WO2007011358A1 - Methodologie pour la mise en oeuvre d'etudes cliniques validees de produits pharmaceutiques - Google Patents

Methodologie pour la mise en oeuvre d'etudes cliniques validees de produits pharmaceutiques Download PDF

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Publication number
WO2007011358A1
WO2007011358A1 PCT/US2005/025480 US2005025480W WO2007011358A1 WO 2007011358 A1 WO2007011358 A1 WO 2007011358A1 US 2005025480 W US2005025480 W US 2005025480W WO 2007011358 A1 WO2007011358 A1 WO 2007011358A1
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WIPO (PCT)
Prior art keywords
documents
data
methodology
document
data collection
Prior art date
Application number
PCT/US2005/025480
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English (en)
Inventor
Thomas Wood
Original Assignee
Clinisys, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Clinisys, Inc. filed Critical Clinisys, Inc.
Priority to PCT/US2005/025480 priority Critical patent/WO2007011358A1/fr
Publication of WO2007011358A1 publication Critical patent/WO2007011358A1/fr

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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
    • G16H10/20—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for electronic clinical trials or questionnaires

Definitions

  • the present invention relates to a methodology for controlled
  • composition of content drug ("drug” as definable by FDA) documents and for organization, storage and retrieval thereof in one or more
  • the document production system includes a data management user interface for providing user access to the database and
  • the data management user interface is capable
  • United States Patent No. 5,666,490 describes an electronic document management system that converts documents into electronic images which can be sequentially routed to individual users in a network system.
  • the network system includes at least two work nodes for processing the documents where one of the nodes is a data entry work node.
  • the documents are subdivided into two or more subdivisions which are classified by subdivision type.
  • the images are routed through the network system according to predefined routing schemes based on its subdivision type.
  • the routing scheme for the documents includes at least one data entry node where data contained in the document is entered into a database. As the data is entered into the database, it is dynamically linked with its corresponding image which is also stored in the network. Notwithstanding the prior art, the present invention is neither taught nor rendered obvious thereby.
  • the present invention involves a methodology for performing validated clinical studies of drug-type products.
  • the steps include: (a) creating a plurality of data collection documents that includes a plurality of diverse types of data collection documents, and a plurality of each diverse type of data collection document, wherein every individual data collection document is provided its own unique identifier; (b) providing
  • opertors and “operator” as used herein shall include the Principal Investigator, Investigators, Study Coordinators and other data collectors and data handlers.
  • complete identification verification before being permitted to proceed to add information into a local system utilizing the plurality of data collection documents; (c) having appropriate operators who have successfully completed operator security fill out and sign specified data collection documents for step (a) above, where required; (d) creating a permanent record of all filled out and signed data collection documents from step (c) and organizing and tracking the filled out and signed documents by their unique identifiers in the local system; (e) uploading said permanent record to a central system; (f) independently (e.g.
  • the present invention methodology step (b) includes a two part security clearance.
  • This two part security clearance may include two different types of security clearance, at least one of which may be selected from the group consisting of password, voice recognition, signature recognition, retina recognition, fingerprint recognition, facial maps, biometric, or other available people identifiers and combinations thereof.
  • the unique identifier includes a unique bar code.
  • This bar code may be an encrypted bar code containing a plurality of document related information, two of the plurality of document information selected from the group consisting of title of study, site of study, operator, patient name, patient identification number, date, document version, interviewer, monitor, query number, and combinations thereof.
  • the step (k) includes a data-by-data point of entry history to create an audit trail for every point of data entry having revisions.
  • the local system is typically one of a plurality of local systems, and the central system is preferably an advanced computerized system with software to perform all of the steps stated above and below.
  • the audit trail may be a drop down window that is click accessed at each point of data entry having a history of at least one revision.
  • the filled out and signed data collection documents may be read by intelligent character recognition (ICR) for handwritten inputs and converted to digital representations for storage and retrieval. If an entry cannot be read by ICR, it will be treated as not clean and processed in accordance with steps (f), (g) and (h) above.
  • the methodology step (m) preferably includes the use of digital signature technology to fully secure the documents wherein the documents cannot be altered without nullifying an attached digital signature. The fully secured documents may be locked by appending a private key generated
  • a privacy masking feature allows capture of source documents (without Patient Identification) using, for example, identification numbers and initials so that transcribed CRFs can be checked against source documents remotely while online.
  • Source documents are linked to transcribe CRFs to eCRFs with related metadata in a manner that authenticates the user reviewing the linked documents, allows for visual validation and reconciliation of one related document to another and freezes in time the "signed off' package of documents.
  • the present invention methodology flow allows for the acknowledgement of specific conditions or the independent measurement of activities never before measured.
  • current paper-based systems have CRFs filled out with the visit date noted. It would not be known if the visit date was correct or when the form was filled out. Our process would note the time the CRF was printed (from a system clock), when it was scanned, when it was further processed, etc.
  • the series of independent system clock times coupled with the recorded visit date would help answer questions like: Was the CRF data recorded on the visit day? Was the SOP protocol of printing CRFs on the visit day followed? or How long after the visit did our process capture the data?
  • the present invention not only tracks documents, but also tracks the absence of events/data on documents.
  • Forms may be printed that register when the workflow demand requires a higher level of security, authentication and document tracking.
  • the present invention process requires verifying local system clocks daily with the central database clock. Dates and times of clinical data and metadata are automatically screened by edit and logic checks.
  • True Remote Monitoring is enabled by having source documents linked metadata, the related transcribed, scanned CRF and eCRF all online and available to remote monitors in a completely secure, validated environment.
  • Figure 1 shows a schematic flow diagram of the present invention methodology in its overall layout in one preferred embodiment, and in Figure 2 shown a flow diagram of steps involved in present invention methodology.
  • the general procedure for introducing a new drug or new FDA covered product in the United States begins with the creation or design of the product, e.g., a prosthesis, or the discovery or synthesis of the drug, or a determination that a previously-known drug may have a new therapeutic use. If the clinical safety of the product, or the chemical make-up of the product is not known on the basis of existing data, preclinical short-term animal studies may be undertaken to develop a pharmacological profile of the product and to determine the toxicity of it. When the reasonable safety of the product is established, the relevant data is then submitted to the FDA in an Investigational New Drug (IND) Application. The DSfD also includes a proposal for determining the safety and efficacy of the drug in clinical trials. The drug developer may then
  • Phase I clinical studies relate to basic safety investigations of the new drug in humans.
  • a typical Phase I clinical study is conducted with a small number of healthy volunteer subjects to whom the drug is administered.
  • the results obtained during Phase I studies are used to determine such parameters as the toxicity, absorption, metabolism, preferred route of administration and safe dosage range of the drug or other product. If the results from Phase I studies are favorable, the developer may proceed to Phase II studies.
  • Phase II studies the product is administered to controlled study group or groups of subjects having the problem for which the new product is believed to reduce or eliminate. Phase II studies are used to gather additional safety data and to provide initial results relating the effectiveness of the product (efficacy).
  • the drug or other product developer may provide data from completed or ongoing Phase I and
  • NDA New Drug Application
  • An NDA is typically a massive document comprising several volumes of reports.
  • the NDA may include an index, a summary, and several sections relating to the chemistry, pharmacology, pharmacokinetics, clinical effects, and proposed labeling of the drug. Each one of these sections typically includes several documents involving thousands, tens of thousands or hundreds of thousands of pages.
  • the clinical section of an NDA may include an index, an abbreviated clinical summary, a risk/benefit analysis, an integrated summary of effectiveness, an integrated summary of safety data, clinical pharmacology study reports, controlled study reports, uncontrolled study reports, and other information pertaining to the accumulated knowledge and experience gained during clinical testing of the drug.
  • Each section of an NDA includes many cross-references among complex documents that relate to studies conducted over a period of time that can extend over several years.
  • composition of textual descriptions of study data, and the integration of such text into a consistent NDA can be a complex and time-consuming process.
  • the NDA is sent to the FDA for their review. The length of
  • EU European Union
  • the EU has instituted a pre-marketing regulatory review program for new drugs that is similar to the NDA review program conducted by the FDA. Because the EU has formulated regulations for the review of new drugs that are in some ways different from the US regulations, the developer is burdened with the task of producing an additional set of hierarchically- related documents which rely upon the same data that was used to produce the NDA. Additionally, the developer may also desire to produce internal company reports which also present the same drug data in yet another customized format.
  • the present invention has been developed to provide an automated system for managing all steps along the process usually conducted by a sponsor and/or a contractor, in real time, with actual original paperwork, computerized control, failsafe procedures, histories, text content and many other steps, reports, details and summaries associated with drug studies, and for integrating such information in whatever forms that are ultimately necessary and desired by the company conducting the studies.
  • Such a methodology is also useful for use in preparing documentation, such as Product License Applications or
  • Another primary objective is to collect and capture many different types of documents, including the standard CRF documents described above, as well as regulating documents, rules, amendments, resumes, trip reports, emails, standard operating procedures.
  • Paper- based data collection is used for 95% of all . clinical trials.
  • a step by step description of clinical data collection follows:
  • a CRF book (case report form book) consisting of NCR tri-part paper divided up by patient visits is provided to investigator sites (where patients are examined) for each site, by the Sponsor (the product company, pharma or CRO - clinical research organization) running the
  • SOURCE is a very key concept in clinical trial data collection.
  • source data or “source documents” refers to where clinical data is first recorded — usually with paper and pen.
  • Source data is collected from patient record files, lab reports, hospital records, etc. regulatory documents and administrative forms and entered by hand onto the CRFs. This transcription usually is performed by a Study Coordinator who is looking at the "source” while transcribing.
  • CRFs are pre-printed tri-part, NCR paper forms (yellow, white and pink copies) broken down into visits as prescribed by trial protocol and kept in three ring binders - one per patient.
  • Monitors employed by the Sponsor/CRO come to the site to verify that the source was transcribed properly, to review records for accuracy and retrieve CRFs. This is done every four to six weeks.
  • Clinical data is now in a computer database (could be spreadsheet or sophisticated database). Data is reviewed by Data Managers that review the data for completeness, errors, etc. At this time, edit checks (range checks) and logic test programs are run against the data. Questionable data is printed out and supplied to the Data Manager. The Data Manager must write up a "Data Query" for each instance of problem data and send the query to the appropriate Investigator or Study
  • the present invention methodology for improving the clinical trial process includes a primary design specification that includes the following: integrate and automate (1) document creation, capture, tracking and storage, (2) tracking clinical trial workflow activities and
  • a second design specification of the present invention methodology assures that data quality issues are best addressed as close as possible to the time and place of data creation, hi other words, collecting, capturing and processing source documents and data at investigator sites as they are created is a necessary element of the present
  • a third design specification of the present invention methodology involves recording changes and modifications to documents and data with new versions of the document or data identified by a new version number, while retaining the original document or data. This process creates a methodology that includes preserving and documenting an audit trail of the history of each document, and in preferred embodiments, an audit trail of history for each separate data entry.
  • the present invention methodology is one that self validates and reconciles documents, work activity and data from the time of data/document capture until the locking of the clinical trial database after the completion of the trial.
  • the present invention methodology includes the following steps:
  • each data collection document the system prints a pre-coded page.
  • a page could be a Patient Consent Form, typical Case Report Form (CRF), an acknowledgement form or sign off form of various types or other data collecting document.
  • CRF typical Case Report Form
  • Each document, and in preferred embodiments, each page, is uniquely bar coded. Information as to date, time, trial protocol, site, ID numbers may be included, and are preferably included, to uniquely identify each page.
  • ICR intelligent character recognition
  • the system will permanently secure the documents for read only and hold in permanent storage.
  • the system will permanently secure the documents for read only and hold in permanent storage.
  • data and documents are assembled as follows: (1) third party source documents, (2) the system printed, filled out in ink and scanned forms, (3) the virtual digital representation of the system printed, filled out, scanned originals and (4) a text file that records the various outcomes of related edit checks, logic tests and metadata (time, date, who, what, when, where) are assembled.
  • the system generated interface walks a security cleared Investigator/Study Coordinator, Principal Investigator or other operator through each document, allowing ample opportunity (regulated procedures) to see mat the ICR' d digital data is a true representation of the handwritten inked or other source document data. If non-ICR'd text data needs to be transcribed into the
  • the system audit trail mechanism keeps track of all documents, data, edit checks, logic tests, data changes and the who, what, when, where, why of all workflow activity for each field of data that is "cleaned” (through the above processes).
  • the terms "locks or locked” refer to the process of appending a Private Key generated Digital Signature to a page file in such a way that the related Public Key can read the file to determine if any change has been made to the file since it was first digitally signed. If there has been no change in the file, the Public Key will successfully "read” the Private Key Digital Signature - i.e. the "locked” page file. If a change occurred, then the Private Key Digital Signature could not be
  • All system documents or data are essentially data files that have a physical page-like appearance when displayed on a video monitor. It is critical that the video monitor page-like appearance be "locked” as a bitmapped image (similar to a scanned image). This page-like image is what the operator sees when reconciling and verifying the original handwritten inked page and the digital representation of the original handwritten page. It is this bit mapped screen image of a page that is being signed by Private Key Digital Signature and is thus “locked”. Signed Off bit mapped
  • the system process reconciles source data and documents with related work activities and digital data in the database at the point of time and place where a Study Coordinator or Principal Investigator or any operator commits documents or data to a clinical trial.
  • various preferred embodiments of the present invention methodology may include one or more of the following steps: a. Other data changes can be made to data at later points in the process similar to the process outlined above. This process is called a "data query process" and is accomplished within the system applications. A complete versioning audit trail is maintained in the data query process where two or more participants question and reply to various document inaccuracies, inconsistencies or other problems. b. Data files may initially be sent to a processing center, e.g. corporate headquarters or other company facility, or to a third party entity for authentication, validation, backup and disaster recovery
  • Work activities could also be described as a series or group of implied tasks such as “site audit”, “monitor site visit”, “patient visit”, etc.
  • Work activity tracking by its very nature is metadata that gives "context” and "validity" to clinical data.
  • the system records the time and date and who of a CRF page: printed time, filled out time, scanned time, cleaned time, transmitted to Process Center time, reviewed by monitor time and monitor signed off time create a logical timeline and audit trail. This would be a significant improvement over a paper-based system because a paper-based system would record only the visit time and maybe the keypunched time.
  • the visit time might or might not correspond to the visit schedule, but the CRF could have been filled out three weeks after the visit and was backdated - one cannot be certain with a paper-based system.
  • the term workflow refers to the logical progression of steps that need to be taken according to the Trial Protocol, Good Clinical Practice (GCP) or administrative SOP. Examples: (1) a Patient Consent
  • -27- Form needs to be signed and countersigned and submitted to the system before the patient's first visit CRF is printed.
  • the system tells the Study Coordinator that a first patient visit must be scheduled.
  • the system prints a CRF and this event triggers the alert that the printed form must be scanned back into the system or be otherwise accounted for within x hours.
  • the approval of a new physician/investigator to the trial triggers alerts requiring the collection of documents (license to practice in the state, curriculum vitae of Investigator), scheduling training classes in how to use the system or the critical aspects of the Protocol and the creation of new documents (revised 1572, signed contract and certification to use the system).
  • Source documents that have been scanned into the system at sites must be purged of patient identification for certain purposes— name, address, phone, SS#, etc.
  • the bitmapped scanned image has to be obscured or removed where such identification information is displayed. In its place, the patient ID# and trial identification numbers would be stamped. These documents would be privacy protected in accordance with preset rules.
  • the purpose of this above process is to allow authenticated copies of source documents to be stored and accepted through the network without compromising the identity of a patient. Any trial related document held by a sponsor is subject to being copied and analyzed by
  • Figure 1 shows a schematic flow diagram of the present invention methodology in its overall layout in one preferred embodiment, and in Figure 2 shown a flow diagram of steps involved in present invention methodology.
  • the present invention methodology 1 is a setup with a central system 100 which may be controlled in part by a sponsor 23 and in part by a contractor 25.
  • a central system 100 which may be controlled in part by a sponsor 23 and in part by a contractor 25.
  • Each local system has a plurality of input operators such as operators 9, 11, 13 and 15 of local system 3.
  • the other local systems 5 and 7 also have groups of input operators 17 and 19 respectively.
  • the central system and local systems work together in accordance with the flow diagram shown in Figure 2.
  • steps 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, and 57 are implemented to achieve to objectives of the present invention. These are generally performed sequentially, but are iteratively revisited for clarifications and monitoring queries. Also, the steps of procuring external documents may occur before or after some of the other steps and the order of

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medical Informatics (AREA)
  • Primary Health Care (AREA)
  • Public Health (AREA)
  • Medical Treatment And Welfare Office Work (AREA)

Abstract

L'invention concerne une méthodologie de validation d'études cliniques de médicaments consistant à créer des documents de collecte de données avec des identifiants uniques ; à faire en sorte que des opérateurs (9, 11, 13 et 15) terminent la vérification d'identification de sécurité avant de poursuivre la procédure ; à faire en sorte que des opérateurs fiables (9, 11, 13 et 15) remplissent et signent des documents de collecte de données spécifiés ; à créer des enregistrements permanents desdits documents ; à les suivre au moyen des identifiants uniques dans un système local (3, 5 et 7) ; à les télécharger vers un système central (100) ; à revoir indépendamment les documents remplis et signés pour accepter ou demander des clarifications ; à conserver des enregistrements permanents en lecture seulement de l'ensemble des documents remplis et signés à l'origine ; à émettre des demandes de clarification de documents ; à revoir chaque réponse ; à attribuer de nouveaux liens d'identification uniques à chaque version de chaque révision ; à répéter itérativement ce qui précède jusqu'à ce que les documents soient sains, et à stocker et à suivre chaque version de chaque document dans le système central (100) ; à fournir une demande de moniteur et un historique d'entrée de documents de l'ensemble des modifications apportées à l'ensemble des documents afin de créer une piste de vérification fiable.
PCT/US2005/025480 2005-07-18 2005-07-18 Methodologie pour la mise en oeuvre d'etudes cliniques validees de produits pharmaceutiques WO2007011358A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5307262A (en) * 1992-01-29 1994-04-26 Applied Medical Data, Inc. Patient data quality review method and system
US5671282A (en) * 1995-01-23 1997-09-23 Ricoh Corporation Method and apparatus for document verification and tracking
US6192381B1 (en) * 1997-10-06 2001-02-20 Megg Associates, Inc. Single-document active user interface, method and system for implementing same
US6205455B1 (en) * 1995-04-27 2001-03-20 Michael Umen & Co. , Inc. Drug document production system
US6556999B1 (en) * 2001-06-08 2003-04-29 Syntex (Usa) Llc System and method for bridging a clinical remote data entry product to a back-end clinical data management system

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5307262A (en) * 1992-01-29 1994-04-26 Applied Medical Data, Inc. Patient data quality review method and system
US5671282A (en) * 1995-01-23 1997-09-23 Ricoh Corporation Method and apparatus for document verification and tracking
US6205455B1 (en) * 1995-04-27 2001-03-20 Michael Umen & Co. , Inc. Drug document production system
US6192381B1 (en) * 1997-10-06 2001-02-20 Megg Associates, Inc. Single-document active user interface, method and system for implementing same
US6556999B1 (en) * 2001-06-08 2003-04-29 Syntex (Usa) Llc System and method for bridging a clinical remote data entry product to a back-end clinical data management system

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