Peer reviewed   Daniel Manak | Jae Chung, MBA, CPA | Sherry Reuter, BSN, MSHS                                             ...
The work begins with site identification,            factored heavily in study delays, with                  they  can  be...
Figure 2 Factors Most Often Causing Study Delays (n=950)                                                   it  should  foc...
●● Time to completion of case report         widely being adopted by sponsors and              on  a  permissioned  basis,...
across multiple product and therapeu-             table 1 Sampling of Electronic Submissionstic lines.                    ...
the  content  of  electronic  records  on     Acknowledgment                                              12.  European Me...
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Study Startup 2.0- Reinventing How Clinical Trials Are Begun


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Are you starting a clinical trial or about to start one? If so, read this article first published in the June 2011 issue of the peer-reviewed journal ,The Monitor. The article discusses challenges in how trials are started today and explore a new wave of cloud-based technologies, which will forever reshape how studies are started around the world.

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Study Startup 2.0- Reinventing How Clinical Trials Are Begun

  1. 1. Peer reviewed Daniel Manak | Jae Chung, MBA, CPA | Sherry Reuter, BSN, MSHS S o l u t i o n S - B a S e d Study Startup 2.0 Reinventing How Clinical Trials Begin t e c h n o l o g y A nyone who has ever participated in clinical study startup for drugs,  devices, or biologics knows that it is a tedious, labor-intensive, and  frustrating process that often fails to meet timelines.1 Methods used to com- plete startup tasks remain largely paper-based and are often inefficient and  slow.2,3 This scenario leaves much room for improvement, and this article ex-This article explores plores  state-of-the-art  approaches  to  bringing  about  the  desired  goal  of  completing startup tasks more efficiently, reducing the number of clinical state-of-the-art trials that do not complete on time and within budget. Specifically, the fo- cus here is on best practices and new technologies for streamlining startup approaches to bringing processes. The technologies are based on cloud computing, a dynamically about the desired goal scalable method of providing software to the end-user from a web-based  server to deliver applications on demand.of completing startup Utilizing shared virtualized resources, these user-friendly programs can  simplify document exchange and decrease repetitive tasks while provid-tasks more efficiently, ing up-to-the minute transparency to all stakeholders involved in startup.  Sponsor-site relations improve, leading to greater buy-in by sites and con-reducing the number of tract research organizations (CROs) and greater motivation to perform. The  sponsor that is functioning in a financially and time-squeezed environment clinical trials that do not may  realize  dramatic  time  and  cost  savings  as  tasks  are  completed  and complete on time and tracked in an organized and simplified manner, allowing studies to proceed  on schedule.within budget. Startup 1.0: The Process Clinical study startup is the multistep practice of selecting and preparing  investigative sites for initiation. It is a collaboration of stakeholders: spon- sor,  CRO,  site,  institutional  review  board  (IRB)  or  ethics  committee  (EC),  and a variety of outsourced providers. It consists of exchanging numerous  documents, communication, and budget and contract negotiations, which  involve: ●● Distribution, collection, and evaluation of pretrial questionnaire  ●● Regulatory document completion and IRB/EC approval ●● Negotiation of contracts and budgets ●● Scheduling and performing site evaluation visits ●● Conducting investigator meetings/site training ●● Provision of supplies and test article Peer reviewed    33 x
  2. 2. The work begins with site identification,  factored heavily in study delays, with  they  can  be  found,  and  what  types an  increasingly  global  function,  and  contract and budget negotiation cited  of sites will be able to access, recruit, continues  until  all  selected  sites  are  as the most frequent cause at 49%, fol- and enroll them. An ideal site profile initiated. lowed by patient recruitment and other  should be used in accordance with the  Each component of startup has sev- routine tasks (see Figure 2).4 Research  protocol to guide every step of site se-eral steps, often tracked using multiple  suggests  that  sponsors  stand  to  lose  lection; otherwise, sites are likely to be spreadsheets created and accessed by  between $600,000 and $8 million each  chosen that will not perform well.various partners. Generally, these cre- day product development is stalled;5 so  Next, the sponsor or CRO compiles ate inefficiencies because the methods  startup processes that drag on cut into  a  list  of  potential  sites  that  meet  the are not standardized across functions  the bottom line in a very direct way. unique criteria defined in the ideal site or centralized for easy access; so they  There  is  a  lot  at  stake  in  startup,  profile, perhaps beginning by identify-tend to be reinvented for each study.  which is why continuing with the sta- ing sites with which they have previ-A view of startup appears in Figure 1.  tus  quo  is  not  a  sustainable  business  ous experience. Other sources of sites The  figure  is  not  meant  to  be  inclu- practice. A better option is to employ  include  online  directories,  referrals sive  of  all  guidelines  from  the  Inter- standards and process changes for site  from trusted sources, social network-national Conference on Harmonization  selection,  complemented  by  technol- ing sites, site networks, site manage-(ICH), but can serve as a framework for  ogy  to  bring  about  startup  improve- ment organizations, and physician lists understanding startup complexity. ments that will extend into other stages  (typically  by  specialty)  from  profes- Given the nature of the startup pro- of  development.6  Some  technologies  sional medical associations. Additional cess, it is not surprising that the cur- designed  for  startup  use  cloud  com- site selection tips include:rent system breeds delays. A LinkedIn  puting, which is described in Figure 3. study  conducted  in  2010  questioned  ●● developing a customized pretrial 205  clinical  trial  professionals  about  questionnaire based on charac- Improving the Processtheir views of the startup process;3 41%  teristics of the ideal site; responded that it was “lengthy, manual,  A critical element of startup is site se- ●● reviewing responses to the ques-and  inefficient,”  while  30%  reported  lection.  Finding  reliable,  performing  tionnaires; andthat it was “OK, but could use improve- sites  begins  with  sponsors  and  CROs  ●● performing site evaluation visits, ment.” In a 2009 CenterWatch survey  developing  a  detailed  plan  to  define  focusing on the principal inves-of investigative sites, startup activities  the  target  patient  population,  where  tigator’s (PI’s) interest in the  Figure 1 The Complex Process of Clinical Study Startup Study offered Initial contact YES Site review of pretrial YES to PI Confidentiality Perform Start regulatory by pharma, biotech, questionnaire and agreement prestudy visit Accepted document collection or device sponsor protocol requirements NO NO • PI declines study PI not interested PI not interested • Sponsor does not select PI/site Budget Budget and Contracts Final; negotiations may need final contracts to submit to IRB/EC Contract Submit to IRB/EC: negotiations • IRB/EC application • CVs/Licenses of personnel • Protocol Approval IRB/EC • Informed consent form with site information submission prep • HIPAA authorization (U.S.) Regulatory • Final contracts (country dependent) documents complete Submit to regulatory agency(s) Site Regulatory/Good Clinical evaluation • FDA Form 1572 Practices document prep visit and/or • Curriculum vitae, medical license of PI • Financial disclosure (U.S. and EU if necessary) investigator meeting x34    Monitor June 2011 
  3. 3. Figure 2 Factors Most Often Causing Study Delays (n=950) it  should  focus  on  honest  discussion  about the targeted population and the  49% site’s ability to recruit and perform the  trial successfully. 41% Statistics indicate that the industry  continues to do a poor job with recruit- ment,  as  evidenced  by  these  dismal  26% 26% facts: 25% ●● 70% of investigative sites are  more than one month behind  in enrollment, and only 7% of  sites report meeting enrollment  timelines.4 Contract and Patient Protocol design Legal review IRB review and ●● A major pharmaceutical com- budget negotiation recruitment and and refinement approval pany reported that between 2000  and approval enrollment and 2006, 26% of sites recruited  80% of participants; 11% of sites Source: CenterWatch Survey of Investigative Sites in the U.S. (2009) recruited one subject; and for  oncology studies, 37% of sites  recruited no subjects.8 study and realistic assessment  tionnaire.  When  there  is  little  scru- of the site’s ability to conduct it  tiny  of  what  is  written  on  the  ques- Recent research highlights the sav- successfully. tionnaire, the phenomenon known as  ings that can be realized by planning  Lasagna’s  Law  comes  into  play;  this  and implementing improved processes  Unfortunately,  all  too  often  sites  law captures the notion that investiga- for  this  basic  clinical  trial  activity.9 are  chosen  that  lack  the  ability  and/ tive sites frequently overestimate the  The  research  makes  the  assumption or motivation to conduct the trial suc- number of subjects they will be able  that  if  65,000  investigator  sites  are cessfully.  This  happens  for  several  to  enroll.7  Second,  there  is  often  in- initiated annually, and the cost of ini-reasons. First, timelines are almost al- adequate communication between the  tiating each one were $20,000, even a ways extremely short, so there is rarely  sponsor and the PI as to the types of  1% reduction in nonperforming sites time to properly identify sites beyond  challenges he or she foresees with the  would save the industry $13 million. a cursory review of the pretrial ques- protocol. Third, the site evaluation vis- By  identifying  nonperforming  sites,  fewer sites would be needed, and more  subjects would be enrolled at each of  Figure 3 What is Cloud Computing? the remaining sites. A  few  words  about  metrics  are  in  Cloud computing refers to a web-based method of providing software to the end-user, order. Sponsors and CROs charged with  similar to the way consumers access applications or “apps” on their BlackBerries, site selection should keep metrics such  iPhones, or Droids. Desired applications are delivered on demand from a web-based as the following on site performance,  server with shared virtualized resources. With this format, cloud computing enables the ramping up or scaling down of computing resources as workload dictates. because they can offer an indication of  site potential: Importantly, with cloud computing, there is no need for local software installation by either the client or end-user. The only requirement is a device with a web browser and ●● Time to screening of first subject an Internet connection, meaning that the desired software can be used from virtually ●● Number of subjects enrolled  anywhere. compared to the number the site  This setup provides an important cost-saving advantage, because with technology forecasted changing at warp speed, users can immediately access the latest functionality without ●● Number of subjects completed purchasing additional hardware or having to update older software applications. Neither ●● Reasons for subjects withdrawing  is there a need for onsite training for users or support. Support is provided by the software provider, and user interfaces are intuitive. Technical support is provided by the from the study software provider, but typically tips and tricks, wizards, and training videos are embed- ●● Number of protocol deviations or  ded within the software itself. violations ●● Accurate document turnaround Source: times Peer reviewed    35 x
  4. 4. ●● Time to completion of case report  widely being adopted by sponsors and  on  a  permissioned  basis,  providing  forms (CRFs) CROs for other aspects of clinical trial  a  visible  measure  of  performance.  ●● Number of data queries management do not necessarily focus  This information enables the team to  on  startup,  either.  A  broad  review  of  quickly identify sources of slowdowns  The evaluation of sponsor and CRO  market solutions is beyond the scope  or other issues needing attention.performance in startup is as important  of this article, but a cloud computing  The  cloud-based  startup  functions as  the  evaluation  of  site  metrics.  For  platform is discussed as a compelling  include:example, a site is not responsible for a  alternative.delay caused by the turnaround time a  ●● streamlining the startup work-sponsor takes with documents such as  flow to save time and money; Applying the Cloud to Startupcontracts or budgets. ●● collaborating with internal and  Successful  startup  relies  on  highly  external partners from a single  organized  project  management  pro- dashboard;Technology and Startup cesses  and  the  ability  to  quickly  ●● optimizing the organization and Bringing  new  technology  to  startup  exchange  documents  among  stake- exchange of documents with can  be  an  important  complement  to  holders. A cloud-based system enables  security;improving the current way startup is  fast  and  secure  document  exchange  ●● maintaining version control of  documents; The evaluation of sponsor and CRO performance in ●● providing real-time and trans- parent startup status to the entire  startup is as important as the evaluation of site metrics. study team; ●● being audit ready; andconducted.  As  electronic  data  cap- and generates an audit trail. The sys- ●● utilizing valuable metrics gath-ture (EDC) and clinical trial manage- tem can be configured to generate real- ered for post-study analysis and ment system (CTMS) products, which  time reports and status alerts and bring  future planning.manage  operational  and  administra- them  to  the  attention  of  the  correct tive clinical trial activities, have been  team members regarding the next step  The importance of this technology adopted,  new  technological  options  in the process. There is also a level of  extends beyond its ability to improve are needed to optimize startup opera- transparency in the cloud that cannot  and accelerate a single trial. Investing tions. Continuing to cling to paper or  be realized otherwise; that is, through- in organization and improved method-spreadsheets  is  not  likely  to  achieve  out the startup process, all members of  ology  can  have  a  positive  impact  on the kinds of improvements needed to  the study team can track and evaluate  current  as  well  as  future  trial  opera-conform  to  increasingly  compressed  processes  and  tasks  instantaneously,  tions,  and  this  benefit  can  extend timelines or facilitate the exchange of documents. The LinkedIn survey referred to ear- Figure 4 Managing Startup Activities (n=205)lier  revealed  that  more  than  53%  of respondents  were  using  Excel  spread- 53.2%sheets  to  track  their  startup  progress, and 6% were using paper (see Figure 4).3  Spreadsheets  may  be  standalone or  part  of  a  patchwork  solution  with a  database,  reporting  software,  and possibly  a  webportal  platform.  These homegrown efforts often require a lev-el of information technology support  15.6% 13.6%that  is  beyond  the  capacity  of  many  11.2%in-house resources. As a result, com- 6.3%panies  may  struggle  to  keep  up  with the latest updates, and may be unable  Excel Sharepoint Internal Third-party Paper-basedto establish and staff a Help Desk. Ad- homegrown solutionditionally, these systems rarely address  softwarethe  specific  needs  of  startup.  Simi-larly,  off-the-shelf  solutions  that  are  Source: LinkedIn Survey 2010 x36    Monitor June 2011 
  5. 5. across multiple product and therapeu- table 1 Sampling of Electronic Submissionstic lines. FDA EMA Ultimately,  a  well-designed  cloud-based  system  will  wield  a  so-called  Electronic Common 1/1/2008 – all electronic 1/1/2010 – all electronic Technical Document submissions to Center for submissions must use eCTD“network  effect”—a  term  borrowed  (eCTD) Drug Evaluation and Research for Centralized Procedurefrom  adoption  of  the  telephone  and,  (CDER) must use eCTDmore  recently,  from  social  network- PIM Labeling Standard N/A Timeline for going live foring. A network effect refers to the fact  Centralized Procedure to bethat a technological tool becomes more  determined; PIM is in pilotvaluable  as  more  people  use  it.10  For  modeexample, smartphones are increasingly  Structured Product 10/31/2005 – all labeling N/Avalued  as  more  people  use  them  and  Labeling (SPL) submission must be in SPLrely  on  them  for  an  ever-expanding  formatrange of functionality. If one considers  Source: FDA, EMAwhere the cellphone was 20 years ago and  where  the  smartphone  is  today,  As  shown  in  Table  1,  some  of  the  to comply with FDA-based 21 Code ofthe technology has advanced beyond  submissions leaning toward or requir- Federal Regulations (CFR) Part 11, the making phone calls. Various uses are  ing  electronic  formatting  include  the  Electronic  Records;  Electronic  Signa-widespread, including texting, online  electronic  common  technical  docu- tures rule.17 According to the rule, elec-banking,  travel  planning,  shopping,  ment,11,12 the Structured Product Label- tronic  records  and  electronic  signa-e-mailing,  and,  in  the  near  future,  ing standard in the U.S.,13 and the Prod- tures can, under specified conditions, clinical trial management. This range  uct  Information  Management  (PIM)  be accepted as their paper equivalent.of  functionality  establishes  a  virtual  labeling  standard  in  pilot-mode  in  Electronic records can be created in community.  Applying  this  methodol- Europe.14,15 Also, in 2006, FDA opened  “closed” or “open” systems. As defined ogy  to  startup,  as  more  stakeholders  the  Electronic  Submissions  Gateway  in  the  rule,  a  closed  system  refers  to adopt  cloud-based  technology,  will  (ESG), a central transmission point for  an  environment  in  which  systems inch  it  toward  becoming  the  norm,  sending  information  electronically  to  access  is  controlled  by  persons  who creating an even larger base of users  its final destination within the agency.  are responsible for the content of elec-as they join the bandwagon. Currently, ESG is migrating to a new  tronic records on the system. An open  data center.16 system  refers  to  an  environment  in  A cloud-based system A second driver toward the cloud is  which system access is not controlled  the fact that solutions can be designed  by  persons  who  are  responsible  for  enables fast and secure document exchange and table 2 Challenges of Cloud Computing for Sites Challenge Mitigation Strategy generates an audit trail. Provide reliable service Design for reliability and build in backup Sites using cloud computing cannot Systems must either be up or covered by backup afford to have interruptions in their systems at all times (industry standard = 99.9%Drivers Toward the Cloud service—ever uptime)For stakeholders still uncertain about  • Ensure automatic nightly backups that are encryptedtaking that first step toward the cloud,  • Redundant power systems for backup powerthere  are  several  key  drivers  pushing  supplythe market in that direction. First, reg- Security Utilize equipment and systems designed forulatory agencies, such as the U.S. Food  Sites have zero tolerance for maximum securityand Drug Administration (FDA) and the  unauthorized access of user data; Secure data centers with 24-hour manned secu-European  Medicines  Agency  (EMA),  data must be safe, backed up, and rity, video surveillance, and buildings engineeredhave started requiring electronic sub- recoverable at all times for local seismic, storm, and flood risksmissions using highly structured for- Interoperability with other systems Interoperability is possible through file format,mats, so they can be transmitted over  It is common for sites to have multi- data sharing, and data integrationthe  Internet  and  read  electronically.  ple systems to run an entire process; File format for study startup data should be for-The goal of these initiatives is to reduce  data must be able to be easily shared matted in XML, which can be generated from anypaper, improve data quality, cut costs,  across multiple systems number of source applications and received andand speed review of information. processed by CTMS and EDC products Peer reviewed    37 x
  6. 6. the  content  of  electronic  records  on  Acknowledgment 12.  European Medicines Agency. December 2008. the system. In this instance, document  EMEA implementation of electronic-only sub- The authors wish to acknowledge Ann  missions and mandatory eCTD submissions in encryption and use of appropriate digi- Neuer of Medical deScriptions, Gen Li,  the Centralised Procedure: Statement of Intent. tal signature standards are required to  Available at PhD, MBA, and Peter DiBiaso, MHSA, ensure  record  authenticity,  integrity,  /document_library/Regulatory_and_procedural  for providing assistance in editing the and confidentiality. Both systems must  _guideline/2009/10/WC500004098.pdf,  manuscript,  and  Lata  Gupta  for  con- accessed February 16, 2011.have appropriate backup, validation of  tributing to the research. 13.  Draft  Guidance  for  Industry  and  Reviewers systems  to  ensure  accuracy  and  reli- on Structured Product Labeling Standard for ability, as well as other controls. The  Content of Labeling Technical Questions and ability  to  use  electronic  records  and  References Answers, Revision; Availability. Federal Regis-signatures in compliance with 21 CFR    1. Panzitta  D.  2010.  Avoiding  the  five  com- ter, October 28, 2009. Available at www.federalPart 11 is essential to spur acceptance  mon  mistakes  at  study  startup.  Applied of cloud-based systems. Clinical Trials  July  27;  available  at  http:// /draft-guidance-for-industry-and-reviewers  -on-structured-product-labeling-standard  Sites implementing cloud comput-  -for-content-of, accessed February 16, 2011. ing will face challenges typical of any  /appliedclinicaltrials/Articles/Avoiding-the  14.  European  Medicines  Agency.  2010.  Update  -5-Common-Mistakes-at-Study-Startup technology adoption, such as connec- report on the Agency’s implementation of EU  /ArticleStandard/Article/detail/680437?ref tivity issues across the globe, firewalls,  =25, accessed February 16, 2011.  Telematics strategy. Management Board Meet-and training. Table 2 describes some of  ing,  16  December  2010.  Available  at  www   2. Farfel G, Neuer A. 2009. Faster Study Start-Up the  challenges  unique  to  cloud  com- and Reduced Costs through the Use of Clini- _library/Report/2010/12/WC500100176.pdf, puting, with special emphasis on site  cal Document Exchange Portals. White Paper,  accessed February 16, 2011. concerns. available  at  www.pharmaceutical-business 15.  EU Telematics. PIM. General Frequently Asked  Questions. Available at http://pim.ema.europa =2025&code=qosnVwdwCOn91B96tym3OA4 .eu/faq.htm#faq9, accessed February 16, 2011. Get Ready for Startup 2.0 8Hps%253d, accessed February 16, 2011. 16. U.S. Food and Drug Administration. Elec-   3. LinkedIn online research study. July 10, 2010.  tronic  Submissions  Gateway,  February  2, Site managers and study coordinators  Contact Dan Manak at  2011. Available at  on  the  front  lines  in  the  ongo- for more information. /ElectronicSubmissionsGateway/default.htm, ing  struggle  to  develop  important    4. CenterWatch Survey of Investigative Sites in  accessed February 16, 2011. the U.S., 2009. new therapies in the safest and most  17. U.S. Food and Drug Administration. 21 Code   5. Cutting Edge Information. 2004. Accelerating  of Federal Regulations Part 11, available at efficient  manner  possible.  Tradi- clinical  trials:  budgets,  patient  recruitment, tional  startup  tools  have  proven  to  and productivity. Proprietary report, available  /cfcfr/cfrsearch.cfm?cfrpart=11, accessed Feb-be inadequate in this quest as stud- at ruary 16, 2011. ies increase in size, complexity, and  /news_0337.htm, accessed March 7, 2011.    6. Fee R. 2007. The cost of clinical trials. Drugscale  across  the  globe.  What  are  Discovery & Development March 1(10): 32.  Daniel Manak is senior director of business develop-needed  are  cutting-edge  solutions    7.  Spilker B, Cramer JA. 1992. Patient Recruit- ment at goBalto. He has worked in pharmaceuticals, health-that will enable end-users to perform  ment in Clinical Trials. New York: Raven Press.  care, and clinical research for more than 20 years. For thisthe array of startup tasks quickly and    8.  Gidron M. 2007. Cultivating clinical investiga- article, he provided oversight of collaborators, as well asaccurately. tors a challenge for Pfizer. Clinical Trials Advi- substantial contributions to research, design, and drafting With the help of processes linked to  sor  12:  3-4;  available  at and revising text, and gave final approval of the version to /ext/files/CTA.pdf, accessed February 15, 2011.  be published. He can be reached at site selection, the availabil-   9. Li G. 2008. Site activation: the key to more ity  of  cloud-based  technology,  and  efficient  clinical  trials.,  Jae Chung, MBA, CPA, is the founder and CeOthe resulting network effect, there is  December 12; available at http://pharmexec of goBalto. Previously, he cofounded Celltrion, a leadingthe  potential  to  dramatically  affect  biopharmaceutical supplier. For this article, he provided Detail.jsp?id=571374&pageID=3,  accessed  substantial contributions to concept development, contrib-the cost and timelines for clinical trial  January 11, 2011.  uted to the drafting and revision of the text, and gave finalconduct.  As  the  next  generation  of  approval of the version to be published. He can be reached 10.  Cox R, Larsen PT. 2010. Facebook’s power, and tech-savvy  workers  enters  the  clini- its weakness. The New York Times, May 27;  at trials workforce, they will expect  available  at Sherry Reuter, BSN, MSHS, has more than 17automation of tasks, similar to what  /business/27views.html, accessed February 15,  years of diverse experience in the clinical research industry,has become standard practice in other  2011. having held positions in pharmaceutical and biotechnol-industries.  With  the  right  tools,  the  11.  U.S.  Food  and  Drug  Administration.  2009.  ogy firms, CrOs, and academia. She now is president of eCTD Submission Waivers, June 18; available  Sherry reuter & Associates, LLC, a consulting companyclinical research industry is poised to  at in the pharmaceutical arena. For this article, she providedreap the same benefits other industries  Process/FormsSubmissionRequirements/  substantial contributions to research, design, and draftinghave  realized  from  optimizing  their  ElectronicSubmissions/ucm163186.htm,  and revising the text, and gave final approval of the versionprocesses.  accessed February 16, 2011.  to be published. She can be reached at x38    Monitor June 2011