Better Medicines for 300Million Children in ChinaReport on Recent Progress

Zhiping Li,1 Li Wang,2 Yi Wang,1 Yonghao H. Gui,1 Alexander A. Vinks3 and Stuart MacLeod4

1 Children’s Hospital of Fudan University, Shanghai, China

2 Peking University First Hospital, Beijing, China

3 Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

4 Centre for International Child Health, University of British Columbia, Vancouver, British Columbia, Canada

China is home to nearly 300million children and, as a con-

sequence, poses a major challenge to those interested in pur-

suing better drug therapy for infants, children, and youth.

While many of China’s children are raised under developed

country conditions there are still substantial numbers, partic-

ularly in rural areas, who experience health disorders associated

with poverty and poor nutrition.[1] China has made remarkable

progress in achieving Millennium Development Goals;[2]

however, there is still much work to be done and clearly uni-

versal access to optimal drug therapy would contribute to even

better health outcomes statistics for children in China.[1]

China’s interest in pediatric pharmacology and pediatric

pharmacy has been growing rapidly. Some of the recent prog-

ress can be traced to China’s hosting of the International Pe-

diatric Association in 2001[3] and the International Union of

Basic and Clinical Pharmacology World Congress in 2006.[4]

The latter meeting was preceded by a satellite conference in

Shanghai that saw an agreement to form an alliance for better

medicines for children of relevance to China and worldwide.[5,6]

Since 2006, a group of dedicated Chinese health professionals,

including pediatricians, pediatric sub-specialists, pharmacists,

and pharmacologists have been meeting to consider a process

that should help to establish more consistent advances in pe-

diatric therapeutics, pediatric therapeutic drug monitoring and

clinical toxicology, and associated training and mentorship.

For all those interested in fostering research that will lead to

amelioration of drug therapy for children and youth, the re-

cruitment of adequate numbers of participants to well designed

clinical trials remains a paramount concern. Although a re-

sponse to this challenge for the future has clearly been made in

the populous nations ofAsia, progress has so far been slow. The

recent WHO figures on registered pediatric clinical trials show

that only a small minority (4%) are being conducted in India

and China.[6] Although these numbers almost certainly under-

represent some clinical trials, the apparent shortfall in Asian

participation nonetheless presents a significant opportunity for

Chinese clinical trialists.

In September 2010, a dual meeting was convened in Beijing.

The first meeting was the inaugural regional meeting of the

International Association for Therapeutic Drug Monitoring

and Clinical Toxicology (IATDMCT). This was hosted by the

TDMCT Center of Peking University and chaired by Pro-

fessors Li Wang and Sander Vinks. In parallel with this meet-

ing, a national congress on pediatric clinical pharmacology and

pharmacy was held, which was planned and actively supported

by the Chinese Pediatric Association.[7]

Individuals in China with an interest in pediatric clinical

pharmacology held an earlier meeting in May 2010 for the

purpose of discussing the formation of the Preparatory Group

to promote rational drug use and safety for children, and the

development of all pediatric disciplines and sub-specialties

relevant to improved drug treatment and safety for children in

China. This group has since received official approval from the

ChineseMedical Association to serve as the National Group of

Pediatric Clinical Pharmacology, and all conditions now ap-

pear to be met for the next stage in development of a range of

complementary activities to advance pediatric treatment.

1. The Needs in China

TheNational Group of Pediatric Clinical Pharmacology has

focused attention on the following priority needs.

1.1 Regulatory Issues for Drug Development in Children

The regulatory environment for pediatric medicines still

needs to be improved in China. Special legislation for pediatric

medicines is missing. Both the US and the EU have introduced

COMMENTARYPediatr Drugs 2011; 13 (3): 137-1401174-5878/11/0003-0137/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

pediatric legislation that facilitates participation of children in

research and pharmaceutical innovation, but parallel initiatives

have not yet occurred in China.

The EU law is undoubtedly having a considerable effect on

drug development in children. The new legislation (European

Regulation [EC] No. 1901/2006), namely the ‘Paediatric Reg-

ulation’ governing the development and authorization for

use of medicine in the child population, entered into force on

26 January 2007.[8]

The Paediatric Regulation brings in many new tasks and

responsibilities for the European Medicines Agency (EMA).

One of the most important is the creation and operation

of a Paediatric Committee (PDCO) within the EMA.[9] The

Committee includes pediatric experts from all over the EU.

The main responsibility of the PDCO is to assess the con-

tent of pediatric investigation plans (PIPs) that are proposed

by industry, and to provide opinions on them in accordance

with the Paediatric Regulation. For new medicinal products

of therapeutic interest for children, the EU requires early

submission of a PIP for approval by the PDCO. PIP sub-

missions are expected to be filed at the time of completion of

adult clinical pharmacology and pharmacokinetic studies

(phase I), i.e. early in product development, in order to fa-

cilitate dialogue and avoid any delay at the time of marketing

authorization application. The objective is to ensure that

medicines intended for eventual use in children are evaluated

and authorized appropriately in all pediatric age groups,

including neonates. To date, more than 1000 PIPs have been

approved since 2007.[10] The experience in the US has been

similar.[11,12]

1.2 The Shortage of Appropriate Pediatric

Formulations of Essential Medicines for Children

China, in common with most countries in the world, has an

urgent need for improved pediatric formulations and flexible

dosage forms. In the early 1990s, Ni andWang[13] analyzed data

from a children’s hospital in high-income cities in China and

showed that <10% of drugs were appropriate for pediatric use.

This percentage remained almost unchanged 15 years later.[14]

The number of pediatric dosage forms in the typical formulary

of a Chinese general hospital is much lower than in children’s

hospitals. Most of the patients in general hospitals are adults;

therefore, most drugs introduced into the hospital formulary,

not surprisingly, are adult dose or dosage forms. Current fig-

ures on availability in general hospitals suggest that access to

child appropriate medications is worse than that reported byNi

and Wang[13] in the early 1990s.

Chinese pharmacists, pharmacologists, and clinicians are in

strong agreement with the current WHO priority of making

medicines child size.[15]

1.3 Establishing Evidence-Based Therapeutic

Guidelines in Each Discipline for Pediatric Patients

China has an enormous number of children. Many medi-

cines commonly used in pediatric patients have not been ad-

equately tested in children, leading to widespread off-label use

of drugs that have been evaluated only in adults. New ther-

apies are regularly introduced without a requirement for pre-

licensure study in infant, child, and adolescent groups. In

common with most countries in the world, there has been no

mandatory requirement for submission of pediatric therapeutic

data by the Ministry of Health of the People’s Republic of

China, either for postmarketing evaluation or as part of the new

drug approval process. In 2003, progress was made in China

with the updating of good clinical practice guidelines, and pe-

diatric patients were accepted for inclusion in clinical drug trials

for the first time by the regulatory authority.[16] Children’s

hospitals in China are encouraged to apply for certification

as qualified participants in national drug clinical trials. Such

participation was previously forbidden because of ethical

concerns. Starting in 2008, more academic forums have focused

on making medicines child size (WHO) and on the safety of

pediatric medicines nationally. However, experience in the

conduct of pediatric clinical trials in China has remained lim-

ited.[17,18] There is now awell recognized need for establishment

of pediatric clinical pharmacology research centers within

China.

1.4 The Critical Shortage of Pediatric Pharmacologists

and Pharmacists in China

When considered against the needs of nearly 300million

children, pediatric therapeutic specialists, especially pediatric

clinical pharmacologists and pharmacists, are in considerable

shortage. Unfortunately, an adequate scientific foundation for

drug therapy for children has not yet been established in China.

Training in pediatric clinical pharmacology domestically is very

limited and there is an urgent need for experienced mentors.

A pediatric clinical pharmacy/pharmacology teaching and train-

ing course is currently being planned by the National Group of

Pediatric Clinical Pharmacology for 2011 (tentative dates

21–25 November) with the support of colleagues abroad who

have shown great passion in facilitating the essential transfer of

pediatric therapeutic research knowledge.

138 Li et al.

ª 2011 Adis Data Information BV. All rights reserved. Pediatr Drugs 2011; 13 (3)

1.5 The Need for Close Attention to be Paid to Adverse

Drug Reactions in Pediatric Patients in the Daily Clinic

Drug safety in children should be seen as a national concern

of high priority. A national adverse drug reaction database

focused particularly on children should be establishedwith data

analyzed and reported on a routine basis. While better epidemiol-

ogic studies will help, further research in genetics/genomics is also

required to facilitate prevention of severe ADRs in children.

2. The Opportunity for China

Because of its demography and its highly developed academic

institutions in relevant healthcare fields, China is well positioned

to promote an integrated national program in pediatric clinical

pharmacology and toxicology that will incorporate all relevant

disciplines from pediatric medicine and pharmacy. Initial areas of

focus of the National Group of Pediatric Clinical Pharmacology

include those mentioned in section 1, as well as:

� formulations and pharmaceutical science;

� laboratory aspects of optimal therapy, including therapeutic

and toxicologic drug monitoring;

� communicable disease management and vaccine evaluation;

� clinical genetics, pharmacogenomics, epigenetics;

� obstetric and placental pharmacology;

� pharmacoepidemiology and drug safety;

� nephrology, hepatology;

� neonatology and treatment of infants;

� pain management, palliation.

National Group members are agreed that initial energies

should be directed to areas that will have the greatest impact on

improving health outcomes for children, including infectious

disease, vaccinology, endocrinology, growth and development,

mental health, cardiorespiratory, oncology, anesthesiology,

pain management, and critical care. The first steps must have a

balanced attention to drug safety as well as efficacy.

While China is fortunate to have a nucleus of clinicians and

scientists with established interests in pediatric pharmacology and

toxicology, it is recognized that human resources must be greatly

augmented to meet even existing needs. It is imperative that the

group now formedwork to develop a comprehensive program for

training and mentoring in all aspects of pediatric pharmacology

and therapeutics, including pharmaceutical sciences, and to create

the environment in which optimal treatment can be promoted

most efficiently though proactive knowledge mobilization.

Priority issues to be addressed in the next planning stages

include:

� curriculum development for relevant disciplines;

� striking of a balance between basic, clinical, and population

health research;

� encouragement of a focus on translational research and

implementation science;

� emphasis on information science and knowledge transfer;

� creation of clinical research networks with access to all

required scientific elements, such as innovative trial design,

modeling and simulation;

� development of an inclusive approach that will see tradi-

tional Chinese medicines represented within the studies

contemplated.

3. The Starting Point

The National Group will concentrate its early efforts on

assessing the needs of clinical pharmacology and toxicology

across China and will, through the assessment process, develop

a mechanism for planning and prioritization of future educa-

tional, research, and clinical training programs.

This group has acknowledged the need to develop a clear

inventory of current expertise available in relevant disciplines.

Within the next 6 months, steps will be taken to create an asset

map that will define available human resources in relevant

disciplines across China.

The National Group also recognizes the importance to the

achievement of optimal pediatric therapeutics of defining a

balance between clinical and research skills in all relevant dis-

ciplines for future practitioners. The ultimate aim is to certify

practitioners in several disciplines in pediatric therapeutics and

toxicology.

This group will establish standards for curriculum de-

velopment and will attempt to reach agreement on a stan-

dardized curriculum. This will also require consideration

of mechanisms for assessment and eventual credentialing

of trainees. In due course it is hoped that all qualified per-

sonnel in relevant clinical and research disciplines will be

certified and engaged in the search for better pediatric

therapies.

Finally, the National Group intends to develop a function-

ing network for promotion of research success, and for over-

sight of research and training activities.

Acknowledgment

No sources of funding were used to prepare this commentary. The

authors have no conflicts of interest to declare that are directly relevant

to the content of this commentary. During the last 4 years, DrMacLeod

has served on several occasions as a consultant or temporary advisor to

the WHO Better Medicines for Children Program.

Better Medicines for Children in China 139

ª 2011 Adis Data Information BV. All rights reserved. Pediatr Drugs 2011; 13 (3)

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Correspondence: Dr Stuart MacLeod, Centre for International Child Health,

University of British Columbia, Rm A4-193, 950 West 28th Avenue,

Vancouver, BC V5Z 4H4, Canada.

E-mail: smacleod@cw.bc.ca

140 Li et al.

ª 2011 Adis Data Information BV. All rights reserved. Pediatr Drugs 2011; 13 (3)