PHT Insights — Fourth Quarter 2009                                                Inspectors and Auditors Require Comprehe...
2PHT Insights – Second Quarter 2009Inspectors and Auditors Require Comprehensive ePRO ArchivesInterview with Nancy Carlson...
3PHT Insights – Second Quarter 2009Inspectors and Auditors Require Comprehensive ePRO Archives                            ...
4PHT Insights – Second Quarter 2009Inspectors and Auditors Require Comprehensive ePRO ArchivesRecent FDA Warning Letters…a...
5PHT Insights – Fourth Quarter 2009Inspectors and Auditors Require Comprehensive ePRO ArchivesInterview with Steve Raymond...
6Need More Detailed PHT Archive Information?Contact your PHTAccount Executive formore comprehensiveinformationValue of eSi...
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ePRO Archives

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Sponsors and regulators rely on the ePRO archive to prove that trial data are attributable and accurate; and that the trial can be reconstructed at any time. Any omissions can risk regulatory warnings, findings and possible data rejection. This issue describes the PTH ePRO Archive, and explains how and why it exceeds regulatory requirements and industry guidelines.

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ePRO Archives

  1. 1. PHT Insights — Fourth Quarter 2009 Inspectors and Auditors Require Comprehensive ePRO ArchivesWhy the PHT ePRO Archive The PHT ePRO Archive: Sophisticated TechnologyRemains the Standard By definition, the PHT Study Archive is a stable record, not a live system. It was developed by scientists trained at MIT and Stanford with assistanceand 100% Successful from former FDA staff members, and is protected by several US Government patents: 5,778,882; 6,095,985; 6,282,441; 6,440,069; 6,640, 134.Sponsors and regulators rely on their trial archive PHT Archive components include:to prove that trial data are attributable and accurate;and that the trial can be reconstructed at any • READ ME FIRST • Media Specificationtime. Any omissions can risk regulatory warnings, • Roadmap • Trial Documentationfindings and possible data rejection. • Archive Certification Letter • Electronic Case Report Forms • Archive Certification Report • XML Data filesAll PHT products meet the requirements of • Archive Orientation Letter • Metadata filesregulatory agencies including the United States • Security and Privacy Provisions • Adobe Acrobat ApplicationFood and Drug Administration (FDA), the European for Sponsors • Metadata ViewerMedicines Agency (EMEA), the European Union (EU), • PHT Systems and the Record • SAS Viewer (as needed)the International Conference on Harmonisation of Keeping Requirements UnderTechnical Requirements for Registration of 21CFR312.62Pharmaceuticals for Human Use (ICH) and thePharmaceuticals and Medical Devices Agencyin Japan (PMDA). The PHT ePRO ArchiveThis issue describes the PHT ePRO Archive andexplains how and why it exceeds regulatory READ ME FIRSTrequirements and industry guidelines. Trial Document Support Trial Data Archive Tools Archive Contents Pre-Deployment Documents SAS Viewer Requirements & Other Meta Data Viewer eCRFs The PHT ePRO Archive Contents p.1 Specifications • LogPad Requirements Adobe Acrobat Reader 5.0 XML Data How the PHT Archive Enables Full Trial p.2 • Specification Metadata Reconstruction Trial System Validation Documents PHT Experience with Site Investigations p.3 • Validation Plan The Study Important Forms & Lists eClinical Trial Data New FDA Guidance for Investigators p.3 • Electronic Signature Archive (raw data on server) • Agreements Clinical: Subject diaries How the PHT Archive Would Have Prevented p.4 User Documentation is a stable Operational: Battery level/ Recent FDA Warning Letters • LP Quick Reference time zones Guide record, How PHT Helps Sites Fulfill Their Regulatory p.5 • Site Manual Administration: Users, Responsibilities Post Deployment not a live roles privileges Documents Metadata: Definition of data Should You Purchase FDA Guidance p.5 • Data Change Authorizations system. Documents? • Final Data Transfer More PHT Archive Details p.6
  2. 2. 2PHT Insights – Second Quarter 2009Inspectors and Auditors Require Comprehensive ePRO ArchivesInterview with Nancy CarlsonPHT Quality Documentation ManagerHow the PHT Archive Enables Full Trial Reconstruction Nancy Carlson joined PHT in 2003. Together with Richard LaFleur who was then PHT’s Director of Quality Compliance and Stephen Raymond, Ph.D, PHT’s Founder, Chief Scientific and Quality Officer, Nancy developed the standards and reporting functions for the PHT Archive which enable every sponsor and CRO to reconstruct their respective trial.What is included in the PHT Archive?The PHT Archive features a data section and a documentsection; and clearly demonstrates that the trial data collectionand preservation process was secure, approved, designed,and validated in compliance with GCP1, 21 CFR Part 112, HIPAA3,and other personal data collection rights, as affirmed in theUniversal Declaration of Human Rights – Article 12, and theConvention for the Protection of Human Rights andFundamental Freedoms – Article 8; and able to passall FDA and international regulatory inspection.What is the PHT Archive Data Section?The data section of the PHT Archive includes the eSource data What is the PHT Archive Documentation Section?collected from patients in native (XML) format, certified as a The documentation section of the PHT Archive includes all trialtrue copy of the original trial database. XML is only “human- documents and document standards, so that the Archive isreadable” format meaning that people fluent in the language able to pass all FDA and international regulatory inspection.can read it as text instead of binary code. It can be confusing to The PHT Archive includes a “…copy of original information thatthe layperson, but examples include has been verified, as indicated by dated signature, as an exact XML format English Translation copy having all of the same attributes and information as the SUChangedIn krPT= “LPPT23.12438.2” original”4 so it can be used as an aid in study reconstruction. krSU= “Assignment” What is your current role? krSE= “LogPad” krPROT= “V1” As Quality Documentation Manager, I’m responsible for ensuring the all of PHT’s policies and standard operatingThe PHT Archive includes a second data presentation - electronic procedures are documented and approved, that thoseCase Report Forms (eCRF). eCRF-formatted data are reviewable documents are reviewed on schedule and revised as needed,in the StudyWorks™ (PHT portal) forms format, with a complete and that PHT’s employees comply with those policies andaudit trial for each form/field entry. All eCRF data collected for a procedures. I continuously audit core product and trialpatient are combined in a single PDF file (readable with Acrobat documentation to assess compliance with approved procedures.Reader). Because the patient eCRF PDFs are generated from As the final reviewer of all PHT Archives immediately prior tothe certified XML, they are also a true copy the original trial shipment, I enforce the compliance standards that I created indatabase – a regulatory requirement. my prior position as Archive Project Manager.
  3. 3. 3PHT Insights – Second Quarter 2009Inspectors and Auditors Require Comprehensive ePRO Archives PHT Experience with Site InspectionsInterview with Nancy Carlson, continued PHT Quality Assurance representatives and archive specialists stand ready to help sites who face regulatory inspections. Such inspections are scheduled, and it can be valuable to siteHow quickly is an archive delivered to the sponsor or CRO? investigators (and sponsors) to have PHT consults availableThe PHT Statement of Work signed by PHT and the Sponsor or during inspections.CRO states that PHT will deliver the Archive within 90 days ofsigned (sponsor) acceptance of the final data transfer. Here are the facts: • PHT experts have been on call for more than ten site inspectionsWhy do some ePRO vendors require sponsors or CROs to since January 2008, where the PHT ePRO System had providedmaintain the server that contains their archive… and not PHT? Primary Endpoint Data in support of a NDA.It’s curious why other ePRO vendors would require sponsors • Therapeutic areas included pain, respiratory andor CROs to maintain an active server, since the study archive is sleep disorders.static, not fluid. • PHT has never been asked during any inspection to provideThe PHT Archive is delivered on DVDs for sponsors and CROs a document that is not part of the current PHT Archive.and CDs for investigator sites. The sponsor and CRO receive all Site endpoint data collection inspections are common amongtrial documentation and the data from all investigator sites. domestic and international FDA inspectors. PHT expertsEach site receives its own data only, and a subset of the trial remain available to support such inspections.documentation. All recipients are advised of the applicablerecord retention requirements, and PHT retains copies of allsponsor and CRO and investigator sites archives in a secureoff-site storage facility. New FDA Guidance for InvestigatorWARNING: If the sponsor or investigator sites have not backedup their archive onto a server and they can’t locate the media Responsibilitiescopy due to misfiling or personnel turnover, they are likely to An updated FDA Guidance entitled ‘Guidance for Industry:be out of compliance with record retention regulations. For Investigator Responsibilities — Protecting the Rights, Safety,a fee, PHT will replace lost archives, but immediate access to and Welfare of Study Subjects’ was published in Octobertrial data is delayed. 2009. This is a supplement, rather than a replacement, ofWhat changes do you anticipate within the future of clinical responsibilities found in 21 C.F.R. §312 and 21 C.F.R. §812.trial archives? This Guidance was originally released as draft in May 2007. This is the final version.Future content enhancements to the PHT Archive will mostly bedriven by expansion of the regulatory requirements for designing Full text available at http://www.fda.gov/RegulatoryInforma-the computerized systems used in clinical investigations, with tion/Guidances/ucm127697.htmongoing feedback from the FDA and PHT’s broad customer base. Two statements worth noting: • Investigators “should be particularly cautious where documentation needed to comply with the investigator’s regulatory responsibilities is developed and maintained by1 Good Clinical Practice as defined by the US FDA. http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm [site management organization (SMO)] staff (e.g., source2 US FDA, US Department of Health and Human Services, CHAPTER I--FOOD AND DRUG documents, case report forms, drug storage and account-ADMINISTRATION, TITLE 21--FOOD AND DRUGS, SUBCHAPTER A—GENERAL, PART 11 ability records, institutional review board correspondence).Electronic Records: Electronic Signatures. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11 A sponsor who retains an SMO shares responsibility for the3 The Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule by the quality of the work performed by the SMO.”U.S. Department of Health & Human Services. http://www.hhs.gov/ocr/privacy/ • Investigators should be available to subjects during studies by4 Guidance for Industry: Computerized Systems Used in Clinical Investigations, U.S.Department of Health and Human Services, Food and Drug Administration (FDA), Office of phone or other electronic communications. Contact shouldthe Commissioner (OC). May 2007 www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.pdf be available “24 hours a day.”
  4. 4. 4PHT Insights – Second Quarter 2009Inspectors and Auditors Require Comprehensive ePRO ArchivesRecent FDA Warning Letters…and How the PHT Archive Would Have Prevented These LettersThere were two warning letters against sites that specifically concerned patient eDiary data. PHT was not theePRO vendor in either case. The PHT Archive would have satisfied the conditions leading to the warning in bothcases, and would have made the warnings unnecessary.9-April-2009 Warning Letter 20-April-2009 Warning Letter‘Two diaries were present which recorded the number and ‘The electronic eDiary information for Subject 3511-007 wasseverity of [(b)(4)] between the periods of June 14 and June 21, not retrieved in a timely manner, such that the information was2006. It is unclear why the subject completed two diaries for not available for review during the FDA inspection. A Note tothis period of time. Furthermore, these two diaries are not in File, dated March 1, 2007, indicates that missing data fromagreement with each other in terms of number and severity of November 1, 2006 to December 4, 2006 was not available[(b)(4)]. Two CRFs were completed to report these [(b)(4)]. These due to the failure of the study coordinator to print the eDiaryCRFs were not in agreement with each other, and one of the readings from the website, which was later rendered inacces-CRFs did not agree with the data reported in either eDiary. In sible. Nonetheless, as clinical investigator, you are requiredaddition, a handwritten log of [(b)(4)] that did not agree with to maintain adequate and accurate study records. We noteeither CRF in number or severity was observed in the subject’s that you did not specifically address this observation in yourrecords. These multiple discrepancies make it impossible to response letters.’determine the actual number/severity of [(b)(4)] experienced bythis subject.’ Full text available at http://www.fda.gov/foi/warning_letters/ s7168c.pdf‘The FDA investigator’s review of the electronic CRFs (eCRFs)for the {xxx} study revealed discrepancies. When the FDA How the PHT Archive Would Have Resolved these Issues:investigator requested hard copies of the eCRFs, you were 1. The PHT web portal (StudyWorks) is available via the Internetunable to provide copies of the eCRFs. Your study coordinator for every study until database lock, when access is cut off so noinformed our investigator that the eCRFs were maintained by further changes can be made during archive generation.another firm and that you had no access to that eCRF database.Accordingly, you could not show that you prepared and • Read-only access CAN be granted upon request.maintained adequate and accurate case histories.’ • Once the archive is delivered to the site, access to the websiteFull Text available at http://www.fda.gov/foi/warning_letters/ is no longer necessary because the site has all of source datas7158c.pdf pertaining to the subjects of that site.How the PHT Archive would have solved this problem:1. Each PHT eEDiary is assigned to one trial subject. 2. The PHT Archive supports study data and contextual• The eCRF’s in the PHT Archive are generated from the source retention for mandated data and include an audit trail. periods.• Sequence controls prevent multiple eDiaries appearing for the same date if the protocol and requirements design for the study stipulate that only one eEDiary is to be done for a given day by any one subject.
  5. 5. 5PHT Insights – Fourth Quarter 2009Inspectors and Auditors Require Comprehensive ePRO ArchivesInterview with Steve Raymond, Ph.D.PHT Founder, Chief Scientific and Quality OfficerHow PHT ePRO Systems Help Site Personnel Fulfill Their Regulatory Responsibilities Are regulatory inspections of sites PHT provides PIs with proof of ePRO report and monitoring via on the upswing? reports from the PHT web portal (StudyWorks). Further, PHT Yes! The increase in regulatory includes messages within device shipments which remind each scrutiny at the site level is a real and site of the importance of using the PHT system to fulfill their important trend. regulatory responsibilities. This last element — encouraging the sites to use StudyWorks so that they will have evidence of Why do you suppose regulatory fulfilling their obligation to “prepare” and “maintain” — arguably inspections are increasing? exceeds the formal obligation of a technology provider. Increasing emphasis on the scrutiny of PHT provides guidance and proof beyond that which is currentlyePRO collected at sites appears to have the effect the regulatory required by the global regulatory agencies. The capacity of thescientists want: It makes subjects more compliant with eDiary PHT ePRO system to support site review is a regulatory requirement,completion, which in turn increases the amount of data and and most providers will have some way of supporting this.strengthens the conclusiveness of a trial. But the cumulative encouragement and support to each site for performing their own obligation with ease of access, dataWhat is the responsibility of an ePRO provider to each site summaries, reminders, emphasis and training at Investigatorthat collects primary or secondary endpoint data for claim Meetings, content of the Study Support Guide, and other sitesubmission? materials are above and beyond current requirements.It is the essential duty of every ePRO provider to ensure thatevery site has the capacity to access the web portal, that their NOTE: PHT Quality Assurance representatives and archiveconnections are functional, and that they have a valid login that specialists stand ready to help sites who face regulatoryis secure. inspections. Such inspections are scheduled, and it can be valuable to site investigators (and sponsors) to have PHTWhat is the regulatory responsibility of each site’s consults during inspections.Principal Investigator?Each Site’s Principal Investigator (PI) is required by regulatoryauthorities to prove that they “prepare” and “maintain” eDiaryrecords; that they are actively monitoring and reviewing the Is it Necessary to Purchase FDA Guideline Documents?ePRO portion of each subject’s participation. The short answer is NO!Compare this to the historical days of using paper diaries: it is Various for-profit organizations are selling productsunlikely that proof of review — preparation and maintenance of purported to help sponsors and CROs create formaldiary records — was anywhere near as compelling as it now is processes to quickly address and solve FDA violations.with ePRO. Verifying site review of paper diaries was probably Documents entitled ‘FDA Inspections’, ‘FDA Inspectionsnot an important part of regulatory inspections because the paper of Clinical Sites’, ‘FDA Inspections of Sponsor Sites’diary was usually not central to the objectives of the trials. and ‘FDA Warning Letters’ are being aggressivelyHow can PIs prove that they are actively monitoring and marketed as to reduce your company’s risk andreviewing the ePRO data? jeopardy with regulatory agencies.One method of proof would be for the PI or site personnel to The Investigations Operations Manual is available atprint out the eCRFs of the subjects’ diaries, and sign them. This no charge on the FDA website: http://www.fda.gov/is considered very conservative and impractical. Another proof ICECI/Inspections/IOM/default.htmmethod would be for either to generate a report that shows thehistory of their usage of the web portal.
  6. 6. 6Need More Detailed PHT Archive Information?Contact your PHTAccount Executive formore comprehensiveinformationValue of eSignatures.• What happens when an Inspector finds an eCRF of a primary efficacy questionnaire completed by a subject that was supposed to have been completed by an examiner at the site?Common and avoidable misstepsby site personnel. Electronic Patient Reported Outcome• CRF issues, training circumstances, and the regulatory (ePRO) Solutions need for an extensive Site Reference Manual. LogPad System SitePad TabletCall: 1-877-360-2910 StudyWorks eSense™ Sensors ePRO Designer Study Archive PROVision Scientific Services Trial Success Program™ (TSP) PHT System Support Center Scientific Review and Validation Site Telecom Assessments Technology TransferPHT SitePad Tablet – The mobile touch-screen PC tablet for PHT LogPad® – The mobileePRO collected at sites Hand Held for home eDiariesPHT Corporation info@phtcorp.com500 Rutherford Avenue www.phtcorp.comBoston, MA 02129 USA Copyright © 2009 PHT Corporation Rev 12.09.8Toll-Free: 877-360-2901

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