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The late phase research environment has changed dramatically in recent years. Regulators inthe United States and abroad ar...
Page 2 of 6Pre FDAAABefore FDAAA, the FDA could require:		 •	 Post-marketing studies or clinical 			 trials to demonstrate...
Page 3 of 6Researchers must likewise contend with the idiosyncratic challenges of collecting post-marketing data. For exam...
Page 4 of 6Because value lies in the eyes of the beholder, sponsors must work to understand the diverse needsof healthcare...
Page 5 of 6Operationally, involving a strategic research partner on the front end working with them duringthe ensuing inve...
Page 6 of 6About MedpaceMedpace is a leading global full-service clinical research organization providing Phase I-IV cored...
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Medpace late phase_white_paper_final


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Medpace late phase_white_paper_final

  1. 1. The late phase research environment has changed dramatically in recent years. Regulators inthe United States and abroad are demanding a much more proactive approach to safety andrisk management. Addressing those mandates requires longer studies, larger patient pools andcomprehensive risk evaluation and mitigation strategies. Payers likewise are demanding data tosupport 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 earlyin the investigative process to anticipate and plan for late phase studies. Effective planning mustinclude a comprehensive strategy for identifying and addressing the therapeutic, regulatory andeconomic concerns of diverse healthcare stakeholders. Failing to take early action and developan integrated strategy can result in expensive missteps, wasted time and failure to obtain drugapproval.The shifting regulatory landscapeRecent regulatory guidance from the U.S. Food and Drug Administration (FDA) and the EuropeanMedicines Agency (EMA) reflects a new mindset that emphasizes accountability and preparedness.As the International Society for Pharmacoeconomic and Outcomes Research Risk ManagementWorking Group observed, “Both agencies independently have implemented proactive approachesfor drug safety surveillance which have reframed the traditional business model of thepharmaceutical industry.”1Historically pharmaceutical companies have taken a wait-and-see approach to developing riskmitigation programs, largely waiting for regulators to raise concerns or objections during theapproval process before laying out detailed strategies for addressing risks. The new regulatoryclimate requires manufacturers identify and address potential safety issues as part of the approvalprocess.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 enablesthe FDA to require research at the time of approval ­— or anytime thereafter — if it learns of newinformation impacting a treatment’s safety.medpace.comlate phaseEarly Planning Essential:Best Practices in Late PhaseDrug and Device Research
  2. 2. Page 2 of 6Pre FDAAABefore 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 FDAAAUnder the FDAAA, post-marketing studies andclinical 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. Whilethe regulator previously used “commitment” as a blanket term for post-marketing research, todayit differentiates mandatory studies and trials from those that are not required. Post-marketingrequirements (PMRs) are mandatory research while post-marketing commitments (PMCs) areinvestigations 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 duringa product’s life cycle. The REMS requirement applies to all new drug, abbreviated new drug, andbiologics license applications. Because risk management depends on numerous factors -- includingthe nature and severity of the risk and the exposed population – strategies can vary. Basic strategycomponents 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 roughlyparallel course. In 2008 the EMA issued guidance for identifying, monitoring and minimizing safetyconcerns. 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 arerequired when the agency considers additional vigilance to be necessary, as in the case of productscontaining a new active substance, those with a significant change in indication, or those whereserious or potentially serious safety risks have been identified.In light of heightened regulatory demands, researchers must begin planning for late phase studies atthe front end of the investigative process.These expanded regulatory requirements have significantly altered the drug developmentprocess and created a snowballing host of associate challenges for manufacturers.Regulatory requirements for more comprehensive safety data have led to more, longer andlarger late phase studies. Increased research activity has created intense competition forpatients, investigators and safety and regulatory specialists.medpace.comlate phase
  3. 3. Page 3 of 6Researchers must likewise contend with the idiosyncratic challenges of collecting post-marketing data. For example, they must increasingly rely on research naïve physicians togather data about approved treatments. They must design data capture processes thatfit into the day-to-day workflow of medical practices often with greatly variable standardsof care. They must gather information from a diverse and growing pool of secondary datasources, including electronic medical records and claims data. They’re challenged to findeffective mechanisms for processing patient-reported outcomes. Finally, they face theubiquitous challenge of recruiting patients in increasingly diverse locations and – becausefollow-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 exampleof observational research, can serve both to generate or test a hypothesis. They are aninvaluable tool in researching practice patterns, collecting disease data, understandingclinical safety and effectiveness, and practical impact of the product in a real worldsetting. Data gathered as a result of observational research can be effectively used forreimbursement support, publications and off-label use, as well as supplement the clinicaltrial data. However, observational research is not without its limitations, the main challengebeing attributing causality to outcomes due to its non-interventional nature, and minimizingselection and enrolment bias.Another option is the use of the pragmatic trial setting, which although not beingobservational by nature, represents a ‘real world’ practice setting. These trials measureeffectiveness as opposed to efficacy in a randomized controlled trial, and allow enrolmentof all patients to whom healthcare providers might offer the intervention within the standardof care, and minimal restrictions on any other co-interventions. This helps to achieve thegeneralizability of the results, which is critical for the best practice decisions, both clinicaland cost effectiveness.2Demonstrating valueLate phase research can be an invaluable tool in establishing a product’smarket position and commercial viability.Pharmaceuticals economic climate is warming up given that U.S. regulators are approvingmore 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 recentyears to generic drug makers because of patent expirations.3However, 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 valuethrough late phase research. Does it cost less? Will more convenient drug administrationresult in better compliance? If so, what is the health and economic value of enhancedcompliance?medpace.comlate phase
  4. 4. Page 4 of 6Because value lies in the eyes of the beholder, sponsors must work to understand the diverse needsof 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 effectiveresearch design.Early in the investigative process sponsors need to assemble multidisciplinary teams to ensurethey have a 360° understanding of their product, current and emerging market conditions, andstakeholder needs. That means seeking input from pricing and reimbursement specialists, healtheconomics teams, and regulatory and therapeutic experts alike.The research process is just that: a progression in which each integrated step builds upon previouslearning. Insights gleaned through early, multidisciplinary collaboration are essential to shaping latephase research design, which in turn is key to identifying new opportunities. Post-marketing analysescan cement a product’s commercial viability. They can help differentiate a product, generate theefficacy and economic data payers demand and point the way toward strategic areas of inquiry thatcan result in additional indications. But they can only live up to those possibilities if the seeds ofinquiry are planted early.The importance of using a collaborative model to demonstrate value can’t be overstated. As Deloitteand Thomson Reuters noted in a recent report, “The companies that are successful in the business ofR&D will be effective in their validation of unmet need, in marshalling the best science and advancesin diagnostics, and in deploying a flexible, collaborative development model that focuses early ongathering evidence of medical value.”4Early Involvement EssentialSponsors want to complete late phase research as quickly, cost effectively and efficiently as possiblewhile extracting the most valuable data possible from their efforts. Traditionally the pharmaceuticalindustry has treated late phase efforts as soley the equivalent of post market research - conductedwith the intent of expanding indications for an already approved compound.However, studies can be conducted more efficiently with thought given to gathering the necessarydata 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 strategicpartners who have the therapeutic, operational and regulatory sophisticationto consider all aspects of trial design and execution.medpace.comlate phase
  5. 5. Page 5 of 6Operationally, involving a strategic research partner on the front end working with them duringthe ensuing investigative phases promotes continuity, communication and efficiency. Continuouscollaboration: • 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 PartnerWhile regulatory and market considerations shape late phase research, therapeutic expertise mustunderlie 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 entirepicture - 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 moresuccessful commercialization.The therapeutic arena is dynamic. Because new and competing treatments are always underdevelopment, sponsors should seek out partners who understand not just the drug or device underinvestigation, but its significance in the broader therapeutic context.Medpace: Therapeutically focused expertiseShepherding a new therapy though the post-approval phase requires up-front strategic planningthat 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 2,000investigator sites globally. Multidisciplinary Medpace research teams include global therapeuticleaders in cardiology, endocrinology, oncology, nephrology, neurology, infectious diseases andregenerative medicine. Medpace teams act as an extension of the research sponsor to develop andexecute effective late phase drug and device development programs.Late Phase LeadershipAlexander Artyomenko, MD, PhD, Global Director, Late Phase Clinical OperationsDr. Artyomenko has over 12 years of experience in late phase clinical research. His unique backgroundencompasses medicine, clinical trials, and project management, with a highly successful trackrecord for planning and executing global Phase IIIb-IV studies. Dr. Artyomenko has conductedstudies with a therapeutic focus in cardiovascular and metabolism, infectious diseases includingHIV, rheumatology, gynecology, and dermatology. Dr. Artyomenko is an expert in global regulatoryconcerning post-marketing and non-interventional studies, including HEOR, registries, andcollaboration with Academic Research Organizations (AROs).medpace.comlate phase
  6. 6. Page 6 of 6About MedpaceMedpace is a leading global full-service clinical research organization providing Phase I-IV coredevelopment services for drug, biologic, and device programs. With more than 1,300 employees andclinical trial experience in over 40 countries, Medpace has the global reach and capability to conductstudies and navigate regulatory requirements worldwide. In addition to Phase II-IV developmentservices, 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 BioanalyticalLaboratories, centralized imaging core laboratory management and reading from Medpace ICL, andmedical device development from Medpace Medical Device.Reference:1A Comparison of US Food and Drug Administration and European Medicines AgencyRegulations for Pharmaceutical Risk Management: Report of the International Society forPharmacoeconomic and Outcomes Research Risk Management Working Group, September/October 2011 ISPOR Connections.2Pragmatic controlled clinical trials in primary care: the struggle between external andinternal validity: Marshall Godwin, Lucia Ruhland, Ian Casson, Susan MacDonald, DianneDelva,Richard Birtwhistle, Miu Lam, and Rachelle Seguin, BMC Medical Research Methodology2003, 3:28 doi:10.1186/1471-2288-3-283Reuters 2012: ( the return from pharmaceutical innovation 2012: Is R&D earning its investment?Deloitte Centre for Health Solutions and Thomson Reuters. phase