# Presentation: 525691

## Who’s in Charge Anyway?Responsibility in Today’s Clinical Trial Environment

**Stan W. Woollen**
**Deputy Director **
** ****Division. of Scientific Investigations,**
**Center for Drug Evaluation and Research, FDA **
**DIA June 12, 2000**

## Who’s in Charge Anyway?

- Today’s Clinical Trial Environment
- Characteristics
- Sorting out the players
- Assigning responsibilities
- Issues in dispersing study functions
- Case Studies in Confusion
**It’s not my job, or is it?**
**The blame game and why FDA doesn’t buy it**

## Today’s Clinical Trial EnvironmentCharacteristics

- Large trials at multiple sites widely dispersed geographically
- Liberal use of “sub-investigators”, CROs, SMOs in dispersing study functions
- Increasing use of central IRBs remote to sites
- Remote data collection and electronic transmission
- Need for speed

## Today’s Clinical Trial EnvironmentSorting Out The Players

- Players defined by regulation:
**Investigator/Subinvestigator****	**
**Sponsor****	****	****	****	**
**Sponsor-investigator****	****	****	**
**Subject****	****	****	****	****	**
**Contract Research Organization (CRO)**
**Applicant**
**Institutional Review Board (IRB)**
**Institution**

## Today’s Clinical Trial EnvironmentSorting Out The Players

- Players defined ***ad hoc***
**Site Management Organization (SMO)**
- Monitors/Clinical Research Associate
- Study Nurse/Coordinator
- Data manager
- Medical monitor
- QA auditor
- Anyone who participates in a study activity

## Today’s Clinical Trial EnvironmentAssigning Responsibility

- Responsibilities assigned by ***regulation***
- 21 CFR 312 Subpart D- Responsibilities of Sponsors and Investigators
- 21 CFR 56 Standards for composition, operation, and responsibility of an IRB
- 21 CFR 50 Responsibility for obtaining informed consent
- Sponsors, Investigators and IRBs by regulation

## Today’s Clinical Trial EnvironmentAssigning Responsibility

- Responsibilities assigned by ***contract***
- 312.52 Transfer of obligations to a CRO
**Any or all sponsor obligations may be transferred**
**Transfer must be described in writing**
**If **_**not all**_** obligations are transferred each obligation being assumed by the CRO must be described**
**If **_**all**_** are transferred a general statement is acceptable**
**Any obligation not covered shall be deemed not to have been transferred**

## Today’s Clinical Trial EnvironmentAssigning Responsibility

- Responsibilities assigned by ***contract***
- 312.52 Transfer of obligations to a CRO, legal liability
**A CRO that assumes any obligation of a sponsor shall comply with the specific regulations applicable to the obligation**
**A CRO is subject to the same regulatory action as a sponsor for failure to comply**
**All reference to “sponsor” in the regs. apply to a CRO to the extent that it assumes one or more obligations of the sponsor**

## Determining Responsibility by Function

- IF YOU DO ANY OF THE FOLLOWING....
**Select Qualified Investigators.**
**Provide investigators with information they need to conduct an investigation properly.**
***Ensure proper monitoring of the investigation(s)****
**Ensure study is conducted in accordance with study plan and protocol**
**Control investigational product(s)**
**Safety reporting**
- YOU MAY BE A SPONSOR
***Delegation High Risk**

## Determining Responsibility by Function

**IF YOU **_***Sign a FDA Form 1572...... ***_**YOU ARE AN INVESTIGATOR FULLY COMMITTED TO**:
***Personally conduct or supervise the investigation****
***Ensure that all associates, colleagues, and employees assisting in study conduct are informed about their obligations****
**Conduct the study in accordance with the protocol**
***Comply with all requirements regarding obligations of clinical investigators****
**Inform subjects drugs are being used for investigational purposes and ensure informed consent and IRB requirements are met**
**Report Adverse Events to the sponsor**
**Read and understand the investigator’s brochure**
*******Delegation  high risk**

## Sponsor Responsibilities of Special ConcernClinical Trial Monitoring

**Explicit regulatory requirements **
** ****312.50- Ensure proper monitoring of investigations**
** ****312.56(a)- The sponsor shall monitor the progress of all clinical investigations being conducted under its IND.**

## Sponsor Responsibilities of Special ConcernClinical Trial Monitoring

**Explicit regulatory requirements**
**312.56 (b) A sponsor who discovers that an investigator is not complying shall promptly either secure compliance or discontinue shipments of the investigational new drug and end the investigator’s participation in the investigation**
***notify FDA if an investigator’s participation is ended under the conditions above***

## Investigator Responsibilities of Special ConcernPrepare and Maintain Adequate Records

**Explicit Regulatory Requirement**
**312.62 (b) An investigator is required to *****prepare and maintain***** adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug..... **
**Case histories include the case report form and *****supporting data......***

## IRB Responsibilities of Special ConcernMembership Knowledgeable of Local Conditions

- Explicit Regulatory Requirement
- 56.107(a)....the IRB shall be able to ascertain the acceptability of proposed research in terms of ***institutional commitments*** and regulations, applicable law, and standards or professional conduct and practice.....

## Issues in Dispersing Study FunctionsClinical Trial Monitoring Experiences

- Objectionable observations made during inspections of clinical investigators often reflect inadequate clinical trial monitoring by the sponsor as well as  failures by the IRB and those performing dispersed study functions

## Issues in Dispersing Study FunctionsDiscovering and reporting misconduct

**Case Study in Confusion- Case #1   **
**Sponsor contracts with CRO to monitor studies.**
**FDA inspection discovers falsified records at site.  Simultaneous follow-up inspections of Sponsor and CRO conducted.**
**Records at CRO indicate falsified data discovered after study completed at site. This was reported to sponsor.**
**Sponsor denies ever getting report from CRO**
**Falsification was never reported to FDA by either party**

## Issues in Dispersing Study FunctionsDiscovering and Reporting Misconduct

- When study monitoring has been contracted out, who is responsible for meeting the requirements of 312.56 (b) to report to FDA when an investigator is terminated for noncompliance
- What if the investigator is not terminated?
- What if false data is discovered after the study is complete?

## Issues in Dispersing Study FunctionsSupervision of Subinvestigators

**Case Study in Confusion- Case #2**
- Sponsor contracts with Dr. X to conduct a drug study.
- Dr. X has 3 subjects at his domestic site and oversees 125 subjects at a foreign site not identified on the 1572
- Many problems uncovered at the foreign site: no x-rays, no IRB approval for the site, falsified data, failure to follow protocol

## Issues in Dispersing Study Functions Who Gets The FDA Letter And For what?

**Case Study in Confusion- Case #3**
**Sponsor contracts with CRO to conduct  a drug study.**
**Sponsor obtains the services of a commercial IRB.**
**CRO hires 10 physicians at different sites to serve as clinical investigators**
**CRO selects Dr. B, 1 of the 10 doctors, to serve as the principal investigator.**
**Dr. B has no direct supervisory authority over the other 9 doctors.**
**One of the 9 falsifies data.**

## Issues in Dispersing Study FunctionsSupervision of  Subinvestigators

- How does the principal investigator meet the responsibilities to prepare and maintain adequate and accurate records and personally conduct or supervise the study at remote locations?
- What legal liability does the principal investigator have for submission of false data by subinvestigators?

## Issues in Dispersing Study Functions Almost everyone is on FDA’s Mailing List for This One

**Case Study in Confusion- Case #4**
- Sponsor hires CRO to select investigators and monitor study
- CRO
**Selects a CI with violative history but does not reveal this to the Sponsor**
**Monitoring fails to detect serious noncompliance**
- Central IRB, remote to site, approves study

## Issues in Dispersing Study Functions Almost Everyone is on FDA’s Mailing List for This One

**Case Study in Confusion- Case #4**
- CI conducts study on indigent subjects at public health hospital which doesn’t permit investigational studies
- CI fails to obtain consent, falsifies signatures, serious protocol and records violations (unblinding, prohibited concomitant meds., missing and discrepant records, you name it)

## Issues in Dispersing Study Functions Knowledge of Local Conditions at Remote Sites

- How do Central IRBs maintain knowledge of local conditions at remote sites
- How do sponsors select CROs and SMOs with confidence.
- How do Sponsors, CROs and SMOs select qualified investigators

## The Blame GameWhy FDA doesn’t buy it !

- 	 		NY Times Allegation“Dr. Fiddes replied that they were going to blame the study nurse for all of the problems, and he was going to say he had no knowledge of what was going on.”

## The Blame GameWho gets the blame?

- n (parties blamed) = 23
- n (cases) = 20

- 39%

- 17%

- 9%

- 9%

- 9%

- 9%

- 4%

- 4%

## Excuses

- “I thought the hospital staff obtained informed consent”
- “We had an inexperienced study coordinator”
- “The study nurse resubmitted the source data to the sponsor”
- “The hospital threw out the records”
- “Our staff did not realize...”
- “The study nurse’s improper conduct...”

## Excuses

- “As to the (forged) signatures of four persons, out of eighty patients, suffice it to say....we are talking of a margin of error of 5%....this is well within recognized statistical limits.”

## Know Your Responsibilities

**It’s better to have them written in a contract  rather than in a letter from the FDA **