Clinical Trial Fraud - Lab Information, General Warning Signs of Misconduct

In my experience, questionable data is readily and easily detected in subject lab information and results. Clinical study staff are trained by education and are expected to know each protocol lab test and understand lab values, IUs and ranges and the proper way to fill out the lab forms. Lab protocols and tests are reviewed extensively during pre-study start Investigator Meetings with staff, monitors and PIs/SCs.

It is my practice as well as my recommendation when reviewing, monitoring and investigating subject lab information and results - do not just log the test...instead, read, read the test and the results, each data entry, read the entire form. A high frequency and incidence of data fraud at the clinical study site will, most definitely, be found in subject lab data.

Where and How?

• Panic values on labs coded "1" and no comment is made by PI
• Labs not evaluated prior to entrance into the clinical study
• Technical units are expressed several different ways by staff and PI/SC.

General Warning Signs of Misconduct - What are these? Easy to identify for a monitor who is clear and present...

• High staff turnover
• Staff are disgruntled
• Staff are fearful
• Staff are anxious
• Staff are depressed
• Staff are defensive
• High pressure work environment
• Obsession with study payments
• Absent PIs
• Absent SCs
• Absent staff
• Lack of GCP training
• Unusually fast recruitment.

Monitoring with Quality Control is a full time job and when done correctly, GCP is clear and misconduct and fraud are easily seen in trends and such. Choose and interview your clinical PIs, SCs, staff, CRO and/or consultant CRAs/CRCs and monitors carefully. Train them on GCP and QC and QA. Monitor their visits, reports, correspondence, communication and performance.

As well, there is clinical study data that falls into the "miscellaneous" subject data category - interestingly, not significant to subject outcomes or endpoints, but will point a finger at data trends leading to the identification of clinical fraud. These categories will be highlighted in my next blog pertaining to clinical fraud at the clinical study site.

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:

• 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.

Questionable Data in Clinical Fraud - Photos, Drug and Supplies

Often the question arises from the sponsor or a concerned clinical site team member - "There is so much data collected per subject per clinical study protocol at the clinical study site, where do we look for questionable data?"

Areas that one may find questionable data are numerous and in my view and years of experience - I can offer hundreds of locations and ideas. As well, I (colleagues) will not be surprised to uncover more areas where questionable data arises in the future.

At this writing, I will share common and not so common areas of questionable data at clinical trial sites suspected of clinical misconduct and fraud, starting with Photos, Drug and Supplies:

• Photos

1. Placards indicated different subject numbers but photos are of the same subject
2. TX area on source documents and CRFs differs from photos - for example cheek vs. back of head
3. Screening photo shows reaction in TX area - subject already dosing?
4. Dates on photos do not agree with visit #
5. Fraudulent photos
6. Missing photos

• Drug Log and Supplies

1. Incorrect subject initials on drug boxes - initials of subject not in our study
2. Date on drug log and drug box different
3. No dates dispensed on drug boxes and/or labels in CRF
4. Drug dispensing log - no entries for several months***
5. Drug dispensing log indicates drug dispensed, however drug boxes are still in inventory
6. Date of drug dispensed pre-dated -----after date of audit
7. Emergency supplies have wrong subject initials on box
8. Drug dispensing forms were pre-dated.

***At the time/visit on dispensing drug to subjects - the drug dispensing log and forms must be filled out at that time. This is GCP regardless of misconduct. This is true for any observation while subject is onsite, on-study. Fill in the appropriate information at the time of that visit - do not wait.

More to come in the next blog - Diary, Source Documents, Lab information.

Strategies for Detecting Clinical Trial Fraud

Monitor the data.
Monitor the monitor.

What do you monitor - what do you ask for when doing an audit? What detection tactics and strategies work?

• Ask for all subject information (data, docs, records) pertinent to the clinical study:

1. CRFs
2. Source worksheets
3. Clinical charts
4. Sign-in sheets
5. Lab requisitions
6. Shipping records.

• Accept no copies -

1. Review originals whenever possible.

• There is no easy way, don't just inventory and log, use your experience and understanding - Read -
  

1. Lab reports
   
2. X-rays.

• Fraud exists, expect fraud on an audit - assume fraud - work backwards.
• Question data, question and follow "open-ended data", "loose-ends" -
  

1. Missing
2. Altered
3. Inconsistent.
   

• Don't be timid - challenge the site to explain suspected fraudulent data.
• "Blame-shifting" during onsite audits "for cause" is pervasive.
  
• Be suspicious and challenge the investigator and remind he or she that clinical study conduct and GCP sits with them.
• Find and engage and cultivate "whistleblowers" - pay attention to -
  

1. Staff complaints
2. Listen to grievances
3. Establish rapport be approachable
4. Follow your leads
5. Don't stray from the data - the data is the data
6. Watch for changes in clinical staff behaviors
7. The list is endless.

GCP is well documented and simple to follow - unless there is serious intent to do otherwise. Detect clinical fraud early in data at a clinical site. The ramifications of doing so saves time and perhaps the integrity of the clinical study and/or clinical submission but most importantly protects subject safety, for those subjects that are real.

Clinical Research Fraud - Investigator Data Identifiers

In my experience, clinical research fraud is pervasive and can be found in many subject data collection systems, source records, subject test results and visit documentation entries at the investigator's clinical trial site. The following are the most common data identifiers:

• Implausible, impossible, in my view, trends and patterns:

1. 100% drug compliance
2. Perfect efficacy responses for all subjects
3. Identical lab results
4. Identical ECG results
5. No SAEs reported
6. Subjects adhering perfectly to visit schedules.

• Clinical site data not consistent with other centers (statistical outliers)
• Perfect diary cards, immaculate subject CRFs
• All source records & CRFs completed with the same pen
• Source records lack an audit trail
  
• No signatures of persons completing documentation
• No dates of persons completing documentation
• Subject handwriting inconsistent across documents (consents, diaries)
• Subject signature inconsistent across documents (consents, diaries)
• Questionable subject visit dates (Sundays, holidays, staff vacations)
• Impossible events (eg, randomization before drug delivery)
• Data contains "digit preference"
• Subject visits cannot be verified in the medical chart, appointment schedule or billing records.

How to avoid clinical trial site, staff and investigator fraud?

How to uncover data identifiers?

• Monitor data.
• Monitor data.
• Then Monitor data again.
• Monitor the Monitors.

FDA - Consequences of Fraud

The consequences of fraud are pervasive, outreaching and forever. If the Sponsor is found guilty of fraud as per FDA, data validity is compromised and the clinical submission is jeopardized. If the Investigator is involved in the fraud, he or she is disqualified, listed, given fines, incarcerated, incur tremendous legal expenses, he or she has just ruined their career. If the Institution, a Hospital, a Phase 1 Facility, a Clinic, a CRO, IRB or otherwise - is found guilty of fraud - lawsuits. What is the consequence to Subjects enrolled in the Clinical Trial - safety and well being at risk, loss of trust in the clinical trial process, lawsuit.

Facts:

• Fraudulent Investigators are often used by multiple Sponsors on Multiple Clinical Trials.
• Since Investigators are often used by multiple Sponsors on Multiple Clinical Trials, these Investigators will have a broad impact on many clinical submissions made by many Sponsors.
• For example, a case in mind - Investigator F, was involved in 91 clinical submissions with 47 different Sponsors during the same calendar year.
• Why? Word gets around that there are Investigators that "want to see their clinical trial site do the best". Which means that prior to selection of that Investigator, he or she understands how to manage the Subject CRF, Subject Informed Consent and Clinical Trial Protocol, for examples, in order to provide the Sponsor with "higher" statistically and clinically significant subject positive outcomes and better endpoints with respect to the efficacy and safety of the drug on clinical trial.

Why does fraud occur and how does it happen? To mention a few of the most obvious reasons:

• Not enough time
• Not enough staff
• Not enough monitoring, frequency or intensity to detail
• Not enough subjects, so subjects are reused and/or subjects are "made-up"
• Lack of GCP
• Lack of the understanding of GCP
• Lack of training GCP
  
• Lack of training FDA requirements and guidance
• Lack of regulatory oversight
• Lack of interest and motivation
• Money
  
• Greed
• Intent
• Pressure to perform
• Pressure to publish
• Pressure from senior management
• Pressure from piers
• Pressure from political arenas within medical societies, institutions, associations
  
• Pressure from CRO
• Pressure from Sponsor.

FDA Regulations (original statements and updates), pertaining to ("early") actions that must be taken by the Sponsor when fraud, misconduct and noncompliance are suspected or proven, can be found:

• 21 CFR 312.56(b)
• ICH E6 - 5.20.1
• ICH E6 - 5.20.2.
  

TRCL: 32KZYNXE6YNW

Clinical Research Fraud - FDA Definition

What does clinical research misconduct, fraud mean? FDA provides a definition that is clear in message and severity. Clinical research misconduct means falsification of data in proposing, processing, designing, performing, recording, supervising, reviewing, analyzing, collecting clinical research or reporting clinical research results, outcomes and endpoints. The manipulation of data and reporting for a self-serving purpose, usually monetary! Simple!

The FDA uses fraud and misconduct interchangeably and includes acts of omission and commission, consciously not revealing all data and consciously altering or fabricating data.
Fraud does not include honest error or honest difference in opinion. Deliberate or repeated non compliance with the protocol and GCP is considered fraud, second to falsification of data which is more severe in penalty and justice and resolve.

Let us review again who commits fraud?

• Investigators
• Study nurses
• Study Coordinators
• Data managers
• CRAs
• Sponsors
• Lab personnel
• IRB staff
• Subjects.

Yes, it is true. Clinical trial subjects have been accused and found guilty of fraud. The reasons are interesting and the content of another blog.

Average breakdown in % of blame:

CRC - 39
Study Nurse - 17
Hospital - 9
Sponsor - 9
Self - 9
Office Staff - 9
PI or Co-PI - 4
CRA - 4.

Monitor and adhere to GCP. Review and monitor repeatedly. Report Fraud.