# Presentation: 242701

## Improving QualityWhat Now?!!

- Stan W. Woollen
- Deputy Director, Division of Scientific Investigations
- June 11,1999

## Improving Quality What Now?

**Quality Concepts in Clinical Trials Revisited **
**Where Quality stands now**
**Good news and bad news (mostly bad)**
**What Now?**
**Moving from concept to reality**

## Quality Concepts in Clinical Trials

- Quality Clinical Trial
- Conforms to _***established specifications***_ for:
- Design
- Conduct
- Reporting
- Reported conclusions and findings can be reconstructed from _***available documentation ***_with the confidence necessary to support regulatory decisions

## Quality Concepts in Clinical Trials

_***Protocol-***_
- Establishes specifications for design, conduct and reporting
_***Case Histories-***_
- Contain documentation necessary to reconstruct study findings and conclusions
_***Study Monitoring***_-
- Ensures documented conformance with specifications for design, conduct and reporting

## Quality Concepts in Clinical Trials

- Quality oriented regulatory requirements
***Clinical Investigator Responsibilities***
- 21 CFR 312.60 -Conduct study according to the _*Protocol*_
- 21 CFR 312.62 (b)-Maintain adequate and accurate _*case histories*_

## Quality Concepts in Clinical Trials

- Quality oriented regulatory requirements
***Sponsor Responsibilities***
- 312.50- Ensure proper _*monitoring*_ of investigations
-  312.56(a)- _*Monitor*_ the progress of all clinical investigations being conducted under its IND.
- 312.56 (b)- Correct and/or report serious noncompliance to FDA

## Improving Quality by Enhancing Compliance

- 	Enhanced compliance with quality oriented regulatory requirements for study conduct, reporting, and monitoring should improve study quality.

## Where We Stand Now...The Good News(Monitoring)

- 38% = NAI; 58% = VAI;  2%=OAI
- Surveys showed in majority of cases that
- CIs felt generally that studies were adequately explained to them by the monitors
- Monitoring logs show who visited sites, dates of visits, and general purpose of visit
- Monitors compared CRFs to source documents, reviewed AE reports, sought clarification and correction of data, examined drug accountability records.

## The Good NewsClinical Inspections - DomesticFY’s 97-98

- The Good NewsClinical Inspections - DomesticFY’s 97-98

- FY97
- n=302

- 40%

- 56%

- 3%

- 41%

- 53%

- 3%

- 3%

- FY98
- n=286

- NAI
- VAI
- OAI
- Pending

## The Bad NewsClinical Inspections - DomesticFY’s 97-98

- The Bad NewsClinical Inspections - DomesticFY’s 97-98

- FY97
- n=302

- 40%

- 56%

- 3%

- 41%

- 53%

- 3%

- 3%

- FY98
- n=286

- NAI
- VAI
- OAI
- Pending

## Where we stand Now... The Bad News(Clinical Sites)

- Where we stand Now... The Bad News(Clinical Sites)

- 	Failure to _*follow the protocol*_ and failure to _*maintain adequate and accurate case histories*_ continue to be among the most frequently encountered findings.

## Clinical Investigator Deficiency Categories - FY 98

**Clinical Investigator Deficiency Categories - FY 98**

**Protocol**

**Consent **
**Form**

**Records**

**Drug**
**Accountability**

**Adverse **
**Events**

**29**

**23**

**15**

**14**

**12**

## Clinical Investigator Deficiency Categories - FY 97

**Clinical Investigator Deficiency Categories - FY 97**

**Protocol**

**Consent **
**Form**

**Records**

**Drug**
**Accountability**

**Adverse **
**Events**

**25**

**21**

**20**

**13**

**5**

## Clinical Investigator Deficiency Categories - FY 96

**Clinical Investigator Deficiency Categories - FY 96**

**Protocol**

**Consent **
**Form**

**Records**

**Drug**
**Accountability**

**Adverse **
**Events**

**34**

**29**

**21**

**11**

**11**

## Clinical Investigator Deficiency Categories - FY 96-98

**Protocol****	****      Consent****	****Records**

## WHAT NOW??Moving from concept to reality

**Quality in Three (not so) Easy Pieces**
**Follow the protocol**
**Keep good records**
**Monitor the study to ensure points above are followed in real time**

## WHAT NOW??Moving from concept to reality

**Why isn’t the protocol followed?**
**The protocol design is impractical in a clinical environment **
**The importance of **_***strictly following***_** the protocol is not emphasized with investigator**
**The investigator doesn’t understand the significance of the protocol and its limits**
**Responsibility for study functions is inappropriately delegated**

## WHAT NOW??Moving from concept to reality

**Enhancing protocol adherence**** **
**Protocol design should be as simple as possible, promoting collection of quality data without compromising study objectives**
**Focus on essential data points**
**Explain significance in terms of study objectives (efficacy/safety) or subject protection**
**Avoid ambiguity and vagueness**
**Inclusion/exclusion criteria**
** ****Adverse experiences**

## WHAT NOW??Moving from concept to reality

**Enhancing protocol adherence**** **
**Protocol design (cont.)**
**All data requirements should pass the ALCOA test**
**Attributable**
**Legible**
**Contemporaneous**
**Original**
**Accurate**

## WHAT NOW??Moving from concept to reality

**Enhancing protocol adherence**** **
**Fully explain protocol limits and stress the importance of strict compliance**
**How much latitude is available for clinical treatment (e.g. concomitant therapy)**
**Is it ok to use the hospital or clinic protocol for performing routine procedures (e.g. chemotherapy)**
**Is it ok to skip procedures that are not medically necessary (lab tests, PEs,Biopsies)**
**Which protocol procedures can be performed by non-physician study support staff**

## WHAT NOW??Moving from concept to reality

**Why aren’t adequate and accurate records maintained?**
**It’s not clear what records are to be maintained**
**What is source data for the study**
**It’s not clear how records are to be completed**
**responsibility**
**quality (ALCOA)**

## WHAT NOW??Moving from concept to reality

**Enhancing Record Quality**
**Clearly identify what records are to be maintained**
**Original source data for critical study endpoints**
**Use the site’s indigenous record-keeping system to the maximum extent possible**
**Explain the peculiarities of regulatory records**
**The need for ALCOA**
**FDA will be inspecting the records (and their investigators are really a pain)**

## WHAT NOW??Moving from concept to reality

**Enhancing Record Quality**
- Case Report forms should be simple to understand and use in the clinic
- Designed to capture only essential information in logical sequence
- Minimize the need for transcription
- Accommodate ALCOA data

## WHAT NOW??Moving from concept to reality

**Enhancing Monitoring Quality**
**Don’t bury your head in the records**
**Talk to personnel performing critical study tasks and observe in real time**
**Educate study personnel as well as the CI on the protocol requirements **
**Listen to and observe what’s going on in the clinic**
**Always go to the source**

## WHAT NOW??Moving from concept to reality

**Enhancing Monitoring Quality**
**Be Politely Persistent**
**Don’t take “no” for an answer when**
**asking for original records**
**insisting on protocol adherence**
**seeking to speak to the CI about visit findings**
**pulling a string to see what unravels**
**Don’t be intimidated by the CI**

## The Bad News - Site #1

- [Dr. X] is a “god of urology!”

## The Bad News - Sites #2 & 3

- Neither the sponsor nor a representative from the sponsor visited the sites *during the study*.
- The protocol, its significance, and the importance of following it were not adequately explained to the CIs.
- CIs never received an investigator’s brochure.
- Some information that was provided was in German; CI did not understand German.

## The Bad News - Sites #2 & 3

- CIs did not sign Form FDA 1572 until *more **than a year after the investigation was completed.*
- IRB granted approval for the study and  a consent form *more than a year after investigation was completed.*
- The consent form that was used lacked most of the elements required under 21 CFR 50.
- No documentation of receipt and return of test article.

## The Bad News - Site #2

- “...led to believe that everything was taken care of, with no further requirements on [his] part.  [He] thought you get FDA approval to do the study and that’s it.”
- “...there was no real protocol”
- “...didn’t think [he] had to follow the protocol.”
- “...felt free to alter the protocol... and did so by varying the doses, for example.”

## The Bad News - Site #2 (continued)

- “I don’t have original notes.” [source documents]
- “[the sponsor] did not explain the need to keep the records”, which were “thrown out...”
- “...didn’t know [he] had to keep them.”
- “was not told that [he] might receive an FDA audit inspection”

## The Bad News - Site #2 (continued)

- “...was not aware that [he] was required to sign a 1572” (Statement of Investigator)
- “... was not aware of [his] responsibility to obtain IRB approval prior to initiation of the clinical investigation.”
- “... was not aware of the required basic elements of informed consent.”

## The Bad News - Site #3

- CI was told to “try to do these things” [listed in the protocol], but that it was more of a “general guide,” that following the protocol was “not necessary”.
- CI threw away study records; sponsor sent backup copies of records for FDA audit.
_*No*_ documentation that informed consent was obtained. (Copies _or_ originals)

## The Bad News - Site #3

- “... came up with the idea of using less of the diluent during treatment to reduce side effects.”
- The protocol and requirements were explained “much later, after the study had been completed”.
- CI was concerned about “running out” of the study drug because it was expensive, so several times he used the contents of one vial on several subjects, and “juggled” the doses to use up the amount on hand so as “not to waste it.”  He “wanted to get mileage out of the product.”

## WHAT NOW?!!!