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Public–Private Collaboration in Clinical Research During Pregnancy, Lactation, and Childhood: Joint Position Statement of the Early Nutrition Academy and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition

Koletzko, Berthold*; Benninga, Marc A.; Godfrey, Keith M.; Hornnes, Peter J.§; Kolaček, Sanja||; Koletzko, Sibylle*; Lentze, Michael J.; Mader, Silke#; McAuliffe, Fionnuala M.**; Oepkes, Dick††; Oddy, Wendy H.‡‡; Phillips, Alan§§; Rzehak, Peter*; Socha, Piotr||||; Szajewska, Hania¶¶; Symonds, Michael E.##; Taminiau, Jan***; Thapar, Nikhil†††; Troncone, Riccardo‡‡‡; Vandenplas, Yvan§§§; Veereman, Gigi§§§

Journal of Pediatric Gastroenterology and Nutrition: April 2014 - Volume 58 - Issue 4 - p 525–530
doi: 10.1097/MPG.0000000000000284
Medical Position Papers
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ABSTRACT This position statement summarises a view of academia regarding standards for clinical research in collaboration with commercial enterprises, focussing on trials in pregnant women, breast-feeding women, and children. It is based on a review of the available literature and an expert workshop cosponsored by the Early Nutrition Academy and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Clinical research collaborations between academic investigators and commercial enterprises are encouraged by universities, public funding agencies, and governmental organisations. One reason is a pressing need to obtain evidence on the effects, safety, and benefits of drugs and other commercial products and services. The credibility and value of results obtained through public–private research collaborations have, however, been questioned because many examples of inappropriate research practice have become known. Clinical research in pregnant and breast-feeding women, and in infants and children, raises sensitive scientific, ethical, and societal questions and requires the application of particularly high standards. Here we provide recommendations for the conduct of public–private research collaborations in these populations. In the interest of all stakeholders, these recommendations should contribute to more reliable, credible, and acceptable results of commercially sponsored trials and to reducing the existing credibility gap.

*Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany

Emma Children's Hospital/Academic Medical Centre, Department of Pediatric Gastroenterology & Nutrition, Amsterdam, The Netherlands

MRC Lifecourse Epidemiology Unit and NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

§Gynecology and Obstetrics, Hvidovre Hospital, Copenhagen, Denmark

||Children's Hospital Zagreb University Medical School, Zagreb, Croatia

Children's Hospital Medical Center, University Hospitals, Bonn, Germany

#European Foundation for the Care of Newborn Infants, Munich, Germany

**UCD Obstetrics & Gynaecology, School of Medicine and Medical Science, University College Dublin, National Maternity Hospital, Dublin, Ireland

††Department of Obstetrics, Leiden University Medical Centre, Leiden, The Netherlands

‡‡Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, West Perth, Australia

§§UCL Institute of Child Health, London, UK

||||Children's Memorial Health Institute

¶¶Department of Paediatrics, Medical University of Warsaw, Poland

##Academic Division of Child Health, School of Clinical Sciences, University of Nottingham, Nottingham, UK

***European Medicine Agency, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands

†††UCL Institute of Child Health, Great Ormond Street Hospital, London, UK

‡‡‡Department of Paediatrics, Universita degli Studi di Napoli Frederico II, Naples, Italy

§§§Department of Paediatrics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

Address correspondence and reprint requests to Professor Berthold Koletzko, Dr med Dr med habil, MD, PhD, Division of Metabolic and Nutritional Medicine, Dr von Hauner Children's Hospital Ludwig-Maximilians-University, Lindwurmstr 4, 80337 München, Germany (e-mail: office.koletzko@med.lmu.de).

Received 9 December, 2013

Accepted 14 December, 2013

This study was supported by the European Association of Perinatal Medicine, the European Board of Colleges of Obstetricians and Gynaecologists, the European Foundation for the Care of Newborn Infants, and the European Society of Human Reproduction and Embryology.

The workshop was jointly organised and cofunded by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (www.espghan.org) and the Early Nutrition Academy (early-nutrition.org), with partial financial support by the Commission of the European Community, specific RTD Programme “Quality of Life and Management of Living Resources,” within the 7th Framework Programme, research grant no. FP7/2007-13 (EarlyNutrition Project; www.project-earlynutrition.eu) and the European Research Council Advanced Grant ERC-2012-AdG—no. 322605 META-GROWTH. This article does not necessarily reflect the views of the Commission and in no way anticipates future policy in this area.

The authors report receiving grants and other compensation from the following entities: B.K.: European Commission, European Research Council (member of National Breastfeeding Committee and tends to bias towards breast-feeding; Ludwig-Maximilians-University of Munich and its employee, B.K., have received support for scientific and educational activities by companies that market parenteral nutrition products [eg, Baxter, B.Braun, Fresenius Kabi] and companies that market human milk fortifiers or infant formulae [eg, Abbott Nutrition, Danone, Fonterra, Mead Johnson, Nestlé], predominantly as part of publically funded research projects with support of the European Commission or the German government); M.A.B.: Shire, Sucampo; K.M.G.: Abbott Nutrition, Danone, International Life Sciences Institute, Nestec, Nestlé Nutrition, UK Medical Research Council; S. Kolaček: Abbott Nutrition, Arla Foods, B.Braun, Bio Gaia, Fresenius, Falk, Merck-Sharpe-Dohme, Nestlé, Nutricia (her institution received compensation from Abbott, BioGaia, Dukat, Nestlé, Nutricia, Podravka); S. Koletzko: Abbott, Danone, Fresenius, HiPP, Merck-Sharpe-Dohme, Nestlé, Phadia (her institution received grants from Mead Johnson, Nestlé Nutrition); F.M.M.: European Commission's 7th Framework Programme for Research and Technological Development, Irish Medical Council, Pfizer, University College Dublin; D.O.: Cambridge University Press; A.P.: ESPGHAN; P.S.: Nestlé, Nutricia, Nutricia/Danone, Sequoia; H.S.: Abbott, Arla, BioGaia, Biocodex, Danone, Dicofarm, ESPGHAN, Nestlé, Nestlé Nutrition Institute, Nutricia, Mead Johnson, Sequoia; N.T.: Abbott Nutrition, Danone, Sucampo; Y.V.: Biocodex, United Pharmaceuticals; G.V.: ESPGHAN. The other authors report no conflicts of interest.

This article presents a position statement from the point of view of academia on standards for clinical research performed in collaboration between academia and commercial enterprises, with a focus on trials in pregnant and breast-feeding women, and in infants and children. This publication is based on a review of the available literature and thorough discussions at an expert workshop held in March 2013 at Obergurgl, Austria. This workshop was cosponsored by the Early Nutrition Academy (ENA, www.early-nutrition.org) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN, www.espghan.org), with support from the European Union–funded EarlyNutrition Research Project (www.project-earlynutrition.eu). ENA is a nonprofit society created by and representing the partners of international research projects funded by the European Commission and the Australian National Health and Medical Research Council that perform research on food and dietetic products in pregnancy and early childhood, in part also in collaboration with commercial partners (eg, project-earlynutrition.eu). ENA aims to promote the knowledge of human nutrition in early life, to stimulate quality research in this and related areas of science, nutrition, and health, and to disseminate such knowledge. ESPGHAN is the European medical-scientific association in the field of paediatric gastroenterology, hepatology, and nutrition. ESPGHAN is a nonprofit organisation with the purposes of promoting the knowledge of paediatric gastroenterology, hepatology, and nutrition, stimulating the research in these fields, and sharing such information. This article and its conclusions have been supported and endorsed by European Association of Perinatal Medicine, the European Board of Colleges of Obstetricians and Gynaecologists, the European Foundation for the Care of Newborn Infants, and the European Society of Human Reproduction and Embryology.

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BACKGROUND

Clinical trials performed in pregnant and breast-feeding women and in children raise sensitive scientific, ethical, and societal questions. Therefore, the application of particularly high standards is required (1). More research studies are needed in these sensitive target populations on diagnostic, therapeutic, and preventive interventions to ensure that the use of medical products and other approaches is safe and effective. A lack of clinical drug trials performed in pregnant women (2) and in infants and children has been emphasized, and active steps have been taken to enhance paediatric clinical investigation (3). Many trials that explore the effects of drugs, medical devices, and dietetic or food products are performed as a collaboration between academic investigators and the commercial enterprises that produce these products. Universities, public funding agencies, and governmental organisations across Europe strongly encourage academic investigators to engage in such public–private research partnership. At the same time, however, a public–private research collaboration is viewed with scepticism, results are often questioned, and the partnership of academia and industry is controversial. The credibility and value of results from the research performed in collaboration with commercial enterprises are often questioned.

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PROS AND CONS OF COLLABORATIVE RESEARCH

Academic investigators become involved in collaborative clinical research in infants and children and in pregnant and lactating women for a variety of reasons. There is a pressing need to gather better evidence on the effects, safety, and benefits of commercial products and services, such as drugs, medical devices, diagnostic tools, foods, and dietetic products, used by and for these populations. Pregnant and lactating women and children should not be excluded from evidence-based approaches to diagnosis, therapy, and prevention. At present, owing to the lack of scientific studies on the use of medicinal products in these target groups, the off-label use of medications is common practice, exposing women during pregnancy and lactation as well as children to unknown risks. Indications and dosages are frequently extrapolated from studies in (nonpregnant) adults, which may result in inappropriate administration, particularly in infants and children. Pregnancy presents unique challenges as possible effects of medicinal products on the developing foetus need to be considered and monitored. The safety and efficacy should be studied for all target group–related paediatric indications, and long-term follow-up studies in children are also needed. A European Paediatric Regulation was implemented in 2007 to facilitate clinical research in children (3). A paediatric investigational plan is required for all drugs studied for adult indications before market authorisation for adult use. The paediatric use is only permitted following an appropriate outcome of paediatric studies. Waivers can be granted if there is no paediatric indication for a specific product. Frequently, the research on drugs and other commercially developed or produced products can only be realised through collaboration with the respective manufacturer or distributor.

Academic investigators also aim at translational application of their knowledge for the benefit of the target populations. This may require collaboration with commercial enterprises. Furthermore, academic research can markedly benefit from opportunities arising from collaborations with scientists working in industry, and from sharing expertise and other resources. The financial burden of performing clinical trials, including compliance with regulatory requirements, can be supported by collaboration with commercial enterprises. In addition, collaboration with commercial entities is often a prerequisite for obtaining public research funding from the European Commission, and national and other funding bodies.

Nevertheless, parts of the scientific community and of the public view such collaborative research rather critically. It has been proposed that there may be large and fundamental differences between the key goals of commercial companies that strive for optimal profitability in the interest of their owners or stakeholders, and those of academic investigators who aim for the best possible diagnostic, therapeutic, and preventive approaches for patients and the population. There may also be differences between the culture and expectations of industry and academia. Industry tends to demand prompt results to promote product development, improvement, and marketing, whereas academia tends to emphasise rigorous research based on a strong methodology to gain reliable and valid results that are reproducible. A research performed in collaboration with commercial companies is sometimes thought to be of lower quality than the one performed with public funding, and it is considered to be biased towards achieving positive results with less than satisfactory scientific quality and conduct. Collaborating researchers have been accused of being in the pockets of companies, and some journal editors and academic reviewers maintain a persistent negative view of industry-sponsored trials (4).

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THE CREDIBILITY GAP

The credibility of the industry-sponsored clinical research has experienced and been undermined by reportedly selective or biased reporting of research results, ghost-writing, guest authorship, and inaccurate or incomplete disclosure of conflicts of interest (4). Krumholz and Ross (5) stated that “Individuals who have placed their interests in profit and influence over patients and public health have overshadowed much of the good work and reputations of those who have engaged in constructive interaction.”

There is reason for concern regarding bias in industry-sponsored studies as they are significantly more likely to demonstrate positive results than nonindustry-sponsored studies (6). For example, a systematic review of clinical drug and device studies found that studies sponsored by industry had more often favourable efficacy results (risk ratio [RR] 1.24, 95% confidence interval [CI] 1.14–1.35), reported less harms results (RR 1.87, 95% CI 1.54–2.27), and more favourable conclusions (RR 1.31, 95% CI 1.20–1.44), compared to nonsponsored studies (7). Of further concern, they showed less agreement between results and conclusions (RR 0.84, 95% CI 0.70–1.01) (7). The analysis of 278 medication trial abstracts presented at meetings of the American Psychiatric Association found that 190 (97%) of 195 industry-supported abstracts reported positive results on the tested drug, compared with only 57 (69%) of 83 nonindustry-supported studies (8). In contrast, a systematic review of 103 randomised controlled trials (RCTs) on drugs for rheumatoid arthritis found that the funding source was not associated with higher likelihood of positive outcomes in published studies (75.5% of industry funded, 68.8% of nonindustry funded, 40% of mixed funding). It, however, revealed that industry-funded RCTs showed a trend towards a higher likelihood of nonpublication, which raises the suspicion that industry-funded RCTs with nonfavourable results are less often published (P = 0.093) (9). Sponsors may also impact on trial results through influencing study design: a meta-analysis of 58 trials on antidepressant treatment showed that the medication produced by the industry sponsors was dosed higher than the medication used in the control groups, resulting in higher remission rates with the sponsor drug (OR 1.28, 95% CI 1.11–1.47, P < 0.001) (10). Moreover, alteration of trial results and interpretation because of sponsor's bias and data omissions have been reported (11). Likewise, a systematic review on publications on food products (soft drinks, juice, and milk) found that the funding source was significantly related to the conclusions drawn: for interventional studies, the proportion with unfavourable conclusions was 0% for all industry-funded compared with 37% for not industry-funded studies (P = 0.009) (12). Moreover, dominance of industry sponsorship in clinical research has been associated with increasing commercialisation and loss of professional ethics (13). Researchers with links to companies were reported to be more likely to report results that are favourable to the products of those companies than researchers without such ties (14). A systematic review of 190 studies in the surgical literature found indications that studies of authors with a conflict of interest owing to financial affiliation with industry were significantly more likely to report positive outcomes than authors without industry funding, which supports the conclusion of a proindustry bias of research sponsored by industry (15). Fisher and Kalbaugh (16) reported a disquieting increase in pharmaceutical contract research in the United States with nonacademic, private sector physicians primarily motivated by financial gain, with a rather worrying trend to align research ethics with industry interests rather than the interests of research participants.

The credibility gap is even greater for studies on infant formulae that serve as breast-milk substitutes. For example, the Nursing Mothers’ Association of Australia stated that formula company sponsorship of paediatric research would exist only to further the commercial interests of the formula company, which were considered incompatible with promoting optimal health worldwide (17). Researchers collaborating with infant formula companies are at risk of being excluded as speakers from meetings, seminars, and conferences, of being excluded from the editorial boards of some journals, of having their articles submitted for publication rejected because of their collaborations, and of being perceived by some of having lesser scientific credibility (17). Conversely, although the health care community strongly agrees that breast-feeding is the optimal feeding for healthy infants and actively promotes, supports, and protects breast-feeding (18), there is an obvious need for infant formula of the best possible quality for the many infants who are not or not fully breast-fed. Both regulatory authorities and the scientific community demand that new or modified infant formulae are thoroughly evaluated, which generally includes the need for clinical trials (19–26).

Collaborative clinical research, and in particular research performed in the very sensitive groups of infants and children, pregnant, and breast-feeding women, needs to follow high scientific, ethical, and societal standards (27). Policies that promote transparency in the clinical trial research process provide full disclosure of investigator contributions and funding, comprehensive publicly available trial registration, and independent analysis of clinical trial data analysis that can improve accountability among industry and investigators (28,29). The implementation of widely accepted standards of practice (Table 1) can contribute to more reliable, credible, and acceptable results of sponsored trials and reduce the existing credibility gap, which is in the common interest of all stakeholders. Therefore, the following conclusions and recommendations are supported.

TABLE 1

TABLE 1

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CONCLUSIONS AND RECOMMENDATIONS FOR CLINICAL RESEARCH IN PREGNANT AND BREAST-FEEDING WOMEN AND IN CHILDREN PERFORMED IN PARTNERSHIP WITH ACADEMIA AND COMMERCIAL ENTERPRISES

  1. Collaborative clinical research between academia and commercial enterprises is in the mutual and the public interest, and it can provide major contributions to improving maternal and child health.
  2. Collaborative research should address important questions for maternal and child health and well-being, rather than favouring a particular outcome or only serving to promote a particular product. Study design needs to address meaningful outcomes and outcome measures that are relevant for clinical practice or public health. Study conditions should support scientific integrity and follow appropriate scientific, ethical, and societal standards.
  3. Pregnant and breast-feeding women and infants and children are particularly vulnerable subjects. The protection of subjects and careful balancing of possible benefits and risks are crucial. Research in these groups should only be performed if research in nonpregnant or nonbreast-feeding adults cannot answer the relevant questions. Clinical trials should be preceded by a thorough safety characterisation of the intervention in preclinical studies or in studies performed in nonpregnant or nonbreast-feeding adults unless this is not suitable for the particular intervention.
  4. Physicians involved in clinical research are bound by the Hippocratic Oath to do no harm and to protect the interests of patients and healthy volunteers to the best of their ability. This includes the avoidance of producing unreliable or inaccurate results or the nonreporting of outcomes because this could lead to harm in future patients or healthy individuals.
  5. The needs and interests of patients, and of healthy children and their families, should be considered in the planning and conduct of research studies. Wherever appropriate, patient or parent organisations should be involved.
  6. Generally accepted standards for developing study protocols, the conduct of the research, and the reporting of clinical research results are to be followed (Table 1).
  7. Informed consent for research conducted in children by their parents or guardians is always needed. Assent of children from about the age of 6 years onwards and consent of children from about the age of 16 years onwards or when they are considered competent is strongly advisable; however, national legislation and/or regulations may take precedence.
  8. An age-related token of appreciation in children age <9 years or a modest financial compensation for study participants age >9 years may be considered if approved by the competent institutional review board/ethics committee.
  9. Breast-feeding is recognised as the optimal feeding choice for healthy infants and should be actively protected, promoted, and supported (18). Conditions of studies performed in breast-feeding women and infants, in particular the strategies for subject recruitment and the interaction with parents and health care professionals, should ensure that there is no interference with breast-feeding.
  10. In accordance with Good Clinical Practice guidelines (30–33), academic investigators should be actively involved from the early stages of study planning and protocol development onwards. A collaborative approach towards study design, selection of outcomes, and their measures, the research and the interpretation, reporting, and publication of results is favoured. The final responsibility for the clinical trial implementation should rest with the academic investigator(s).
  11. Trial registration on a public trial registration database before the start of the study, and access to protocol information that is as complete as feasible, without compromising intellectual property rights, is required.
  12. External review and monitoring of all aspects of the study from study design through to reporting the results can reduce the risk of bias and is encouraged. Academic institutions should establish advisory boards that advise on and supervise the planning, conduct, and reporting of clinical trials. Cofunding by public research grants, such as those provided by the European Commission's Framework Programmes or many national funding agencies, also generally ensures an external peer review of study concept and execution and thus can lead to enhanced quality and credibility of clinical trials.
  13. A written contract overseen by the academic investigator(s)'s university or hospital should serve as the basis for any clinical research collaboration and should be established before the commencement of any study. The written agreement should include clauses that address the responsibilities of all partners, intellectual property protection, and the freedom and obligation of the academic investigators to publish the results within an adequate, specified time frame.
  14. Finances provided for the study by the sponsor should be transferred to and administered by public institutions, such as universities or hospitals. Funding must not be linked to the results or conclusions drawn from the study.
  15. If a contract research organisation is involved in the study, there should be agreement and full transparency on the respective roles and responsibilities of the contract research organisation, the sponsor, and the academic investigator(s).
  16. The approach to statistical analysis and the aims should be discussed and planned during the phase of study design and included in the study contract. At least 1 principal investigator should have access to industry independent statistical expertise and respective funding, which should be allocated at the beginning of the trial.
  17. The academic investigator(s) should have full access to the complete study data (which may be anonymised or pseudoanonymised), case report forms, and other original data, and the detailed statistical analysis reports, while respecting the protection of personal privacy of the subjects.
  18. The data, their interpretation, and the conclusions drawn should be discussed with all of the investigators involved and the sponsor with the aim of reaching consensus; however, the final responsibility on interpretation and decisions on publications needs to rest with the academic investigator(s).
  19. The roles, contributions, and responsibilities of all of the participating partners should be transparently reported. There should be no undisclosed ghost-writing, for example, by interested companies or by agents working on their behalf.
  20. The results of all clinical studies should be published or at least be made publically available, for example, by putting a report of the study results on a trial registration platform (34,35). A moderate delay period until publication to allow for intellectual property protection that is mutually agreed upon is acceptable.
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    Keywords:

    biomedical research; clinical trials; drug industry; food industry; public–private sector partnership; research ethics

    © 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,