, each party had to register to the evaluation website to obtain a registration number and provide a comprehensive profile and financial reports to establish the eligibility to apply according to categories (research institute, industry or SME). This partner validation occurs in parallel with the application but funding can only be awarded to parties who have been validated and verified eligible by the EC.
How does the EU monitor the spending and the work performed as the study progresses?
Each EU project is obliged to provide periodic and final technical and financial reports according to a set procedure using a specific electronic system and guidelines. The Project Officer reviews the planned versus actual financial spending in view of technological progress according to planned tasks, deliverables and milestones. The Project Officer pays special attention to the coherence of spending with achievement, while the financial officer checks the reporting according to EU financial regulations. After the submission and review, the financial reports are either approved or the EU requires additional evidence of spending and sends specific spending queries. Then the expenditures are approved according to the quality of explanation.
The financial reports of each partner are accompanied by audit certificates. A signed letter, approved by a Certified Public Accountant (CPA), reviews the detailed financial report on personnel, other expenditures and indirect cost claims, and checks the actual spending reported for each of the R&D tasks, management tasks and dissemination activity. The CPA has to be accredited by the EU and possess a good knowledge of both national and EU financial law and guidelines. The EU issues periodically updated financial guidelines with detailed explanations of eligible costs, book keeping, and method of expenditures recording and reporting.
It is important to mention that the EU recognizes the allocation of certain financial resources (2-5% of EC contribution) for financial and managerial expenditures. The payments to the CPA is an eligible cost that the EU covers (according to some standards) and in this way it creates an unusual framework to encourage the partners to manage the financial reports according to the guidelines.
The partner validation, mentioned above, and the post factum financial auditing helps to guide the partners in complying with the required financial regulation. After the final reporting the EU will send an accredited CPA to check the company financial book keeping on site and may do a post factum report that may require return of expenditures reported and spent, which were not according to the guidelines. Parties try to work according to guidelines so as to avoid this kind of unpleasant shock.
In ASPRE we introduced an internal process to assist the partners in evaluating their reports and do periodic checking. As a part of our budget we employ experienced CPAs, familiar with the EU financial guidelines, and all partners benefit from the advice and experience of these individuals.
It is important to emphasize that as we are involved in a research and development framework, the project must have the opportunity to adjust to certain needs for update and changes. The EC creates the opportunity for this and in ASPRE we already used it twice and are in the process of additional project update. The introduction of such amendments to the project requires a high level of cooperation between the beneficiaries, and open consideration by the EC, and we are lucky to have both.
Are you happy with the level of funding available?
"The project has reached this stage of progress because ALL partners were willing to make many financial compromises in view of the strategic and social/medical value of the project."
The EC contribution to ASPRE is approximately 6.0 million EUR. The budget is certainly an important asset for the implementation and conduct of this project. However, without the strong will and the compromise of all partners, the money would not be enough. To be honest with you, ASPRE’s budget is quite modest to fund a project that involves a randomized study of this size. The market price for screening one woman is approximately 100 EUR and we screen around 30,000 thus screening alone would reach 3 million EUR. Randomizing 1700 patients at a market price around 1000 EUR, would add additional 1.7 million EUR. The cost of product development, analyzers, kits, software development and installation, the development of algorithms and the conduction of statistical analysis and on line services and regulatory cost for operating 13 clinical sites would easily be an additional 4 million EUR. Accordingly, the actual cost is close to 9 million EUR. The project has reached this stage of progress because ALL partners were willing to make many financial compromises in view of the strategic and social/medical value of the project. The Project Coordinator, Prof. Nicolaides and the Project Administrator, Thanos Kotsis are offering their time free of charge to the project, and so are all clinical PIs. The regulatory work of the Comprehensive Clinical Trial Unit of the University College London is at modest cost compared to the cost of comparable for profit Clinical Research Organizations. The commercial partners agreed to dedicate larger expenditures to compensate for unexpected spending which were required to bring the project to where we are. For example - we experienced difficulties in aspirin and placebo supply to the project, and had to implement a contingency plan for increasing the enrolment sites from 9 to 13. We also introduced the screening quality study. These steps involved investment in analyzers, kits, software packages, and multiple applications to ethics committees, etc. All of us are fighting many odds to make sure that the unique opportunity that the ASPRE project represents will leverage years of clinical and industrial efforts in promoting health and safety of women pregnancies.
Would the ASPRE project have been possible without the support of the EU?
This is a hard question to answer. Knowing Professor Nicolaides, his drive and commitment, I assume he may have been able to get us all on board to implement the study. However, the EU funding was certainly a major asset in turning this dream project into a reality, in getting all parties on board and dictating a time frame and deadline for delivering. ASPRE will be recorded as a world record in the rapid pace of product development, training, and patient recruitment. As a woman, mother, grandmother and as a scientist and technology person, I feel extremely privileged to be a member of the ASPRE team and the opportunity to be involved in such an important and valuable project to combine the front edge innovation for securing the health and life of pregnant women and our future generation.
*Dr Hamutal Meiri is the Director of Exploitation for ASPRE and she has been involved in the project since its inception. PerkinElmer offers warmest thanks to Dr Meiri for answering our questions.
Randomized control trial methodology makes ASPRE powerful
The present understanding that low-dose aspirin treatment is of value in pregnancies at high risk of pre-eclampsia has been gained using meta-analyses, a methodology with admitted limitations. The ASPRE project, set up to provide definitive answers, relies on a more powerful tool - it is a large scale prospective randomized control trial.
Guidelines on pre-eclampsia prevention in various countries (e.g. Australia, Canada, France, Germany, Italy, UK) recommend the administration of low-dose aspirin in all pregnancies that are at risk, starting during the first trimester, or at least before week 16.
The existing evidence on the importance of aspirin in combatting pre-eclampsia comes from a number of key meta-analyses (e.g. Bujold, 2010; Roberge, 2012). The benefit of the meta-analysis technique is that it allows the findings from a number of independent studies to be combined, so as to draw on information from a large number of pregnancies. A major limitation, though, is the difficulty in accounting for heterogeneity between the studies included. Setting inclusion criteria such that acceptable homogeneity is achieved can lead to an unacceptably small sample size.
In his 2010 paper, Bujold recognized the limitations of meta-analysis and called for large-scale randomized studies in which the entry criterion would be high risk for pre-eclampsia identified by first-trimester screening. The ASPRE study answers this call in both its scale and its design. It is a prospective randomized control trial, considered to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice.
The special benefit of the ASPRE design is the large number of participants; a total of 33,680 pregnancies will be screened, providing the capability to conclude, with enough power, that differences between groups are unlikely to be due to chance. In addition, Europe-wide participation, with recruitment in six countries allows a broad representation of the European population.
What is meta-analysis?
Commonly used to assess the effectiveness of healthcare interventions, meta-analysis is a statistical technique that involves combining the data from a number of independent studies. The individual studies may themselves be randomized control trials. Review methodology involves finding and assessing the available research, whether published or unpublished. Explicit and objective criteria are applied to decide which studies are sufficiently well-conducted to be included.
What is a randomized control trial?
A randomized control trial is a clinical trial in which participants are assigned randomly into groups, of which one is a control group. There may be one or more treatment group. The method is used to examine the effect of interventions on particular outcomes or the recurrence of disease.
The act of randomizing patients to receive or not receive an intervention ensures that, on average, all other possible causes are equal between the control and treatment groups. Thus, any significant differences between groups in the outcome event can be attributed to the intervention and not to some other unidentified factor (Stolberg, 2004).
Why does ASPRE require 33,680 pregnancies?
The ASPRE sample size calculation is based on a 76% detection rate of the multi-parameter screening for preterm-pre-eclampsia at a screen positive rate of 10%. With the aim to achieve a significant 50% reduction in the prevalence of preterm-pre-eclampsia from 7.6% in the placebo group to 3.8% in the aspirin group, with a power of 90%, and 5% significance level, it is necessary to randomize 1,600 high-risk pregnancies. Allowing for 5% loss to follow up, it becomes necessary to randomize a total of 1,684 high-risk pregnancies, 842 women in each of the aspirin and placebo arms. On the assumption that 50% of high-risk pregnancies will agree to randomization 3,368 high-risk pregnancies need to be identified. As these will constitute 10% of the screened population the total number of pregnancies in the screening study needs to be 33,680.
1. Roberge, 2012
Early administration of low-dose aspirin for the prevention of severe and mild pre-eclampsia: a systematic review and meta-analysis. View abstract
2. Bujold, 2010
Prevention of pre-eclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. View abstract
3. Stolberg, 2004
Randomized Controlled Trials