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WHITE PAPER
Indication Expansion
Maximizing Potential and Efficiencies: Regulatory and Practical Considerations for Investigational New Drug Applications
Author
Dawn Chitty, MSSenior Director, Regulatory Strategy & Agency Liaison PRA Health Sciences
Receiving a “May Proceed” letter from the US Food and
Drug Administration (FDA) is a cause for celebration. As the
company looks forward to the studies ahead, the regulatory
affairs team will plan for the required or expected changes
while building time to address unexpected amendments
as they arise. Fast forward 12 months and you will find the
regulatory team managing multiple INDs for the same product,
but all with different timelines and requirements.
Given the cost and time needed to develop new products,
understanding potential uses across indications is critical to
increasing a product’s value in the expensive, time-consuming
world of drug development. If a molecule shows solid
potential for a new indication, researchers can often bypass
preliminary safety studies, shaving years off of the safety
and efficacy research needed to satisfy FDA requirements.
Researchers can also gain insight into the ways patients are
likely to respond to various dose levels and further understand
the biomarkers that will help to identify the most likely
responders, further streamlining future studies. Additional
efficiencies can be realized by ensuring development projects
using the same drug are not treated like separate drugs.
Consolidating General Information Into One PlaceCrossreferencing previously filed INDs is common for Modules
3 (Quality) and 4 (Non-clinical Study Reports). This ability to
crossreference presents an opportunity to centralize most
information in these modules of 1 IND, typically the first IND
filed and often referred to as the “parent” IND. In instances
where the same formulation is used for multiple indications,
there is an opportunity to centralize most information in
Module 3 of 1 IND. Managing data that come from advancing
the manufacturing process for a product becomes less
daunting when all available data, from scale up work to
ongoing stability evaluations, are submitted only once. At
times, pre-clinical summaries and tabulations in Module
2 (2.4 and 2.6) focus only on studies relevant to a specific
indication. If written in a general manner to cover all available
data and indications, minimal updates will be required as new
information becomes available. Taking this approach lends
itself to easy referencing of information and also allows new
data to be submitted once rather than sequentially submitting
the same information into multiple INDs.
Aligning Dates to Streamline ReportingAligning dates across INDs can lead to several efficiencies.
For example, if all INDs have the same date for annual reports,
the Development Safety Update Reports (DSURs) can be
syncronized. It is often recommended to move all studies into a
consolidated DSUR to ensure a complete and comprehensive
review of all study data rather than reviewing a study-specific
DSUR for each indication. As the project progresses, this also
allows for easier and faster integration of data for integrated
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Executive SummaryWhether you are a large pharma or small biotech company, there are many potential benefits and challenges when developing a
single product candidate that provides clinical benefit across multiple indications. A single mechanism of action (MoA) applicable to
different indications and patient populations means more conditions can be treated quicker and can result in more efficient research
and development (R&D) for clients. Challenges include the growing need to pursue indication-specific pricing and to develop
a strategy that optimizes expected patent term extensions. Taking time to strategically plan for Investigational New Drug (IND)
management can maximize limited resources, simplify activities surrounding IND maintenance, and ensure IND holders comply with
required responsibilities.
safety and efficacy summaries needed upon New Drug
Application (NDA) or Biologics License Application (BLA)
submission. Most programs will use multiple CROs during
product development but that does not necessitate separate
DSURs from each CRO. With some planning and forethought,
DSUR writing can be centralized with one CRO even though
multiple CROs may conduct the studies. There are a variety of
mechanisms that promote data sharing and consolidation, from
integrating databases to sharing data in an agreed upon format
that allows the data to be migrated into a centralized database.
Furthermore, aligning the safety data evaluation will set the
review schedule for the Investigator’s Brochure (IB). Most
companies conduct (and many regulators expect) an annual
IB review. Having the consolidated data and conclusions
from a centralized DSUR makes this activity more efficient
by eliminating redundant safety data reviews that would
otherwise be available in a rolling format.
Pediatric ConsiderationsPediatric studies are required for new drugs and biologics by
the Pediatric Research Equity Act (PREA) with few exceptions,
mostly for orphan drugs. With the recent implementation
of the RACE Act and renewed focus on pediatric patients,
the oncology field has fewer opportunities for waivers.
The Pediatric Study Plan should be planned early in the
development timeline. Because additional indications may
amount to additional pediatric requirements, the targeted
pediatric population for the new indication should also be
considered early in the development process. The ability
to plan and execute one pediatric pharmacokinetic study
that covers the entire potential dose range expected across
multiple indications is much more desirable and, in most cases,
more cost-effective than executing multiple, similar studies.
Think About Labeling Sooner Rather than LaterEarly in a development program, a Target Product Profile (TPP)
should be developed to ensure the commercial goals (eg,
targeted indications and patient populations) are identified
and the development program is designed to support these
goals. There are two possible labeling scenarios when one
drug is being developed for multiple indications:
1. Similar indications will likely have similar class labeling
(eg, multiple oncology indications)
2. Different indications may have multiple sets of class
labeling required (eg, Rheumatoid Arthritis/Crohn’s
disease, Parkinson’s disease/restless leg syndrome)
Companies may need to consider differences among the
indications as they develop the label. If there are class labeling
requirements that cannot be accepted from a marketing
standpoint, now is the time to plan a strategy that allows for
development activities that may support modified or deleted
class labeling requirements.
Opportunities for Accelerating Development and Eventual ApprovalOpportunities for basket/master protocols should be
evaluated when appropriate. Basket/master protocols are
becoming more prevalent and allow multiple indications to be
evaluated, facilitating faster development timelines. Oncology
and anti-inflammatory drugs, for example, commonly use
basket/master protocols as the same MoA may impact multiple
similar conditions. Early engagement with the FDA and other
health authorities is critical to determine whether a basket/
master protocol is appropriate.
There are also many regulatory tools and designation
programs available to accelerate the review of NDAs/BLAs
or that provide other financial incentives. Depending on
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the indications being pursued, the impact and timing of
participation in these programs may dictate priorities in
development. Expedited reviews will result in faster time to
market and the impact on the patent landscape should be
carefully reviewed. Obtaining orphan designation has many
benefits but can also cause downstream development issues
if pursued too early and/or without sufficient support.
ConclusionManaging multiple projects is complex. PRA understands
the essential role regulatory affairs plays in helping expedite
time to market and in positioning a product for commercial
success. A clear regulatory strategy is invaluable to navigate
the many challenges of drug development, registration,
and commercialization. Proactive steps such as those
discussed above, as well as others, can simplify the complex
development journey.
While the specific items discussed are US-focused, a
comprehensive global development or expansion strategy
can provide similar opportunities across multiple markets.
PRA has the depth of experience and knowledge to
determine the optimal path forward for each client. We
serve as a consultative, full-service, or a hybrid partner to
our clients, depending on their needs. Our team has the
regulatory and drug development expertise to help clients
determine the best approach to maximize IND efficiencies.
White Paper | Indication ExpansionSEP 2020
PRA Health Sciences conducts comprehensive Phase I-IV biopharmaceutical drug development. To learn more about our solutions, please visit us at prahs.com or email us at [email protected].
Contact Information
For further information, or to discuss any aspect of PRA’s services offered in the field of indication expansion, please contact your PRA account director or one of the employees listed below:
Dawn Chitty, MS
Senior Director, Regulatory Strategy & Agency Liaison
World Headquarters
4130 ParkLake Avenue, Suite 400
Raleigh, North Carolina 27612 USA
Phone: +1 (919) 786 8200
Fax: +1 (919) 786 8201
www.prahs.com
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