Delese Mimi DarkoHead of Pharmacovigilance & Clinical

TrialsFood and Drugs Board, Ghana

ICDRA 2010, Singapore

• Ghana and its people• Standard Treatment Guidelines and Essential

Medicines List• Medicines for Children in STG and EML• Registration of medicines for children• Challenges in making medicines for children

available– Quality– Efficacy– Safety

• Clinical Trials of medicines for children• Way forward

• BORDERS• Burkina Faso 549 km,

Cote d'Ivoire 668 km, Togo 877 km

• POPULATION• 23,382,848

• GDP PER CAPITA• $572.77 per capita

• CAPITAL WITH POPULATION

• Accra - 1,970,400

• LARGEST CITY WITH POPULATION:

• Accra - 1,970,400

• ALTERNATIVE NAMES • Ghana, Republic of

Ghana

• National Standard Treatment Guidelines exist• Designed for all levels of healthcare• Describes the main prevailing conditions,

specifies laboratory investigations to be undertaken and makes treatment recommendations

• Treatment recommendations in the STG specifies how ADULTS and children should be treated

• Essential Medicines List extracted from STG and then added on for conditions like cancers etc. to permit procurement

• Both STG and EML focus significantly on treatment of children

• Dosages and dosage forms for treating infants specified

• However:– List made by MOH in conjunction with stakeholders– Manufacturers and importers are not necessarily

obliged to produce or import products on the list– Business considerations sometimes make several

formulations and dosage forms unavailable

• For the majority of medicines used in children, the appropriate formulations are available on the market

Analgesics • Usually not all the required strengths are available (e.g.

paracetamol 120mg/5ml but 250mg/5ml for ages 6+ is relatively rare)

Anthelmintics – Syrups(+large single dose tablet but chewable)Antibacterials – usually suspensions & powder for reconstitution.• Higher dosage strength for the penicillins like amoxycillin

are not readily available (usually 125mg/5ml available)Multivitamins – Mainly syrups and very large soft gel caps. • Chewable and chewy tablets available but all imported and

not affordable

Antimalarials• The more popular (available)formulations are:

• Syrups, elixirs, suspensions, powders for reconstitution,

• The less popular (available) formulations are: • suppositories, dispersible tablets,

granules for single dose reconstitution, single dose, convenient, easy to dispense suspensions

• Lack of appropriate formulations for orphans medicines for children:– Caffeine citrate for neonatal apnoea in pre-term babies– Nitrofurantoin– Frusemide, Spirinolactone, Propranolol, Quinolones– Clindamycin

• In these instances, the capsules/tablets have to be crushed and or dispersed in syrup bases as extemporaneous preparations. These need to be refrigerated (feasibility??)

• Challenges in obtaining cold storage at all levels for reconstituted products– What happens to the stability of medicines prepared in

facilities in rural areas where refrigerators are not available?• What about excipients and coating agents in tablets

that may not be suitable for use in children?

• The Food and Drugs Board (FDB) is the national regulatory authority with legal mandate for the registration of all medicines including vaccines.

• It is also responsible for the authorisation and monitoring of clinical trials.

• Evaluation of dossiers for children’s medicines follows the same stringent process as for adult medicines – ** in new drug applications**

• Non clinical data in juvenile animals• Clinical data in specific age groups

• For new paediatric/children’s medicines and formulations, expert opinion is sought from the FDB’s Technical Advisory Committee on Safety and the Ghana Paediatric Society

• Requirement in Ghana for the packages of all liquid formulations to contain appropriate graduated plastic dosing measure (in some rural and in fact some homes the idea of a teaspoon could well be a volume of 7+ mls).

• Previous for literacy reasons, dosages for medicines were should using the picture of the number of teaspoons to be taken at a time.

• Dosing information should state specific age ranges for administration in addition to ml or mg/body weight.

• For all over-the-counter medicines, dosage and directions should also be clearly stated on the secondary labels so they are easily and immediately recognized (antimalarials)

• QUALITY ISSUES– Lack of official monographs for a lot of paediatric

formulations especially those that are formulated as fixed-dose combinations e.g. new ACT antimalarials,cough and cold preparations, multivitamins

– Quality assessment of paediatric versions of ACTs especially when such products are not available in ICH countries

– Stability of reconstituted fixed-dose combinations e.g. ACTs for malaria due to the instability of artemisinin derivatives in water

– Quality issues have been found with respect to disintegration of suppositories. (“over-formulation” in anticipation of climatic conditions that exist in Zone IV??)

PATIENTS/GENERAL PUBLIC

PRIMARY REPORTERS

ICPs, SMCPs & PV CENTRES

ZDOs

SMU of FDB

FDB SAFETY DATABASE WHO DATABASE

SIGNAL GENERATION POSSIBLE REGULATORY ACTION

TECH

NIC

AL

AD

VISO

RY

COM

MIIT

TEE

Safety Reporting Pathway in Ghana

• No specific safety monitoring of medicines for children • National pharmacovigilance systems collects safety

information from ALL age groups• The only “special” childhood safety monitoring is as part of

the Expanded Programme on Immunization (EPI) for childhood vaccines

• Challenges in reporting ADRs involving children– Pediatricians unsure of what terminologies to use and are hesitant

to draw obvious conclusions– Sometimes safety issues come up only as part of over-dosing– Neurological events and convulsions tend to be blamed on

“malaria” though the causes are often different and though these may sometimes be the result of exposure to medicines

– Physicians are generally more interested in the outcome of the reactions and the well-being of the child than to reporting safety issues especially when workload is heavy. (1:50,0000)

• New initiatives to examine safety of medicines for children– Discussions on-going with National Paediatric Hospital

(Princess Marie Louise Hospital, Accra) to explore possibilities for pilot programme on monitoring safety of medicines used in children

• Training of healthcare workers to identify and understand ADRs in children and to report the ADRs

• Possibility for collaboration with on-going activities in ICH countries, especially UK, US???

• Any suggestions???

Currently there are 12 active clinical trials in Ghana ◦ 2 rotavirus trials just completedOut of these 6 (50%) are involve childrenAll the on-going clinical trials are authorized by the FDB in accordance with Section 23 of the Food and Drugs LawThe following trials are ongoing in children:◦ Meningococcal vaccine◦ Malaria Vaccine◦ Vitamin A in neonates◦ Seasonal Impact of Iron ◦ Antimalarial combination therapy◦ Intermittent preventive treatment of malaria in

infants (IPTi)

Drug formulation◦ Crushing of tablets:

Tablets given to children in one trial needed to be crushed and dissolved in water before administering. Extra care and vigilance is required to avoid losses of the crushed tablet and spillage of the solution prepared.How would a busy mother be expected to appropriately crush a tablet

◦ Breaking of tabletsextra care is required to prevent unequal parts thus either under dosing or overdosing.

◦ ColourOrange and yellow colours seem to be appealing to children, however further qualitative assessments need to be done.

Tablets that can completely dissolve in water (readily available solvent) will be preferable

Pharmocokinetics◦ In another trial, a high fat diet such as ‘condensed

milk” was needed to be given to enrolled children before study drug administration. This was to aid absorption of the study medicine

In some cases children refused the study drug which was not as sweet as the ‘condensed milk’In reality, such diets are unavailable in poor home settings, therefore absorption of study medicine in real life will be poor

• Ghana’s health policies, treatment guidelines and essential medicines list take the issues of children medicines very seriously

• Clear guidelines exist in the STG on how to manage conditions in children using medicines

• Despite these however, manufacturers do not necessarily produce or import all the medicines required for children– Gaps exist especially in unprofitable areas– Several important low-usage products do not have paediatric

formulations on the local market hence tablets are still being crushed for intake by children

• Quality and stability of some existing paediatric formulations need re-assessment especially with regard to storage conditions

• Safety monitoring of medicines for children remain an area which requires urgent attention and innovative models

• Ghana taking part in the “Make Medicines Child Size” project

• Medicines for children remain a priority in Ghana• FDB uses the same stringent regulations in

assessing dossiers for paediatric medicines as it does for all medicines

• 50% of clinical trials currently on-going in Ghana involve children– Approval for these trials were given by the FDB after

careful scrutiny of the Clinical Trials Application and consultation with local experts. Provision of Ethical Clearance from the Ghana Health Service is an absolute must before any clinical trial application is examined

• Gaps exist in ability to monitor safety of medicines in children but innovative approaches are being considered