HISTORY OF DATA INTEGRITY - cbinet.com · HISTORY OF DATA INTEGRITY August 16-17, 2017 Institute of Validation Technology 3rd Annual Data Integrity Validation James Stumpff, RPh,

CONFIDENTIAL © 2016 PAREXEL INTERNATIONAL CORP.

HISTORY OF

DATA INTEGRITY August 16-17, 2017

Institute of Validation Technology 3rd Annual Data Integrity Validation

James Stumpff, RPh, Principal Consultant

© 2016 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL2

AGENDA

THANK YOU FOR

YOUR INTEREST

Suggested Reading

Industry Regulation

Historical Events

Current Trends

Case Studies


RECOMMENDED READING - WWW.PDA.ORG

List of Authors:

Alicia (Pruett) Langhans

Bob McDowall

Christoph Jansen

David Stokes

Jeanne Moldenhauer

Jim Stumpff

Joe Liscouski

Magdalena Kurpierz

Ron Tetzlaff

Siegfried Schmitt

Yingying Liu


RECOMMENDED READING - WWW.PDA.ORG

Other PDA Publications

Elements of a Code of Conduct

for Data Integrity in

Pharmaceutical Manufacturing

PDA Points to Consider:

Fundamental Concepts for Data

Integrity

PDA Technical Report: Data

Integrity in Laboratory Systems

Coming Soon!


RECOMMENDED READING - WWW.ISPE.ORG

ISPE GAMP Records and Data

Integrity Guide


RECOMMENDED READING – WWW.FDA.GOV


RECOMMENDED READING – WWW.WHO.INT


RECOMMENDED READING – WWW.EMA.EUROPA.EU


RECOMMENDED READING – WWW.HC-SC.GC.CA


RECOMMENDED READING – WWW.GOV.UK


RECOMMENDED READING –

HTTPS://PICSCHEME.ORG/EN/PUBLICATIONS

Draft PIC/S Good Practices for Data Management and Integrity in

Regulated GMP/GDP Environments


INDUSTRY REGULATION

• In the United Kingdom, the Thalidomide incidents in the 1950s and

1960s led to the creation of the Committee on Safety of Drugs in

1963.

• In the United States, the Food, Drug and Cosmetic Act of 1938

required the safety of new drugs be shown prior to their marketing.

• In Europe, the Council of the European Economic Community

Directive765/65/EEC of January 1965 and subsequent amendments

established the regulatory framework for European Member States.

• In Japan, the Fund for Adverse Drug Reactions Suffering Relief was

established in October of 1979 and in 1993 became the

Organization for Pharmaceutical Safety and Research to perform

the generic drug reviews.


DATA MANAGEMENT HAS CHANGED

• Historically, data was paper based and thus subject to the integrity

of the individuals responsible for recording and checking the data

entries. The computer age has introduced electronic data which

when properly managed increases the ability to assure the integrity

of data.

• Data may be generated from a variety of sources including

toxicology studies, clinical studies, manufacturing operations and

laboratory testing. The data may support regulatory submissions

and/or required documentation for current Good Manufacturing

Practice (cGMP) activities.


DATA INTEGRITY MAJOR EVENTS

• In the 1970s the G.D. Searle Co. investigation revealed fraudulent

animal data submitted in applications to the FDA.

• If the integrity of that data is questioned, then the whole regulatory

process is questioned. If the data are proved false and misleading,

then the regulatory decisions may be tragically wrong.



• The Congressional Subcommittee hearings summed up the impact

of the [FDA] investigation.

• “…Accurate science is the best protection the American people

have from an unsafe and ineffective drug supply. Inaccurate

science, sloppy science, fraudulent science – these are the greatest

threats to the health and safety of the American people. Whether

the science is wrong because of clerical error, or because of poor

technique, or because of incompetence, or because of criminal

negligence, is less important than the fact that it is wrong. For if it

is wrong, and if, as in this case, the FDA did not – indeed, under

current practice, could not – know it was wrong, then the protective

regulatory barrier between a potentially dangerous drug and the

patient is removed.”

Drug Regulation: History, Present and Future, World Health Organization (WHO) website

http://www.who.int/medicines/technical_briefing/tbs/Drug_Regulation_History_Present_Future.pdf. Accessed

8/12/15.

http://www.who.int/medicines/technical_briefing/tbs/Drug_Regulation_History_Present_Future.pdf


RESPONSE TO THE EVENT

• The FDA investigations into the toxicological animal data integrity

issues led to the Good Laboratory Practices regulations which were

put in place in 1979.



• In the late 1980s the Generic Drug Scandals were the headlines.

Numerous generic drug manufacturers submitted fraudulent data to

the FDA in support of their Abbreviated New Drug Application

(ANDA) or other submissions.

• Bio-equivalency Testing

• ANDA Submission Batch Records

• Stability Summaries

• Manufacturing Site

• Retained Samples Inspection


RESPONSE TO THE EVENTS

• Changes were implemented to improve data integrity compliance

and strengthen the penalties for such egregious acts.

• Updating the Pre-approval Inspection Program

• The Application Integrity Policy (AIP)

• Compliance Policy Guide Sec. 120.100, Fraud, Untrue Statements of

Material Facts, Bribery, and Illegal Gratuities

• The Generic Drug Enforcement Act of 1992 (GDEA).


FDA PRE-APPROVAL PROGRAM

• In the 1990s the FDA update to the Pre-approval Program was made

in part to put more emphasis on data integrity and this is clearly

stated in the three objectives of the program: readiness for

commercial manufacturing, conformance to application and data

integrity audit.


APPLICATION INTEGRITY PROGRAM (AIP)

• In September 1991, the FDA Application Integrity Policy (AIP),

Fraud, Untrue Statements of Material Facts, Bribery, and Illegal

Gratuities; Final Policy was published.

• Review of applications suspended and/or withdrawing an approved

application for reasons of fraud, untrue statements of material fact


COMPLIANCE POLICY GUIDE

• In July 1991 the FDA issued Compliance Policy Guide Sec. 120.100,

Fraud, Untrue Statements of Material Facts, Bribery, and Illegal

Gratuities.

• Ensure validity of data submissions called into question by the

agency's discovery of wrongful acts such as fraud, untrue

statements of material fact, bribery, and illegal gratuities

• Withdraw approval of, or refuse to approve, applications containing

fraudulent data.

• This guide sets forth the agency's general approach to applications

that have been called into question by such wrongful acts and

applications found to contain fraudulent data.


GENERIC DRUG ENFORCEMENT ACT OF 1992

• Provisions for Debarment of Corporations and Individuals;

Authority to Deny or Withdraw Product Approval, Suspend Product

Distribution, Agency Hearings, Judicial Review of GDEA Decisions,

Civil Penalties, Certifications and Effect on Other Laws


CLINICAL INVESTIGATIONS

• Clinical Investigator Robert A. Fiddes, MD

• “In just a few years, Dr. Fiddes transformed his sleepy medical

practice here into a research juggernaut, recruiting patients for

drug experiments at a breakneck pace. His success made him a

magnet for an industry desperately scouring the nation for test

subjects. Companies large and small showered him not only with

more than 170 studies to conduct, but with millions of dollars in

compensation for his work… But amid the glitter and cash was a

fact that no one outside his office knew: It was all a scam.


CLINICAL INVESTIGATIONS

For Dr. Fiddes was conducting research fraud of audacious

proportions, cutting corners and inventing data to keep the money

flowing from the drug industry. Fictitious patients were enrolled in

studies. Blood pressure readings were fabricated. Bodily fluids that

met certain lab values were kept on hand in the office refrigerator,

ready to be substituted for the urine or blood of patients who did not

qualify for studies.”

• Dr. Fiddes eventually plead guilty to fraud and remains permanently

on the FDA Debarment List.

K. Eichenwald and G. Kolata, A Doctor's Drug Trials Turn Into Fraud, New York Times Published: May 17, 1999. NY

Times website http://www.nytimes.com/1999/05/17/business/a-doctor-s-drug-trials-turn-into-fraud.html. Accessed

20 August 2015.

http://www.nytimes.com/1999/05/17/business/a-doctor-s-drug-trials-turn-into-fraud.html. Accessed 20 August 2015


INDUSTRY PERSONNEL

• “There are three types of principled people in the pharmaceutical

industry. First, there are those who directly participate in company

activities which do public harm, but who sincerely believe the

company propaganda which tells them that they are contributing to

the improvement of community health. Second, there are people

who perceive the company to be engaging in certain social harmful

practices and fight tooth and nail within the organisation to stop

those practices. Third, there are people who have no direct contact

with socially harmful practices. The job they do produces social

benefits, and they do that job with integrity and dedication.”

J. Brathwaite, Corporate Crime in the Pharmaceutical Industry, London, Boston, Melbourne and Henly, Rutledge &

Kegan Paul plc, (1984)


ETHOS (GREEK FOR CHARACTER)

Do your staff have the right character?

Does your company or institution provide guidance on good

behaviour?

Is the right behaviour supported and encouraged?

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MORE RECENT EVENTS

• In the 2000s there has been a resurgence of data integrity issues

found by regulatory authorities all over the world leading to

increased information sharing amongst regulatory authorities.

• The MHRA announced in December 2013 their expectation that

pharmaceutical firms assess data integrity as part of their self-

inspection program including outsourced activities. This will be

covered during MHRA inspections.

• The FDA and EMA announced in December 2013 the Generic Drug

Initiatives to facilitate regulatory actions against non-compliant

companies through the sharing of inspection information and

bioequivalence data. Earlier in the year a large generic drug

manufacturer plead guilty to charges of falsifying bioequivalence

data in support of several generic drug applications.


MORE RECENT EVENTS

• On August 21, 2015 the European Commission announced an EU-

wide ban on sales of around 700 generic drugs due to data integrity.

Bioequivalence studies conducted by GVK Biosciences,

Hyderabad, India were found to have systematic data manipulation

that took place over several years leading to doubt in the integrity

of the trials and the data.

• The China Food and Drug Administration (CDFA) gave drug

manufacturers until August 25, 2015 to conduct self-audits for the

purpose of authenticating clinical trial data submitted in

applications.


TRENDS- WARNING LETTERSJANUARY 1, 2005 TO DECEMBER 31, 2016

0

5

10

15

20

25

30

35

2011 (23) 2012 (23) 2013 (25) 2014 (31) 2015 (14) 2016 (25)

FDA Warning Letters


TRENDS- WARNING LETTERS AREA CITEDJANUARY 1, 2005 TO DECEMBER 31, 2016

NOTE MANY OF THE WARNING LETTERS SITE BOTH ANALYTICAL AND MANUFACTURING DATA INTEGRITY ISSUES

Clincal19%

Manaufacturing41%

Analytical38%

Post Market Surveillance2%

Area Cited


STANDARD LANGUAGE IN WARNING LETTERS

We expect that you hire a third party auditor, with experience in

detecting data integrity problems, to assist you with this evaluation

and assist with your overall compliance with CGMP. It is your

responsibility to ensure that data generated during operations is

accurate and that the results reported are a true representation of the

quality of your drug products.

Your data integrity expert should:

1. Identify all instances in which unofficial and scratch paper

records have been used in your manufacturing and laboratory

facilities and assess the possibility of misrepresentation of data on

official records in each case.

• 2



2. Interview current and former employees to identify activities,

systems, procedures, and management behaviors that may have

resulted in or contributed to inaccurate data reporting in CGMP

records.

3. Identify the specific managers in place who participated in,

facilitated, encouraged, or failed to stop subordinates from falsifying

data in CGMP records, and determine the extent of top and middle

management’s involvement in or awareness of data manipulation.

4. Determine whether any managers identified in item (3) above are

still in a position to influence data integrity with respect to CGMP

requirements or the submission of applications to FDA.



5. Audit past distribution practices and complete a detailed

accounting of the distribution of all batches of product manufactured

within the past two years to determine under what circumstances

batches were distributed prior to release by the Quality Unit.

6. Perform a comprehensive data integrity audit of all data

submitted to FDA supporting drug applications and describe any

discrepancies between data or information submitted to FDA and any

“unofficial” accounting of actual data or practices onsite. This audit

should include both manufacturing data and laboratory data,

including data used in process validation studies and analytical

method validation studies.


THE CASE OF THE FILTER CARTRIDGE

1) Pick up cartridge

2) Find nice, well-lit environment

3) Use scrap paper to note cartridge numbers

4) Go into plant and transcribe into batch record

Can’t read the number, so what do you do?


THE CASE OF THE DEEP POCKETS

The warehouse is managed by a supervisor

For each incoming assignment, a receipt slip is filled in, which then has to

be transcribed into the ERP system

Filling in the receipt slip takes 2 minutes

Transcribing the data takes another 2 minutes

During the mid-morning audit it was observed that the pockets of the

supervisor’s overcoat were so full of receipt slips, some were falling out

The intention was to enter all the information into the ERP system at the

end of the day when it was “quieter”

Too busy right now


THE CASE OF “NEARLY THERE”

The laboratory team has performed data integrity assessments in order to

assure compliance of all activities

One particular form for environmental monitoring is issued only available

via secure printing, which applies a unique (consecutive) number and a

date & time stamp

The team is very proud of their diligence and will to comply

The auditors asked whether the completed forms were reconciled - they

were not

The auditors considered it necessary to verify all forms printed are also

filed

The auditees comment was: “Don’t you trust us?”

Beware of emotions


THE CASE OF DATA PRIVACY

The original, signed Informed Consent Forms for a clinical trial were kept

safe and secure by the Principal Investigator (PI)

The PI left the hospital a few years after the completion of the clinical

study and handed the documents over to the hospital’s archive team

Two years later the sponsor wanted to check if these documents are still

maintained at the hospital

The hospital replied: “For data privacy concerns we cannot provide you

with such information, nor can we allow you access to our archive”

Fact is that the sponsor cannot ascertain whether the hospital has lost the

files, destroyed the files, or whether everything is just fine

It’s all in a secure location - very, very secure


THE CASE OF HOW COULD WE MISS IT?

The filling line fills non-sterile powder into pouches

The pouches are delivered as an endless strip - i.e. before a strip ends, a

new one is spliced on

At the end of the day, the strip of empty pouches remains in the machine.

The next day, a specified set of pouches from the previous day are

removed unfilled, before normal operation resumes

This operation is necessary and is performed diligently, but somehow this

was never written into the master batch record and it was never noticed

that it isn’t documented

As this was one of several line clearance operations (all others were

correctly documented), routine made the team blind to the issue

It’s routine, it’s done well and it is documented, isn’t it?


SUMMARY

Audits often provide interesting insights into Data Integrity Issues

that might otherwise remain hidden

Issues are not necessarily the result of wilful wrongdoing or

malpractice

Audits by external persons provide a fresh (unbiased) view of the

compliance status


THANK YOU


Documents

HISTORY OF DATA INTEGRITY - cbinet.com · HISTORY OF DATA INTEGRITY August 16-17, 2017 Institute of Validation Technology 3rd Annual Data Integrity Validation James Stumpff, RPh,