E-DRUG: Medications for children
--------------------------------
[This article is quite long but it addresses many
issues that interest e-druggers. BS]
Improving drug use for children in the developing world
Archives of Disease in Childhood 2005; 90 :1091-1093
S A Beggs1, N E Cranswick1 and M D Reed2
1 Clinical Pharmacology, Royal Childrens Hospital, Melbourne, Australia
2 Dept of Paediatrics, School of Medicine, Case
Western Reserve University, Cleveland, Ohio, USA
[Copied as fair use]
ABSTRACT
Children differ significantly from adults in the
way they absorb, metabolise, and excrete
drugs.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R1>1
These parameters also vary as children grow from
neonates through to adolescence. The practical
implications and challenges that this presents
are well know to anyone who is involved in the
medical management of sick children. The
importance of paediatric medication safety and
efficacy has been gaining increasing attention in
the developed world over the past decade. The
United States has introduced a carrot and stick
approach to increase research into medications
for children with the "paediatric exclusivity
provision" and the "paediatric rule". The
European Union is also investigating ways of
improving the availability of medications for
children. Unfortunately, this increased focus on
appropriate medicines for children, which has
occurred in the developed world, has not been
mirrored in developing nations. Currently more
than 10 million children under the age of 5 years
die each
year,<http://adc.bmjjournals.com/cgi/content/full/90/10/#R2>2,<http://adc.bmjjournals.com/cgi/content/full/90/10/#R3>3
with only six countries accounting for 50% of
these deaths. The majority of these deaths are
from treatable or preventable
diseases.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R4>4
The developed world has a moral and ethical
obligation to share its gains with the children
of the world.
Keywords: clinical pharmacology; international
health; rational drug use; essential medicines
As significant advances are made in the treatment
of children in the developed world it is time to
expand our areas of research to improve the
health care of children in resource poor
settings. As a priority we need to focus on a few
key areas where we can affect a significant
impact: the rational use of medications in
children, including guidelines for appropriate
drug choice and use in paediatrics; the
development of appropriate formulations for
children, and where such formulations are not
available, guidelines for preparation of
extemporaneous formulations appropriate for
resource poor settings; and finally the methods
by which medications are purchased and
distributed within each country. It is also
important to recognise that effective methods
used to maintain compliance with drug
administration may also be specific to the
culture and belief system in a country.
It is paramount that all interventions are
individualised to the needs of a given country or
even a given region within a country, as one size
will not fit all. The importance of a country
specific assessment cannot be overemphasised.
This glaring need is underscored by assessing the
burden of disease for children under 5 years of
age, as measured by mortality. For example, the
causes of under 5 mortality in sub-Saharan Africa
are: neonatal causes (25%), malaria (22%),
pneumonia (21%), diarrhoea (20%), and AIDS
(8%).<http://adc.bmjjournals.com/cgi/content/full/90/10/#R4>4
On the surface this aggregate might suggest that
the priority areas for all countries in the
region should be malaria and AIDS. This would be
inappropriate as some countries in sub-Saharan
Africa have very little malaria, others very few
AIDS deaths, while some are severely affected by
both.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R5>5
One plan for the enhancement of paediatric
therapeutics will not be applicable to all
countries.
The irrational use of medications is a
significant problem worldwide. It is estimated
that 2575% of antibiotic prescriptions in
teaching hospitals are inappropriate and that
half of the worlds 15 billion injections are
unsafe.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R6>6
The rational use of medication starts with
choosing appropriate medications in the first
instance. The WHO model essential medicine list
(EML) helps countries develop their own EML with
the aim of improving drug use through rational
choice. The EML has been in existence for more
than 25 years. It has proven to be a very
successful public health initiative, with over
156 countries adopting the concept and developing
their own
EML.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R6>6
Currently however, both the WHO model EML and
formulary lack a paediatric focus. This is shown
by the fact that of the 160 medication listings
on the core list that could include a paediatric
formulation, only 47 do
so.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R7>7
The Expert Committee on the Selection and Use of
Essential Medicines have themselves noted the
need for a special review of the use of
medications in
paediatrics.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R8>8
The development of a paediatric specific
essential medicine list would have a number of
benefits. It would increase the awareness of the
need for paediatric specific medications and
formulations, and highlight areas of priority
where medications or formulations are lacking.
WHO and UNICEF only promote the use of
medications that are on the EML, so a paediatric
list would also stimulate pharmaceutical
companies to produce paediatric medications.
Through increasing the availability of paediatric
oral formulations, such a list could also
decrease the reliance on parenteral medications
in children and thus the morbidity associated
with their use. The need for paediatric specific
formularies and drug references is shown by the
fact that many countries have recently produced
such publications, namely Medicines for
children<http://adc.bmjjournals.com/cgi/content/full/90/10/#R9>9
in the UK and Paediatric
pharmacopoeia<http://adc.bmjjournals.com/cgi/content/full/90/10/#R10>10
in Australia.
The compilation of an appropriate essential
medicines list for children is just the first
step to improving the use of medicines for the
worlds children. Regardless of how comprehensive
or practical such a list is, it will have little
impact on child health if significant numbers of
children worldwide continue to be denied access
to these important, listed medications. Currently
it is estimated that a third of the worlds
population, 2 billion people, do not have regular
access to essential
medicines;<http://adc.bmjjournals.com/cgi/content/full/90/10/#R11>11
this percentage rises to 50% in the poorest parts
of Africa and
Asia.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R12>12
The Commission on Macroeconomics and Health
estimates that 8 million deaths a year could be
prevented by 2015, through merely scaling up
essential health services. The majority of such
essential health services require reliable access
to essential
medicines.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R13>13
To improve access to essential medicines for
children we have to strengthen health services
for children in developing countries and ensure
that they have a high priority. As identified by
the Millennium Project Task force on HIV/AIDS,
Malaria, TB and Access to Essential Medicines,
the grading up of health facilities is very
complex.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R14>14
It requires concerted and prolonged commitment
from multiple stakeholders, including
international donors and recipient governments. A
coordinated, long term, all encompassing approach
needs to replace the often fragmented single
programme, short term and unpredictable approach
that currently occurs. Developed countries need
to commit to providing development aid while
developing countries need to realise the
importance of investing in health. Individual
countries themselves must initiate these measures
or else they are destined to fail.
The cost of medications is one of the key
barriers to their full access. In developing and
transitional economies, 5090% of medications are
paid for directly by
patients.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R15>15
This disadvantages the poorest and most
vulnerable in a community, such as children,
leading to delays in or absence of seeking health
care and subsequent under-treated morbidity and
mortality. User pay systems need to be abolished
to remove a significant barrier to access. The
price of new medications in particular has become
a significant concern in recent years.
Anti-retroviral medications are an excellent
example of how new essential medicines can be
priced outside the grasp of the countries that
need them most. Drug development is an expensive
process. Patent laws have been implemented to
allow manufactures time to recoup costs and make
profits before they are exposed to competition.
Members of the World Trade Organisation are bound
by the agreement on Trade-Related Aspects of
Intellectual Property Rights (TRIPS), which
established a global minimum for patent
protection.
Patent protection is a two edged sword when it
comes to the pharmaceutical industry and the
development of new medications. On the one hand,
patents stimulate research and development of new
and important therapeutic advances, while on the
other hand they decrease competition from
generics, thus maintaining the high cost of
medicines. The international community has
attempted to address this issue through the Doha
Declaration on the TRIPS Agreement in 2001 and
the Paragraph 6 decision in 2003. These
agreements theoretically enable countries with
public health needs and insufficient
manufacturing capacity to import lower cost
products from other countries. This will become
increasingly difficult however as countries such
as India implement laws preventing the reverse
engineering of pharmaceuticals and sale of
cheaper generic equivalents. The Indian generics
industry has played a major role in reducing the
cost of treating an AIDS patient in the
developing world, where it now costs $140 per
year compared with $10 00030 000 per year in
Europe or the
USA.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R16>16
The UK Department for International Development
(DIFD) report, Access to medicines in
under-served
markets,<http://adc.bmjjournals.com/cgi/content/full/90/10/#R16>16
provides a comprehensive review of this very
complex area.
In addition to accessibility, an extremely
important but often overlooked characteristic of
essential medications is their available
formulation(s) and storage requirements. The
majority of medications worldwide are not
formulated for easy or accurate administration to
children. The lack of appropriate formulations
for children makes dosing of medications in this
population less precise and less safe than in
adults. The younger the child the less likely
there will be an appropriate
formulation.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R17>17
The need for paediatric formulations has recently
had increased publicity in relation to HIV
medications. The WHO and non-government
organisations, such as Médecins Sans Frontières,
have been advocating strongly for industry to
development paediatric anti-retroviral
formulations. The problem of formulations is not
limited to HIV medications, however; it is an
issue for the majority of therapeutic drug
classes used in children. It is important to
convince industry of the need and value of
developing paediatric formulations applicable to
the developing world. It must be ensured that
such formulations are safe. The hundreds of child
fatalities from diethylene glycol poisoning
through the preparations of liquid formulations
in
Nigeria,<http://adc.bmjjournals.com/cgi/content/full/90/10/#R18>18
Bangladesh,<http://adc.bmjjournals.com/cgi/content/full/90/10/#R19>19
India,<http://adc.bmjjournals.com/cgi/content/full/90/10/#R20>20
and
Haiti<http://adc.bmjjournals.com/cgi/content/full/90/10/#R21>21
in the 1990s serve as poignant and recent
reminders of the disasters that can occur when
paediatric formulations are not prepared safely.
Relying solely on industry will take time, and
appropriate formulations are required now. In the
absence of commercially prepared formulations
appropriate for paediatrics, a compendium of
analytically defined stability recommendations
encompassing multiple time and temperature
conditions for extemporaneous formulations of
"essential" medications must be undertaken. This
information is available for many compounds used
in developed countries (for example, Pediatric
drug
formulations<http://adc.bmjjournals.com/cgi/content/full/90/10/#R22>22\);
unfortunately, these resources are generally not
applicable to developing countries. The methods
outlined and resources required are often not
feasible in resource poor settings. Medication
storage conditions and facilities (for example,
refrigeration) that are routine in developed
countries may not be easily accessible in
developing countries, resulting in unacceptable
wastage. Another problem with currently available
references is their lack of focus on drugs used
in developing countries as well as a lack of
uniformity in stability testing methodology.
These important deficiencies must be addressed in
a methodical and coordinated fashion with a
primary focus on practicality within resource
poor settings. Research into the preparation and
stability of extemporaneous formulations under
multiple storage conditions appropriate for the
developing world needs to be undertaken
immediately.
Many obstacles to performing clinical research by
local investigators and practitioners within
developing countries exist, including a lack of
resources and large clinical demands. Researchers
in resource poor settings need to be supported
and assisted by those from more affluent
countries. There is a great need for research
into the development of new treatments focused on
neglected diseases, which plague developing
countries. Of the 1393 new chemical entities
developed over the past 25 years, only 1% have
been aimed at these neglected diseases despite
their significant burden of morbidity and
mortality.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R23>23
This significant imbalance in research has lead
to the term "10/90 gap" to underscore the fact
that of the $70 billion spent each year on global
health research, less than 10% is spent on
research into diseases that represent 90% of the
global disease
burden.<http://adc.bmjjournals.com/cgi/content/full/90/10/#R24>24
Research into drug safety and efficacy
appropriate to children in developing countries
must focus on the established treatments used in
the less developed countries as well as
contemporary treatment regimens available in
developed countries. We all have a responsibility
to assist in such research while simultaneously
ensuring strict adherence to defined ethical
standards.
A way to start addressing these issues would be
through the formation of regional collaborations,
or networks, such as North AmericaSouth America,
EuropeAfrica, JapanNorthern Asia,
AustraliaAsia Pacific. Such integrated alliances
would allow the development of in-depth local
knowledge that is not possible from a global
level. Formal collaborative research units could
be developed within these networks and they could
also participate in the refinement of essential
medicine lists appropriate for children.
Education would be a useful approach for
addressing as well as increasing the
understanding and visibility of the many problems
of pharmaceutical care in developing countries.
Strategies could include mini training programmes
for counterparts to study with established
preceptors in their programme, and/or visiting
professor programmes for intensive "hands-on"
training by established individuals within target
areas. Numerous organisations (for example, the
WHO) support such experiences, but much, much
more must be done now that embraces a larger
segment of needy countries in a manner that
ensures lasting effects. Another approach could
include conferences hosted by organisations such
as the WHO, National Institutes of Health,
IUPHAR, DIA, International Network for Rational
Drug Use, and Médecins Sans Frontières, focusing
on the problems of children in developing
countries, in the areas of hospital and
ambulatory pharmacotherapeutics and
pharmacovigilance.
In October 2002, paediatric clinical
pharmacologists from around the globe met to form
an international consortium to begin to address
some of these issues. A public health working
group was formed which committed the
International Consortium of Paediatric Clinical
Pharmacology (ICPCP) to addressing issues
relating to child public health. Paediatric
clinical pharmacology has the opportunity and the
obligation to make a significant contribution to
the health of the children of the world. Over the
past three decades it has made significant
progress in attempting to rescue the therapeutic
orphan in the developed world. The skills,
experience, and knowledge gained from this
experience in the areas of research, advocacy,
and policy must be put to invaluable use in
addressing many of the health issues facing
children in developing countries. This is the
broad aim of the International Consortium of
Paediatric Clinical Pharmacologists Public
Health Working Group.
ACKNOWLEDGEMENTS
Members of the International Consortium of
Paediatric Clinical Pharmacology public health
working group: Drs Jack Aranda, USA; Michael
Christensen, USA; Noel Cranswick (co-chair),
Australia; Ralph Gorodisher, Israel; George
Giacoia, USA; Kalle Hoppu Finland, Michael D.
Reed (co-chair), USA, John Wilson, USA.
FOOTNOTES
Funding: Dr Reed is supported by a Pediatric
Pharmacology Research Unit grant from the
National Institute of Child Health and Human
Development (HD31323-10)
Competing interests: none declared
REFERENCES
1. Kearns GL, Abdel-Rahman SM, Alander SW,
et al. Developmental pharmacology-drug
disposition, action, and therapy in infants and
children. N Engl J Med
2003;349:115767.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=FULL&journalCode=nejm&resid=349/12/1157>\[Free<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=FULL&journalCode=nejm&resid=349/12/1157>Full
Text]
2. Ahmad OB, Lopez AD, Inoue M. The decline
in child mortality: a reappraisal. Bull World
Health Organ
2000;78:117591.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=11100613&link_type=MED>\[Medline\]
3. WHO. The world health report 2002:
reducing the risks, promoting healthy life.
Geneva: World Health Organization, 2002.
4. Black RE, Morris SS, Bryce J. Where and
why are 10 million children dying every year?
Lancet
2003;361:222634.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=10.1016/S0140-6736(03)13779-8&link_type=DOI>\[CrossRef\]<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=12842379&link_type=MED>\[Medline\]
5. Morris SS, Black RE, Tomaskovic L.
Predicting the distribution of under-five deaths
by cause in countries without adequate vital
registration systems. Int J Epidemiol
2003;32:104151.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=ABST&journalCode=intjepid&resid=32/6/1041>\[Abstract/Free<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=ABST&journalCode=intjepid&resid=32/6/1041>Full
Text]
6. Quick JD, Hogerzeil HV, Velasquez G, et
al. Twenty-five years of essential medicines.
Bull World Health Organ
2002;80:91314.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=12481216&link_type=MED>\[Medline\]
7. WHO.Essential medicines: WHO model list,
13th edn. Geneva: World Health Organization 2003.
8. WHO. The selection and use of essential
medicines: report of the WHO Expert Committee.
Geneva: World Health Organization, 2003,
<http://www.who.int/medicines/organization/par/edl/expertcomm13.shtml>http://www.who.int/medicines/organization/par/edl/expertcomm13.shtml
(accessed 21 May 2004).
9. RCPCH, NPPG. Medicines for children, 2nd
edn. London: RCPCH Publications 2003.
10. Royal Childrens Hospital. Paediatric
pharmacopoeia, 13th edn. Melbourne: Royal
Childrens Hospital 2002.
11. Quick JD. Essential medicines twenty-five
years on: closing the access gap. Health Policy
Plan
2003;18:13.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=PDF&journalCode=heapol&resid=18/1/1>\[Free<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=PDF&journalCode=heapol&resid=18/1/1>Full
Text]
12. WHO Policy Perspective on Medicines. WHO
medicines strategy: 20002003. Geneva: WHO, 2000,
<http://www.who.int/medicines/library/edm_general/6pagers/PPM01ENG.pdf>http://www.who.int/medicines/library/edm_general/6pagers/PPM01ENG.pdf
(accessed 21 May 2004).
13. Commission on Macroeconomics and Health.
Macroeconomics and Health. Investing in health
for economic development. Geneva: WHO, 2001,
<http://www3.who.int/whosis/cmh/cmh_report/report.cfm?path=cmh,cmh_report&language=english#>http://www3.who.int/whosis/cmh/cmh_report/report.cfm?path=cmh,cmh_report&language=english#
(accessed 18 June 2004).
14. Ruxin J, Paluzzi JE, Wilson PA, et al.
Millennium project: emerging consensus in
HIV/AIDS, malaria, tuberculosis, and access to
essential medicines. Lancet
2005;365:61821.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=15708108&link_type=MED>\[Medline\]
15. WHO. Selected topics in health reform and
drug financing. Geneva: WHO, 1998,
<http://www.who.int/medicines/library/dap/who-dap-98-3/who-dap-98-3.pdf>http://www.who.int/medicines/library/dap/who-dap-98-3/who-dap-98-3.pdf
(accessed 20 April 2005).
16. DFID HSRC. Access to medicines in
under-served markets. London: DFID Health Systems
Resource Centre, 2004,
<http://www.dfidhealthrc.org/shared/publications/Issues_papers/ATM/DFID_synthesis_aw.pdf>http://www.dfidhealthrc.org/shared/publications/Issues_papers/ATM/DFID_synthesis_aw.pdf
(accessed 20 April 2005).
17. Tan E, Cranswick N, Rayner C, et al.
Dosing information for paediatric patients: are
they really "therapeutic orphans"? Med J Aust
2003;179:1958.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=12914509&link_type=MED>\[Medline\]
18. Okuonghae HO, Ighogboja IS, Lawson JO, et
al. Diethylene glycol poisoning in Nigerian
children. Ann Trop Paediatr
1992;12:2358.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=1280035&link_type=MED>\[Medline\]
19. Hanif M, Mobarak MR, Ronan A, et al.
Fatal renal failure caused by diethylene glycol
in paracetamol elixir: the Bangladesh epidemic.
BMJ
1995;311:8891.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=ABST&journalCode=bmj&resid=311/6997/88>\[Abstract/Free<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=ABST&journalCode=bmj&resid=311/6997/88>Full
Text]
20. Singh J, Dutta AK, Khare S, et al.
Diethylene glycol poisoning in Gurgaon, India,
1998. Bull World Health Organ
2001;79:8895.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=11242827&link_type=MED>\[Medline\]
21. OBrien KL, Selanikio JD, Hecdivert C, et
al. Epidemic of pediatric deaths from acute renal
failure caused by diethylene glycol poisoning.
Acute Renal Failure Investigation Team. JAMA
1998;279:117580.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=ABST&journalCode=jama&resid=279/15/1175>\[Abstract/Free<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/ijlink?linkType=ABST&journalCode=jama&resid=279/15/1175>Full
Text]
22. Nahata MC, Pai VB, Hipple TF. Pediatric
drug formulations, 5th edn. Cincinnati, OH:
Harvey Whitney Books.
23. Trouiller P, Torreele E, Olliaro P, et
al. Drugs for neglected diseases: a failure of
the market and a public health failure? Trop Med
Int Health
2001;6:94551.<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=10.1046/j.1365-3156.2001.00803.x&link_type=DOI>\[CrossRef\]<http://adc.bmjjournals.com/cgi/content/full/90/10//cgi/external_ref?access_num=11703850&link_type=MED>\[Medline\]
24. Global Forum for Health Research. The
10/90 report on health research 20032004.
Geneva: Global Forum for Health Research, 2004,
<http://www.globalforumhealth.org/pages/index.asp>http://www.globalforumhealth.org/pages/index.asp
(accessed 18 June 2004).
Dr Sean Beggs
General Paediatrician
Clinical Pharmacology Fellow
Royal Children's Hospital
Flemington Rd, Parkville
Victoria
Australia 3052
Ph +61 3 9345 4995
Fax +61 3 9345 4825
Web www.appru.com
email sean.beggs@rch.org.au