pediatric drugs: stakeholders’ … of pediatric exclusivity on safety and effectiveness of...
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IMPACT OF PEDIATRIC EXCLUSIVITY ON SAFETY AND EFFECTIVENESS OF
PEDIATRIC DRUGS: STAKEHOLDERS’ PERSPECTIVES
by
TIKA RAM RIZAL
(Under the Direction of Paul J. Brooks)
ABSTRACT
Two-thirds of pediatric drugs currently prescribed have not been studied and labeled for
pediatric use. The pediatric exclusivity provision established by the Food and Drug
Administration (FDA) under Food and Drug Administration Modernization Act of 1997
(FDAMA) granted drug manufacturers six months of patent extension for conducting pediatric
studies. This study seeks to identify by surveys and interviews of key stakeholders if the
pediatric exclusivity provision has improved the safety and effectiveness of pediatric drugs vis-a-
vis their improved labeling, dosing, and formulation information. In general, the pediatric
exclusivity provision has been successful in stimulating pediatric studies by improving the
labeling, dosing, and formulation of pediatric drugs. Respondents reported inadequate pediatric
doses as the main problem and expensive pediatric trials as the main challenges in pediatric drug
development. Well-designed pediatric studies conducted by highly trained investigators with
active collaboration by parents are the key factors determining the success of studies for pediatric
exclusivity.
INDEX WORDS: Pediatric, Pediatric drugs, Pediatric Exclusivity, Safety, Effectiveness, FDA,
Purposive sampling, Clinical trials, Pediatric labeling, Pediatric dosing
IMPACT OF PEDIATRIC EXCLUSIVITY ON SAFETY AND EFFECTIVENESS OF
PEDIATRIC DRUGS: STAKEHOLDERS’ PERSPECTIVES
by
TIKA RAM RIZAL
FORB., Tribhuvan University, Nepal, 2003
A Thesis Submitted to the Graduate Faculty of The University of Georgia in Partial
Fulfillment of the Requirements for the Degree
MASTER OF SCIENCE
ATHENS, GEORGIA
2012
© 2012
Tika Ram Rizal
All Rights Reserved
IMPACT OF PEDIATRIC EXCLUSIVITY ON SAFETY AND EFFECTIVENESS OF
PEDIATRIC DRUGS: STAKEHOLDERS’ PERSPECTIVES
by
TIKA RAM RIZAL
Major Professor: Paul Brooks
Committee: Ronald Arkin
David Mullis
Randall Tackett
Electronic Version Approved:
Maureen Grasso
Dean of the Graduate School
The University of Georgia
May 2012
iv
DEDICATION
This thesis is dedicated to my loving parents Laxmi and Kaushila Rizal. Thank you for being my
inspiration and support to better myself through higher education. Your sacrifices for me are
always appreciated. Where I am today is because of you. Mum, though you passed away, you are
always in my heart and truly missed.
v
ACKNOWLEDGEMENTS
I would like to thank my thesis advisor Dr. Brooks for his advice and constructive criticism
during my research work. I want to thank my advisory committee-Dr. Mullis, Dr. Tackett, and
Ron Arkin, for their valuable expertise and guidance. I would like to thank Hye-Joo Kim,
Associate Director, Regulatory Affairs, at the Centers for Disease Control and Prevention (CDC)
Atlanta, for helping me realize my thesis topic. I would like to thank Johnna Hodges for her
continuous support and guidance throughout my studies at the Pharmaceutical and Biomedical
Regulatory Affairs program. I would like to thank my classmates for sharing their experiences
and knowledge throughout the program. Also, I would like to thank the pediatricians, clinicians,
pharmacists, regulatory affairs personnel, and the FDA staff for participating in the surveys and
interviews, in spite of their busy schedules, and providing me their valuable insights on pediatric
drugs and pediatric exclusivity. Finally, I would like to thank my wife for being so supportive of
my studies and for putting up with many days and nights of homework and projects. I could not
have done this without you all.
vi
TABLE OF CONTENTS
Page
ACKNOWLEDGEMENTS ................................................................................................................ v
LIST OF FIGURES.......................................................................................................................... viii
CHAPTER
1 INTRODUCTION .......................................................................................................................... 1
1.1 Statement of the Research Problem ..................................................................................... 1
1.2 Purpose of Research ............................................................................................................ 2
1.3 Potential Outcomes of this Research ................................................................................... 3
2 LITERATURE REVIEW ............................................................................................................... 4
2.1 Pediatric Regulatory History ............................................................................................... 4
2.2 Challenges of Pediatric Drug Development ........................................................................ 6
2.3 Comments on Pediatric Studies conducted ......................................................................... 9
3 METHODOLOGY ....................................................................................................................... 11
3.1 Research Question ............................................................................................................. 11
3.2 Subsidiary Questions ......................................................................................................... 11
3.3 Study Design ..................................................................................................................... 12
3.4 Institutional Review Process ............................................................................................. 18
3.5 Data Analysis .................................................................................................................... 18
4 RESULTS .................................................................................................................................... 20
4.1 Survey and Interview Responses ....................................................................................... 20
4.2 Awareness of Pediatric Exclusivity ................................................................................... 21
4.3 Voluntary versus Mandatory Studies ................................................................................ 22
4.4 Studies conducted under Pediatric Exclusivity ................................................................. 24
vii
4.5 Pediatric Conditions Requiring Studies ............................................................................. 28
4.6 Problems/Concerns with Pediatric Drugs .......................................................................... 31
4.7 Challenges of Pediatric Drug Development under Pediatric Exclusivity .......................... 35
4.8 Impact of Pediatric Exclusivity on Pediatric Age Category .............................................. 38
4.9 Advantages of Pediatric Exclusivity to Stakeholders ........................................................ 40
4.10 Disadvantages of Pediatric Exclusivity to Stakeholders ................................................. 41
4.11 Support for Pediatric Exclusivity Provisions .................................................................. 42
4.12 Pediatric Exclusivity and Drug Labeling ........................................................................ 43
4.13 Pediatric Exclusivity and Pediatric Dosing ..................................................................... 45
4.14 Pediatric Exclusivity and Pediatric Formulation ............................................................. 47
4.15 Duration of Pediatric Exclusivity .................................................................................... 48
4.16 Factors Affecting the Success of Studies for Pediatric Exclusivity ................................ 49
4.17 Adequateness of Incentive ............................................................................................... 50
4.18 Alternatives to Pediatric Exclusivity ............................................................................... 51
4.19 Comparison of Drugs Granted Pediatric Exclusivity and Drugs used by Children ........ 52
4.20 Criticisms for Pediatric Exclusivity ................................................................................. 54
5 CONCLUSION AND RECOMMENDATION ........................................................................... 56
5.1 Conclusion ......................................................................................................................... 56
5.2 Recommendation ............................................................................................................... 59
5.3 Study Limitations .............................................................................................................. 61
REFERENCES ................................................................................................................................ 64
APPENDICES……………………………………..…………………………………….………………..68
A SURVEY QUESTIONS .............................................................................................................. 68
B INTERVIEW QUESTIONS ......................................................................................................... 75
C INTERVIEW TRANSCRIPTS…………………………………………………….……………79
viii
LIST OF FIGURES
Page
Figure 4.1: The number of pediatric drugs granted pediatric exclusivity between
1998 and 2011 .......................................................................................................... 26
Figure 4.2: Pediatric conditions requiring studies ....................................................................... 29
Figure 4.3: Problems/concerns with pediatric drugs.................................................................... 32
Figure 4.4: Challenges of pediatric drug development under pediatric exclusivity .................... 35
Figure 4.5: Impact of pediatric exclusivity on pediatric age category ......................................... 39
Figure 4.6: Number of labeling changes for drug products granted pediatric exclusivity
falling within the scope of BPCA, PREA, and Pediatric Rule ................................. 43
Figure 4.7: Benefits of improved pediatric labeling as a result of pediatric exclusivity ............ 45
Figure 4.8: Factors affecting the success of studies for pediatric exclusivity ............................. 50
1
CHAPTER 1
INTRODUCTION
1.1 Statement of the Research Problem
At a time when there is a need for safe, effective, and tested drugs, two thirds of pediatric
drugs currently prescribed have not been studied and labeled for pediatric use 1,2.
Up to 80% of
prescriptions for children in the hospital and in general practice are either unlicensed (without a
license for children) or used off-label (outside the indication or age for use approved by the
FDA) 3 as these drugs have not been subjected to clinical testing in pediatric patients. There are
significant deficits in our current knowledge of the quality and efficacy of many therapeutic
measures in children,4
and much pediatric therapeutic data is derived from studies in adults5.
Pediatric studies are needed for a number of reasons. Pediatric diseases are different from
adults. There is no analogy to neonatal diseases in adults, and illnesses affect children and adults
differently2. The effect of drugs can be different
2. Children may not tolerate some treatments
because of the taste or method of administration. The absence of adequate pediatric studies has
led to inadequate dosing information, drug safety issues, and ineffective treatment in children.2
Inadequate dosing information can create adverse reactions. The lack of pediatric safety
information can produce age-specific adverse reactions in children. The absence of pediatric
testing can lead to ineffective treatment through under dosing or prevent access to therapeutic
advances because physicians choose to prescribe existing, less effective medications in the face
of insufficient pediatric information about a new medicine.4
2
Ideally, pediatric drugs should taste good, require reduced dosing frequency, have
minimal side effects, and employ improved delivery systems6. However, most pediatric
medications do not have adequate pediatric formulations and dosing guidelines for children
younger than 12 years of age6. In the absence of pediatric formulations, children are prescribed
adult formulations denying many important pediatric therapies with consistent bioavailability3.
Aimed at correcting this deficiency, Congress passed the Food and Drug Administration
Modernization Act (FDAMA) in 19972. Under Section 505A of the Act,
7 the Pediatric
Exclusivity Provision was established, which granted an additional 6 month patent extension, or
marketing exclusivity, to previously earned patent protection for certain drugs if the
manufacturers submitted requested information to the FDA regarding the use of the drug in
children.
1.2 Purpose of Research
The purpose of this study was to explore if the incentive scheme granted under the
pediatric provisions of FDAMA 1997 has stimulated pediatric studies in terms of number,
quality, and safety of pediatric drugs. Specifically, this study analyzed, by way of a questionnaire
survey and interviews based on stakeholders’ perspectives, if the pediatric exclusivity provisions
have improved the pediatric dosage forms, formulations, and labeling of drugs. Also, the
advantages and disadvantages of pediatric exclusivity provisions to pediatric patients and
consumers, medical practitioners, the FDA, and pediatric drug companies are discussed. Further,
the pediatric age categories where the impact of pediatric exclusivity was felt the most was
identified and suggestions are made as to which age categories need more studies. The major
problems and challenges of pediatric drug development, under the pediatric exclusivity
provisions are discussed and factors determining the success of the studies are outlined. A
3
determination is made if the pediatric exclusivity provisions have helped to generate more useful
information to guide physicians in better prescribing drugs for children.
1.3 Potential Outcomes of this Research
The research has evaluated the impact of the pediatric exclusivity provisions in
improving the safety and effectiveness of pediatric drugs vis-à-vis improved dosage forms,
pediatric formulations and pediatric labeling, and increased number and improved quality of
drugs developed. Specifically, this study has provided information about the pediatric conditions
for which more studies are required, the kinds of studies required, the pediatric age categories
where more studies are required, the dosing type, labeling and formulation changes for an met
pediatric need. Suggestions are made as to what factors contribute the most to the success of
pediatric studies under the pediatric exclusivity provisions. Further, the adequacy of the
incentives and the appropriateness of its duration were analyzed. The results obtained from this
study should provide helpful information in formulation of any future regulations on pediatric
exclusivity. The study has provided suggestions for strengthening the quality and quantity of
pediatric clinical trials under the pediatric exclusivity to improve their efficacy and safety on
pediatric labeling and dosage. Overall, by identifying and analyzing the key factors affecting the
safety and effectiveness of pediatric drugs under the pediatric exclusivity provisions, the
pediatric drug development programs may be specialized to address the unmet pediatric medical
needs identified in this study.
4
CHAPTER 2
LITERATURE REVIEW
2.1 Pediatric Regulatory History
Recognizing the need to have a determination of pediatric applicability and adequate
labeling instructions for children, Congress included incentives for conducting needed studies in
the Food and Drug Administration Modernization Act of 1997 (FDAMA). In 1998, Congress
passed the Pediatric Rule, which became effective in April 1999. The rule requires
manufacturers of new drugs to conduct studies to provide adequate labeling for the use of these
products in children if the drug is likely to be used in a substantial number of pediatric patients or
would provide a meaningful therapeutic benefit to pediatric patients over existing therapies 8,9
.
Due to slow progress, Congress added additional incentives in the Best Pharmaceuticals for
Children Act (BPCA) 10
in January 2002, which extended the economic incentives offered under
the Pediatric Exclusivity Provision by six months if adequate pediatric studies were performed
and allowed the FDA to formally request that such studies be performed 11
.
In 2003, the Pediatric Research Equity Act (PREA)12
which replaced the Pediatric Rule,
mandated pediatric studies for new active ingredients, new indications, new dosage forms, new
dosing regimens and new routes of administration, in support of New Drug Application (NDA)
and Biologics License Applications (BLA)13.
Additionally, the Act provided the FDA with the
authority to use bridging data from adult studies in approving pediatric medicines14
. These three
acts, together with continuing enabling legislation through the Prescription Drug User Fee Act
(PDUFA) renewals, encourage the development of pediatric drugs. In 2007, the Food and Drug
5
Administration Amendment Act (FDAAA) reauthorized BPCA and PREA whereby a Pediatric
Review Committee (PeRC) was established 15
. The total number of studies completed under
BPCA and PREA pursuant to FDAAA16
between September 27, 2007 and December 31,
2011 was 360. Under these acts, the most studies were conducted within PREA (219), followed
by BPCA and PREA combined (72), and BPCA (69). The total number of patients in completed
FDAAA studies was 166,646. 16
The pediatric patient enrollment in studies conducted under
different Acts shows that the highest number of patients (114,731, 68.8%) were enrolled in
CBER PREA studies (vaccines and blood products), followed by CDER PREA studies (30,093,
18.1%). BPCA studies employed 21, 822 (13.1%) pediatric patients16
. Progress of pediatric
studies from September 27, 2007 (FDAAA) through December 31, 2011, based on the
information submitted by the applicants to the FDA, showed that in four years, 139 studies were
ongoing, 1104 studies were pending, 120 studies were submitted, 57 studies were fulfilled, 57
studies were released, 234 studies were delayed, and 13 studies were terminated.17
Studies were
delayed if their progression was behind the original study schedule. Delays have occurred in all
phases of the study, including patient enrollment, analysis of study results, or submission of the
final study report to the FDA. Pending studies are not delayed (i.e., the original projected date for
initiation of patient accrual or initiation of animal dosing has not passed) but they have not been
initiated (i.e., no subjects have been enrolled or animals dosed). More studies were delayed and
pending than were submitted and fulfilled, showing that the required studies are hard to come by
from pediatric clinical trials. The BPCA and PREA are set to expire on October 1, 2012 unless
Congress reauthorizes them. Many pediatric studies are expected to be conducted15
before these
key pieces of legislation expire.
6
Until these acts (BPCA, PREA, and FDAAA) were passed, the approach in pediatric
drugs was first to develop a drug for adults and then adjust the dose for use in children15
. The
belief was if a drug was safe enough for adults, it would be safe enough for children. The three
acts (BPCA, PREA, and FDAAA) make the development of an "age-appropriate formulation" a
legal requirement if the drug under development is appropriate for children. Since the
implementation of FDAAA, the BPCA, the Pediatric Final Rule, and the PREA, hundreds of
drug trials have been conducted in children.
Many of these trials resulted in added FDA-approved indications for these drugs in
children. Similarly, many of these studies resulted in critical new warnings and safety data, new
pharmacokinetic data and dosing instructions, and even new designs for pediatric drug trials15
.
The present study will analyze the effectiveness of pediatric exclusivity provisions in stimulating
drug research in children, and should add valuable knowledge to this important regulatory arena.
2.2 Challenges of Pediatric Drug Development
Of the total global pediatric research conducted worldwide, only 6.5% is conducted in the
US compared to 47% in China, 33% in Russia, and 24.6% in the Czech Republic18
. More than
one-third of trials conducted under pediatric exclusivity provisions enrolled patients in sites
outside the US in developing/transition countries.19
This is mainly because of the reduced cost
and timeline of clinical trials conducted in less stringent regulatory environments overseas and
the ease of pediatric patient recruitment. 19
Some of these studies raise serious ethical and
scientific concerns. So, the need to conduct more pediatric trials is urgently felt in the US. Thus,
the US should increase its share of pediatric studies to obtain quality information rather than
depending excessively on pediatric studies outsourced to the emerging regions of the third world
countries.
7
Pharmaceutical companies can earn pediatric exclusivity for an approved drug as well as one
in the approval process. To be eligible for pediatric exclusivity, an approved product must meet
the following three essential elements20
:
The applicant must receive a Written Request from the FDA asking for pediatric studies.
The request describes the studies needed to determine if the use of a drug could have
meaningful health benefits in the pediatric population. The FDA may issue a Written
Request for those studies at the request of an interested party or on its own initiative.
The studies must be submitted within the time-frame specified in the written request.
The studies performed must meet the terms specified in the written request.
The FDA has issued a Written Request (WR) For Pediatric Studies under the Best
Pharmaceuticals for Children Act (BPCA) to 19 approved active moieties with no marketing
protection (As of 11/24/2009). These moieties include: ampicillin, azithromycin, baclofen,
dactinomycin, daunomycin, griseofulvin, hydrochlorothiazide, hydrocortisone (hydrocortisone
valerate), isotretinoin, lindane, lithium, lorazepam, meropenem, methotrexate, metoclopramide,
morphine, rifampin, sodium nitroprusside, and vincristine 21
.
The development of pediatric drugs poses a number of challenges including ethical,
economical, logistical, and technical. There are ethical considerations when conducting studies in
diseases where a treatment is already available, where a placebo control is relevant,22
and in an
emergency setting. All of these affect the willingness of patients to participate in clinical
research. Even more challenging are the complex ethical issues presented by pediatric studies:
the unique requirements of recruiting minors and obtaining the appropriate level of informed
consent (or assent in the agreeing child's case), avoiding coercive or improper inducements, and
minimizing the distress and undue risk to the young patients who participate. Children, as a class,
8
may be harmed due to lack of research into a disease and the effect of drugs. Further, the risks of
using drugs untested in children will always have greater potential for harm, given the high
figures for off-label and off-license use. Separate age-appropriate information sheets and consent
or assent forms should be developed for the parents or legal representatives and for the child.
Other ethical questions also constantly arise when sponsors consider pediatric trials. For
example, can healthy children participate in taste tests of pediatric liquid formulations? How
does one define “minimum risk” in terms of venipuncture and sample collection? Should
currently symptom-free children with cystic fibrosis participate in pharmacokinetic studies of
inhaled aerosolized antibiotics?22
How should investigators handle the need for contraceptives
for adolescents involved in therapeutic trials where teratogenesis may be of concern, such as
trials of new antiepileptics? What are the standards for off-license, off-label drug use in very low
birth weight infants (under 1 kg)? Do we need placebo-controlled trials when there is no existing
comparator, as in the case of antiviral agents?22
The ethical issues around compensation for
pediatric participants are also more challenging than in adult trials. Pediatric trials often find it
difficult to address several of these ethical challenges. The pediatric investigator and site staff
must be trained in the least-invasive and non-coercive methods for conducting pediatric studies,
and they must know how to budget their time and costs to prevent the patient or the practice from
unwittingly subsidizing the research. 22 A child’s response to illness varies with age. For
example, neonates and infants may be far more ill with a particular infection than an older child.
However, they may not be able to provide an assessment of pain due to an illness unlike an
adolescent. This can render statistical analysis difficult and perhaps inconclusive. Also, there is
lack of established relevance of surrogate markers for children. 22
9
2.3 Comments on Pediatric Studies conducted
Inconsistent and confusing labels are present on pediatric drugs23
. There is dosing
information based on age, weight or both. Which is the best method is still unclear. Further, there
are pediatric labels of only a few medicines in children less than two years of age, but more
labels in drugs for children older than two years of age. Larger companies requiring additional
clinical studies were found to be better at filing exclusivity than smaller firms and the
competition level in each drug’s therapeutic class was positively associated with having
exclusivity. The drugs with exclusivities were more likely to treat chronic conditions that include
many blockbuster drugs.24
The European Union (EU) is of the opinion that pharmaceutical companies lack the
commercial interest to develop medicines for use in children.25
Studies in children are described
as being difficult to conduct, ethically challenging, and expensive26
. The development of specific
formulations adapted for use in children presents an additional expense. Furthermore, there is
little incentive to apply for the authorization of products for use in the pediatric population. To
stimulate the development of pediatric formulation, legislations were introduced in the EU
providing market incentives and regulatory requirements.27
The goals of these initiatives,
however, are difficult to reach if the challenges in pediatric formulation and taste optimization
are not well managed25
.
Mixed opinions have been reported on the adequacy of incentives provided under
FDAMA.28
The exclusivity provisions are not without criticisms. Some critics have described the
incentive provisions as a “carrot and stick” policy.28
The “carrot” is the voluntary pediatric
exclusivity provision of the Food and Drug Administration Modernization Act of 1997
(FDAMA), which was reauthorized in January 2002 and extended through 2007 as the Best
10
Pharmaceuticals for Children Act (BPCA). The “stick” is the Pediatric Research Equity Act
(PREA), which allows the FDA to require pediatric studies. Some pediatric drug companies,
citing high costs, have tried to eliminate the pediatric rule for several years. Historically, many
pharmaceutical companies have opted not to conduct extensive pediatric clinical trials because of
the substantial fiscal, scientific, and ethical challenges they present. The comparative
effectiveness of medical interventions in adults versus children shows that treatment effects are
on average similar in adults and children,29
but available evidence leaves large uncertainty about
their relative efficacy. Clinically important discrepancies may occur29
. Extrapolation of adult
data to medicinal products for the child population is inappropriate. Many differences exist in
physiology, pathology, pharmacokinetics, and pharmacodynamics between children and adults
30. For example, in pharmacokinetics, there are differences in metabolic pathways, in organic
functions, and in metabolic rates. In pharmacodynamics, differences exist in receptor functions,
effector systems, and homeostatic mechanisms. Growth and development influence side effects,
and the dose of medications is dependent on body weight or surface area. Finally, age influences
severity of disease, pathological agents, and natural history. Children have become therapeutic
orphans due to the lack of adequate pediatric dosing information among drugs that are on the
market31
. Pediatric studies have reported improvements in dosage forms for children over the age
of six, but not much for younger children32
.
11
CHAPTER 3
METHODOLOGY
3.1 Research Question
Has the incentive scheme granted under the pediatric exclusivity provisions of FDAMA
1997 stimulated pediatric studies in terms of number, quality, and safety of pediatric drugs? This
research has explored, by way of a questionnaire survey and interviews of key stakeholders, if
the pediatric exclusivity provisions have improved the safety and effectiveness of pediatric
drugs, vis-a vis their improved labeling, dosing, and formulation information.
3.2 Subsidiary Questions
1. Has the number of pediatric drugs developed changed before and after the passage of the
pediatric exclusivity provisions?
2. Were the development of pediatric drugs enhanced due to economic incentive provisions of
pediatric exclusivity?
3. Have the dosage forms, formulations, and labeling of drugs improved as a result of the market
incentive provision?
4. What are the advantages and disadvantages of pediatric exclusivity provisions to pediatric
patients and consumers, medical practitioners, and pediatric drug companies?
5. For what pediatric age categories are the impact of pediatric exclusivity felt the most and for
what age categories are more studies needed?
6. What factors could determine the success of studies for pediatric exclusivity?
7. What are the major problems with pediatric drugs?
12
8. What are the challenges of pediatric drug development under the pediatric exclusivity
provisions?
The study determined whether the pediatric exclusivity provisions have improved the quality
of pediatric drugs making them more safe and efficacious, thus meeting the FDA’s intention of
passing the regulatory provision to a considerable extent. The information obtained from this
study should guide the formulation of any future regulations on pediatric exclusivity.
3.3 Study Design
A literature search was performed to identify prior studies conducted on pediatric drugs
and pediatric exclusivity. The search involved the following key words: children, pediatrics,
pediatric drugs, pediatric exclusivity, and pediatric clinical trials. Based on the titles and
abstracts, full copies of relevant studies were obtained. The FDA website was extensively used to
gather information to analyze data on the number and types of drugs granted pediatric
exclusivity. Based on the literature review conducted during the research proposal phase, a set of
interview questions was compiled and applied to the second level of research involving specific
human subject experts on the topic. The sample respondents for the survey and interview
included regulatory affairs personnel at pediatric drug manufacturing companies, pharmacists,
clinicians, pediatric consultants, and relevant FDA staff involved with regulating pediatric drugs.
The participants were identified through their company’s website, contact addresses, and
published articles. The pediatricians were identified through their hospital affiliations and contact
addresses available in the public domain, as well as through their contact information located
with their articles published in the peer-reviewed journals. All the respondents had demonstrated
experience and proven expertise with pediatric drugs.
13
The inclusion criteria for the survey and interview were participants having essential
knowledge of pediatric drugs or having direct (manufacturing, research, clinical trials,
prescribing) or indirect (regulating) involvement with pediatric drugs for a minimum of two
years. Similarly, participants who willingly provided their informed consent were included in the
survey and interview to preserve the ethic of the study and to meet the IRB requirement.
Informed consent was obtained from each participant through an informational letter. The
exclusion criteria for the study were participants with less than two years of direct or indirect
experience with pediatric drugs. Also, participants not providing their informed consent to
participate were excluded from the study.
The author developed his own survey and interview instruments based on the literature
review. This was done because of unavailability of previously validated instruments. The survey
and interview questionnaires were the same except for one structural difference. A majority of
survey questionnaires were structured which asked for graded responses on a scale of 1-10
(where 1 denoted least or the lowest response and 10 denoted the most or the highest response)
to guide respondents to the best possible answers. However, most of the interview questions
were unstructured and did not ask for graded responses to allow respondents the flexibility to
state their perspectives. Moreover, the interview participants were asked additional questions if
necessary, based on their responses, for an in depth perspective on issues of central importance
to the research question. The draft questionnaire was preliminarily administered on a pilot scale
as a pre-test to three informed participants who met the inclusion criteria as the actual
participants. The participants’ responses were observed to determine the adequacy of the
questions for the research purpose. Responses were considered adequate if all the respondents
graded all structured questions on a scale of 1-10 as well as offered their perspectives on all
14
open-ended questions. Accordingly, questions were improved, and modified to suit the purpose
of the research. Similarly, a follow-up post-test of the survey was conducted by way of phone
calls/email to participants to increase the validity of the data collected. In post-test, respondents
were asked to elaborate on certain points and illustrate others. A qualitative, non-random,
purposive sampling methodology was used for data collection. Using a purposive sampling,
which is a type of non-probability sampling, a specific predefined group of stakeholders with a
sound knowledge of pediatric drugs and pediatric exclusivity was sampled. Expert sampling,
which is a type of purposive sampling, was the best way to obtain information from stakeholders
with particular expertise in pediatric drugs. The expertise that was required during the
exploratory phase of qualitative research formed the basis of the study. Since there is lack of
empirical evidence and high levels of uncertainty of the impact of pediatric exclusivity on the
safety and effectiveness of pediatric drugs, expert sampling formed the cornerstone of the present
research design. The goal of the purposive sampling was to provide justification to make
generalizations from the sample that was studied. . Due to the complexity of the pediatric
exclusivity provisions, the respondents who were knowledgeable of the regulatory provisions
only participated in the survey and interviews while people who were not well informed of the
provision did not. Thus, responses obtained from well qualified and experienced participants
increased the validity of the study. A probability or random sampling method was not used for
the study. Probability or random sampling method if used would not have generated credible and
meaningful information on topics that required a highly specialized knowledge of pediatric drugs
and pediatric exclusivity. All survey and interview respondents were identified by using a
purposive sampling33
approach. Based on their knowledge and experience with pediatric drug
development, the author chose appropriate respondents for the study rather than random
15
selection. This sampling method was used as there was a limited number of people with
sufficient expertise in pediatric drugs and pediatric exclusivity that could be accessed with ease.
Besides purposive sampling, a snowball-sampling method was also used. In this method,
regulatory affairs (RA) personnel who met the criteria for inclusion in the study were identified,
who in turn were asked to recommend another person in the similar field for the survey.
Similarly, pediatricians referred other pediatricians. The referred pediatricians generally had
authored several research articles related to the topic of interest that were published in peer-
reviewed journals. Many company-based RA personnel who were otherwise normally
inaccessible were reached by snowball-sampling method. Convenience sampling was used for
the research participation. The researchers whose articles on pediatric drugs were published in
peer-reviewed journals were contacted by email for the survey participation. These respondents
in addition to being knowledgeable in their respective fields were easy to access.
To minimize selection/sampling bias, respondents from across all stakeholders of
pediatric exclusivity were included. To avoid procedural bias in the response time, respondents
were given ample time (three weeks) to complete the survey. The respondents’ names have
remained anonymous and no individually identifiable information about them has been shared
with others. The results of the research study have been presented in summary form only and the
participants’ identity has not been associated with their responses in any published format. Since
all respondents were selected on meeting the set criteria, the sampling ensured strong quality
assurance and credible information.
For the survey, structured and open-ended questionnaires were administered via e-mail to
regulatory staff of pediatric drug manufacturing companies, pharmacists, and clinicians (n=10),
and pediatric consultants (n=10). Since the goal of the study was qualitative, sample size
16
justification was also qualitative. Sampling of respondents was continued until saturation
occurred or upper bound was reached with the convergence of themes. Saturation occurred with
20 respondents when the same themes related to the research questions were repeated over and
over again and no new themes emerged. Though the sample sizes were small due to typically
busy and readily inaccessible respondents, the “information richness” of the cases and the
author’s analytical capabilities have made the qualitative inquiry in-depth, insightful, valid, and
meaningful.
The survey questionnaires were designed to obtain information about the number and
type of studies conducted for pediatric exclusivity, the motives behind the studies, and the
challenges faced in drug development. Also, questions pertained to challenges in developing
pediatric drugs, medical conditions for which pediatric exclusivity studies are required, kinds of
studies performed, pediatric age categories impacted, improvement in dosage form, formulations,
and labeling of drugs because of the incentive. Criticisms regarding pediatric exclusivity
provisions were questioned and suggestions for improvement sought along with factors affecting
the success of pediatric exclusivity provision. The survey questions are presented in Appendix A.
An inductive qualitative study34
was undertaken to identify and categorize perceptions
regarding the impact of pediatric exclusivity. The survey respondents were asked to rate their
responses to questions with multiple answers with varying degree of correctness on a scale of 1-
10. Responses below 5 were considered low in the descending order while responses above 5
were considered high in the ascending order. The average response from all participants for each
question was summed on a scale of 1-10 for analysis. The average score and percentage for each
response were calculated by a constant comparison process to determine the most common and
least common response from the sample. Constant comparison can be defined as a method to
17
analyze word data by creating categories that are scored and used to develop conclusions,
themes, or hypotheses35
. Each item of datum was compared to the rest of the data to establish the
conclusion categories. This process was used to create numeric data from the qualitative word
data collected in the research interview process. The conceptual data were integrated to reveal
patterns and consensus among the group of stakeholders regarding the impact of pediatric
exclusivity. From the sampling observations and results, broader generalizations were theorized
and conclusions drawn from qualitative analysis of the data. As the study participants were
generally unknown to each other and to the author, they were expected to bring varied and
independent ideas to the research.
For the interview, a set of 10 participants were targeted. Over the phone interviews were
conducted with senior directors of regulatory affairs from two major pediatric drug
manufacturing companies (n=2) and FDA staff at the Office of Pediatric Therapeutics (OPT),
Center for Drug Evaluation and Research (CDER) (n=1), to obtain their experiences, thoughts,
and perceptions on the impact of pediatric exclusivity on the safety and effectiveness of pediatric
drugs. Although the interview target was not met, the responses collected were so consistent
from respondent to respondent for many questions that conclusions could still be drawn on the
pediatric population as a whole even with the smaller than desired sample size. Most of the
interview questions were unstructured and open-ended to allow maximum flexibility of
responses. The interview questions are presented in Appendix B. In designing the interview
questions, care was taken to ensure that when these questions were answered, they would
provide adequate data to develop conclusions that would answer the thesis question. The
questions intended for the industry respondents were same or very similar to questions intended
18
for the FDA to facilitate comparison of responses. However, due to the different perspectives of
these two groups, this was not always feasible.
3.4 Institutional Review Process
This study proposal was submitted to The University of Georgia's (UGA) Institutional
Review Board (IRB) Office after completion of the IRB online training, for approval as required
by departmental policy, The University of Georgia policy,36
state law, 45 CFR part 46 37
, and 21
CFR part 5638
. For ethical considerations, the study was conducted only after the research
methods, study design, and survey/interview questionnaire obtained the UGA IRB approval
(Project Number: 2012-10182-0 Dated 9/27/2011).
3.5 Data Analysis
After the survey responses were received and interviews were conducted, inductive
qualitative studies were used to summarize and analyze the data39
. In inductive studies, broader
generalizations and theories are made from specific observations and patterns. Concepts are
usually associated with qualitative methods and often involve informal logic and critical
thinking. In inductive studies, related types of narratives are clustered together into a coherent
scheme based on the number of responses, their frequency, ratings, and commonality40
.
Qualitative data in the form of transcripts were analyzed by their content following Michael
Patton’s method as described in Qualitative Research & Evaluation Methods,34
In this method,
texts are explored to obtain reoccurring themes and patterns of thoughts between the
respondents. Phillip Burnard in his 16th volume of the 1996 Teaching the Analysis of Textual
Data: An Experimental Approach41
describes three steps to content analysis. First, the data, i.e.
transcripts, are read and categories are identified. Next, the data are divided into the identified
categories and finally, the data is presented in written form in which the identified categories
19
from step one become the sub headings35
. Step 3 would also include "...verbatim sections of the
interviews..." which Burnard terms "...illustrations..." that show conclusions directly drawn from
the data and not personal opinion35
. Data from the study were analyzed utilizing Burnards's
method. The transcripts from each focus group were reviewed and categories identified. Then,
the participant's responses were separated into the appropriate category as identified previously.
As far as possible, research findings were “grounded” in the data that were received from the
survey and interview participants. Quotes from the interviews were transcribed on to the thesis
and key concepts were identified. These interview transcripts were used as evidence to
emphasize the primary interview findings. The interview transcripts are presented in Appendix
C. The interview responses served to supplement the survey responses for added clarity on issues
central to the research question. Numerical survey data were analyzed as a percentage for
comparison of impact to get the most common perspectives. Qualitative survey data were
analyzed from their narrative description. Finally, the numerical and qualitative survey data were
combined with the interview transcripts to identify themes to draw conclusions from them.
Conclusions were drawn to emphasize group responses of participants. Based on the research
findings, recommendations were made about the type of pediatric studies that should be explored
in greater depth in future studies on pediatric exclusivity.
20
CHAPTER 4
RESULTS
4.1 Survey and Interview Responses
A total of 108 email requests for research participation, in the form of IRB approved
informational letter, were sent out to participants. Thirty-two (29.6%) informed participants
agreed to participate in the survey, to whom a questionnaire was sent out with their informed
consent. These participants included personnel from drug manufacturing companies,
pharmacists, clinicians, and pediatricians.
Among the pediatricians who participated in the surveys, 5 (50%) worked as instructors,
associate professors, or professors in pediatrics in various medical colleges, as well as practiced
medicines in their affiliated hospitals in the US. Four (40%) pediatricians were senior practicing
physicians, and one (10%) worked at the Child and Adolescent Treatment and Preventive
Intervention Research Branch at National Institutes of Health, Maryland. The industry
respondents were comprised of 2 associate directors of regulatory affairs, 2 directors of
regulatory affairs, 2 senior directors of regulatory affairs, 2 senior pharmacists, and 2 senior
clinicians. One of the two pharmacists worked for a pharmaceutical law group. Nine (45%)
respondents had one or more of their articles related to pediatric drugs published in peer-
reviewed journals. While 18 of the 20 survey respondents were US-based, two respondents were
non US-based-one a Canadian and the other a German. Both the international participants had
worked at the FDA and had expertise regulating pediatric drugs. The overall pool of respondents
21
was knowledgeable and experienced in their respective positions to provide meaningful answers
to the survey questions.
Out of 32 respondents, 20 responses were received from pediatricians (n=10) and drug
companies, pharmacists, and clinicians (n=10), with a response rate of 62.5 % based on the
questionnaire sent. While the pediatricians answered 24.6% of the total questionnaires sent, the
respondents from companies, pharmacists, and clinicians answered 16.8%. The response rate
from pediatricians was 76.9% (10 out of 13) while the response rate from companies,
pharmacist, and clinicians was 52.6% (10 out of 19). The results indicate that while the
pediatricians involved in research and academia were more willing to respond to the survey, the
drug companies were more willing to talk about their own drugs than pediatric drugs in general.
Similarly, three over-the-phone interviews were conducted with two senior regulatory
affairs personnel in pediatric drug companies and one with the FDA staff at the Office of the
Pediatric Therapeutics (OPT). Although six FDA personnel were contacted for the purpose of
this research, only one agreed to participate. The primary reason given by other staff for not
participating was the inappropriateness for them to respond to many of the interview and survey
questions concerning the FDA’s positions on policy issues related to pediatric exclusivity,
BPCA, and PREA. While one respondent expressed his reluctance to give interviews without
permission from a supervisor or from the FDA’s Press Office, another respondent said that she
was advised by the FDA lawyers not to answer the survey.
4.2 Awareness of Pediatric Exclusivity
While 15 respondents (75%) were fully aware (awareness rating of 8.7 on a scale of 1-10)
of pediatric exclusivity provisions, 5 respondents (25%) were reasonably aware (awareness
rating of 5.5 on a scale of 1-10). Those respondents who were reasonably aware of pediatric
22
exclusivity stated that the BPCA requires the FDA to issue summaries of data submitted under
the Pediatric Exclusivity Program but the agency policy requires the FDA to keep data secret.
Due to this “inconsistent policy,” respondents reported limited dissemination of the results of
the pediatric studies in the peer-reviewed literature, which was the reason for their reasonable
level of awareness of pediatric exclusivity. Comparison of the level of self reported awareness
of pediatric exclusivity provisions among stakeholders surveyed showed that the regulatory
affairs professionals (associate directors, directors, and senior directors) were fully aware
(awareness rating of 10 on a scale of 1-10) of pediatric exclusivity. The senior pharmacists and
senior clinicians were better aware (awareness rating of 8 on a scale of 1-10) than pediatricians
(awareness rating of 6 on a scale of 1-10). Since the regulatory affairs professionals most often
dealt with the FDA in their long pediatric product approval process, they had the highest level of
awareness of pediatric exclusivity. Similarly, the two senior RA professional and the FDA staff
interviewed said that they were “fully aware of pediatric exclusivity”. “For at least two studies
that I was involved, the FDA granted pediatric exclusivity,” said one RA personnel The
respondents who benefitted the most from the incentive provisions stated that they were “fully
aware of the regulatory requirements of pediatric exclusivity”. Overall results indicate a high
level of awareness of pediatric exclusivity provisions among stakeholders.
4.3 Voluntary versus Mandatory Studies
Fifteen (75%) survey respondents from industries and pediatricians said that they were
“fully satisfied with the flexibility and voluntary requirements” of pediatric exclusivity
provisions as opposed to a forced approach. These respondents stated that if these studies were
not voluntary, people would be “hesitant to conduct trials on children”, and hence there would be
no new trials and no novel medicines for pediatric conditions. Interview responses also offered
23
support for voluntary and flexibility requirements of pediatric exclusivity. For example,
participants stated: “…it is up to the industry to decide if they want to take advantage of the
program”.., “…getting corporate buy-in by offering increased/prolonged profits on still useful
drugs seems more positive than a forced approach…” “…you don’t obtain exclusivity unless you
provide pediatric data…”, and “…the flexibility, sadly, is necessary…” The FDA staff
interviewed expressed his support for voluntary requirements stating “the economic incentive to
comply with the voluntary requirements balance the effort of compliance”.
To the question whether the FDA should make pediatric studies mandatory, 9 respondents (45%)
said that they supported “mandatory studies, in compliance with PREA” as long as they were
feasible, and assured that all pediatric age groups were appropriately treated. One RA staff
interviewed stated: “The FDA does make pediatric studies mandatory for applicable products in
accordance with PREA.” However, 18 respondents (90%) expressed concern that if these studies
were mandatory, it may “…cause fewer drugs to be available for children or delay drug
development…” while waiting on studies that were difficult to conduct. One RA staff
interviewed stated: “…I’d be concerned about the unintended consequences of mandated
pediatric research”, while one other RA staff said “…not sure it is feasible. The FDA cannot
make them [referring to pediatric studies] mandatory based on the current law. It is not a
regulatory issue but a legislative one.” Also, concerns were raised that making pediatric studies
mandatory could be problematic as there was very often a “force-fit”. Respondents cited, for
instance, that “children have different reasons to take antihypertensive than adults. So requiring
pediatric studies might be difficult, expensive, and not ultimately that beneficial”. However, all
respondents agreed that the need for pediatric studies should reflect “potential utility” and
expressed concern about unintended consequences of mandated pediatric research including high
24
financial costs of drug development and risks of inadequate return on investment. Overall results
indicate that the regulatory affairs professionals, pharmacists, and clinicians more strongly
favored the mandatory studies in compliance with PREA than the pediatricians did.
4.4 Studies conducted under Pediatric Exclusivity
The FDA issues a written request (WR) to pharmaceutical companies before initiation of
pediatric exclusivity studies. The WR contains the required elements of the requested studies,
including indication, number of studies, sample sizes, trial design, and age ranges. Respondents
said that their company’s main motive behind conducting studies for pediatric exclusivity was
“improvement in pediatric dosages, labeling, and formulation”. For instance, an industry based
RA staff interviewed stated: “…primarily we had a pediatric indication. Exclusivity was granted
for work conducted to generate long-term safety and pharmacokinetic data to update the labeling
of the product”. One RA staff stated “…commitment of my industry to provide safe and effective
drugs to children”, “…compliance with PREA requirements”, as the main motives to conduct
studies for pediatric exclusivity followed by “financial rewards of pediatric exclusivity”.
The Best Pharmaceuticals for Children and Pediatric Research Equity Acts
(BPCA/PREA) have continued industry incentives and opportunities for pediatric drug trials
(PDTs). However, respondents opined that there was “…no current assessment of the capacity to
perform PDTs”. While 18 (90%) survey respondents noted an increase in PDTs since the initial
passage of BPCA/PREA, a dominant theme that emerged was that it was “insufficient” given the
high capacity of US PDTs. Respondents noted that this insufficient trials might hinder the
development of new drugs for children. Respondents stated the need for a more “transparent
pediatric testing process” where both positive as well as negative trial results are published or
otherwise publicly available post-trial. One pediatrician surveyed stated, “Future PDTs should
25
provide additional information on “cardiovascular medicines, mental health medications, and
sedatives”. Eighteen (90%) survey respondents and all interview participants claimed that the 10
year period between the introduction of pediatric exclusivity (1997) and the reauthorization of
BPCA and PREA (September 2007) was a “great success, having generated some 800 studies
that have resulted in labeling changes for more than 100 drugs”. Respondents opined that, during
this period, more drugs were granted pediatric exclusivity than any other time due to the high
number of pediatric studies generated and much useful labeling changes resulted from them. One
RA staff interviewed stated “While the adult drug development is industry driven, pediatric drug
development is regulatory driven” [indicating the impact of pediatric exclusivity provision under
FDAMA in stimulating pediatric studies]. One other RA staff interviewed stated “Nothing has
worked better than incentives to get the pharmaceutical industry conduct pediatric clinical trials”.
The FDA staff interviewed stated that the exclusivity provision resulted in new studies and “has
been highly effective in generating pediatric studies on many drugs and in providing useful new
information regarding safety, efficacy, dosing, and unique risks of drugs in pediatric patients”.
The staff noted that the incentive “naturally tended to produce pediatric studies on those products
where the exclusivity has the greatest value” [referring to blockbuster drugs]. The FDA staff
further stated: The BPCA and PREA are “real success stories”; the pediatric exclusivity is “the
most successful pediatric initiative that the Agency has participated in to date” and the
regulations have been a “big advance” in developing pediatric medicines. Furthermore, the FDA
staff reported a “substantial increase in the number of pediatric clinical trial data” submitted to
the Agency under the BPCA and PREA. However, the FDA staff cautioned, “to what extent can
policy makers rely on incentives alone as a means of ensuring appropriate testing” remains
unclear. One survey respondent reported “numerous gaps” in current pediatric testing of both
26
“off-and on-patent” drugs and said that pediatric exclusivity is “far from perfect”. One other
respondent stated, “Pediatric exclusivity has been undeniably successful but could have been
more successful”. Overall responses indicate that though pediatric exclusivity provision has been
successful in stimulating pediatric studies, the pharmaceutical industries need to conduct testing
of more pediatric drugs and make results publically available to ensure that they are safe and
effective.
The number of drugs granted pediatric exclusivity year wise from 1998 through 2011 was
counted from the FDA website and assembled into a chart. In 13 years, 185 drugs were granted
pediatric exclusivity* (Figure 4.1).
Figure 4.1: The number of pediatric drugs granted pediatric exclusivity* between 1998 and 2011
Note: *Figure based on the numbers and data that have been extracted from the FDA website from information
published in: Pediatric Exclusivity Granted. Available at:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM223058.pdf.
The most frequent drug groups that were granted pediatric exclusivity were reported to be
lipid-lowering preparations, antidepressants and mood stabilizers, ACE inhibitors, HIV
Year
No.
of
dru
gs
gra
nte
d p
edia
tric
excl
usi
vit
y
27
antivirals, and non-steroidal anti-inflammatory and anti-rheumatic drugs, and drugs to treat
hypertension and elevated cholesterol. Respondents reported that numerous pharmaceutical
manufacturers initiated trials of their drugs in pediatric patients after the pediatric exclusivity
provisions were enacted to “take advantage of the incentive provisions”. Respondents reported
that nearly all drugs evaluated in exclusivity-inspired pediatric research had no serious adverse
events necessitating enhanced adverse event monitoring.
Analysis of the number of drugs granted pediatric exclusivity company-wise showed that
AstraZeneca had the most drugs granted pediatric exclusivity (14 or 7.6% of total pediatric
exclusivity granted until 2011), followed by GSK and Merck (13 or 7% of total pediatric
exclusivity granted until 2011) and Novartis had the third highest pediatric exclusivity granted (9
or 4.9% of total pediatric exclusivity granted till 2011). Though these multinational
pharmaceutical companies do not specialize in pediatric drugs, these firms with their high
volume of research and development have produced many drugs including several pediatric
drugs that were granted pediatric exclusivity. Big companies have availed incentive provisions of
pediatric exclusivity the most and developed many pediatric drugs.
The survey results from informed participants, on the kinds of studies conducted under the
pediatric exclusivity provisions showed 6.5 (65%) for efficacy and safety studies, 1.8 (18%) for
pharmacokinetics/safety studies, 1.0 (10%) for safety studies, and 0.7 (7%) for
pharmacokinetics/pharmacodynamics and pharmacokinetics/safety studies. Similarly, the
interview respondents reported that the most common studies conducted under pediatric
exclusivity were “efficacy/safety” followed by “pharmacokinetics/safety” studies.
In general, respondents stated that the type of study conducted depended on the “type of drug
developed and its risk benefit profile”. Although safety information was collected on all studies,
28
only the safety and efficacy studies were generally designed and/or powered to detect safety
signals. One interview respondent stated, “If we understand how a drug works in adults, then
pharmacokinetic studies are sufficient for pediatric population…” Respondents reported that
pharmacokinetic studies. Interview respondents reported that the time to complete efficacy
studies was approximately 50% longer than pharmacokinetic studies (median 24 months vs 16
months). The median duration of bioequivalence studies was reported to be 6 months (range 5-7
months). Similarly, most respondents reported a higher cost of completing safety and efficacy
trials than pharmacokinetic trials. Interview respondents reported that many pediatric studies
were delayed and pending. The FDA staff interviewed stated: “…for timely development of
pediatric drugs, all pediatric studies that are delayed and pending need to be expedited”. One
pediatrician working with the NIH stated, “NIH has to conduct more studies of off-patent
pediatric drugs for which specific appropriation should be granted”.
While 17 (85%) respondents agreed that safety, pharmacokinetics, and
pharmacodynamics studies are a must, 2 (10%) respondents perceived that more short-term
efficacy and safety and pharmacokinetics and long term safety data are needed. One respondent
(5%) outlined that efficacy studies can be difficult or unethical depending on the product, and the
regulations have allowed for extrapolation of efficacy under certain circumstances. All 20
(100%) survey respondents and all 3 (100%) interview respondents agreed that studies conducted
under a written request (WR) with the FDA are adequate.
4.5 Pediatric Conditions Requiring Studies
When asked about their thoughts on which pediatric medicines currently available in the market
need non-clinical and clinical studies to establish their safety and efficacy, pediatric cancer
topped the list (7.5, 75%), followed by neonatal conditions (6.9, 69%), pediatric MRSA (6.4,
29
64%), heart disease (6.3, 63%), HIV (6.2, 62%), and pediatric hypertension and asthma (5.3,
53%) (Figure 4.2).
Figure 4.2: Pediatric conditions requiring studies
Respondents outlined the need to generate information regarding the pharmacokinetics,
safety, and efficacy of pediatric cancer drugs specifically for neuroblastoma. Respondents stated
the urgent need of studies to better understand the biology and causes of childhood cancer to help
develop targeted therapeutics by integrating the latest molecular techniques. One RA personnel
interviewed stated, “Pediatric cancer studies are needed depending on the type of malignancy as
the pathogenesis may be similar in certain cancer”. Similarly, respondents outlined the need to
perform clinical studies on drugs for the treatment of pediatric pain, neonatal seizures, and
bronchopulmonary dysplasia among others. One interview respondent stated: “Neonatal studies
are very hard to conduct but the inherent safety concerns are a critical question especially for
long term development”. Also, a need to generate “safety and pharmacokinetics data in the use
of drugs like tetracycline, doxycycline, clindamycin, trimethoprim-sulfamethoxazole, in the
Sca
le (
1-1
0)
Pediatric conditions requiring studies
30
treatment of pediatric MRSA was expressed”. Respondents stated, pediatric HIV studies are a
“major ongoing concern worldwide” but a minor concern in the US. The need of long-term
safety assessments of drugs in the treatment of pediatric asthma and their delivery systems was
also emphasized. Similarly, respondents outlined the need to conduct studies on pediatric
“antidepressants, ADHD medications, antiepileptics, and anti-infectives (especially antivirals
directed towards influenza”. Additionally, the respondents suggested “childhood obesity, fragile
X syndrome, sickle cell anemia, and Attention Deficit Hyperactivity Disorder (ADHD)” as
future areas of research consideration.
In general, responses indicated that for conditions that are common in children such as asthma,
bacterial/viral infections, dermatologic conditions (like eczema), medications targeting these
conditions should always be studied pre-approval in this important population. Also, for
conditions where there are safety concerns like developmental or neoplastic conditions due to
rapidly dividing cells, pediatric studies are required. Overall responses indicated that pediatric
conditions requiring studies was dependent upon the science of the medication, the safety &
pharmacokinetic profile, and the prevalence/incidence of the condition.
While 17 (85%) respondents outlined the unmet medical needs for pediatric conditions,
two (10%) respondents said that they did not have sufficient expertise to prioritize a list and one
(5%) respondent said that he did not use the pediatric medicines enough to answer all the
questions.
When queried about what pediatric medicines currently available in the market do not
require pediatric studies (non-clinical and clinical), 16 (80%) respondents said that ideally all
medications require pediatric studies as none of the medicines that they use are completely and
thoroughly studied. These respondents felt that out of hundreds of pediatric medications in the
31
market, they had no clues, which have an adequate evidence base of safety and efficacy, and
which do not. The safety and efficacy range is much too broad. One pediatrician, specializing in
infectious diseases with 20 years of experience, opined that even in his own field, he did not
“know the full evidence base”. Twelve (60%) respondents said that medicines which are “rarely
used in the pediatric population, and medicines for diseases in which the affected physiological
systems are not altered” in pediatric patients, do not require pediatric studies. One interview
respondent said, “No further pediatric hypertension trials are needed in teenagers as there are at
least a dozen studies already conducted in them”. The respondent further stated, “if you want to
spend government dollars [referring to incentives of pediatric exclusivity] in pediatrics, I would
not recommend hypertension trials in obese teenagers, a disease caused by overeating. I am
ready to cure cancer as a tax payer”. In general, responses indicated that drugs that are already
labeled in pediatrics with published data and known to be fairly safe and effective do not require
pediatric studies.
4.6 Problems/Concerns with Pediatric Drugs
Eighteen (90%) out of 20 respondents expressed one or more problems/concerns with pediatric
drugs. On averaging the concerns, pediatric doses (8, 80%) ranked the number one, followed by
pediatric formulations (6.5, 65%) and pediatric labeling (6.4, 64%). Other concerns expressed
included indications for use (6.3, 63%), off- label use (6.2, 62%), unlicensed pediatric drugs (6.0,
60%), and routes of administration (5.6, 56%) (Figure 4.3). Respondents said that pediatric doses
are different from adult doses, which is not always taken into consideration seriously, resulting in
inadequate dosing information. For instance, pediatricians, pharmacist, and clinicians surveyed
stated that pediatric doses are “not standard” and there can be “errors in dose calculations”,
“suspensions often have to be compounded,” and “tablets may have to be cut”. Concerns were
32
Figure 4.3: Problems/concerns with pediatric drugs
expressed that the “therapeutic and toxic dose” can be very close and there is no clear distinction
between the two. Concerns were raised that very little research exists to demonstrate what dose
would be appropriate for use in children to achieve a “therapeutic effect”. One survey respondent
stated that, within the pediatric population, the “appropriate dose for a 5-year old is different
from that for a 15-year old”. This may lead to “ineffective treatment through under dosing or
overdosing”. Participants recommended a flexible oral dosage form for children that can be taken
whole, dissolved in a variety of liquids, or sprinkled on foods, making it easier for children to
swallow.
The second major concern expressed was that drugs are given in formulations not
accepted in children, which may be poorly or inconsistently bioavailable. Participants outlined
that not all commercially available pediatric drugs meet the ideal pediatric dosage form
33
requirements to be “orally dissolvable, tasteless, having minimal amounts of excipients, stable in
light, humidity, and heat, and having necessary release characteristics and dosage increments for
infants”. One interview participant suggested that formulation issues can be solved through
“research involving advanced knowledge in formulation (e,g reaction kinetics, taste–masking
technologies, physical chemistry of drug solubility and forms, taste assessment/optimization and
biopharmaceutics)”. Formulations for pediatrics, preferably a liquid, covering a broad age range
was recommended for children.
The third major concern expressed was that some drugs prescribed for children are not
labeled for them. The labeling of cough and cold medicines for children under 2 years of age
advising parents to “consult your physician” infers that pediatricians have access to dosing and
safety information unavailable to consumers. Participants expressed concerns that drugs are often
prescribed in children for different indications than in adults.
Participants outlined that many pediatric drugs are used “off-label and off-license” by
physicians, the scale of which is unknown. Participants reported that drugs were prescribed off-
label in relation to either “indication or age”. Many pediatricians, in their efforts to provide the
newest and best treatments, even adapt information developed in adult trials on children. The
acceptance of off label use provides companies less incentives to conduct pediatric trials.
Besides, the absence of strict statutory mandates and market demands often lead to a sponsor's
decision to not pursue pediatric studies. When questioned if the FDA does not control off-label
use, one RA personnel stated: “The FDA cannot deny treatment to kids when there are no better
medications for them”. One pediatrician who had published articles on off-label use of pediatric
drugs said that the majority of indication-related off-label use involved “gastrointestinal and
respiratory disorders”, while age-related off-label uses mainly involved “asthma medications and
34
anti-convulsants”. Interviewed participants stated that the most frequently used “off-label drugs
are analgesics, bronchodilators, and antibiotics”. One pediatric respondent cited propofol, a
short-acting intravenous anesthetic, not licensed in children but used in intensive care units for
their sedation that caused metabolic acidosis and 15 deaths in children. The problem with off-
label and off-license use was that the drug manufacturing company has no product liability, thus
posing risks of adverse events associated with the drug.
When asked how the problems with pediatric drugs can be solved, all participants stressed the
need to conduct enhanced research on these issues by making “clear assessment of overall
benefits and risks”. Respondents overwhelmingly stated that one has to balance the degree to
which a certain medication is needed versus its potential side effects. Respondents recommended
that the drug should only be commercialized if its potential benefits outweigh its risks in specific
age pediatric population. One interview respondent stated, “if there is a significant benefit with a
minimal risk based on cumulative data, there should be minimal need for companies/physicians
to waste valuable resources on specific development studies”. The FDA staff interviewed stated,
“If there is uncertainty regarding either the benefits or the risks, the FDA under the authority
given by Congress mandates post-licensure studies to companies, and should also be able to have
significant sanctions in the event these post-marketing studies are not completed”.
When asked if the pediatric exclusivity provisions have helped to resolve the identified issues, all
respondents were affirmative. They stated that pediatric exclusivity has provided the economic
incentives to conduct pediatric studies to develop “pediatric specific dosing, formulations, and
labeling changes” in hundreds of therapeutics in children. Participants stated that pediatric
exclusivity has driven the need to determine the “risk benefit profile” of pediatric products prior
to being able to actively advertise for this patient population. This provides better confidence that
35
the results will be pediatric patients beneficial. However, all participants suggested that much
more work still needs to be done to ensure the safety and efficacy of pediatric drugs.
4.7 Challenges of Pediatric Drug Development under Pediatric Exclusivity
When asked about the challenges of pediatric drug development under pediatric
exclusivity, (the average of responses of all 20 participants listed on a scale of 1-10) the main
challenges outlined were expensive trials (8.5, 85%), pediatric patient recruitment difficulties
(8.0, 80%), consent and assent process (6.1, 61%), scientific challenges (5.8, 58%), and cultural
bias against pediatric trials (5.8, 58%) (Figure 4.4).
Figure 4.4: Challenges of pediatric drug development under pediatric exclusivity
Participants explained that pediatric clinical trials performed under the pediatric
exclusivity program were “expensive and their economic returns were variable”. Participants
expressed their concerns that not all trials were profitable and remunerative. For new or
established drugs, the participants feared “possible lack of return on investment”, which may
deter drug firms from conducting any new clinical research. Participants opined that while the 6-
month patent extension granted under pediatric exclusivity is a huge incentive for blockbuster
drugs, the incentive is not enough to stimulate studies for rare pediatric indications or orphan
Challenges of pediatric drug development under pediatric exclusivity
Sca
le (
1-1
0)
36
drugs. However, overall responses show that economic incentives to comply with the voluntary
requirements generally balance the effort of compliance by way of increased/prolonged profits
and favorable return on investments.
Participants outlined that recruiting pediatric subjects was difficult since many diseases
are less common in children. Therefore, pediatric patients with the same conditions were more
scattered, difficult to find, and a few in number, leading to additional logistical and cost issues.
Further, participants stated that there was likely pressure being placed on children with chronic
diseases to enter a series of studies because their target population was small. The survey
participants, who were parents themselves, expressed their reluctance to enroll their children in
basic research with no perceivable immediate benefit. Further, the participants noted, “healthy
children were difficult to recruit” because research to them was perceived as “non-therapeutic”.
In addition, concerns were raised that many parents have reservation about enrolling their
children in placebo-controlled trials, as they do not understand these trials, which benefit
pediatric populations rather than the research participant directly. One interview participant,
however, noted “parents with children with life threatening diseases like leukemia and cystic
fibrosis for which standard therapies were unsatisfactory, were more willing to enroll their
children into research”.
Participants recommended that adequate and appropriate information about the potential
benefits and risks of clinical trials should be provided to parents and children in a child friendly
and unambiguous language. Also, appropriate transportation facilities to investigative sites,
research facilities, and communication in multilingual and multicultural populations will enhance
recruitment and retention and positively affect the quality and timeliness of a trial. Further,
participants unanimously agreed that for children to benefit from advances in pediatric research,
37
both healthy children as well as children with chronic diseases should be enrolled as subjects in
potentially harmful research or research involving high risks.
Eighteen (90%) survey participants stated that pediatric research presents complex ethical
issues of “informed consent and assent” (in case of an agreeing child) processes to protect
vulnerable populations from undue risk. Participants stated that as children are unable to give
informed consent for their participation, they are particularly vulnerable to research-related
abuses. Also, they have greater potential for harm from the risks of using drugs untested in them
or being used as “guinea pigs”. “Can a 7 year old (the age arbitrarily recommended for including
children in the assent process) fully understand the complexities of clinical trials to which he/she
is assenting to?,” remarked one interview participant. However, 2 (10%) survey participants
stated that unless there is a risk of undesired effects there should be no major ethical concerns;
nonetheless the ethical controls surrounding the conduct of the study should be heightened.
“Whether pediatric participants are adequately compensated for their research participation is
another area of concern”, one respondent noted. Respondents also noted that researchers
sometimes underestimate “the stress of short-term pain (such as blood sampling)” in young
children. Because of small blood volume of children, not more than 5% of the circulating volume
can be taken for pharmacokinetic studies with frequent blood sampling, respondents stated.
Respondents suggested that researchers “conduct a proper informed consent and assent
process, avoid coercive or improper inducements, use less complex information sheets, and
minimize the distress of pediatric participants”. Researchers should make every effort to
anticipate safety issues and design pediatric studies that minimize patient risk while balancing
the potential benefit and harm of research, respondents noted.
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Respondents noted that there is only a “small pool of trained pediatric investigators” at a
time when there is increased demand for pediatric studies. They note that this has increased the
competition for resources and raised the cost of pediatric trials. Respondents noted that because
there are inherent “biological, psychological, and pharmacological differences between various
pediatric age groups”, trial designs are challenged to carefully weigh and balance these factors to
ensure valid results. The other issue that was pointed out by the participants was “the lack of
established relevance of surrogate markers for children”. Participants stated that “quality-of-life
questionnaire” to assess the impact of a disease or treatment on various aspects of a patient’s life
needs to be validated in children.
Respondents noted that since drug development programs were more geared towards
adults due to the high frequency of their illness and large market share of their drugs, pediatric
drug development programs get side tracked. Three survey respondents stated that some
pharmaceutical industries manifest a “corporate inertia” that favors the development and
marketing of new drugs for adult populations, thus delaying pediatric studies. However, this was
not true for all pharmaceutical companies. For instance, one interview participant stated,
“…really depends on your legal perspective; we have no bias against conducting pediatric
studies”.
4.8 Impact of Pediatric Exclusivity on Pediatric Age Category
When respondents were asked which pediatric age categories benefitted the most from
the incentive provisions of pediatric exclusivity (benefits rated on as scale of 1-10) they ranked
adolescents (12-16 years) at the top (9, 90%), followed by children (2-12 years) (7.4, 74%),
infants (1 month-2 years) (4, 40%), and neonates (0-1 month) (3.8, 38%) ranked at the bottom
(Figure 4.5).
39
Figure 4.5: Impact of pediatric exclusivity on pediatric age category
The respondents cited “ease of recruitment of older pediatric patients” as the main reason
why the majority of studies were conducted in adolescents under pediatric exclusivity. Besides,
they stated, “… the size of the patient population and the economic incentive expected with each
of these age groups is directly correlated with the increase in pediatric age”. Participants cited
less challenges with recruitment and study procedures with older children who are also able to
give meaningful feedback on the effect of drug. Also, respondents stated that due to “ethical and
logistical issues”, older children are easier to recruit than neonates and infants. Most respondents
stated in general terms that younger children have benefitted more from the exclusivity
provisions than neonates and infants. They stated, “Adolescents due to their closer relevance to
adults in physiological maturity and overlap of broad indications”, have benefitted the most, but
not to the same degree as adults. In contrast, respondents felt that the youngest age children,
which are the most difficult to study, make it the hardest to demonstrate overlap with adult-use
drugs. Thus, respondents opined that in general, improvements in licensing of medicines have
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occurred for “children over the age of six, but not much for younger children”, subsequent to the
pediatric exclusivity provision.
4.9 Advantages of Pediatric Exclusivity to Stakeholders
The main advantage of pediatric exclusivity as reported by the stakeholders is improved
global health care of children because of “better dosage, labeling, and drug safety information”
provided based on clinical studies. Respondents from pediatric drug companies (8, 80%)
reported that the main advantage of pediatric exclusivity to them was the “high profit earning”
due to increased drug sales and bigger market share of their drugs because of the 6 month patent
extension. Respondents stated that the high profit/ high return on investment was also due to
“slow generic intrusion” as a result of exclusivity, which led to “optimization of pediatric
product marketing”. Six (60%) pediatric drug company respondents stated that since the FDA
lists applications submitted as a result of pediatric study under the BPCA as a “priority
application”, they are granted a faster review and 6 month patent exclusivity to all forms of a
drug product line containing the active moiety. This “additional marketing control”, the
respondents reported, is the “financial incentive” of pediatric exclusivity. One interview
respondent stated that the primary beneficiaries of pediatric exclusivity are the pharmaceutical
companies rather than study participants or pediatric population. Pediatricians (9, 90%) reported
easier “prescription justification” and avoidance of possible lawsuits because of better dosing
and labeling information for pediatric drugs. Four (40%) pediatricians reported “increased
practitioner loyalty and trust by patients” as a result of better prescription and safety information
provided to them, based on studies conducted under pediatric exclusivity. One RA personnel
interviewed stated, “I would say these [referring to the benefits of pediatric exclusivity to
stakeholders] are equally aligned. Companies receive the economic benefit for conducting the
41
studies while pediatric patients and pediatricians receive the assurance that the products will
have a positive benefit risk profile”.
4.10 Disadvantages of Pediatric Exclusivity to Stakeholders
A majority of survey respondents (18, 90%) reported that the main disadvantage of
pediatric exclusivity provisions was that it “raised consumer expenditure on brand name or
patent drugs” by delaying the time for generics to appear by 6 months. Two (10%) respondents
reported that pediatric exclusivity “raised the economic costs of government” due to higher
expenditures by Medicaid during the sales of brand name drugs during 6 month exclusivity
periods. Three (30%) pediatricians felt that they were challenged to “keep abreast with” all the
recent drugs granted pediatric exclusivity, amidst their busy schedules, which added “confusion
in prescribing” to pediatric patients. While 4 (40%) respondents from pediatric drug companies
voiced concern over the loss of revenue by the generic drug industry and retail pharmacies
during the exclusivity period, 6 (60%) respondents voiced concern over the problems with
meeting the high costs of clinical studies for pediatric drug development. One RA staff
interviewed stated that pediatric exclusivity puts a “financial burden on consumers” [indicating
the high cost the consumers are forced to pay on brand name drugs during the exclusivity period
when less expensive generics are delayed by 6 months] while delivering a “windfall” [indicating
the high profit earnings from sales of brand name drugs which are expensive] to the prescription
drug industry. In general, findings indicated that for drug companies, the main disadvantage of
pediatric exclusivity was the burden of conducting pediatric studies with the return on
investment not always apparent. For patients, taxpayers, and prescribers, the main disadvantage
of pediatric exclusivity was the economic impact of longer term for branded medicines before
generics can enter as well as the burden of study involvement.
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4.11 Support for Pediatric Exclusivity Provisions
When queried if they support pediatric exclusivity, 18 (90%) respondents said that they
overwhelmingly support the provision because it grants companies the “incentive to conduct
clinical studies” to provide useful information on dosing, labeling, and safety of pediatric drugs.
Additionally, the respondents stated that the exclusivity provision provides the consumer with
the much needed confidence that the drug product has been adequately “tested in the intended
patient population”. However, 2 (10%) respondents expressed their concerns regarding
exclusivity. They stated that since pediatric studies are “costly to taxpayers” in the form of
Medicaid payments for brand name drugs, NIH should fund research for those drugs that
industries decline to take on. When asked for the level of support for pediatric exclusivity (on a
scale of 1-10) the average responses of all participants earned a score of 9.2 (92%), which is
overwhelming.
Eight (40%) respondents stated that the results of pediatric studies need to be more
“transparent” (i.e. published in the peer-reviewed literature). They expressed ethical concern
about the appropriateness of financial incentives to participants, since the majority of the studies
are performed in the developing world, not in the US. They questioned, “Will children in the
third world reap possible benefits of research?” Three (15%) participants, citing a heavy tax
burden on consumers, stated that Congress should “reduce exclusivity or scrap” the program all-
together. They felt that NIH should study off patent pediatric drugs but continue to require
industries to conduct pediatric studies for new drugs. However, most participants (15, 75%)
stated that a reduction or cancellation of the exclusivity will “curb industry enthusiasm” for
undertaking new and costly pediatric trials, especially on drugs with small market sizes.
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4.12 Pediatric Exclusivity and Drug Labeling
Eighteen (90%) respondents reported that pediatric exclusivity has resulted in improved
pediatric drug labeling. A study of pediatric labeling changes information in the FDA web site
through January 4, 2012, showed that a total of 426 labeling changes were made for pediatric
drugs*. This included 388 (91%) labeling changes for drugs with new pediatric studies and 38
(9%) labeling changes for drugs with no new pediatric studies (NNPS).
One hundred forty seven (35%) of the labeling changes in the drugs granted pediatric
exclusivity fell within the scope of BPCA only, 50 (12%) with BPCA and PREA, 181 (42%)
PREA only, and 48 (11%) Pediatric Rule. All these labeling changes were based on information
obtained from clinical trials in pediatric patients (Figure 4.6). Respondents reported that under
Figure 4.6: Number of labeling changes for drug products granted pediatric exclusivity
falling within the scope of BPCA, PREA, and Pediatric Rule.*
Note: *The number of labeling changes under different pediatric regulations have been extracted from the FDA
website and assembled into a chart from New Pediatric Labeling Information Database. Available at:
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/UCM163159.pdf
PREA, when the FDA mandated pediatric studies, companies conducted a substantial number of
pediatric studies resulting in the largest labeling changes ever in the history of pediatric drug
Pediatric Regulations
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regulation. Respondents stated that the pediatric exclusivity provisions have provided new and
useful information about whether and how drugs work in children. Respondents stated that
labeling changes have included “new child-safety information, new or altered pediatric dosing
information, additional warnings about adverse events in children, recommended dosage
modifications, and findings of lack of efficacy for some drugs”. Improved drug labeling resulted
in “improvement in compliance” by prescribing physicians and pediatric patients, reported the
surveyed pediatricians. One pediatrician stated, “We have an improved understanding of the
pharmacokinetics of drugs we prescribe in pediatric population. Thanks to the exclusivity-
inspired pediatric clinical studies”. However, one RA staff questioned “Can it [referring to
pediatric exclusivity provision] guarantee that companies receiving exclusivity make the results
of their studies known through the labeling changes necessary for safe and effective use of
drugs?” All pediatricians surveyed said, that the clinically important pediatric drug labeling
information updates from pediatric dosage book influenced their prescribing behavior. Thus,
pediatric exclusivity was effective in stimulating pediatric testing and the resulting
improvements in labeling for the development of safer and more effective pediatric drugs.
When participants were asked about the benefits of added pediatric labeling (average
responses rated on a scale of 1-10), they reported reduced medical errors (6.5, 65%) as the top
benefit, followed by decreased hospitalizations (4.8, 48 %), and fewer physician visits (4.5,
45%). Other benefits reported were less days missed from school and work by children (4.1.
41%), lower treatment costs (3.7, 37%), and lower health insurance premiums (3.0, 30%) (Figure
4.7).
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Pediatricians, pharmacists, and clinicians noted the increasing implementation of various
risk reduction strategies to reduce pediatric medication errors. Reported strategies include
“development and maintenance of pediatric formulary, limiting concentrations and dosage
strengths, and using oral syringes to administer oral medications”. Two (10%) respondents,
however, said, “they did not think that there were sufficient data available to justify that pediatric
exclusivity had resulted in improved drug labeling”. The overall response indicated most of the
pediatric exclusivity awards led to “labeling changes for drugs” that treated a wide range of
diseases, including some life-threatening conditions for children.
Figure 4.7: Benefits of improved pediatric labeling as a result of pediatric exclusivity
4.13 Pediatric Exclusivity and Pediatric Dosing
Seventeen (85%) of the survey respondents stated that pediatric drugs did not provide
health care professionals with adequate dosing information for children less than 2 years of age
but provided better dosing information for children over 2 years of age. For instance, one
pediatrician surveyed stated, “…neonates have decreased activity of many enzymes than older
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children. That is why drug dosages should be decreased for neonates compared to older
children”. This pharmacokinetic information is not always provided in pediatric drug label.
When asked to compare the dosing improvements across pediatric age categories, the
respondents felt that, in general, more dosing improvement was seen in “adolescents (12-16
years) than in neonates (0-1 month) and infants (1 month-2 years)”. The dosing improvement in
adolescents is mainly because of their resemblance to adult dosing where abundant studies have
been conducted. One RA staff interviewed stated, “Pediatric exclusivity has resulted in providing
dosing recommendations for high b.p. and fungal medicines that I am aware of.” In general, most
participants stated that the incentive provisions of pediatric exclusivity have led to the
availability of meaningful information to allow for dosing pediatric patients safely and
effectively.
Respondents preferred a combination of weight and age-based dosing (9.7, 97%)
followed by weight-based dosing (6.6, 66%) in pediatric Drug Facts Labels. Respondents said
that while age-based dosing is “more typical”, dosing by weight in some cases (i.e. in infants and
young children) may achieve “better efficacy results and may be safer”. These respondents stated
that the weight-based dosing schedule provides more consistent dosing in the targeted 10-15
mg/kg dosing range for most children when compared with age-based dosing. One pharmacist
and five pediatricians stated that in weight-based dosing, “doses for patients are customized”
requiring accurate calculations of child weight. Pediatric medication errors have occurred
because of “variation in children’s weight”. Respondents stated that caregivers expressed their
preference for weight-based dosing to select a correct dose, to prevent any dosing error,
compared to age-related dosing only. One respondent stated that in some situations, dosing
should be based on “body surface area such as in cancer drugs”. One participant stated that an
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ideal pediatric medicine should suit the “age, physiological condition and body weight” of the
child taking it. In general, respondents stated that exclusivity-inspired studies have resulted in the
correction of several dosing errors that may have prevented potential overdoses and under-doses
and possible detrimental health-related consequences. The participants outlined an unmet need
for pediatric dosing information for biologics as the key issue for future research.
4.14 Pediatric Exclusivity and Pediatric Formulation
Two pharmacists and five pediatricians surveyed stated that “adult capsules/tablets are
often manipulated into solutions for pediatric use”, solution concentrations can differ, leading to
prescribing errors when volume doses are written”. “Since pediatric drug prescription is often
off-label, finding dosing information can be challenging,” noted one pharmacist. Surveyed
participants and the FDA staff interviewed said that the FDA in a written request (WR) to the
drug companies, “requests pediatric formulation” in most cases, and studies are being conducted
towards that end. Participants noted that solid doses that are scored or different doses are usually
followed for drugs that require weight-based dosing or dosing based on endocrine status (e.g.
puberty). However, participants were concerned that it is not easy for children under 12 years of
age to swallow or chew tablets. Therefore, for dose flexibility and ease of swallowing, a “liquid
formulation” is often chosen for pediatric administration. Participants stated that to ensure ease
of dose titration and dose administration, liquid formulations are chosen, which are tasty as well
as stable in bottles. Participants expressed the need to develop more commercially available “oral
pediatric formulations” under the pediatric exclusivity program. Also, participants recommended
a more coherent approach to the development of pediatric formulations from all stakeholders.
This included an interdisciplinary input from formulation and sensory scientists to address
excipient compatibility, physical and chemical stability, taste, preservative, bioavailability,
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regulatory, and packaging issues as early as possible in the drug development process. For this,
respondents recommended a good understanding of the “technical, clinical, regulatory and
market requirements” using a multidisciplinary development approach, to develop pediatric
formulations.
4.15 Duration of Pediatric Exclusivity
When asked about their views on the duration of pediatric exclusivity, respondents had
mixed opinions. While 15 (75%) respondents were satisfied with the current 6 months of
exclusivity program, 12 (60%) participants wanted it to be extended to 12 months. In contrast, 4
(20%) participants wanted it to be reduced to 3 months. Three (15%) respondents wanted the
provision to be extended to 18, 24, or 36 months. The duration preference for pediatric
exclusivity earned a score of 8.8 (88%) for 6 months, 6.6 (66%) for 12 months, and 5.8 (58%)
for 3 months. Scores indicated a preference for the existing 6 months of pediatric exclusivity
compared to the hypothetical 12 months and 3 months. The permanent extension of duration of
pediatric exclusivity earned no point, which indicates that it is impractical.
Participants who were fine with the current 6 months of pediatric exclusivity stated that it
has been “effective in encouraging studies in pediatric drugs without crippling the generic drug
manufacturers for long”. However, participants opined that moving forward, “the exclusivity
provision will need to be adjusted to provide incentives for manufacturers who are not taking
advantage of market exclusivity” due to a small market size or lack of existing patent/market
exclusivity. The FDA staff interviewed declined to speak his views on the duration of exclusivity
citing the Agency’s rule not to comment on its policy issues.
Participants who viewed the extension of pediatric exclusivity program to one year felt
that it would be “enough incentive given the length of time and investment required to conduct
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pediatric studies”. They felt that the current duration of 6 months of exclusivity is often
inadequate to permit companies to take advantage of the incentive program. “Why stop at six
months?” questioned one survey respondent indicating the need for longer patent extension. For
certain pediatric drugs with small market sizes, respondents felt that the extension of exclusivity
provision to one year would “boost industry enthusiasm” for undertaking pediatric studies that
would potentially yield “modest return on investment”.
The respondents who opined for a reduction of pediatric exclusivity provision to 3
months were mainly for blockbuster drugs with sales over $1 billion. These respondents felt that
the current 6 month exclusivity program provides a big “windfall” to blockbuster drugs, at the
cost of high consumer expenditure on innovator drugs and high taxpayer burden. These
respondents who mainly comprised the patient advocates and generic drug makers, favored for
less costly and quicker availability of generic drugs. The respondents stated that the generic drug
makers generally favored the early expiry of patents for brand name drugs so that they could
make some extra income from the sale of generics. One respondent, however, was unsure about
the specifics of the balance between the pros and cons of extension and reduction of exclusivity.
4.16 Factors Affecting the Success of Studies for Pediatric Exclusivity
When respondents were asked to list the factors determining the success of studies for
pediatric exclusivity (the average of responses rated on a scale of 1-10), they listed well-
organized study as the most important requirement (8.5, 85%), followed by well-trained
investigators (8.2, 82%), and parents collaboration in research (6.8, 68%). The other important
factors reported were no other available therapeutic options (6.4, 64%), and high quality facilities
(5.1, 51%). The investigators’ financial compensation was of the lowest importance for the
feasibility of the trials (4.2, 42%) (Figure 4.8). By well-organized trials, participants referred to
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studies that were “well designed, properly analyzed, and based on good science”. Also, the study
procedures should be properly undertaken and documented to ensure the well-being and
protection of research subjects, respondents stated. Respondents stated that parental collaboration
is critical in successful recruitment of pediatric patients for maintaining an adequate sample size
and in the consent and assent processes of on-going studies. The respondents unanimously
agreed that “prior results suggesting benefit (and minimal risk)” are critical for any study to have
a good chance to recruit and follow-up pediatric patients.
Figure 4.8: Factors affecting the success of studies for pediatric exclusivity
4.17 Adequateness of Incentive
To the question, “is the incentive provided by the pediatric exclusivity regulation potentially
sufficient to offset the cost of pediatric drug development?” respondents had mixed opinions.
They said that the adequacy of the incentive depends on the “drug, its market share, and its
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indications”. Fifteen (75%) respondents stated that for drugs with a large size of the market and
reasonable ease of recruitment of pediatric patients, the additional 6 month of exclusivity is
“generally sufficient” to recuperate the investment in clinical studies as well as an economic
“windfall” in some instances. One respondent stated that the incentives are “absurdly generous”
for some drugs with large market share. One RA personnel interviewed stated, “this [referring to
adequateness of incentive] really depends on the medication, the condition, and the competitive
situation for this medication. For example, a condition with no known treatments can easily
result in a positive return on investment as the manufacturer will be able to set a very high price;
however, if there are multiple products available, recruitment will be difficult and sales
diminished due to the competition”. Similarly, one other RA personnel interviewed stated, “in all
instances they [referring to pharmaceutical companies] make money and in most instances they
make a whole lot of money”.
Participants stated that the only studies that are pursued under the voluntary program (the
only program that provides exclusivity) are those that are “cost-effective”. However, six (30%)
participants stated that the 6 month exclusivity is not an enough of an incentive to recuperate
investment generally for drugs with a “small market share, rare pediatric conditions, and
difficulty in patient recruitment”. The two regulatory staff interviewed stated that the incentive
was not adequate for “old antibiotics and other drugs lacking patent protections or drugs for
certain younger age groups, especially neonates”.
4.18 Alternatives to Pediatric Exclusivity
When respondents were asked if there is any better/practical alternative to pediatric
exclusivity to encourage drug manufacturers to conduct pediatric clinical studies, 16 (75%)
survey respondents said that there is “none” that is practically viable at this time. Participants
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stated: “None that are politically viable”, “none that I can think of”, “not really”, “ok with what
we have”, and “unsure” as their responses. However, one respondent said that something has to
be done to incentivize or require generic and over the counter (OTC) product companies to
conduct pediatric studies, like PREA requirements which has mandated pediatric studies for
applicable branded products. With PREA requirements, there will not be a need to give
companies an additional six months of market protection to encourage them to “test their drugs
in children”, the respondent opined. Further, one RA personnel interviewed stated, “companies
need an incentive to evaluate special populations because of the cost involved”. One RA
personnel interviewed stated: “To address outstanding pediatric data needs, Congress should
grant a program allowing the FDA to fund pediatric clinical research directly”. However,
concerns were raised that due to shortage of funding and the limited infrastructure at the FDA,
such an ambitious program is not a practical alternative to pediatric exclusivity. One RA
personnel interviewed stated, “the only other incentive that could be granted to pediatric drug
companies is to provide them tax breaks or grants similar to what is done for orphan conditions,
the viability of which is unknown”. The FDA staff interviewed declined to comment on the topic
stating it is a “policy issue which the Agency staff cannot comment on”.
4.19 Comparison of Drugs Granted Pediatric Exclusivity and Drugs used by Children
Eleven (55%) respondents stated that the drugs granted pediatric exclusivity are not the
drugs most used by children. They stated, while the most frequent drug groups granted pediatric
exclusivity were “central nervous system drugs such as antidepressants and psychotropics,
cardiovascular drugs mainly ACE inhibitors and lipid-lowering preparations, systemic anti-
infectives among which largely HIV antivirals, and cytostatics, and alimentary tract medication
among which proton pump inhibitors and oral antihyperglycemic medication”. The respondents
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cited “anti-infectives, respiratory drugs, and dermatologicals” as the drugs most frequently used
by children. Further, the participants stated that the drugs studied under pediatric exclusivity are
likely to be blockbuster adult drugs. Participants cited examples of anti hypertensives and lipid
lowering agents that are granted exclusivity, though frequently only used in overweight
teenagers. One RA respondent stated, “The distribution of these drugs [referring to drugs granted
pediatric exclusivity] closely matched the distribution of these drugs over the adult market, and
not the drug utilization by children”. One RA staff interviewed questioned, “Can it [referring to
pediatric exclusivity provision] assure that drugs likely to be used in children are tested in
children before they are prescribed for their use?” One pediatrician criticizing the incentive
provision stated that pediatric exclusivity creates a system in which big rewards are received for
“testing drugs that sell the most” but not the drugs that are “used by children the most”.
Similarly, respondents felt that the drugs most commonly used by children are OTC drugs, which
as a whole, have inadequate data for pediatric administration. Since OTC drugs are ineligible to
receive the benefits of pediatric exclusivity, there are no incentives for companies that
manufacture these products to conduct pediatric studies, respondents stated.
Nine (45%) respondents said that they are not familiar enough with the specific drugs that
have been granted pediatric exclusivity to make a general statement about the relationship
between drugs granted pediatric exclusivity and drugs actually used by children. Overall survey
findings indicate that children have infrequently used the drugs granted pediatric exclusivity. In
light of this finding, participants recommended that the priorities for pediatric drug research
should be set by the “need of the patients, not by the market considerations”.
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4.20 Criticisms for Pediatric Exclusivity
Respondents stated that although pediatric exclusivity was successful in stimulating
pediatric studies, the provision was not without criticism. Respondents felt that pediatric
exclusivity provided excessive incentives to some manufacturers, while not enough to others.
Respondents had the following criticisms for pediatric exclusivity:
1. Respondents reported that pediatric exclusivity has been “inefficient” to study drugs citing that
the government could fund several studies with the same amount of money than allowing
pharmaceutical companies to conduct studies on one drug and make several billion dollars. For
instance, one RA personnel interviewed stated, “suppose if we extend the patent of a drug
making 5 billion dollars a year by 6 months, then the drug company is going to make an excess
of a billion dollars out of the patent extension. People are paying a billion dollar extra for that
drug. How many drugs could you study for that 1 billion dollar? Probably the government pays
50% of that billion dollar and 50% is paid by insurance companies, which still comes out of
taxpayers’ pockets. The government gives a billion dollar to companies to treat fat teenagers
with hypertension or high blood pressure. The government can take that billion dollars and give
it to NIH to study 20 therapeutic agents. How can you let drug companies walk away with
hundreds of millions of dollars in profit studying drugs when you can just pay for it to do it?”
One RA professional interviewed questioned, “Why drug makers should be rewarded for
something they are required to do under PREA?”
2. Because the program offers manufacturers a fixed incentive, respondents stated that products
with a larger sales volume might yield “excessive returns” that exceed the cost of performing
pediatric studies-regardless of the actual uses of these products in children. For example,
respondents cited drugs like atorvastatin (Lipitor), pravastatin (Pravachol), celecoxib (Celebrex),
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and a variety of anticancer agents, which are mainly used in adults, but have still received
exclusivity. Respondents stated that since the purpose of the exclusivity program is to “generate
data rather than increase drug use”, a product could gain the full six months of exclusivity even if
pediatric studies demonstrate that the drug should never be used by children. Respondents have
opined that the rewards of pediatric exclusivity are “too large for companies manufacturing
blockbuster drugs”. Respondents have criticized the pediatric exclusivity program for over
compensating the pediatric drug companies with sales greater than $1 billion. They have stated
that while the financial incentives for most products are modest, they are negative for some
products with small market share.
3. Respondents noted that BPCA has no provisions encouraging “testing of off-patent pediatric
drugs”. Due to this, respondents stated that pediatric exclusivity leaves many medications needed
by children “unstudied”. Respondents stated that the regulations like pediatric exclusivity and
BPCA are “voluntary, complex, and difficult to enforce”. Respondents opined that even for the
drugs still on patent, some industries might not believe that pediatric exclusivity is an adequate
incentive to compensate them for the modest cost of studying and labeling these drugs for use in
children.
4. Respondents noted that while a number of drug labels have been changed to incorporate
findings from research conducted under the pediatric exclusivity provisions, some label changes
typically occur long after the FDA has granted the extension of market exclusivity. One RA staff
interviewed suggested that by granting exclusivity only after companies have made labeling
changes, the FDA would retain a “powerful carrot” to assure that labeling changes are made.
Besides, respondents expressed concerns that not all studies lead to label changes under the
pediatric exclusivity program.
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CHAPTER 5
CONCLUSION AND RECOMMENDATION
5.1 Conclusion
The study demonstrated that stakeholders who were surveyed and interviewed were
generally aware of the pediatric exclusivity provisions and were satisfied with its flexibility and
voluntary requirements. However, the respondents expressed concerns that if the FDA made
these studies mandatory especially for drugs on which studies are difficult to conduct; industries
would have to invest huge sums of money to develop these products. The return on investment
on these drugs may be potentially low.
Respondents reported that the pediatric exclusivity provision has been effective in
generating pediatric studies to provide useful dosage and labeling information. The drugs granted
pediatric exclusivity were generally safe as they had no serious adverse events. Large drug
companies with their high volume of research and development were better at filing pediatric
exclusivity than small companies. The studies conducted by companies under a written request
(WR) with the FDA were adequate to ensure the safety and effectiveness of pediatric drugs. The
study findings were similar to a study by Li et al., which reported that pediatric exclusivity has
created a strong incentive to conduct FDA requested safety studies.26
The type of drug developed
and its risk benefit profile generally determined the type of studies conducted under pediatric
exclusivity. Most studies conducted under pediatric exclusivity, as reported by participants were
efficacy and safety studies, followed by pharmacokinetics (pk) /safety studies, safety studies,
and pharmacokinetics/pharmacodynamics and pharmacokinetics/safety (pk/pd pk/safety) studies.
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The study findings are similar to FDA’s breakdown of FDAAA completed pediatric studies16
.
All pediatric medicines without an adequate evidence base require pediatric studies under
pediatric exclusivity while drugs that were well studied and known to be fairly safe and effective
do not require pediatric studies.
The study results on pediatric conditions requiring studies are similar to the ‘‘priority list
of drugs for which pediatric studies are needed’’42
developed by the NIH in consultation with the
FDA and pediatric experts in 2007. The NIH list has included, similar to the survey findings,
infectious diseases, with a focus on Methicillin-resistant Staphylococcus aureus (MRSA)
infections, pediatric cancer, specifically neuroblastoma, neonatal pain, and asthma, as the
conditions for which research priorities are required. This priority list was developed based on
the gaps in scientific knowledge of pediatric drugs and their labeling, and their potential for
providing health benefit in the general pediatric population. However, the survey findings
pointed out three additional pediatric conditions-heart diseases, HIV, and epilepsy-that require
further research. These conditions did not fall in the NIH ‘‘priority list of drugs for which
pediatric studies are needed.’’
Respondents ranked inadequate pediatric doses as the main problem with pediatric drugs, which
can be solved by conducting enhanced research making clear assessment of overall benefits and
risks. Participants stated expensive pediatric trials with uncertain return on investment as the
biggest challenge that held them back from conducting studies under pediatric exclusivity. The
impact of pediatric exclusivity has been felt the most in adolescents where more studies are
conducted while felt least in neonates and infants where more studies are required.
While pediatric drug companies have benefitted from high profits from sales of pediatric
drugs, all stakeholders have benefitted from improved health care of children as result of better
58
dosage, labeling, and drug safety information provided. In contrast, the main disadvantage of
pediatric exclusivity provisions was the high consumer cost on brand name drugs because of
delayed market entry of generics due to the added duration of exclusivity. Respondents
overwhelmingly supported the pediatric exclusivity for its incentive program on pediatric drug
development but feared the consequences of its reduction or cancellation. The pediatric
exclusivity has facilitated pediatric testing that generated a substantial number of labeling
changes resulting in reduced medical errors. The comparison of dosing improvement across
pediatric age categories showed better results in adolescents than in neonates and infants because
of their resemblance to adult dosing where abundant studies have been conducted. Similarly, the
pediatric exclusivity has provided better pediatric dosing based on children’s weight as well as
age. Respondents generally preferred a combination of weight and age-based dosing in pediatric
Drug Facts Labels. Respondents stated that caregivers preferred weight-based dosing for better
efficacy and safety compared to the typical age-based dosing. Respondents have reported
development of adequate pediatric formulation in solid and liquid doses, covering a broad age
range, in children over 2 years of age but not in children less than 2 years old. Respondents felt
that though pediatric exclusivity has resulted in many labeling changes for pediatric drugs, the
need for pediatric labels in all pediatric drugs was still strong. The pediatric labels, in addition to
providing better pediatric dosage information and reduced medical errors minimize off-label use
of drugs. Nearly all drugs evaluated in exclusivity-inspired pediatric research had no serious
adverse events necessitating enhanced adverse event monitoring. Absence of serious adverse
events indicated improved safety of pediatric drugs.
While the majority of respondents were satisfied with 6 months of exclusivity, some wanted it
extended to 12 months to boost industry enthusiasm to make a high investment in pediatric
59
studies. Well-designed pediatric studies conducted by highly trained investigators with active
collaboration by parents were the key factors determining the success of studies for pediatric
exclusivity. For the success of exclusivity studies, prior results suggesting benefits and minimal
risks were critical for any study to have a good chance to recruit and follow-up pediatric patients.
Further, the incentive provisions of pediatric exclusivity were adequate for drugs with large
market share but not enough for drugs with small market share and rare pediatric conditions. Li
and colleagues at Duke University examined the likely cost of clinical studies under the pediatric
exclusivity program26
, and reported similar findings of variable returns. They found that the net
return-to-cost ratios varied widely, from negative returns for products with relatively small sales
volumes to a 73-fold return for a blockbuster drug. The returns ranged from -$8.9 million to $
507.9 million.26
The pediatric exclusivity provision has been criticized as too costly and
inefficient to study pediatric drugs. Respondents said that there was no practical alternative to
pediatric exclusivity at this time to encourage pediatric studies. Respondents felt that the FDA
should grant exclusivity to drugs that are mostly used by children and not adults.
5.2 Recommendation
This research, through surveys and interviews, has explicated the beliefs of key
stakeholders regarding the pediatric exclusivity provision established by the FDAMA, 1997. In
general, the research participants believe that the pediatric exclusivity provision has been
successful in stimulating pediatric studies. These studies under the guidance of the FDA have
been successful in providing significant changes in labeling, dosing, and formulation of pediatric
drugs, to make them more safe and effective for pediatric use. Despite the successes, there is
more work to be done. A large number of drug products need to be adequately labeled for
children. Long-term safety and effects on drugs on growth, learning, and behavior of children
60
need further studies. Due to technical challenges and the need for sequential studies, neonates
remain mostly unstudied and little is known about the safety and efficacy of the therapies being
used to treat them. The study proposes the following recommendations:
1. Cost reduction of pediatric exclusivity
To reduce the high costs of the pediatric exclusivity program to the consumers and the
government, the US Congress could consider a few options. These alternatives could include
prioritizing data collection for pediatric drugs by making a better assessment of its need and the
potential benefits on children’s health. The incentive could be adjusted to encourage timely data
collection on pediatric drugs post marketing. Additional alternatives include reducing the size of
the financial incentive to pediatric drug manufacturers without cancelling it all together.
However, this approach to reduce the incentive must be sensitive to the needs of drug companies
with small market shares and low return on investment. Similarly, drugs with a primary pediatric
indication can only be allowed to have access to the incentive program.
2. Reauthorization of BPCA and PREA
Though stakeholders have raised concerns over the cost of pediatric exclusivity to the
federal government and consumers, evidence suggests value in reauthorizing the BPCA and
PREA. Congress could renew these key pieces of legislation that are set to expire in October 1
2012, to continue to incentivize pediatric drug manufacturers to develop safe and effective
medications for children. Additionally, the reauthorization of these legislations would provide
pharmaceutical industries more predictable regulatory path and certainty that would help spur
increased pediatric research.
61
3. Pediatric drug trial assessment and information dissemination
Although there is no current assessment of the US capacity to perform pediatric drug
trials (PDTs), stakeholders feel that there is insufficient US PDTs. Future studies should focus
on assessing the capacity of US drug trials. Based on this assessment, recommendation should
be made to aid the development of new pediatric drugs. Additionally, pediatric labeling claims
should be supported by adequate pediatric test data derived from clinical trials. The BPCA
requirement of the FDA to issue summaries of data submitted under the pediatric exclusivity
program does not align with the FDA’s policy to keep the pediatric data secret. A consistent
policy should be developed by the FDA in line with the BPCA to disseminate information to
the public about pediatric drug trials. Mechanisms should be developed to more widely
disseminate this information through publication and broadcast media like radio and
television programs, which are more effective in information dissemination than peer-
reviewed literature. This recommendation is similar to a finding by Benjamin et al. of Duke
University43
.
5.3 Study Limitations
Since the respondents for the survey on pediatric exclusivity including regulatory affairs
professionals, pharmacists, clinicians, pediatricians, and FDA staff at the division of Pediatric
Drug Development, were a small number of people selected by purposive sampling, the study
findings may not cover all stakeholders’ perceptions and is limited in scope. If future researchers
choose to repeat this study, taking larger sample sizes of survey and interview respondents would
allow extrapolation of the results of the studies to larger pediatric populations. Since the survey
and interview instruments were not validated, bias may have occurred in the question design and
consequently the responses obtained. For instance, some respondents stated that questions were
62
hard to interpret in terms of what was expected as answers especially when there were many
possible answers that were to be graded on a scale. Since a purposive, non-random, and non-
probability sampling method was used for the survey, selection bias may have affected the
results which cannot be generalized to broader population. In spite of the limited scope of the
study, the expert sampling has provided a lot of empirical evidence to justify the generalizations
made. The perspectives of key stakeholders of pediatric exclusivity are documented which have
contributed to our knowledge of pediatric drug development under pediatric exclusivity. The
research has provided new insights into the prevalent knowledge of pediatric conditions
requiring studies, challenges of pediatric drug development under pediatric exclusivity, and
pediatric age categories impacted. Further, advantages and disadvantages of pediatric exclusivity
to stakeholders are outlined and factors contributing to the success of of studies under pediatric
exclusivity are explained. Researchers need to update themselves with the safety and
effectiveness of prevailing pediatric medicines and the regulatory guidance as well. Additionally,
this research covers pediatric drugs only and not medical devices and biologics. Thus, the study
represents only the safety and efficacy of pediatric drugs but in no case the whole spectrum of
pediatric treatment.
Future studies to investigate the effectiveness of pediatric exclusivity should analyze
relevant summaries of medical and clinical pharmacology reviews and labeling information of
drugs granted pediatric exclusivity. Further, studies on pediatric exclusivity should explore the
settings of published studies, the therapeutic area of drug studied, and the types of studies
conducted. Studies should also explore a greater understanding of the capacity for US pediatric
drug trials (PDTs) by assessing PDT infrastructure, barriers to PDTs, and potential approaches
and solutions to identified issues. Research needs to be conducted to explore the frequency and
63
type of adverse events and new safety information arising from studies conducted under pediatric
exclusivity program.
64
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(Brussels), Dec. 12, 2006.
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APPENDIX A - SURVEY QUESTIONS
Questions to Pediatric Drug Manufacturing Companies, Pharmacists, Clinicians,
Pediatricians, the FDA, and people having knowledge of pediatric drugs
Name of Respondent ………………………………………
Job Title:…… ……………………………………………...
Name of the Company: … ………………………………..
Work Address:……………………………………………...
1. Are you aware of pediatric exclusivity provision?
No
Yes
If yes, rate your awareness on a scale of 1-10, where 1 being minimally aware and 10 being
fully aware.
2. Under the pediatric exclusivity provision, conducting studies on pediatric drugs are voluntary
and encouraged.
Are you satisfied with the voluntary requirements?
Yes (Give reasons)
No (Give reasons)
If yes, rate the level of satisfaction on a scale of 1-10, where 1 being least satisfied and 10 being
most satisfied.
69
If not, do you think the FDA should make these studies mandatory? What are its pros and cons?
3. In your opinion, which pediatric medicines currently available in the market need studies
(non-clinical and clinical) to establish their safety and efficacy? List on a scale of 1-10,
where 1 being the condition for which least studies are required and 10 being the conditions
for which most studies are required.
a. __Pediatric cancer
b. __Pediatric MRSA
c. __Pediatric hypertension
d. __ Asthma
e. __Neonatal conditions
f. __Heart diseases
g. __ HIV
h. __Others (specify)
4. In your opinion, which pediatric medicines currently available in the market do not require
pediatric studies (non-clinical and clinical)? Give reasons
5. The following are some problems/concerns with pediatric drugs. Which one do you think is
the major problem? List on a scale of 1-10, where 1 being the minor problem and 10 the
major problem.
a. __Some drugs prescribed for children are not labeled for children
b. __Different doses in children than in adults
c. __Different indications for use
d. __Different routes of administration than those recommended
e. __Unlicensed drugs for pediatric use
70
f. __Drugs are given in formulations not accepted in children
g. __Off-label use of drugs
h. Others (specify)
Explain how individual problems can be resolved.
Has the pediatric exclusivity provisions helped to resolve the above-mentioned problems?
Yes
If yes, how has the pediatric exclusivity provision helped the manufacturers to make pediatric
drugs more safe and efficacious?
No If no, give reasons
6. What are the challenges of pediatric drug development under pediatric exclusivity? List the
individual challenges on a scale of 1-10, where 1 being the smallest and 10 being the biggest
challenge.
a. Ethical challenges
__Informed consent and assent process
b. Economic challenges
__Expensive trials, low profit potential, and less remunerative
c. Logistical challenges
__Recruitment of pediatric subjects
d. Technical challenges
__Scientific challenges, complexity of trials, and small pool of pediatric investigators
e. Corporate cultural bias against pediatric trials
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7. Which of the following kinds of studies is most commonly conducted in children under the
pediatric exclusivity provisions? Give reasons. List on a scale of 1-10, where 1 being the
least common studies and 10 being the most common studies.
a. __Efficacy/Safety
b. __Pharmacokinetics/Safety
c. __Pharmacodynamics/Safety
d. __Safety
e. __ All of the above
f. __ Others (Specify)
Are the studies conducted adequate? Give reasons.
Impact of Pediatric Exclusivity
8. Under pediatric exclusivity provisions, in what pediatric age categories has the impact of
pediatric studies conducted been felt the most? Rate the impact on a scale of 1-10, where 1
being of minimal impact and 10 being of maximal impact.
(Age categories are set as: neonates (0-1 month), infants (1 month to 2 years); children (2
years to 12 years); adolescents (12 years to 16 years).
a. __Neonates (0-1 month)
b. __Infants (1 month to 2 years)
c. __Children (2–12 years)
d. __Adolescents (12–16 years)
Give reasons why the impact is felt maximum at the selected age group?
Give reasons why the impact is felt minimum at the selected age group?
72
9. What are the gains/ advantages of FDA’s pediatric exclusivity provision to the following
assuming that companies conduct pediatric studies to avail the incentives?
a. Pediatric patients and consumers
b. Medical practitioners
c. Pediatric drug companies
10. What are the disadvantages of pediatric exclusivity program to:
a. Pediatric patients and consumers
b. Medical practitioners
c. Pediatric drug companies
11. Do you support pediatric exclusivity provisions?
Yes (Give reasons) No (Give reasons)
If yes, list your level of support on a scale of 1-10, where 1 being minimal support and 10 being
the strongest support.
12. Do you have any concerns regarding FDA’s grant of pediatric exclusivity?
Yes (Explain) No
If yes, rate the concern on a scale of 1-10; where 1 being lowest level of concern and 10 being
the highest level of concern.
13. Do you have any suggestions on improving the FDA’s pediatric exclusivity provisions?
Explain.
Drug Labeling
14. It is said that pediatric exclusivity has resulted in improved pediatric drug labeling. List the
main benefits of added pediatric labeling to consumers and the health-care system. Rate the
benefits on a scale of 1-10, where 1 being the least benefit and 10 being the highest benefit.
73
15. Which one of the following dosing types do you prefer for pediatric drug labeling? Give
reasons for your choice of dosing.
Rate your dosing preference on a scale of 1-10, where 1 being the least preferred and 10 being
the most preferred.
a. __ Weight–based dosing
b. __ Age-based dosing
c. __ Both
d. __ Others (specify)
Views on the duration of pediatric exclusivity
16. What is your view on the duration of pediatric exclusivity? How long do you think should it
be? Give reasons
Rate your duration preference on a scale of 1-10, where 1 being the least preferred and 10 being
the most preferred duration.
a. __3 months
b. __ 6 months
c. __12 months
d. __18 months
e. __24 months
f. __36 months
g. __permanent
17. What factors could determine the success of studies for pediatric exclusivity. Rate the factors
based on their importance on a scale of 1-10, where 1 being the least important factor and 10
74
being the most important factor contributing to the success of studies for pediatric
exclusivity.
18. Is the incentive provided by the Pediatric Exclusivity Regulation potentially sufficient to
offset the cost of developing drugs for use in children? Give reasons.
19. In your opinion, is there any better/practical alternative to pediatric exclusivity to encourage
drug manufacturers to conduct clinical studies on pediatric drugs? Explain.
Criticisms
20. Some critics say the drugs granted pediatric exclusivity are not the drugs most used by the
children. Do you agree? Give reasons. How do you compare the drugs granted pediatric
exclusivity and drugs used by children?
21. What are your criticisms for pediatric exclusivity provisions? Explain.
22. Any questions/comments
75
APPENDIX B - INTERVIEW QUESTIONS
Name of Respondent:……………………………………..
Position:…………………………………………………….
Name of the Company: …………………………………..
Work Address:……………………………………………..
1. How aware are you of the Food and Drug Administration’s (FDA’s) pediatric exclusivity
provision? Please rate your awareness on a scale of 1-10, where 1 being minimally aware and
10 being fully aware.
2. Under the pediatric exclusivity provisions, conducting studies on pediatric drugs are
voluntary and encouraged. Are you getting the expected number and quality of studies from
pediatric drug companies, with the voluntary requirements? Explain.
If not, do you think the FDA should make these studies mandatory? What are its pros and
cons?
3. What is your company’s main motive behind conducting studies for pediatric exclusivity?
4. Could you comment on the pediatric studies conducted under pediatric exclusivity?
5. Which of the following kinds of studies is most commonly conducted in children under the
pediatric exclusivity provisions? Give reasons.
a. __Efficacy/Safety
b. __Pharmacokinetics/Safety
c. __Pharmacodynamics/Safety
d. __Safety
76
e. __ All of the above
f. __ Others (Specify)
Are the studies conducted adequate? Give reasons.
6. In your opinion, which pediatric medicines currently available in the market need studies
(non-clinical and clinical) to establish their safety and efficacy?
7. In your opinion, which pediatric medicines currently available in the market do not require
pediatric studies (non-clinical and clinical)? Give reasons
8. What do you think are some major problems/concerns with pediatric drugs? Explain how
individual problems can be resolved to make pediatric drugs more safe and efficacious.
Has the pediatric exclusivity provisions helped to resolve the above-mentioned problems?
Yes
No
If no, give reasons
9. What major challenges do pharmaceutical companies encounter in the development of
pediatric drugs? How have the companies been handling these challenges?
10. Under pediatric exclusivity provisions, in what pediatric age categories has the impact of
pediatric studies conducted been felt the most?
(Age categories are set as neonates (0-1 month), infants (1 month to 2 years); children (2
years to 12 years); adolescents (12 years to 16 years).
a. __Neonates (0-1 month)
b. __Infants (1 month to 2 years)
c. __Children (2–12 years)
d. __Adolescents (12–16 years)
77
Give reasons why the impact is felt maximum at the selected age group?
Give reasons why the impact is felt minimum at the selected age group?
11. What are the gains/ advantages of FDA’s pediatric exclusivity provision to the following
assuming that companies conduct pediatric studies to avail the incentives?
a. Pediatric patients and consumers
b. Medical practitioners
c. Pediatric drug companies
12. What are the disadvantages of pediatric exclusivity program to:
a. Pediatric patients and consumers
b. Medical practitioners
c. Pediatric drug companies
13. Do you support pediatric exclusivity provisions? Give reasons.
14. How has pediatric exclusivity influenced pediatric drug labeling? Explain the changes.
15. How has pediatric exclusivity influenced pediatric drug dosing? Explain the changes.
16. Which of the dosing types- age-based, weight-based, or both do you prefer for pediatric drug
labeling? Give reasons for your choice of dosing.
17. How has pediatric exclusivity influenced pediatric formulation? Explain the changes.
18. What is your view on the current 6 months duration of pediatric exclusivity? Does it serve its
intended purpose? If not, should the duration of pediatric exclusivity be reduced or extended?
Give reasons.
19. What are the factors that determine the success of studies for pediatric exclusivity? List the
factors.
78
20. Is the incentive provided by the pediatric exclusivity regulation potentially sufficient to offset
the cost of pediatric drug development? Explain.
21. In your opinion, is there any better/practical alternative to pediatric exclusivity to encourage
drug manufacturers to conduct clinical studies on pediatric drugs? Explain.
22. Some critics say the drugs granted pediatric exclusivity are not the drugs most used by the
children. Do you agree? Give reasons. How do you compare the number of drugs granted
pediatric exclusivity and the number of drugs used by children?
23. Do you have any criticism on FDA’s pediatric exclusivity program? Explain.
24. Do you have any comments and suggestions?
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APPENDIX C-INTERVIEW TRANSCRIPTS
1. How aware are you of the Food and Drug Administration’s (FDA’s) pediatric exclusivity
provision? Please rate your awareness on a scale of 1-10, where 1 being minimally aware
and 10 being fully aware.
Participant 1: 10- “…fully aware of pediatric exclusivity. For at least two studies that I was
involved, the FDA granted pediatric exclusivity to generate safety and pharmacokinetic data for
labeling update…”
Participant 2: 10- “…“fully aware of the regulatory requirements of pediatric exclusivity.We
have utilized the incentive provisions of pediatric exclusivity on three of our pediatric drugs”.
Participant 3: 10- “… fully aware of the incentive provisions of pediatric exclusivity”.
2. Under the pediatric exclusivity provisions, conducting studies on pediatric drugs are
voluntary and encouraged. Are you getting the expected number and quality of studies
from pediatric drug companies, with the voluntary requirements? Explain.
Participant 1: “…it is up to the industry to decide if they want to take advantage of the
program”.., “…getting corporate buy-in by offering increased/prolonged profits on still
useful drugs seems more positive than a forced approach…” “…you don’t obtain exclusivity
unless you provide pediatric data…”, and “…the flexibility, sadly, is necessary…”
Participant 2: “…a number of quality pediatric studies have been done…”, “… much more
needs to be done…”
Participant 3: “…“the economic incentive to comply with the voluntary requirements balance the
effort of compliance”.
If not, do you think the FDA should make these studies mandatory? What are its pros and
cons?
Participant 1: “…“The FDA does make pediatric studies mandatory for applicable products in
accordance with PREA.”
Participant 2: “…if these studies were mandatory, it may cause fewer drugs to be available for
children or delay drug development… while waiting on studies that were difficult to
conduct. “…I’d be concerned about the unintended consequences of mandated pediatric
research”, “…not sure it is feasible”, “…force fit…”
Participant 3: “…The FDA cannot make them mandatory based on the current law. It is not a
regulatory issue but a legislative one.” “I support mandatory studies, in compliance with
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PREA as long as they are feasible and assure that all pediatric age groups are appropriately
treated”.
3. What is your company’s main motive behind conducting studies for pediatric
exclusivity?
Participant 1: “…improvement in pediatric dosages, labeling, and formulation…”,
“…commitment to produce safe and effective drugs…”, “…patient safety first…”
Participant 2: “…primarily we had a pediatric indication. Exclusivity was granted for work
conducted to generate long-term safety and pharmacokinetic data to update the labeling of
the product”.
“…commitment of my industry to provide safe and effective drugs to children”, “…compliance
with PREA requirements”, “…financial rewards of pediatric exclusivity…”
4. Could you comment on the pediatric studies conducted under pediatric exclusivity?
Participant 1: “…no current assessment of the capacity to perform PDTs”. Need for a more
“transparent pediatric testing process”, “…PDTs should provide additional information on
“cardiovascular medicines, mental health medications, and sedatives”.
Participant 2: “While the adult drug development is industry driven, pediatric drug development
is regulatory driven”, “Nothing has worked better than incentives to get the pharmaceutical
industry conduct pediatric clinical trials”, “…great success…”
Participant 3: “…has been highly effective in generating pediatric studies on many drugs and in
providing useful new information regarding safety, efficacy, dosing, and unique risks of
drugs in pediatric patients”, “…naturally tended to produce pediatric studies on those
products where the exclusivity has the greatest value”, “…real success stories”, “…the most
successful pediatric initiative that the Agency has participated in to date”, “…big
advance…” in developing pediatric medicines, “…substantial increase in the number of
pediatric clinical trial data…”, “…to what extent can policy makers rely on incentives alone
as a means of ensuring appropriate testing” remains unclear.
5. Which of the following kinds of studies is most commonly conducted in children under
the pediatric exclusivity provisions? Give reasons.
a. __Efficacy/Safety
b. __Pharmacokinetics/Safety
c. __Pharmacodynamics/Safety
d. __Safety
e. __ All of the above
f. __ Others (Specify)
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Participant 1: The type of study conducted depends on the “type of drug developed and its risk
benefit profile”.
Most common studies “efficacy/safety” followed by “pharmacokinetics/safety”, “… if we
understand how a drug works in adults, then pharmacokinetic studies are sufficient for
pediatric population…”
Participant 2: Most common studies “efficacy/safety” followed by “pharmacokinetics/safety”
“…the time to complete efficacy studies is approximately 50% longer than pharmacokinetic
studies (median 24 months vs 16 months). The median duration of bioequivalence studies is
6 months (range 5-7 months)”.
Participant 3: Most common studies “efficacy/safety” followed by “pharmacokinetics/safety,”
“…efficacy studies takes approximately 50% longer than pharmacokinetic studies”.
“…for timely development of pediatric drugs, all pediatric studies that are delayed and pending
need to be expedited”.
Are the studies conducted adequate? Give reasons.
Participant 1: Studies conducted under a “written request (WR) with the FDA” are adequate.
Participant 2: Studies conducted under a “written request (WR) with the FDA” are adequate.
Participant 3: Studies conducted under a “written request (WR) with the FDA” are adequate.
6. In your opinion, which pediatric medicines currently available in the market need
studies (non-clinical and clinical) to establish their safety and efficacy?
Participant 1: “…Pediatric cancer studies are needed depending on the type of malignancy as the
pathogenesis may be similar in certain cancer”.
Participant 2: Pediatric HIV studies are a “major ongoing concern worldwide”.
“…neonatal studies are very hard to conduct but the inherent safety concerns are a critical
question especially for long term development”.
Participant 3: “safety and pharmacokinetics data in the use of drugs like tetracycline,
doxycycline, clindamycin, trimethoprim-sulfamethoxazole, in the treatment of pediatric
MRSA”.
“antidepressants, ADHD medications, antiepileptics, and anti-infectives (especially antivirals
directed towards influenza”.
7. In your opinion, which pediatric medicines currently available in the market do not
require pediatric studies (non-clinical and clinical)? Give reasons
Participant 1: “…none are completely and thoroughly studied”.
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Participant 2: “…pediatric hypertension…”, “…medicines which are rarely used in the pediatric
population…”,
Participant 3: “…drugs that are already labeled in pediatrics with published data and known to be
fairly safe and effective…”
8. What do you think are some major problems/concerns with pediatric drugs? Explain
how individual problems can be resolved to make pediatric drugs more safe and
efficacious.
Participant 1: “…not standard doses…” “… dose calculation error…”, develop “…pediatric
specific dosing, formulations, and labeling changes…”
“…pediatric formulation”- solved through “…research involving advanced knowledge in
formulation…”
Participant 2: “…labeling…”, “consult your physician” “…“off-label and off-license use-
“…analgesics, bronchodilators, and antibiotics”.
Resolved through study of- “…risk benefit profile…”.
Participant 3: “…off-label and off-license use…”,
Resolved through study of- “ …risk benefit assessment…”
“…“If there is uncertainty regarding either the benefits or the risks, the FDA under the authority
given by Congress mandates post-licensure studies to companies, and should also be able to
have significant sanctions in the event these post-marketing studies are not completed”.
Has the pediatric exclusivity provisions helped to resolve the above-mentioned problems?
Yes
Participant 1: “Yes”
Participant 1: “Yes”
Participant 1: “Yes”
No
If no, give reasons
9. What major challenges do pharmaceutical companies encounter in the development of
pediatric drugs? How have the companies been handling these challenges?
Participant 1: “…expensive trials and their economic returns are variable…”, “…possible lack of
return on investment…”, “…small pool of trained pediatric investigators…”, “…“corporate
inertia” to develop and market drugs for adults over pediatric drugs
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Participant 2: “…costly trials…”, “…pediatric patient recruitment difficulties…”, “the stress of
short-term pain (such as blood sampling)”, “…trial designs challenging …”, difficulty in
validating “…quality-of-life questionnaire…”
Participant 3: “…expensive trials…” “…healthy children were difficult to recruit…”, “…“non-
therapeutic” research, ethical issues of “informed consent and assent”
“Can a 7 year old (the age arbitrarily recommended for including children in the assent process)
fully understand the complexities of clinical trials to which he/she is assenting to?”,
“the lack of established relevance of surrogate markers for children”.
Impact of Pediatric Exclusivity
10. Under pediatric exclusivity provisions, in what pediatric age categories has the impact
of pediatric studies conducted been felt the most?
(Age categories are set as: neonates (0-1 month), infants (1 month to 2 years); children (2
years to 12 years); adolescents (12 years to 16 years).
a. __Neonates (0-1 month)
b. __Infants (1 month to 2 years)
c. __Children (2–12 years)
d. __Adolescents (12–16 years)
Participant 1: “Adolescents >Children> Infants> Neonates”
Participant 2: “Adolescents >Children> Infants> Neonates”
Participant 3: “Adolescents >Children> Infants> Neonates”
Give reasons why the impact is felt maximum at the selected age group?
Participant 1: “…ease of recruitment of older pediatric patients…” “…younger children have
benefitted more…”
Participant 2: “…easier to recruit and study older children…”, “…ethical and logistical issues…”
Participant 3: “… Adolescents due to their closer relevance to adults in physiological maturity
and overlap of broad indications…”, Impact felt more in “…children over the age of six, but not
much for younger children…”,
Give reasons why the impact is felt minimum at the selected age group?
11. What are the gains/ advantages of FDA’s pediatric exclusivity provision to the following
assuming that companies conduct pediatric studies to avail the incentives?
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a. Pediatric patients and consumers
b. Medical practitioners
c. Pediatric drug companies
Participant 1: “…better dosage, labeling, and drug safety information…”, “…the biggest benefit
of pediatric exclusivity is the right dosage information for the pediatric medicine studied…”,
“…high profit earning…”, “…priority application…”, “…all stakeholders benefit…”
“…I would say these are equally aligned. Companies receive the economic benefit for
conducting the studies while pediatric patients and pediatricians receive the assurance that the
products will have a positive benefit risk profile”.
Participant 2: “…high return on investment, “…slow generic intrusion…” “…better dosage,
labeling, and drug safety information…”, “…high profit earning…”, “…additional marketing
control …”, “…profit optimization…”
Participant 3: “…better dosage, labeling, and drug safety information…”, “…prescription
justification…”, “…high return on investment…”
12. What are the disadvantages of pediatric exclusivity program to:
a. Pediatric patients and consumers
b. Medical practitioners
c. Pediatric drug companies
Participant 1: “… “raised consumer expenditure on brand name or patent drugs”, “…financial
burden on consumers…” “…burden of conducting studies with uncertain return on
investment…”
Participant 2: “…expensive to taxpayers…”, “…raised the economic costs of government”,
“…pediatricians challenged to “keep abreast with” all the recent drugs granted pediatric
exclusivity…”, “…burden of study involvement...”.
Participant 3: “…economic impact of longer term for branded medicines…”
13. Do you support pediatric exclusivity provisions? Give reasons.
Participant 1: “yes”, it grants companies the “incentive to conduct clinical studies” though a
“…heavy burden on tax payers…”
Participant 2: “yes”, it provides confidence that the drug product has been adequately “tested in
the intended patient population”, “…boosts industry enthusiasm” for conducting pediatric studies
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Participant 3: “yes”, “…incentive to conduct pediatric studies…” to develop “…safe and
effective pediatric drugs…”
14. How has pediatric exclusivity influenced pediatric drug labeling? Explain the changes.
Participant 1: “…improved pediatric drug labeling…”, “…provided new and useful information
on drug labels…”
Participant 2: “…improved pediatric drug labeling…” “…but can it guarantee that companies
receiving exclusivity make the results of their studies known through the labeling changes
necessary for safe and effective use of drugs…?”
Participant 3: “…improved pediatric drug labeling…”, provided “…new child-safety
information, new or altered pediatric dosing information, additional warnings about adverse
events in children, recommended dosage modifications, and findings of lack of efficacy for some
drugs”.
15. How has pediatric exclusivity influenced pediatric drug dosing? Explain the changes.
Participant 1: “…generally provided better dosing information for children over 2 years of
age...”, “…corrected dosing errors…”
Participant 2: “…more dosing improvement is seen in “adolescents (12-16 years) than in
neonates (0-1 month) and infants (1 month-2 years)”.
“Pediatric exclusivity has resulted in providing dosing recommendations for high b.p. and fungal
medicines that I am aware of.”
Participant 3: “…provided information for safely and effectively dosing pediatric population but
much needs to be done mainly in neonate dosing…”
16. Which of the dosing types- age-based, weight-based, or both do you prefer for pediatric
drug labeling? Give reasons for your choice of dosing.
Participant 1: “…combination of weight and age…”, age-based dosing “more typical”,
“…widespread but probably not the best…”, dosing by weight in some cases (i.e. in infants and
young children) may achieve “better efficacy results and may be safer”, “…male vs female
dosing difference in some cases…”
Participant 1: “…both…”, “…weight-based dosing to select a correct dose, to prevent any
dosing error, compared to age-related dosing only…”
Participant 1: “…combination of weight and age…”, “…weight-based dosing for dosing
consistency…”
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17. How has pediatric exclusivity influenced pediatric formulation? Explain the changes.
Participant 1: “…liquid formulation” is often chosen for pediatric administration, “…solid doses
that are scored…” for weight-based dosing
Participant 2: “…need to develop more commercially available “oral pediatric formulations”
under the pediatric exclusivity program, “…flexible dose liquid formulation…”
Participant 3: FDA in a written request (WR) to the drug companies, “requests pediatric
formulation” in most cases,
18. What is your view on the current 6 months duration of pediatric exclusivity? Does it
serve its intended purpose? If not, should the duration of pediatric exclusivity be reduced
or extended? Give reasons.
Participant 1: “…6 months is fine…”, “…satisfied with 6 months of pediatric exclusivity …”,
“…effective in encouraging studies in pediatric drugs without crippling the generic drug
manufacturers for long”, “…12 months for some drugs to be able to recover and recoup pediatric
development cost, given the investment and time required…”
“…current 6 month exclusivity program provides a big windfall to blockbuster drugs…”
Participant 2: “…6 months of pediatric exclusivity has been serving its purpose adequately…”,
“…“the exclusivity provision will need to be adjusted to provide incentives for manufacturers
who are not taking advantage of market exclusivity…”
Participant 3: “…has been serving its intended purpose…” “…no comments…”
19. What are the factors that determine the success of studies for pediatric exclusivity? List
the factors.
Participant 1: “… “prior results suggesting benefit (and minimal risk)”, “…well designed studies,
expert investigators, properly analyzed data based on good science…”
Participant 2: “…well-organized study, well-trained investigators. parents collaboration in
research, no other available therapeutic options, and high quality facilities…”
Participant 3: “…well-organized study conducted in high quality facilities by well-trained
investigators with parental collaboration…”
20. Is the incentive provided by the pediatric exclusivity regulation potentially sufficient to
offset the cost of pediatric drug development? Explain.
Participant 1: depends on the “drug, its market share, and its indications…”, “…this
really depends on the medication, the condition, and the competitive situation for this
medication...”, incentive was not adequate for “old antibiotics and other drugs lacking patent
protections or drugs for certain younger age groups, especially neonates”, “… incentive is never
too much…”
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Participant 2: “…“generally sufficient”, “economic windfall in some cases…”, “in all
instances they make money and in most instances they make a whole lot of money”, incentive
not adequate for “old antibiotics and other drugs lacking patent protections or drugs for certain
younger age groups, especially neonates”.
Participant 3: “…“generally sufficient for most drugs…”
21. In your opinion, is there any better/practical alternative to pediatric exclusivity to
encourage drug manufacturers to conduct clinical studies on pediatric drugs? Explain.
Participant 1: “…none…” that is practically viable at this time, “…PREA requirements to test
their drugs in children…”, “…Providing tax breaks or grants…”, “…ok with what we have,
need no more regs…”, “…rare pediatric indications need more studies…”
Participant 2: “…not really…”, “…“companies need an incentive to evaluate special populations
because of the cost involved…”, “…To address outstanding pediatric data needs, Congress
should grant a program allowing the FDA to fund pediatric clinical research directly…”.
Participant 3: “…none that is practical…”, “…policy issue which the Agency staff cannot
comment on…”.
22. Some critics say the drugs granted pediatric exclusivity are not the drugs most used by
the children. Do you agree? Give reasons. How do you compare the number of drugs
granted pediatric exclusivity and the number of drugs used by children?
Participant 1: “…yes…”, “…the distribution of these drugs closely matched the distribution of
these drugs over the adult market, and not the drug utilization by children…”, “…“Can it
[referring to pediatric exclusivity provision] assure that drugs likely to be used in children are
tested in children before they are prescribed for their use?”
Participant 2: “…yes…”, “…big rewards for testing drugs that sell the most” but not the drugs
that are “used by children the most”.
Participant 3: “…generally yes…”, “…priorities for pediatric drug research should be set by the
need of the patients, not by the market considerations…”.
23. Do you have any criticism on FDA’s pediatric exclusivity program? Explain.
Participant 1: “…“inefficient to study pediatric drugs…”, “… returns variable and uncertain…”,
“…no testing of off-patent pediatric drugs…”, “… by granting exclusivity only after companies
have made labeling changes, the FDA would retain a powerful carrot to assure that labeling
changes are made…”.
Participant 2: “…Why drug makers should be rewarded for something they are required to do
under PREA…?”, Purpose- “…to generate data rather than increase drug use”, “…BPCA
voluntary, complex, and difficult to enforce…”
Participant 3: “…No comment…”
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24. Do you have any comments and suggestions?