Sunday, November 29, 2009

Questionable Data in Clinical Fraud - Diary, Source Documents

A Diary is a collection of observations recorded by the subject when home. Source documents record the subject's experience onsite, on-study and are data entered by clinical staff. Interestingly, this is an area where misconduct and fraudulent data is plentiful, the subject most of the time has no vested interest in the fraud and will not therefore record untruthful data. Whereas, data entries into the source documents are at the "mercy" of the clinical staff onsite, conducting the study, who may have a vested interest in the misconduct. Often, when FDA performs an unannounced, onsite audit for cause, Subject Diaries are always asked for and reviewed and compared to the source documents, CRFs, etc.

  • Diary states "dose not taken"- dosing record CRF page indicates date taken
  • Diary card information written over
  • Diary and dosing records are out of synch
  • Handwriting is the same for several diary cards
  • Handwriting of SC/PI is the same as writing on the diary cards
  • Date on diary and dosing record is a date that does not exist
  • Subject diaries not collected at each visit
  • Subject diaries altered by SC/PI to match dosing dates in dosing record.
Source Documents:
  • Source document and drug log dates differ
  • Data on source documents not present at previous CRA visit appears at future visit
  • No SAE reported on source documents but an entry added in different handwriting and different ink indicates "except erythyma, edema"
  • Use of pencil in source documents
  • Source documents indicates no PI available to do LSR's that day, yet subject had PE performed
  • PE information in source documents and CRF differ.
During an onsite for cause audit by FDA, FDA inspectors (DSI, OCI Divisions at FDA) come in and have already determined that fraud exists and will confiscate everything related to data or the collection of data at the clinical study site, including computers, electronic data capture systems, hand and pocket data collections systems are well as all paper trails. In some cases, FDA will order biologic samples taken from the subjects on-study to be carted away to a "forensics" lab for future investigation.

Good Quality Control and GCP Monitoring cannot be stressed at the clinical study site. Each clinical study and the data derived from the subjects at each site serve as a building block to the foundation of what will eventually be an integrated global database, a GIDB, leading to a clinical submission to FDA. Clinical studies identified with fraudulent data often are censored from the mix. This often impacts the ability to effectively evaluate the safety of the clinical drug under study as well as subject exposure measurements, efficacy/therapeutic endpoints, clinical summaries of safety and efficacy, benefit/risk statements, clinical summary overviews and the label in the clinical submission. In my experience, and in many cases, data censored at the last moment for misconduct leading to fraud will delay the clinical submission timelines, delay the filing date of the clinical submission and/or FDA may reject the clinical submission in its entirety, a RTF. Several warning letters will be issued, a clinical hold is ordered for the study to halt immediately, while the investigation continues. After the investigation (and data censor) is completed and if the filing of the clinical submission is accepted by FDA - the approvability of the content of the clinical submission, is still in question and is in serious jeopardy for "data quality, non-reporting and integrity" issues.

Monitor, Monitor and Monitor with GCP and Quality Control.

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