THE CHANGING SITE LANDSCAPE                                                   Volume 28 Number 9 September 2019




                                                                                             o   f Se r v i


        DATA SHARING                                      STUDY START-UP

        STEPS TO INTEGRATE                                REFORM IN ACTION
        EXECUTIVE PROFILE            TRIAL INSIGHTS                        CLOSING THOUGHT
        Championing Clinical         Benchmarking                          Digital Implementation:
        Trial Diversification        Rare Disease R&D                      A Site-First Mindset
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Taking Care of Site Business

                                 ’m really excited about this issue of Applied                         begin to accredit investigative sites. The Association of Clinical Research
                                   Clinical Trials. Tagged as “The Changing Site                       Professionals (ACRP) offers certifications of varying clinical research roles,
                                   Landscape,” this is our foray to update in-                         as does the UK-based International Academy of Clinical Research (IAOCR).
                                formation presented in September 2018 (see                             ACRP also rolled out its ACRP Core Competency Framework two years
                       around different site                          ago, initiated so industry could begin to level set the various roles at sites
                                models and bringing clinical trials closer to the                      and is discussed as a tool used by many in our main feature (see page 24).
                                point of care. This year, we offer a more in-
                                depth look at representative models that are                           Remote Trials. There is some backlash around the terminology of re-
                                changing the way investigative sites work. The                         mote or virtual trials. While many have started calling them decentralized
                               “traditional, dedicated research site” is morphing                      trials, these trials really are around patient centricity and making conve-
to model more efficient, professional, and technologically robust practices                            nience and location (or inability to get to a site location more specifically)
and processes that rival those of CROs, while specialty physician groups                               a reality for participants. Clearly, decentralized trials are reserved for the
and large IDNs integrate professional providers that operationalize clinical                           most appropriate of therapeutic areas and populations. More often than
research within their unique clinical care workflows. Academic centers,                                not, hybrid trials is the word of the day and means that you offer patients
long the bastion of both innovation and bureaucracy associated with                                    a mix of both on-site and virtual. To that end, sites are incorporating tech-
clinical trial conduct, have instituted change to streamline their business.                           nologies that enable them to be more competitive for the hybrid models.
And at the Veteran’s Administration, executives are attacking their own
bureaucracies to unify study start-up and make VA clinics a competitive                                Remove Recruitment from the Site. I attended a meeting where
option for sponsored research. What follows are highlights of trends from                              physician speakers discussed their role as clinical event adjudicators. One
this issue, as well as trends heard around site practices during the year.                             view shared was that sponsors or CROs spend about 1% of their time
                                                                                                       educating the investigative staff on the study protocol, and 99% on pa-
Professionalism. One recognized problem at sites is the varying levels of                              tient recruitment. The physicians felt this time allocation should be flipped
performance quality and consistency in staff capabilities. There are many                              given the importance of protocol adherence for both data and safety
ways now available to help clinical research professionals, as well as sites,                          reasons. Given the dire straits of patient enrollment, as well as the diverse
establish credibility and professionalism. For example, the Alliance for                               ways to reach potential participants, it makes sense to take recruitment
Clinical Research Excellence and Safety (ACRES) recently announced it will                             out of the core site responsibility, and make it a more strategic process.

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September 2019                                                                                              APPLIED CLINICAL TRIALS                                                       3



24  The Changing Landscape

                                                                                                                                                                                       JAKKAPAN - STOCK.ADOBE.COM
for Clinical Trial Sites
Cindy H. Dubin
Exploring how clinical research sites are redefining their business
models to be more flexible, collaborative, and customized.

30 Improving Information                                      EXECUTIVE PROFILE                                      EYE ON PATIENT ADVOCACY
Exchange in Clinical Trials                                   22 Creating Medicines                                  20 Retention Strategies for
Jason Methia                                                 ‘Appropriate for All’                                   Keeping Participants Engaged
Executives from across the clinical                           Christen Harm                                          The MJFF Recruitment
research enterprise converge                                 Bristol-Myers Squibb’s cardiovascular                   and Retention Team
to discuss the steps—and                                     development leader Charlotte                            Findings and learnings from a
technology—needed to strengthen                              Jones-Burton on the importance                          case study of the Parkinson’s
industrywide data sharing.                                   of diversifying clinical trials for                     Progression Markers Initiative.
                                                             better patient outcomes.
18 The VA Gets
Real on Reform                                                                                                       COMMENTARY
                                                              NEWS AND ANALYSIS
Sony Salzman
                                                             6 WASHINGTON REPORT                                     A CLOSING THOUGHT
After years of siloed focus—and
slow study start-ups—the U.S.                                7 EU REPORT                                             34 Putting Sites First When
Veterans Affairs agency embarks                              10 Q&A                                                  Implementing New Trial Technology
on implementing its multi-year
initiative to bolster clinical research.
                                                             16 CLINICAL TRIAL INSIGHTS                              KK Rumrill

                                                                   EDITORIAL ADVISORY BOARD

Moe Alsumidaie                               Srini Dagalur, PhD                   Michael R. Hamrell, PhD, RAC                VIcky Parikh, MD, MPH
Thought Leader and Expert in the             Specialist Leader, Life Sciences     President                                   Executive Director
Application of Business Analytics            Technology Strategy                  MORIAH Consultants                          Mid-Atlantic Medical Research Centers
Towards Clinical Trials and Healthcare       Deloitte                             Huntington Beach, CA                        Hollywood, MD
New York, NY                                 Parsippany, NJ
                                                                                  Wayne Kubick                                Prof Stephen Senn, PhD, FRSE
Kiran Avancha, PhD, RPh                      Yakov Datsenko, MD                   Chief Technology Officer                    Consultant Statistician
Chief Operating Officer                      Senior Clinical Research Physician   Health Level Seven International            Edinburgh, UK
HonorHealth Research Institute               Team Leader Immunology/Respiratory   Chicago, IL
HonorHealth                                  Boehringer Ingelheim Pharma GmbH &
Scottsdale, AZ                               Co. KG
                                                                                  Darshan Kulkarni, PharmD, Esq
                                                                                  Principal Attorney
                                             Biberach, Germany
Townsend N. Barnett, Jr.                                                          The Kulkarni Law Firm
Vice President, Global Head                  Edward Stewart Geary, MD             Philadelphia, PA
of Pre-Clinical and Clinical QA              Chief Medical Officer &
                                             Vice President
                                                                                  Jeffrey Litwin, MD
UCB Pharma S.A.
Chemin du Foriest, Belgium                   Eisai Co., Ltd.
                                             Tokyo, Japan
Kenny Blades, PhD                                                                 Princeton, NJ
Director, Global Project Management          Ashok K. Ghone, PhD
                                             VP, Global Services                  Barrie Nelson
DOCS International
                                                                                  Chief Standards Officer
Kent, UK                                     MakroCare
                                             Newark, NJ
Anthony J. Costello                                                               Austin, TX                                  The expertise of Editorial Advisory Board mem-
Vice President, Mobile Health                Rahlyn Gossen                                                                    bers is essential to the credibility and integrity of
Medidata                                     Founder                                                                          Applied Clinical Trials. These clinical trials experts
                                                                                                                              share with the editors the wisdom gained through
San Francisco, CA                            Rebar Interactive                                                                their experience in many areas of drug develop-
                                             New Orleans, LA                                                                  ment. EAB members review manuscripts, suggest
Domenico Criscuolo, MD, PhD, FFPM
                                                                                                                              topics for coverage, and advise the editors on
Chief Executive Officer                      Uwe Gudat, MD                                                                    industry issues. All manuscripts must first be
Genovax                                      Head of Safety, Biosimilars                                                      submitted to the Editor-in-Chief, Applied Clinical
Colleretto Giacosa, Italy                    Merck Serono                                                                     Trials, 485 Route 1 South, Building F, Second Floor,
                                             Geneva, Switzerland                                                              Iselin, NJ 08830 USA.

4   APPLIED CLINICAL TRIALS                                                                                         September 2019
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                                                         WASHIN GTO N RE P OR T

    SPONSORS, REGULATORS                                procedures, and processes, as outlined in        ter,” he commented. An analysis of 334 OSI
    CAUTIOUS ABOUT RISK-BASED                           guidance issued in 2013 and updated earlier      clinical investigation summaries over three
    OVERSIGHT OF CLINICAL TRIALS                        this year. Such situations can be described      years reveals relatively few “active recom-
    Despite the high cost and extensive re-             in risk-based monitoring (RBM) strategies        mendations” that raise questions about
    sources involved in monitoring the con-             laid out in RBM plans.                           application quality likely to delay approval.
    duct of and data produced by clinical trials,          Despite these efforts, biopharma com-         The vast majority of clinical inspections find
    the research community has been slow to             panies have been slow to adopt RBM ap-           appropriate compliance with requirements.
    embrace strategies for reducing on-site             proaches, as seen at a public workshop in           Similar efforts by the European Medi-
    oversight to reflect risk. Sponsors appear          July organized by the Margolis Center for        cines Agency (EMA) support risk-based
    willing to spend more to ensure that results        Health Policy at Duke University to gain         approaches to clinical trial monitoring to
    meet regulatory expectations and avoid              more feedback from stakeholders on the           ensure that studies generate reliable in-
    raising issues that could delay the review          challenges and barriers influencing the          formation, while protecting study subjects,
    and approval of a market application. FDA           adoption of RBM. Jacqueline Corrigan-            commented Camelia Mihaescu, of the EMA
    and other regulators are responding with            Curay, director of the Office of Medical         Committees and Inspections Department.
    support for more flexible monitoring of             Policy in the Center for Drug Evaluation         Risk-based approaches, she noted, should
    clinical investigators and review of study          and Research (CDER), opened the meeting          reflect trial-specific issues.
    records in order to limit study monitoring to       by emphasizing the importance of lever-             Yet, regional differences in monitoring
    situations where less oversight raises clear        aging tools and methods to improve the           practices, inspection procedures, and ac-
    difficulties for investigators, participants,       efficiency and reliability of clinical trials.   ceptance of RBM by regulatory agencies
    and data integrity.                                 FDA wants to make risk-based monitoring          create barriers to wider adoption of RBM,
       To this end, FDA has encouraged spon-           “a reality for everyone,” she said, and is        observed Tim Rolfe, director of research-
    sors to focus on risk in monitoring clinical        reviewing comments from the recent draft         based monitoring at GlaxoSmithKline. Spon-
    trials, similar to agency initiatives to modify     guidance to move forward.                        sors have concerns about ensuring qual-
    pharmaceutical plant inspections and pre-              The process begins with risk assessment       ity data at multiple study sites that follow
    approval of product changes to situations           to help shape the resulting clinical research    a range of research methods, with large,
    likely to compromise product quality and            protocol, explained David Burrow, direc-         complex trials raising issues that differ with
    safety. Instead of using on-site monitoring         tor of the Office of Scientific Investigations   very small studies. He advised FDA to up-
    for every clinical site to verify study data        (OSI) in CDER’s Office of Compliance. An         date its inspection guide for clinical sites
    and conduct, FDA advises sponsors to limit          RBM plan then can be built to support prod-      and to train inspectors in RBM expectations
    oversight to the most critical data elements,       uct approval and reduce errors “that mat-        through case examples. Research sites ex-
                                                                                                         perience “general discomfort” with RBM
                                                                                                         approaches, according to a study by the
                                         F DA N OTES                                                     Society for Clinical Research Sites, and often
                                                                                                         feel left out of planning for RBM approaches,
                                                                                                         which vary notably with each sponsor.
    The FDA recently released the following           7/30/19: Rare Pediatric Disease Priority              Burrow of OSI was optimistic that recent
    industry guidance documents:                      Review Vouchers                                    changes in FDA’s Office of Regional Affairs
                                                                                                         (ORA) to create specialized teams of clinical
    8/13/19: Gastroparesis: Clinical Evalua-          The following committee meetings were              site inspectors may address some inspec-
    tion of Drugs for Treatment                       scheduled for September:                           tion issues. But OSI still finds problems with
                                                      • Allergenic Products Advisory                     initial RBM efforts, particularly with record
    8/7/19: Fabry Disease: Developing Drugs
                                                        Committee, Sept. 13. Discuss the                 sampling and source-data verification, and
    for Treatment
                                                        safety and efficacy of Peanut Allergen           limited coordination between sponsors
                                                        Powder, indicated to reduce the                  and CROs can be a problem. FDA officials
    8/2/19: Testing and Labeling Medical
                                                        risk of anaphylaxis after accidental             advise sponsors to involve all stakehold-
    Devices for Safety in the Magnetic Reso-
                                                        exposure in patients aged 4 to 17 with a         ers in the RBM process,
    nance (MR) Environment
                                                        confirmed diagnosis of peanut allergy.           which should be adapt-
    7/31/19: E8 (R1) General Considerations                                                              able and promote hu-
                                                      • Patient Engagement Advisory                      man subject protection
    for Clinical Studies
                                                         Committee, Sept. 10. Discussed and              and data integrity.
    7/31/19: General Clinical Pharmacology               made recommendations on the topic
    Considerations for Neonatal Studies for             “Cybersecurity in Medical Devices:
    Drugs and Biological Products                        Communication That Empowers Patients.”                    — Jill Wechsler

6   APPLIED CLINICAL TRIALS                                                                             September 2019

                                                              EU REP OR T

   NO END IN SIGHT TO EUROPEAN                    fully manage the contacts its evaluators          ing pre-submission activities needs be im-
   DEBATES ABOUT DRUG FIRMS’                      have with medicine developers during the          proved to enhance the objectivity of how
   INFLUENCE ON REGULATORS                        pre-submission phase,” and that “EMA              medicines are evaluated,” remarked the
   Persistent concerns that European drug         should provide greater transparency on its        Ombudsman’s decision.
   evaluators are too cozy with pharmaceu-        pre-submission activities, with the aim of           The criticisms focused partly on the risk
   tical companies are unlikely to be fully       maintaining public trust in its work.” But        of bias where the same individuals are in-
   allayed by a recent decision from the          some of those who have levelled strident          volved in providing scientific advice and in
   European Ombudsman that “no further            and repeated attacks on the agency’s op-          subsequently evaluating that same medi-
   inquiries are justified” into the provision    erations in the last five years will not be so    cine. EMA should widen its pool of experts,
   of early scientific advice. The two-year in-   easily appeased.                                  and where it was absolutely necessary to
   quiry into possible maladministration at                                                         have such overlap, EMA should publicly
   the European Medicines Agency (EMA) has        Keeping things separate                           justify it. And there was also frequent criti-
   intensified as much as it has resolved long-   EU law specifically allows for medicine de-       cism of the lack of transparency over the
   running controversies over potential con-      velopers to seek advice from EMA’s ex-            procedures and calls for the scientific ad-
   flicts of interest and lack of transparency    perts long before they submit a marketing         vice provided to be open to public scrutiny.
   within the agency.                             authorization application. It is considered           Health Action International (HAI) cited
       It was two years ago that the Ombuds-      legitimate for companies to seek advice on        allegations purporting to come from EMA
   man—an official European Union body—           the relevant procedures, the requirements         staff that “manufacturers see pre-sub-
   decided to follow up on anxieties among        for demonstrating that medicines are safe         mission processes as a way to lobby the
   many healthcare campaigners and aca-           and effective, or the design or conduct of        agency.” The European Public Health Al-
   demics about the risk of what they saw as      clinical trials.                                  liance warns of “regulatory capture.” The
   a hazardous overlap: the EMA’s roles both        But questions have been posed for years         International Society of Drug Bulletins says:
   in giving early scientific advice to drug      about whether EMA’s recommendations on           “EMA’s confidential pre-submission “sci-
                                                                                                    entific advice” to companies jeopardizes
                                                                                                    its ability to make independent decisions.
                                                                                                    Pre-submission activities effectively make
      Questions have been posed for years                                                           EMA a co-developer of the medicine, yet
      about whether EMA’s recommendations on                                                        it is subsequently called upon to issue its
                                                                                                    opinion on whether or not the medicine
      authorization of a medicine is influenced                                                     should be granted marketing authorization.”
      by the prior interaction its evaluators                                                           Critic s make complaint s ab out the
                                                                                                    negative impact of the confidentiality sur-
      have with medicine developers.                                                                rounding the process. EPHA warns of the
                                                                                                    dangers of giving scientific advice “be-
                                                                                                    hind closed doors” and of how EMA “black
   developers, and its subsequent engage-         authorization of a medicine is influenced         boxes” and “revolving doors” impede
   ment in evaluating marketing authorization     by the prior interaction its evaluators have      transparency. ISDB says “companies that
   applications from the very same products       with medicine developers. The Ombudsman           request pre-submission scientific advice
   it had advised on. “These ‘pre-submis-                                                           could exert control from an early stage
                                                  chose to assess how far this may have hap-
   sion activities’ may have some positive                                                          over ever ybody involved in the assess-
                                                  pened, or even be perceived to happen. And
   consequences for public health,” said the                                                        ment of marketing authorization applica-
                                                  it concluded that not much needs to change.
   formal inquiry, but it insisted that it was                                                      tions at both national and European level.”
   also “important to avoid even the percep-      Plenty of interest, plenty of ambition            According to HAI, “It is impossible to know
   tion that the eventual opinions of EMA on      Among the numerous representations                from the onset the advice a company has
   medicines were influenced by these earlier     made to the Ombudsman during the in-              requested, and the EMA has subsequently
   interactions.”                                 quiry, national medicine evaluation authori-      provided, even though this would be rel-
      This summer, after extensive consulta-      ties and the pharmaceutical industry felt         evant information to patients who are con-
   tions and discussions, the outcome was         the system was broadly sound and pro-             sidering enrolling in a clinical trial, and to
   nothing more than “a number of sugges-         tected the public adequately from risk of         independent clinical trial reviewers.” By
   tions for improvement”—and the decision        overlap. But “by way of contrast, many            providing “tailored and confidential advice
   to, in effect, drop the case. The Ombuds-      civil society organizations and academics         to one company only,” EMA may even be
   man merely urged that “EMA should care-        argued that the current practice concern-         in breach of competition law, it suggests.

September 2019                                                                   APPLIED CLINICAL TRIALS    7

                                                                    EU REP OR T

        HAI has made clear its concerns that            trials, and maximize the value of the data       words of welcome from EMA for some el-
    “at the time of assessing an application for        that clinical trials generate; and by avoid-     ements of the decision cannot disguise
     marketing authorization, (the relevant com-        ing misunderstandings in the assessment          the reality that it will continue to proceed
     mittee) members might feel bound by the            process, it can ease administrative burdens      as before, despite its commitments to a
     advice that the very same committee they           and cut the risk of preventable delays at a      few equally soft additional gestures toward
     represent gave in the past to a company/           later stage.                                     transparency.
     marketing authorization applicant.” It says           The agency maintained stoutly through-           The more trenchant criticisms of the sys-
     EMA should draw a firm line to prevent             out that a scrupulous distinction is main-       tem will, therefore, remain unsatisfied—
     overlaps: “A clear separation of roles be-         tained between the two levels of inter-          and, hence, they will continue to feature
     tween advisors and marketing authoriza-            action, so as to give a guarantee of fair        just as much as before in the public dis-
     tion assessors should be established.”             dealing and impartiality, Scientific advice      course about EMA’s independence from
        And the European Consumer Organi-               is not a pre-evaluation of the data gath-        industry influence.
     zation (BEUC) says it wants to know how            ered during clinical trials. It is prepared by      The fact that the sharpest criticisms are
     EMA’s pre-submission activities contrib-           nominated experts who report to a specific       made by only a relatively small number of
     ute to the development of safe and ef-             working party, and not by the committee          contributors to the inquiry does not reduce
     fective medicines. “A growing number of
     medicines seem to come to the market for
     which less robust data is available. How do
     pre-submission activities contribute to the           The fact that the sharpest criticisms are
     availability of robust and useful data, while         made by only a relatively small number
     also minimizing the number of unneces-
     sary clinical trials?,” the bureau asks.
                                                           of contributors to the inquiry does not
    On the fence
                                                           reduce their significance. Both HAI and
    The Ombudsman came down firmly in the                  EPHA are influential organizations.
    middle of this divergence of views. Yes,
    there is an element of risk in overlap, in
    acknowledgement of the critics—but, over-
                                                        that conducts evaluations of marketing au-       their significance. Both HAI and EPHA are
    all, the system offers protection against
                                                        thorization applications. In the rare cases      influential organizations—both of them are
    undue influence, it concluded, in line with
                                                        where the same expert contributes to both        represented on EMA’s own bodies—and
    most comments from regulators and indus-
                                                        scientific advice and product evaluation, it     they command a prominent position in
    try. So there is not a lot that needs to be
                                                        is because of scarcity of experts in certain     European public debates about health and
    done. The toughest recommendation the
                                                        areas of science and medicine, and public        medicines. They and the other organiza-
    Ombudsman makes is that “to the great-
                                                        health could be impaired by a prohibition        tions that share their views will ensure that
    est extent possible, EMA should ensure
                                                        of this practice. If EMA identifies possible     the debate will continue to grow over the
    that there is a separation between those
                                                        conflicting interests among any of the ex-       role of EMA and the influence of the drug
    responsible for providing scientific advice
                                                        perts, it can exclude them from partici-         industry on regulatory decision-making.
    to a medicine developer and those subse-
                                                        pating in discussions on particular topics.      And this at a particularly crucial moment
    quently involved in evaluating” it.
                                                        And it is not binding, since it is based by      for European rulemaking in general, with
       The operational result is that EMA’s own
                                                        definition on the current state of the art,      a new European Parliament and European
    arguments—essentially that scientific ad-
                                                        and may consequently be superseded as            Commission just about to take up the man-
    vice is a force for good and should not be
                                                        understanding advances.                          agement of policy for the next five years.
    tampered with lightly—largely prevailed in
    the Ombudsman’s decision.                          No change, but no relief
                                                       The Ombudsman’s decision leaves the
    EMA defense
                                                       situation unchanged. EMA will continue
    EMA argued that the provision of scientific
                                                       to maintain that on balance, the system
    advice can minimize the risks of exposing
                                                       is good and fair. Critics will continue to
    patients to useless or less useful clinical
                                                       say the balance is wrong, and that partial-
    trials, and maximize the value of the data
                                                       ity remains built into the system. And the
    that clinical trials generate; and by avoid-
                                                       Ombudsman’s views, taking some from
    ing misunderstandings in the assessment
                                                       column A and some from column B, and of-
    process, it can ease administrative burdens
                                                       fering no more than a heavily-qualified sug-
    and cut can minimize the risks of exposing
                                                       gestion of maximum caution, fully satisfies
    patients to useless or less useful clinical                                                                — Peter O’Donnell
                                                       neither side. The flurry of soft diplomatic

8   APPLIED CLINICAL TRIALS                                                                            September 2019

                                                                            Q& A

     WORKFORCE READINESS                                tion across a diverse set of study sites and
     TECHNOLOGY MINIMIZES                               asked if ArcheMedX could help.
     RISK IN CLINICAL TRIALS                               We ultimately enabled them to design
     Clinical trials often encounter operational        and deliver an innovative site readiness
     challenges and sponsors and CROs seek              program powered by the ArcheMedX plat-
     effective site-readiness practices. In this        form that accelerated site initiation for a
     interview, Joel B. Selzer, co-founder and CEO,     neurology focused trial. That effort opened
     ArcheMedX, Inc., discusses the impact that         our eyes to the operational challenges thou-
     healthcare technology has on clinical trials,      sands of trials encounter and led us to ex-
     focusing on the development of the com-            plore the industry further. In the course of
     pany’s workforce readiness platform.               our market research, we conducted infor-
                                                        mational interviews with dozens of spon-                 Joel Selzer
     Q: Can you tell us a bit about yourself?           sors, CROs, and other trial stakeholders and
     Joel Selzer: I have spent the past 15 years        the critical need to more effectively evalu-
     envisioning and delivering innovative technol-     ate and improve the preparedness of staff
     ogy and data-driven solutions across the life                                                           therapeutics and advanced protocol simula-
                                                        and sites became increasingly clear.
     sciences and healthcare industries as an en-                                                            tions to data-driven workforce improvement,
                                                           The result was the development and
     trepreneur, board member, and advisor. Dur-                                                             the industry can more rapidly and accu-
                                                        launch of Ready.
     ing this time, I have co-founded and led three                                                          rately analyze novel sources of data that will
     technology companies, Medical Funding Ser-                                                              inform better decision-making, decrease
                                                        Q: We are seeing more technologies                   the costs of clinical trials, and provide the
     vices, Ozmosis, and currently ArcheMedX.           coming from healthcare into clinical
     In each venture, we have applied creative          trials, which is but one part of the                 right therapies to the right patients.
     approaches to improve the lives of our cus-        overall healthcare picture. Why do
                                                        you think that is? What impact will                  Q: Investigative site burden is
     tomers, thousands of clinicians, and most                                                               quite often a topic of concern
                                                        that continue to have in clinical trials?
     importantly millions of patients.                                                                       in this industry. Does the
                                                        JS: There are a number of macro trends driv-         implementation of Ready increase
     Q: Can you give us a brief                         ing the adoption of technology within clinical       a site’s burden of tasks?
     overview of your product?                          trials. For example, rising trial costs, increas-    JS: Many sites today are already struggling
     JS: Ready is an operational intelligence           ing complexity, the continued low success            to implement a dozen or more trial appli-
     and workforce readiness platform that re-          rates of getting to market, and the extreme          cations, ever-changing study tools, and in-
     duces the risks and costs associated with          challenges of recruiting and retaining par-          creasingly complex protocols. Adding to this
     underperforming clinical trials. The plat-         ticipants are all multiplied by the continued        burden, they are rushed through training on
     form enables clinical operations leaders to
     evaluate and improve the preparedness of
     project teams and site personnel by ana-
     lyzing the behavior of each participant as             Sponsors and CROs are now using advanced
     they engage in personalized learning ex-               data analytics and deep learning to more
     periences that are designed and delivered
     within the platform. Ready serves as an
                                                            effectively design and implement clinical trials
     early warning detection system to identify             that result in more personalized and consumable
     risks sooner, ensure resources are more ef-
                                                            therapies that benefit patients and providers.
     fectively deployed, and enhance staff and
     site performance.

     Q: This product came out of a                      growth of active clinical studies. This creates      each system and protocol and often lack the
     healthcare and continuing medical
     education history. What made you                   a great deal of opportunity for technology-          time and interest to properly focus on critical
     choose clinical trials for this service?           based solutions to make a positive impact.           information. By centralizing and personaliz-
     J S: We sp en t t h e f ir s t si x ye ar s a t       In particular, clinical trials are accelerating   ing each training experience, Ready makes it
     ArcheMedX powering hundreds of online              the adoption of digital tools and data-driven        easier and more enjoyable for site personnel
     medical education activities for national          strategies. Sponsors and CROs are now                to engage in critical content over time, in-
     medical societies, leading academic medical        using advanced data analytics and deep               creasing their confidence and interest in the
     and research centers, global medical educa-        learning to more effectively design and im-          study or tool. Ready can also be integrated
     tion providers, and major pharmaceutical           plement clinical trials that result in more          via web services with nearly any IT system
     firms. One of our academic research part-          personalized and consumable therapies that           making it simple to create a seamless user
     ners ran into challenges standardizing initia-     benefit patients and providers. From digital         experience and securely share data.

10    APPLIED CLINICAL TRIALS                                                                               September 2019
|_;r-ঞ;m|Ľv_ol;                                     Recognized as the industry leader,
                                                      along with our comprehensive
                                                      v;ub1;vŌ;mvu;|_-| ;1-ml;;|
                                                      you at any point along the virtual
                                                      clinical trial journey.

                                   PHYSICIAN VISITS

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     HIGHLY SKILLED                                             SHIPPED DIRECTLY TO
     COORDINATORS                                               THE PATIENT’S HOME

                                                       CLINIC VISITS WHEN
               NURSE VISITS

                      Reimagine clinical research with us.

                                                                            Q& A

     Q: How would you envision Ready                    the protocol or other content they may have          ered by Ready are often delivered during
     changing the way sponsors plan                     skipped or struggled with and will continually       study start-up, the insights the platform
     their investigator meetings and
                                                        measure their engagement and response.               provides into the readiness and mindset of
     subsequent site training?
                                                           Ready can also power a virtual SIV and any        participants serve as an early warning de-
     JS: Ready creates opportunities for spon-
                                                        subsequent site training, such as protocol           tection system that compliments traditional
     sors to augment, re-focus, or even replace
                                                        amendments and the sharing of recruitment            risk-based data and strategies. This unique
     their investigator meetings, and subsequent
                                                        best practices. In each of these use cases,          analysis of behavioral data drives risk mitiga-
     site training. By deploying Ready prior to an
                                                        Ready will analyze the unique behavioral data        tion, as well as more effective allocation and
                                                                                                             deployment of resources that leads to better
                                                                                                             staff and site performance.
        This unique analysis of behavioral data drives
                                                                                                             Q: There is also a lot of positive
        risk mitigation, as well as more effective                                                           change in the industry to raise the
        allocation and deployment of resources that                                                          level of education and professional
                                                                                                             credentials at the site level. How
        leads to better staff and site performance.                                                          does Ready help sites raise their bar?
                                                                                                             JS: More than 40,000 clinicians have already
                                                                                                             improved their knowledge, competence,
     investigator meeting, the insights it gener-                                                            and confidence with ArcheMedX and this
                                                        it captures to provide insights that help spon-      positive change continues to raise the bar at
     ates can help to focus the meeting on the
                                                        sors focus where additional training, site visits,   sites across the globe. By deploying Ready,
     areas of greatest need and risk. This can re-
                                                        and/or remote monitoring may be required.            sponsors and CROs can now accelerate this
     sult in a more engaging and targeted meet-
     ing that accelerates site initiation, better                                                            change by more effectively measuring and
                                                        Q: Does Ready impact other
     enrollment, and overall compliance.                oversight practices such as risk-                    improving the competence, readiness, and
        Ready can be utilized in place of an inves-     based monitoring (RBM)?                              mindset of their staff and sites. Ready can
     tigator meeting to significantly reduce meet-      JS: Yes. The operational intelligence and            enable the industry to identify skill and knowl-
     ing costs and provide more measurable data         workforce readiness data generated by                edge gaps across roles, years of tenure, certi-
     and insights that identify which PIs (principal    Ready creates early insight around areas             fication levels, and therapeutic areas and then
     investigators) are most likely to struggle. The    of clinical operation risk and are key pieces        target workforce improvement efforts on the
     platform can then automatically re-engage          of information for any RBM strategy. Since           segments of staff and sites that need it most.
     any participant to focus on critical aspects of    the personalized learning experiences pow-                                            — Staff Report

                                                                    ACT O NLINE

     GO TO:                                             eLEARNING:                                           the print! The Digital Edition Archive (link
                                                        While risk management efforts in drug devel-         below) features a quick list of the contents
     to read these exclusive stories                    opment have focused mostly on post-mar-              for each issue.
                                                        keting drug safety, the clinical trials process
     and other featured content.
                                                        has its own mix of potential risks waiting to
     TOP 3 SOCIAL MEDIA                                 derail a company’s multimillion-dollar devel-        Medical monitors play an integral role in
                                                        opment programs. This webcast focuses on             ensuring patient safety, as trials increase in
     1. Big CROs Dive into Offering                                                                          complexity and as the volume of participant
                                                        why risk management and assessment are
        AI/ML Solutions                                                                                      medical data grows. Medical Monitor Mod-
                                                        most effective when integrated into clini-
                                                        cal trials from the beginning (study start-up        ernist: Driving Productivity Protecting Sub-
                                                        phase), rather than as an afterthought.              jects is our latest e-book that shows how
     2. Five Strategies for Conducting
        Successful Pediatric Trials                                           the medical monitor role is evolving. It also                                                                                explores how new, intuitive data visualization
                                                        As Applied Clinical Trials continues its move        and analysis software technology is helping
     3. How AI is Transforming Clinical                 to a more enhanced digital experience, be            medical monitors identify outliers and trends
        Trials: A Look Into the Code                    sure to visit our online digital edition of the      in clinical trial data.                           magazine, with the same look and feel as   

12    APPLIED CLINICAL TRIALS                                                                                September 2019
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                                                                  DATA SH A RIN G

     MIXED PATIENT SUPPORT OF                           risks that their information may otherwise         many institutions do not have a culture
     DATA-SHARING INITIATIVES                           be shared with third parties without their         that promotes new data-sharing initia-
     Do patients really want to share their data?       consent, and be used in a context different        tives. And researchers remain subject not
     The question goes to the heart of the digi-        from the one in which they disclosed it.           only to geographic, institutional, or disci-
     tal health revolution that strategists love           It includes recommendations to policy-          plinary boundaries, but often governed by
     to celebrate—and the strategists will be           makers, researchers, funders, and patient         “silo mentalities” that see sharing data as a
     heartened by the results of a new poll by Eu-      organizations creating data-sharing initia-        risk to personal and professional benefits
     rope’s leading rare disease organization, Eu-      tives, centered on issues of trust. Gover-         conferred by data ownership. Increasingly
     rordis. The vast majority of the 2,000+ rare       nance should be in the hands of people             prominent attacks on—and sensitivity to—
     disease patients responding to an interna-         whom patients consider impartial—such              data security compound the difficulties. One
     tional survey are supportive of data-sharing       as general practitioners—and serious at-           of the key recommendations, accordingly,
     initiatives to foster research and improve         tention should be given to keeping patients        is that policymakers should pursue cultural,
     healthcare, and willing to share their data        informed about progress and outcomes of            technological, and infrastructural changes to
     to help research and treatment on diseases         research for which their data has been used.       make a reality of international data sharing.
     other than their own.                                 The full report is published in the Or-            Eurordis and its numerous fellow advo-
        But this is no carte blanche. Nearly half       phanet Journal of Rare Diseases and makes          cates of data sharing had better factor the
     the respondents are against their data being       challenging reading. It identifies the “numer-     results of this survey into their planning.
     shared outside the medical field, and even         ous technical and regulatory boundaries            Because for all the potential of digital health,
     within the medical field, nearly all of them       that make sharing difficult and for many           without access to the data, not much is ever
     want something close to full control over          researchers, clinicians and institutions, still    going to change.
     the data they share, both over who gets it,        not standard practice.” Aside from tech-
     and what it is to be used for. They see big        nical issues, Eurordis also points out that                                    —Peter O’Donnell

                                                                  NE WS NOTES

     NEW COLLABORATION TARGETS                          sphere leading us down a path to the clinic,      shareholders receive an upfront payment
     PANCREATIC CANCER                                  and commercial development of a lead can-         of $52.5 million and have the potential to
     Genisphere LLC and University Hospitals            didate for the treatment of pancreatic cancer.”   receive additional payments of up to $260
     Cleveland Medical Center are partnering to         Harbour BioMed and PPD team up                    million upon the achievement of certain clini-
     study and develop unique strategies to treat       Harbour BioMed (HBM), a global clinical-          cal, regulatory, and commercial milestones.
     pancreatic cancer. According to their agree-       stage biopharmaceutical company, and the             Cavion, a clinical-stage biotech and now
     ment, investigators will optimize 3DNA®-           CRO PPD have entered into a strategic col-        a wholly-owned subsidiary of Jazz, creates
     based therapeutics designed to target and          laboration to develop HBM’s therapeutics          therapies aimed at modulating the T-type
     kill pancreatic tumors. Projects will include      in the fields of oncology and immunology.         calcium channel for the treatment of chronic
     delivering a variety of therapeutic cargos,           The selection of PPD as a preferred CRO        and rare neurological diseases.
     including small molecules and siRNA, formu-        partner enables HBM, which has operations         Pact focused on mRNA-based drugs
     lated with pancreatic tumor-targeting mol-         in the U.S., the European Union, and China,       Biopharma company CureVac AG has struck
     ecules on Genisphere’s 3DNA® nanocarrier.          to conduct global clinical studies on its in-     a collaborative research agreement with Yale
         Jordan Winter, MD, chief of the Division       research pipeline. HBM’s portfolio includes       University for discovery research into mRNA-
     of Surgical Oncology at University Hospitals       five clinical-stage, in-licensed compounds        based pulmonary therapeutic candidates.
     Cleveland Medical Center and director of sur-      and drugs generated by its internal discov-       Under terms of the deal, the Yale University
     gical services at UH Seidman Cancer Center,        ery efforts, as well as co-discovery/develop-     team will perform discovery research on tar-
     is the lead researcher on the project. “My lab     ment collaborations with academic institu-        gets related to pulmonary diseases and pres-
     studies the harsh, nutrient-deprived micro-        tions and biopharmaceutical companies.            ent therapeutic candidates to CureVac for
     environment of pancreatic cancer to exploit        Jazz Pharmaceuticals acquires Cavion              preclinical and subsequent clinical develop-
     metabolic vulnerabilities,” he said. “By spe-      Jazz Pharmaceuticals Inc. announced the           ment. CureVac will provide all funding for the
     cifically targeting these hypoxic pathways in      acquisition of Cavion Inc. last month through     discovery research and retains the option to
     a multifaceted approach, we can shut down          a merger with a Jazz subsidiary. Under the        acquire any rights regarding the candidates.
     tumor progression. I see our work with Geni-       terms of the agreement, the former Cavion                                         — Wire reports

14    APPLIED CLINICAL TRIALS                                                                              September 2019

                                                      CLINICA L TRIA L INSIG HTS

     PROLIFERATION OF RARE                                (MEANS PER                             NO. OF         NO. OF             PATIENTS
     DISEASE R&D NECESSITATING                            CLINICAL TRIAL)                        SITES          PATIENTS           PER SITE
                                                          Phase I Rare Diseases                  6              31                 5
     Interest in benchmark data on the                    Phase I Non-Rare Diseases              1              20                 20
     scope, performance, and economics
     of these efforts has grown                           Phase II Rare Diseases                 14             107                8
                                                          Phase II Non-Rare Diseases             27             268                10
     Ken Getz
                                                          Phase III Rare Diseases                42             524                13
                                                          Phase III Non-Rare Diseases            65             3,434              62
     Nearly every week, the Tufts Center for the
                                                          Source: Tufts CSDD
     Study of Drug Development (Tufts CSDD)
     receives a request for benchmark data                Table 1. Comparing the average enrollment for rare and non-rare
     on rare disease drug development perfor-             disease clinical trials during the 2014 to 2018 time period.
     mance and economics. These benchmarks
     have been hard to come by, as a large per-         Recent Tufts CSDD research suggests that       Clinical trial challenges
     centage of companies active in this space          rare disease drug development presents         and their Impact
     are privately held. Sponsor companies and          scientific and operational challenges that     Sponsor-company investment in R&D for
     contract research organizations (CROs)             will necessitate — and perhaps acceler-        rare diseases has seen substantial growth
     have been looking for this benchmark data          ate—the adoption of novel and less tradi-      in global, FDA-regulated Phase I-III clinical
     to guide portfolio and development project         tional clinical development strategies, op-    trial activity. In total, between 2014 and
     planning and optimization. Tufts CSDD has          erating practices, and solutions. Consider     2018, there have been more than 4,000
     compiled some useful benchmarks.                   a few key findings:                            FDA-regulated clinical trials initiated world-
        At the present time, rare disease drug                                                         wide for rare disease treatments. In 2018
                                                        • The average direct cost to conduct
     development is one of the most active and                                                         alone, there were 372 new Phase I clinical
                                                          a Phase III pivotal trial of an
     fastest growing areas in drug R&D. Rare                                                           trial starts; 422 new Phase II clinical trial
                                                          investigational rare disease treatment
     diseases are defined as medical conditions                                                        starts; and 148 new Phase III clinical trial
                                                          is approximately half that of
     that affect 200,000 or fewer people in the                                                        starts.
                                                          investigational treatments for non-rare
     U.S. or fewer than five people per 10,000                                                             The vast majority (84%) of active stud-
                                                          diseases ($103 million vs. $193 million).
     population in the European Union. In 2018,                                                        ies on rare diseases are currently in early-
     approximately one-third (31%) of all prod-         • Although clinical trials for rare disease    stage clinical development. But sustained
     ucts in the global R&D pipeline targeted             drugs recruit fewer patients, clinical       long-term pharmaceutical company in-
     treatments for rare disease indications.             phase through approval durations             vestment in rare diseases is driving up the
     This is up from 15% only 10 years ago. And           for rare disease drug development            volume of later-stage clinical trial activ-
     nearly six-out-of-10 (58%) drug and biologic         take, on average, four years longer          ity. New clinical trials initiated for Phase II
     approvals in 2018 were for rare diseases;            than those for non-rare diseases             and III clinical trials are increasing at three
     up from 26% in 2008.                                 due to site and patient recruitment          times the rate as those for Phase I trials
        Biopharmaceutic al companies have                 and retention challenges.                    (12% vs. 4%).
     substantially increased R&D investment                                                               Pharmaceutical companies and CROs
     in rare diseases, not only to meet unmet              What follows are benchmarks that Tufts      have noted the unprecedented challenges
     medical needs, but also to support devel-          CSDD —and others— have been compil-            they face in finding clinical research pro-
     opment programs at lower relative cost,            ing. We analyzed data on 4,562 clinical        fessionals with expertise and experience
     with fewer competitors, strong demand              trials for all rare disease medicines in ac-   in specific rare diseases and in identifying
     from patient advocates, and greater op-            tive FDA-regulated clinical trials worldwide   and enrolling patients who are managing
     portunities for favorable pricing. This latter     between 2014 and 2018. This data was           and living with specific rare diseases. To
     expectation in particular appears aspira-          gathered from the       address these challenges, sponsors and
     tional given current public perceptions and        website. Data on the economics of rare         CROs have typically engaged a much larger
     the political climate.                             disease drug development comes from            relative number of clinical investigators in
        As more data is gathered characterizing         EvaluatePharma. The author thanks Beth         early-stage clinical trials to each enroll a
     the scope, performance, and economics              Harper (Clinical Performance Par tners)        smaller number of patients. To put this into
     of rare disease drug development, the op-          for her input and assistance on analyzing      perspective and characterize the magnitude
     portunity for pharmaceutical and biotech-          rare disease clinical trial recruitment and    of this challenge during the 2014 – 2018
     nology companies appears more nuanced.             retention rates.                               timeframe (see table above):

16    APPLIED CLINICAL TRIALS                                                                         September 2019

                                                     CLINICA L TRIA L INSIG HTS

   • For Phase I clinical trials of rare diseases,    class observed during the 2014-2018 pe-          Analysts and observers anticipate that
     sponsors and CROs engaged, on average,           riod: for example, they were 41% longer for   sponsor company reliance on data and
     six times the number of investigative            all cancer-related diseases; 79% longer for   sophisticated analy tics to identif y rare
     sites to recruit one quarter of the              all endocrine diseases; and 64% longer for    disease-focused investigators and eligi-
     number of patients per study, compared           CNS diseases.                                 ble patients will intensify. The adoption
     with those for non-rare diseases.                   Given unmet medical need, regulatory       of patient-centric approaches is also ex-
                                                      review durations are four months faster,      pected to accelerate. Sponsors and CROs
   • For Phase II and III clinical trials of rare
                                                      on average, for rare disease drug applica-    will increasingly look to virtual (direct-to-
     diseases, sponsors and CROs engaged
                                                      tions, compared to review time for non-       patient) and hybrid (investigative site with
     half to 60% of the average total number
     of investigative sites, respectively, to
     enroll as few as 15% of the total average
     number of study volunteers per trial.               Analysts and observers anticipate that sponsor
      The challenges associated with rare dis-
                                                         company reliance on data and sophisticated
   ease patient recruitment and retention                analytics to identify rare disease-focused
   are even clearer in the substantially higher
   observed screen and randomization failure
                                                         investigators and eligible patients will intensify.
   rates relative to those rates for non-rare
   diseases. Eight-out-of-10 (81%) patients
   screened for clinical trials for rare diseases
                                                      rare diseases across all therapeutic areas.   intermittent direct-to-patient) models and
   are not eligible to enroll, compared to 57%
                                                      Submission to approval decisions for rare     convenience-enhancing approaches (e.g.,
   screen failure rates for non-rare diseases
                                                      disease drug applications are 47% faster in   home nursing, telemedicine, wearable and
   (all therapeutic areas). More than half (56%)
                                                      CNS diseases; 30% faster in endocrine dis-    mobile devices, and patient assistance
   of rare disease study volunteers fail to be
                                                      eases; and 10% in cancer-related illnesses.   programs) to bring clinical trials to wher-
   randomized, compared to 36% randomiza-
                                                                                                    ever it is easiest and the most efficient for
   tion failure rates for non-rare diseases.         Responding to a new
                                                                                                    study volunteers to participate. Observers
       But once rare disease patients have           risk-return profile
                                                                                                    and analysts also expect sponsor and CRO
   enrolled in a clinical trial, they’re far less    The high proportion of rare diseases in
                                                                                                    demand for clinical trials embedded within
   likely to drop out. The premature termina-        R&D and the growing number achieving
                                                                                                    clinical care settings to increase, as will
   tion rate —associated with all causes—            commercialization will necessitate the
                                                                                                    demand for real-world data and evidence
   of rare disease patients randomized for           adoption of new clinical development
                                                                                                    to supplement, and even replace, tradi-
   clinical trials is 14%, compared to 21% for       models to accelerate timelines and drive
                                                                                                    tional clinical research data.
   those in non-rare disease clinical trials.        greater efficiency. Very small relative mar-
                                                                                                       And at Tufts CSDD, we can expect a
                                                     kets and long relative development dura-
                                                                                                    growing number of inquiries into base-
   Drug development and                              tions challenge the traditional risk-return
                                                                                                    line and benchmark data on the impact
   approval durations                                profile for new drug therapies.
                                                                                                    of these approaches on rare disease drug
   Major difficulties finding and engaging in-          Worldwide, in 2018 an estimated 3,500
                                                                                                    development performance and economics.
   vestigative sites and identifying and enroll-     small and large molecules targeting rare
   ing study volunteers in rare disease clinical     diseases were active in R&D. This is more
   trials adds considerable time and delays          than double the level observed 10 years
   recouping development investment. Over-           ago. And during the past 25 years, there
   all development durations (i.e., IND filing       has been a six-fold increase in the num-
   to regulatory decision) for rare disease ap-      ber of orphan designations granted by the
   plications are four years longer than for all     FDA—growing from 301 designations in
   other disease segments.                           the four-year timeframe between 1994 to
      Between 2014 and 2018, clinical dura-          1998 to 1,800 designations in the 2014 to      — Ken Getz, MBA, is the
   tions—overall Phase I-III cycle time—for          2018 period. As the volume of designations       Director of Sponsored
   rare disease investigational drugs took 131       has increased, so too has the absolute            Research at the Tufts
   months, on average. This was 68% lon-             number of approvals: The total number of           CSDD and Chairman
   ger than the average 78 months for all            orphan drug approvals increased from 84          of CISCRP, both based
   non-rare diseases. Rare disease clinical          in the 1994 to 1998 timeframe to 316 in the       in Boston, MA. email:
   durations are longer in every therapeutic         2014 to 2018 period.                 

September 2019                                                                   APPLIED CLINICAL TRIALS   17
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