Depatiment of Health and Human Services 

OFFICE OF 

INSPECTOR GENERAL 

INVESTIGATIONAL DEVICES:


FOUR CASE STUDIES


JUNE GIBBS BROWN 

Inspector General 

APRIL 1995 

OEI-O5-94-OO1OO 
EXECUTIVE SUMMARY


PURPOSE 

To assess in four case studies whether controls over clinical testing of investigational 

devices ensure patient safety and sound clinical research. 

BACKGROUND 

The Food and Drug Administration (FDA) oversees the development of new medical 

devices. For some medical devices, manufacturers must establish the safety and 

efficacy of the devices through clinical trials before FDA will clear the device for 

marketing. To further guard patient safety, Institutional Review Boards (IRBs) 

approve and monitor clinical research within local hospitals. The FDA requested that 

we assess various aspects of the testing process, particularly whether devices are being 

distributed outside approved clinical trials. .. 

We used four case studies to develop a picture of clinical trials for investigational 

medical devices. We spoke with each device’s manufacturer, and selected clinical 

investigators and IRB representatives. We reviewed FDA’s files for the devices, 

obtained shipping records and other documents from the manufacturers, and inspected 

documents from the IRBs we visited. 

FINDINGS 

During our assessment of the testing process, we found problems in three major 

control areas: the accounting and tracking of investigational devices; and the local 

oversight by IRBs including the informed consent process, The exhibit below 

summarizes the kind of problems we found for each device. 

Problems Found in Four Case Studies 

Device A Device B Device C Device D 

Device Tracking 

d 4 d 

IRB Oversight 

J J 4 4 

Informed 

Consent d J 

i 
We Uncovered Problems With The Distniution Or Acemmtability Of Three


Investigational Devices.


Device A was distributed in excess of the approved protocol. This raised questions


about whether patients were properly informed about the devices, and whether


appropriate data was reported to FDA. Also, there was a lack of accountability for


Devices B and C. Clinical investigators and hospitals are unclear regarding their


responsibilities for tracking the use and disposal of investigational devices.


Our Case Studies Also Identified Potential Weaknesses In The Oversight Of Clinical


Trials At Local Sites.


We found that IRBs are dependent on information provided by clinical investigators,


have difficulty monitoring clinical trials, and have difficulty deciding whether a device


study poses significant or non-significant risk. In addition, we found problems with the


informed consent process including missing or incomplete informed consent


documents, questions about how informed consent is obtained, and difficulty in


reading informed consent documents.


CONCLUSION


We believe that in the current environment, investigational devices are often treated


as if they were already approved as safe and effective. In particular, although the


regulations clearly require the careful tracking and disposal of investigational devices,


our case studies show that accounting mechanisms sometimes fail. In addition, some


investigational devices are being used inappropriately outside of approved clinical


trials.


Our case study method does not provide sufficient evidence to determine the precise


extent of problems with the testing of medical devices. Nevertheless, it does raise


serious concerns about systemic weaknesses and casts reasonable doubt on the efficacy


and reliability of the current oversight process.


The FDA commented on the report (see Appendix D) and takes seriously our


findings. The FDA intends to carefully review the regulations and policies regarding


clinical investigations, and take whatever actions are warranted to ensure that clinical


investigations of medical devices are conducted with high ethical standards and in


accordance with all Federal rules pertaining to patient protection.


ii 
TABLE OF CONTENTS 

PAGE 

EXECUTIVE suMMARY 

INTRODUCI’ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..”” ”””” .-s” .”s” 1 

FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. s”””””..””””” 8 

�	 Problems with distribution and accountability 

of investigational devices . . . . . . . . . . . . . . . . . . . . . . . . . ...-...”””””””” 8 

�	 Potential weaknesses in the oversight of clinical 

trials at local sites. . . . . . . . . . . . . . . . . . . . . . . . . . ...” S. .””. ”.”. ”””S”” 10 

CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. s””””””” 16 

MPE~I- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..” O.”” ”O”””” O”o 

k Device Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..”” .””” sA-l 

B: Glossa~ . . . . . . . . . . . . . . . . . . . . . . . . . ...........o..o-.”0”o”.-” “B-l 

CFDA Study Request . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ”.”” .”o-”” C-l 

D: FDA Report Comments.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..”” ”””s. D-l 
INTRODUCTION 

PURPOSE 

To assess in four case studies whether controls over clinical testing of investigational 

devices ensure patient safety and sound clinical research. 

BACKGROUND 

Medical devices range from simple ear swabs and tongue depressors to highly complex 

diagnostic imaging equipment, surgical props and physical implants suchas 

pacemakers. The Food and Drug Administration (FDA) oversees the development of 

new medical devices through the Center for Devices and Radiologic Health. The 

Center for Devices and Radiological Health requested that we conduct a study 

regarding the Investigational Device Exemption (IDE) process (see Appendix C.) The 

IDE regulation (21 CFR Part 812) sets forth the provisions for the conduct of clinical 

investigations of medical devices in the United States. 

Medical Device Ckssijication.s 

As established by the Medical Device Amendments of 1976, there are three 

classifications of medical devices. Class I devices consist of low-risk devices, such as 

bed pans and tongue depressors, and are subject to general controls that include 

premarket notification and prohibitions against misbranding. Class II devices, such as 

hearing aids and electrocardiogram machines, are subject to additional special controls 

that include performance standards and postmarked surveillance. Class III devices, 

such as pacemakers and catheters, generally sustain or support life, are implanted in 

the body, or pose a potential risk of illness or injury. Class III devices are subject to 

general controls, some special controls, as well as the more stringent Premarket 

Approval (PMA) process. 

FDA Markdhg Approval 

Manufacturers gain marketing clearance for many Class I and Class 11devices, and a 

limited number of Class 111devices through the premarket notification process known 

as the 510(k) process. The 510(k) refers to that section of the Federal Food, Drug 

and Cosmetic Act (the Act) that allows a manufacturer to submit an application to 

FDA for a device that is substantially equivalent to a device previously approved for 

marketing by FDA. If FDA agrees that the devices are substantially equivalent, then 

the review time for the new device should be reduced. The FDA might require a 

manufacturer to conduct a clinical investigation of a device in support of their 510(k) 

application, 

For devices that do not meet 510(k) specifications, a manufacturer applies for 

marketing clearance through the PMA process. Before submitting the PMA, the 

1

manufacturer establishes the safety and efficacy of their device through clinical trials. 

The trial is conducted by a study sponsor, who may or may not be the manufacturer. 

(In this report, we use the term manufacturer to refer to manufacturers and study 

sponsors,) The data from these clinical trials are what FDA reviewers will analyze to 

determine that a device is safe and effective enough for commercial distribution. 

ZDE Approval Process 

To conduct a clinical investigation of a medical device, the manufacturer must first


determine whether their study presents a significant risk or non-significant risk to the


patients, known as study subjects. According to the FDA a significant risk study poses


potential harm to clinical trial subjects either from the device or other procedures in


the study. For example studies using infusion pumps, pacemakers, and catheters are


considered significant risk studies. If the study poses significant risk, the manufacturer


submits an IDE application to FDA that details how the clinical trial will be


conducted.


The IDE application includes (but is not limited to) a clinical trial protocol. The


protocol should have well-defined trial end points (what constitutes success, failure, or


complications with the device). The protocol also establishes the number of subjects


that the device must be tested on to prove that the device will work safely and


effectively in a larger population. The characterizations of the test subjects should


also be defined; who in terms of age, medical condition and other factors will be


allowed into the study. Well-defined historical controls or control groups to compare


outcomes may also be necessary. The protocol will describe at how many sites, usually


hospitals, the testing will be done, and how many subjects per site will be included in


the trial. The protocol will also estimate how long it should take to conduct the trial.


Clinical trials conducted at more than one site are called multi-site trials.


In addition to FDA an Institutional Review Board (IRB) must approve the clinical


trial protocol at the specific sites where the clinical trials take place. The IRBs are


boards or committees within an institution which oversee the protection of human


subjects involved in clinical trials. The IRBs review protocols and the informed


consent forms given to the subjects of the clinical trials for both significant and non-


significant risk studies. The IRBs must review all clinical trials occurring within their


institutions on an on-going basis.


If a manufacturer determines that their study is non-significant risk, then only the


IRBs at the sites where the manufacturer wants to conduct the trial will review the


protocol. Examples of non-significant risk devices include daily wear contact lens,


wound dressings and some magnetic resonance imaging devices. If the IRBs agree


with the non-significant risk determination, they may grant what is known as an


“abbreviated IDE’ to the manufacturer and allow the manufacturer to begin the


clinical trial at that institution. However, if any single IRB that reviews the protocol


does not agree with the manufacturer that the study is non-significant risk, then the


manufacturer must inform FDA of the IRB’s decision. The FDA may agree with the


2 
manufacturer that the study poses non-significant risk, and the manufacturer may 

conduct the study at any institution where the protocol is approved. However, if FDA 

determines the study is significant risk, then the manufacturer must submit a full IDE 

application to FDA. 

lDE Clinical Investigators 

Before or after a manufacturer obtains IDE approval, they may recruit the physicians, 

known as investigators, to conduct the clinical trial. These clinical investigators might 

be preeminent specialists in their field or major customers of the manufacturer. In 

some cases, the manufacturer recruits clinical investigators based on the referral of 

another investigator. 

The clinical investigators are responsible for obtaining IRB approval for trial research 

conducted at their institutions. Once the clinical investigator secures IRB approval, 

they may begin recruiting subjects for the clinical trials. In most cases the subjects for 

device trials come from the clinical investigator’s private practice. The clinical 

investigator is responsible for obtaining the subject’s informed consent, recording study 

data and conducting subject follow-up. 

Concerns about the IDE Process 

There have been concerns about the IDE process and the quality of the clinical data 

obtained through this process. A recent report by FDA’s Committee for Clinical 

Review found enough deficiencies in the design, conduct and analysis of clinical trials 

in enough medical device applications to suggest an industry-wide problem. In some 

cases, these deficiencies were determined serious enough to impede FDA’s ability to 

judge the safety and efficacy of the device. 

Adherence to Clinical BotocoLr 

Some staff at the Center for Devices and Radiological Health have explained that one 

way clinical data is compromised is that clinical investigators and manufacturers do not 

adhere to the protocol subject limit and allow more subjects into the clinical trials than 

necessa~. They may also admit subjects into the clinical trial that do not always meet 

the criteria for admission stated in the clinical protocol. If this happens, trial data 

could be compromised because investigators and/or manufacturers might only report 

the best outcomes of selected subjects. 

There have been several documented cases where manufacturers have distributed 

investigational devices more widely than is stated in the clinical protocol. A report by 

the House Subcommittee on Oversight and Investigations cites a recent example of 

uncontrolled growth of a clinical trial involving a silicone angioplasty balloon used in 

controlling cranial bleeding. The company responded to the increased demand of 

3

physicians byproviding thedevice inuncontrolled numbers. According to FD~the 

uncontrolled expansion of the trial compromised the validity of the clinical data.1 

Cost Recoveiy Concerns 

One possible reason why more subjects are admitted to clinical trials than necessa~ is 

that per the IDE regulations, manufacturers may recover the cost of developing and 

testing devices in the investigational stage. Drug manufacturers, on the other hand, 

are prohibited from recovering any costs until the drug has been approved, except in 

rare circumstances. The Congress allowed cost recovery of investigational medical 

devices to foster the development of new medical devices by small companies. 

In addition to the manufacturer being permitted to recover costs, clinical investigators 

are allowed to charge the subjects not only for the device, but also for any procedures 

or services involving the device. This provision may lead some manufacturers and 

clinical investigators to include more subjects and to continue clinical trials beyond 

what is necessary to establish safety and efficacy. 

Rwnotibn Cimcems 

Additional concerns exist that some manufacturers are promoting devices as safe and 

effective while still in the investigational stage. Although manufacturers can recover 

the actual cost of development, under FDA regulations, manufacturers may not 

describe an investigational device as safe or effective, commercially distribute the 

device beyond the scope of the clinical trial, or recover costs beyond what is 

reasonable for device development before FDA approves the device. 

One example of how a manufacturer used their IDE to commercially promote a 

device was described in an Office of Inspector General report dated February 1991. 

In this case, the manufacturer developed a device which had a 510(k) approval for one 

use and an IDE for another use. However, the manufacturer, through training 

seminars, catalogs, videotapes and technical manuals, commercially promoted the 

experimental use of the device.z 

Heallh Care In­ Envuonment 

The general environment of the health care industry may promote the distribution and 

use of unapproved medical devices beyond clinical protocol design. Hospitals 

lLess Than the Sum of Its Parts, Subcommittee on Oversight and Investigations, 

May 1993, page 12. 

2FDA Medical Device Re~ulation From Premarket Review to Recall, Office of 

Inspector General, February 1991, page 8. 

4 
experience pressure to acquire the latest in equipment to compete with other 

hospitals, and physicians also want to stay competitive as well as provide their subjects 

with potentially more effective treatments. 

Informed Consent IYocess 

Questions have also been raised regarding the informed consent process both in 

investigational device studies and other studies. The Congress held hearings in 1994 

regarding informed consent and some of the potential problems with subjects not 

giving informed consent. The hearing also discussed the appropriateness of using 

investigational devices without a subject’s informed consent. 

FDA Eflo~ 

The FDA is attempting to improve the quality of clinical data it receives by more 

outreach and education of the medical device industry about clinical protocol design 

and conduct. The FDA also attempts to ensure the integrity of the clinical trial data 

through its Bioresearch Monitoring program. Through this program, FDA audits 

manufacturers, IRBs and clinical investigators. 

METHODO~GY 

We were asked by the Center for Devices and Radiological Health to examine the 

IDE process, particularly whether manufacturers were using the IDE process to 

commercialize investigational medical devices. To understand how and why medical 

devices might be commercialized, we believed that we needed to fully assess the 

environment in which medical devices are tested. To accomplish these tasks, we 

choose a case study methodology. 

Using a case study approach presents both limitations and advantages. Devices 

chosen for the case study and any problems found may not be representative of all 

investigational medical devices. However, the case study approach provides a 

comprehensive picture of how investigational medical devices are developed. A 

shallower, though broader based review would not provide this understanding. 

Selection of Devices 

To select the investigational medical devices for inclusion in our case study, we 

examined FDA’s entire IDE database which is used for tracking the status of an IDE 

application. There were 1,509 IDE applications in the database. Over one-third of 

the IDE applications were denied by FDA. We automatically dropped these 

applications for our case study review. 

We did not consider IDE applications dated before January 1986. We dropped from 

consideration IDE applications for intraocular lens since these applications are 

5

regulated by a different set of regulations than IDE applications for investigational 

medical devices. 

We eventually narrowed the number of IDE applications for review to 30 files. 

Included in these files were several devices and device types suggested by FDA. After 

a comprehensive review of these 30 files, we eliminated seven IDE applications for 

devices with previous 510(k) or PMA approval. We eliminated these applications 

because of the difficulty in distinguishing those devices shipped for use in clinical trials 

and those devices shipped for commercial distribution. We also eliminated seven IDE 

applications that were single-sites because we thought that commercialization would be 

more prevalent in multi-site trials. 

We chose devices that were used in different regions of the body. This allowed us to 

speak with clinical investigators in different medical specialties. Once we selected an 

IDE application, we eliminated any similar devices. 

Ultimately, we selected four devices for our review. One of these devices was 

suggested by FDA because of their suspicions about commercialization of the device. 

A description of the devices are located in Appendix A. The names of the devices are 

protected from disclosure under the Freedom of Information Act because of the 

proprietary nature of the information. 

Inform.ation Gathered 

For each device selected, we spoke with the device’s sponsor or manufacturer.3 We 

asked general questions about the current IDE process. We also asked specific 

questions about the device selected for the case study, One manufacturer, on advice 

of attorney, would not discuss the specifics of the clinical trials for the device selected. 

We spoke with selected clinical investigators and institutional review board 

chairpersons or their designates for each of the devices. We did not interview every 

clinical investigator or IRB representative involved in the clinical trials. We selected 

the clinical investigators and IRBs based on their geographic location. In our 

interviews with IRB representatives, we asked about their experiences not only with 

the case study device, but also with investigational devices in general. 

In addition, for Devices A and B, we obtained information from FDA audits of clinical 

investigators or IRBs. For one of the devices, we spoke with the FDA reviewers. 

Exhibit 1 summarizes the total number of the devices’ investigative sites and out of 

that number, how many clinical investigators and IRB representatives we interviewed 

and/or reviewed files for the study. 

3For one device, the manufacturer sold the technology. In this case, we spoke with 

both the original manufacturer and the current manufacturer. 

6 
Exhibit 1 

We reviewed the IDE files 

for each device. We 

reviewed in depth the 

original application, and 

any amendments or 

supplements to the 

application. When 

applicable, we also 

reviewed the PMA for the 

device. 

We obtained the shipping 

records for each of the 

devices. For the device 

DEVICE Total # of # of # of IRBs 

Investigative Investigators We 

Sites in the We Reviewed 

Clinical Trial Reviewed 

A 191414 

B I 13 1515 

c I 47 I 10 18 

D I 11 ]213 

that was sold, the current manufacturer could not find the original shipping invoices,


but was able to provide us with a spreadsheet detailing how many were shipped, how


many were returned and how many were used. The manufacturers also provided us


with copies of investigator agreements, informed consent documents, clinical protocols,


and other information relevant to the devices.


We obtained pertinent documents from the IRBs we visited. These documents


included any material submitted to the IRB by the clinical investigator,


correspondence between the IRB and the clinical investigator, or the IRB and the


manufacturer, progress reports, and copies of the minutes of the IRB meetings where


the device was discussed. From one hospital, we obtained hospital purchase orders for


the investigational device.


We supplemented our interviews and data gathered through a review of FDA audit


reports for the devices selected. We also accompanied FDA inspectors during their


audits of two separate clinical investigators for one of the devices. During these


audits, we completed a file review of subjects involved in the clinical study.


Data Ana@iY 

We entered all the shipping records received into a database. We analyzed this 

database and related records to determine whether investigational devices had been 

shipped in excess of protocol limits. We reviewed all other submitted and gathered 

documents. 

We also subjected informed consent documents to the computer based application 

Grammatik IV, which analyzes overall readability of documents, and calculates an 

index of reading difficulty for written material. 

We conducted this inspection in accordance with the Quality Standards for Inspections 

as developed by the President’s Council on Integrity and Efficiency. 

7

FINDINGS


During our assessment of the IDEprocess in four case studies, we found problemsin 

three maior control areas: the accounting and tracking of investigational devices; and 

the local-oversight by IRBs including the ~nformed con<ent proce~s. Exhibit 2 

summarizes what kind of problems we found for each device. 

Exhibit 2 

Device A Device B Device C Device D 

Device Tracking 

J d d 

IRB Oversight 

d J J d 

Informed 

Consent d d 

The first finding below discusses in detail the accounting and tracking issues that FDA 

asked us to look at. The second finding describes problems we discovered regarding 

IRB oversight and informed consent as we looked at the broader IDE environment. 

WE UNCOVERED PROBLEMS WITH THE DISTRIBUTION OR 

ACCOUNTABILITY OF THREE INVESTIGATIONAL DEVICES. 

One of the most important elements of clinical trial design is total number of subjects 

the device will be tested on, and the defined characteristics of those subjects, including 

age and medical conditions. The FDA reviewers must be sure that the data from the 

studies they analyze accurately reflects the outcomes and effects from the use of the 

device. Limiting the numbers of subjects in a clinical trial protects the overall 

population until determinations of safety and efficacy can be made. The distribution 

and use of investigational devices beyond the protocol limit potentially compromises 

the data; investigators or manufacturers might only report on the best outcomes, or 

not report poor outcomes, or certain side effects. To ensure that subject limits are 

being complied with, accurate distribution, use, and disposal records must be kept. 

While not generalizable to all clinical investigations of devices, these problems portray 

how unchecked distribution can happen, and why it is difficult to monitor. 

Device A Was Dhtn”buted In ficess of lhe Approved Protocol 

The approved clinical trial for Device A consists of nine separate sites. Each site may 

test no more than 75 devices. We analyzed the shipping records for Device A. 

8

Device A consists of three separate components. Each component is available in 

different sizes. We limited the analysis to one of the three types of components used 

in the device. No more than two of these components can be used in a surgery, with 

a majority of surgeries only utilizing one component. 

Our initial analysis of the shipping records for all nine clinical investigators for Device 

A showed significantly more of these components shipped than reported to FDA as 

implanted. The manufacturer’s 1994 annual progress report to FDA says a total of 

284 components were implanted nationwide; however, the shipping records show that 

1,319 components were shipped. The manufacturer explained that the large number 

of devices shipped were warranted because of the need to have a number of different 

sizes in stock and available at the time of surgery. 

To check the manufacturer’s assertion, we reviewed documents for two different 

clinical investigators for Device A. 

For one of the clinical investigators, we obtained hospital purchase orders for Device 

A. According to the hospital representative, in addition to their use for accounting 

purposes, the purchase orders are also used to track subjects who received the device. 

The purchase order date for the device is usually the day of surgery or within 1 to 2 

days following the surgery. 

Analysis of the shipping records for this clinical investigator show that the 

manufacturer shipped a total of 327 components to the regional distributor who 

supplies the clinical investigator with the investigational device. The hospital purchase 

orders show that a total of 264 components were implanted in 258 subjects by either 

the clinical investigator or the co-investigators. However, the 1994 annual progress 

report submitted by the manufacturer to FDA and by the clinical investigator to the 

IRB says that a total of only 37 components were used by this clinical investigator. 

Clearly the clinical investigator has exceeded the 75 case limit of the approved 

protocol at the local sites. 

It is unknown whether this clinical investigator or the manufacturer only reported data 

on the first 37 subjects who entered the study, if the clinical investigator or 

manufacturer selected certain subjects to report on, or if these 37 cases were the only 

subjects who met the subject selection criteria, In any case, it raises questions on the 

quality of information being reported to FDA. 

We also reviewed an FDA audit report for a Device A clinical investigator who died 

in December 1992. According to the FDA audit report, the clinical investigator 

reported completing a total of 19 device implants during the entire trial period. Our 

analysis of the manufacturer’s shipping records show that a total of 77 components 

were shipped to the distributor for the clinical investigator. After the death of the 

clinical investigator, the distributor returned only 15 components, leaving 43 

components unaccounted for. We are unsure of the status of these 43 components 

9

since the components should have been returned to the manufacturer when the 

clinical protocol was terminated. 

A recent FDA audit of the manufacturer found that the manufacturer could not 

account for up to 25 percent of all the components shipped. 

l%ere Ww A Lack of Accountability for Devkes C and B 

Under the IDE regulations, clinical investigators are responsible for documenting the 

receipt and distribution of investigational medical devices: the type and quantity, the 

names of all persons who received the device, and why and how many were returned, 

repaired or otherwise disposed of. However, according to 12 of 20 of the clinical 

investigators we spoke with, the responsibility for maintaining the inventory of 

investigational medical devices lies with the hospital, and not the investigator. The 

hospital may or may not choose to track these devices. 

Our analysis of the shipping records for Device C indicate that the number of devices 

shipped to various clinical investigators exceed the number of cases reported to FDA. 

These numbers range from one or two extra devices per investigator, up to 100 extra 

devices. According to one investigator we spoke with, in some circumstances, a device 

may be opened in surgery (thereby destroying its viability for future use), but not used 

on a subject. However, we were unable to determine whether some devices were 

actually used in unreported subjects or whether the devices were disposed of by the 

clinical investigator. There was no accountability or tracking for these extra devices by 

the clinical investigators we reviewed. 

The use of an investigational device is supposed to be limited to subjects enrolled in 

clinical trials or in rare emergency use with the IRB and FDA approval after obtaining 

the subject’s informed consent. Our inability to account for the devices raises 

questions regarding whether the devices were used, whether subjects were informed, 

and whether data was collected and submitted on the subjects. 

During an FDA audit, one of the clinical investigators for Device B claimed that all 

tracking records for the device were kept by the hospital. However, the hospital could 

not produce any records because they did not keep them. The FDA auditor had to 

rely solely on records provided by the manufacturer. 

OUR CASE STUDIES ALSO IDENTIFIED POTENTIAL WEAKNESSES IN THE 

OVERSIGHT OF CLINICAL TRIALS AT LOCAL SITES. 

During the course of our study, we attempted to understand how clinical trials are 

conducted. We were struck by how the current system of clinical trials for medical 

devices merges scientific research with patient care. Physicians practicing in their 

normal environment are asked to conduct scientific research on patients. 

10

We realize that physicians are concerned about obtaining potentially more effective 

treatments for their patients. While becoming a clinical investigator may ensure the 

supply of these potentially more effective treatments, it also adds to the physician’s 

responsibilities. For many physicians, clinical research is an area where they have little 

training or experience. 

We found that FDA manufacturers, IRBs and clinical investigators are all responsible 

for ensuring that clinical trials are properly conducted. If clinical trials are not 

conducted properly at all levels then the study results may be invalid. We focused our 

review on the local levels of oversight and controls in the IDE process. 

Two major controls in the IDE process are local oversight of clinical investigators by 

institutional review boards and the informed consent process for human subjects. 

These controls not only ensure proper clinical trials, but also ensure subject safety and 

the collection of reliable data from clinical trials. 

We found that IRBs are dependent on information provided by clinical investigators, 

have difficulty monitoring clinical trials, and have difficulty deciding whether a device 

is a significant risk versus non-significant risk device. In addition, we found problems 

with the informed consent process including missing or incomplete informed consent 

documents, questions about the informed consent process, and reading level difficulty 

of informed consent documents. While these problems may not be representative of 

all clinical trials being conducted in the United States, we found one or more 

problems in 11 of 20 sites we examined. 

Local Overnight of Clinical Inveshgaton by Institutional Review Boards 

Institutional Review Boards monitor human subject research occurring within their 

hospital or institution. Members of an IRB generally include physicians - usually of 

different specialties - nurses, pharmacists, hospital administrators, a lay member of the 

community, and often a member of the clergy or a medical ethicist. The IRBs in our 

case studies ranged from large university based teaching hospitals with 26 members 

overseeing 2,600 ongoing studies to small community hospitals with 8 members and 55 

ongoing studies. 

To conduct its oversight of all protocols, including devices, an IRB will first review a 

clinical protocol submitted by a potential investigator, primarily to determine the risk 

versus benefit to the subject in the clinical trial. An IRB can require that changes be 

made to a protocol. The IRBs also focus attention on the informed consent 

document, and may require content or wording changes. In addjtion, IRBs have the 

authority to suspend or terminate studies within their institutions. 

Reliance on information provided by clinical investigators 

The IRBs generally rely exclusively on information provided to them by the 

investigator, and sometimes a manufacturer. As noted earlier, in one of our case 

11 
studies the investigator reported in an annual report that 37 cases had been completed 

using Device A. Our review of that hospital’s invoice records showed that 264 

investigational devices had been implanted by the date of the annual review. Relying 

on the information provided by the investigator, the IRB continued to approve the 

study which had an institutional limit of 50 to 75 implants, even though the hospital 

records indicate that the clinical investigator had far exceeded that limit. 

For Device D, the clinical investigator reported to the IRB that zero devices were 

implanted during the course of the study. Reports from the manufacturer showed that 

three devices had been implanted at that institution, including one device that was 

implanted after the investigator informed the IRB that the study was closed. 

Monitoring a clinical trial 

Although IRBs have authority to suspend or terminate studies, they do not always 

follow up or veri~ that their orders have been carried out. A clinical investigator for 

Device A was told to suspend the investigation, pending submission of an annual 

report. This investigator implanted 15 investigational devices during the six week 

period of the suspension. It also appears that the same investigator implanted two 

devices prior to FDA or IRB approval for the device. 

In an example from Device B, the IRB approved the protocol pending changes to the 

informed consent document. The investigator responded that the changes would be 

made, yet we found they were not. The IRB had not followed up to see if the 

changes had been made. 

Two IRBs for Device A were not aware of a change made by the manufacturer to the 

protocol during the course of the study. This change involved the addition of a 

different sized device to the study. The IRBs should have been made aware of and 

approved this change as it affects the rights, safety, and welfare of the trial subjects. 

However, the IRB must rely on investigators and manufacturers to submit this 

information. 

In another example, an investigator for Device B did not inform the IRB that he had 

moved to another city, and was no longer practicing at that institution. The IRB only 

became aware that the investigator had moved when a human subject from the trial 

went to a hospital clinic complaining of pain in the investigational device implant area. 

The investigator had referred the trial subjects to this clinic, without ever officially 

transferring the study and the participating subjects to a new investigator. The IRB 

then assigned a new investigator to the study. In further communication with the IRB, 

the former investigator did not understand why such a transfer needed to occur, as he 

intended to conduct follow-up during periodic visits to the city. The IRB informed the 

investigator that the subjects were human subjects in a trial at an institution, not 

private patients. This example raises some questions regarding the respective 

responsibilities of IRBs and manufacturers. Who should educate the clinical 

12

� 

� 

� 

� 

� 

� 

investigator regarding reporting and subject care responsibilities in a clinical trial, as 

these differ from private practice? 

Deciding Whether a Clinical Trial poses Significant or Non-significant Risk 

One of the duties that FDA has delegated to IRBs is the determination of significant 

versus non-significant risk device studies. This in an important determination, because 

all significant risk studies must receive an IDE from FDA before beginning a clinical 

trial. If a manufacturer determines that its study poses non-significant risk, and if the 

IRBs also determine the study is non-significant risk, the manufacturer can begin a 

clinical trial on the device without knowledge or approval from FDA. 

Our interviews with IRB representatives revealed that many IRBs are confused or 

unclear about what constitutes significant risk studies. In some cases, an IRB bases its 

determination by comparing the risk of the device or procedure to other approved 

devices. Thus, an IRB might consider the implantation of a pacemaker to be nonsignificant risk, because the risk is compared to the risk of implanting an approved 

pacemaker. Our review of IRB records revealed that 3 out of 10 IRBs for Device B 

determined the study as non-significant risk. The FDA through its own study of this 

issue found that nearly one-quarter of the non-significant risk devices approved should 

have been significant ~isk de~isions. Although FDA is available to answ~r IRB 

questions about this and other matters, an IRB will not call if they believe they have 

made a correct determination. 

Informed Consent for Human Subject3 

Most medical ethicists view informed Exhibit 3 

consent as a process in which the 

investigator thoroughly communicates 

to the subject the significance of their 

participation in a clinical trial. 

Informed consent means that subjects 

clearly understand that they are 

participating in research for devices 

that have not yet been proven safe or 

effective. Although informed consent 

ideally involves both verbal and written 

communication, most government 

officials, manufacturers, IRBs, and 

clinical investigators deem that 

informed consent has been given when 

a subject signs the informed consent 

document. However, as Exhibit 3 

illustrates, the extensive and sometimes 

complicated information that must be 

Informed Consent Should: 

Explain that the device has not been 

approved as safe and effective by FDA. 

Describe any potential risks and 

benefits expected from participating in 

the clinical trial. 

Describe the length, nature and 

number of subjects in the clinical trial. 

Explain the patient’s rights including 

that their participation is voluntary 

and they can withdraw at any time. 

Explain who they should contact if 

they have any questions about the 

research or their rights as research 

subjects. 

Explain the patient’s responsibilities as 

a research subject including their 

responsibilities for follow-up visits for 

data collection. 

13

relayed through an informed consent 

consent that much more important. 

Missing or incomplete documents 

document makes the verbal process of informed 

We found no informed consent documents in the individual case files of one 

investigator for Device C. There were surgical release forms, but no informed consent 

documents. The surgical consent forms did not explain that the device was 

investigational and the risks associated with the device. Although the investigator 

claimed that all research subjects received informed consent, an interview with the 

investigator’s assistant revealed that while the subjects for another study for a similar 

device received informed consent, the subjects for the Device C study did not. 

A review of a clinical investigator’s files for Device B revealed that the informed 

consent document was missing information about who (other than the investigator) the 

subject should contact with questions or complaints about the study. This was the 

case, even though the IRB requested that the informed consent document be 

amended to show who to contact regarding questions about the study. 

Cluestions about the process 

Two clinical investigators for Device C sometimes waited to obtain subjects’ informed 

consent until after the surgery was performed. The physician would decide during the 

surgery whether the subject should receive the investigational device or some other 

device. Both physicians claimed that the investigational nature of the device was 

discussed with the subject prior to surgery. Because of this practice, one of these 

clinical investigators never obtained informed consent from some of the subjects. 

For Device B, FDA received complaints from a physician (not an investigator for the 

device) alleging that a subject was not aware that the implanted device was 

investigational. To date FDA has not completed an audit of the clinical investigator 

and we are unsure if the subject signed the informed consent document. Nevertheless, 

even if the subject had signed an informed consent document, this allegation indicates 

that some subjects might not know what they are signing. 

In several cases, investigators we interviewed acknowledged that they have little to do 

with actually informing the subject about the study or device. This communication is 

usually left up to an assistant or nurse. While this may not lead to subjects not being 

informed, it does add to the “business as usual” atmosphere in doctor’s offices where 

medical device research is conducted. The investigator behaves more as a treating 

physician than as a clinical investigator. 

Evidence obtained during a FDA audit of an investigator for Device B, showed that 

most subjects signed the informed consent documents the day before surgery. This, 

we were informed, is the norm for many clinical investigations. Furthermore, the 

regulations do not indicate when, prior to a procedure or surgery, informed consent 

14 
must be given, Technically, there is nothing wrong with this practice. However, the 

process of informed consent means that subjects understand and volunteer for 

participation in a study before agreeing to surgeries with investigational devices. 

Considering that most physicians schedule non-emergency surgeries in advance, this 

raises questions as to why the informed consent documents are not signed before 

scheduling surgery. There is no evidence that a subject has been verbally informed of 

the investigational nature of the device. An informed consent document signed 1 day 

before surgery could easily be lost among the other hospital forms, including surgical 

release forms, that must be signed before surgeries. 

Difficulty reading informed consent documents 

We gathered samples of informed consent documents from each of the investigators 

we interviewed. Because of IRB requirements, and limited manufacturer guidelines, 

documents may vary from site to site. Overall we found informed consent documents 

range from providing direct, numbered, and simple statements, to convoluted and long 

paragraphs. In any case, due to the extent of the information that must be provided, 

these documents usually run four pages or more. 

A reading difficulty and fog index analysis of four of the informed consent documents 

(one for each device in our case studies) revealed reading grade levels of college level 

to graduate level ability, and reading difficulty from fairly difficult to difficult. Some of 

the verbage involved, such as technical device names and other medical terminology, 

contribute to such high levels. Yet the question remains, do patients understand what 

they are signing, and if not, is it adequately explained? 

15

CONCLUSION


We believe that in the current environment, investigational devices are often treated 

as if they were already approved as safe and effective. In particular, although the 

regulations clearly require the careful tracking and disposal of investigational devices, 

our case studies show that accounting mechanisms sometimes fail. In addition, some 

investigational devices are being used inappropriately outside of approved clinical 

trials. 

Our case study method does not provide sufficient evidence to determine the precise 

extent of problems with the testing of medical devices. Nevertheless, it does raise 

serious concerns about systemic weaknesses and casts reasonable doubt on the efficacy 

and reliability of the current oversight process. 

The FDA commented on the report (see Appendix D) and takes seriously our 

findings. The FDA intends to carefully review the regulations and policies regarding 

clinical investigations, and take whatever actions are warranted to ensure that clinical 

investigations of medical devices are conducted with high ethical standards and in 

accordance with all Federal rules pertaining to patient protection. 

16

APPENDIX A 

Device Descriptions 

A-1 
Device A 

This is a prosthetic device with a chemical coating to promote bone growth. The FDA 

has approved versions of the device without the coating for marketing. 

The manufacturer submitted an application for an IDE in September 1988. The FDA 

initially denied the application citing concerns with the material used in the device and 

questions regarding the clinical protocol. The manufacturer amended their original 

application. The FDA approved the IDE in February 1989. 

In July 1989, the manufacturer submitted a supplement to their IDE requesting FDA 

approval to manufacture and test two modifications of the device. The FDA 

approved the modifications in November 1989 and set a limit for the clinical study of 

600 implants at 15 institutions. 

The manufacturer originally recruited a total of 11 clinical investigators to conduct 

clinical trials at their respective institutions. However, two clinical investigators 

dropped out before the study began. A total of nine clinical investigators participated 

in the study. 

The clinical trials are currently active and ongoing. 

Device B 

This is an orthopedic device which promotes the growth of bone mass between two 

bones. The device comes both coated with a chemical substance to promote bone 

growth and uncoated. 

The manufacturer submitted an original IDE application in January 1991, The FDA 

had concerns with the application. The manufacturer submitted a number of 

amendments addressing FDA’s concerns. The FDA approved the IDE in September 

1991. 

The FDA limited the number of subjects in the study to 240 at 15 centers. A total of 

number of 13 clinical investigators participated at 10 institutions. 

The clinical trials are currently nearing completion with a planned PMA submission. 

Device C 

This opthalmic device is used in eye surgeries. Originally, nine individual sponsorinvestigators received IDE approval from FDA for use of the device. In 1988, FDA 

requested that one sponsor apply for an IDE under which a number of clinical 

investigators would be covered. 

A-2

The sponsor submitted a PMA which initially was not accepted by FDA. The original 

sponsor transferred the IDE to another sponsor. This sponsor submitted a PMA 

which was accepted by FDA in March 1992. A number of individual clinical 

investigators applied for their IDE to receive the investigational device. The FDA 

granted most of the IDE applications submitted. In total 47 clinical investigators 

conducted clinical trials on the device. The total number of subjects that were allowed 

to participate is difficult to distinguish because of the number of independent IDEs. 

The FDA has approved the device for marketing. 

Device D 

The device treats urinary obstructions. The manufacturer submitted their original IDE 

application in April 1991. The FDA initially disapproved the application citing 

concerns about the performance of the device and the clinical protocol. The 

manufacturer submitted an amendment to their original IDE addressing FDA’s 

concerns. The FDA approved the IDE in July 1991. 

The FDA approved a limit of 150 subjects at 10 investigational sites for the clinical 

study. However, during the course of the study the number of sites increased to 11. 

The clinical trials are closed with no further subject enrollment. 

A-3

APPENDIX B 

Glossary 

B-1 
Terms are described in terms of medical device development and research.


Centerfor Devices and Radiological Health (CDRH) - the Center within the Food


and Drug Administration which regulates the development and marketing of medical


devices in the United States.


Clinical Investigator or Investigator - the person, usually a physician, who tests an


investigational device on a human subject.


Clinical Trial - a study involving humans in which a medical device, is tested to


establish safety, efficacy, or new indications.


Federal Foe@ Drug, and Cosmetic Act (the Act) - the legislation that established


FDA’s oversight of, among other things, medical devices.


Food and Drug Administration (FDA) - the Agency within the Public Health Service


of the United States Department of Health and Human Services which protects the


public health by, among other duties, regulating medical devices.


510(k) - the section of the Federal Food, Drug, and Cosmetic Act which allows a


manufacturer of a medical device to bring a new device to the United States market


because it is substantially equivalent to a device that is already on the market.


Human Subject or Subject - a person who undergoes the testing of a medical device.


Informed Consent - the cognizant approval of a human being to participate as a test


subject in medical research.


Informed Consent Document - the form which explains the purpose and description of


a clinical trial, as well as the rights of participating human subjects. A human subject


is deemed to have given their informed consent to participate in the described


research when they sign the informed consent document.


Institutional Review Board (IRB) - the committee or board that reviews and approves


research involving human subjects at a local institution.


Investigational Device Exemption (IDE) - the regulation (21 CFR Part 812) that sets


forth the provisions for the conduct of clinical trials for medical devices in the United


States.


Manufacturer - the company that makes the medical device.


Medic-al Device - any equipment that is used in the diagnosis and/or treatment of a


medical condition. Medical devices range from band-aids to pacemakers.


B-2

Premarket Approval (PMA) - the process and application to FDA by which a 

manufacturer of a new medical device brings their new device to the United States 

market. 

Protocol - the design of a clinical trial, simply put, what will be tested, how it will be 

tested, on whom will it be tested, how many will be tested, how long it will be tested, 

and what will be established through the testing. 

Significant and Non-Significant Risk Studies - before conducting a clinical trial for 

medical devices, a sponsor must determine if their study poses significant risk for harm 

to the human subjects participating in the study. The determination of significant risk 

for a study requires that a study sponsor or manufacturer apply for an IDE from FDA 

in order to conduct the study in the United States. 

Study Sponsor or Sponsor - the person or persons who organize and run the clinical 

trial. This may be the manufacturer, or someone the manufacturer has contracted 

with to perform the duties. 

Sponsor/Investigator - a clinical investigator who is both the sponsor and the 

investigator in a clinical trial. Usually a sponsor/investigator has a single-site trial. 

B-3

APPENDIX C 

FDA Study Request 

c-1 
DEPARTMENT O1; liliAL’I’11 N liUMAN SERVICES I’ubllc ticallll Selvlcc ‘Jg z. — 

-z.’ 

%,,,,,0 > Memorandum 

Date . MAR 2 Isa 

From Director, Center for Devices and Radiological Health (HFZ-1 ) 

Subject Request for OIG Study 

To	 Mr. George Grob 

Deputy Inspector General for Evaluations and Inspections 

CDRH is currently considering possible revisions of the Investigational Device Exemption 

(IDE) regulation, 21 C.F.R $812 et seq. The IDE regulation encourages the development 

of usefi.d new medical devices, while protecting the safety and rights of study participants, by 

establishing procedures for the conduct of clinical studies of devices. During the course of 

a study under the IDE regulation, the investigational device is mempt from many FDA 

requirements that would otherwise apply, such as performance standards and premarket 

approval requirements. 

Among the revisions we are considering are changes affecting FDA’s controls over 

commercialtition of investigational devices.. To help determine the extent the regulation 

needs to be revised, it would be helpful to have objective data on the degree to which 

inappropriate commercialization is occurring and on the economic and public health 

significance of such commercialization. It would be useful to have data for three types of 

investigations: 

�	 Studies of simificant-risk devices. An IDE application and FDA approval are required 

for a study of an investigational device that presents significant risks. 

�	 Studies of non-simificant-risk devices. No IDE application is required to study a 

device that does not present significant risks, but an institutional review board (IRB) 

must approve and monitor the study. 

�	 Studies of diamostic devices. Diagnostic devices, such as in vizro diagnostics, that are 

non-invasive and are not used as a diagnostic procedure without confirmation through 

another, medically-lished, diagnostic product or procedure are currently exempt 

from the IDE regulation. 

CDRH would need reliable data within six months to be of use in revising the IDE regulation. 

If OIG is willing to undertake this effort, I would ask that you work with Robert Eccleston 

of my office to define measurable objectives for the study and to develop an appropriate study 

plan. Mr. Eccleston can be reached on (301) 443-4690. 

Du.w’ill,.>!= 

D. Bruce Burlington, M.D. 

c-2 
+-

,’ DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service : 

s s 

%2

%,,,,,oct d

Memorandum 

Date Lpril 14, 1995 

From 

Commissioner of Food and Drugs 

Subject	 FDA Response to the Office of Inspector General 

Evaluation of Investigational Device Practices 

To 

Inspector General 

Department of Health and Human Services 

I am appreciative of the recently completed evaluation by 

the OIG Office of Evaluations and inspections of the Food and 

Drug Administration’s regulatory controls over clinical studies 

involving investigational medical devices and the cooperative 

spirit with which it was conducted. 

Notwithstanding the lirni,ted scope of the evaluation, FDA takes 

seriously the findings presented in the report. Following 

a careful review of them, we will take whatever actions are 

warranted to further assure that investigational device studies 

are conducted i.n accordance with the highest ethical standards 

and all applicable Federal rules designed to protect patients. 

This could include actions against individual sponsors if 

evidence of scientific misconduct is sufficient to justify 

FDA intervention. 

Although it is premature to specify what actions may be merited, 

FDA generally acknowledges the apparent need to enhance the 

training of clinical investigators and local institutional 

review boards to ensure they have a clear understanding of their 

regulatory and ethical obligations. In addition, the agency 

may consider other measures to ensure the integrity of clinical 

investigators and the investigational studies they perform, 

particularly with respect to accountability of investigational 

medical devices. - -“------n /“ 

cc : Assistant Secretary for Health


D-2