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Authors:
  • klausrose Consulting

Abstract

Background Characterizing children as "therapeutic orphans" alleges that children were/are denied the use of many drugs. Both the United States (US) and the European Union (EU) issued laws based on this concept, promoting industry-sponsored pediatric studies that recruit worldwide. We challenge their medical usefulness. Methods We analyzed pediatric studies with Chinese centers sponsored by international pharmaceutical companies listed in www.clinicaltrials.gov for their medical value. Results Some studies have medical significance, but the majority are without medical value. Adolescents' bodies are physiologically mature. For children, pharmacokinetic and dose-finding studies are sufficient. Only newborns/babies are so different that separate proof of efficacy is medically justified. The identified questionable studies are formally regulatorily justified, but are medically futile and unethical. A fraction of international pediatric academia is corrupted by industry funds channeled via regulatory decisions into medically pointless studies. Compared to other countries, the portion of studies sponsored by international pharmaceutical companies in China is limited, but China has been involved nonetheless. Conclusions Pediatric studies triggered by regulatory demands are a serious abuse of young patients worldwide. They are medically redundant at best and deter patients with serious potentially life-threatening diseases from access to effective innovative therapy. They have the potential to jeopardize public trust in science and research. Also Chinese Institutional Review Boards (IRBs)/ ethics committees (ECs) should be alerted, suspend questionable pediatric studies, and reject newly submitted ones. Innovative Chinese legislation that bases pharmacological treatment on the body's physiology, not the date of birth, is recommended.
page 1 of 11ISSN:XXXX-XXXX SFPJ, an open access journal
Volume 1 · Issue 2 · 1000006SF Pharma J
Research Article Open Access
Publishers
SCIFED
SciFed Journal of Pharmaceutics Journal
Rose K, Grant-Kels JM, SF Pharma J, 2018, 1:2
Questionable Industry-Sponsored Pediatric Studies in China Triggered
by United States of America (US) and European Union (EU) Regulatory
Authorities
*1Klaus Rose, 2Grant-Kels
*1klausrose Consulting, Pediatric Drug Development and More, Riehen, Switzerland
2University of Connecticut Health Center, Farmington, Connecticut, USA
Keywords
Pediatric Drug Development; Pediatric Legis-
lation; Pediatric Investigation Plan (PIP); Better Medicines
for Children; Pediatric Clinical Pharmacology; Pediatric
Pharmaceutical Laws
Abbreviations
AAP: American Academia of Pediatric
ADME: Absorption, Distribution, Metabolism, Excretion
EC: Ethics Committee
EMA: European Medicines Agency
ENPR-EMA: European Network of Pediatric Research at
the EMA
*Corresponding author: Rose K, Grant-Kels JM, klausrose Consulting,
Pediatric Drug Development and More, Riehen, Switzerland. E-mail:
klaus.rose@klausrose.net Tel: +41 61 312 0510
Received February 27, 2018; Accepted April 05, 2018; Published April
19, 2018
Citation: Rose K, Grant-Kels JM (2018) Questionable Industry-Sponsored
Pediatric Studies in China Triggerd By United States of America (US) and
European Union (EU) Regulatory Authorities SF Pharma J 1:2
Copyright: © 2018 Rose K, Grant-Kels JM. This is an open-access article
distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are credited.
Abstract
Background
Characterizing children as “therapeutic orphans” alleges that children were/are denied the use of many drugs.
Both the United States (US) and the European Union (EU) issued laws based on this concept, promoting industry-
sponsored pediatric studies that recruit worldwide. We challenge their medical usefulness.
Methods
We analyzed pediatric studies with Chinese centers sponsored by international pharmaceutical companies
listed in www.clinicaltrials.gov for their medical value.
Results
Some studies have medical significance, but the majority are without medical value. Adolescents’ bodies are
physiologically mature. For children, pharmacokinetic and dose-finding studies are sufficient. Only newborns/babies
are so different that separate proof of efficacy is medically justified. The identified questionable studies are formally
regulatorily justified, but are medically futile and unethical. A fraction of international pediatric academia is corrupted
by industry funds channeled via regulatory decisions into medically pointless studies. Compared to other countries,
the portion of studies sponsored by international pharmaceutical companies in China is limited, but China has been
involved nonetheless.
Conclusions
Pediatric studies triggered by regulatory demands are a serious abuse of young patients worldwide. They are
medically redundant at best and deter patients with serious potentially life-threatening diseases from access to effective
innovative therapy. They have the potential to jeopardize public trust in science and research. Also Chinese Institutional
Review Boards (IRBs)/ ethics committees (ECs) should be alerted, suspend questionable pediatric studies, and reject
newly submitted ones. Innovative Chinese legislation that bases pharmacological treatment on the body’s physiology,
not the date of birth, is recommended.
page 2 of 11ISSN:XXXX-XXXX SFPJ, an open access journal
Volume 1 · Issue 2 · 1000006SF Pharma J
Citation: Rose K, Grant-Kels JM (2018) Questionable Industry-Sponsored Pediatric Studies in China Triggered by United States of America (US) and
European Union (EU) Regulatory Authorities. SF Pharma J 1:2.
EU: European Union
FDA: US Food and Drug Administration
GRiP: Global Research in Pediatrics
IRB: Institutional Review Board
MRI: Magnetic Resonance Imaging
MS: Multiple Sclerosis
NCT Number: National Clinical Trials registration number
in www.clinicaltrials.gov
OTC: Over the Counter
PK: Pharmacokinetics
PIP: Pediatric Investigation Plan
PREA: Pediatric Research Equity Act
S and E: Safety and Efficacy
US: United States of America
WHO: World Health Organisation
WR: FDA Pediatric Written Request
Introduction
The United States of America (US) and the
European Union (EU) promote pediatric clinical studies
sponsored by pharmaceutical industry [1-3], but the
medical value of these studies is now being increasingly
challenged [4-8]. We analyzed to what degree pediatric
studies that were/are performed in China and were/are
sponsored by international pharmaceutical companies
were triggered by requests from US and EU regulatory
authorities, and we investigated to what degree these
studies correspond to the primary aim of medical
research as defined in the declaration of Helsinki, i.e. “to
understand the causes, development and effects of diseases
and improve preventive, diagnostic and therapeutic
interventions (methods, procedures and treatments)” [9].
The theory that children are discriminated in
drug development and drug treatment [10] evolved after
US law established in 1962 clinical trials as the basis
for regulatory approval [11], a principle now recognized
worldwide [12]. The same law also transferred jurisdiction
over prescription drug advertising to the FDA [13]. In
the 1950‘s, drug toxicities in preterm newborns had been
reported [14, 15]. In follow-up, drug manufacturers inserted
pediatric warnings into labels to avoid potential litigation.
Due to the new FDA judicial authority, such drugs could
no longer be advertised for children. Shirkey stated this
denied children the use of drugs and characterized them
as ‟therapeutic orphans” [10]. The American Academy of
Pediatrics (AAP) took up Shirkey‘s position. In 1977, it
claimed that that drug prescription for children without
explicit FDA certification was experimental [16], and
in 1995, that for children of all age groups separate
pharmacological evaluation of new drugs were necessary
[17]. FDA and AAP lobbying resulted in 1997 in US law
that rewarded industry-sponsored pediatric studies with
voluntary ‟pediatric exclusivity”: an additional six months
protection against generic competition [1]. The company
first submits a proposal; if this is accepted by the FDA,
it issues a ‟Written Request” (WR). Once the report of
the requested study/studies has been submitted, examined
and accepted, the FDA grants pediatric exclusivity [1].
The financial worth of such a pediatric exclusivity can be
substantial [18]. Later, the ‟Pediatric Research Equity Act”
(PREA), a second law, authorized the FDA to mandate
pediatric studies without reward [1, 19].
The US pediatric laws inspired the EU to establish
its own pediatric regulation, which has been operational
since 2007 [1, 20]. Without PIP, new drugs can no longer be
approved for adults in the EU, unless the targeted disease
is PIP-exempted [1, 21, 22]. PIPs must propose juvenile
animal studies, child-friendly formulations (e.g. liquids
vs. tablets), clinical studies, and more. The PIP negotiation
takes approximately one year from initial submission to
EMA for approval. The EMA has so far issued >1000 PIPs
[21]. In response to a recent paper that critically reviewed
the PIPs [7], EMA employees published a counter-position
[2], which might be useful for any reader who wants to
compare the arguments of both sides.
The toxicities the AAP referred to were reported
in premature newborns [14, 15]. The AAP warnings
extrapolated potential toxicities from immature newborns
to all children. Furthermore, this extrapolation used the
legal, not the physiological term of children [17]. US
and EU pediatric laws responded to the AAP‘s ‟moral
imperative to formally study drugs in children” [17],
which was not based on science, but was an emotional
appeal to protective instincts the word ‟child” triggers in
most civilized persons. US and EU pediatric laws define
children not physiologically, but administratively: <16
(FDA)/ <18 years (EU) [1, 20, 24].
Methods
We identified in www.clinicaltrial.gov pediatric
studies sponsored by international pharmaceutical
companies in 0-17 year old patients. We disregarded
studies that involved either adolescents and adults or
children as well as those involving adolescents and adults
in an effort to focus on truly pediatric studies, but we
included studies recruiting patients up to 21 years old. We
page 3 of 11ISSN:XXXX-XXXX SFPJ, an open access journal
Volume 1 · Issue 2 · 1000006SF Pharma J
Citation: Rose K, Grant-Kels JM (2018) Questionable Industry-Sponsored Pediatric Studies in China Triggered by United States of America (US) and
European Union (EU) Regulatory Authorities. SF Pharma J 1:2.
also excluded vaccination studies. We retrieved related
US Food and Drug (FDA)/ European Medicines Agency
(EMA) documents from the internet. We examined if these
studies were justified by the principles of medical research
as defined by the declaration of Helsinki [9], and further
key documents that define the ethics of human research
[25-27]. We also analyzed the studies‘ design, justification
and main endpoints with the background of what is now
known regarding developmental pharmacology [28]. EMA
pediatric investigation plan (PIP) decisions and studies in
www.clinicaltrials.gov are given by the respective PIP/
NCT-number, allowing immediate internet-retrieval.
Results
Table 1 contains the pediatric studies listed in www.
clinicaltrials.gov with study centers only in China (studies
9, 10, 11, 13, 19) or centers in China and other countries,
sponsored by international pharmaceutical companies.
The column ‟PIP#/WR” indicates if the respective study
was triggered by an EMA-issued PIP (studies 3, 4, 11,
14, 15, 17-21), by FDA written requests (WRs) (studies
1, 2, 6-8), by FDA PREA demands (study 16), or was/is
sponsored for other reasons. Cetaphil Restoraderm (study
5) is a cream containing soaps and moisturizers, available
‟over the counter” (OTC). This study appears to be a
marketing study, as do the two fluticasone studies (#9-
10), for which we could not identify FDA/EMA pediatric
requests/demands.
Table 2 lists in alphabetic order description and
indication of the compounds in Table 1.
Discussion
Individual Studies
Numerous publications confirm the efficacy of
innovative anti-inflammatory biologics in “underage”
patients [35, 36]. Why should these drugs not work in
patients that are younger than 16 or 18 years old? The
immune system, receptors and organs of adolescents
are the same before and after the 16th/18th birthday.
Representatives of the pediatric rheumatology international
trials organization (PRINTO) report that “children” up to
17 years were successfully treated with anti-inflammatory
biologics by PIP-triggered studies [35, 36]. However, 17
years old patients are physiologically no longer children,
but rather young adults. Multiple clinical trials with anti-
inflammatory biologics have recruited worldwide over a
thousand “pediatric” patients, but the justification for these
trials was/is formal and regulatory, not medical [35, 36].
For prepubertal children dose finding is necessary. Once
the body is mature, adult doses are adequate. The planned
study to evaluate efficacy and safety (E&S) of tocilizumab
in Chinese patients (table 1, study 19) will not answer
medically relevant questions. The efficacy of tocilizumab
in humans is already well known. It is not relevant if this
study is directly triggered by the tocilizumab PIP or is
being repeated in China for marketing reasons. This trial
is medically unnecessary, questionable, unethical, and
should be suspended before it starts recruiting.
Why investigate peg interferon alpha-2a separately
in children and adolescents if the drug has been proven
efficacious in adults? (Study 15 table 1). Peg interferon
alpha-2a is a well-established treatment for chronic
hepatitis B [37]. Study 15 table 1 is precisely the same
clinical study no. 4 demanded in the EMA peg interferon
alpha-2a PIP. Roche was forced to accept this PIP and to
execute it. If they had not, the EMA would have blocked
adult EU-approval. This clinical study is not driven by
clinical beneficence as all clinical trials should be [26].
But by the EMA’s obsession to enforce more pediatric
studies. Since physiologically adolescent patients are no
longer children, this study is unnecessary, questionable,
unethical, and should be suspended in our opinion.
Why should a chemotherapy agent like clofarabine
work differently in patients older or younger than 21
years? Based on an FDA WR [30]. This study afforded
the sponsoring company a “pediatric exclusivity”, i.e.
protecting the drug against generic competition for 6 more
months, which can for a company be quite rewarding n
[18]. But this study was not in the participating patients’
interest. When the study started in 2009, the role of
clofarabine in the treatment of relapsing or remitting acute
lymphatic leukemia was already well known.
Similarly, why should an antifungal compound
like voriconazole work differently in patients older or
younger than 17 years? (Study 21, table 1).
Bosentan is a compound for pulmonary arterial
hypertension. Study 2, table 1 investigated PK, tolerability,
and S&E in patients 3 months to 12 years of age; study 3
was an extension study. PK and dose finding studies in
neonates and babies < 1 year old are medically justified,
but not in patients up to 12 years. The bosentan studies
were medically justified only in a small proportion of the
participating patients. Performed worldwide in 64 patients
in 48 centers, these studies were to a large degree a waste
of time and resources and were ethically questionable.
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Volume 1 · Issue 2 · 1000006SF Pharma J
Citation: Rose K, Grant-Kels JM (2018) Questionable Industry-Sponsored Pediatric Studies in China Triggered by United States of America (US) and
European Union (EU) Regulatory Authorities. SF Pharma J 1:2.
# NCT# / PIP# Abbreviated Study
Description Sponsor Age Pts/Centers Status PIP#/WR
1 NCT00486083 Atomoxetine in
ADHD** Eli Lilly 6-16y 330/? C 2003-2004 FDA WR [29]
2 NCT00471354 Atomoxetine in
ADHD*** Eli Lilly 8-11y 228/? C 2007-2008 FDA WR [29]
3 NCT01223352 Bosentan in PAH Actelion 3mo-
12y 64/ 48 C 2011-2013 EMEA-000425-PIP02-
10-M04
4 NCT01338415 Bosentan in PAH Actelion 3mo-
12y 58/ 47 C 2011-2014 EMEA-000425-PIP02-
10-M04
5 NCT02589392 Cetaphil Restoraderm in
AD**** Galderma 2-12y 120/ 8 C 2015-2016 NRI - OTC
6 NCT02544789 Clofarabine in R/R ALL Betta 1-21y 44/ 6 C 2009-2012 FDA WR [30]
7 NCT00396877 E&S of clopidogrel in
STPASP Sanofi <92
days 906/ 31 C 2006-2010 FDA WR [31]
8 NCT00565448 Docetaxel + cisplatin in
NPC Sanofi 1mo-
21y 75/ 26 C 2007-2012 FDA WR [32]
9 NCT01915914 OL R Fluticasone cream
in AD* GSK 1-18y 107/ 4 C 2013-2015 NRI - phase IV study
10 NCT02424539 Two fluticasone doses
in AR* GSK 2-12y 360/ 16 Recruiting NRI - phase IV study
11 NCT01687296 Fluticasone vs
prednisone in A* GSK 4-16y 261/ 11 C 2012-2013 EMEA-000431-PIP01-
08-M10
12 NCT01223131 Insulin glargine vs. NPH
insulin Sanofi 6-17y 162/ 10 C 2011-2014 Chinese reg.
requirements
13 NCT02427958 E&S of leuprorelin in
CPP* Takeda 1-9y 300/ 9 Active NR NRI - phase IV study
14 NCT02932410 Macitentan Actelion 2-17y 300/ 86 Recruiting EMEA-001032-PIP01-
10-M02
15 NCT01519960 Peginterferon α-2a in
HEP B Roche 3-17y 165/ 44 Active NR EMEA-000298-PIP01-
08-M05
16 NCT02072824 Pregabalin in POS Pfizer 1mo -
3y 113/ 118 Recruiting FDA PREA [33,34]
17 NCT02234843 Rivaroxaban in venous
Thromb Bayer 6mo-
17y 270/ 162 Recruiting EMEA-000430-PIP01-
08-M10
18 NCT02201108 Teriflunomide in MS Genzyme 10-17y 166/ 69 Active NR EMEA-001094-PIP01-
10-M04
19 NCT03301883 Tocilizumab Ph4 study
in sJIA* Roche 2-17y 65/? not yet recr EMEA-000309-PIP01-
08-M07
20 NCT01493778 Turoctocog in
hemophilia A Novo N <6y 60/69 Active NR EMEA-001174-PIP02-
12-M02
21 NCT01092832 Voriconazole in TCI Pfizer 2-17y 23/ 14 Terminated EMEA-000191-PIP01-
08-M05
Centers: *China ( ) only ** , Korea, Mexico *** , Korea, Taiwan **** , Philippines All others: + ROW
Abbreviations in alphabetic order: China A asthma AD atopic dermatitis • ALL acute lymphoblastic leukemia • ADHD attention deficit
hyperactivity syndrome AR allergic rhinitis • CPP central precocious puberty • C completed DM diabetes mellitus • E&S efficacy & safety
GHD growth hormone deficiency GS GeneScience • GSK GlaxoSmithKline • HEP hepatitis •MS multiple sclerosis • Novo N Novo Nordisk •
NPC nasopharyngeal carcinoma • PMR post-marketing requirement • NPH neutral protamine hagedorn • NR non recruiting • NRI No regulatory
involvement • OTC over-the-counter •OL open label • PAH pulmonary arterial hypertension • PEG pegylated • POS partial onset seizures PREA
Pediatric Research Equity Act R randomized • recr recruiting • reg regulatory • ROW rest of the world • R/R refractory or relapsed • S Syndrome
sJIA systemic juvenile idiopathic arthritis • STPASP Systemic To Pulmonary Artery Shunt Palliation • TCI throat candida infection • TS Turner
Syndrome • venous Thromb venous Thrombosis •
Table 1: International Industry Sponsored PIP-Triggered Pediatric Studies In China
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Volume 1 · Issue 2 · 1000006SF Pharma J
Citation: Rose K, Grant-Kels JM (2018) Questionable Industry-Sponsored Pediatric Studies in China Triggered by United States of America (US) and
European Union (EU) Regulatory Authorities. SF Pharma J 1:2.
The study of fluticasone in asthma (study 11,
table 1) was triggered by a PIP. However, there is no
question regarding the efficacy of inhaled fluticasone in
patients younger than 16 years. This study was therefore
superfluous.
Why should insulin glargine or neutral protamine
Hagedorn (NPH) insulin work differently in persons above
or below the 18th birthday? The FDA issued in 1998 a WR
for insulin glargine [38], which triggered a clinical trial
in 349 children and adolescents? [39], which led to FDA
pediatric exclusivity and registration in children? [38].
Study 12 table 1, was initiated many years later. The insulin
glargine study was initiated because the drug was not
licensed in children in China [40]. The reason that Sanofi
paid for this study, as documented in www.clinicaltrials.
gov, was probably that Sanofi wanted pediatric approval
also in China. While this made sense from an economic
point of view, there was no medical value in this study. It
simply repeated what was already well known.
Docetaxel is a chemotherapy agent used for
various cancers. Cytotoxics are also cytotoxic in children
and adolescents. The development of pediatric oncology
involved the systematic investigation of chemotherapy
in various pediatric cancers, which improved survival of
child malignancies considerably [41]. Although there was
no medical logic in a separate investigation of docetaxel
efficacy in pediatric patients, the FDA nonetheless
had issued a docetaxel WR. Study no. 8, table 1, which
corresponds to study no. 3 of the FDA WR [32]. Performed
worldwide including centers in China. The study was
reported in 2015 [42]. And not surprisingly the outcome
was negative. This is a good example of pediatric studies
that are triggered by regulatory requests/demands, but have
no medical value. For patients and parents, such studies
create(d) unfounded hope. The drug manufacturer could
balance the study costs with 6 months pediatric exclusivity,
so economically this study made sense. Apart from the
manufacturer, the other group that profits are pediatric
oncologists. These international studies are complex,
require demanding logistics, and result in international
meetings, networking, and publishing.
Multiple sclerosis (MS) is an inflammatory
autoimmune disease that predominantly affects adults,
but rarely also underage patients. Although pediatric MS
appears to be overall a more inflammatory disease than
adult MS, with more frequent relapses and magnetic
resonance imaging (MRI) lesion accrual [43]. There is
no doubt that it is an inflammatory autoimmune disease
Table 2: Compound Description/ Indication In Alphabetic Order
Compound Description/ Indication
Atomoxetine Noradrenaline reuptake inhibitor for ADHD
Bosentan Dual endothelin receptor antagonist for pulmonary arterial hypertension
Cetaphil Restoraderm OTC product for eczema, containing soaps and moisturizers
Clofarabine Chemotherapy drug for relapsed or refractory ALL
Clopidogrel Platelet activation inhibitor for prevention of heart disease and stroke
Docetaxel Chemotherapy drug for various cancer types
Fluticasone Glucocorticoid: anti-inflammatory and vasoconstriction effects
Insulin glargine Long-acting basal insulin analogue
Leuprorelin GnRH receptor agonist, used for various cancer types and early puberty
Macitentan Endothelin receptor antagonist for pulmonary arterial hypertension
Peginterferon α-2a Pegylated interferon alpha-2a
Pregabalin Drug against epilepsy, neuropathic pain, fibromyalgia, and GAD
Rivaroxaban Oral anticoagulant
Teriflunomide Immunomodulatory drug for multiple sclerosis
Tocilizumab Humanized MAB against IL-6R
Turoctocog Recombinant antihemophilic factor VIII, used in haemophelia A
Voriconazole Antifungal drug
Abbreviations in alphabetic order: ADHD attention deficit hyperactivity disorder • ALL acute
lymphoblastic leukemia • GAD generalized anxiety disorder • GnRH gonadotropin releasing
hormone • IL-6R interleukin-6 receptor • MAB monoclonal antibody OTC over-the-counter •
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Volume 1 · Issue 2 · 1000006SF Pharma J
Citation: Rose K, Grant-Kels JM (2018) Questionable Industry-Sponsored Pediatric Studies in China Triggered by United States of America (US) and
European Union (EU) Regulatory Authorities. SF Pharma J 1:2.
in younger patients as in adults [44, 45]. A well-known
specialist in pediatric MS stated that whether ‟both
children and adolescents should be included in the same
‚paediatric‘ category is also a matter of debate; however,
most societies have, for social, judicial, ethical and
educational purposes, made this distinction for those under
the age of 16–18” [45]. And: ‟If we truly believed that
this was the same disease, then there would be no need to
study the effect of treatments in the paediatric population,
because ‚equipoise‘ would not exist as to their efficacy”
[45]. We fully agree with this statement, but challenge her
fundamental assumption. Even though for social, judicial,
ethical and educational purposes the age limit of adulthood
is somewhere around 16-18 years, that does not imply that
this must also be the case for pharmaceutical treatment.
There is no equipoise in separate pediatric MS trials.
Treatment regimens in younger MS patients might be
required and could/should be the aim of meaningful clinical
studies. But these studies should not be regulatory studies.
Also in MS, the best approach is personalized medicine
and combination therapy [46]. Study no. 18, table 1
compares teriflunomide vs. placebo in young MS patients.
There is no doubt regarding the anti-inflammatory efficacy
of teriflunomide. To expose young patients to placebo is
regulatory excess and not in the patients‘ interest. This
study was triggered by one of the numerous MS PIPs [47].
It prevents adequate treatment of the enrolled patients, is
not driven by clinical beneficence [26]. Is unethical and
should be suspended.
Similarly, why investigate rivaroxaban in
treatment/ prevention of venous thrombosis separately in
patients 2-17 years old? (Study 17 table 1).
Study no. 16, table 1, pregabalin in patients with
partial onset seizures, was triggered by an FDA PREA
demand, corresponding to study no. 1576-2 in the approval
letter [33, 34]. Why perform a placebo-controlled study
with a compound whose clinical efficacy has already been
proven? Dose finding in younger children (aged 1 to 3
years old) is necessary, but not separate proof of efficacy.
Atomoxetin is FDA-approved in adults and
children >6 years for attention deficit hyperactivity
syndrome (ADHD). Ely Lilly received an FDA WR in
2001. The FDA requested two double-blind randomized
placebo-controlled trials in children plus a pharmacokinetic
(PK) study [29]. While a PK study is justified, separate
proof of efficacy in 6-16 years old patients represents
regulatory excess.
What is the need to investigate macitentan
separately in patients 2-17 years of age, i.e. including
children and adolescents? (Study 14 table 1).
In contrast, the study of clopidogrel in systemic
to pulmonary artery shunt palliation, triggered by an FDA
WR [31]. was performed in newborns and small babies
and was medically justified.
A study of leuprorelin/leuprolide in 22 patients with
central prococious puberty had launched the basis of FDA
approval of a special pediatric injection of leuprorelin/
leuprolide [48]. Study 13, table 1 appears to be a marketing
study run by Takeda without involvement from US or EU
regulatory authorities.
Why should toroctocog work differently in
children above or below 6 years of age? There is no doubt
about the compound’s efficacy (study 20, table 1).
Studies triggered by PIPs and PREA are not
performed voluntarily by pharmaceutical companies,
but they are coerced into doing so by FDA/EMA. WR-
triggered studies reward companies financially. It is natural
for companies to respond to offered rewards. It is not the
companies who are at fault but the authorities who request/
demand them.
Pharmaceutical industry, academia, patient
organisations and science have so far failed to
conceptualize intellectually the flaw in the „therapeutic
orphans“ concept, which has become a dogma by and large
accepted worldwide. In the classical triangle of influence
between academia, industry and regulatory authorities it
would and should be the job of academia to counterbalance
regulatory overzealousness; however, essential parts of
pediatric academia have become corrupted by industry
funds channeled by FDA/EMA-decisions. This is not a
conspiracy of dishonest indivdiuals, but a flawed concept
that blurs the difference between the physiological
assessment of the body‘s maturity and legal definitions of
childhood vs. adulthood. This issue is amplified by the bad
reputation of pharmaceutical industry in western countries
and the “Robin-Hood”-sentiment of the regulatory
authorities of protecting the vulnerable [49]. This creates
a dilemma for international pharmaceutical companies. If
they do not execute the requested pediatric studies, they are
putting their business in jeopardy. However, by executing
FDA/EMA-demanded studies, they make themselves
vulnerable to a possible lawsuit by parents whose child
was harmed. This danger is specifically relevant in life-
threatening diseases. For example, the FDA approved
avelumab for Merkel-cell carcinoma [50], while the EMA
PIP EMEA-001849-PIP02-15-M01 demands clinical trials
page 7 of 11ISSN:XXXX-XXXX SFPJ, an open access journal
Volume 1 · Issue 2 · 1000006SF Pharma J
Citation: Rose K, Grant-Kels JM (2018) Questionable Industry-Sponsored Pediatric Studies in China Triggered by United States of America (US) and
European Union (EU) Regulatory Authorities. SF Pharma J 1:2.
in patients from birth to 17 years in all solid cancer types
except central nervous system tumours, haematopoietic
and lymphoid tissue neoplasms. If a young US melanoma
patient should be treated within a PIP-triggerd avelumab
study, and later the parents learn that this study prevented
effective combination treatment [4-6], the parents could
demand punitive damages against the pharmaceutical
company who sponsored the trials and thereby withheld
potentially effective therapy.
General Discussion
Overall, children have profited from medical/
pharmaceutical progress. Pediatric cancer is no longer an
automatic death sentence. Most diseases that in the past
killed children are today prevented, can be treated, or both.
When pediatric oncology began, the treating physicians
ignored drug labels and treated their patients with
available drugs. Even Shirkey noted that most physicians
simply ignored pediatric warnings [10]. The demand for
separate regulatory studies for persons <18 years old
reflects the turmoil created by traditional eminence-based
medicine and the state’s demand for double-blind studies
and anonymous studies data. Replacement of hands-on
experience by clinical studies data became a mantra [51].
The AAP guidelines for pediatric studies were historically
innovative because systemic clinical trials in children had
until then been taboo. However, the guidelines also created
conflicts of interest as specific sub-groups wanted access
to funds for pediatric research to enhance their careers. It
is time to re-assess the “therapeutic orphans” dogma and
the use of the words “children” and “pediatric” as far as
this use confuses legal age and physiology [21]. Many
malignancies in minors are the same or similar to adult
malignancies despite that minors’ bodies are different and
dose adjustment is required. There are also differences
we still don’t understand completely, such as young
patients’ reserves, or the reasons why MS in younger
patients has often a different clinical course [43-45]. The
decision to develop tisagenlecleucel first in young patients
was physiology-based [52]. In contrast to FDA/EMA’s
obsession for “pediatric” trials, absorption, distribution,
metabolism, excretion (ADME) of the child reach levels
comparable to the adult body after the first six months of
life.[28] From then on, dose adjusting and PK measurement
are still required, but not separate repetition of proof of
E&S in underage patients.
The discussion about pediatric clinical studies
reached truly global dimensions when in 2007 the World
Health Organization (WHO) launched its compaign
“make medicines child size” [53, 54]. It accused the
“usual suspects”[55] that too many children die in this
world, claiming that pharmaceutical industry didn’t
develop medicines for children, and that many drugs are
used in children in an unlicensed or off-label manner,
provoking adverse events and death. The Pediatric
medicines Regulators’ Network (PmRN) was established,
[56] international conferences were organized, funds
were assigned, and numerous articles were published
[57-60]. The EMA established the European Network
of Pediatric Research at the EMA (Enpr-EMA) which
annually organizes a conference and offers ample
opportunities for pediatric researchers to network [61-63].
The EU funded the Global Research in Pediatrics (GRiP)
network to stimulate and facilitate the development and
safe use of medicines in children, justified by “lack of
appropriate testing of pediatric drugs, with most drugs
having inadequate information about dosing regimen, dose
adjustment and administration”; it lists 21 partners on its
website, including the WHO [64]. The regulatory global
“pediatric cluster” is also mentioned in the FDA report to
congress 2016 [65]. An investigation of the impact of this
activism in Uganda showed that essentially nothing had
happened on a country level [66]. Essentially, almost all
alleged accomplishments are regulatory accomplishments
[57-59]. They have not improved child healthcare.
It is essential to start differentiating between real
needs for children, and empty demands and promises. Most
children below the age of 7 years cannot swallow tablets,
so they need child-friendly formulations. Children’s’
bodies are vulnerable during the first months of their life.
The link of China to international western
regulatory authority-triggered pediatric studies is still
rather weak. Challenges offer also opportunities. The
tragedy of unprecedented abuse of children, adolescents
and young adults in medically useless studies evolved
not on the basis of malicious intentions of individuals,
but on the basis of society’s struggle to intellectually
conceptualize the place of innovative drugs in medicine
and society. Shirkey’s concept of children as therapeutic
orphans, born in the US in 1968 [10], has moved towards
the EU, Japan and is now triggering worldwide medically
questionable studies. But much has changed. Today, we
know much more about development of ADME in young
person’s [28]. China’s voice is heard worldwide. Which
country will be the first to introduce innovative legislation
that allows pharmaceutical treatment of young person’s
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Volume 1 · Issue 2 · 1000006SF Pharma J
Citation: Rose K, Grant-Kels JM (2018) Questionable Industry-Sponsored Pediatric Studies in China Triggered by United States of America (US) and
European Union (EU) Regulatory Authorities. SF Pharma J 1:2.
based on physiology, not the date of birth? The treating
physician should make such decisions, not bureaucrats
with a legal, administrative or regulatory background.
This challenge offers the opportunity to non-US and non-
EU countries to set an innovative precedent. Innovative
Chinese pediatric pharmaceutical legislation could help
to correct the framework of pharmaceutical treatment of
minors [4-6, 21, 22].
Conclusions
With the exception of newborns and babies, pre-
pubertal children need PK and dose-finding, not separate
efficacy studies. Adolescents with mature ADME deserve
adult treatment. Rare adverse events are rarely caught in
clinical trials; registries should be used more. The AAP’s
definition of pediatric vs. adult patients as patients up to 21
years of age (and even older for patients with special needs
as regards clinical bedside care) [67] is not adequate as an
age limit for pharmaceutical treatment.
Most WRs, PREA demands and PIPs are a waste
of money and resources and a senseless abuse of children,
adolescents and young adults. They harm young patients
with serious and lethal diseases by deterring them from
innovative, effective treatment. They have become a
worldwide obstacle against innovative drug development.
They have poisoned and corrupted parts of pediatric
academia into performing medically senseless clinical
trials, into competing for participation in such studies, and
into demanding more such studies. The less scientific value
the EMA‘s pediatric activism has, the more it emphasizes
its ‟scientific” content. The PIP template on the EMA
website is named ‟Template for scientific document (part
B-F)” [68]. But there is nothing scientific in it. Minors
and young adults with serious and lethal diseases are
enrolled in needless studies that are potentially the largest
systematic abuse of patients in history [69].
US and EU pediatric legislation need revision.
Institution Review Boards (IRBs)/ ethics committees
(ECs) have failed to detect medically unwarranted studies.
IRBs/ECs should suspend ongoing superfluous studies
and reject new ones. Also, IRBs/ECs need instructions on
the role of developmental physiology in pharmaceutical
treatment and drug testing. Innovative Chinese
pharmaceutical legislation, allowing physiology-adapted
drug treatment instead of a rigid focus on the date of birth
would be welcome and would have the potential to vitalize
a worldwide debate that is overdue.
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Aim/objective: Since 2007, companies in the EU must submit paediatric investigation plans (PIPs) for new drugs, unless the PIP is waived and the review article investigated if that improve the child healthcare. Methods: We analysed the EU Paediatric Regulation (EUPR), PIP decisions, PIP decision patterns, EU key documents on "better medicines for children" and examined PIP studies versus the epidemiology described in the reference literature. We examined how PIPs translate into studies by checking www. clinicaltrials.gov and www.clinicaltrialsregister.org. We also investigated the medical sense of PIP-demanded clinical studies in adolescents. Results: The EUPR in Art. 2 (1) defines “paediatric population” as those between birth and 18 years. It lists challenges in dosing and safety of drugs in neonates and infants as if these challenges apply to anybody < 18 years. PIPs demand studies in adolescents although this group needs separate dose finding and efficacy studies only in exceptional cases, if at all. Most PIP studies in rare diseases are unfeasible: too many studies for too few patients in general. Two questionable PIP studies were discontinued in 2016, in one of them several patients died. Conclusions: Neonates and infants have immature organs, with resulting potential for drug over/underdosing. PIPs equalize the legal definition of childhood with a biological limit. The resulting automatism leads to a worldwide threat to children. Most PIP-demanded studies are medically senseless, some even worse. Ethics committees should reject questionable PIP studies and suspend such ongoing studies immediately.
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As human experimentation continues to grow into an ever more complex and sophisticated endeavor, the relevant ethical and regulatory structures become more intricate. When pediatricians and general practitioners are invited by pharmaceutical companies to enroll their offices in a clinical trial or a multicenter observational study or when they develop their own research questions, they frequently find themselves at a loss in the human research environment. The legal and regulatory complexity may have an unintended deterring effect at a time when office-based high quality pediatric research is urgently needed to support evidence-based medicine. Unfortunately, in many instances, unaware practitioners become involved in low-risk research activities without knowing it and become entangled in legal, auditing, and compliance procedures. This paper, written in 2 parts, aims at providing a general guidance on the principles that regulate human research with a focus on pediatrics. Part 1 discusses the history, the legal framework, and the consent process and highlights some practical aspects of initial protocol submission, continued review, and institutional review board determinations with the main focus on multicenter clinical trials (industry-sponsored research). Part 2 focuses on pediatric research regulation, also known as subpart-D, and minimal risk research, which encompasses many research activities aimed at addressing questions that may emerge in pediatricians' practices (investigator-initiated research).
Article
Purpose: US pediatric legislation was introduced in 1997 and was followed by European Union pediatric legislation that, since 2007, requires a European Medicines Agency (EMA)-approved pediatric investigation plan (PIP) for registration of new medicines unless they are PIP exempted. In 2008, the EMA decided that enough adolescent patients with melanoma existed and removed melanoma from the list of PIP-exempted diseases (class waiver list). We examined the logic and the results of this decision. Methods: We analyzed the EMA class waiver decision, the melanoma PIP decisions, the wording of the European Union pediatric legislation, and melanoma trials listed in www.clinicaltrials.gov and www.clinicaltrialsregister.eu that recruit adults and minors or only minors. Findings: There are 12 melanoma PIP decisions. Two apparently PIP-triggered melanoma trials were terminated in 2016 because of slow recruitment, and 4 are ongoing. Numerous non-PIP-driven trials are recruiting both adults and minors with melanoma worldwide, thus competing with PIP-triggered melanoma trials. Implications: Revoking the melanoma class waiver was not based on science but on flawed logic. It resulted in PIP-demanded pediatric trials that do not make medical sense, fail to recruit adequately, and prevent participants from more promising off-label treatment or treatment in clinically, scientifically, and ethically superior non-PIP-triggered studies. Institutional review boards and ethics committees should consult both www.clinicaltrials.gov and www.clinicaltrialsregister.eu for competing trials in the same population and reject or withdraw approval for questionable trials. A major revision or replacement of the European Union pediatric legislation is needed to prevent children from being enrolled in unnecessary, unfeasible, or scientifically invalid trials.