Advancing the Use of Complex Innovative Trial Designs (CID): Introduction

Advancing the Use of Complex Innovative Trial Designs (CID): Introduction


• Welcome to the U.S. Food and Drug Administration’s
presentation series on Complex Innovative Trial Designs, often referred to as CIDs. • In this session, I’ll introduce you
to some of FDA’s efforts to advance the use of CIDs. • The landscape of drug development is changing,
as evidenced by increased attention in areas such as:
o Real-world evidence o Patient-focused drug development, and o Innovative clinical trial designs such as
master protocols. • As drug development evolves, we are facing
unique challenges and opportunities. • Some of FDA’s approaches to meeting
these challenges are included in the sixth iteration of the Prescription Drug User Fee
Amendments of 2017, commonly referred to as PDUFA VI (puh-DOO-fuh six). • Signed into law on August 18, 2017, as
part of the Food and Drug Administration Reauthorization Act, PDUFA VI incorporates specific measures
to enhance regulatory decision tools supporting drug development and review. • This presentation focuses on one aspect
of PDUFA VI: complex innovative trial designs. • The goal of FDA’s CID efforts is to
facilitate the advancement and use of complex adaptive, Bayesian (BAY-zee-uhn), and other
novel clinical trial designs, including those requiring simulations to determine statistical
properties, such as the chance of erroneously concluding that an ineffective medical product
is effective. This is also known as Type 1 error. • To advance the use of CIDs, FDA is:
o Developing greater staff capacity; o Conducting a CID Pilot Meeting Program;
and o Developing or revising supporting regulatory
processes and documents. • FDA also:
o Published a draft guidance on complex adaptive trial designs in September 2018 and
o Convened a public workshop in mid-March 2018. • The statistical units within FDA’s Center
for Drug Evaluation and Research (CDER [SEE-der]) and the Center for Biologics Evaluation and
Research (CBER [SEE-ber]) are the leads for CID efforts. Staff from other relevant disciplines are
active participants. • Why do we need CIDs? • In many cases, there are straightforward
and well-known approaches to designing and analyzing studies of medical products. • But in other scenarios, the path is not
so clear. Innovative thinking and methodology can help
establish optimal study designs and may even provide a solution for challenging clinical
drug development problems. That’s where CIDs come in. • There are many ways in which CIDs can
be used in drug development. For instance, drug development for rare diseases
is challenging because of small patient populations for clinical trials. Certain types of CIDs could allow drug developers
to leverage other data sources such as early clinical studies or natural history data to
gain additional power to detect differences in therapeutic options. • In the anti-infective space, data could
be leveraged across multiple body sites when trying to establish the effect of a treatment
for a rare pathogen. • CIDs might also be used to assess multiple
interventions, diseases, or subgroups under a master protocol, defined as a single overarching
protocol designed to answer multiple questions. • One example of a master protocol is the
Partnership for Research on Ebola Virus in Liberia II (also known as PREVAIL II). I will discuss PREVAIL II in more detail in
subsequent slides. • Another example is Lung-MAP, which can
be thought of as a collection of separate sub-studies corresponding to genetic subgroups,
conducted under a single master protocol designed to generate evidence of safety and effectiveness
for biomarker-matched therapies. • Leveraging data and using master protocols
are just two examples of how CIDs might benefit drug development. The possibilities are endless. • What are some possible features of CIDs? • CIDs may include any of several features—or
a combination of features—including: o Use of external controls,
o Incorporation of adaptations to multiple design features, and
o Formal incorporation of prior knowledge. • These features allow one to envision several
different ways CIDs could be used in drug development. • Think back to the Ebola outbreak that
began in 2014 as an example of a drug development challenge where a complex design could prove
beneficial. • As we all recall, there was an urgent
need to identify safe and effective therapies. Supplies of several potential therapeutic
agents were limited or intermittent. • We needed to maximize information from
limited data. • Given the situation, there was agreement
that a flexible design and analysis approach were needed. • Borrowing a quote from a paper by Doctors
Woodcock and LaVange, of FDA CDER, we needed to “answer more questions more efficiently
and in less time.” • Designed as a master protocol for Ebola
therapies, the PREVAIL II study included a shared control arm and provided the ability
to evaluate multiple Ebola therapies simultaneously. • Treatments could be added or dropped. The novel adaptive design applied Bayesian
decision rules for concluding effectiveness at interim and final analyses. • Although the Ebola outbreak waned before
the study was fully enrolled, the results showed a trend toward increased survival among
patients who received the experimental treatment. • Now that we’ve explored the “why”
behind CIDs, let’s move to the “what.” • As previously mentioned, FDA is conducting
activities to advance the use of complex innovative trial designs, including a public workshop
and a Pilot Meeting Program. • FDA convened a CID public workshop on
March 20, 2018. • The purpose of the public workshop was
twofold: o To facilitate discussion and information
sharing about the use of CIDs in drug development and regulatory decision making, and
o To obtain input from stakeholders about the CID Pilot Meeting Program. • On August 30, 2018, FDA announced the
launch of the CID Pilot Meeting Program in the Federal Register. • The Pilot Meeting Program is designed
for highly innovative trials for which analytically derived properties may not be feasible and
simulations are needed to determine statistical properties. • Interested sponsors should submit meeting
requests to discuss proposed CIDs. For details on the submission process, please
refer to the CID Process presentation on this website. • FDA selects up to two meeting requests
for the program per quarter. • For granted meeting requests, FDA will
conduct an initial and a follow-up meeting to discuss regulatory approaches on the same
proposed CID and medical product within the span of approximately 120 days. • FDA may present trial designs as case
studies for continuing education and information sharing, contingent on FDA and the sponsor
reaching a disclosure agreement. • We have now concluded our brief overview
of the FDA’s CID efforts. • These efforts will:
o Support innovative medical product development, o Increase opportunities for collaboration
among a variety of stakeholders, and o Advance the use of CIDs. • But the most important outcome may be
the benefit to patients, because the overall goal of FDA’s CID efforts is to promote
the development of innovative designs and analyses that may advance new therapies across
a diverse range of areas of need. Thank you for your interest in the FDA’s
CID efforts. • We hope that you will also view FDA’s
companion presentation on the CID Pilot Meeting Program process. • For more information, please visit the
CID website or submit questions via email to [email protected]

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