Pediatr Blood Cancer 2014;61:1513–1517
SPECIAL REPORT Regulatory and Logistical Issues Influencing Access to Antineoplastic and Supportive Care Medications for Children With Cancer in Developing Countries John T. Wiernikowski, PharmD,1,2* a,b Stuart MacLeod, MD, PhD,3,4 c,d and for The Working Group on Essential Medicines of the Pediatric Oncology in Developing Countries committee of SIOP Globally there are numerous impediments, both logistical, regulatory and more recently global drug shortages, hindering pediatric access to therapeutic drugs of all types. Efforts to reduce barriers are ongoing and are especially important in low and middle income countries and for children requiring treatment of conditions such as those encountered in pediatric oncology characterized by the risk of life threatening treatment failures. Progress has been made through the efforts of the World Health Organization and regulators in the US and Europe to encourage the development of therapeutic agents for use in pediatrics and measures
taken have fostered the availability of stronger pediatric data to guide therapeutic decisions. Nonetheless, pharmaceuticals remain a global commodity, subject to regulation by the World Trade Organization and this has often had detrimental effects in low and middle income countries. This article emphasizes the need for closer international collaboration to address the barriers currently impeding access to antineoplastic and supportive care medicines for children. Pediatr Blood Cancer 2014;61:1513–1517. # 2014 Wiley Periodicals, Inc.
Key words: cancer pharmacology; drug access; low/middle income countries; pediatrics
BACKGROUND Limited pediatric therapeutic access poses a particular problem in low and middle income counties (LMICs) and in treatment of conditions such as those encountered in pediatric oncology, characterized by serious adverse reactions and the risk of lifethreatening consequences of treatment failure. Cure rates for childhood cancers have improved significantly in the last quarter century; approaching approximately 80% today [1]. These advances have occurred for the most part in developed nations, restricting benefit to fewer than 20% of the world’s children. For children who live in LMICs, improvements in cancer therapy continue to lag behind those achieved in the most productive economies [2]. Timely, consistent and continuous access to high quality, affordable pharmaceuticals continues to be an important objective for governments and health-care providers pursuing optimal benefits for all citizens. Since pharmaceuticals are often curative, significantly prolong survival and improve quality of life or provide palliation in situations where cure is not possible; they cannot be treated in the same way as conventional commodities. Access to pharmaceuticals has been a fundamental human rights concern and the focus of international policy development since the WHO initiated its essential medicines program in 1977 [3]. Since its creation the program has over time, been embraced by governments, non-governmental organizations (NGO’s), policy experts and clinician researchers as presenting a workable framework for local/regional policy initiatives to improve drug access in LMICs. The WHO Essential Medicines program has been a positive and important step forward, and underscores the issue of equitable, economically supportable access to drugs globally. Unfortunately for the first 30 years following introduction it had a singular adult focus [4]. Efforts at highlighting deficiencies in the pediatric context were eclipsed by other health care priorities, such as the HIV epidemic of the 1980s and 1990s. Recently, a significant number of initiatives have been undertaken that will have global impact on drug access for children and will strengthen the evidence base for pediatric drug therapy [5]. Important early initiatives include the Best Pharmaceuticals for Children Act (BPCA) put forth by the United States Food and Drug C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25049 Published online 19 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
Administration (FDA) in 1997 and subsequently amended in 2003 as the Pediatric Research Equity Act (PREA) [6,7]. In the European Union (EU) similar regulations have developed under the direction of the European Medicines Agency (EMA) coming into full effect in 2007 [8]. The timeline for introduction of these policy initiatives is shown in Figure 1 [8]. Both policy initiatives require the pharmaceutical industry to partner with government to improve information on drug dosing, labeling, establishment of treatment guidelines and development of appropriate dosage forms/packaging of drugs for pediatric use. Drugs both on and off patent are included and the FDA has created a priority list to encourage research on the latter products. In the US and Europe, provision of pediatric data that results in a labeling change or provides additional safety 1
Pediatric Hematology/Oncology, McMaster Children’s Hospital, Hamilton, Ontario, Canada; 2Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; 3Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; 4 Child and Family Research Institute, Vancouver, British Columbia, Canada Grant sponsor: The Office of International Affairs, National Cancer Institute, Bethesda, MD, USA; Grant sponsor: Kids Care Cancer, Edmonton, Canada; Grant sponsor: Pediatric Oncology Group of Ontario, Toronto, Canada; Grant sponsor: Roche Pharmaceuticals, Lausanne, Switzeraland; Grant sponsor: St Baldrick’s Foundation, Monrovia, USA 2014 Working group members: Barr R, Casanova M, Denburg A, Frazier L, Grynszpancholc E, Kienesberger A, MacLeod S, McGoldrick D, Petrilli S, Rousseau R, Weerasuriya K, and Wiernikowski J. a
Clinical Pharmacist
b
Clinical Assistant Professor
c
Professor
d
Senior Clinician Scientist
Correspondence to: John T. Wiernikowski, Pediatric Hematology/ Oncology, 3F Clinic, McMaster Children’s Hospital, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5. E-mail: [email protected] Received 13 January 2014; Accepted 7 March 2014
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Fig. 1. Timeline for introduction of regulatory changes by the FDA (United States) and the EMA (European Union) impacting drugs for children.
information for a patented medication qualifies the manufacturer for six additional months of patent protection. For off patent drugs, provision of pediatric data is voluntary, however, the EMA offers 10 years of data protection as an incentive. Public funds are also made available to manufacturers to support additional pediatric studies of medications that address dosing or safety issues or explore innovative treatments for rare conditions. In the United States, the FDA through PREA may require that pediatric data be submitted prior to licensure of any new drug; while within the EU, manufacturers making new drug submissions must submit pediatric along with adult data, or file a Pediatric Investigation Plan (PIP) designating a timeline for submission of pediatric data. To date, more than 1,000 PIPs have been filed as a result of this legislation [9]. Manufacturers may apply for an exemption if the drug is not clinically useful in children. American and European initiatives hold considerable promise; in the first decade after the FDA legislation came into effect, 365 trials involving 153 different agents were performed resulting in 137 labeling changes and 26% of these provided significant new pediatric safety data [10]. Newer data from the current FDA amendments act (FDAAA) indicate that more than 111,000 children have participated in 305 studies between 2007 and 2010, resulting in more than 350 labeling changes involving 170 drugs [11]. In Europe more than 450 of 1,000 applications submitted for a Pediatric Investigation Plan (PIP) have received a positive response from the Pediatric committee of the EMA, with only 1/3 being requests for a waiver [12,13]. While these trends are encouraging, the concerns persist. In both the US and EU, the incentive of additional patent protection has leveraged resources to pediatric clinical trials, but this has primarily been for drugs that promise a sizeable adult market (e.g., antihypertensives). The proportion of pediatric trials as a percentage of all clinical trials in Europe has only increased to 9.4% from 8.2% in 2007. Furthermore, all studies were undertaken with agents eligible for patent extension [14,15]; to date, no off-patent medication has had additional pediatric data provided from its manufacturer. In 2007 the World Health Assembly passed resolution 60.20 Better Medicines for Children [16] committing WHO and its Pediatr Blood Cancer DOI 10.1002/pbc
member states to promote and fund pediatric clinical pharmacology training and research, improved drug regulation, access and rational use and foster the development of child friendly formulations. Immediately after passage of the resolution the first WHO essential medicines list for children was developed and has now undergone two revisions [17]. The EMLc has also served as the basis for a Model Formulary for Children [18] and WHO has partnered with international researchers to pursue optimal drug use in children including the development of methods to improve estimation of body weight when no weighing scale is available [19]. Formulation efforts aimed at flexible solid oral dosage forms have also been promoted [20]. It is anticipated that these initiatives will bear fruit in the form of improved care and outcomes for children in LMICs. While none of these efforts are entirely specific to pediatric cancer treatment it is reasonable to expect that progress in antineoplastic and supportive palliative therapy will inevitably follow on the comprehensive improvements that have been encouraged by WHO and partner organizations such as UNICEF, Save the Children Fund, the Clinton Foundation and the Wellcome Trust acting in concert with government regulators in the European Union and the US. Since the introduction of the EU legislation, of 29 antineoplastic agents licensed before 2009, only 6 have received pediatric authorization and labeling [21]. However, multi-national pharmaceutical companies that generate pediatric data because of American or European regulations have often failed to submit such data in other jurisdictions to provide parallel prescribing improvements. This is of concern when one considers that 65% of published studies undertaken according to US regulators between 1998 and 2007 were conducted in at least one country external to the US and 11% were conducted exclusively in non-American sites [22,23].
ACCESS TO PHARMACEUTICALS FOR CHILDREN WITH CANCER Due to the rarity of childhood cancer, the establishment of clinical trial groups/networks to answer therapy questions remains a
Access to Drugs for Children in LMICs necessity. Such groups have existed for over 30 years, varying in size from a few centers to over 200. Within these groups, consortia exist with a specific focus on pediatric cancer drug development such as the Novel Approaches to Neuroblastoma Therapy (NANT) in the US and the Innovative Therapies for Children with Cancer (ITTC) consortium in Europe [24,25]. However, for children without malignancy, disease focused clinical trial groups are not the norm. In recognition of the demands put on the pharmaceutical industry by policy changes in the 1990s, the US National Institutes of Health created the Pediatric Pharmacology Research Unit (PPRU) network as a branch of its Institute of Child Health and Human Development and subsequently reworked this into the Pediatric Trials Network (PTN) [26]. The PTN has funding committed over 7 years to study off-patent medications on the FDA priority list established as part of the BPCA. Similarly, the European Network of Paediatric Research at the EMA (enpr-EMA) was established in March of 2011 with a mandate to foster high quality ethical research on drugs to treat children through stakeholder networking [27]. Unlike it’s American counterpart, the EMA provides no funding to enpr-EMA so these networks/ consortia must rely on national grants and funding from public and private donations. In Canada the Maternal, Infant, Child and Youth research network (MICYRN), comprised of 17 academic child/ maternal health centers, has identified over 120 research networks and 450 pediatric clinical trials enrolling children from Canadian and international centers [28]. The rarity of pediatric malignancy relative to the adult context makes the economics of drug development specifically for children a daunting task. However, the increasing recognition of children as an unique and underserved patient population by health care advocates, academia, regulators and society as a whole is bringing this issue into focus, and resulting in innovative ideas such as financial incentives to generic drug manufacturers to begin to address these challenges [29–31]. While these initiatives represent a beginning attempt to solve such issues the legislative changes in the United States and European Union have stimulated the development of a positive environment within which industry in partnership with governments and academia have begun to address decades of neglect in pediatric pharmacotherapy.
BARRIERS TO EQUITABLE DRUG ACCESS FOR CHILDREN IN LMICs Regulatory agencies in developed countries review licensing submissions with respect to efficacy, safety, quality and costeffectiveness versus existing agents before granting the manufacturer a notice of compliance (NOC) with regulations and a licence to manufacture and sell the drug within said jurisdiction. Developing countries may lack adequate resources to support adjudication of such submissions. These countries rely, in part, on international agencies such as WHO for guidance and support of programs that can assist with drug evaluations. A fundamental guiding document is the WHO list of essential medicines (adult, pediatric) which Health ministries in developing countries can access and tailor to the needs of their population. This may best be done in conjunction with standardized treatment guidelines that now exist for many medical conditions. A proposed framework is shown in Figure 2 [32]. Drug quality in developing countries is of increasing concern; reports of patients receiving substandard (less than specified amount of active ingredient) or counterfeit drugs (zero active Pediatr Blood Cancer DOI 10.1002/pbc
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Fig. 2. Framework for integrating Essential Medicines and Treatment Guidelines in establishing national priorities in LMICs.
ingredient) are appearing more often [33,34]. Due to the high cost of imported brand name drugs, a number of governments have begun to promote the development of generic drug manufacturing capacity within their own borders; this has been successfully accomplished in Israel and India and is being additionally developed in Brazil. For many other nations, importing drugs remains the only option and has resulted in the importing of poorly manufactured versions, unsafe or non-efficacious products. The most common reason for this is that drugs manufactured for export do not undergo quality control within the manufacturing country, and the importing country often lacks the infrastructure to assess the quality of imported pharmaceuticals [35,36]. To address the issue of access to high quality pharmaceuticals, in 2004 the WHO developed a Prequalification Program for pharmaceutical manufacturers. The program encompasses all aspects of good manufacturing practice, quality assurance, provides for inspections and employs quality control laboratories. Drugs passing quality control appear on the WHO prequalification website for reference by those purchasing on behalf of LMICs [37]. There are additional, but no less important factors impacting drug availability and access in developing countries that are particularly related to infrastructure. The lack of local production, forces many LMICs to import some if not all required pharmaceuticals. Once imported, distribution of drugs to hospitals, clinics or pharmacies may be difficult. Roads may be in poor states of repair, or non-existent during some periods of the year. Some drugs require storage under controlled temperature/humidity conditions or refrigeration which may be problematic during transport or at the destination if consistent electrical supply or refrigeration is lacking. With respect to narcotic analgesics, many governments in LMICs are adopting overly restrictive national drug control policies due to their high resale value and concern about addiction [38,39]. This is particularly tragic, resulting in pain being the most undertreated symptom in patients in the developing world; and for a child or adult with cancer and low prospects for cure, appropriate palliation is often unavailable [40,41]. While most drugs lack child friendly formulations, the problem is especially acute for anti-neoplastics. Injectable drugs are almost universally available in sizes suited to adults; a problem not unique
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to developing countries. Given the cost of these agents, and potential lack of proper storage facilities (i.e., refrigeration) there is often enormous waste if a second or third child cannot benefit from a dose of injectable drug that has been reconstituted. When liquid formulations are not available the use of oral anti-neoplastics may prove challenging because of the need for splitting tablets or opening capsules, often without proper protective equipment. The dominant barrier impeding equitable access to antineoplastic and supportive care medicines continues to be cost. Healthcare, where publicly funded, takes a growing proportion of available resources every year. Pharmaceutical expenditures continue to show growth, fueled by innovative products, particularly new biologicals and personalized therapies. LMICs are affected by the World Trade Organization (WTO) Trade Related Intellectual Property Rights (TRIPS) agreement ratified in 1994, and clarified in 2001 through the Doha Accord [42]. The agreement strengthened intellectual property law, procedures and remedies. For governments in LMICs, especially those with thriving generic drug industry such as India, a significant curtailing of activity resulted. The TRIPS agreement generated significant debate concerning its impact on cost and access to drugs within LMICs. Various mitigating solutions have been suggested to offset the perceived or real negative impact of the TRIPS agreement. These include intensified loans/grants from organizations such as the World Bank to LMICs to purchase essential drugs that are still covered by patents. Alternatively, debt cancellation of poor nations to free up capital to purchase essential medicines has also been debated, as has the purchasing of patents by a Bank or NGO with the aim of assigning licensing of patented drugs to generic firms in developing countries. A final proposal warranting consideration is establishment of a global equity-based pricing system for high, middle, and low income countries [43–45]. In 2011, the United Nations issued a declaration regarding the need to address non-communicable diseases (NCDs) as the world’s next greatest health priority. This declaration has also increased activity in LMIC’s in co-operation with developed countries and the pharmaceutical industry and the WHO to begin to address health system issues and access to Essential medications for NCDs in LMICs [46,47]. The newer global challenge with medications is the increasing occurrence of drug “shortages.” The reasons for these are multi-factorial and range from shortage of raw indgredient(s), to manufacturing shut-downs as a result of issues related to good manufacturing process (GMP) identified by inspectors, to out-dated/inadequate production capacity to meet demand. Unfortunately, these events cannot be regulated out of existence. Recently, the FDA in the United States has within it’s statutory mandate, required all drug manufacturers to notify the FDA of impending drug shortages as soon as they are identified and give 6 months notice of the discontinuation of any product, to allow alternative sources of drug to be identified if needed [48,49].
CONCLUSIONS Initiatives undertaken in the past 15 years have brought more focus to the plight of children and medicines globally than occurred in the previous 50 years. Supporting initiatives taken by American and European governments and by WHO are key advances in providing LMICs governments with useful tools for establishing pediatric pharmacotherapy priorities. The WHO pre-qualification Pediatr Blood Cancer DOI 10.1002/pbc
program additionally aims to address issues of pharmaceutical quality so that governments in LMICs can purchase/import pharmaceuticals from reliable manufacturers. In the future, through policies now legislated in the US and EU, we can anticipate that medicines will come to market supported by evidence-informed pediatric indications. The formidable cost of new drug research and development is the next hurdle to overcome if equitable drug access is to be provided at a reasonable cost for children living in LMICs. An essential element in this achievement will be the further development of clinical and population health research capacity in the countries of greatest need. Continuing changes to global trade regulations mediated by the WTO may be a starting point to address some of the challenges identified but significant paradigm shifts in our thinking about global pediatric therapeutics must still occur. The formation of SIOP working group on essential medicines for pediatric oncology and the evolving role of SIOP as a catalyst for change in childhood cancer control globally [50] represent additional and important efforts on behalf of such issues.
ACKNOWLEDGMENTS The activities of the Working Group on Essential Medicines have been supported with funds from The Office of International Affairs, National Cancer Institute, Bethesda MD, USA; Kids Care Cancer, Edmonton, Canada; Pediatric Oncology Group of Ontario, Toronto, Canada; Roche Pharmaceuticals, Lausanne, Switzeraland; and St Baldrick’s Foundation, Monrovia, USA.
REFERENCES 1. American Childhood Cancer Organization. http://www.acco.org/. 2. Kruger M, Hendricks M, Davidson A, et al. Childhood cancer in Africa. Pediatr Blood Cancer 2014;61:587–592. 3. Laing R, Waning B, Gary A, et al. 25 years of the WHO Essential Medicines lists: Progress and challenges. Lancet 2003;361:1723–1729. 4. Brain T. WHO to launch first essential medicines list for children. Bull World Health Organ 2007;85:249– 250. 5. Hoppu K. Pediatric clinical pharmacology: At the beginning of a new era. Eur J Clin Pharmacol 2008;64:201–205. 6. Ward RM, Kauffman R. Future of pediatric therapeutics: Reauthorization of BPCA and PREA. Clin Pharmacol Ther 2007;81:477–479. 7. US FDA. Pediatric Research Equity Act. 2003. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM077853.pdf 8. European Commission. Regulation (EC) no1901/2006 of the European parliament and of the Council on medicinal products for paediatric use and amending Regulation (EEC) no 1768/92, Directive 2001/20/ EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (2006). 2006. http://ec.europa.eu/health/ files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf 9. Hoppu K, Anabwani G, Garcia-Bournissen F, et al. The status of pediatric medicines initiatives around the world—What has happened and what has not? Eur J Clin Pharmacol 2012;68:1–10. 10. Benjamin DK, Jr., Smith PB, Sun MJ, et al. Safety and transparency of pediatric drug trials. Arch Pediatr Adolesc Med 2009;163:1080–1086. DOI: 10.1001/archpediatrics.2009.229 11. US FDA Office of Pediatric Therapeutics. Breakdown of FDAAA completed pediatric studies. 2011. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm190622.htm 12. European Medicines Agency. Report to the European Commission. 2010. http://ec.europa.eu/health/files/ paediatrics/article_50_report2010.pdf 13. European Medicines Agency. European Medicines Agency receives 1000th application for a Paediatric Investigation Plan or Waiver. 2010. http://www.ema.europa.eu/ema/index.jsp?curl¼pages/news_and_ events/news/2010/10/news_detail_001128.jsp&murl¼menus/news_and_events/news_and_events.jsp& mid¼WC0b01ac058004d5c1 14. Baker-Smith CM, Benjamin DK, Jr., Grabowski HG, et al. The economic returns of pediatric clinical trials of anti-hypertensive drugs. Am Heart J 2008;156:682–688. DOI: 10.1016/j.ahj.2008.05.001 15. Olski TM, Lampus SF, Gherarducci G, et al. Three years of paediatric regulation in the European Union. Eur J Clin Pharmacol 2011;67:245–252. 16. WHO. 60th World Health Assembly Resolution. WHA 60.20: 649 Better medicines for children. 23 May 2007. 17. World Health Organization. The selection and use of essential medicines. Report of the WHO Expert committee, 2009 (including the 16th WHO model list of essential medicines and the 2nd WHO model list of essential medicines for children), Technical report series, vol. 958. 2009. 18. WHO, Geneva. WHO model formulary for children. 2010. http://www.who.int/selection_medicines/list/ WMFc_2010.pdf 19. WHO. WHO report of the informal expert meeting on better medicines for children (Geneva, October 2010). 2008. http://www.who.int/childmedicines/progress/Dosage_form_reportDEC2008.pdf 20. World Health Organization. Report of the informal expert meeting on dosage forms of medicines for children. Geneva, Switzerland. December 15–16, 2008 (online). http://www.who.int/childmedicines/ progress/Dosage_form_reportDEC2008.pdf
Access to Drugs for Children in LMICs 21. Vassal G. Will children with cancer benefit from the new European Paediatric Medicines Regulation. Eur J Cancer 2009;45:1535–1546. 22. Pasquali SK, Burstein DS, Benjamin DK, Jr., et al. Globalization of pediatric research: Analysis of clinical trials completed for pediatric exclusivity. Pediatrics 2010;126:e687–e692. 23. Peterson B, Hebert PC, MacDonald N. Industry’s neglect of prescribing information for Children [Editorial]. CMAJ 2011;183:994. 24. New approaches to neuroblastoma therapy. http://www.nant.org 25. Innovative Therapies for Children with Cancer (ITTC). http://www.itcc-consortium.org 26. National Institutes of Health. Pediatric trials network. 2010. http://bpca.nichd.nih.gov/clinical/network/ index.cfm 27. European Medicines Agency. enpr-EMA membership. 2011. http://www.ema.europa.eu/ema/index.jsp? curl¼pages/partners_and_networks/q_and_a/q_and_a?detail_000108. jsp&mid¼WC0b01ac05801df74a 28. Maternal, Infant, Child and Youth Research Network (MICYRN). Home page. 2011. www.micyrn.ca 29. Milne CP, Bruss JB. The economics of pediatric formulation development for off-patent drug. Clin Ther 2008;30:2133–2145. 30. Alrasheedi AA, Hassali MA, Aljadhey H, et al. Is there a need for a formulary of clinically interchangeable medicines to guide generic substitution in Saudi Arabia? J Young Pharm 2013;5: 73–75. 31. Rocchi F, Tomasi P. The development of medicines for children. Part of a series on pediatric pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni. Pharmacol Res 2011;64:169–175. 32. Hoppu K, Hogerzeil HV. Global aspects of drug development. In: Seyberth HW, et al. editors. Pediatric clinical pharmacology. Berlin, Heidelberg: Springer-Verlag; 2011. 33. Caudron JM, Ford N, Henkens M, et al. Substandard medicines in resource-poor settings: A problem that can no longer be ignored. Trop Med Int Health 2008;13:162–172. 34. Gautem CS, Utreja A, Singal GL. Spurious and counterfeit drugs: A growing industry in the developing world. Postgrad Med J 2009;85:251–256. 35. Sengaloundeth S, Green MD, Fernandez FM, et al. A stratified random survey of the proportion of poor quality oral artesunate sold at medicine outlets in the Lao PDR. Implications for therapeutic failure and drug resistance. Malar J 2009;8:172.
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36. Obaid A. Quality of ceftriaxone in Pakistan: Reality and resonance. Pak J Pharm Sci 2009;22:22–229. 37. WHO Prequalification Program. http://apps.who.int/prequal/default.htm 38. International Narcotics Control Board. Report of the International Narcotics Control Board on the availability of Internationally controlled drugs: Ensuring adequate access for medical and scientific purposes. New York, United Nations; 2011. 39. WHO. Access to Controlled Medications Programme. Quality assurance and safety: Medicines, Department of Medicines Policy and Standards, WHO Briefing Note, March 2007. Geneva, Switzerland: WHO. 40. Madadi P, Enato EFO, Fulga S, et al. Patterns of paediatric analgesic use in Africa: A systematic review. Arch Dis Child 2012;97:1086–1091. 41. Molyneux E. Needless pain in African children: An affront to human dignity. Arch Dis Child 2012;97:1078–1079. 42. Smith RD, Correa C, Oh C. Trade, TRIPS and pharmaceuticals. Lancet 2009;373:684–691. 43. Ashcroft RE. Access to essential medicines: A Hobbesian social contract approach. Dev World Bioeth 2005;5:121–141. 44. Cohen-Kohler JC. The morally uncomfortable global drug gap. Ethics 2007;82:610. 45. Cohen-Kohler JC, Forman L, Lipkus N. Addressing legal and political barriers to global pharmaceutical access: Options for remedying the impact of the agreement on trade-related aspects of intellectual property rights (TRIPS) and the imposition of TRIPS-plus standards. Health Econ Policy Law 2008;3:229–256. 46. Hogerzeil HV, Liberman J, Wirtz VJ, et al. Promotion of access to essential medicines for non-communicable diseases: Practical implications of the UN political declaration. Lancet 2013; 381:680–689. 47. Atun R, Jaffar S, Nishtar S, et al. Improving responsiveness of health systems to non-communicable diseases. Lancet 2013;381:690–697. 48. Fox ER, Tyler LS. Call to action: Finding solutions to the drug shortage crisis in the United States. Clin Pharm Ther 2013;93, 145–147. 49. Born K. Time and money: An analysis of the legislative efforts to address the prescription drug shortage crisis in America. J Legal Med 2012;33:235–251. 50. Calaminus G, Birch JR, Hollis R, et al. The role of SIOP as a platform for communication in the global response to childhood cancer. Pediatr Blood Cancer 2013;60:2080–2086.
SPECIAL REPORT Regulatory and Logistical Issues Influencing Access to Antineoplastic and Supportive Care Medications for Children With Cancer in Developing Countries John T. Wiernikowski, PharmD,1,2* a,b Stuart MacLeod, MD, PhD,3,4 c,d and for The Working Group on Essential Medicines of the Pediatric Oncology in Developing Countries committee of SIOP Globally there are numerous impediments, both logistical, regulatory and more recently global drug shortages, hindering pediatric access to therapeutic drugs of all types. Efforts to reduce barriers are ongoing and are especially important in low and middle income countries and for children requiring treatment of conditions such as those encountered in pediatric oncology characterized by the risk of life threatening treatment failures. Progress has been made through the efforts of the World Health Organization and regulators in the US and Europe to encourage the development of therapeutic agents for use in pediatrics and measures
taken have fostered the availability of stronger pediatric data to guide therapeutic decisions. Nonetheless, pharmaceuticals remain a global commodity, subject to regulation by the World Trade Organization and this has often had detrimental effects in low and middle income countries. This article emphasizes the need for closer international collaboration to address the barriers currently impeding access to antineoplastic and supportive care medicines for children. Pediatr Blood Cancer 2014;61:1513–1517. # 2014 Wiley Periodicals, Inc.
Key words: cancer pharmacology; drug access; low/middle income countries; pediatrics
BACKGROUND Limited pediatric therapeutic access poses a particular problem in low and middle income counties (LMICs) and in treatment of conditions such as those encountered in pediatric oncology, characterized by serious adverse reactions and the risk of lifethreatening consequences of treatment failure. Cure rates for childhood cancers have improved significantly in the last quarter century; approaching approximately 80% today [1]. These advances have occurred for the most part in developed nations, restricting benefit to fewer than 20% of the world’s children. For children who live in LMICs, improvements in cancer therapy continue to lag behind those achieved in the most productive economies [2]. Timely, consistent and continuous access to high quality, affordable pharmaceuticals continues to be an important objective for governments and health-care providers pursuing optimal benefits for all citizens. Since pharmaceuticals are often curative, significantly prolong survival and improve quality of life or provide palliation in situations where cure is not possible; they cannot be treated in the same way as conventional commodities. Access to pharmaceuticals has been a fundamental human rights concern and the focus of international policy development since the WHO initiated its essential medicines program in 1977 [3]. Since its creation the program has over time, been embraced by governments, non-governmental organizations (NGO’s), policy experts and clinician researchers as presenting a workable framework for local/regional policy initiatives to improve drug access in LMICs. The WHO Essential Medicines program has been a positive and important step forward, and underscores the issue of equitable, economically supportable access to drugs globally. Unfortunately for the first 30 years following introduction it had a singular adult focus [4]. Efforts at highlighting deficiencies in the pediatric context were eclipsed by other health care priorities, such as the HIV epidemic of the 1980s and 1990s. Recently, a significant number of initiatives have been undertaken that will have global impact on drug access for children and will strengthen the evidence base for pediatric drug therapy [5]. Important early initiatives include the Best Pharmaceuticals for Children Act (BPCA) put forth by the United States Food and Drug C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25049 Published online 19 April 2014 in Wiley Online Library (wileyonlinelibrary.com).
Administration (FDA) in 1997 and subsequently amended in 2003 as the Pediatric Research Equity Act (PREA) [6,7]. In the European Union (EU) similar regulations have developed under the direction of the European Medicines Agency (EMA) coming into full effect in 2007 [8]. The timeline for introduction of these policy initiatives is shown in Figure 1 [8]. Both policy initiatives require the pharmaceutical industry to partner with government to improve information on drug dosing, labeling, establishment of treatment guidelines and development of appropriate dosage forms/packaging of drugs for pediatric use. Drugs both on and off patent are included and the FDA has created a priority list to encourage research on the latter products. In the US and Europe, provision of pediatric data that results in a labeling change or provides additional safety 1
Pediatric Hematology/Oncology, McMaster Children’s Hospital, Hamilton, Ontario, Canada; 2Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; 3Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; 4 Child and Family Research Institute, Vancouver, British Columbia, Canada Grant sponsor: The Office of International Affairs, National Cancer Institute, Bethesda, MD, USA; Grant sponsor: Kids Care Cancer, Edmonton, Canada; Grant sponsor: Pediatric Oncology Group of Ontario, Toronto, Canada; Grant sponsor: Roche Pharmaceuticals, Lausanne, Switzeraland; Grant sponsor: St Baldrick’s Foundation, Monrovia, USA 2014 Working group members: Barr R, Casanova M, Denburg A, Frazier L, Grynszpancholc E, Kienesberger A, MacLeod S, McGoldrick D, Petrilli S, Rousseau R, Weerasuriya K, and Wiernikowski J. a
Clinical Pharmacist
b
Clinical Assistant Professor
c
Professor
d
Senior Clinician Scientist
Correspondence to: John T. Wiernikowski, Pediatric Hematology/ Oncology, 3F Clinic, McMaster Children’s Hospital, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5. E-mail: [email protected] Received 13 January 2014; Accepted 7 March 2014
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Fig. 1. Timeline for introduction of regulatory changes by the FDA (United States) and the EMA (European Union) impacting drugs for children.
information for a patented medication qualifies the manufacturer for six additional months of patent protection. For off patent drugs, provision of pediatric data is voluntary, however, the EMA offers 10 years of data protection as an incentive. Public funds are also made available to manufacturers to support additional pediatric studies of medications that address dosing or safety issues or explore innovative treatments for rare conditions. In the United States, the FDA through PREA may require that pediatric data be submitted prior to licensure of any new drug; while within the EU, manufacturers making new drug submissions must submit pediatric along with adult data, or file a Pediatric Investigation Plan (PIP) designating a timeline for submission of pediatric data. To date, more than 1,000 PIPs have been filed as a result of this legislation [9]. Manufacturers may apply for an exemption if the drug is not clinically useful in children. American and European initiatives hold considerable promise; in the first decade after the FDA legislation came into effect, 365 trials involving 153 different agents were performed resulting in 137 labeling changes and 26% of these provided significant new pediatric safety data [10]. Newer data from the current FDA amendments act (FDAAA) indicate that more than 111,000 children have participated in 305 studies between 2007 and 2010, resulting in more than 350 labeling changes involving 170 drugs [11]. In Europe more than 450 of 1,000 applications submitted for a Pediatric Investigation Plan (PIP) have received a positive response from the Pediatric committee of the EMA, with only 1/3 being requests for a waiver [12,13]. While these trends are encouraging, the concerns persist. In both the US and EU, the incentive of additional patent protection has leveraged resources to pediatric clinical trials, but this has primarily been for drugs that promise a sizeable adult market (e.g., antihypertensives). The proportion of pediatric trials as a percentage of all clinical trials in Europe has only increased to 9.4% from 8.2% in 2007. Furthermore, all studies were undertaken with agents eligible for patent extension [14,15]; to date, no off-patent medication has had additional pediatric data provided from its manufacturer. In 2007 the World Health Assembly passed resolution 60.20 Better Medicines for Children [16] committing WHO and its Pediatr Blood Cancer DOI 10.1002/pbc
member states to promote and fund pediatric clinical pharmacology training and research, improved drug regulation, access and rational use and foster the development of child friendly formulations. Immediately after passage of the resolution the first WHO essential medicines list for children was developed and has now undergone two revisions [17]. The EMLc has also served as the basis for a Model Formulary for Children [18] and WHO has partnered with international researchers to pursue optimal drug use in children including the development of methods to improve estimation of body weight when no weighing scale is available [19]. Formulation efforts aimed at flexible solid oral dosage forms have also been promoted [20]. It is anticipated that these initiatives will bear fruit in the form of improved care and outcomes for children in LMICs. While none of these efforts are entirely specific to pediatric cancer treatment it is reasonable to expect that progress in antineoplastic and supportive palliative therapy will inevitably follow on the comprehensive improvements that have been encouraged by WHO and partner organizations such as UNICEF, Save the Children Fund, the Clinton Foundation and the Wellcome Trust acting in concert with government regulators in the European Union and the US. Since the introduction of the EU legislation, of 29 antineoplastic agents licensed before 2009, only 6 have received pediatric authorization and labeling [21]. However, multi-national pharmaceutical companies that generate pediatric data because of American or European regulations have often failed to submit such data in other jurisdictions to provide parallel prescribing improvements. This is of concern when one considers that 65% of published studies undertaken according to US regulators between 1998 and 2007 were conducted in at least one country external to the US and 11% were conducted exclusively in non-American sites [22,23].
ACCESS TO PHARMACEUTICALS FOR CHILDREN WITH CANCER Due to the rarity of childhood cancer, the establishment of clinical trial groups/networks to answer therapy questions remains a
Access to Drugs for Children in LMICs necessity. Such groups have existed for over 30 years, varying in size from a few centers to over 200. Within these groups, consortia exist with a specific focus on pediatric cancer drug development such as the Novel Approaches to Neuroblastoma Therapy (NANT) in the US and the Innovative Therapies for Children with Cancer (ITTC) consortium in Europe [24,25]. However, for children without malignancy, disease focused clinical trial groups are not the norm. In recognition of the demands put on the pharmaceutical industry by policy changes in the 1990s, the US National Institutes of Health created the Pediatric Pharmacology Research Unit (PPRU) network as a branch of its Institute of Child Health and Human Development and subsequently reworked this into the Pediatric Trials Network (PTN) [26]. The PTN has funding committed over 7 years to study off-patent medications on the FDA priority list established as part of the BPCA. Similarly, the European Network of Paediatric Research at the EMA (enpr-EMA) was established in March of 2011 with a mandate to foster high quality ethical research on drugs to treat children through stakeholder networking [27]. Unlike it’s American counterpart, the EMA provides no funding to enpr-EMA so these networks/ consortia must rely on national grants and funding from public and private donations. In Canada the Maternal, Infant, Child and Youth research network (MICYRN), comprised of 17 academic child/ maternal health centers, has identified over 120 research networks and 450 pediatric clinical trials enrolling children from Canadian and international centers [28]. The rarity of pediatric malignancy relative to the adult context makes the economics of drug development specifically for children a daunting task. However, the increasing recognition of children as an unique and underserved patient population by health care advocates, academia, regulators and society as a whole is bringing this issue into focus, and resulting in innovative ideas such as financial incentives to generic drug manufacturers to begin to address these challenges [29–31]. While these initiatives represent a beginning attempt to solve such issues the legislative changes in the United States and European Union have stimulated the development of a positive environment within which industry in partnership with governments and academia have begun to address decades of neglect in pediatric pharmacotherapy.
BARRIERS TO EQUITABLE DRUG ACCESS FOR CHILDREN IN LMICs Regulatory agencies in developed countries review licensing submissions with respect to efficacy, safety, quality and costeffectiveness versus existing agents before granting the manufacturer a notice of compliance (NOC) with regulations and a licence to manufacture and sell the drug within said jurisdiction. Developing countries may lack adequate resources to support adjudication of such submissions. These countries rely, in part, on international agencies such as WHO for guidance and support of programs that can assist with drug evaluations. A fundamental guiding document is the WHO list of essential medicines (adult, pediatric) which Health ministries in developing countries can access and tailor to the needs of their population. This may best be done in conjunction with standardized treatment guidelines that now exist for many medical conditions. A proposed framework is shown in Figure 2 [32]. Drug quality in developing countries is of increasing concern; reports of patients receiving substandard (less than specified amount of active ingredient) or counterfeit drugs (zero active Pediatr Blood Cancer DOI 10.1002/pbc
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Fig. 2. Framework for integrating Essential Medicines and Treatment Guidelines in establishing national priorities in LMICs.
ingredient) are appearing more often [33,34]. Due to the high cost of imported brand name drugs, a number of governments have begun to promote the development of generic drug manufacturing capacity within their own borders; this has been successfully accomplished in Israel and India and is being additionally developed in Brazil. For many other nations, importing drugs remains the only option and has resulted in the importing of poorly manufactured versions, unsafe or non-efficacious products. The most common reason for this is that drugs manufactured for export do not undergo quality control within the manufacturing country, and the importing country often lacks the infrastructure to assess the quality of imported pharmaceuticals [35,36]. To address the issue of access to high quality pharmaceuticals, in 2004 the WHO developed a Prequalification Program for pharmaceutical manufacturers. The program encompasses all aspects of good manufacturing practice, quality assurance, provides for inspections and employs quality control laboratories. Drugs passing quality control appear on the WHO prequalification website for reference by those purchasing on behalf of LMICs [37]. There are additional, but no less important factors impacting drug availability and access in developing countries that are particularly related to infrastructure. The lack of local production, forces many LMICs to import some if not all required pharmaceuticals. Once imported, distribution of drugs to hospitals, clinics or pharmacies may be difficult. Roads may be in poor states of repair, or non-existent during some periods of the year. Some drugs require storage under controlled temperature/humidity conditions or refrigeration which may be problematic during transport or at the destination if consistent electrical supply or refrigeration is lacking. With respect to narcotic analgesics, many governments in LMICs are adopting overly restrictive national drug control policies due to their high resale value and concern about addiction [38,39]. This is particularly tragic, resulting in pain being the most undertreated symptom in patients in the developing world; and for a child or adult with cancer and low prospects for cure, appropriate palliation is often unavailable [40,41]. While most drugs lack child friendly formulations, the problem is especially acute for anti-neoplastics. Injectable drugs are almost universally available in sizes suited to adults; a problem not unique
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to developing countries. Given the cost of these agents, and potential lack of proper storage facilities (i.e., refrigeration) there is often enormous waste if a second or third child cannot benefit from a dose of injectable drug that has been reconstituted. When liquid formulations are not available the use of oral anti-neoplastics may prove challenging because of the need for splitting tablets or opening capsules, often without proper protective equipment. The dominant barrier impeding equitable access to antineoplastic and supportive care medicines continues to be cost. Healthcare, where publicly funded, takes a growing proportion of available resources every year. Pharmaceutical expenditures continue to show growth, fueled by innovative products, particularly new biologicals and personalized therapies. LMICs are affected by the World Trade Organization (WTO) Trade Related Intellectual Property Rights (TRIPS) agreement ratified in 1994, and clarified in 2001 through the Doha Accord [42]. The agreement strengthened intellectual property law, procedures and remedies. For governments in LMICs, especially those with thriving generic drug industry such as India, a significant curtailing of activity resulted. The TRIPS agreement generated significant debate concerning its impact on cost and access to drugs within LMICs. Various mitigating solutions have been suggested to offset the perceived or real negative impact of the TRIPS agreement. These include intensified loans/grants from organizations such as the World Bank to LMICs to purchase essential drugs that are still covered by patents. Alternatively, debt cancellation of poor nations to free up capital to purchase essential medicines has also been debated, as has the purchasing of patents by a Bank or NGO with the aim of assigning licensing of patented drugs to generic firms in developing countries. A final proposal warranting consideration is establishment of a global equity-based pricing system for high, middle, and low income countries [43–45]. In 2011, the United Nations issued a declaration regarding the need to address non-communicable diseases (NCDs) as the world’s next greatest health priority. This declaration has also increased activity in LMIC’s in co-operation with developed countries and the pharmaceutical industry and the WHO to begin to address health system issues and access to Essential medications for NCDs in LMICs [46,47]. The newer global challenge with medications is the increasing occurrence of drug “shortages.” The reasons for these are multi-factorial and range from shortage of raw indgredient(s), to manufacturing shut-downs as a result of issues related to good manufacturing process (GMP) identified by inspectors, to out-dated/inadequate production capacity to meet demand. Unfortunately, these events cannot be regulated out of existence. Recently, the FDA in the United States has within it’s statutory mandate, required all drug manufacturers to notify the FDA of impending drug shortages as soon as they are identified and give 6 months notice of the discontinuation of any product, to allow alternative sources of drug to be identified if needed [48,49].
CONCLUSIONS Initiatives undertaken in the past 15 years have brought more focus to the plight of children and medicines globally than occurred in the previous 50 years. Supporting initiatives taken by American and European governments and by WHO are key advances in providing LMICs governments with useful tools for establishing pediatric pharmacotherapy priorities. The WHO pre-qualification Pediatr Blood Cancer DOI 10.1002/pbc
program additionally aims to address issues of pharmaceutical quality so that governments in LMICs can purchase/import pharmaceuticals from reliable manufacturers. In the future, through policies now legislated in the US and EU, we can anticipate that medicines will come to market supported by evidence-informed pediatric indications. The formidable cost of new drug research and development is the next hurdle to overcome if equitable drug access is to be provided at a reasonable cost for children living in LMICs. An essential element in this achievement will be the further development of clinical and population health research capacity in the countries of greatest need. Continuing changes to global trade regulations mediated by the WTO may be a starting point to address some of the challenges identified but significant paradigm shifts in our thinking about global pediatric therapeutics must still occur. The formation of SIOP working group on essential medicines for pediatric oncology and the evolving role of SIOP as a catalyst for change in childhood cancer control globally [50] represent additional and important efforts on behalf of such issues.
ACKNOWLEDGMENTS The activities of the Working Group on Essential Medicines have been supported with funds from The Office of International Affairs, National Cancer Institute, Bethesda MD, USA; Kids Care Cancer, Edmonton, Canada; Pediatric Oncology Group of Ontario, Toronto, Canada; Roche Pharmaceuticals, Lausanne, Switzeraland; and St Baldrick’s Foundation, Monrovia, USA.
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