U.S.  Department  of  Health and Human Services 
Office of Inspector  General
Data Snapshot
September 2022,  OEI--01--21--00401 
Delays in  Confirmatory  Trials for Drug  Applications  Granted FDAs  
Accelerated  Approval Raise Concerns 
Key Takeaway 
Background 
More than one-third 
The Food and Drug Administrations  (FDA) 2021  approval of aducanumab 
of accelerated  
(Aduhelm),  a drug intended  to treat  Alzheimers  disease raised concerns  about   approval drug  
FDAs accelerated  approval  pathway.1  Subsequently, the Office of Inspector   applications with  
General  (OIG) announced  plans to conduct  evaluations of the accelerated  approval   incomplete 
confirmatory  trials are  
pathway.  This data snapshot focuses on confirmatory  trials, given ongoing  
past their trials 
concerns that sponsors  of drug applications  granted accelerated approval  fail  to  
original planned  
complete their statutorily  required confirmatory trials  on schedule,  and concerns   completion dates,  
that FDAs oversight of the trials is  lax.2 including four that  are 
more than 5 years 
past those dates. 
The accelerated  approval  pathway allows FDA to approve certain drugs that  treat  
serious or life-threatening diseases  and offer  meaningful therapeutic  benefit to 
patients over existing  treatments  before confirmatory  trials are completed.3  To gain approval in this pathway,  
drug  sponsors  must meet  the same FDA standards for safety and efficacy  as traditionally approved drugs.   
However, they may rely on a surrogate or intermediate endpoint and do  not need to  show clinical  benefit  
before approval,  rather  that the predicted clinical benefit is  reasonably  likely.4  Federal law grants FDA the 
authority  to require sponsors  to  conduct  confirmatory  trials  after  approval to verify that  the drugs provide the 
predicted clinical benefit.5  Typically,  sponsors conduct  such trials while these drugs  are available to  the public  
on a timeline agreed to  by FDA and the sponsor.6
Results 
Accelerated  approvals have increased over time, and more than one-third of  drug applications  
(104 of all 278)  have incomplete confirmatory  trials 
Since the accelerated  approval pathway  
50
began in 1992,  drug applications  granted  
accelerated  approval  by  FDAs Center for  
40
Drug Evaluation and Research (CDER)  have 
steadily increasedwith 278 approved  
30
between 1992 and  December  31, 2021.   
One-quarter of these approvals (70  of 278)  
occurred  in 2020  and 2021.  Of all   20
278 drug  applications granted accelerated  
approval from  the start of  this approval   10
pathway, 104  have incomplete 
confirmatory  trials.  The 139 applications   0
with completed trials  took  on average  ~  ~  ~  ~ RB   R&   R~  R~  R&   R~  R~  R~  R~  R~  R&  
~  ~  ~  ~ 
48 months  from  when FDA granted  them  
 Drug Applications with Incomplete Trials 
accelerated approval to  when FDA  
 Drug Applications with Completed Trials 
deemed their  trials  to  be completed.  
Source: OIG  analysis  of  FDA  accelerated approval data, 2022. 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  1  Thirty-four  percent of  accelerated  approval drug applications with incomplete confirmatory  
trials (35  of 104)  have at least one trial past its original planned  completion date 
Of the 104  drug  applications with incomplete confirmatory  trials, 34  percent  of themor 35 drug 
applicationsare past their original  planned completion dates.  For these 35 drug applications,  sponsors  
have not met the original planned completion date for 37  confirmatory  trials as  of  May  5,  2022.  On 
average, the 37  trials  are about 20  months, or  about 1.5 years,  past their original planned completion 
dates.  FDA  may require multiple confirmatory  trials  for  an application to verify the predicted  clinical  
benefit.  For example, FDA required two  confirmatory  trials for  the application for ibrutinib (Imbruvica),  
which treats  blood cancers.  Of the 37 confirmatory  trials  past their  original planned completion dates,  
14 are delayed more than 1 year and 23  are delayed less  than 1  year past their original completion dates.   
Accelerated  approval drug  applications  with  incomplete confirmatory trials  
Of all accelerated  approval drug  applications,  One-third  (35 of  104)  of  those applications with 
almost 40 percent  (104 of  278) have  incomplete  confirmatory  trials are  past their  
incomplete confirmatory  trials.  original planned completion  dates.  
 
 
 
 
Source: OIG  analysis  of  FDA  confirmatory trial data, 2022. 
Sponsors must submit annual status reports to  FDA  for their confirmatory  trials;  these reports  may include  
information about  why trials are past their original completion dates.7  If a sponsor changes a trials  planned 
dates, it must submit a revised  schedule to  FDA and reasons  for  the revision.  However, FDA uses  the 
original schedule to  determine whether  it considers a trial to  be delayed.8 
As  a  requirement of  granting accelerated approval,  FDA requires sponsors to commit  to  complete 
confirmatory  trials with due diligence, meaning the trials must be conducted  promptly.9  Per FDAs  
guidance,  FDA  and  sponsors  should agree on the design and  conduct  of trials, including their  timelines.10 
FDA staff reported  that, although not a requirement,  the agency  generally  reaches  an agreement with 
sponsors  on timelines.  FDA specifies these timelines in the drug  application approval letters it sends  to  
sponsors.   
FDA and  sponsors  withdrew  13 percent  of all accelerated  approval  drug  applications,  half  of  
which  were withdrawn  since January  2021 
Under  certain conditions, FDA  can withdraw  its  accelerated approval  of a  drug  application.   Those 
conditions  include, for  example,  if a confirmatory  trial fails to verify the predicted  clinical benefit  of a drug  
or if a sponsor does not  conduct  the trial promptly.11 Alternatively, sponsors  could  request that  a drug  
application be withdrawn or voluntarily withdraw  a drug  from  the market.12, 13  Since the inception of  the 
pathway in 1992  through May  2022,  35  of  the 278  drug  applications (13  percent) granted accelerated 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  2  approval have been withdrawn.  Slightly more than half of  these withdrawals  (18)  have come since January  
2021. 
FDA has  stated that  the process to  withdraw  a  drug's  approval can be cumbersome,  and  can take months to  
years,  particularly  if the sponsor does not  voluntarily withdraw  the drug from  the market.  For example,  in 
December  2010,  FDA announced  that  it would  seek  to remove an indication for bevacizumab (Avastin), for  
which it  granted accelerated  approval in 2008  to treat  breast cancer.14  In November 2011,  FDA  finalized the 
withdrawal.15  The process to  withdraw  a drug application involves  numerous steps, including  FDA  detailing  
the reasons for withdrawal,  a withdrawal  hearing  if requested by the sponsor, presentation of  evidence and  
questioning by FDA and the sponsor, and a decision by the FDA  Commissioner.16  The sponsor may then 
petition a  court  to review  the Commissioners  decision and request an order  to stay the action pending  
review.17
Half of  all  withdrawals  of  accelerated  approval  drug applications have occurred since January 2021. 
13 
5 
4  I 
3  I 
2  I 2  2 
I  I  I 
I  I  I  I 
~ ~ ~ 9)  ~ ~ &  &.....   &  &  ~ ~ ~ ~  ~ ~ ;2  ......... .  ~ ::::  ~ ::::  ~ :?}  &  &.....   &1 
:?}  :?}  :?}  :?}  :?}  :?}  R  'v  R  R  R  R  R  R  R  R  ~ ~ ~ ~ ~ ~ ~ ~ ~ 'v  ~ 
Source: OIG  analysis  of  FDA  accelerated approval data, 2022. 
Four  drug  applications have confirmatory trials that are significantly  lateranging  from more  
than 5 years to nearly  12 years past their  original planned  completion dates 
Four drug  applications granted  accelerated  approval each have confirmatory  trials significantly past their  
original planned completion dates,  overdue by at least  64  months or  about 5  years.  One trial for  
mafenide acetate (Sulfamylon) is overdue by 140  months, or nearly 12  years.  Trials for two  other  drug  
applications, midodrine  hydrochloride  (Proamatine) and pralatrexate  (Folotyn), are 85  months and  
72 months  late, respectively.  One trial for  hydroxyprogesterone caproate (Makena)  is 64  months late.18
Four  drug  applications trials are more than  5 years past their original planned completion  dates. 
HYDROXY
i=l 
PROGESTERONE 
CAPROATE 
~ 
0  12  24  36  48  60  72  84  96  108  120  132  144 
Months By  Which Applications  Are Past Their  Original Completion Dates 
Note: Each  data points  size proportionally  reflects how many drug applications  are delayed by  the number of months  shown. 
Source: OIG  analysis  of  FDA  accelerated approval data, 2022. 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  3 FDA  staff  cited two common challenges  that affect sponsors abilities  to complete confirmatory  trials  
promptly.  These challenges also apply  to  three of  the four  drug applications  with significantly late trials. 
 
   
Advances in Standard of  Care  Ownership of Drug  Applications 
Advances in the standard of care for  a   Changes  in ownership of a drug  application can 
particular  condition can improve  slow its progress.  With each change in ownership,  
patient outcomes,  making it difficult  for   FDA must establish a working  relationship with the 
a drugs confirmatory  trial to detect  new  sponsor.  The new  sponsor is  responsible for  
those improvements attributable to  the  completing  confirmatory  trials and the FDA-
drug.  negotiated  timelines,  and the transfer  of ownership 
can cause delays  in ongoing  trials. 
FDA is addressing, and  has been  for years in some cases, drug  applications with  the 
longest-delayed  confirmatory trials, including by withdrawing  one application 
FDA staff provided details on each of the four  drug  applications furthest  past  their  completion dates.   
Mafenide acetate  (Sulfamylon,  topical antimicrobial treatment for burns,  approved in 1998,  
trial is  140 months  past the original planned  date) 
FDA approved the drug  application through the accelerated  approval pathway  in the 1990s,  
before FDA  and sponsors agreed on trial milestones  and timelines.  FDA  staff acknowledged  
that the lack of trial milestones undermined  their ability to hold the sponsor accountable for  
completing  the trials  promptly.  Furthermore,  advances in standards of care likely  created  
challenges for  the sponsor.  According  to  FDAs  Postmarketing Commitments  Database, the 
agency  is  having ongoing  discussions  with the sponsor regarding  the trial design.   
Midodrine hydrochloride  (Proamatine, treatment  for  postural  hypotension, approved  in  
1996,  trial is 85 months  past the original planned  date) 
FDA attempted to withdraw  this drug application  in 2010.  Media  reports  stated that 
professional organizations,  health care professionals,  and patients appealed to  the FDA directly  
e to keep the drug  on the market.19,  20  Additionally,  Proamatine has numerous generic  
alternatives,  which increases  market competition and may  decrease the original  sponsors  
incentive to  complete confirmatory  trials with due diligence.21  In fact,  the sponsor of  
  Proamatine has  discontinued  the drug  and does not currently  market it.21  Finally, in the  time  
since its approval, ownership of the drug  application moved among three different  sponsors,  
slowing  the pace  of confirmatory trials.  
Pralatrexate (Folotyn,  treatment for T-cell lymphoma, approved  in  2009, trial is 72 months  
past  the original planned date) 
This  drug  application faced  several  common challenges since it was granted  accelerated  
approval.  Specifically,  changes in the standard of  care for T-cell lymphoma rendered  the 
original planned confirmatory  trial infeasible.  In response,  FDA and the sponsor agreed on two  
new  trials  in which the sponsor would  incorporate the new  standard of care.  The sponsor  
completed the  first trial in 2021  after a delay,  and it submitted to  FDA  its protocol  for the  
second  trial, which was dependent  on results  from  the first trial, in early  2022.  Additionally, the 
drug application changed ownership several  times,  which further delayed  the trials.   
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  4 Hydroxyprogesterone  caproate (Makena,  to reduce  risk of preterm  birth, approved  in  2011,  
trial is 64 months past the  original planned  date) 
In 2020  FDA began the process of  withdrawing  this drug application's  approval after the 
sponsors  2018  trial failed to  demonstrate a clinical  benefit.  The sponsor disagreed with 
 
CDERs  action,  explaining that the drug  is  effective in certain patient  subgroups.  FDA  staff  
cited  this case as  an example of how  lengthy and burdensome the withdrawal  process may be 
when a sponsor disagrees  with FDAs  decision to  withdraw  a  drugs approval.  The sponsor  
has  requested  a hearing to discuss CDERs  proposal to  withdraw  the approval.  The current  
docket  for  the case includes numerous  exchanges between CDER  and the sponsor,  including  
sponsor requests to extend deadlines,  communications  between CDER  and the sponsor  
regarding  technical  and legal aspects of the hearing, and letters from  patient advocates and  
physicians.   A hearing  is  scheduled for October 2022. 
Medicare and Medicaid spent more than $18  billion  from 2018  to 2021  for  accelerated  
approval drugs  with  incomplete confirmatory trials  past their  original planned  completion  
dates 
We estimated Medicare and Medicaid spending from  2018  to 2021  for  the 18  drugs that  correspond  to  the 
35 drug  applications granted accelerated approval  with incomplete confirmatory  trials  past  their  original  
planned completion dates  as of May 5,  2022.  We estimated that Medicare Part B  and Part  D spent more than 
$14 billion.22  We also estimated that Medicare Part C  spent nearly $6  billion on these drugs.23  Finally, we  
estimated that Medicaid spendingfor  both fee-for-service and managed carefor  these drugs was nearly  
$3.6 billion. 
Due to data limitations, these estimates  are conservative, and they should be understood  to be the best  
available estimates,  not  exact amounts.  These estimates demonstrate that  Medicare and Medicaid are 
spending billions  of  dollars on drugs that  have yet to  verify  a clinical  benefit. 
Medicare and Medicaid  spent billions of  dollars on  drugs that have yet to  verify clinical benefit. 
$12.6 
Part B 
Billion 
$5.9 
Part C 
Billion 
$1.7 
Part D 
Billion  
$3.6 
Medicaid  
Billion  
Note:  Estimated spending calculations are  limited to only indications associated with accelerated approval. 
Source: OIG  analysis  of  Medicare claims  and Medicaid T-MSIS data,  2022. 
Of the four  drugs with confirmatory  trials furthest past their original  planned completion dates, midodrine 
hydrochloride (Proamatine)  had  the highest Medicare Part  D estimated spending at $142  million and  
hydroxyprogesterone caproate (Makena)  had the highest estimated  Medicaid spending, nearly  
$700 million. 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  5  Medicare and Medicaid  spending  from  2018  to  2021  for  the four drugs with the most 
delayed  confirmatory trials. 
$620,000,000 
$520,000,000 
$420,000,000 
$320,000,000 
$220,000,000 
l 
$120,000,000 
Y-Axis Break* 
 $100,000,000 
 $80,000,000
 $60,000,000
 $40,000,000
I_.  -- 
 $20,000,000
 $-
Midodrine 
Hydroxyprogesterone  Mafenide Acetate 
Pralatrexate (Folotyn)  Hydrochloride 
Caproate (Makena)  (Sulfamylon) 
(Proamatine) 
 Part B  $76,582,$97366, 582,936  $1,020,72$41 ,020,724  $2,954  $2,954  $381  $381 
 Part C  $32,792,$73128, 792,718  $506,574 $506,574  $18,100  $18,100  $167  $167 
 Part D  $2,429,77$52 ,429,775  $9,284,77$19 ,284,771  $142,37$01,24121,3 70,211  $14,939  $14,939 
 Medicaid  $8,004,52$18 ,004,521  $697,67$86,69172,6 78,612  $7,689,64$17 ,689,641  $11,564 $11,564 
 Part B   Part C   Part D   Medicaid 
*Y-axis  break  utilized to display total spending for  Makena and Proamatine.  
Note:  Estimated spending calculations are  limited to only indications associated with accelerated approval. 
Source:  OIG  analysis  of Medicare  and Medicaid prescriptions filled during 2022. 
Why  This Matters 
The accelerated  approval  pathway holds promise for  patients who  face serious illnesses  where adequate 
treatments  are lacking.  In the best-case scenarios, sponsors complete  confirmatory  trials promptly and  
provide evidence to verify the drugs clinical  benefits.  In those cases,  FDA enables  patients to  access drugs  
that can help them  and Medicare and Medicaid to pay for  effective treatments. 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  6  Why  This Matters, continued 
However, for  a variety  of  reasons,  sponsors  do  not always complete trials promptly.  In fact,  more than 
one-third of  accelerated  approval drug  applications with incomplete confirmatory  trials are past their original  
planned completion dates,  including  four  that are more than 5 years  past those dates.  In addition, sponsors  
may have little incentive to complete trials  promptly  once they can market a drug  under accelerated  
approval.24  Likewise,  patients may have little incentive to enroll in a confirmatory  trial when the therapeutic  
treatment  is already  available.25  Finally,  FDAs  process  to withdraw a  drug approved through the accelerated  
approval pathway  can be lengthy and contentious.  These challenges can result in drugs staying on the 
marketand being administered to  patientsfor years without  the predicted  clinical  benefit being verified.   
Also, insurersincluding Medicare and Medicaidcould  end up paying billions of dollars for treatments  that  
are not  verified to have clinical benefit. 
This  data  snapshot  offers  insights  into FDAs  ability to  hold sponsors  to  their original completion schedules and  
to withdraw  drugs  with unverified  clinical benefit,  as  well as the challenges FDA faces in doing so, even as  it has  
approved greater  numbers of  drugs through the accelerated  pathway  in recent  years.  Ensuring that FDA has  
the tools to  effectively administer the accelerated  approval  pathway  is crucial  to  FDAs mission to  protect  the 
public  health by ensuring the safety, efficacy,  and security of human drugs and biologics. 
Methodology 
Assessing Confirmatory  Trial Status 
Our review  included all accelerated  approval drug applications  approved by FDAs  CDER,  from  the pathways  
inception in 1992  through December  2021.  We first created  a subset  of  drug applications  for which sponsors  
had  not yet  completed their  required confirmatory  trials,  using  FDAs  publicly available list  of accelerated  
approval drug  applications.  For those drug  applications, we identified the statuses  of  their incomplete trials,  
using data from FDAs  Postmarketing Commitments Database.  We used the most recent  publicly available 
data as of May  2022,  following  FDAs  quarterly update of the database.  We conducted  followup with  FDA to  
obtain missing data for six drug applications,  and additional data on six  other  drug applications.  We  then  
calculated  the length of time a  trial  was past  its original planned  completion date.  We conducted  structured  
interviews with FDA staff about four  drug  applications with confirmatory  trials that are long overdue and  
discussed  reasons  for the delays.   Additionally,  for drugs  with completed confirmatory  trials,  we calculated the 
elapsed  time it took to  complete the trials.   
Estimating Medicare and Medicaid  Spending 
We used claims data to  calculate how  much Medicare Parts  B,  C,  and D  spent in 2018  through 2021  for  
accelerated  approval  drugs whose trials failed to meet  their original planned completion dates.  For  each drug,  
we identified all  corresponding  National Drug Codes  and ICD-10  diagnosis codes associated with  an  
accelerated  approval  drugs indication.  To limit our spending calculations  to  only  accelerated  approval  
indications, we reviewed prescriptions  in Medicare Parts  A, B,  and C claims and then went  back  365  days  to  
identify diagnosis  codes  associated with those claims.  If a drug indication involved more than just  the 
diagnosis  (e.g., specifics of  treatment  history or remission/relapse events),  we could  not identify and separate 
claims based on these additional elements beyond the diagnosis. 
We conducted  a parallel  analysis using the Transformed  Medicaid  Statistical  Information System (T-MSIS) data  
to calculate total Medicaid spending on accelerated  approval drugs whose trials failed to meet  their original  
planned  completion dates.   
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  7  Methodology, continued 
Because we did not conduct  a  medical  record  review, this analysis  relied on the accuracy  of Parts  A and B claims,  
Part  C encounter  data, Part D  prescription drug event records,  and T-MSIS  data for  drug utilization and diagnosis  
information.   We did  not determine whether  all  required Part  C  encounter records were submitted  or were 
accurate.  We also  did not  account  for  manufacturer  rebates in Part D  data.  We did not determine whether  
T-MSIS  data are complete or accurate.  Finally,  we could  not  identify and separate claims for  off-label use.  
We included  spending for  therapeutically  equivalent  generic  drugs  that were approved based on FDA granting  
accelerated  approval  to the original  drug.  Our results include claims billed during  the COVID-19 pandemic  and  
therefore may not reflect  typical  utilization and spending. 
Limitations 
We did  not assess  the scientific  appropriateness of  FDAs  clinical  judgment regarding  any of the drugs under  
review.  We also  did not  independently verify information we analyzed in FDAs  Postmarketing Commitments  
Database,  including  original completion dates.  Our spending calculations  are estimates  due to limitations with 
the data. 
Standards 
We conducted  this  study in accordance with the Quality  Standards for  Inspection and Evaluation issued  by the 
Council of the Inspectors General on Integrity  and Efficiency. 
Acknowledgments 
Melissa  Baker  and Ivan Troy served  as team leaders for this study.  Others in the Office of  Evaluation and  
Inspections (OEI) who  conducted  the study  include Jac Carreiro, Anna Lin, and Shweta Palakkode.  OEI  staff  
who provided  support include Robert Gibbons  and  Michael  Novello. 
We would  also like to  acknowledge the contributions  of other  OIG staff, including  Marissa  Baron,  Emily Chou,  
and Erin Fratangelo. 
This  report  was  prepared under  the direction of Joyce Greenleaf,  Regional Inspector  General for Evaluation and  
Inspections in the Boston Regional Office, and Kenneth Price, Deputy  Regional  Inspector  General. 
Endnotes 
1 We refer to  pharmaceutical  drug  products  and biological products  as  drugs. 
2 Institute for Clinical and Economic  Review,  Strengthening  the Accelerated  Approval Pathway: An Analysis  of  
Potential Policy  Reforms and  Their  Impact  on  Uncertainty, Access,  Innovation, And  Costs, April 2021.  Accessed  
online at  https://icer.org/wp-content/uploads/2021/04/Strengthening-the-Accelerated-Approval-Pathway-_-
ICER-White-Paper-_-April-2021.pdf on  June  23, 2022. 
3 Federal Food, Drug, and Cosmetic Act  (FD&C Act)   506(c)(1)(A) and  21 CFR   314.500. 
4 FD&C Act   507(e)(9) and  FDA,  Guidance for Industry  Expedited  Programs for Serious ConditionsDrugs and  
Biologics, May 2014.   A  surrogate endpoint  is  a marker, such as  a laboratory  measurement or  physical  sign,  
that is either known to predict  clinical  benefit or  is  reasonably likely  to predict  clinical benefit.  For example,  
FDA may grant accelerated  approval to a drug  based on evidence that  the drug  shrinks  tumors, because 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  8  Endnotes, continued 
tumor  shrinkage in some cancers  is  considered  a surrogate endpoint  reasonably likely  to predict  clinical  
benefit (i.e., overall  survival).  Similarly, an intermediate endpoint  is  a clinical  endpoint  that can be measured  
earlier than irreversible morbidity  or mortality,  that is  reasonably likely  to  predict  an effect  on irreversible 
morbidity  or mortality  or other  clinical benefit (see FD&C  Act   506(c)(1)(A)).  
5 FD&C Act   506(c)(2). 
6 FDA, What  Are the Different  Types  of Clinical Research?  Accessed  online at  
https://www.fda.gov/patients/clinical-trials-what-patients-need-know/what-are-different-types-clinical-
research on June 23,  2022,  and FDA,  Guidance for  Industry  Expedited Programs  for Serious ConditionsDrugs 
and Biologics, May 2014. 
7 21 CFR  314.81(b)(2)(vii). 
8 21 CFR  314.81(b)(2)(vii)(a)(9) and  FDA,  Guidance for  Industry,  Reports  on the Status of  Postmarketing Study  
CommitmentsImplementation of  Section 130 of  the Food  and  Drug  Administration Modernization Act  of  
1997, February  2006. 
9 FD&C Act   506(c)(3)(A) and  FDA,  Guidance for  Industry  Expedited Programs  for Serious  ConditionsDrugs 
and Biologics, May 2014. 
10 FDA,  Guidance for Industry  Expedited  Programs for Serious ConditionsDrugs and  Biologics, May 2014. 
11 21 CFR  314.530. 
12 21 CFR  314.150(c). 
13 For  example, see: Fierce Pharma, FDA: Pfizer Voluntarily  Withdraws  Cancer  Treatment  Mylotarg from  
U.S. Market,  June 21,  2010.  Accessed  online at  https://www.fiercepharma.com/pharma/fda-pfizer-
voluntarily-withdraws-cancer-treatment-mylotarg-from-u-s-market on June 23,  2022. 
14 FDA,  Avastin (bevacizumab) Information.  Accessed  online at  https://www.fda.gov/drugs/postmarket-drug-
safety-information-patients-and-providers/avastin-bevacizumab-information on  July  21, 2022. 
15 Shari Roan, FDA  Withdraws Approval  of Avastin to Treat  Breast  Cancer,  Los  Angeles Times,  
November 18, 2011.  Accessed  online at  https://www.latimes.com/nation/la-xpm-2011-nov-18-la-he-avastin-
breast-cancer-20111119-story.html on  July  25, 2022. 
16 21 CFR  314.530. 
17 21 CFR  314.530(f). 
18 Although results  of  the confirmatory trial for  hydroxyprogesterone caproate (Makena)  were submitted to  
FDA, FDAs  assessment  of the trial and CDERs  proposal to  withdraw  the drugs approval will  be discussed  in 
a hearing scheduled  for October  1719, 2022. 
19 Gardiner Harris, F.D.A. Backtracks and Returns Drug to Market,  The New York Times,  September  3,  2010.   
Accessed at  https://www.nytimes.com/2010/09/04/health/policy/04fda.html on  July  6, 2022.  
20 Sanket S.  Dhruva, MD,  and  Rita F.  Redberg,  MD, MSc, Accelerated  Approval  and  Possible Withdrawal  of  
Midodrine,  JAMA, Vol. 304,  No.  19,  November 17,  2010,  pp.  2172-2173. 
21 FDA,  Orange Book:  Approved  Drug  Products with  Therapeutic Equivalence Evaluations. 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  9  Endnotes, continued 
22 Drug  sponsors  typically submit  separate applications for FDA  approval  of different treatment indications  
for  the same drug.  For example, FDA  granted  accelerated  approval to numerous separate applications  for  
pembrolizumab (Keytruda)  to treat  different conditions, including renal  cell  cancer,  non-small cell lung  
cancer, and  endometrial cancer, among others. 
23 We report  Medicare Part C  spending estimates  separately from Parts  B and D  because payment  fields  in 
Part C  encounter  data are not  always  complete or accurate. 
24 Institute for Clinical and Economic  Review,  Strengthening  the Accelerated  Approval Pathway:  An Analysis of  
Potential Policy  Reforms and  Their  Impact  on  Uncertainty, Access,  Innovation, and  Costs,  April  2021.   Accessed  
online at  https://icer.org/wp-content/uploads/2021/04/Strengthening-the-Accelerated-Approval-Pathway-_-
ICER-White-Paper-_-April-2021.pdf on  June  23, 2022. 
25 Ibid. 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  10  Appendix A: Delay of  drug applications confirmatory  trials by  months 
Mafenide  acetate (Sulfamylon)  140 
Midrodine hydrochloride  (Proamatine)  85 
Pralatrexate (Folotyn)  72 
Hydroxyprogesterone caproate (Makena)  - NDA  021945  64 
Hydroxyprogesterone caproate (Makena)  - NDA  021945  42 
Ibrutinib (Imbruvica) - NDA 205552 Original 1  37 
Ibrutinib (Imbruvica) - NDA 210563 Original 2  37 
Ibrutinib (Imbruvica) - NDA 205552 Supplement 16  32 
Ibrutinib (Imbruvica) - NDA 210563 Original 2  32 
Pembrolixumab  (Keytruda)  - BLA 125514 Supplement 42  30 
-
Clofarabine (Clolar)  28 
-
Methylene blue (Provayblue)  19 
I 
-
Pralatrexate (Folotyn)  15 
I 
Belinostat   (Beleodaq)  - 15 
I 
Eteplirsen (Exondys 51)  - 11 
I 
Bedaquiline (Sirturo) - NDA 204384 Supplement 10  -8 
I 
Bedaquiline (Sirturo) - NDA 204384 Supplement 13  -8 
I 
Droxidopa (Northera)  -8 
I 
Nivolumab (Opdivo)  7 
I 
Selpercatinib (Retevmo)  5 
I 
Polatuzumab  vedotin-piiq (Polivy)   4 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 80  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 79  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 63  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 83  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 82  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 81  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 78  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 77  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 76  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 69  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 62  2 
Pembrolizumab (Keytruda)  - BLA 125514 Supplement 59  2 
Nifurtimox (Lampit)  2 
Cemiplimab-rwlc (Libtayo)  2 
Blinatumomab (Blincyto)  1 
Bedaquiline (Sirturo) - NDA 204384  1 
Note:  Sponsors may submit multiple drug applications (via either  New Drug Applications/Biologic  License  Applications  or  
supplemental applications)  for  the  same  drug for  different  indications or  routes  of administration.  Also, FDA  can require  some 
sponsors  to  conduct more than  one  confirmatory  trial for a single drug application. 
Source:  OIG analysis  of  FDAs  Postmarketing Commitments Database,  2022. 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  11  Appendix  B:  Medicare  and Medicaid utilization  and spending for  drugs with trials 
past  original planned  completion dates  (20182021) 
Spending 
Medicare  Medicaid  Medicare  Medicaid 
Fee for  Managed  Fee for  Managed 
Part B  Part C  Part D  Part B  Part C  Part D 
Service  Care  Service  Care 
Bedaquiline (Sirturo)  0  0  89  5  146  $0  $0  $347,759  $19,199  $553,799 
Belinostat (Beleodaq)  6,132  1,961  18  199  792  $27,387,420  $10,000,837  $574,294  $498,256  $2,170,709 
Blinatumomab (Blincyto)  9,647  3,477  175  2,858  5,084  $90,554,863  $36,347,641  $4,003,180  $22,200,250  $64,954,075 
Cemiplimab-rwlc (Libtayo)  17,281  6,729  173  394  598  $162,223,766  $60,583,482  $1,659,843  $1,513,769  $3,358,076 
Clofarabine (Clolar)  43  15  0  58  33  $162,212  $69,654  $0  $79,568  $312,660 
Droxidopa (Northera)  0  0  68,769  759  2,128  $0  $0  $643,604,481  $4,872,887  $15,905,566 
Eteplirsen (Exondys 51)  101  26  745  11,114  13,855  $2,499,449  $657,455  $47,031,620  $297,063,447  $327,001,302 
Hydroxyprogesterone caproate 
(Makena)  2,279  993  3,172  92,674  313,903  $1,020,724  $506,574  $9,284,771  $138,868,573  $558,406,017 
lbrutinib (lmbruvica)  0  0  51,944  784  2,281  $0  $0  $668,882,920  $10,146,083  $28,167,563 
Mafenide acetate (Sulfamylon)  2  1  10  8  12  $381  $167  $14,939  $2,534  $9,031 
Methylene blue (Provayblue)  13  6  0  4  18  $8,551  $1,697  $0  $642  $11,214 
Midodrine hydrochloride 
(Proamatine)  419  675  1,633,413  38,496  105,359  $2,954  $18,100  $142,370,211  $1,908,508  $5,841,505 
Nifurtimox (Lampit)  0  0  0  5  0  $0  $0  $0  $1,497  $0 
Nivolumab (Opdivo)  55,531  24,640  916  4,786  7,686  $375,526,078  $175,786,606  $10,196,369  $18,250,499  $51,054,768 
Pembrolizumab (Keytruda)  1,273,846  596,626  17,186  128,707  172,510  $11,726,796,104  $5,494,073,858  $174,755,065  $561,231,656  $1,438,827,176 
Polatuzumab vedotin-piiq (Polivy)  8,637  3,886  34  386  611  $98,101,874  $47,172,402  $676,965  $2,581,187  $6,773,639 
Pralatrexate (Folotyn)  10,487  4,067  45  857  694  $76,582,936  $32,792,718  $2,429,775  $2,552,513  $5,452,008 
Selpercatinib (Retevmo)  0  0  1,282  109  373  $0  $0  $22,633,101  $1,714,196  $6,199,495 
Note: Utilization  is  the number of prescriptions  for  Medicare Part D  and Medicaid prescriptions  or  claim  line items  for Medicare Parts B and C  and 
for  other Medicaid claims. Estimated spending calculations are  limited to only indications associated with accelerated approval. 
Source:  OIG  analysis  of Medicare  and Medicaid prescriptions filled during 2022. 
OEI-01-21-00401  Delays in Confirmatory  Trials for  Drug Applications  Granted FDAs  Accelerated Approval Raise  Concerns  12