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http://dij.sagepub.com/content/early/2014/11/20/2168479014558275The online version of this article can be found at:

 DOI: 10.1177/2168479014558275

published online 21 November 2014Therapeutic Innovation & Regulatory ScienceHong H. Vu and Anne R. Pariser

of Applications for New Drug and Biologic ProductsInvestigational New Drug Meetings With the FDA: Evaluation of Meeting Content and Characteristics−Pre

  

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Pre–Investigational New Drug Meetings

With the FDA: Evaluation of Meeting

Content and Characteristics of Applications

for New Drug and Biologic Products

Hong H. Vu, PharmD, MS1, and Anne R. Pariser, MD1

Abstract

Introduction: Prior studies suggested that holding preinvestigational new drug application (PIND) meetings with FDA has a positive

effect on clinical development time (CDT). Methods: New product marketing applications submitted to FDA CDER during fiscal

years 2008-2012 were assessed for whether a PIND meeting was held and, if so, a qualitative assessment of meeting content was

performed. Results: Discussions contained in the PIND meeting minutes tended to reflect topics appropriate to an early phase of

drug development, including chemistry, manufacturing, and controls (CMC) and safety topics (eg, nonclinical and clinical domains).

Additionally, FDA commonly provided additional advice most often in the clinical and CMC domains. Applications for which a

PIND meeting was held during drug development had shorter CDTs than those that did not. Conclusions: This analysis showed the

importance of early communication with FDA during development, and small companies with limited regulatory experience may

gain the greatest benefit from early communication with FDA.

Keywords

drug approval process, rare diseases, orphan drugs, FDA

Introduction

A pre–investigational new drug (PIND) meeting is often the

first communication between the US Food and Drug Adminis-

tration (FDA) and a drug developer (‘‘sponsor’’) regarding clin-

ical development of an investigational new drug (IND). PIND

meetings are intended to provide advice to sponsors regarding

IND-enabling work (eg, preclinical studies, product manufac-

turing and characterization) and the design of early-phase

clinical trials (eg, first-in-human, phase 1 trials).1 Clinical

development is typically sequential: the design and conduct

of later-phase trials will rely on foundational information

gained in earlier-phase trials, and the results from later-phase

(pivotal) trials, if successful, will then be used to support mar-

keting approval. Early-phase advice can help sponsors navigate

the complex drug development and regulatory environment

and avoid mistakes that may be costly in terms of time, avail-

able patients, and drug development resources. Thus, early-

phase advice has the potential to contribute to the efficiency

and success of drug development programs. While PIND

meetings may be useful for most drug development programs,

meetings for original biological products and new molecular

entities (‘‘drugs’’), defined as drugs for which the active

substance has not previously been approved by the FDA,2 and

for disease indications without prior-approved drugs (first-in-

disease indications) may be particularly beneficial because

there is likely to be limited clinical, nonclinical, regulatory, and

manufacturing experience with these drugs.

Drug development programs are influenced by many

factors, of which early communication between the FDA and

drug sponsors is only one consideration. A recent preliminary

analysis of new drugs approved by the FDA’s Center for Drug

Evaluation and Research (CDER) from January 2010 through

July 2012 suggests that applications for which a PIND meeting

was held with the FDA during clinical development had shorter

clinical development time (CDT) than those that did not hold a

1 Office of New Drugs, Rare Diseases Program, Center for Drug Evaluation

and Research, Food and Drug Administration, Silver Spring, MD, USA

Submitted 6-Aug-2014; accepted 7-Oct-2014

Corresponding Author:

Hong H. Vu, PharmD, 10903 New Hampshire Avenue, White Oak, Building 22,

Room 6480, Silver Spring, MD 20993, USA.

Email: hong.vu@fda.hhs.gov

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PIND meeting.3 The shorter CDT was particularly noted for

drugs developed by small companies and especially for drugs

indicated for rare diseases. Rare diseases, often referred to as

‘‘orphan diseases,’’ are defined in the US as disorders that

affect 200,000 or fewer Americans.4 Considering the

challenges of developing new drugs, particularly drugs indi-

cated for rare diseases and unmet medical needs, conducting

efficient, scientifically sound clinical development programs

is in the interest of furthering the public health.

To assist drug sponsors and to inform advice on how to con-

duct good quality PIND meetings, we undertook an analysis of

a recent 5-year period (fiscal years 2008-2012) of marketing

applications for new molecular entity and original biological

products for which an action (eg, approval) was taken by the

FDA CDER during this time frame. We identified those appli-

cations for which a PIND meeting was held, and assessed the

contents of these meetings. The goal of this assessment was

to identify topics appropriate to the phase of drug development

to assist sponsors in holding efficient and productive PIND

meetings with the FDA. We also sought to assess factors relat-

ing to application characteristics that can affect a drug develop-

ment program (eg, company size) to identify applications that

may benefit the most from early interactions with the FDA.

Study Data and Methods

Data Source

A retrospective analysis was performed of new molecular

entity and original biological product marketing applications

(new drug applications and biologics license applications,

respectively) for which an action was taken by the FDA CDER

from October 1, 2007, to September 30, 2012 (fiscal years

2008-2012). ‘‘Action’’ included approval, complete response

(drug was not approved), or refuse-to-file (application was not

sufficiently complete to permit a substantive review)5 decisions

by the FDA CDER and applications that were withdrawn by the

sponsor prior to an action being taken by the FDA. Some appli-

cations had more than one action taken and were categorized by

the last regulatory action taken during the 5-year period. For

example, if an application was issued a complete response and

then later approved during the period being analyzed, it was

counted only once as an approval action. Applications with

multiple disease indications, all of which were reviewed by the

same review division within CDER, were counted as a single

application. This 5-year time frame was chosen, as it is the

most recent complete 5-year period and best reflects current

FDA CDER review practices. However, because PIND meet-

ings occur during investigational phases of drug development

and because drug development is typically a multiyear process

of varying length depending on the application, the PIND meet-

ings analyzed for these applications occurred across an

approximately 2-decade span and thus may reflect FDA

practices over a longer period than 5 years.

All the information for these marketing applications, inclu-

ding the official minutes of the PIND meetings (the primary

source documents for these meetings) and application charac-

teristics (eg, review type), were obtained from the FDA’s

website6 and internal database (Document Archiving, Report-

ing, and Regulatory Tracking System).

Data Collection: Characteristics of PINDMeeting Content

The applications were evaluated to determine whether a PIND

meeting was held and, if so, a qualitative assessment of meet-

ing content was performed from the official minutes of the

PIND meetings. This included minutes from PIND meetings

conducted in various formats, such as face-to-face, telecon-

ference, and written response–only interactions. Most of the

meeting minutes contained a variable number of questions

asked by the sponsor and associated responses provided by

the FDA.

All questions were collected and analyzed in a standardized

fashion. Each question and associated response (Q&A), being

the unit of analysis, was scored separately according to vari-

ables at two levels: domains and subdomains (Figure 1). The

content of each Q&A was assessed according to the following

domains: chemistry, manufacturing, and controls (CMC); non-

clinical; clinical; and regulatory. The subdomains classified the

content into more detailed categories. For example, a nonclini-

cal study can be further classified as a reproductive or genetic

toxicology study. All the domains were classified into more

detailed categories, with the exception of CMC. Generally,

CMC topics can be highly specific to the drug substance, drug

product, and stage of development, which can lead to a high

degree of fragmentation by topic area and make it difficult to

classify the content into subdomains in a meaningful way.

Therefore, subdomain analysis of CMC was not performed, and

only general findings were reported. Scoring more than 1

domain (or subdomain) was allowed—for example, a question

addressed both toxicology (nonclinical domain) and phase 1

study design (clinical domain). For this reason, the sum totals

of the domains and subdomains can be greater than 100%. For

PIND meeting minutes that did not have a general Q&A format

but contained discussions written in a paragraph form or cate-

gorized in a specified heading, the discussion provided under a

specific heading was counted as a single Q&A unit. For exam-

ple, some meeting minutes contained several headings,

wherein each heading consisted of multiple bullet points. The

discussion topics in the bullet points under each heading were

considered a single Q&A unit.

2 Therapeutic Innovation & Regulatory Science

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Characteristics of Marketing Applications

We examined the following application characteristics: PIND

meeting (yes vs no), application type (new molecular entity

vs biologic), approval as the last regulatory action (vs non-

approval; herein includes complete response, refuse-to-file,

and applications withdrawn by the sponsor), first review cycle

approval (vs approval in >1 cycle or nonapproval action), and

disease indication (rare vs common). Application characteris-

tics including company size, sponsor’s regulatory experience,

first-in-disease indication, and priority review designation were

defined as follow:

1. Company size was defined as small (<150 employees),

medium (150-14,999), or large (�15,000) based on the

number of employees reported in publicly available

sources (eg, the company’s annual report or form 10-K

filed with the US Securities and Exchange Commission).

Companies that lacked publically available information

regarding the number of employees were categorized

as small because the best available evidence suggested

that most were small, privately held firms. Company size

categories were based on a similar criterion to those used

in previous studies.7,8

2. Regulatory experience was defined as the sponsor hav-

ing successfully brought at least 1 FDA-approved prod-

uct to market at the time of submission of the marketing

application analyzed for this study.

3. First in disease was defined as a drug for a disease indi-

cation for which there was no drug previously approved

by the FDA.

4. ‘‘Priority review’’ is a designation given by the FDA to

a drug that treats a serious condition that, if approved,

would provide a significant improvement in safety or

effectiveness over existing treatments.9 The FDA’s

review goal is 6 months for a priority review, compared

to a 10-month standard review.

The CDT was calculated for applications that received an

approval action from the FDA. CDT was defined as the time

from receipt by the FDA of the key IND through to the day

of marketing application approval. The key IND was defined

as the initial IND under which clinical development and impor-

tant regulatory milestones (ie, formal meetings) primarily

occurred.

Because the initial submission of an IND to the FDA does

not necessarily reflect the actual development phase of a drug,

we additionally considered the ‘‘true phase’’ of the drug at the

time of the PIND meeting. PIND meetings are usually granted

for the first meeting interaction with the FDA, even if some

applications were actually at a later phase of development.

True phase was based on the phase of the development program

in which the sponsor opened the IND in the US, identified from

either the PIND meeting minute or supporting documentation

for the meeting. For example, if a drug has undergone

Subdomain

Content

REMS orpostmarke�ng

Sta�s�calanalysis plan

CLINICAL

Diseasemodel/nonclinicaloutcome/endpoint

NONCLINICALDOMAIN REGULATORY

Pediatrics

Specialpopula�on

Safety

Toxicology

Toxicokine�c

Labeling &packaging

Format &documenta�on

Pharmacodynamic

Biomarker

Pharmcodynamic Efficacy

Pharmacokine�c Safety(premarke�ng)

Pharmacogenomics Study popula�on

Indica�on

Endpoint

Inspec�on

CMC

Study design

Reprotoxicity

Genotoxicity

Proof of concept(efficacy)

Carcinogenicity

ClinicalPharmacology

Clinical

Figure 1. Domain and subdomain scoring method for sponsor’s questions and FDA’s responses. CMC ¼ chemistry, manufacturing, andcontrols; REMS ¼ risk evaluation and mitigation strategy.

Vu and Pariser 3

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development in another region of the world and had completed

phase 2 investigations by the time that the PIND meeting was

held, the true phase was assessed as end of phase 2. For

applications that did not hold a PIND meeting, true phase was

determined from the FDA review documents of the IND

protocol submission.

Statistical Analysis

This was a descriptive retrospective study primarily designed

to characterize the content of PIND meetings and application

characteristics by company size. A prespecified hypothesis was

not included in the study, because it was not designed to show

association or causality. Descriptive statistics were used to

characterize the content of the PIND meeting minutes accord-

ing to prespecified domains, as well as to identify factors relat-

ing to application characteristics by company size. For

qualitative data, absolute frequencies and percentages are pro-

vided; for quantitative data (eg, CDT), median and range are

reported. To measure the strength of the relationships, the fac-

tors relating to application characteristics and company sizes

(small, medium, and large) were further compared according

to the following data types: categorical data (eg, PIND meet-

ing, new molecular entity, approval, first review cycle

approval, rare disease indication, regulatory experience, first

in disease, priority review designation, and true phase) were

assessed via the chi-square test; continuous data (eg, CDT)

were assessed with the Kruskal-Wallis test. Analyses were per-

formed with JMP 9.0.2 software. Two-sided nominal P values

are provided for descriptive purposes only.

Results

In the 5-year period studied (fiscal years 2008-2012), an action

was taken by the FDA CDER on a total of 200 marketing

applications. Of these applications, there were 135 (67%)

approval and 65 (33%) nonapproval actions. The nonapproval

actions included applications that received FDA letters for

complete response or refuse to file or were withdrawn by the

sponsor prior to an action being taken by the FDA. Among the

135 approved marketing applications, 36% had a PIND meet-

ing, and among the 65 applications that did not receive an

approval action, 37% had a PIND meeting.

PIND Meeting Content

Of the 200 applications analyzed, PIND meetings were held for

73 applications (36%), from which a total of 599 Q&As were

identified. Based on the 599 Q&As, occurrences for each

domain from high to low frequency were as follow: clinical

(54%), nonclinical (29%), regulatory (eg, labeling, submission

format, pediatric study plans) (17%), and CMC (17%)

(Figure 2A). In addition to responding to questions posed by

sponsors, FDA review staff often gave additional advice

(Figure 2B). As a result, 32 (44%) of the 73 PIND meeting min-

utes included additional comments provided by the FDA. The

additional advice was usually related to topics not raised by the

sponsor. For example, the sponsor may have asked questions

relating only to its phase 2 study design. However, in respond-

ing to those questions, the FDA also brought attention to CMC

issues or the need for additional animal studies based on the

FDA’s review of the materials submitted by the sponsor. Based

on the additional FDA comments provided in the 32 applica-

tions, the topical breakdown was as follows: clinical (78%),

CMC (44%), regulatory (25%), and nonclinical (22%).

Generally, CMC topics comprised two categories: drug sub-

stance (or active pharmaceutical ingredient) and drug product

(defined as a finished end product that contains the drug

substance that is generally but not necessarily in association

0%10%20%30%40%50%60%70%80%90%

100%

CMC Nonclinical Clinical Regulatory

Perc

enta

ge o

f Occ

urre

nces

Occurence of topics by domain (73 drug applica�ons):599 Q&As iden�fied from the applica�ons

A B

Domain

0%10%20%30%40%50%60%70%80%90%

100%

CMC Nonclinical Clinical Regulatory

Perc

enta

ge o

f Occ

urre

nces

Occurence of topics by domain (73 drug applica�ons):32 (44%) applica�ons with addi�onal FDA comments only

Domain

Figure 2. A, Questions posed by sponsors and responses provided by FDA at pre–investigational new drug (PIND) meetings by domain. B,Additional advice provided by FDA at PIND meetings by domain. In each figure, the sum of the percentages is greater than 100% because a singlequestion and associated response can include topics that fall into multiple domains. Percentages were based on denominators of 599 (A) and 32 (B).

4 Therapeutic Innovation & Regulatory Science

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with 1 or more other ingredients; eg, excipients).10 Some fre-

quent examples of drug substance topics discussed included

characterization, method of preparation, stability testing,

impurity profiles, and analytic methods to ensure identity and

strength. As for the drug product, general topics included com-

ponents used in the manufacturing, quantitative composition,

drug manufacture information, and analytical methods to

ensure identity and strength of the drug product.

Table 1 summarizes the proportion of the topics at the

subdomain level for the following domains: nonclinical

(175 Q&As), clinical (324 Q&As), and regulatory

(104 Q&As). The most frequently discussed subdomain topics

included the following:

Within the nonclinical domain: Safety-related nonclinical

Q&As (78%), most notably toxicology (61%).

Within the clinical domain: General clinical topics

(76%)—notably Q&As relating to premarketing safety

(47%), study design (31%), and efficacy (27%); the

next most frequent were clinical pharmacology topics

(46%), most commonly related to pharmacodynamics

(34%) and pharmacokinetics (24%).

Within the regulatory domain: Q&As related to format

and documentation (22%).

Application Characteristics

Table 2 summarizes the results from the analysis of company

size in relation to the characteristics of marketing applications.

The proportion of applications for which a PIND meeting was

held was similar among the companies of different sizes. Spon-

sors asked an average of 8 questions per meeting, and this also

did not differ by company size. Applications submitted by

small companies accounted for 32% of the reviewed applica-

tions. Notable trends observed between the small and larger

companies include the following:

� Applications submitted by small companies had the low-

est approval rate (50%) compared with submissions by

the large (70%) and medium (85%) companies.

� Compared to large companies, a higher proportion of

small companies pursued product development for rare

disease indications (40% of small vs 18% of large

companies).

� Compared to larger companies, small companies had the

lowest proportion of sponsors with regulatory experi-

ence (15% of small vs 97% of large and 74% of medium

companies).

Of the 135 approved marketing applications, 3 were

excluded from the CDT analysis because the sponsors did not

submit an IND application and the CDT could not be

calculated. As a result, the CDT was determined for 132 appli-

cations. Differences in CDTs were observed by company size,

with applications from small companies having a longer med-

ian CDT (8.8 years; range, 1.6-43.8) compared to large compa-

nies (6.7 years; range, 1.6-29.5). Another notable finding was

that 49 marketing applications for which a PIND meeting was

held had a shorter CDT (median, 6.4 years; range, 1.6-12.3),

compared to 83 applications for which a PIND meeting was not

held (median, 8.3 years; range, 1.6-43.8).

Table 1. Meeting content at subdomain level for nonclinical, clinical,and regulatory domains.a

TopicsOccurrences, %

In Q&AIn Additional FDAComments Only

Nonclinical subdomain n ¼ 175 n ¼ 7Safety 78 71

Toxicology 61 71Toxicokinetic 10 14Carcinogenicity 13 29Reprotoxicity 15 29Genotoxicity 13 0

Proof of concept 13 43Pharmacodynamic 4 14Biomarker 2 14Disease modelb 5 14

Clinical subdomain n ¼ 324 n ¼ 25Clinical pharmacology 46 52

PD including dose finding, DI 34 48PK including bioequivalence 24 36Pharmacogenomics 0 4

Clinical 76 68Efficacy 27 16Premarketing safety 47 44Study population 23 16Indication 13 20Endpoint 15 44Study design 31 12

Statistical analysis plan 17 36Regulatory subdomain n ¼ 104 n ¼ 8

Pediatrics 15 25Special population 10 38Inspection 2 0Labeling and packaging 16 25Format and documentation 22 13REMS/postmarketing 0 0

DI ¼ drug interactions; PD ¼ pharmacodynamics; PK ¼ pharmacokinetics;

Q&A¼ questions and answers; REMS¼ risk evaluation and mitigation strategy.aThe percentages of the specific topics were based on the denominator of the

domain from which they are categorized. For example, within the nonclinical

domain, the proportion of toxicology (61%) was based on a denominator of

175, whereas within the clinical domain, the proportion of clinical

pharmacology (46%) was based on a denominator of 324.bIncludes nonclinical outcome and endpoint.

Vu and Pariser 5

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With regard to the true phase, there was a higher proportion

of large companies (69%) opening their INDs in phase 1 com-

pared with small companies (55%). Moreover, a greater pro-

portion of small companies (21%) opened their INDs in

phase 3 as compared with large (11%) and medium (10%) com-

panies. Differences in company size were not observed for

INDs opened in phase 2. Interestingly, we noted that sponsors

opening INDs in the US earlier in the development process

(phase 1) tended to have higher US approval rates when com-

pared to those entering in the later phases (phases 2 and 3),

regardless of whether a PIND meeting was held. As shown in

Figure 3, the proportions of approval rates for whether a PIND

meeting was held compared to not held, according to the phase

of drug development in which the sponsors begun their INDs,

are as follow: phase 1, 54% versus 70% (approval rates for

PIND meeting held vs not held, respectively); phase 2, 33%

versus 18%; and phase 3, 13% versus 12%.

Additionally, the evaluation showed that for marketing

applications in which a regulatory action was taken in fiscal

years 2011 and 2012, the percentages of applications that held

a PIND meeting were higher than those in previous years

(Figure 4). The reasons behind this trend are unknown.

Table 2. Characteristics of marketing applications by company size.

CharacteristicCompany Size, No. (%)

Large(n ¼ 88)

Medium(n ¼ 47)

Small(n ¼ 65)

Total(N ¼ 200) P Value

PIND meeting 33 (37) 20 (42) 20 (30) 73 (36) .527NME application 72 (81) 34 (72) 62 (95) 168 (84) .0099Approval 62 (70) 40 (85) 33 (50) 135 (67) .0013First-review-cycle approval 43 (48) 29 (61) 20 (30) 92 (46) .5744Rare disease indication 16 (18) 20 (42) 26 (40) 62 (31) .0016Regulatory experience 86 (97) 35 (74) 10 (15) 131 (65) <.0001First in disease 16 (18) 7 (14) 22 (33) 45 (22) .0602Priority review 30 (34) 21 (44) 14 (21) 65 (32) .0685CDT, y, median (range)a 6.7 (1.6-13.5) 7.2 (3.3-29.5) 8.8 (1.6-43.8) 7.4 (1.6-43.8) .0198True phase

Phase 1 61 (69) 28 (59) 36 (55) 125 (62) .0326Phase 2 16 (18) 14 (29) 11 (16) 41 (20) .1539Phase 3 10 (11) 5 (10) 14 (21) 29 (14) .0398Unknown 1 (1) 0 (0) 4 (6) 5 (2) na

PIND ¼ pre-investigational new drug; NME ¼ new molecular entity; CDT ¼ clinical development time; na ¼ not applicableaExcluded 3 applications for which CDT could not be calculated, because an investigational new drug application was not submitted.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

PIND meetings(n = 48)

No PIND meetings(n = 84)

Perc

enta

ge o

f App

rova

ls

True phasePhase 1

Phase 2

Phase 3

Figure 3. Approval rate by whether a pre–investigational new drug(PIND)meetingwasheld and the truephaseof drugdevelopment atwhichthe sponsor submitted the investigational new drug application to FDA.

0%

10%

20%

30%

40%

50%

60%

2008(n = 36)

2009(n = 45)

2010(n = 38)

2011(n = 37)

2012(n = 44)

Perc

enta

ge o

f app

lica�

ons

for w

hich

a P

IND

mee

�ng

was

hel

d

Fiscal Year*

Figure 4. Marketing applications with pre–investigational new drug(PIND) meetings by fiscal year. Percentage of marketing applicationsfor which a PIND meeting was held by fiscal year in which the lastregulatory action was taken by FDA Center for Drug Evaluation andResearch. This figure includes fiscal years 2008-2012, starting with2008 covering the period from October 1, 2007, to September 30,2008; ‘‘n’’ denotes the total number of applications per fiscal year inwhich the last regulatory action was taken.

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Discussion

To our knowledge, this is the first study to analyze the con-

tent of PIND meetings conducted between the FDA and

drug sponsors and to provide a comprehensive assessment

of the contents found in official minutes of PIND meetings.

The primary purpose of a PIND meeting is to review and

reach agreement on the design of IND-enabling work

needed to initiate testing in human subjects and to discuss

the scope and design of early-phase trials. The data revealed

that, in general, the topics frequently discussed in the PIND

meeting minutes tended to reflect topics appropriate to an

early phase of drug development, such as nonclinical

toxicology, clinical pharmacology, and clinical safety. We

additionally noted that the FDA frequently provided addi-

tional advice to sponsors at PIND meetings, most commonly

in the clinical (particularly pharmacodynamic and pharma-

cokinetic subdomains) and CMC domains, which implies

that sponsors were asking too few questions in these

domains in early-phase development.

The topics identified from our assessment of the content of

PIND meetings were intended to provide insight into the types

of information exchanges that occurred between the FDA and

sponsors during the presubmission phase and may be helpful

items for sponsors to consider when developing their drug

development programs. The findings may also help sponsors

plan for meetings by making a careful selection of questions

that are appropriate to the clinical development phase and may

enable better transition to the next development phase. The

data also suggested that even though holding a PIND meeting

does not appear to affect approval rate, it may have a positive

effect on a program’s overall development time. The results

showed a 22.8-month difference in median CDT between

applications for which a PIND meeting was held and applica-

tions that did not hold a meeting. Overall, the results were con-

sistent with previous findings that early communication

between sponsors and the FDA is important and may contribute

to more efficient and successful drug development pro-

grams.7,11,12 However, we recognize that there are various

factors that can influence the speed of drug development and

approval processes (eg, unanticipated safety signal), with

communication being only one factor. Regardless, the identifi-

cation of efficient drug development strategies occurs in incre-

mental steps, of which the findings from our analysis may serve

as a basis for future research to explore other factors that may

influence drug development time. We additionally note that

early communication with the FDA is not always fully utilized

by sponsors, since a PIND meeting was held for only 36% of

the applications analyzed.

On examination of application characteristics, we found

that the proportions of applications for which a PIND meeting

was held during development were similar regardless of com-

pany size. Notable trends observed for company size were

that small companies had lower approval rates and longer

CDTs when compared with larger companies. Small compa-

nies also had less regulatory experience than larger compa-

nies, tended to open INDs at later phases of development,

and were more likely to submit applications for rare disease

drugs. While a number of small companies opened their INDs

in phase 3, most commonly, these applications were for prod-

ucts that were originally developed and marketed in another

country.

The development of drugs for rare diseases is particularly

challenging, since there are limited patient populations avail-

able to participate in clinical trials, often poor or incomplete

understanding of the underlying disease, and a lack of clini-

cal outcome assessments that may be available to assess the

effectiveness of an intervention (among other challenges).

The FDA recognizes the unique challenges associated with

rare disease drug development and has exercised flexibility

in applying the statutory standards for approval of these

drugs.13 Regulatory flexibility is an important factor in rare

disease drug development because it allows for a customized

approach to the FDA’s review, as well as the drug develop-

ment and approval process. Enhanced transparency and com-

munication between sponsors and the FDA enable the

exercise of flexibility during drug development. Preferably,

areas where flexibility may be applied should be prospec-

tively agreed on, prior to the exposure of patients to the

investigational drug and to the commitment of drug develop-

ment resources. Early communication may therefore be par-

ticularly beneficial in this situation.

There were limitations to this analysis. First, we analyzed

drug programs only for which a marketing application has been

submitted. Investigational drugs fail for many reasons, commu-

nication issues being only one, and failed programs most often

occur during developmental phases, which were not captured in

this analysis and should be an area of future study. Second, the

scoring method used for the meeting contents, even though

standardized, required some subjective assessments, which

may have influenced the results. To minimize the bias, the vari-

ables were derived from various sources (eg, published litera-

tures, internal scientific documents, and FDA regulatory

guidelines) and reviewed by specialists and scientific staff at

the FDA. Additionally, data collection and analysis were

performed by a single reviewer to ensure consistency on how

the criteria were applied across the scope of all the meeting

minutes, and the results were then examined by a second

reviewer to ensure consistency. Last, because company size

was assessed at the time that the marketing application was

submitted, our data might underrepresent the contribution by

small companies, where acquisition by a larger company might

Vu and Pariser 7

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have occurred during developmental phases. Nevertheless,

small companies composed approximately a third of the study

sample, and trends seen by company size are consistent with

findings by others in previous studies7,11,14,15 and thus are

likely to be valid.

This study was performed with the intention of identifying

attributes of PIND meetings and application characteristics that

could be used to inform advice on holding productive PIND

meetings. Early discussions between sponsors and the FDA

may assist in overcoming unique challenges associated with

certain drug development programs. Therefore, it is not surpris-

ing that larger differences in CDT were seen between product

applications that held a PIND meeting and those that did not.

Early discussion and communications between the FDA and

sponsors can positively affect the drug development process

in many ways—for example, agreement on clinical trial

designs and drug development programs, efficient use of avail-

able resources, early identification of problems or areas of

delay, and decreased needs for multiple review cycles, thereby

saving time and resources. This can be highly beneficial for

sponsors developing drugs for serious disorders and rare dis-

eases due to the high unmet needs and the limited regulatory

precedent for these diseases.

In conclusion, small companies with limited regulatory and

drug development experience, particularly those developing

new drugs for rare diseases, may face extra challenges when

designing and conducting clinical trials for their drug develop-

ment programs, and these companies may realize the greatest

benefits from regulatory assistance and advice offered by the

FDA during PIND meetings. Our study presents specific topics,

either posed by the sponsor or discussed by the FDA, to assist

sponsors in considering important points for discussion with

the FDA during PIND meetings. We acknowledge that the

development of a new drug is influenced by many factors, and

holding a PIND meeting cannot address all the challenges asso-

ciated with drug development that are likely to have also

affected approval rates and CDT. Nevertheless, these findings

underscore the importance of early communication between

drug sponsors and the FDA during drug development and

encourage sponsors to avail themselves of all opportunities for

communication with the FDA during the drug development

process.

Acknowledgments

The authors are indebted to John K. Jenkins, MD, and Lisa M.

LaVange, PhD, for their careful reading of this manuscript and their

thoughtful comments.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, author-

ship, and/or publication of this article.

Notes

Preliminary results of this work were published as an abstract in

Therapeutic Innovation & Regulatory Science (volume 47:5; 2013)

and presented in a poster format at the Rare Disease Day at the

National Institutes of Health; Bethesda, MD; February 28, 2014.

The opinions presented herein are those of the authors and do not

represent the views or policies of the FDA.

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