1. The late phase research environment has changed dramatically in recent years. Regulators in
the United States and abroad are demanding a much more proactive approach to safety and
risk management. Addressing those mandates requires longer studies, larger patient pools and
comprehensive risk evaluation and mitigation strategies. Payers likewise are demanding data to
support their therapeutic choices. These demands, and the ever-expanding pool of data sources,
have made late phase research studies increasingly important and complex.
In light of these changes sponsors must begin working with their strategic research partners early
in the investigative process to anticipate and plan for late phase studies. Effective planning must
include a comprehensive strategy for identifying and addressing the therapeutic, regulatory and
economic concerns of diverse healthcare stakeholders. Failing to take early action and develop
an integrated strategy can result in expensive missteps, wasted time and failure to obtain drug
approval.
The shifting regulatory landscape
Recent regulatory guidance from the U.S. Food and Drug Administration (FDA) and the European
Medicines Agency (EMA) reflects a new mindset that emphasizes accountability and preparedness.
As the International Society for Pharmacoeconomic and Outcomes Research Risk Management
Working Group observed, “Both agencies independently have implemented proactive approaches
for drug safety surveillance which have reframed the traditional business model of the
pharmaceutical industry.”1
Historically pharmaceutical companies have taken a wait-and-see approach to developing risk
mitigation programs, largely waiting for regulators to raise concerns or objections during the
approval process before laying out detailed strategies for addressing risks. The new regulatory
climate requires manufacturers identify and address potential safety issues as part of the approval
process.
In the United States passage of the Food and Drug Administration Amendments Act (FDAAA)
in 2007 dramatically increased the FDA’s authority to mandate research. The new law enables
the FDA to require research at the time of approval ­— or anytime thereafter — if it learns of new
information impacting a treatment’s safety.
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Early Planning Essential:
Best Practices in Late Phase
Drug and Device Research

2. Page 2 of 6
Pre FDAAA
Before FDAAA, the FDA could require:
• Post-marketing studies or clinical
trials to demonstrate clinical benefit
for drugs approved under accelerated
approval requirements
• Deferred pediatric studies where
required under the Pediatric Research
Equity Act
• Studies or clinical trials to
demonstrate safety and efficacy in
humans to be conducted at the time
of use of products approved under
the Animal Efficacy Rule.
Post FDAAA
Under the FDAAA, post-marketing studies and
clinical trials can now also be required to:
• Assess a known serious risk related to
the use of the drug
• Assess signals of serious risk related
to the use of the drug
• Identify an unexpected serious risk
when available data indicate the
potential for a serious risk.
Given the expanded scope of requirements, the FDA has adopted more specific terminology. While
the regulator previously used “commitment” as a blanket term for post-marketing research, today
it differentiates mandatory studies and trials from those that are not required. Post-marketing
requirements (PMRs) are mandatory research while post-marketing commitments (PMCs) are
investigations a sponsor has agreed to conduct, but which are not mandated.
In addition, the FDA can request a Risk Evaluation and Mitigation Strategy (REMS) at any point during
a product’s life cycle. The REMS requirement applies to all new drug, abbreviated new drug, and
biologics license applications. Because risk management depends on numerous factors -- including
the nature and severity of the risk and the exposed population – strategies can vary. Basic strategy
components might include a medication guide, a patient package insert or a communication plan.
At the same time the FDA has implemented new requirements, the EMA has been on a roughly
parallel course. In 2008 the EMA issued guidance for identifying, monitoring and minimizing safety
concerns. New drug approval applications must now include a Risk Management Plan (RMP)
outlining known and potential risks as well as systems for mitigating and controlling them. RMPs are
required when the agency considers additional vigilance to be necessary, as in the case of products
containing a new active substance, those with a significant change in indication, or those where
serious or potentially serious safety risks have been identified.
In light of heightened regulatory demands, researchers must begin planning for late phase studies at
the front end of the investigative process.
These expanded regulatory requirements have significantly altered the drug development
process and created a snowballing host of associate challenges for manufacturers.
Regulatory requirements for more comprehensive safety data have led to more, longer and
larger late phase studies. Increased research activity has created intense competition for
patients, investigators and safety and regulatory specialists.
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Researchers must likewise contend with the idiosyncratic challenges of collecting post-
marketing data. For example, they must increasingly rely on research naïve physicians to
gather data about approved treatments. They must design data capture processes that
fit into the day-to-day workflow of medical practices often with greatly variable standards
of care. They must gather information from a diverse and growing pool of secondary data
sources, including electronic medical records and claims data. They’re challenged to find
effective mechanisms for processing patient-reported outcomes. Finally, they face the
ubiquitous challenge of recruiting patients in increasingly diverse locations and – because
follow-up studies may last many years – devising effective long-term retention strategies.
Given the expanding scope and complexity of late phase research,
comprehensive planning is essential to avoiding costly delays.
Complexity adds to study costs for developers. One option of lowering the costs of post-
marketing research is resorting to observational studies. Registry studies, being an example
of observational research, can serve both to generate or test a hypothesis. They are an
invaluable tool in researching practice patterns, collecting disease data, understanding
clinical safety and effectiveness, and practical impact of the product in a real world
setting. Data gathered as a result of observational research can be effectively used for
reimbursement support, publications and off-label use, as well as supplement the clinical
trial data. However, observational research is not without its limitations, the main challenge
being attributing causality to outcomes due to its non-interventional nature, and minimizing
selection and enrolment bias.
Another option is the use of the pragmatic trial setting, which although not being
observational by nature, represents a ‘real world’ practice setting. These trials measure
effectiveness as opposed to efficacy in a randomized controlled trial, and allow enrolment
of all patients to whom healthcare providers might offer the intervention within the standard
of care, and minimal restrictions on any other co-interventions. This helps to achieve the
generalizability of the results, which is critical for the best practice decisions, both clinical
and cost effectiveness.2
Demonstrating value
Late phase research can be an invaluable tool in establishing a product’s
market position and commercial viability.
Pharmaceuticals economic climate is warming up given that U.S. regulators are approving
more new drugs than ever. In 2012, 39 new drugs - the most in 16 years- were approved,
giving the pharmaceutical makers hope for growth after losing billions of dollars in recent
years to generic drug makers because of patent expirations.3
However, this will spur the need for developers to demonstrate value early on in the process.
Late phase research presents a unique opportunity to demonstrate a product’s medical value
through late phase research. Does it cost less? Will more convenient drug administration
result in better compliance? If so, what is the health and economic value of enhanced
compliance?
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Because value lies in the eyes of the beholder, sponsors must work to understand the diverse needs
of healthcare stakeholders from the outset of the research process. Understanding what patients,
clinicians and payers value -- and the best metrics for gauging that value -- are critical to effective
research design.
Early in the investigative process sponsors need to assemble multidisciplinary teams to ensure
they have a 360° understanding of their product, current and emerging market conditions, and
stakeholder needs. That means seeking input from pricing and reimbursement specialists, health
economics teams, and regulatory and therapeutic experts alike.
The research process is just that: a progression in which each integrated step builds upon previous
learning. Insights gleaned through early, multidisciplinary collaboration are essential to shaping late
phase research design, which in turn is key to identifying new opportunities. Post-marketing analyses
can cement a product’s commercial viability. They can help differentiate a product, generate the
efficacy and economic data payers demand and point the way toward strategic areas of inquiry that
can result in additional indications. But they can only live up to those possibilities if the seeds of
inquiry are planted early.
The importance of using a collaborative model to demonstrate value can’t be overstated. As Deloitte
and Thomson Reuters noted in a recent report, “The companies that are successful in the business of
R&D will be effective in their validation of unmet need, in marshalling the best science and advances
in diagnostics, and in deploying a flexible, collaborative development model that focuses early on
gathering evidence of medical value.”4
Early Involvement Essential
Sponsors want to complete late phase research as quickly, cost effectively and efficiently as possible
while extracting the most valuable data possible from their efforts. Traditionally the pharmaceutical
industry has treated late phase efforts as soley the equivalent of post market research - conducted
with the intent of expanding indications for an already approved compound.
However, studies can be conducted more efficiently with thought given to gathering the necessary
data early on with a multi indication NDA plan. By strategically planning early for late phase,
sponsors can improve study efficiency, allowing for multiple use of the study data in post approval.
To do that sponsors need to ensure early engagement with strategic
partners who have the therapeutic, operational and regulatory sophistication
to consider all aspects of trial design and execution.
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Operationally, involving a strategic research partner on the front end working with them during
the ensuing investigative phases promotes continuity, communication and efficiency. Continuous
collaboration:
• Facilitates early planning. Teams can start planning for late phase activity years before
filing for registration. Embedding late phase considerations into the process before key trial
protocols are established ensures optimal research design.
• Leverages previous learning. Every study has a learning curve. Engaging a strategic
partner at the beginning of the process and working with them throughout means the
research team climbs the learning curve only once. What’s more, the team can integrate its
growing body of knowledge into each successive phase of the research.
• Ensures process clarity. A long-term strategic relationship ensures consistent
communication, process clarity and research continuity.
• Saves time and money. Greater efficiency translates to faster, more economical research.
Selecting a Strategic Partner
While regulatory and market considerations shape late phase research, therapeutic expertise must
underlie it. Partnering with a therapeutic leader can streamline and accelerate the research process.
There’s no substitute for therapeutic expertise. A therapeutic specialist who understands the entire
picture - underlying disease activity, existing treatment options, safety concerns, market gaps,
patient and provider needs, etc. – can share strategic insights that can lead to faster, and more
successful commercialization.
The therapeutic arena is dynamic. Because new and competing treatments are always under
development, sponsors should seek out partners who understand not just the drug or device under
investigation, but its significance in the broader therapeutic context.
Medpace: Therapeutically focused expertise
Shepherding a new therapy though the post-approval phase requires up-front strategic planning
that encompasses a broad range of therapeutic, operational, regulatory and safety considerations.
Medpace has conducted more than 100 late phase studies involving 40,000 patients at 2,000
investigator sites globally. Multidisciplinary Medpace research teams include global therapeutic
leaders in cardiology, endocrinology, oncology, nephrology, neurology, infectious diseases and
regenerative medicine. Medpace teams act as an extension of the research sponsor to develop and
execute effective late phase drug and device development programs.
Late Phase Leadership
Alexander Artyomenko, MD, PhD, Global Director, Late Phase Clinical Operations
Dr. Artyomenko has over 12 years of experience in late phase clinical research. His unique background
encompasses medicine, clinical trials, and project management, with a highly successful track
record for planning and executing global Phase IIIb-IV studies. Dr. Artyomenko has conducted
studies with a therapeutic focus in cardiovascular and metabolism, infectious diseases including
HIV, rheumatology, gynecology, and dermatology. Dr. Artyomenko is an expert in global regulatory
concerning post-marketing and non-interventional studies, including HEOR, registries, and
collaboration with Academic Research Organizations (AROs).
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About Medpace
Medpace is a leading global full-service clinical research organization providing Phase I-IV core
development services for drug, biologic, and device programs. With more than 1,300 employees and
clinical trial experience in over 40 countries, Medpace has the global reach and capability to conduct
studies and navigate regulatory requirements worldwide. In addition to Phase II-IV development
services, Medpace provides Phase I / IIA clinical services from Medpace Clinical Pharmacology,
central laboratory and therapeutically specialized testing from Medpace Reference Laboratories,
complete bioanalytical services in all stages of drug development from Medpace Bioanalytical
Laboratories, centralized imaging core laboratory management and reading from Medpace ICL, and
medical device development from Medpace Medical Device.
Reference:
1
A Comparison of US Food and Drug Administration and European Medicines Agency
Regulations for Pharmaceutical Risk Management: Report of the International Society for
Pharmacoeconomic and Outcomes Research Risk Management Working Group, September/
October 2011 ISPOR Connections.
2
Pragmatic controlled clinical trials in primary care: the struggle between external and
internal validity: Marshall Godwin, Lucia Ruhland, Ian Casson, Susan MacDonald, Dianne
Delva,Richard Birtwhistle, Miu Lam, and Rachelle Seguin, BMC Medical Research Methodology
2003, 3:28 doi:10.1186/1471-2288-3-28
3
Reuters 2012: (http://www.reuters.com/article/2012/12/31/us-pharmaceuticals-fda-approvals-
idUSBRE8BU0EK20121231)
4
Measuring the return from pharmaceutical innovation 2012: Is R&D earning its investment?
Deloitte Centre for Health Solutions and Thomson Reuters.
http://www.deloitte.com/view/en_GB/uk/industries/life-sciences/09f684e759abc210VgnVCM20000
01b56f00aRCRD.htm
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