Cultural, geographical and ethical questions when looking to enroll pediatric patients in rare disease clinical trials

References

• Wirtz VJ. Priority medicines for Europe and the World: setting a public-health-based medicines development agenda. J Pharma Pol Prac. 2015;8(Suppl 1):K4.
   Google Scholar
• EURORDIS: what is a rare disease? [Internet]. [cited 2017 Feb 1]. Available from: http://www.eurordis.org/content/what-rare-disease.
   Google Scholar
• Livingston EH. German Medical Group: apology for Nazi physicians’ actions, warning for future. JAMA J Am Med Assoc. 2012;308:657–658.
   Google Scholar
• Schweizer-Martinschek P. Medical experiments of the Nazis: “Nicht gerade körperlich besonders wertvolle Kinder.”. Dtsch Arztebl. 2008;105:A1445–A1446.
   Google Scholar
• Annas GJ, Grodin MA. The Nazi doctors and the Nuremberg Code: relevance for modern medical research. Med War. 1990;6:120–123.
   Google Scholar
• WHO: global burden of disease [Internet]. [cited 2017 Feb 1]. Available from: http://www.who.int/topics/global_burden_of_disease/en/.
   Google Scholar
• Collier R. Bye, bye blockbusters, hello niche busters. Can Med Assoc J. 2011;183:E697–E698.
   Google Scholar
• Palau F. Personalized medicine in rare diseases. Per Med. 2012;9:137–141.
   Google Scholar
• Globalgenes.org [Internet]. [cited 2017 Feb 15]. Available from: https://globalgenes.org/rare-diseases-facts-statistics/.
   Google Scholar
• Caldwell PHY, Murphy SB, Butow PN, et al. Review: clinical trials in children. Lancet. 2004;364:803–811.
   Google Scholar
• Steinbrook R. Testing medications in children. N Engl J Med. 2002;347:1462–1470.
   Google Scholar
• Haffner ME. History of orphan drug regulation – United States and beyond. Clin Pharmacol Ther. 2016;100:342–343.
   Google Scholar
• Mostaghim S, Kesselheim AS. Suitability of expanding the priority review voucher into rare disease drug development. Expert Opin Orphan Drugs. 2016;4:1001–1003.
   Google Scholar
• BioMarin reports sale of rare pediatric disease priority review voucher programme for USD67.5m [Internet]. Press release. Biomarin; 2014 [cited 2017 Feb 1]. Available from: http://investors.biomarin.com/2014-07-30-BioMarin-Sells-Priority-Review-Voucher-for-67-5-Million.
   Google Scholar
• Kesselheim AS, Maggs LR, Sarpatwari A. Experience with the priority review voucher program for drug development. JAMA. 2015;314:1687–1688.
   Google Scholar
• Westermark K, Holm BB, Söderholm M, et al. European regulation on orphan medicinal products: 10 years of experience and future perspectives. Nat Rev Drug Discov. 2011;10:341–349.
   Google Scholar
• Rodriguez-Monguio R, Spargo T, Seoane-Vazquez E. Ethical imperatives of timely access to orphan drugs: is possible to reconcile economic incentives and patients’ health needs? Orphanet J Rare Dis. 2017;12:1–8.
   Google Scholar
• European Medicines Agency – pediatric regulation [Internet]. 1995-2017 Eur. Med. Agency. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000068.jsp.
   Google Scholar
• Quintana-Murci L. Understanding rare and common diseases in the context of human evolution. Genome Biol. 2016;17:225.
   Google Scholar
• Ingram GI. The history of haemophilia. J Clin Pathol. 1976;29:469–479.
   Google Scholar
• Davies H. Ethical reflections on Edward Jenner’s experimental treatment. J Med Ethics. 2007;33:174–176.
   Google Scholar
• Shulman ST. The history of pediatric infectious diseases. Pediatr Res. 2004;55:163–176.
   Google Scholar
• Tan SY. Edward Jenner (1749-1823): conqueror of smallpox. Singapore Med J. 2004;45:507–508.
   Google Scholar
• Smolin DM. The Tuskegee Syphilis experiment, social change, and the future of bioethics. Faulkner Law Rev. 2012;3:229–251.
   Google Scholar
• Rothman DJ. Were Tuskegee & Willowbrook “Studies in Nature”? Hastings Cent Rep. 1982;12:5–7.
   Google Scholar
• Vollmer SH, Howard G. Statistical power, the Belmont report, and the ethics of clinical trials. Sci Eng Ethics. 2010;16:675–691.
   Google Scholar
• The Belmont report: ethical principles and guidelines for the protection of human subjects of research. [Internet]. 1978 [cited 2017 Feb 1]. p. 30. Available from: https://eric.ed.gov/?id=ED183582.
   Google Scholar
• Bavdekar SB, Sadawarte PA, Gogtay NJ, et al. Off-label drug use in a pediatric intensive care unit. Indian J Pediatr. 2009;76:1113–1118.
   Google Scholar
• Jain S, Saini SS, Chawla D, et al. Off-label use of drugs in neonatal intensive care units. INDIAN Pediatr. 2014;51:644–646.
   Google Scholar
• Kimland E, Odlind V. Off-label drug use in pediatric patients. Clin Pharmacol Ther. 2012;91:796–801.
   Google Scholar
• Convention on the Rights of the Child, 20 November 1989. [Internet]. 1989 [cited 2017 Feb 1]. p. 95. Available from: https://ihl-databases.icrc.org/ihl/INTRO/540?OpenDocument.
   Google Scholar
• Bavdekar SB. Off-label drug use in neonatal intensive care unit. Indian Pediatr. 2015;52:167.
   Google Scholar
• International Council for Harmonisation (ICH), International Conference on Harmonisation; guidance on E11 clinical investigation of medicinal products in the pediatric population; availability. Notice Fed Regist. 2000;65:78493–78494.
   Google Scholar
• Gill D, Kurz R. Practical and ethical issues in pediatric clinical trials. Appl Clin Trials. 2003;12:41.
   Google Scholar
• Amiel P, Moreau D, Vincent-Genod C, et al. Noninvitation of eligible individuals to participate in pediatric studies: a qualitative study. Arch Pediatr Adolesc Med. 2007;161:446–450.
   Google Scholar
• Sharma A, Jacob A, Tandon M, et al. Orphan drug: development trends and strategies. J Pharm Bioallied Sci. 2010;2:290–299.
   Google Scholar
• Prasad V, Rajkumar SV. Conflict of interest in academic oncology: moving beyond the blame game and forging a path forward. Blood Cancer J. 2016;6:e489–e489.
   Google Scholar
• Brewer GJ. Drug development for orphan diseases in the context of personalized medicine. Transl Res. 2009;154:314–322.
   Google Scholar
• Wendler D. Can we ensure that all research subjects give valid consent? Arch Intern Med. 2004;164:2201–2204.
   Google Scholar
• Palmer R, Gillespie G. Consent and capacity in children and young people. Arch Dis Childhood-Educ Pract Ed. 2014;99:2–7.
   Google Scholar
• Slomka J. Manufacturing mistrust: issues in the controversy regarding foster children in the pediatric HIV/AIDS clinical trials. Sci Eng Ethics. 2009;15:503–516.
   Google Scholar
• Hansson MG, Gattorno M, Forsberg JS, et al. Ethics bureaucracy: a significant hurdle for collaborative follow-up of drug effectiveness in rare childhood diseases. Arch Dis Child. 2012;97:561–563.
   Google Scholar
• Ozen S, Frenkel J, Ruperto N, et al. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr. 2011;170:445–452.
   Google Scholar
• Ruperto N. Networking in paediatrics: the example of the Paediatric Rheumatology International Trials Organisation (PRINTO). Arch Dis Child. 2011;96:596–601.
   Google Scholar
• MacLeod SM, Knoppert DC, Stanton-Jean M, et al. Pediatric clinical drug trials in low-income countries: key ethical issues. Paediatr Drugs. 2015;17:83–90.
   Google Scholar
• Kipnis K. Seven vulnerabilities in the pediatric research subject. Theor Med Bioeth. 2003;24:107–120.
   Google Scholar
• Bloom BE. Patients often go without effective new treatments, especially in rare disease patient populations where profit potential is limited. Contemp Clin Trials. 2011;32:151–152.
   Google Scholar
• Getz KA. A swift predominance of Ex-U.S. sites. Appl Clin Trials. 2005;14:21–22.
   Google Scholar
• Bloom BE. Editorial letter: editorial. Contemp Clin Trials. 2011;32:151–152.
   Google Scholar
• Van der Lee JH, Wesseling J, Tanck MW, et al. Sequential design with boundaries approach in pediatric intervention research reduces sample size. J Clin Epidemiol. 2010;63:19–27.
   Google Scholar
• Abrahamyan L, Feldman BM, Tomlinson G, et al. Alternative designs for clinical trials in rare diseases. Am J Med Genet Part C Semin Med Genet. 2016;172:313–331.
   Google Scholar
• Hilgers R-D, Roes K, Stallard N. Directions for new developments on statistical design and analysis of small population group trials. Orphanet J Rare Dis. 2016;11:1–10.
   Google Scholar
• Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med. 2009;360:816–823.
   Google Scholar
• Thiers FA, Berndt ER, Sinskey AJ. Trends in the globalization of clinical trials. Nat Rev Drug Discov. 2008;7:13–14.
   Google Scholar
• Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2:0696–0701.
   Google Scholar
• Taruscio D, Capozzoli F, Frank C. Rare diseases and orphan drugs. Ann DELL Ist Super DI SANITA. 2011;47:83–93.
   Google Scholar
• Directorate-General for Health and Food Safety, European Commission, CHAFEA – Consumers H and FEA. Reaching out to rare disease patients across Europe. Eur Union. 2011;1:1–40. doi:10.2772/58184.
   Google Scholar
• Pennisi E. A low number wins the GeneSweep pool. Science (80-.). 2003;300:1484.
   Google Scholar
• Collins FS, Lander ES, Rogers J, et al. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931–945.
   Google Scholar
• Ezkurdia I, Juan D, Rodriguez JM, et al. Multiple evidence strands suggest that there may be as few as 19 000 human protein-coding genes. Hum Mol Genet. 2014;23:5866–5878.
   Google Scholar
• Lek M, Karczewski KJ, E V M, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291.
   Google Scholar
• Moroz V, Morland B, Tiao G, et al. The paediatric hepatic international tumour trial (PHITT): clinical trial design in rare disease. Trials. 2015;16(Suppl 2):P224.
   Google Scholar
• University of Birmingham. Paediatric Hepatic International Tumour Trial (PHITT) [Internet]. University of Birmingham; 2017 [cited 2017 Feb 1]. Available from: https://clinicaltrials.gov/show/NCT03017326.
   Google Scholar
• Aronson DC, Czauderna P, Maibach R, et al. The treatment of hepatoblastoma: its evolution and the current status as per the SIOPEL trials. J Indian Assoc Pediatr Surg. 2014;19:201–207.
   Google Scholar
• Slora EJ, Harris DL, Bocian AB, et al. Pediatric clinical research networks: current status, common challenges, and potential solutions. Pediatrics. 2010;126:740–745.
   Google Scholar
• Czauderna P, Haeberle B, Hiyama E, et al. Clinical trial: the Children’s Hepatic tumors International Collaboration (CHIC): novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer. 2016;52:92–101.
   Google Scholar
• Czauderna P, Lopez-Terrada D, Hiyama E, et al. Hepatoblastoma state of the art: pathology, genetics, risk stratification, and chemotherapy. Curr Opin Pediatr. 2014;26:19–28.
   Google Scholar
• Rebora P, Antolini L, Valsecchi M, et al. Crude incidence in two-phase designs in the presence of competing risks data analysis, statistics and modelling. BMC Med Res Methodol. 2016;16:1–16.
   Google Scholar
• Bernasconi DP, Rebora P, Valsecchi MG, et al. Survival probabilities with time-dependent treatment indicator: quantities and non-parametric estimators. Stat Med. 2016;35:1032–1048.
   Google Scholar
• Myles A. On not reinventing the wheel. Nat Genet. 2012;44:233.
   Google Scholar
• Pavan S, Rommel K, Mateo Marquina ME, et al. Clinical practice guidelines for rare diseases: the Orphanet database. PLoS One. 2017;12:1–14.
   Google Scholar
• Krischer JP, Gopal-Srivastava R, Groft SC, et al. The Rare Diseases Clinical Research Network’s organization and approach to observational research and health outcomes research. J Gen Intern Med. 2014;29 Suppl 3:S739–S744.
   Google Scholar
• Le Cam Y. A hidden priority: the paradox of rarity (EURORDIS perspective). Expert Opinion Orphan Drugs. 2014;2:1123–1125.
   Google Scholar
• Rangaswami A, Rinaldi E, O’Neill A, et al. Development of a novel web-based consultation service for a paediatric rare tumor: the SIOPEL clinician online consultation service. Pediatr Blood Cancer. 2014;61:S129–S129.
   Google Scholar
• Evangelista T, Hedley V, Atalaia A, et al. The context for the thematic grouping of rare diseases to facilitate the establishment of European Reference Networks. Orphanet J Rare Dis. 2016;11:1–8.
   Google Scholar
• Johnson KJ, Mueller NL, Williams K, et al. Evaluation of participant recruitment methods to a rare disease online registry. Am J Med Genet A. 2014;164A:1686–1694.
   Google Scholar
• Amon KL, Campbell AJ, Hawke C, et al. Facebook as a recruitment tool for adolescent health research: a systematic review. Acad Pediatr. 2014;14:439–447.e4.
   Google Scholar
• Fenner Y, Garland SM, Moore EE, et al. Web-based recruiting for health research using a social networking site: an exploratory study. J Med Internet Res. 2012;14:e20.
   Google Scholar
• Reaves AC, Bianchi DW. The role of social networking sites in medical genetics research. Am J Med Genet A. 2013;161A:951–957.
   Google Scholar
• Bavdekar SB. Pediatric clinical trials. Perspect Clin Res. 2013;4:89–99.
   Google Scholar
• Körholz D, Schneider D, Von Kries R, et al. How to overcome scientific standstill for very rare diseases: clinical trials or clinical registries? Klin PäDiatrie. 2015;227:303–304.
   Google Scholar
• Pappo AS, Furman WL, Schultz KA, et al. Rare tumors in children: progress through collaboration. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33:3047–3054.
   Google Scholar
• Terry SF. The study is open: participants are now recruiting investigators. Sci Transl Med. 2017;4:371.
   Google Scholar
• Anderson M, McCleary KK. From passengers to co-pilots: patient roles expand. Sci Transl Med. 2015;7:291fs25–291fs25.
   Google Scholar
• Hoos A, Anderson J, Boutin M, et al. Partnering with patients in the development and lifecycle of medicines: a call for action. Ther Innov Regul Sci. 2015;49:929–939.
   Google Scholar
• Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev DRUG Discov. 2010;9:203–214.
   Google Scholar
• DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20–33.
   Google Scholar
• Javaid MK, Forestier-Zhang L, Watts L, et al. The RUDY study platform – a novel approach to patient driven research in rare musculoskeletal diseases. Orphanet J Rare Dis. 2016;11:150.
   Google Scholar