# Presentation: 933505

## Building Quality into Device Clinical Trials

- Michael E. Marcarelli, PharmD
- Director, Division of Bioresearch Monitoring
- Office of Compliance
- Center for Devices and Radiological Health
- US Food and Drug Administration

**Notes:**
How many of you are familiar with FDA’s BIMO program?

How many of you have experienced a BIMO inspection?

How did a speech on BIMO become a discussion on building quality into clinical trials?

Let’s take a look....

## Bioresearch Monitoring

- Known as _**BIMO**_
- Mandated by Congress in 1976
- Agency-wide program
- _Inspection-based_

**Notes:**
It’s a 30 year old inspection based program that covers all product areas: drugs, devices, biologics, foods, and veterinary medicine

## FDA BIMO Goals

- assure that _human subjects_ taking part in investigations are _protected_ from undue hazard and risk
- assure the _quality and reliability_ of data and information supporting premarket submissions

**Notes:**
The primary goals of the BIMO program are to assure HSP and to assure high quality data/information in submissions.   

A common misconception is that the Office of Compliance’s job is only to prevent unsafe products from entering the marketplace.    We are also interested in assuring that needed medical technologies get into the marketplace top promote public health.

This is where quality systems fit into the equation....

## FDA BIMO Inspections

** ****Four (4) Areas of Focus**
-  Sponsor/Monitor/Contract Research    Organization
-  Clinical Investigator (CIs)
-  Institutional Review Board (IRB)
-  Non-clinical laboratory (GLP)

**Notes:**
All Centers use the same compliance programs to conduct their inspections; we differ in the emphasis we place on certain inspection types.  

For example, CDRH conducts the highest percentage of sponsor inspections compared to other Centers.   This is due to the nature of the device industry and the nature of device research.

As you can see, we cover the entire spectrum of the device research enterprise.

## What should you do when a FDA inspector shows up at your site?

-     Polish the FDA Inspector’s badge
- 9.		Pull the fire alarm
- 8.		Ask if FDA is hiring
-     Beg for forgiveness
- 6.	    Take two aspirin
- 5.		Call your mom and ask her what to do
- 4.		Call a “rag sheet” and tell them your side of the story
- 3.		Hire a crisis management firm
-     Tell inspector that FDA deserves more user fee $$$

**Notes:**
Ok....I was so excited to have the opportunity to speak with you this morning that I had some trouble sleeping last night.  While I was watching late night television, I was quite amused by David Letterman’s Top Ten list, that I decided to create my own Top Ten List.  

What should you do if an FDA BIMO inspector shows up at your site?  

## What should you do when FDA shows up at your facility?

- 1. Just smile and say, “Good morning.”

## Scientific Misconduct Percentage in survey of US based scientists who engaged in questionable research practices

**15.5%** - Changed a study’s results to satisfy a funding source
**15.3%** - Dropped data from analysis based upon a “gut feeling”
**12.5%** - Overlooked other’s use of flawed/questionable data
**10.8%** - Withheld research results
**7.6%** - Circumvented minor rules protecting humans subjects

***Source: Nature June 2005***
***n = 3247***

**Notes:**
What are we seeing in the general research population?

A recent survey published in the June 12005 issue of nature points to some interesting facts regarding questionable research practices.

If the practices outlined in the first 4 bullets occurred during the development of your device, then it could have a significant impact on its approvability.

## CDRH BIMO Compliance Rates

**10-Year CDER OAI rate = 3%**

**Notes:**
What is CDRH BIMO seeing during its inspections of FDA regulated device research?

Discuss EIR classification scheme

Overall non-compliance rate of 15% in all program areas (CI, S/Ms, IRBs, & GLP)

Note OAI comparison to drug research...

## Keys to Compliance

- Changing behaviors
- Involves every one
- Risk-management approach
- Value added
- Documentation

**Notes:**
What are the critical factors for gaining compliance over your device development activities?

Behavioral change is critical.  This means getting everyone’s buy-in regarding the importance of repeatedly producing a product to a consistent, hi quality standard.  In this case, your product is the data/information necessary to gain market clearance.

Your staff needs to know that there is value added in using QS principles in this endeavor and the importance of documentation of the entire device development process.

## A Research Quality System for the 21st Century

** ****	**Based upon QS principles – Quality Unit
-  	Clear understanding of HACCP as it relates 	to the research process
- 	- risk based approach
-  	Data quality by design
- - fitness for use
- -“data lifecycle”

**Notes:**
What can you expect to see in the near future?

The expanded use of QS principles to the conduct of research.  The next revision to ISO 14155 (Clinical Investigation of Devices) will require a quality system.

1. Quality Statement. 
2. Mission Statement for Clinical Research. 
3. Operations Manual. 
4. Job Descriptions (optional). 
5. Standard Operating Procedures. 
6. Work Instructions. 
7. Records and Documents. 
8. Reference Materials, Library. 
9. Glossary. 

Possibly a HACCP based approach to your research.  Where are the critical control points in your device development?

Design quality into the research process?   What is data quality to you?   How do you set tolerances for data quality?  Do you know the quality of your data through various stages of its life-cycle?

## Role of a Quality Unit

- Compliance with all relevant regulations and commitments made in applications or supplements
- _Systems_ that assure control over the collection, recording, and reporting of key data regardless of location
- Assure that _“product”_ meet all quality and reliability characteristics

**Notes:**
What would a quality unit look at during device development?

Again, think of data as the manufactured product.  Where are the risks? What do you do if you find deviations?

How do you account for the need for potential postmarket market data?  Or CMS reimbursemnent data?

## Bottom Line....

- Are you looking at your data and
- are you acting upon it?

**Notes:**
What will the regulatory agencies want to see?

Can you justify deviations?

## Characteristics of Successful Firms

- Responsive to public
- Use Risk Management
- Utilize Quality Systems
- Emphasize the basics

**Notes:**
How do you become a successful firm?

Build TRUST and ensure an ethical approach to business practices.

Device firms are small; 93% have less than 100 employees.  Focus your attention on areas of greatest risk.  Such as SR devices, electronic recordkeeping, vulnerable subject populations....

Operate in control; highlight issues before they become a crisis.  Prevent recurring deviations....

Data quality drives the review process and HSP is the foundation of the research process.

## Suggestions for a Successful Study

- Select qualified investigators and sites
- Obtain feedback on protocol requirements
- Provide adequate training up front
- Stress importance of informed consent process
- Ensure adequate monitoring of data lifecycle
- Bring investigators into compliance

**Notes:**
Using a QS approach....

CIs are like any other contractor.  How do you qualify them?  Is their site set up for this kind of work?  Is their staff qualified? Do they have the tools or time to conduct the research? How do you train them on the use of the device, protocol etc?

Design a strong protocol.  Use pre-IDE meetings.  Get feedback from your CIs.   Collect only essential data.

How do you train your CIs and their staff.   Clinician vs. Investigator.

Monitoring is a process throughout the data lifecycle.   Early to assure sites are ready and to build quality in.  The last thing you want to find is data variances at the latter stages of research.   Fail early....

Have a strategy for reducing recurring deviations and bringing sites into compliance.

## Remember...

- Provide adequate training/qualification  of staff
- Correct issues before they jeopardize submissions
- Focus company culture on good ethics and research practices
- Avoid potential conflicts of interest

## IVD Case Study 

** **

## Background

- OIVD received a marketing submission from _Sponsor A_ for an Rx to OTC chromatographic immunoassay test kit.
- _OIVD Decision:_ Not market-worthy
- _Decision Rationale:_
- Large number % of false positive/negative results obtained from consumer testing.

**Notes:**
Consumer studies: label comprehension and readability.  Get the right result.

## Background

-    Later, a 2nd firm, _Sponsor B_, submitted a 510(k) for essentially the same product.
- _Sponsor B_ consumer test results almost perfect
- BIMO inspection to verify the data quality at _Sponsor B_
_*Suppose you are the FDA; how would *_
_*you approach this inspection?*_

**Notes:**
999/1000 correct answers; 99% readability 95% comprehension.
Included samples at the +25% and –25% of the cutoff concentration.
Qualitative tests point below is neg...point above is positive.

## Sponsor B Inspection

- Characterization Data Records
- Where did samples come from?
- Who prepared samples?
- When were they prepared?
- How were they pkg?
- How were they stored?
- How many were shipped?
- Consumer Study Data Records

## Sponsor B Inspection Results

- No professional analysis of samples/controls used
- No GC/MS validation records
- No protocol
- Incomplete and inaccurate shipment, receipt, disposition of investigational device and controls

**Notes:**
No records to describe component, ingredient, or property of the device used during clinical study
150 subjects; 300 devices shipped.  No records.

## Sponsor B Inspection Results

- Randomization issues
- Records of subjects’ participation in the study were incomplete or inaccurate
- Other marketing submissions questioned
- QSR issues
- Commonalities with Sponsor A

**Notes:**
Firm employees or family members not lay consumers with various ethnic,education and ages.
Over 50% of subjects records changed: Questionnaire recording of test results
Records changed with no explanation
Participant ID numbers were interchanged and renumbered without explanation
 Some signatures predate start of study

## Sponsor A Inspection

- The inspection of Sponsor A identified
- similar data reliability problems
- associated with several submissions
-  & questionable study conduct.

## Expected FDA Actions

- Stop substantive review until data reliability issues are resolved
- Request independent _data/systems audit_
*AND*...

## Expected FDA Actions

**Request a meeting at FDA...**

_**Expected FDA Actions**_

## Possible Firm Responses 

- Develop a Corrective and Preventative Action Plan
- Withdrawal of marketing submission(s)
- Recall of products associated with the questionable data
- Create new oversight systems and procedures
- Revert to damage control
- Reputation
- stockholders
- Shake-up
- System overhaul
- Personnel firing and hiring
- Ethics training

## Clearance to market is grand; clearance of your reputation is 500 grand.

- 			anonymous 2006

## RESOURCES

**FDA Good Clinical Practices**
- http://www.fda.gov/oc/gcp/default.htm
**Device Advice**
- www.fda.gov/cdrh/devadvice

## CONTACT INFORMATION

- mwm@cdrh.fda.gov
- Food and Drug Administration
- Center for Devices and Radiological Health
- Office of Compliance
- Division of Bioresearch Monitoring (HFZ-310)
- 2098 Gaither Road
- Rockville, MD 20850