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  devices manufacturer,  and  selected  clinical 
investigators  and  IRB  representatives.  We  reviewed  FDAs  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 
INTRODUCIION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..    .-s  .s  1 
FINDINGS  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 
s..  8 
Problems  with  distribution  and  accountability 
	
8 
of investigational  devices  . . . . . . . . . . . . . . . . . . . . . . . . . ...-... 
Potential  weaknesses  in the  oversight  of clinical 
	
10 
trials  at local  sites.  . . . . . . . . . . . . . . . . . . . . . . . . . ...  S. ..  ..  S 
16 
CONCLUSION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..  s 
MPE~I- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..  O.  O  Oo 
k  Device  Descriptions  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..  .  sA-l 
B:  Glossa~  . . . . . . . . . . . . . . . . . . . . . . . . . 
...........o..o-.0o.-  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  IRBs 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  investigators  private  practice.  The  clinical 
investigator  is responsible  for obtaining  the  subjects  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 FDAs  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  FDAs  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&shy  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 subjects  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  FDAs  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  devices  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 
DEVICE  Total  #  of  #  of  #  of IRBs 
reviewed  in depth  the 
Investigative  Investigators  We 
original  application,  and 
Sites in the  We  Reviewed 
any amendments  or 
Clinical  Trial  Reviewed 
supplements  to the 
application.  When  A  191414 
applicable,  we also  B  I  13  1515 
reviewed  the  PMA  for the  I 
c  47  I 10 18 
device. 
D  I  11  ]213 
We  obtained  the  shipping 
records  for  each  of the 
devices.  For  the  device 
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  Presidents  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 Dhtnbuted 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  manufacturers  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  manufacturers  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  manufacturers  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  subjects  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  physicians 
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  hospitals  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  non-
significant  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 
Exhibit  3 
Most  medical  ethicists  view informed 
consent  as a process  in which  the 
investigator  thoroughly  communicates  Informed  Consent  Should: 
to the  subject  the  significance  of their 
  Explain  that  the device has not  been 
participation  in a clinical  trial. 
approved  as safe and effective  by FDA. 
Informed  consent  means  that  subjects 
  Describe  any potential  risks and 
clearly  understand  that  they  are  benefits  expected  from  participating  in 
participating  in research  for devices  the clinical  trial. 
that  have  not  yet been  proven  safe  or    Describe  the length,  nature  and 
number  of subjects  in the clinical  trial. 
effective.  Although  informed  consent 
  Explain  the patients  rights  including 
ideally  involves  both  verbal  and  written 
that  their  participation  is voluntary 
communication,  most  government 
and they can withdraw  at any time. 
officials,  manufacturers,  IRBs,  and    Explain  who they should  contact  if 
clinical  investigators  deem  that  they have any questions  about  the 
informed  consent  has been  given when  research  or their  rights  as research 
subjects. 
a subject  signs the  informed  consent 
  Explain  the  patients  responsibilities  as 
document.  However,  as Exhibit  3 
a research  subject  including  their 
illustrates,  the  extensive  and  sometimes 
responsibilities  for follow-up  visits for 
complicated  information  that  must  be  data  collection. 
13
 relayed  through  an informed  consent  document  makes  the  verbal  process  of informed 
consent  that  much  more  important. 
Missing  or incomplete  documents 
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 
investigators  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  investigators  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 doctors  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  FDAs  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  sponsor-
investigators  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  FDAs 
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

FDAs  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  Jg 
DEPARTMENT  O1;  liliALI11  N  liUMAN  SERVICES  Iubllc  ticallll  Selvlcc 
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%,,,,,0 Memorandum 
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Date  . 
Director,  Center  for Devices  and Radiological  Health  (HFZ-1 ) 
From 
Request  for OIG  Study 
Subject 
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  FDAs  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.will,.>!= 
D. Bruce Burlington,  M.D. 
c-2  +- d
,  DEPARTMENT  OF  HEALTH  &  HUMAN  SERVICES  Public  Health  Service 
: 
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%,,,,,oct 
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  Administrations  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