Clinical Therapeutics/Volume 36, Number 2, 2014
Commentary
Challenges for Academic Investigator–Initiated Pediatric Trials for Rare Diseases Raees Ahmed, PhD1,*; Ulrike Duerr, PhD1,*; Karsten Gavenis, PhD1; Reinhard Hilgers, MD2; and Oliver Gross, MD3 1
Institute for Applied Research and Clinical Trials GmbH, Georg August University Go¨ttingen, Go¨ttingen, Germany; 2University Medical Center Go¨ttingen, Institute of Medical Statistics, Go¨ttingen, Germany; and 3 University Medical Center Go¨ttingen, Clinic for Nephrology and Rheumatology, Go¨ttingen, Germany ABSTRACT Background: Clinical trials require great effort, time, expertise, and money. For clinicians at university hospitals with their full work load of teaching and medical care, the planning of an investigator-initiated clinical trial seems almost unthinkable. Despite their expertise in distinct diseases, university clinicians lack the time necessary to organize the funding and to initiate and conduct Phase III clinical trials in adults or in children. Objective: We sought to determine whether the difficulties faced by a clinician conducting a pediatric clinical trial can be overcome by passionate motivation and external support. Methods: Critical aspects of the application process of the world's first clinical trial in children with the rare hereditary kidney disease Alport syndrome treated with an angiotensin-converting enzyme inhibitor (Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome [EARLY PRO-TECT Alport]; http://www.clinicaltrials.gov NCT01485978; EudraCT 2010-024300-10) are described. Results: The following crucial factors enabled the investigator to complete this trial: (1) support through clinical trial, biometrician, and regulatory experts (Institute for Applied Research and Clinical Studies [IFS], Göttingen, Germany); (2) advice from the university's ethics committee (University Medicine Göttingen, Göttingen, Germany); (3) public funding (€1 million from the German Federal Ministry of *
Drs. Ahmed and Duerr contributed equally to this work.
Accepted for publication January 16, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.01.013 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
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Education and Research); (4) support from the respective medical society, aiming at the resolution of an important clinical problem (German Society of Pediatric Nephrology); and (5) support from the investigator's university as the official sponsor of the trial, providing long-term commitment and covering financial risks (University Medical Center Göttingen, Göttingen, Germany). Conclusions: The study could pave the way for approval of ramipril as a drug to treat children with Alport syndrome. Even though the study might not result in label changes, the EARLY PRO-TECT Alport trial provides the basis of an educational campaign to sensitize physicians, especially pediatricians, general practitioners, and nephrologists, to pay special attention to the early detection of kidney diseases in children, which could improve medical care for all children with kidney diseases. (Clin Ther. 2014;36:184–190) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: COL4A5, European Alport Registry, hematuria, microalbuminuria, pediatric glomerulopathy, pediatric investigation, proteinuria, ramipril, renal failure.
INTRODUCTION Universities have definite scientific interest in conducting investigator-initiated clinical trials (IITs). However, limited financial resources and remarkable Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.
Volume 36 Number 2
R. Ahmed et al. regulatory requirements hamper trial conduct. In addition, the long delay from application for funding to approval and to the actual start of a clinical trial takes several years. Special legal and ethical requirements apply in clinical trials that involve minors. In addition, many of the dedicated researchers at academic institutions struggle with short-term employment contracts and the pressure to publish rapidly. Engagement in long-term strategic clinical research is therefore rather counterproductive for the individual clinician because results remain unpublishable for many years.
CHILDREN ARE NOT SMALL ADULTS “Children are not small adults” is a doctrine in the field of pediatrics. This means, among other things, that the doses of adult medications cannot simply be downscaled to fit children because body composition and maturity of the organs in minors differ quantitatively and qualitatively from adults.1 Yet, pediatricians are often required to use adult medications despite the lack of child-specific efficacy and tolerability data. Worldwide, only approximately 50% of the drugs used in a pediatric general ward have been tested and approved for the respective pediatric indication.2 This off-label drug use not only poses a medical risk for the child but also creates a liability risk for the physician and an unpleasant feeling of uncertainty. Physicians are obliged to treat minors with “special and reasonable care,” while at the same time they worry about being held liable for their actions by health insurance companies and lawyers.3–8
WHY ARE THERE NOT MORE DRUGS FOR CHILDREN? For several decades, because of ethical concerns, minors have not been sufficiently included in drug development, which has caused the development of pediatric medicines to lag behind. Fortunately, drug development now also focuses on children. Clinical trials of pharmaceuticals in minors are now considered imperative to ensure child-friendly therapy, even if the pediatric use promises only small profits for pharmaceutical companies.9
CHILDREN AS ORPHANS IN MEDICAL THERAPY Despite the recognition of a clear need for pediatric medicines, minors can still be systematically excluded
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from the drug development process. Ethics committees, among others, demand that drugs be tested in adults first and only then in children of decreasing ages. In Germany, despite regulations that encourage studies in children, the number of clinical trials in children did not increase at all between 2000 and 200810; children are still orphans in medical therapy.
RARE AND CHRONIC DISEASES IN CHILDREN Large gaps exist in our knowledge of medical treatment, especially of rare and chronic diseases in children, for which the number of patients is naturally small, drug development costs are high, and subsequent drug sales profits are extremely small to nonexistent.
“CARROT AND STICK” FOR THE PHARMACEUTICAL INDUSTRY To encourage the development of medicines for children, enactment 1901/2006 of the European Parliament and of the Council on Medicines in Children came into force in 2008.11 The enactment obliges pharmaceutical companies to test the tolerability and efficacy of new drugs in the pediatric population to obtain drug approval or authorization amendments for still patented drugs. Furthermore, evidence on the current use of approved drugs shall be collected in minors, including data on off-label use. The following incentives are being promised to the pharmaceutical industry: (1) patent extension for 6 months; (2) patent extension for drugs used in orphan diseases from 10 to 12 years; or (3) 10 years of data protection for data collected on children. To our knowledge, these incentives apply for new medications and for new indications of already approved drugs.
STRINGENT REQUIREMENTS FOR TRIALS IN A PEDIATRIC POPULATION Today, regulatory requirements and regulatory supervision of clinical trials in minors are stringent. For example, approval by the federal authority is needed on top of all other approvals. The Central Ethics Committee of the German Medical Association has laid down principles for the protection of persons unable to give consent in biomedical research. In addition, the World Medical Association issued Declaration of Helsinki recommendations for clinical research in minors, which are designed to ensure medical protection in research and trials. All major points of these recommendations have been
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Clinical Therapeutics incorporated into the German Medicinal Products Act (AMG).1 The 12th AMG amendment from 2004 implemented the European Directive 2001/20/EC11 and also discussed the special features of clinical trials in children and adolescents.12 In addition to the basic requirements for the conduct of clinical trials, additional punitive rules apply for clinical trials with minors.13 These special punitive rules were maintained in the current 16th amendment of the AMG (§§40-41).
ETHICAL ASPECTS OF CLINICAL RESEARCH ON MINORS When planning and performing pediatric studies in accordance with the AMG, one has to consider the following: The research must relate to a clinical condition that the underage patient has.14 This sounds simple, but it can be difficult to meet this requirement in rare conditions because so few children may be available for a study that the study risks being underpowered. Today, the group benefits principle applies, meaning that a clinical trial may be conducted in minors despite the absence of any individual patient benefit, as long as a future benefit for the patient population can be expected. Previously, trials had to benefit the individual pediatric patient, which hindered many clinical trials (eg, by making placebo control impossible). Additional invasive procedures can be especially painful or frightening for children. Research in minors must be limited to a minimal burden. Invasive investigations must therefore be minimal and are to be embedded into necessary routine examinations. Legal requirements are designed to protect children from profit-seeking parents who wish their child to participate in a trial solely because of financial interests. These requirements make it impossible to compensate children (or their parents) for the traveling costs and inconvenience of participation in studies, which is likely to hamper recruitment in pediatric trials. In Germany, prior written consent must be obtained from both parents or both legal representatives for clinical trials in minors. The suspected will of the child also has to be taken into account and must be documented in writing wherever possible given the limits of the child’s age. The setting of the clinical trial should be appropriate for children.
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Only physicians and study personnel with proven pediatric training and experience are allowed to handle and investigate children. It is mandatory that patients‘ have insurance. Even if all these legal requirements are met, a positive vote can still often be refused by the responsible ethics committee. This may be due to the ignorance of most institutional review board (IRB) members concerning the pediatric legislation, even though the statutes of most ethics committees require that at least one member be a pediatrician.
DEALING WITH MINORS AND THEIR FAMILIES After receiving the approval of both the ethics committee and the Federal Institute for Drugs and Medical Devices, in Germany there are special challenges to trial sites in the recruitment and support of minors and their families. Clinical trials with children often have a high dropout rate. In part this is because minors, by law, can terminate their participation in the study at any time without notice and for any reason. In addition, children are always part of a family and attend the examination program together with their parents. For that reason, the study team must establish an appropriate level of trust. Trust challenges studies in adults but even much more so in pediatric studies.
TARGETING THE MEDICAL PROBLEM AS A CLINICIAN AND RESEARCHER Biochemical, Genetic, and Preclinical Data on AS Alport syndrome (AS) is a rare hereditary kidney disease of infants, which inevitably progresses to the final state of renal failure during adolescence.15 The genetic diagnosis can be made many years before kidney failure. This early diagnosis provides the opportunity for early (preemptive) therapeutic intervention. In Alport mice, early application of the angiotensinconverting enzyme inhibitor (ACEI) ramipril considerably delayed kidney failure.16 Ramipril is approved by the Food and Drug Administration and the European Medicines Agency for antihypertensive therapy in adults. On the basis of the results in mice, many children with AS are treated off-label with ACEIs, even though data on the efficiency and adverse effects in minors are incomplete.17 Because of pain experienced by their child, affected families are willing to accept the
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100 percentage on renal replacement therapy
no therapy
80
therapy start with impaired renal function
60
therapy start with proteinuria
40 20
earlier therapy even better and safe ???
0 0
10 20 30 40 time until end stage renal disease (in years)
50
Figure 1. European Alport registry data on angiotensin-converting enzyme inhibitor therapy in Alport syndrome. Patients without therapy (red curve) develop end-stage renal disease at a median age of 22 years. Late start of therapy (yellow) with ongoing renal failure significantly delays end-stage renal disease by 3 years; early therapy start in patients with proteinuria (green) delays disease by 18 years. The Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome will investigate whether a yet earlier start (blue) before onset of proteinuria does even better and appears to be well tolerated.
increased risks of such off-label therapy. Encouraging safety profile data on the use of ramipril in children evolved from the Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) Study which examined intensified blood pressure control using ramipril in children with chronic renal disease.18,19
Retrospective Clinical Data on AS: The European Alport Registry Since 2003, our group has assessed patient medical records concerning the actual treatment of patients with AS. The European Alport registry has allowed data to be evaluated from 4283 patients, with the duration of individual data averaging 42 decades.20 The results suggest that ACEIs delay renal failure in patients with AS with proteinuria and that starting treatment early works better than starting later (Figure 1). These retrospective data have caused the use of ACEIs to
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become standard off-label therapy in patients with AS. However, retrospective evaluation of treatment data is generally incomplete, especially regarding risks and adverse effects. Nontrial documentation is never as complete as controlled clinical trial data. For this reason, we decided in 2007 to investigate the use of the ACEI ramipril in a prospective, controlled study performed in accordance with International Conference on Harmonisation Good Clinical Practice in pediatric patients with AS. The application process for public funding was guided by an experienced biometrician and clinical trial and regulatory experts from the IFS (Appendix). The study was initiated 45 years later, in summer 2012, and is estimated to end in 2018. This delay illustrates how much endurance and enthusiasm such a project requires.
THE STUDY OBJECTIVES OF EARLY PRO-TECT ALPORT The randomized, placebo-controlled, double-blind EARLY PRO-TECT Alport study is a prospective examination of the efficacy, risks, and benefits of early initiation of therapy in children with early stages of AS. The recruitment period is anticipated to be 2 years. All patients with newly diagnosed and pretreated earlystage AS enrolled in Germany will be treated with ramipril or placebo for 3 years. In our experience, the lack of pediatric labeling does not affect recruitment; however, the long and thorough consent forms hinder enrollment in pediatric trials. For drug tolerability reasons, children must be Z2 years to participate in our trial. Only patients in the early stages of AS will be included, and patients will be unblinded on disease progression to allow placebo patients to be switched to ramipril and continue open label. If parents refuse randomization, patients may be treated open label with ramipril or receive no treatment at all while their data are also documented prospectively.
PROFESSIONAL HELP FOR ACADEMICS IN THE COMPLICATED REGULATORY PROCESS OF IITS Financing Academically Initiated Clinical Trials: The Role of Government Funding The principal investigator and initiator of EARLY PRO-TECT Alport is head attending physician and professor at the Clinic for Nephrology and Rheumatology at the University Medical Center Göttingen. Thus, the proposed study is academically initiated. Such IITs)
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Clinical Therapeutics are characterized by the fact that a dedicated physician wishes to develop a new research idea for use in humans, to improve an existing treatment, or to make it more tolerable. No pharmaceutical company supports the idea. Thus, IITs usually lack the financial support and established infrastructure that pharmaceutical companies have for the preparation, conduct, and evaluation of studies. Public or private sources of funding for IITs are sparse. Since 2003, the German Federal Ministry of Education and Research, together with the German Research Foundation, funds noncommercial clinical trials with a total of €30 million per year. The competition for these financial resources is an important step to improve the high quality of applications, but competition is also brutal, and clinical trials that receive funding (of only €1 million) are almost underfunded. Although unwilling to support a pediatric investigation plan (PIP), which is required for labeling, Sanofi-Aventis Germany GmbH generously provided the trial medication (ramipril and placebo) free of cost.
The Role of University Institutes for Applied Research and Clinical Studies in Catalyzing IITs University hospital physicians are generally not well trained in clinical research and usually have heavy daily clinical responsibilities. Therefore, university-associated institutes for applied research and clinical studies, such as the IFS in Göttingen, play a vital role in catalyzing and accelerating the application and planning process of IITs. Research proposals for the funding of clinical trials must comply with the highest international quality standards. During the 5-year application process of EARLY PRO-TECT Alport, the initiator was guided by expert support from the IFS and a biometrician. The IFS brought together a team of experienced medical biometricians, study managers, regulatory affairs experts and medical writers who developed the complete trial outline together with the investigator. After a preliminary funding approval in September 2010 and before receiving any funds, the IFS developed the study protocol, and all regulatory documents were created and submitted to authorities and ethics committees. This full commitment and prefunding investment of both the clinical investigator and the IFS were crucial for the success of this project. No matter how easy the whole process might look for professionals, the complete application and regulatory process would have been far too complex for a clinician to do alone.
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Specific Requirements for Monitoring of IITs: Close Contact Among Study Management, Regulatory Affairs, the Ethic Committee, the Medical Society, and the Investigator’s University Study managers and monitors from the IFS trained the study personnel at the 15 pediatric trial sites in Germany. Pediatric studies are a particular challenge for study managers and monitors, requiring close communication with the trial sites. Not all of the participating pediatric nephrology trial sites were experienced in doing clinical studies. Common sense and instinct are needed to help the on-site study team integrate the trial processes into their everyday routine. It is important to involve staff and parents as much as possible and to create an atmosphere of trust. The children and families need to feel comfortable at their trial site because after all they must visit their trial site every 6 months for 3 years and need to stay in close contact between visits. Because cooperation between the IFS and the investigator is also extremely important during the recruitment phase, official channels to study management and authorities need to remain short. This can only be realized by personal commitment and the common goal to perform the trial successfully. The expertise and help by the university ethics committee (University Medical Center Göttingen IRB) improved the trial protocol, informed consent, and patient information documents, which were adapted to different age groups (Figure 2). The guidance, supervision, and skills of the IRB also helped the investigator through the jungle of legal contracts. To improve recruitment, the clinical trial and the trial protocol should be supported by the respective medical society. A written commitment of the clinicians at the trial sites stating the need for the trial to answer an important clinical problem also helps to complete the complicated regulatory process. Finally, the support of the investigator’s university as the official trial sponsor reflects long-term commitment and reduced financial risks, which is another essential puzzle piece for IITs. It does not matter how easy the process of setting up a clinical trial might seem to professionals or legal authorities. For a clinician, failure of any of the essential puzzle pieces (study management, regulatory affairs, ethic committee, medical society, and investigator’s university) will cause even the best IIT to fail before it has begun.
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Figure 2. From the patient information document of the Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome for patients age Z6 years. “Hi, my name is Nick. Nick Kidney. Me and my brother Nack are your kidneys: Nick and Nack Kidney. We are very important for your body. We clean your pee and wash the dirt out of your body. And we keep your blood clean. We are like washing machines. The dirty socks are cleaned and the dirty water ends up in the drain. Sometimes, people get sick because their kidneys do not work well. The kidney-washing machines can have holes. A dirty sock may escape into the drain together with the dirty water. Well, with kidneys, it is not socks that get lost. Rather things from the blood like red blood cells and proteins that should stay in the blood.”
Can the Study Design of an IIT Be Transmitted and Improve Other Trials? The EARLY PRO-TECT Alport trial is the world's first and only clinical prevention study of its kind in oligosymptomatic children with the chronic kidney disease type of AS. The study protocol was written at the IFS in English to encourage other countries, such as China, England, France, and the United States, to replicate the study using the same protocol. The trial outline and rationale have been published in an open access journal.21 The European Union legislation11 was not of any use convincing an industry sponsor to support this trial. England, France, the United States, and pharmaceutical companies (such as Genzyme/SanofiAventis) (personal communication with Christoph Licht, University of Toronto, Toronto, Canada; December 30, 2013) have shown interest in conducting a similar study with similar medications, which if done would increase the total number of patients studied and thus the validity of the findings. The study could pave the way for approval of ramipril as a drug to treat children with AS; however, the study is not part of an approved PIP. One should be aware of the difference between getting an IIT completed and published versus having the results be used to register a drug or a new indication. The results of the ongoing trial have the potential to alter ramipril labeling; however, until now,
February 2014
no manufacturer has shown interest in getting a PIP approval for the study (and none is required to obtain one). Again, the European Union legislation11 was not of any use convincing an industry sponsor to support this trial or to obtain a PIP. However, the tolerability data obtained from this trial together with the persuasive nephroprotective effect of ACEIs in proteinuric AS patients20 can assist pediatricians in the more tolerable use of ramipril in the future. Even if our study does not result in label changes, the EARLY PRO-TECT Alport trial is intended as part of an educational campaign to sensitize physicians, especially pediatricians, general practitioners, and nephrologists, about the need for the early detection of kidney diseases in children. If this campaign is successful, the trial might further improve medical care in all children with kidney diseases.
APPENDIX: ABOUT THE IFS The Institute for Applied Research and Clinical Studies (IFS) is a subsidiary of the University Medical Center Göttingen (UMG). The IFS is a comprehensive academic clinical research organization working both as Site Management Organization for the UMG and as a contract research organization. The IFS connects investigators, research-based pharmaceutical companies, and public funding bodies. It supports university-
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Clinical Therapeutics based and external partners in the planning, execution, and evaluation of clinical trials and ensures compliance with highest national and international quality standards. Special knowledge and experience currently exist in the areas of regulatory affairs, pediatrics, and the development of medical devices, including the development of standards. In 2012, the IFS provided service in 27 trials in Phase I to IV in the fields of pharmaceuticals and medical devices. Six new studies started in 2012, and 7 studies were completed successfully.
REFERENCES 1. Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Exp Opin Drug Saf. 2006;5:703–718. 2. Lindell-Osuagwu L, Korhonen MJ, Saano S, HelinTanninen M, Naaranlahti T, Kokki H. Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther. 2009;34:277–287. 3. Ceci A, Felisi M, Baiardi F, et al. Medicines for children licensed by the European Medicines Agency (EMEA): the balance after 10 years. Eur J Clin Pharmacol. 2006;62:947–952. 4. Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off-label drug use in paediatric wards: prospective study. BMJ. 1998;316:343–345. 5. Conroy S, McIntyre J, Choonara I. Unlicensed and offlabel drug use in neonates. Arch Dis Child Fetal Neonatal; Ed. 1999:F142–F145. 6. Conroy S, Choonara I, Impicciatore P, et al. European Network for Drug Investigation in Children. Survey of unlicensed and off-label drug use in paediatric wards in European countries. BMJ. 2000;320:79–82. 7. McDonnell F. Prescription survey of unlicensed and off label medicines in pediatrics at Our Lady’s Hospital for Sick Children. Irish Pharmacy J (Ireland). 2001;79:292, 294–296. 8. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr. 2005;164:552–558. 9. Seyberth HW, Brochhausen C, Kurz R. Probleme der pädiatrischen Pharmakotherapie und deren internationale Lösungsansätze. Monatsschrift Kinderheilkunde. 2002;150:218–225.
10. Khan-Boluki J, Hundt F. Children in clinical trials: survey on the current situation in paediatric university clinics in Germany. Ger Med Sci. 2008:6:Doc010. 11. Verordnung (EG) Nr. 1901/2006 des Europäischen Parlaments und des Rates vom 12. Dezember 2006 über Kinderarzneimittel und zur Änderung der Verordnung (EWG) Nr. 1768/92, der Richtlinien 2001/20/EG und 2001/83/EG sowie der Verordnung (EG) Nr. 726/2004. http://ec.europa.eu/ health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_ en.pdf. Accessed November 30, 2013. 12. Wachenhausen: AMG §40, in: Kügel/Müller/Hofmann, AMG, 1. Aufl. München 2012, Rn. 12. 13. Listl: MPG §20, Allgemeine Voraussetzungen zur klinischen Prüfung, in Spickhoff: Medizinrecht, 1. Aufl. München, 2011, Rn 16-18. 14. Kügel. In: Terbille: Münchener Anwaltshandbuch Medizinrecht, 1. Aufl., München 2009, Rn 158-165. 15. Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotypephenotype correlations in males. J Am Soc Nephrol. 2000;11:649–657. 16. Gross O, Beirowski B, Koepke M-L, et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int. 2003;63:438–446. 17. Gross O, Kashtan C. Treatment of Alport syndrome: beyond animal models. Kidney Int. 2009;76:599–603. 18. Wühl E, Trivelli A, Picca S, et al. ESCAPE Trial Group. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361:1639–1650. 19. Ingelfinger JR. Blood-pressure control and delay in progression of kidney disease in children. N Engl J Med. 2009;361:1701–1703. 20. Gross O, Licht C, Anders HJ, et al, Study Group Members of the Gesellschaft für Pädiatrische Nephrologie (GPN), Knebelmann B, Pirson Y, Grunfeld JP, et al. Early angiotensin converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012;81:494–501. 21. Gross O, Friede T, Hilgers R, Study Group Members of the Gesellschaft für Pädiatrische Nephrologie (GPN), Görlitz A, Gavenis K, Ahmed R, Duerr U. Safety and efficacy of the ACE-inhibitor ramipril in Alport syndrome: the double-blind, randomized, placebo-controlled, multicenter phase III EARLY PRO-TECT Alport trial in pediatric patients. ISRN Pediatr. 2012:436046.
Address correspondence to: Oliver Gross, MD, Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075 Göttingen, Germany. E-mail: [email protected]
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Volume 36 Number 2
Commentary
Challenges for Academic Investigator–Initiated Pediatric Trials for Rare Diseases Raees Ahmed, PhD1,*; Ulrike Duerr, PhD1,*; Karsten Gavenis, PhD1; Reinhard Hilgers, MD2; and Oliver Gross, MD3 1
Institute for Applied Research and Clinical Trials GmbH, Georg August University Go¨ttingen, Go¨ttingen, Germany; 2University Medical Center Go¨ttingen, Institute of Medical Statistics, Go¨ttingen, Germany; and 3 University Medical Center Go¨ttingen, Clinic for Nephrology and Rheumatology, Go¨ttingen, Germany ABSTRACT Background: Clinical trials require great effort, time, expertise, and money. For clinicians at university hospitals with their full work load of teaching and medical care, the planning of an investigator-initiated clinical trial seems almost unthinkable. Despite their expertise in distinct diseases, university clinicians lack the time necessary to organize the funding and to initiate and conduct Phase III clinical trials in adults or in children. Objective: We sought to determine whether the difficulties faced by a clinician conducting a pediatric clinical trial can be overcome by passionate motivation and external support. Methods: Critical aspects of the application process of the world's first clinical trial in children with the rare hereditary kidney disease Alport syndrome treated with an angiotensin-converting enzyme inhibitor (Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome [EARLY PRO-TECT Alport]; http://www.clinicaltrials.gov NCT01485978; EudraCT 2010-024300-10) are described. Results: The following crucial factors enabled the investigator to complete this trial: (1) support through clinical trial, biometrician, and regulatory experts (Institute for Applied Research and Clinical Studies [IFS], Göttingen, Germany); (2) advice from the university's ethics committee (University Medicine Göttingen, Göttingen, Germany); (3) public funding (€1 million from the German Federal Ministry of *
Drs. Ahmed and Duerr contributed equally to this work.
Accepted for publication January 16, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.01.013 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.
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Education and Research); (4) support from the respective medical society, aiming at the resolution of an important clinical problem (German Society of Pediatric Nephrology); and (5) support from the investigator's university as the official sponsor of the trial, providing long-term commitment and covering financial risks (University Medical Center Göttingen, Göttingen, Germany). Conclusions: The study could pave the way for approval of ramipril as a drug to treat children with Alport syndrome. Even though the study might not result in label changes, the EARLY PRO-TECT Alport trial provides the basis of an educational campaign to sensitize physicians, especially pediatricians, general practitioners, and nephrologists, to pay special attention to the early detection of kidney diseases in children, which could improve medical care for all children with kidney diseases. (Clin Ther. 2014;36:184–190) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: COL4A5, European Alport Registry, hematuria, microalbuminuria, pediatric glomerulopathy, pediatric investigation, proteinuria, ramipril, renal failure.
INTRODUCTION Universities have definite scientific interest in conducting investigator-initiated clinical trials (IITs). However, limited financial resources and remarkable Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.
Volume 36 Number 2
R. Ahmed et al. regulatory requirements hamper trial conduct. In addition, the long delay from application for funding to approval and to the actual start of a clinical trial takes several years. Special legal and ethical requirements apply in clinical trials that involve minors. In addition, many of the dedicated researchers at academic institutions struggle with short-term employment contracts and the pressure to publish rapidly. Engagement in long-term strategic clinical research is therefore rather counterproductive for the individual clinician because results remain unpublishable for many years.
CHILDREN ARE NOT SMALL ADULTS “Children are not small adults” is a doctrine in the field of pediatrics. This means, among other things, that the doses of adult medications cannot simply be downscaled to fit children because body composition and maturity of the organs in minors differ quantitatively and qualitatively from adults.1 Yet, pediatricians are often required to use adult medications despite the lack of child-specific efficacy and tolerability data. Worldwide, only approximately 50% of the drugs used in a pediatric general ward have been tested and approved for the respective pediatric indication.2 This off-label drug use not only poses a medical risk for the child but also creates a liability risk for the physician and an unpleasant feeling of uncertainty. Physicians are obliged to treat minors with “special and reasonable care,” while at the same time they worry about being held liable for their actions by health insurance companies and lawyers.3–8
WHY ARE THERE NOT MORE DRUGS FOR CHILDREN? For several decades, because of ethical concerns, minors have not been sufficiently included in drug development, which has caused the development of pediatric medicines to lag behind. Fortunately, drug development now also focuses on children. Clinical trials of pharmaceuticals in minors are now considered imperative to ensure child-friendly therapy, even if the pediatric use promises only small profits for pharmaceutical companies.9
CHILDREN AS ORPHANS IN MEDICAL THERAPY Despite the recognition of a clear need for pediatric medicines, minors can still be systematically excluded
February 2014
from the drug development process. Ethics committees, among others, demand that drugs be tested in adults first and only then in children of decreasing ages. In Germany, despite regulations that encourage studies in children, the number of clinical trials in children did not increase at all between 2000 and 200810; children are still orphans in medical therapy.
RARE AND CHRONIC DISEASES IN CHILDREN Large gaps exist in our knowledge of medical treatment, especially of rare and chronic diseases in children, for which the number of patients is naturally small, drug development costs are high, and subsequent drug sales profits are extremely small to nonexistent.
“CARROT AND STICK” FOR THE PHARMACEUTICAL INDUSTRY To encourage the development of medicines for children, enactment 1901/2006 of the European Parliament and of the Council on Medicines in Children came into force in 2008.11 The enactment obliges pharmaceutical companies to test the tolerability and efficacy of new drugs in the pediatric population to obtain drug approval or authorization amendments for still patented drugs. Furthermore, evidence on the current use of approved drugs shall be collected in minors, including data on off-label use. The following incentives are being promised to the pharmaceutical industry: (1) patent extension for 6 months; (2) patent extension for drugs used in orphan diseases from 10 to 12 years; or (3) 10 years of data protection for data collected on children. To our knowledge, these incentives apply for new medications and for new indications of already approved drugs.
STRINGENT REQUIREMENTS FOR TRIALS IN A PEDIATRIC POPULATION Today, regulatory requirements and regulatory supervision of clinical trials in minors are stringent. For example, approval by the federal authority is needed on top of all other approvals. The Central Ethics Committee of the German Medical Association has laid down principles for the protection of persons unable to give consent in biomedical research. In addition, the World Medical Association issued Declaration of Helsinki recommendations for clinical research in minors, which are designed to ensure medical protection in research and trials. All major points of these recommendations have been
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Clinical Therapeutics incorporated into the German Medicinal Products Act (AMG).1 The 12th AMG amendment from 2004 implemented the European Directive 2001/20/EC11 and also discussed the special features of clinical trials in children and adolescents.12 In addition to the basic requirements for the conduct of clinical trials, additional punitive rules apply for clinical trials with minors.13 These special punitive rules were maintained in the current 16th amendment of the AMG (§§40-41).
ETHICAL ASPECTS OF CLINICAL RESEARCH ON MINORS When planning and performing pediatric studies in accordance with the AMG, one has to consider the following: The research must relate to a clinical condition that the underage patient has.14 This sounds simple, but it can be difficult to meet this requirement in rare conditions because so few children may be available for a study that the study risks being underpowered. Today, the group benefits principle applies, meaning that a clinical trial may be conducted in minors despite the absence of any individual patient benefit, as long as a future benefit for the patient population can be expected. Previously, trials had to benefit the individual pediatric patient, which hindered many clinical trials (eg, by making placebo control impossible). Additional invasive procedures can be especially painful or frightening for children. Research in minors must be limited to a minimal burden. Invasive investigations must therefore be minimal and are to be embedded into necessary routine examinations. Legal requirements are designed to protect children from profit-seeking parents who wish their child to participate in a trial solely because of financial interests. These requirements make it impossible to compensate children (or their parents) for the traveling costs and inconvenience of participation in studies, which is likely to hamper recruitment in pediatric trials. In Germany, prior written consent must be obtained from both parents or both legal representatives for clinical trials in minors. The suspected will of the child also has to be taken into account and must be documented in writing wherever possible given the limits of the child’s age. The setting of the clinical trial should be appropriate for children.
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Only physicians and study personnel with proven pediatric training and experience are allowed to handle and investigate children. It is mandatory that patients‘ have insurance. Even if all these legal requirements are met, a positive vote can still often be refused by the responsible ethics committee. This may be due to the ignorance of most institutional review board (IRB) members concerning the pediatric legislation, even though the statutes of most ethics committees require that at least one member be a pediatrician.
DEALING WITH MINORS AND THEIR FAMILIES After receiving the approval of both the ethics committee and the Federal Institute for Drugs and Medical Devices, in Germany there are special challenges to trial sites in the recruitment and support of minors and their families. Clinical trials with children often have a high dropout rate. In part this is because minors, by law, can terminate their participation in the study at any time without notice and for any reason. In addition, children are always part of a family and attend the examination program together with their parents. For that reason, the study team must establish an appropriate level of trust. Trust challenges studies in adults but even much more so in pediatric studies.
TARGETING THE MEDICAL PROBLEM AS A CLINICIAN AND RESEARCHER Biochemical, Genetic, and Preclinical Data on AS Alport syndrome (AS) is a rare hereditary kidney disease of infants, which inevitably progresses to the final state of renal failure during adolescence.15 The genetic diagnosis can be made many years before kidney failure. This early diagnosis provides the opportunity for early (preemptive) therapeutic intervention. In Alport mice, early application of the angiotensinconverting enzyme inhibitor (ACEI) ramipril considerably delayed kidney failure.16 Ramipril is approved by the Food and Drug Administration and the European Medicines Agency for antihypertensive therapy in adults. On the basis of the results in mice, many children with AS are treated off-label with ACEIs, even though data on the efficiency and adverse effects in minors are incomplete.17 Because of pain experienced by their child, affected families are willing to accept the
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100 percentage on renal replacement therapy
no therapy
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therapy start with impaired renal function
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therapy start with proteinuria
40 20
earlier therapy even better and safe ???
0 0
10 20 30 40 time until end stage renal disease (in years)
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Figure 1. European Alport registry data on angiotensin-converting enzyme inhibitor therapy in Alport syndrome. Patients without therapy (red curve) develop end-stage renal disease at a median age of 22 years. Late start of therapy (yellow) with ongoing renal failure significantly delays end-stage renal disease by 3 years; early therapy start in patients with proteinuria (green) delays disease by 18 years. The Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome will investigate whether a yet earlier start (blue) before onset of proteinuria does even better and appears to be well tolerated.
increased risks of such off-label therapy. Encouraging safety profile data on the use of ramipril in children evolved from the Effect of Strict Blood Pressure Control and ACE-Inhibition on Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) Study which examined intensified blood pressure control using ramipril in children with chronic renal disease.18,19
Retrospective Clinical Data on AS: The European Alport Registry Since 2003, our group has assessed patient medical records concerning the actual treatment of patients with AS. The European Alport registry has allowed data to be evaluated from 4283 patients, with the duration of individual data averaging 42 decades.20 The results suggest that ACEIs delay renal failure in patients with AS with proteinuria and that starting treatment early works better than starting later (Figure 1). These retrospective data have caused the use of ACEIs to
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become standard off-label therapy in patients with AS. However, retrospective evaluation of treatment data is generally incomplete, especially regarding risks and adverse effects. Nontrial documentation is never as complete as controlled clinical trial data. For this reason, we decided in 2007 to investigate the use of the ACEI ramipril in a prospective, controlled study performed in accordance with International Conference on Harmonisation Good Clinical Practice in pediatric patients with AS. The application process for public funding was guided by an experienced biometrician and clinical trial and regulatory experts from the IFS (Appendix). The study was initiated 45 years later, in summer 2012, and is estimated to end in 2018. This delay illustrates how much endurance and enthusiasm such a project requires.
THE STUDY OBJECTIVES OF EARLY PRO-TECT ALPORT The randomized, placebo-controlled, double-blind EARLY PRO-TECT Alport study is a prospective examination of the efficacy, risks, and benefits of early initiation of therapy in children with early stages of AS. The recruitment period is anticipated to be 2 years. All patients with newly diagnosed and pretreated earlystage AS enrolled in Germany will be treated with ramipril or placebo for 3 years. In our experience, the lack of pediatric labeling does not affect recruitment; however, the long and thorough consent forms hinder enrollment in pediatric trials. For drug tolerability reasons, children must be Z2 years to participate in our trial. Only patients in the early stages of AS will be included, and patients will be unblinded on disease progression to allow placebo patients to be switched to ramipril and continue open label. If parents refuse randomization, patients may be treated open label with ramipril or receive no treatment at all while their data are also documented prospectively.
PROFESSIONAL HELP FOR ACADEMICS IN THE COMPLICATED REGULATORY PROCESS OF IITS Financing Academically Initiated Clinical Trials: The Role of Government Funding The principal investigator and initiator of EARLY PRO-TECT Alport is head attending physician and professor at the Clinic for Nephrology and Rheumatology at the University Medical Center Göttingen. Thus, the proposed study is academically initiated. Such IITs)
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Clinical Therapeutics are characterized by the fact that a dedicated physician wishes to develop a new research idea for use in humans, to improve an existing treatment, or to make it more tolerable. No pharmaceutical company supports the idea. Thus, IITs usually lack the financial support and established infrastructure that pharmaceutical companies have for the preparation, conduct, and evaluation of studies. Public or private sources of funding for IITs are sparse. Since 2003, the German Federal Ministry of Education and Research, together with the German Research Foundation, funds noncommercial clinical trials with a total of €30 million per year. The competition for these financial resources is an important step to improve the high quality of applications, but competition is also brutal, and clinical trials that receive funding (of only €1 million) are almost underfunded. Although unwilling to support a pediatric investigation plan (PIP), which is required for labeling, Sanofi-Aventis Germany GmbH generously provided the trial medication (ramipril and placebo) free of cost.
The Role of University Institutes for Applied Research and Clinical Studies in Catalyzing IITs University hospital physicians are generally not well trained in clinical research and usually have heavy daily clinical responsibilities. Therefore, university-associated institutes for applied research and clinical studies, such as the IFS in Göttingen, play a vital role in catalyzing and accelerating the application and planning process of IITs. Research proposals for the funding of clinical trials must comply with the highest international quality standards. During the 5-year application process of EARLY PRO-TECT Alport, the initiator was guided by expert support from the IFS and a biometrician. The IFS brought together a team of experienced medical biometricians, study managers, regulatory affairs experts and medical writers who developed the complete trial outline together with the investigator. After a preliminary funding approval in September 2010 and before receiving any funds, the IFS developed the study protocol, and all regulatory documents were created and submitted to authorities and ethics committees. This full commitment and prefunding investment of both the clinical investigator and the IFS were crucial for the success of this project. No matter how easy the whole process might look for professionals, the complete application and regulatory process would have been far too complex for a clinician to do alone.
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Specific Requirements for Monitoring of IITs: Close Contact Among Study Management, Regulatory Affairs, the Ethic Committee, the Medical Society, and the Investigator’s University Study managers and monitors from the IFS trained the study personnel at the 15 pediatric trial sites in Germany. Pediatric studies are a particular challenge for study managers and monitors, requiring close communication with the trial sites. Not all of the participating pediatric nephrology trial sites were experienced in doing clinical studies. Common sense and instinct are needed to help the on-site study team integrate the trial processes into their everyday routine. It is important to involve staff and parents as much as possible and to create an atmosphere of trust. The children and families need to feel comfortable at their trial site because after all they must visit their trial site every 6 months for 3 years and need to stay in close contact between visits. Because cooperation between the IFS and the investigator is also extremely important during the recruitment phase, official channels to study management and authorities need to remain short. This can only be realized by personal commitment and the common goal to perform the trial successfully. The expertise and help by the university ethics committee (University Medical Center Göttingen IRB) improved the trial protocol, informed consent, and patient information documents, which were adapted to different age groups (Figure 2). The guidance, supervision, and skills of the IRB also helped the investigator through the jungle of legal contracts. To improve recruitment, the clinical trial and the trial protocol should be supported by the respective medical society. A written commitment of the clinicians at the trial sites stating the need for the trial to answer an important clinical problem also helps to complete the complicated regulatory process. Finally, the support of the investigator’s university as the official trial sponsor reflects long-term commitment and reduced financial risks, which is another essential puzzle piece for IITs. It does not matter how easy the process of setting up a clinical trial might seem to professionals or legal authorities. For a clinician, failure of any of the essential puzzle pieces (study management, regulatory affairs, ethic committee, medical society, and investigator’s university) will cause even the best IIT to fail before it has begun.
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Figure 2. From the patient information document of the Early Prospective Therapy Trial to Delay Renal Failure in Children With Alport Syndrome for patients age Z6 years. “Hi, my name is Nick. Nick Kidney. Me and my brother Nack are your kidneys: Nick and Nack Kidney. We are very important for your body. We clean your pee and wash the dirt out of your body. And we keep your blood clean. We are like washing machines. The dirty socks are cleaned and the dirty water ends up in the drain. Sometimes, people get sick because their kidneys do not work well. The kidney-washing machines can have holes. A dirty sock may escape into the drain together with the dirty water. Well, with kidneys, it is not socks that get lost. Rather things from the blood like red blood cells and proteins that should stay in the blood.”
Can the Study Design of an IIT Be Transmitted and Improve Other Trials? The EARLY PRO-TECT Alport trial is the world's first and only clinical prevention study of its kind in oligosymptomatic children with the chronic kidney disease type of AS. The study protocol was written at the IFS in English to encourage other countries, such as China, England, France, and the United States, to replicate the study using the same protocol. The trial outline and rationale have been published in an open access journal.21 The European Union legislation11 was not of any use convincing an industry sponsor to support this trial. England, France, the United States, and pharmaceutical companies (such as Genzyme/SanofiAventis) (personal communication with Christoph Licht, University of Toronto, Toronto, Canada; December 30, 2013) have shown interest in conducting a similar study with similar medications, which if done would increase the total number of patients studied and thus the validity of the findings. The study could pave the way for approval of ramipril as a drug to treat children with AS; however, the study is not part of an approved PIP. One should be aware of the difference between getting an IIT completed and published versus having the results be used to register a drug or a new indication. The results of the ongoing trial have the potential to alter ramipril labeling; however, until now,
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no manufacturer has shown interest in getting a PIP approval for the study (and none is required to obtain one). Again, the European Union legislation11 was not of any use convincing an industry sponsor to support this trial or to obtain a PIP. However, the tolerability data obtained from this trial together with the persuasive nephroprotective effect of ACEIs in proteinuric AS patients20 can assist pediatricians in the more tolerable use of ramipril in the future. Even if our study does not result in label changes, the EARLY PRO-TECT Alport trial is intended as part of an educational campaign to sensitize physicians, especially pediatricians, general practitioners, and nephrologists, about the need for the early detection of kidney diseases in children. If this campaign is successful, the trial might further improve medical care in all children with kidney diseases.
APPENDIX: ABOUT THE IFS The Institute for Applied Research and Clinical Studies (IFS) is a subsidiary of the University Medical Center Göttingen (UMG). The IFS is a comprehensive academic clinical research organization working both as Site Management Organization for the UMG and as a contract research organization. The IFS connects investigators, research-based pharmaceutical companies, and public funding bodies. It supports university-
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Clinical Therapeutics based and external partners in the planning, execution, and evaluation of clinical trials and ensures compliance with highest national and international quality standards. Special knowledge and experience currently exist in the areas of regulatory affairs, pediatrics, and the development of medical devices, including the development of standards. In 2012, the IFS provided service in 27 trials in Phase I to IV in the fields of pharmaceuticals and medical devices. Six new studies started in 2012, and 7 studies were completed successfully.
REFERENCES 1. Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Exp Opin Drug Saf. 2006;5:703–718. 2. Lindell-Osuagwu L, Korhonen MJ, Saano S, HelinTanninen M, Naaranlahti T, Kokki H. Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther. 2009;34:277–287. 3. Ceci A, Felisi M, Baiardi F, et al. Medicines for children licensed by the European Medicines Agency (EMEA): the balance after 10 years. Eur J Clin Pharmacol. 2006;62:947–952. 4. Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off-label drug use in paediatric wards: prospective study. BMJ. 1998;316:343–345. 5. Conroy S, McIntyre J, Choonara I. Unlicensed and offlabel drug use in neonates. Arch Dis Child Fetal Neonatal; Ed. 1999:F142–F145. 6. Conroy S, Choonara I, Impicciatore P, et al. European Network for Drug Investigation in Children. Survey of unlicensed and off-label drug use in paediatric wards in European countries. BMJ. 2000;320:79–82. 7. McDonnell F. Prescription survey of unlicensed and off label medicines in pediatrics at Our Lady’s Hospital for Sick Children. Irish Pharmacy J (Ireland). 2001;79:292, 294–296. 8. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr. 2005;164:552–558. 9. Seyberth HW, Brochhausen C, Kurz R. Probleme der pädiatrischen Pharmakotherapie und deren internationale Lösungsansätze. Monatsschrift Kinderheilkunde. 2002;150:218–225.
10. Khan-Boluki J, Hundt F. Children in clinical trials: survey on the current situation in paediatric university clinics in Germany. Ger Med Sci. 2008:6:Doc010. 11. Verordnung (EG) Nr. 1901/2006 des Europäischen Parlaments und des Rates vom 12. Dezember 2006 über Kinderarzneimittel und zur Änderung der Verordnung (EWG) Nr. 1768/92, der Richtlinien 2001/20/EG und 2001/83/EG sowie der Verordnung (EG) Nr. 726/2004. http://ec.europa.eu/ health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_ en.pdf. Accessed November 30, 2013. 12. Wachenhausen: AMG §40, in: Kügel/Müller/Hofmann, AMG, 1. Aufl. München 2012, Rn. 12. 13. Listl: MPG §20, Allgemeine Voraussetzungen zur klinischen Prüfung, in Spickhoff: Medizinrecht, 1. Aufl. München, 2011, Rn 16-18. 14. Kügel. In: Terbille: Münchener Anwaltshandbuch Medizinrecht, 1. Aufl., München 2009, Rn 158-165. 15. Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotypephenotype correlations in males. J Am Soc Nephrol. 2000;11:649–657. 16. Gross O, Beirowski B, Koepke M-L, et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int. 2003;63:438–446. 17. Gross O, Kashtan C. Treatment of Alport syndrome: beyond animal models. Kidney Int. 2009;76:599–603. 18. Wühl E, Trivelli A, Picca S, et al. ESCAPE Trial Group. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361:1639–1650. 19. Ingelfinger JR. Blood-pressure control and delay in progression of kidney disease in children. N Engl J Med. 2009;361:1701–1703. 20. Gross O, Licht C, Anders HJ, et al, Study Group Members of the Gesellschaft für Pädiatrische Nephrologie (GPN), Knebelmann B, Pirson Y, Grunfeld JP, et al. Early angiotensin converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012;81:494–501. 21. Gross O, Friede T, Hilgers R, Study Group Members of the Gesellschaft für Pädiatrische Nephrologie (GPN), Görlitz A, Gavenis K, Ahmed R, Duerr U. Safety and efficacy of the ACE-inhibitor ramipril in Alport syndrome: the double-blind, randomized, placebo-controlled, multicenter phase III EARLY PRO-TECT Alport trial in pediatric patients. ISRN Pediatr. 2012:436046.
Address correspondence to: Oliver Gross, MD, Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075 Göttingen, Germany. E-mail: [email protected]
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