Brenda Fielding

Nik Burlew
Mapping a Path to Market: Creating a
Comprehensive Drug Development Strategy
clinipace.com 11
Mapping a Path to Market: Creating a Comprehensive
Drug Development Strategy
Theres no getting around itdrug development is
expensive, time consuming, and risky.
The Pharmaceutical Research and Manufacturers of America estimate that for
every 5,000 to 10,000 compounds entering the pipeline, only one will make
it to market.
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With approximately 5,200 drugs in preclinical testing in 2012,
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pharmaceutical and biotechnology companies large and small are looking for
ways to cut costs, shorten timelines, and increase the probability that their
compound will be one of the few to succeed.
Clearly, the key determinate of success is the efcacy and safety of the drug itself.
If your compound for Type II diabetes doesnt cause signifcant decreases in blood
sugar levelsor if 25% of study participants develop migraines while on drug
then its time to stop development. But many compounds fail for less clear-cut
reasons, such as slow study enrollment, trial designs that do not meet regulatory
expectations, or prohibitively expensive raw materials. Many of these issues can
be more easily managed or, in some cases, avoided altogether if development starts
with a comprehensive strategy. Unfortunately, this critical step is often overlooked
or undervalued because of the time and signifcant energy required to think through
the various scenarios.
This paper provides an overview of a comprehensive
drug development strategy, starting with three
foundational questions and moving through the
key areas of regulatory, manufacturing/quality,
preclinical/nonclinical development, clinical
development, and other (e.g., intellectual
property, marketplace, and reimbursement).
The Pharmaceutical Research and
Manufacturers of America estimate that for
every 5,000 to 10,000 compounds entering
the pipeline, only one will make it to market.
Figure 1. Concept of Drug Development
DRUG OR BIOLOGIC
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The Foundation of a Comprehensive
Drug Development Strategy

Drug development has been described as the process of obtaining
the information you want to be included your drugs prescribing
information. This approach can be visualized as an inverted triangle
(Figure 1). At the bottom tip is the drug itself, and across the broad
top is the prescribing information. Everything in between is drug
development.
But before diving straight into regulatory strategy or clinical trial
design, stop and consider three foundational questions that form
a base for building the specifc sections of the comprehensive drug
development strategy:
1. What is the end goal?
While the obvious answer to this question is get the drug on the market,
many small companies may choose instead to focus on attracting a larger
biopharmaceutical frm to buy, in-license, or partner on the compound
in development. To borrow a popular phrase, if you dont know where
youre going, how will you know when you get there?
2. What are the desired product attributes?
A good way to approach this question is to draft the ideal prescribing
information for your product. At this stage much of the information
is educated guesses and conjecture, but the process helps companies
focus their objectives before building a detailed plan. In particular,
consider indication/usage, dosage/administration, clinical pharmacology,
adverse reactions/toxicology, and clinical data. In whom will the drug
be used? How much of an effect is needed for the drug to be considered
worthwhile by patients, providers, or payers? What level of toxicity will
be acceptable?
3. Where will the drug be marketed?
It may be tempting to start by seeking approval in the United States and
planning to fle the paperwork for other regions later, but the process just
isnt that simple. No single country or region has the most conservative
regulations in all areas, and having to repeat key studies because the air
handling procedures on the tablet compression line didnt meet European
standards or because the Phase III trial included only one investigative
site in Europe is time consuming, expensive, and frustrating. In most
cases, it is worthwhile to plan the development program to meet the most
stringent criteria among the intended markets. That may mean using the
US standard for safety monitoring, the European Union (EU) standard
for manufacturing quality controls, and including at least 100 patients in
from several sites in Europe in the Phase III trials.
Figure 2. Three Foundational Questions
What
is the
end goal
?
GETTING YOUR DRUG TO MARKET?
LICENSING YOUR COMPOUND?
What are
the desired
product
attributes
?
INDICATION/USAGE & DOSAGE?
ADMINISTRATION & PHARMACOLOGY?
ADVERSE REACTIONS & TOXICOLOGY?
CLINICAL DATA?
Where
will the
drug be
marketed
?
UNITED STATES?
EUROPE?
clinipace.com 3
With robust answers to these foundational questions, its time to move
into more detailed strategic planning in fve key areas: regulatory,
manufacturing/quality, preclinical/nonclinical development, clinical
development, and other. While the areas do not need to be addressed
in this order, each of the parallel tracks depicted in Figure 1 must reach
its endpoint before a product can be introduced into the market.
Regulatory
As soon as you have a promising compound identifed, its time to
start regulatory planning. Earlier is better, and having a basic plan
in place before preclinical testing is ideal. The regulatory strategy
should include:
An analysis of the current regulatory policies, procedures, and
guidelines that apply to your product in each target market.
The likely path to approval (e.g., does your product meet the criteria
for an orphan drug? Does it fulfll an unmet medical need and

qualify for accelerate approved? In the EU, will the product be
reviewed by the centralized procedure via the European Medicines
Agency or by the decentralized procedure via an individual
member country? If the latter, which country is most appropriate?)
An assessment of similar products currently approved or in
development. What are the indications for those products?
How were they tested? How effective are they? What are the most
common adverse events? Have there been any unusual regulatory
requirements (e.g., studies in special populations) or limitations
for use? How is your product similar or different?
A proposed timeline for submission of regulatory documents in
each target market. Key milestones are the Investigational New
Drug application (IND) before the start of human trials and the
New Drug Application/Biologics License Application (NDA/BLA)
for permission to market the product. Note that these terms are
used by US Food and Drug Administration (FDA). Other countries
may have different nomenclatures.
An assessment of the data/information needed to fle each
regulatory document. For example:
IND: compilation of the chemistry, manufacturing, and control (CMC)
and nonclinical data, rationale for design of clinical program,
Phase I trial protocol(s), investigator brochure
IND maintenance: CMC and nonclinical updates, protocol amendments,
safety reports, annual report
NDA/BLA: clinical study reports, fnal CMC and nonclinical reports,
integrated safety summary
A proposed timeline for meetings with FDA and/or other regulatory
authorities (Figure 4). Well-planned meetings at critical time points
can clarify expectations and lead to shorter development times
and fewer questions during review. Most agencies are committed
to prioritizing interactions with sponsors, and FDA has stated
publically that it strongly recommends (though does not require)
pre-IND and pre-NDA/BLA meetings.
Figure 3. Regulatory Strategy Overview
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Proposed timeline
for submission of
regulatory documents
Assessment of data
required to fle
regulatory docs
Proposed timeline for
meeting with FDA and
other regulatory authorities
Likely path to approval
Assessment of similar products
Analysis of current regulatory
policies, procedures, & guidelines
clinipace.com 4
Figure 4. Basic Timeline for FDA Involvement
The regulatory strategy document, and the timelines in particular,
often serve as a tracking tool for overall project status and can help
identify risks to the program (e.g., cost overruns, delays, and competitor
activities). However, its important to view the strategy as living
document that must be periodically reassessed and updated to retain
its usefulness. This proactive approach is vital when the end goal is
to get the product to market, but it can also be valuable to companies
looking to license or sell their asset. A strong strategy, particularly when
validated by external experts and/or regulatory authorities, can help
attract potential buyers or partners.
A number of contract research organizations (CROs), including
Clinipace, have consulting teams that can be engaged for regulatory
strategy activities ranging from a quick, 90-minute reality check on
the table of contents for an IND to a longer-term partnership to help a
company to develop its strategic plan.
Manufacturing/Quality
The manufacturing and quality aspects of strategic drug development
include all activities related to the production of the fnal dosage
form, including sourcing the active pharmaceutical ingredient (API),
creating a viable formulation, assessing and maintaining quality,
packaging, and shipping. Robust answers for the three foundational
questions are particularly important in this area, but the potential time
and cost savings associated with advanced planning are also easy to
see. A failure to integrate all of the disciplines in drug development
from the beginning can very quickly leave the manufacturing/quality
group making guesses and ill-informed decisions that can have costly
implications.
When creating a strategic plan for manufacturing/quality, consider the
following questions:
WHO is going to make the active drug ingredient (API)? Who is going
to make the drug product? How much can they produce? Do they have
the engineering and quality expertise to scale up production for clinical
trials and/or commercial use? Is the cost per unit of drug feasible? Based
on your end goal, are you looking for a manufacturer to get you through
Phase II or all the way to the commercial product? Will you need to
import API before your IND is in effect? How will you evaluate and
qualify your contract manufacturers?
WHAT are the properties of the fnal dosage form? Using your desired
product attributes, what is the preferred route of administration (e.g.,
oral, injectable, inhaled, topical)? What is its potency and likely dose
(or dose range)? If needed, how easily can the dose per tablet/vial/
canister/etc. be increased or decreased? Will you need a pediatric or
alternate dosing form? What about a matching placebo? Does the route
of administration require stringent control of endotoxins or other
contaminants? Can your manufacturers meet those requirements?
Meeting with Regulatory Authorities
Regulatory Submissions
LEGEND: BLA = biologics license application; IND = investigational new drug application; NDA = new drug application.
Compound
Section
Preclinical
Development
Phase I Phase II Phase III
Approval
Pre-IND
Meeting
IND
Submission
IND
Maintenance
NDA/BLA
Submission
End of
Phase II
Meeting
Pre-NDA/
BLA
Meeting
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WHERE will the product be used? Do the planned manufacturing
processes meet standards for all target markets (see foundational
question #3)? Good Manufacturing Practices (GMPs) for early stage
clinical materials are more stringent in the EU than in the US,
particularly regarding facility requirements and quality control.
If there is any possibility of running clinical trials or seeking marketing
approval in the EU, it is almost always better to start with a EU-certifed
GMP manufacturer.

WHEN will the product be needed? Does is make sense to order a
dirty (not fully purifed) batch to cover preclinical research needs?
This option is available because GMPs are a sliding scale based not only
on the stage of development, but also on the dosage form, indication
and critical quality attributes of the drug itself. Are there advantages
for your product if it demonstrates low toxicity in animals even if
the drug has higher-than-normal levels of impurities? Or would it be
better to order a single, fully GMP-compliant batch to cover preclinical,
nonclinical, and clinical research? If so, how much time will elapse
before the product is used? What kind of stability data will be needed?
HOW are you going to measure quality? Around the world, there
are a myriad of standards governing the quality and control of
biopharmaceutical products, including regional GMPs, Good Tissue
Practices (GTPs), International Conference on Harmonisation (ICH)
Guidance, EU Directives, regional and dosage form specifc guidance,
and recommendations from the World Health Organization (WHO)
and the International Organization for Standardization (ISO). How
are you planning to implement these standards? Which standards
even apply to you? How will quality be ensured, and by whom?
There are a lot of questions here, and companies new to drug
development may wish to consider partnering with a CRO that has
experience in the broader aspects of drug development, quality
control, and supply chain management. Like regulatory strategy,
manufacturing/quality strategy is fuid and needs to be updated
frequently, particularly when new preclinical/nonclinical data
become available.
Preclinical/Nonclinical Development
Both preclinical and nonclinical development refer to studies not
performed in humans: the only difference is when they are performed.
Preclinical studies occur before Phase I trials (to establish safety
before the drug is given to humans) and nonclinical studies occur
after Phase I trials begin (to gather additional information, usually
on safety or pharmacokinetics, and to identify potential biomarkers
for the development of a companion diagnostic test).
Figure 5. 5 Key Questions to Creating a Strategic
Plan for Manufacturing/Quality
Who is going to make
the API/drug product ?
What are the properties
of the fnal dosage form ?
How are you going
to measure quality ?
When will the product be needed ?
Where will the product be used ?
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FOUNDATIONAL
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There are many types of preclinical/nonclinical studies (Figure 6),
and the details of what studies are needed in which cells lines or animal
species is a key part of strategic planning in this area. Note that while
some preclinical studies do not have to be performed using GLP, any
preclinical study assessing safety and intended for submission in support
of a human clinical trial must adhere to those practices as well as
applicable standards and guidance issued by ISO, ICH, the International
Electrotechnical Commission (IEC), and regulatory authorities. Animal
toxicology studies should use the same route of administration as is
planned for humans, and the drug tested should be as similar as possible
to the clinical material. However, as mentioned in the Manufacturing/
Quality section, the drug used in animal studies does not need to be
manufactured in a GMP-compliant facility.
The goal of both preclinical and nonclinical research is the same:
support the clinical trials that lead to product approval. While the
strategic plan should include the must have studies in this area, it
is often valuable to consider the nice to have studies. For example,
depending on the availability of funding and API, it may be advantageous
to combine the single and multiple dose studies or the short- and
long-term toxicity studies. This approach, which costs more upfront
but has the potential to save time and money later on in development,
may be most benefcial to companies whose end goal is bringing the
product to market.
As with other areas of strategic planning, seeking advice from experts in
preclinical/nonclinical development is often well worth the investment.
Based on their experience, consultants can make recommendations
about issues ranging from which animal species would be most appro-
priate to which diagnostics company might be best suited to scale up
the in-house bioanalytical assay used to measure the drugs impact on
the body. Preclinical/nonclinical research is an integral part of the drug
development process, and making a poor or misinformed decision in
this area can signifcantly delay or even kill a project.
Preclinical/nonclinical research
is an integral part of the drug
development process, and making
a poor or misinformed decision
in this area can signifcantly
delay or even kill a project.
Figure 6. Examples of Preclinical and Nonclinical Development
Two often overlooked topics within a clinical
development strategy: Contingency
planning and risk management.
Preclinical Studies
Clinical Studies (Phase I, II, III)
Nonclinical Studies
Approval
IND
Submission
NDA/BLA
Submission
Pharmacokinetics
(absorbtion, distribution,
metabolism, excretion)

Pharmacodynamics

Animal toxicology
(2 to 12 week duration)

Mechanism of action

Bioanalytical methods
(for measuring drug
product or outcomes)

Therapeutic index
More detailed analysis of
metabolism and distribution
(often radiolabeled)

Animal toxicology
(usually 6 months in rats,
9 to 12 months in dogs/primates)

Carcinogenesis, mutagenesis and
impairment of fertility in animals

Drug interactions

Identifcation of
potential biomarkers
clinipace.com 7
Clinical Development
Clinical testing establishes that a drug is safe and effective for human
use. Many volumes have been written on clinical development, and
this paper presents only a brief overview of the objectives, population,
and study design associated with each phase (Figure 7).
Clearly, a clinical development strategy should include detailed plans
about study designs, identifcation of investigators, statistical analyses,
and timelines. However, two important but often overlooked topics
are contingency planning and risk management.
It can be argued that successful drug development is all about
contingency planning. What if the API can only be made in small
batches? What if the formulation isnt stable? What if regulatory
authorities dont agree with your planned approach? What if trial
enrollment is slow? What if a competitor product launches frst? What
if trial data is inconclusive? The list of what ifs can easily grow to
an unmanageable size, so concentrate on items that are most likely to
happen. Spend less time on freak occurrences (e.g., the ship carrying
the API from China sinks) and more time on highly probable events
(e.g., development timelines are lagging).
Finally, consider your risk management plan (RMP) or risk evaluation
and mitigation strategy (REMS), which can be defned as a set of
pharmacovigilance activities designed to identify, characterize, prevent,
or minimize risks related to the medicine; to assess the effectiveness
of those interventions; and to communicate those risks to patients and
health care providers.
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Put more simply, this type of document is meant
to ensure that the benefts of a medicine outweigh the risks. Creation
of a RMP/REMS is often a collaboration between clinical and regulatory
teams, and external input from experts and regulatory agencies is
typically needed.
Figure 7. Brief Overview of Clinical Development
Contingency planning. What if?
Spend time planning highly probable events.
Establish
pharmacokinetic
profle & dosing
regimens
Assess safety
& tolerability
Establish
proof-of-concept
Test safety in
afected patients
Test special
populations
Prove safety
& efcacy
Establish
long-term safety
Expand
indications
12 to 40 subjects
Healthy volunteers,
patients with
advanced disease
maybe used for
life-threatening
conditions

20 to 400
patients with the
targeted disease
300 to 1,500
patients with
the disease
The size of the safety
population depends
on the seriousness
of the disease
Open-label
Uncontrolled

Randomized
Controlled
(if used for regulatory
submissions)
Randomized
Controlled

(either placebo
or standard of care)
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Other
The fnal area of strategic drug development is a catch-all for a range
of other activities integral to the process. Issues to consider include:
Intellectual property. Has your compound been patented? What
about any novel processes used to create it? Do you need to license
any technology (e.g., slow-release tablet coatings, needleless injection
systems) to create the fnal dosing form?
Reimbursement. Does your product advance the standard of care?
What data will be needed to convince payers that the drug is worth
covering, and at what price? Do your projected sales cover the cost of
manufacturing the drug? What about the total development program?
Marketing. Who is the target audience for your product (e.g., general
practitioners, oncologists, cardiologists, etc.)? Will you use direct-to-
consumer marketing (where allowed)? How is your product different
from the competitors?
Figure 8. The Final Catch-All
Risk Evaluation and Mitigation Strategy
(REMS). Ensure the benefts of a
compound outweigh the risks.
Conclusion
A comprehensive strategic drug development plan is a guide to achieving your end goal, whether that is selling your asset to a larger company
or bringing your product to market around the world. This living document evolves over time as more information about the compound becomes
available as a result of preclinical, nonclinical, and clinical research. It should also updated based on changes in science, regulatory requirements,
and the marketplace during the estimated 10 to 15 years it takes to get a drug from preclinical testing to approval.
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Creating a comprehensive drug development strategy is hard work that is likely to require signifcant research, thought, and discussion.
Consider seeking input from experts in the feld, whether as part of a company advisory board or as consultants from a CRO or other company.
The time and effort required to develop a rigorous development strategy may mean rescheduling a meeting with potential investors or delaying
the start of a toxicity study, but these setbacks should be more than offset by the long-term benefts of clear direction, up-front problem solving,
and contingency planning.
Marketing
Target audience?
Diferentiators?
How will you market?
Reimbursement
Is the drug
worth covering?
At what price?
Intellectual property
Patents,
novel processes,
licenses?
clinipace.com 9
Author Bios
Brenda Fielding
EVP, Regulatory Afairs at Clinipace Worldwide
Brenda Fielding has more than 25 years of experience in the pharmaceutical and biotechnology industries, primarily in the area of drug and
biologics regulatory affairs. Brenda serves as a resource to clients and the team at Clinipace Worldwide for regulatory affairs and drug and biologic
development strategy. Prior to this, Brenda was the President of Regulus Pharmaceutical Consulting, a drug development and regulatory affairs
consulting company, which she co-founded in 2003. She has held senior management positions in pharmaceutical and biotechnology companies.
Nik Burlew
Vice President, GxP/CMC Quality Assurance
In Niks position he reviews new manufacturing practice warning letters, drug and biologic guidance documents and federal register notices,
answers ad hoc quality assurance questions and defnes a formal QA stance on issues ranging from packaging to API validation. Nik is part of
several professional organizations, including the Parenteral Drug Association (PDA), Mountain States Chapter of the PDA and Society of Quality
Assurance (SQA), Rocky Mountain Regional Chapter of the SQA.
References
1. Pharmaceutical Research and Manufacturers of America. 2013 Profle: Biopharmaceutical Research Industry. July 2013. Available at: http://www.
phrma.org/sites/default/fles/pdf/PhRMA%20Profle%202013.pdf.
2. Parexel Consulting. Industry-sponsored clinical trials by region and phase, 2006-2010. Paraxel Biopharmaceutical R&D Statistical Sourcebook,
2012/2013:81.
3. Pfzer Inc. What is a risk management plan? Available at: https://www.pfzer.com/fles/health/medicine_safety/2-2_What_is_a_Risk_Management_
Plan.pdf.