4

New Drug Application Content and

Review Process for Clinical
Pharmacology and Biopharmaceutics
Chandrahas Sahajwalla, Veneeta Tandon,
and Vanitha J.Sekar*
Food and Drug Administration
Rockville, Maryland, U.S.A.

INTRODUCTION
The regulation and control of new drugs in the United States has been based
on the new drug application (NDA) that is evaluated by the U.S. Food and
Drug Administration (FDA). The data gathered in preclinical studies and
human clinical trials as an investigational new drug (IND) during the drug
development process become part of the NDA. The goal of the drug
development process is to provide sufficient information to the FDA in the
NDA to evaluate the efficacy and safety of the new drug as well as
recommendations to adjust the dose in special circumstances. The drug
development process for new drugs has evolved over the years especially in the
field of Clinical Pharmacology and Biopharmaceutics. In response to the
* Current affiliation: Aventis Pharmaceuticals, Bridgewater, New Jersey, U.S.A.

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evolving technology, advancement of knowledge in the field, and to ascertain

consistency and quality of the data available during the development process,
the US FDA, including, office of clinical pharmacology and biopharmaceutics
(OCPB) has issued several regulatory guidance documents. Office of clinical
pharmacology and biopharmaceutics has several guidances in the public
domain that are available to drug companies (often referred to as sponsors)
which provide recommendations in the areas of clinical pharmacology/
biopharmaceutics such as exposure-response assessments, design and conduct
of population pharmacokinetic studies, in vitro and in vivo drug metabolism
and drug interactions, dissolution testing requirements for immediate and
extended release dosage forms, design and conduct of bioavailability,
bioequivalence and food-effect studies, and studies in patients with renal and
hepatic impairment. This chapter integrates the information from available
OCPB and other FDA-issued guidances that aid in the drug development
process, and also provides insight into some of the issues that should be
considered from a regulatory perspective regarding the Clinical
Pharmacology and Biopharmaceutics aspects of drug development. It should
be noted that some of the guidances are published as a draft and reflect
current scientific understanding and thinking of the FDA scientist.
The sponsors now have option submitting new drug application in NDA
format or Common Technical Document (CTD) format. Common technical
document format is a format in which clinical, pharmacology/ toxicology
and manufacturing data can be submitted to obtain marketing
authorization for new drugs in the United States, European Union, and
Japan. It should however be noted that CTD and NDA do not differ in the
content of the information but mainly the format in which data should be
provided.
This chapter provides an insight into the review process by the Clinical
Pharmacology and Biopharmaceutics staff.
STAGES IN DRUG DEVELOPMENT AND REGULATORY
PROCESS
Once the sponsor has identified a lead compound, traditionally, the drug
development process follows a plan. Most pharmaceutical companies have
a drug development plan that is unique to their company based on their own
experiences. In general all pharmaceutical companies proceed with
development to answer several questions about the drug, i.e., is the drug
safe, up to what dose or exposure it is safe, how should the dose be adjusted
in certain specific populations or when co-administered with other drugs to
have optimized formulation for delivery of the drug.

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When a compound has been identified, a Pre-IND (IND-investigational

new drug) meeting is occasionally requested with the FDA by sponsors.
Sponsor may be a pharmaceutical company or individual investigators.
Prior to the meeting, the sponsor usually submits a Pre-IND package. The
Pre-IND package may include summary of preclinical data and a concept
sheet of a study protocol in order to obtain scientific input from the FDA
reviewers regarding the initial IND. The FDA review team consists of a
Medical Officer, Clinical Pharmacologist and Pharmacokineticist, Chemist,
Pharmacologist/Toxicologist Statistician, and a Microbiologist (depending
on the proposed indication). Input requested by the sponsor before the filing
of the initial IND usually involves questions regarding appropriate dose
and/or dosing regimen selection, safety parameters to be assessed, sampling
times (pharmacokinetics and safety), etc., for the first time in humans
study. Generally, the first study conducted in human volunteers is a clinical
pharmacology study to evaluate the safety and pharmacokinetics/
pharmacodynamics of the drug in healthy volunteers or, in some cases,
patients. Prior to conducting this first-time-in-humans study, the FDA
requires the sponsor to have conducted adequate preclinical studies to
support such a study. The sponsor may also request FDA input regarding
the development plan for their compound, generally if human data on the
drug is available from studies conducted outside the USA. In this case, the
OCPB reviewer would review the sponsors plan and provide additional
suggestions, whenever necessary. Examples of OCPB input at the Pre-IND
stage regarding overall drug development include formulation development
plans, dissolution method development, exploring mechanisms of action,
design and conduct of in vitro metabolism studies, clinical pharmacology
study designs, identifying potentially useful biomarkers, proof of concept
and doseranging studies, exposure-response and/or population
pharmacokineticpharmacodynamic assessments, as well as design and dose
selection plans for Phase 3 studies. Depending on the complexity of the PreIND, the Agency would respond either via a letter or a meeting may be set
up with the sponsor.
Protocols for all studies conducted in human volunteers in the United
States or that would become part of the NDA have to be submitted to the
FDA. Once an IND has been filed FDA assigns a number to the IND.
Subsequent study protocols, study reports or sponsors correspondences
have to refer to the IND number.
Once the sponsor has submitted an IND to the FDA, FDA has 30 days to
review the submitted protocol for human study. During this review, if there
are any concerns about the safety of the subjects to be enrolled in the study,
FDA would call the sponsor and place the protocol on clinical hold until the
concerns identified by the FDA reviewers are satisfactorily addressed. The
IND review process is shown schematically in Fig. 1.

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FIGURE 1 The IND review process, http://www.fda.gov/cder.

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There is keen interest on the part of the pharmaceutical companies to be

involved in screening INDs (at the time of the initial IND submission) in
which several drugs are screened at the same time and one of the
compounds is identified for further development. Further details of this
approach can be found in manual of policy and procedures (MAPP) on the
FDA website [1].
The drug development stages are not rigid, that is, several phases of early
drug development (traditionally called Phase 1 and 2 studies) are generally
on going simultaneously. Typically, Phase 1 studies are in healthy
volunteers, Phase 2 are studies in small numbers of patients, and Phase 3 are
larger clinical trials with adequate number of subjects to determine safety
and efficacy of the drug. Phase 1 studies typically include studies related to
formulation development, assessment of metabolic pathways, assessment of
effects of extrinsic and intrinsic factors such as age, gender, disease, other
drugs and food, and assessment of PKPD. Phase 2 studies are typically
dose-ranging and proof of concept studies in a small number of patients
who comprise the target population (traditionally called Phase 2A).
Assessment of PK-PD is also performed in these studies to help provide an
understanding of the doses and dose regimens to be further studied. These
studies provide the sponsor as well as the regulatory agencies with the type
of knowledge about the drug that is needed to design appropriate
confirmatory or definitive large clinical trials in the target patient
population (traditionally known as Phase 3 trials). Generally, the FDA needs
two positive adequately well controlled Phase 3 trials that support the safety
and efficacy of the drug in the target population prior to approval for
marketing in the U.S. The overall drug development stages are shown
schematically in Fig. 2.
Prior to the start of definitive efficacy or Phase 3 trials, the sponsor
usually requests to meet with the FDA at an End-of-Phase 2 meeting. At this
meeting, the sponsor discusses with the Agency the information that has
been learned about the clinical pharmacology and the limited information
obtained in patients about the safety and efficacy of the drug. End-of-Phase
2 meeting discussions with the FDA usually revolve around the decision as
to whether the sponsor should proceed to conduct the larger Phase 3 trials
and, if so, the appropriate study design for these larger Phase 3 studies.
Clinical trial simulations using the in vitro and in vivo data collected from
the early phases of development may also aid in optimal design of the Phase
3 trials. The sponsor can request a special protocol assessment [1] for
evaluating issues related to the adequacy (e.g., design, conduct, analysis) of
certain proposed studies associated with the development of their drug
products. Three types of protocols are eligible for this special protocol
assessment: (1) animal carcinogenicity protocols, (2) final product stability
protocols, and (3) clinical protocols of Phase 3 trails whose data will form

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FIGURE 2 Stages in drug development and regulatory process. http://www.

fda.gov/cder.

the primary basis for an efficacy claim (if the trials had been discussed at an
End-of-Phase 2/pre-Phase 3 meeting or if the review division is aware of the
developmental context in which the protocol is being reviewed). The FDA
has 45 days to review the protocol and provide scientific/regulatory
comments to the sponsor as needed [2]. The guidance recommends that a
sponsor submit a protocol intended for special protocol assessment to the
Agency at least 90 days prior to anticipated commencement of the study.
The protocol should be complete and sufficient time should be allowed to
discuss and resolve any issues before the study begins. Special protocol
assessments are not to be provided after a study has begun.
There is also a keen interest on the part of the sponsors and the FDA to
have a pre-Phase 2 meeting (Phase 2A meeting; i.e., prior to starting the
pivotal Phase 2 study in a small set of patients). During this meeting,
information available on preclinical studies and Phase 1 studies conducted
up to that time can be integrated to assess and discuss Phase 2 protocols.
These meetings could provide great opportunity to discuss dosing rationale
for the Phase 2 trials, evaluation of appropriate biomarkers, and assessment
of exposure-response relationships. There is great interest in these early
interactions between the sponsor and the FDA because resources can be
used more efficiently and effectively by early communications. There is great

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opportunity for the sponsor and FDA to identify any limitations in the drug
development plan early on, so that all relevant information is available at
the time NDA/CTD is submitted to the FDA. These meetings have potential
to reduce number of review cycles that some times result, and to produce a
better drug product label.
Data and information from all studies conducted during the IND phase
are summarized and submitted in one package, i.e., NDA. Prior to
submission of the NDA, generally the sponsor requests the FDA for a faceto-face Pre-NDA meeting (usually a few months prior to the submission of
the NDA). Issues discussed during this meeting include the content and
format of the different sections of the NDA that would be considered
fileable, including issues related to electronic submission of the NDA. At
this meeting, assessment is also made if any critical piece essential for
regulatory decision-making is missing. The FDA has issued a guidance to the
industry on the format and content of electronic submissions that are made
to the Agency and are available on the FDA Website.
Once an NDA is submitted to the FDA, the agency assigns an NDA
number to the drug. Since not all drugs being investigated as IND become a
successful candidate for marketing, it should be noted that NDA number is
a different number than an IND number. Once an NDA has been submitted,
all correspondence for that NDA should reference that NDA number. FDA
has 60 days to file that submitted NDA, or FDA could refuse to file an NDA
due to format and content issues or absence of critical piece(s) of
information/data needed for the FDA to make a decision on the
approvability of the NDA.
Under the Prescription Drug User Fee Act of 1992 (PDUFA), the FDA
has defined timeframes applicable to drug application reviews. The FDA
usually takes 6 to 10 months from the date of submission of the NDA to
make a decision of the acceptability of the application, often referred to as
NDA action. This time frame depends on the type of NDA submitted. The
FDA gives a priority designation for a product that if approved would be a
significant improvement compared to marketed products in the treatment,
diagnosis, or prevention of a disease. Evidence of increased effectiveness,
elimination, or reduction of treatment related drug reactions, safety, and
effectiveness in a new subpopulation, or enhanced patient compliance can
demonstrate improvement. All applications not qualifying as priority are
classified as standard applications. Priority applications are reviewed
within six months, where as standard applications have a 10-month
review clock. A decision regarding the assignment of a standard or a
priority rating to the application is made before the 60 day filing of
the NDA.
There are certain types of drug approval processes that facilitate the
development and expedite the review of the new drugs that are intended to

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treat serious life threatening conditions and to demonstrate the potential

as treatment for an unmet medical need. Some of these programs are the
accelerated drug approval/fast track programs or rolling submissions. The
accelerated drug approval program (Subpart H) is a highly specialized
mechanism for speeding the development/review of drugs that promise
significant benefit over existing therapy for serious or life-threatening
illnesses like AIDS, cancer, Parkinsons disease etc., and for a condition for
which no therapy exists. This program involves the modification of the
criteria on which the approval is based on. It allows for approval to be
based on a surrogate endpoint or an effect on a clinical end point other
than survival or irreversible morbidity. Under such circumstances, the
program may require appropriate post approval studies to validate the
surrogate endpoint or otherwise confirm the effect on a valid clinical
endpoint.
When certain sections of an application are accepted by the Agency prior
to the receipt of the complete application, the submissions are referred to as
rolling NDA submissions (i.e., pre-submission of pharm-tox reports, clinical
study reports, and even data summaries and listings from the first of two or
more pivotal trials). Sponsors of designated fast track products can request
this type of submission by submitting certain completed portions of an NDA
prior to submitting the other sections of the application. In such cases the
sponsor is required to provide a schedule for submitting the information
necessary to make the NDA submission complete. Further details of these
programs can be found under Regulatory Guidance and Mapp (Manual of
Policy and Procedure) on the FDA website [1, 3].
Sometimes there is a need for either an Advisory Committee Meeting or a
face-to-face meeting with the sponsor to discuss issues that arise during the
NDA review process. Once the NDA is submitted, pivotal study sites are
identified and inspected for good clinical practices (GCP) and good
laboratory practices (GLP) compliance by the Office of Compliance. An
NDA action is taken after obtaining results from the inspection of the study
site. The action could result in the approval or non-approval of an NDA, or
in an approvable NDA. An approvable NDA implies that the information
that has been reviewed by the FDA appears to be an acceptable data;
however, some additional information is needed to approve the product for
marketing in the United States. This could involve collection of additional
data, data re-analysis or negotiation of labeling language. The overall NDA
review process is shown schematically in Fig. 3.
Table 1 summarizes the type of studies that are typically part of the
clinical pharmacology and biopharmaceutics plan for a new drug, and Table
2 gives an example of how all of the clinical pharmacology and
biopharmaceutics information can be summarized concisely. Readers are

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FIGURE 3 NDA review process, http://www.fda.gov/cder.

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TABLE 1 General list of Studies Submitted to Support the Clinical Pharmacology

and Biopharmaceutics Portion of the NDA

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also encouraged to refer to the FDA website and the ICH Common
Technical Document that provides information on what information an
new drug application should contain.
CLINICAL PHARMACOLOGY CONSIDERATIONS IN NEW
DRUG DEVELOPMENT
In a new drug application, the OCPB reviewer is looking for data and
analyses that provide a rational justification for the selected dose/dosing
regimen as well as the sponsors attempt to individualize doses in certain
populations and/or scenarios, e.g., in pediatrics, in elderly, in renal/hepatic
impairment, and in presence of concomitant medications. The sponsor
usually generates this information in the IND stage of the regulatory
process. The reader is also encouraged to read the article that describes the
question-based review approach that the Office of Clinical Pharmacology
and Biopharmaceutics follows [4]. The chapters presented in this book
provide a general approach to drug development.
There may be some classes of drugs with certain characteristics (e.g.,
chirality), formulation (e.g., liposomes) or certain indications (e.g.,
biologicals) which may need additional consideration in their evaluation.
Some of these cases are discussed in various chapters of this book.
BIOPHARMACEUTICS CONSIDERATIONS IN NEW DRUG
DEVELOPMENT
Biopharmaceutics is a comprehensive term denoting the study of the
influence of pharmaceutical formulation variables on the performance of
the drug in vivo [5]. In a new drug application, the OCPB reviewer generally
looks for the pH solubility profile, pKa of the drug substance, drug
permeability or octanol/water partition coefficient measurement which may
be useful in selecting the dissolution methodology and specifications.
Dissolution of the drug under physiological conditions is one of the
factors assessing drug absorption after oral administration. Dissolution
testing is required for all solid oral dosage forms in which absorption of the
drug is necessary for the product to exert the desired therapeutic effect. In
addition to predicting in vivo performance of the dosage units, dissolution
tests help in assuring drug product quality from batch to batch and may also
be a guide in the development of new formulations. The dissolution
specifications set forth also ensure the drug products sameness under
scaleup and postapproval changes. Dissolution data also provides for
assessing the waiver of a bioequivalence study. For NDAs the dissolution

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TABLE 2 Summary of Clinical Pharmacology and Biopharmaceutics Characteristic of the Drug

Sahajwalla et al.

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specifications are based on acceptable clinical, pivotal bioavailability and/or

bioequivalence batches.
Biopharmaceutics issues depend on the route of administration as well as
the kind of dosage forms (oral versus other routes of administration,
immediate release dosage form, and modified release dosage forms). Some
of these issues have been covered in the various chapters of this book.
The final formulation the sponsor wishes to market may not always be
the one that has been used during the drug development. These formulation
changes may be necessary due to variety of reasons ranging from aesthetic to
overall improvement in formulation performance or to accommodate
manufacturing convenience. It is essential to know that the to-be-marketed
formulation will perform in the same way as the clinical trial formulation
performed in the pivotal clinical studies. For an NDA, bioequi valence
studies provide a link between the pivotal and early clinical trial
formulation, a link between the formulations used in the pivotal clinical
trial, and the to-be-marketed formulation or any other comparisons as
appropriate. Bioequivalence studies provide information on the product
quality and performance, when there are changes in components,
composition and method of manufacture after approval of the drug
product. The FDA has provided Guidance for the industry, such as BA/BE
guidance [6], SUPAC-IR [7], and SUP AC-MR [8], to determine when the
changes in the components and composition and/or method of manufacture
of the drug product suggest a need to perform further in vitro/in vivo
studies. Although, SUP AC stands for Scale-up and Post Approval Changes
to the formulation, the same principals outlined in these guidances are
utilized at the preapproval stage of the drug to determine the level of data
needed for bio waivers.
PRODUCT LABEL
One of the most important products of the drug development is the drug
product labeling. Since this is the document that will be utilized by the
prescribing Physicians to appropriately dose the patients, great care is taken
by the FDA and Industry Scientist to provide accurate information in a clear
and concise way in the product labeling. Labeling guides the prescriber,
based on data obtained from clinical trials, in optimizing the dose and
dosage regimen for all populations and outlines the adverse events which
were experienced by patients in the clinical trials etc. Labeling generally has
the following subheadings: Warnings, Description, Chemical Structure,
Clinical Pharmacology, Indication and Usage, Contraindications,
Precautions, Adverse Reactions, Overdosage, Dosage and Administration,
How Supplied, and Product Photos. In general, Clinical Pharmacology

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sections describe the clinical studies conducted to obtain pharmacokinetic

data in healthy subjects, patients, special populations and drug-drug
interactions.
Precautions and contradictions will generally highlight data that would
require a caution or adjustment of dose. The dosage administration section
gives the approved dose and recommended dosage adjustments under
special circumstances. Presently, there is an initiative where a working group
at FDA is working on reforming the label so that important information for
the prescriber is highlighted in the beginning of the label.
SUMMARY
Drug development is a complex process that requires collaboration of
scientists with varying expertise. For any new drug being developed, teams
of scientists are responsible within an industry to develop the drug, and a
team of scientists at the FDA are responsible to review the IND and NDA
submitted to the FDA.
Involvement of FDA scientists generally starts with the submission of a
pre-IND meeting request by the sponsor. Although FDA scientists are
involved and interact with the sponsor during the entire drug development
process, some of the key interaction occurs when the sponsor submits an
IND, drug development plan, pre-Phase 2 meetings, End-of-Phase 2
meeting, pre-NDA meeting, and when the protocols are submitted during
the IND phase of development. For optimal drug development, FDA
encourages sponsor to have open communication and reviewers are
available to meet the industry scientists at any stage of drug development.
These meetings provide a forum for interactive exchange of scientific ideas.
To encourage and facilitate meeting between the industry and sponsor
scientists, a document describing process of arranging meetings has been
published as manual for policies and procedures for meetings and is
published on the FDA website [1].
For ease of understanding and getting an overview of the drug
development, it is important to summarize the assessment of new drug
application in one table. One example of such a table has been provided in
Table 2 in this chapter.
Once the FDA scientist has completed the review, the important part is to
convey the data in a clear way, so that the physicians can make informed
decision as to what is best for the patients. Readers are encouraged to look
at completed NDA reviews available on FDAs, Freedom of Information
(FOI) Website to gain insight into the regulatory issues that may arise during
reviews of NDAs.

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In this chapter we have briefly covered the IND and NDA review process.
However, it is beyond the scope of this book to cover in detail several
regulatory considerations such as good clinical practices, good laboratory
processes, advisory committee meetings, orphan drugs, supple-mental
NDA, post approval changes, etc. Readers are referred to the FDA, ICH,
and other regulatory agency Websites to get additional information or
updates on scientific and regulatory issues related to new drug development.
REFERENCES
1.
2.
3.

4.

5.
6.

7.

8.

http://www.fda.gov/cder/guidance/index.html
Guidance for Industry: Special Protocol Assessment, Food and Drug Administration, May 2003.
Guidance for Industry: Fast Track Development Programs-Designation,
Development and Application review, Food and Drug Administration, September
1998.
Lesko, L.J.; Williams, R.L. The Question-Based Review: A Conceptual
Framework for Good Review Practices. Applied Clinical Practice 1999,8, 56
62.
Rowland; Tozer. Clinical Pharmacokinetics. Concepts and Application, 3rd Ed.,
Williams and Wilkins, 1995.
Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally
Administered Drug ProductsGeneral Considerations, Food and Drug
Administration, October 2000.
Guidance for Industry: Immediate Release Solid Oral Dosage Forms Scale-Up
and Postapproval Changes: Chemistry, Manufacturing, and Controls, In-Vitro
Dissolution Testing, and In-Vivo Bioequivalence Documentation, Food and Drug
Administration, November 1995.
Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage Forms
Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls;
In Vitro Dissolution Testing and In Vivo Bioequivalence Documenta-tion, Food
and Drug Administration, October 1997.

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