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.

1. PHT Insights — Fourth Quarter 2009
Inspectors and Auditors Require Comprehensive ePRO Archives
Why the PHT ePRO Archive The PHT ePRO Archive: Sophisticated Technology
Remains 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 assistance
and 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 Specification
time. Any omissions can risk regulatory warnings, • Roadmap • Trial Documentation
findings and possible data rejection. • Archive Certification Letter • Electronic Case Report Forms
• Archive Certification Report • XML Data files
All PHT products meet the requirements of
• Archive Orientation Letter • Metadata files
regulatory agencies including the United States
• Security and Privacy Provisions • Adobe Acrobat Application
Food and Drug Administration (FDA), the European
for Sponsors • Metadata Viewer
Medicines Agency (EMEA), the European Union (EU),
• PHT Systems and the Record • SAS Viewer (as needed)
the International Conference on Harmonisation of
Keeping Requirements Under
Technical Requirements for Registration of 21CFR312.62
Pharmaceuticals for Human Use (ICH) and the
Pharmaceuticals and Medical Devices Agency
in Japan (PMDA).
The PHT ePRO Archive
This issue describes the PHT ePRO Archive and
explains how and why it exceeds regulatory READ ME FIRST
requirements 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
PHT Insights – Second Quarter 2009
Inspectors and Auditors Require Comprehensive ePRO Archives
Interview with Nancy Carlson
PHT Quality Documentation Manager
How 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 document
section; and clearly demonstrates that the trial data collection
and 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 the
Universal Declaration of Human Rights – Article 12, and the
Convention for the Protection of Human Rights and
Fundamental Freedoms – Article 8; and able to pass
all 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 trial
true copy of the original trial database. XML is only “human- documents and document standards, so that the Archive is
readable” 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 that
the 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 operating
The PHT Archive includes a second data presentation - electronic procedures are documented and approved, that those
Case 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 and
audit trial for each form/field entry. All eCRF data collected for a procedures. I continuously audit core product and trial
patient 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 to
the certified XML, they are also a true copy the original trial shipment, I enforce the compliance standards that I created in
database – a regulatory requirement. my prior position as Archive Project Manager.

3. 3
PHT Insights – Second Quarter 2009
Inspectors and Auditors Require Comprehensive ePRO Archives
PHT Experience with Site Inspections
Interview 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 site
How quickly is an archive delivered to the sponsor or CRO?
investigators (and sponsors) to have PHT consults available
The PHT Statement of Work signed by PHT and the Sponsor or during inspections.
CRO states that PHT will deliver the Archive within 90 days of
signed (sponsor) acceptance of the final data transfer. Here are the facts:
• PHT experts have been on call for more than ten site inspections
Why do some ePRO vendors require sponsors or CROs to since January 2008, where the PHT ePRO System had provided
maintain 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 and
or 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 provide
The 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 among
trial documentation and the data from all investigator sites.
domestic and international FDA inspectors. PHT experts
Each 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 applicable
record retention requirements, and PHT retains copies of all
sponsor and CRO and investigator sites archives in a secure
off-site storage facility.
New FDA Guidance for Investigator
WARNING: If the sponsor or investigator sites have not backed
up their archive onto a server and they can’t locate the media Responsibilities
copy 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 October
trial data is delayed.
2009. This is a supplement, rather than a replacement, of
What 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 be
driven 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.htm
ongoing 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 by
1
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., source
2
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 the
3
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 by
4
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 should
the Commissioner (OC). May 2007 www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.pdf be available “24 hours a day.”

4. 4
PHT Insights – Second Quarter 2009
Inspectors and Auditors Require Comprehensive ePRO Archives
Recent FDA Warning Letters…
and How the PHT Archive Would Have Prevented These Letters
There were two warning letters against sites that specifically concerned patient eDiary data. PHT was not the
ePRO vendor in either case. The PHT Archive would have satisfied the conditions leading to the warning in both
cases, 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 was
severity of [(b)(4)] between the periods of June 14 and June 21, not retrieved in a timely manner, such that the information was
2006. It is unclear why the subject completed two diaries for not available for review during the FDA inspection. A Note to
this period of time. Furthermore, these two diaries are not in File, dated March 1, 2007, indicates that missing data from
agreement 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 eDiary
CRFs 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 required
addition, a handwritten log of [(b)(4)] that did not agree with to maintain adequate and accurate study records. We note
either CRF in number or severity was observed in the subject’s that you did not specifically address this observation in your
records. These multiple discrepancies make it impossible to response letters.’
determine the actual number/severity of [(b)(4)] experienced by
this 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 Internet
unable to provide copies of the eCRFs. Your study coordinator
for every study until database lock, when access is cut off so no
informed 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 website
Full Text available at http://www.fda.gov/foi/warning_letters/ is no longer necessary because the site has all of source data
s7158c.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
PHT Insights – Fourth Quarter 2009
Inspectors and Auditors Require Comprehensive ePRO Archives
Interview with Steve Raymond, Ph.D.
PHT Founder, Chief Scientific and Quality Officer
How 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 currently
ePRO collected at sites appears to have the effect the regulatory required by the global regulatory agencies. The capacity of the
scientists 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, data
What is the responsibility of an ePRO provider to each site summaries, reminders, emphasis and training at Investigator
that collects primary or secondary endpoint data for claim Meetings, content of the Study Support Guide, and other site
submission? materials are above and beyond current requirements.
It is the essential duty of every ePRO provider to ensure that
every site has the capacity to access the web portal, that their NOTE: PHT Quality Assurance representatives and archive
connections are functional, and that they have a valid login that specialists stand ready to help sites who face regulatory
is secure. inspections. Such inspections are scheduled, and it can be
valuable to site investigators (and sponsors) to have PHT
What is the regulatory responsibility of each site’s consults during inspections.
Principal Investigator?
Each Site’s Principal Investigator (PI) is required by regulatory
authorities to prove that they “prepare” and “maintain” eDiary
records; 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 products
unlikely that proof of review — preparation and maintenance of purported to help sponsors and CROs create formal
diary 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 Inspections
not 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 aggressively
How can PIs prove that they are actively monitoring and marketed as to reduce your company’s risk and
reviewing 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 at
print 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.htm
method would be for either to generate a report that shows the
history of their usage of the web portal.

6. 6
Need More Detailed PHT Archive Information?
Contact your PHT
Account Executive for
more comprehensive
information
Value 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 missteps
by 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 Tablet
Call: 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 Transfer
PHT SitePad Tablet – The mobile touch-screen PC tablet for PHT LogPad® – The mobile
ePRO collected at sites Hand Held for home eDiaries
PHT Corporation info@phtcorp.com
500 Rutherford Avenue www.phtcorp.com
Boston, MA 02129 USA Copyright © 2009 PHT Corporation Rev 12.09.8
Toll-Free: 877-360-2901