Department of Health and Human Services 
OFFICE OF 
INSPECTOR GENERAL 
FDA WARNING LETTERS 
Timeliness And Effectiveness 
JUNE GIBBS BROWN 
Inspector General 
FEBRUARY 1999 
OEI-09-97-00381  OFFICE OF INSPECTOR GENERAL 
The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, is to 
protect the integrity of the Department of Health and Human Services programs as well as the 
health and welfare of beneficiaries served by them.  This statutory mission is carried out through a 
nationwide program of audits, investigations, inspections, sanctions, and fraud alerts.  The 
Inspector General informs the Secretary of program and management problems and recommends 
legislative, regulatory, and operational approaches to correct them. 
Office of Evaluation and Inspections 
The Office of Evaluation and Inspections (OEI) is one of several components of the Office of 
Inspector General.  It conducts short-term management and program evaluations (called 
inspections) that focus on issues of concern to the Department, the Congress, and the public.  The 
inspection reports provide findings and recommendations on the efficiency, vulnerability, and 
effectiveness of departmental programs. 
OEI's San Francisco Regional Office  prepared this report under the direction of Kaye D. Kidwell, 
Regional Inspector General, and Paul A. Gottlober, Deputy Regional Inspector General.  Principal 
OEI staff included: 
REGION  HEADQUARTERS 
Brad Rollin, Project Leader  Elise Stein, Program Specialist

Robert Gibbons, Program Analyst  Barbara Tedesco, Mathematical Statistician

Scott Hutchison, Program Analyst

Don Loeb, Program Analyst

Steven Zerebecki, Program Analyst

To obtain copies of this report, please call the San Francisco Regional Office at 415-437-7900. 
Reports are also available on the World Wide Web at our home page address: 
http://www.dhhs.gov/progorg/oei  E X E C U T I V E   S U M M A R Y  
PURPOSE 
To determine how the Food and Drug Administration (FDA) uses warning letters and the 
extent to which they result in timely compliance with Federal laws and regulations. 
BACKGROUND 
The FDA is the Federal agency charged with enforcing the Federal Food, Drug, and

Cosmetic Act and several related laws.  At the headquarters level, FDA primarily is

comprised of five centers and the Office of Regulatory Affairs.  The Office of Regulatory

Affairs coordinates FDA's compliance activities and oversees the activities of FDA's 

5 regional offices, 20 district offices, and 130 resident posts.

The FDA's district offices and resident posts conduct almost all inspections of the firms

that FDA regulates.  When investigators find objectionable conditions, they are required to

provide the firm with their findings using form FDA-483.  If violations uncovered during

an inspection meet a threshold of regulatory significance, FDA also may issue a warning

letter.  Both FDA centers and district offices issue warning letters, depending on the type

of firm and violation.  Some warning letters issued by the district office require

headquarters review and approval.  The warning letter generally represents FDA's first

official notification that it has found one or more products, practices, processes, or other

activities that are in violation of the Food, Drug, and Cosmetic Act.  The warning letter

affords firms the opportunity to voluntarily correct violations prior to the initiation of

formal enforcement action.

In fiscal year 1997, FDA issued 1,175 warning letters.  This reversed a trend during which

the number of warning letters decreased 36.2 percent from 1994 (1,626) to 

1996 (1,037).  District offices issue approximately 80 percent of all warning letters.

The General Accounting Office raised concerns about how FDA uses warning letters in

two 1997 studies.  Based on their findings, we determined that this inspection was

warranted.  We conducted on-site reviews at a stratified random sample of six district

offices.  At each district office, we reviewed warning letter and establishment files and

tracked the outcome of all warning letters issued during fiscal year 1996.  We also

conducted interviews with FDA headquarters, all district offices, and 24 firms that

received warning letters during 1996.

Warning Letters--Timeliness and Effectiveness  1  OEI-09-97-00381  FINDINGS 
Warning letters are an effective compliance tool 
When FDA conducts follow-up activities, it finds that firms have either corrected the 
violations cited in warning letters or have made significant progress toward doing so. 
Almost 90 percent of firms respond in writing to warning letters within 15 days of 
receiving them, detailing corrective actions that they intend to take. 
The warning letters effectiveness depends on conscientious follow-up 
The FDA completes appropriate follow-up in approximately 97 percent of cases.  Follow-
up may involve reinspecting the firm, soliciting documentation of corrections, or meeting 
with the firm to address compliance issues.  In other cases, FDA does not need to follow 
up except to ensure that the firm responds to the warning letter.  Follow-up inspections 
frequently uncover other violations, but FDA rarely has to initiate compliance actions.  On 
average, follow-up inspections take place more than 9 months after the warning letter is 
issued. 
Warning letters are not always timely 
Headquarters rarely reviews and concurs with warning letter recommendations within 
FDAs 15-day guideline.  Even when headquarters review is not required, district offices 
frequently take more than a month to issue a warning letter. 
Discrepancies between headquarters and district office data on warning letters 
are extensive 
Almost 20 percent of the warning letters in the district offices are not accounted for in the 
headquarters database.  Conversely, 16 percent of the warning letters in the headquarters 
database do not appear in the district offices files. 
RECOMMENDATION 
The warning letter is an effective tool in motivating firms to comply with Federal laws and 
regulations.  To increase its effectiveness, FDA should (1) improve the timeliness of the 
warning letter process and follow-up activities and (2) revamp its warning letter data 
collection system to ensure accuracy. 
AGENCY COMMENTS 
We received comments on the draft report from FDA in which the agency concurred with 
our recommendation.  Where appropriate, we have made revisions in the report in 
Warning Letters--Timeliness and Effectiveness  2  OEI-09-97-00381  response to these comments.  We also have responded to several of FDAs comments in 
the appendix. 
This report is the one of two reports on the FDA warning letter process.  A companion report, 
FDA Warning Letters:  Trends and Perspectives (OEI-09-97-00380), determined (1) why the 
number of warning letters has decreased in recent years, (2) what accounts for variations in 
district office warning letters, and (3) how firms view the warning letter process. 
Warning Letters--Timeliness and Effectiveness  3  OEI-09-97-00381  T A B L E   O F   C O N T E N T S  
PAGE

EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

INTRODUCTION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  11

Warning letter effectiveness  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

FDA follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  12

Timeliness of the warning letter process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Discrepancies in warning letter databases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

RECOMMENDATION  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  18

APPENDICES

A:  Agency comments  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

B:  OIG response to agency comments  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Warning Letters--Timeliness and Effectiveness  4  OEI-09-97-00381  I N T R O D U C T I O N  
PURPOSE 
To determine how the Food and Drug Administration (FDA) uses warning letters and the 
extent to which they result in timely compliance with Federal laws and regulations. 
BACKGROUND 
The Food and Drug Administration 
The Food and Drug Administration (FDA) within the Department of Health and Human 
Services is the Federal agency charged with enforcing the Federal Food, Drug, and 
Cosmetic Act and several related laws.  At the headquarters level, FDA primarily is 
comprised of five centers and the Office of Regulatory Affairs.1  The five centers are: 
<  Biologics Evaluation and Research 
<  Drug Evaluation and Research 
<  Devices and Radiological Health 
<  Food Safety and Applied Nutrition 
<  Veterinary Medicine 
Each center promulgates regulations, oversees the review and approval for the marketing 
of new products, develops policy and compliance standards for regulated industries, and 
undertakes other initiatives to ensure the safety and effectiveness of products under FDA's 
purview.  The Office of Regulatory Affairs coordinates FDA's compliance activities and 
oversees the activities of FDA's 5 regional offices, 20 district offices, and approximately 
130 resident posts. 
On-site Inspections 
Staff from FDA's district offices and resident posts conduct almost all inspections of the 
firms that FDA regulates.2  Section 702(a) of the Food, Drug, and Cosmetic Act 
authorizes FDA to conduct inspections to enforce the provisions of that statute as well as 
other applicable laws.  Inspections focus on manufacturing, laboratory, production, and/or 
1  The FDA also operates the National Center for Toxicological Research in Jefferson, Arkansas and the 
Engineering and Analytical Center in Winchester, Massachusetts. 
2  The FDA contracts with State agencies to conduct some inspections, and headquarters staff sometimes 
participate in inspections of foreign or domestic firms. 
Warning Letters--Timeliness and Effectiveness  5  OEI-09-97-00381  storage processes but may include examining a firm's administrative practices and controls 
as well as collecting samples, labels, and promotional materials. 
The FDA requires investigators to follow a standard protocol when conducting an 
inspection.  Upon arriving at a facility, investigators issue a Notice of Inspection (Form 
FDA-482) to the top management official.  The scope of the inspection generally is 
determined by the type of facility being inspected, the firm's history, general knowledge 
about the industry and its problems, and conditions found as the inspection progresses. 
Investigators are authorized to collect samples or other physical evidence while 
conducting inspections.  Examples include food, drugs, devices, or cosmetics.  Samples 
also may include evidence of violative conditions, such as rodent droppings or any other 
evidence of noncompliance with Federal laws and regulations. 
When investigators find objectionable conditions, they are required to provide the top 
management official with their findings on an Inspectional Observations form (Form FDA-
483).  The FDA-483 should include any observed problems with the facility, equipment, 
processes, controls, products, employee practices, or records.  Some examples of 
reportable observations include: 
<  filthy, putrid, or decomposed substances, unsanitary conditions, or evidence of 
contamination; 
<  careless handling of rodenticides or pesticides; 
<  results of field tests that reveal adulteration; 
<  observations of faulty manufacturing, processing, packaging, or holding of food, 
drug, or device products as related to Good Manufacturing Practice regulations;3 
and 
<  observations indicating noncompliance with medical device reporting 
requirements. 
Some observations require that action be taken by the centers only.  The FDA's 
Investigations Operations Manual instructs investigators to not report observations related 
to most labeling issues, promotional materials, the classification of a cosmetic or device as 
a drug, or the classification of a drug as a new drug on the FDA-483.  These issues are 
referred to the centers for compliance action. 
3  The Good Manufacturing Practice regulations specify FDA's expectations as to how firms should operate in 
manufacturing products regulated by the FDA. The regulation includes provisions related to personnel, quality 
control, facility design and maintenance, equipment, internal controls, production and process controls, packaging 
and labeling, storage and distribution, laboratory process, and reports and record keeping. 
Warning Letters--Timeliness and Effectiveness  6  OEI-09-97-00381  Warning Letters 
What is a warning letter?  The warning letter generally represents FDA's first official 
notification to a firm or individual that FDA has found that one or more products, 
practices, processes, or other activities are in violation of the Food, Drug, and Cosmetic 
Act.  The warning letter affords firms the opportunity to voluntarily take corrective action 
prior to the initiation of formal enforcement action. 
The FDA is not required by law to warn firms or individuals that they are in violation of 
the law prior to initiating a formal regulatory action.4  The FDA believes, however, that: 
...documentation of notice of violative conduct strengthens the agency's 
position in regulatory actions by establishing that responsible individuals 
continued violative conduct despite warnings by the agency.5 
Who issues warning letters, and what time frames exist?  The FDA centers and district 
offices issue warning letters.  In general, district offices issue warning letters to domestic 
firms based on inspections.  Some centers issue warning letters for advertising and 
promotional violations or to foreign firms that market products in the United States. 
Others, such as the Center for Veterinary Medicine, issue few or no warning letters at all. 
At the district office level, although some warning letters can be issued at the discretion of 
the district director without center or other headquarters review or concurrence, FDA's 
Regulatory Procedures Manual lists numerous specific program area violations that 
require review by the appropriate center.  The Regulatory Procedures Manual also states 
that when a warning letter is warranted, a district office should issue it to the firm or 
submit a recommendation for headquarters review within 15 days of the end of the 
inspection.  When center review is required, centers are supposed to review and approve 
the issuance of a warning letter within 15 days of receipt.  If a center disagrees with a 
warning letter recommendation, it must provide a justification to the district office within 
30 days. 
The following table illustrates how many warning letters the centers and district offices 
issued from fiscal years 1994 to 1997.  The district office tally includes all warning letters 
sent under district directors' signatures, including those that underwent center review: 
4  One exception to this statement is a requirement that when acting under the authority of the Radiation Control 
for Health and Safety Act, FDA is required by law to provide a written notification to manufacturers when the 
agency discovers products that fail to comply with a performance standard or that contain a radiation safety defect. 
5  FDA Regulatory Procedures Manual, Chapter 10, Subchapter  Prior Notice. 
Warning Letters--Timeliness and Effectiveness  7  OEI-09-97-00381  District offices annually issue approximately 
80 percent of all warning letters 
Year  Total  District office-issued  Center-issued 
1994  1,626  1,282 (78.8%)  344 (21.2%) 
1995  1,501  1,175 (78.3%)  326 (21.7%) 
1996  1,037  841 (81.1%)  196 (18.9%) 
1997  1,175  1,003 (85.4%)  172 (14.6%) 
In fiscal year 1997, FDA issued 1,175 warning letters.  This reversed a trend during which

the number of warning letters decreased 36.2 percent from 1994 (1,626) to 

1996 (1,037).  More warning letters are issued for devices and radiological products than

for any of FDA's other product areas.  In fact, from 1994 to 1997, the Center for Devices

and Radiological Health issued more warning letters than any district office.  The district

offices issuing the most letters in 1997 were San Francisco (96), Florida (88), and Dallas

(74).  The district offices issuing the fewest warning letters in 1997 were Boston (16),

Detroit (19), and Nashville (20).

What does a warning letter say?  The warning letter instructs the firm to correct the

issues noted and to respond in writing within 15 days of receipt of the letter.  District

offices coordinate with the appropriate center to determine whether a firm's response to a

warning letter is adequate.  If the district or appropriate center deems the firm's response

adequate, it will notify other appropriate agency units.  This may require a reinspection of

the firm.

The FDA issues warning letters for regulatory violations, not for violations of

nonregulatory guidance documents.  It states that "the threshold for determination of what

constitutes 'regulatory significance' is that failure to adequately and promptly achieve

correction to the warning letter may be expected to result in enforcement action."

Follow-up and Subsequent Compliance Actions 
The FDAs Regulatory Procedures Manual states that the district offices and/or centers 
should verify that corrections have been achieved.  This generally involves conducting a 
follow-up inspection.  If more appropriate, however, districts may require that a firm 
document corrections or may undertake educational efforts with the firm to address the 
issues.  Continued noncompliance can result in administrative or regulatory actions. 
Administrative actions include detentions, civil penalties, and requesting voluntary recalls. 
Warning Letters--Timeliness and Effectiveness  8  OEI-09-97-00381  Regulatory actions include license revocations, license suspensions, citations, 
prosecutions, judicial civil penalties, injunctions, and seizures.6 
Related Work 
The General Accounting Office (GAO) issued two studies in 1997 that questioned the 
consistency of FDA's inspection and compliance activities: 
<	 In "Blood Supply:  FDA Oversight and Remaining Issues of Safety" 
(GAO/PEMD-97-1, February 1997), GAO found that FDA issued warning letters 
to blood suppliers inconsistently.  The GAO also reported that some inspections 
yielded multiple FDA-483 observations but did not result in a warning letter, while 
other inspections with relatively few or minor observations resulted in the issuance 
of a warning letter. 
<	 In "FDA Mammography Inspections:  While Some Problems Need Attention, 
Facility Compliance is Growing" (GAO/HEHS-97-25, January 1997), 
GAO questioned the consistency of inspectors who used different criteria in citing 
mammography facilities.  The GAO stated that FDA's monitoring and enforcement 
process did not ensure timely correction of deficiencies in these facilities.  The 
GAO also noted that FDA district offices needed better information systems to 
manage inspections. 
Based on GAOs concerns, we determined that this inspection was warranted. 
METHODOLOGY 
On-site Warning Letter Tracking 
We conducted on-site reviews at six district offices.  We selected a stratified random 
sample of district offices to conduct the on-site fieldwork: 
Number of warning letters  Number of 
Sample size 
issued during 1996  district offices 
Fewer than 27  7  2 
28 to 54  10  2 
More than 54  4  2 
6  FDA has recall authority only for infant formula, human tissue, and certain medical devices. Recalls of 
other products are voluntary. License suspensions and revocations are regulatory actions taken for biologicals. 
Warning Letters--Timeliness and Effectiveness  9  OEI-09-97-00381  At each district office, we reviewed warning letter and establishment files.  We tracked the 
outcome of all warning letters issued by the district office during fiscal year 1996 to 
determine whether FDA conducted follow-up inspections where appropriate and whether 
the firm had sufficiently addressed the issues noted in the warning letter.  We projected 
our findings to the universe of district offices to assess the overall effectiveness of warning 
letters. 
Interviews with FDA and Regulated Firms 
We conducted either in-person or telephone interviews with each district office.  We asked 
district office staff about their organizational structure, their experiences with warning 
letters, the factors that contributed to their increase or decrease in warning letters, and the 
responsiveness of the centers to their warning letter recommendations.  We also 
interviewed staff from FDA headquarters, analyzed inspection and warning letter trends, 
and reviewed FDAs Regulatory Procedures Manual. 
We selected a simple random sample of 40 firms that received warning letters during fiscal 
year 1996 and completed telephone interviews with 24 of them.  The remaining firms did 
not return phone calls or had gone out of business.  We asked firms about the violations 
that resulted in the warning letter and their experiences with FDA. 
This report is the one of two reports on the FDA warning letter process.  In a companion report, 
FDA Warning Letters:  Trends and Perspectives (OEI-09-97-00380), we found that changes 
in FDA policies and practices and better industry compliance have contributed to decreases in 
warning letters since 1994.  Despite the existence of clear warning letter guidance, differences in 
district office attitudes, experience, and the types of firms in the district affect warning letter 
volume.  Firms would like to better understand the warning letter process and suggested some 
minor changes.  With some exceptions, firms were satisfied with FDAs customer service during 
the warning letter process. 
Warning Letters--Timeliness and Effectiveness  10  OEI-09-97-00381  F I N D I N G S  
Warning letters are an effective compliance tool 
When FDA conducts follow-up activities, it finds that firms have either corrected the 
violations cited in warning letters or have made significant progress toward doing so. 
Firms take warning letters very seriously.  Almost 90 percent of firms respond in writing 
to warning letters within 15 days of receiving them, detailing corrective actions that they 
intend to take.  The following examples describe the effect that warning letters have on 
firm compliance with FDA laws and regulations: 
<	 A district office issued a warning letter to a firm for inadequate procedures and 
product labeling.  The firm responded within 15 working days and requested 
information about how to come into compliance.  The FDA provided educational 
materials and training.  Upon reinspecting the firm 5 months after the warning 
letter, FDA found no violations. 
<	 A district office issued a warning letter to a firm that had failed to report several 
recalls and product withdrawals.  The firm provided FDA with extensive 
documentation on the recalls and changed its policies to avoid repeating the same 
violation in the future.  Upon reinspecting the firm, FDA found that, although most 
of the violations had been corrected, some remained and new ones appeared.  The 
investigator issued a new FDA-483.  Based on the firms progress and 
cooperation, FDA determined that additional compliance action was not necessary 
pending the firms next routine inspection. 
<	 A district office issued a warning letter to a firm that had advertised a product as 
FDA-approved.  Within a few days of receiving the warning letter, the firm 
submitted a revised advertisement that did not include that phrase. 
The threat of subsequent compliance actions or other remedies enhances the value of the 
warning letter.  For example, FDA may refuse to take action on 510(k) or premarket 
approval applications or refuse to issue export certificates until firms correct warning 
letter violations.  In addition, the publicity associated with a warning letter--and a firms 
failure to correct the violations--can cause major harm to the firms reputation and 
revenue. 
Warning Letters--Timeliness and Effectiveness  11  OEI-09-97-00381  The warning letters effectiveness depends on conscientious 
follow-up 
The FDA completed appropriate follow-up in approximately 97 percent of cases 
If investigators feel it is necessary, FDA may reinspect a firm to verify that the warning 
letter violations have been corrected.  If more appropriate, districts may conduct other 
follow-up, such as soliciting documentation or meeting with industry officials to address 
compliance issues.  In some cases, such as with tissue residue violations, FDA does not 
require any follow-up except to ensure that the firm responds to the warning letter. 
In almost all of the cases that we reviewed, FDA conducted some type of follow-up 
activity to assess firm compliance.  The following table illustrates the types of follow-up 
district offices conducted in 1996 and the result of that follow-up: 
FDA follow-up activities confirm firms compliance 
Follow-up Method  Result  FDA Action  Percentage 
Reinspection  Observations noted  New FDA-483 issued  30 percent 
Reinspection  Observations noted  New warning letter issued  1 percent 
Other compliance action 
Reinspection  Observations noted  5 percent 
taken 
Reinspection  Observations noted  No action taken  3 percent 
No observations 
Reinspection  N/A  20 percent 
noted 
Documentation of compliance 
N/A  N/A  12 percent 
submitted by firm 
No follow-up per FDA 
guidelines (other than to 
N/A  N/A  23 percent 
assure written response from 
firm) 
Other follow-up occurred 
N/A  N/A  3 percent 
(meetings, phone calls) 
No follow-up although it 
N/A  N/A  3 percent 
appears to be warranted 
Follow-up inspections frequently uncover other violations, but FDA rarely has to initiate 
compliance actions.  As this table shows, FDA reinspected almost 60 percent of the firms 
that received warning letters.  Of the firms that FDA reinspected, investigators found 
violations--repeat or new--in approximately two-thirds of the cases.  Despite the discovery 
Warning Letters--Timeliness and Effectiveness  12  OEI-09-97-00381  of new violations, FDA rarely determined that another warning letter or a more serious
compliance action was warranted.  As the table shows, and the following chart illustrates,
new violations are most frequently cited by using an FDA-483:
New warning letters are the least common
outcome of a follow-up inspection
District office staff were not concerned that they found new or uncorrected violations
during two-thirds of reinspections.  In almost all of these cases, investigators were
satisfied with the firms progress or correction of other warning letters violations.  They
did not believe that a more serious compliance action, such as a seizure, was necessary. 
According to district office staff, some warning letters cite numerous violations, and
investigators often believe that issuing an additional warning letter or initiating a more
serious compliance action would not help assure compliance.  This is particularly true if a
firm has responded to the warning letter and indicates that it is willing to correct all
violations.
Follow-up inspections generally occur long after the warning letter is issued
When FDA conducts a follow-up inspection, it occurs 278 days after the warning letter is
issued, on average.  Almost one-quarter of follow-up inspections are delayed by more than
a year.  The timing of the follow-up inspection depends on multiple factors:
  < Workload:  District offices frequently must shift their priorities to meet agency
demands and goals.  Follow-up inspections sometimes are delayed in order to
focus on other priorities.
  < Type of violation:  If the district office decides to conduct a follow-up inspection,
the timing depends on whether the violations are easy to correct or require
significant time to correct (e.g., developing new manufacturing guidelines).
Warning Letters--Timeliness and Effectiveness                                    1   3                                                                                  OEI-09-97-00381 <	 Severity of violation:  If an inspection uncovers very severe violations, a district 
office might decide to conduct an immediate follow-up inspection.  On the other 
hand, if the violations are less grievous, the district office may simply verify 
corrections during its next routine inspection of the firm. 
<	 Number of violations:  District offices sometimes allow a firm extra time to correct 
multiple violations prior to conducting a follow-up inspection. 
<	 Firm history:  District offices keep a close watch on firms with a history of 
violations.  These firms are more likely to receive a follow-up inspection soon after 
the warning letter is issued. 
Warning letters are not always timely 
Headquarters rarely reviews and concurs with warning letter recommendations 
within FDAs 15-day guideline 
The FDA has a goal of 15 days for completion of headquarters warning letter review. 
However, less than 2 percent of letters that undergo headquarters review are completed 
within this time frame.  In one case, review required well over one year, and, on average, 
review takes 121 days to complete.  According to some district office staff, warning letters 
are a low priority in some of the centers.  Districts believe that the centers have too much 
higher priority work to complete review within 15 days.  One district office noted that all 
FDA time frames are difficult to meet, especially for the centers.  The following table 
illustrates how long it took for the centers to complete their review of warning letters that 
were approved for issuance in 1996: 
Warning Letters--Timeliness and Effectiveness  14  OEI-09-97-00381  Almost all center reviews of 1996 warning letters 
took more than 30 days 
None of FDAs district offices credited the centers with consistently meeting 

FDAs guideline.  District office staff understand the need for more time when the warning

letter concerns a technical or complicated issue but described other instances where delays

were unwarranted.  District office staff stated that they frequently have to call the centers

to determine the status of a warning letter recommendation.

The Center for Food Safety and Applied Nutrition received the most criticism for being

slowest, and complicating the process with multiple layers of review.  The other centers

did not fare well either in our survey.  Most district offices stated that none of the centers

consistently met the 15-day guideline to approve warning letter recommendations or the

30-day guideline to justify nonconcurrence.

Even when headquarters does not review warning letters, it frequently takes 
district offices more than a month to issue a warning letter 
The Regulatory Procedures Manual states that district offices should submit warning letter

recommendations to headquarters or issue warning letters to firms within 15 days of the

end of an inspection.  Excluding those cases where headquarters review was required, the

average delay between the end of inspection and the date of the warning letter is

38 days, with about 6 percent requiring more than 90 days:

Warning Letters--Timeliness and Effectiveness  15  OEI-09-97-00381  Almost half of district offices warning letters 
took 30 days or more to issue 
Firms reported that FDA was slow in issuing the warning letter after an inspection 
was completed but diligent in responding to their requests for information 
Approximately 40 percent of firms reported that FDA was not timely in issuing their 
warning letter.  As a result, they were more likely to be surprised by receipt of the warning 
letter and less likely to believe that the warning letter was appropriate.  Firms noted that 
they frequently have corrected all of the violations noted in the FDA-483 weeks or months 
before receiving a warning letter.  Consequently, they believe that they are being unduly 
and inappropriately punished. 
Firms were pleased by their district offices responsiveness to inquiries, however. 
Approximately three-quarters of the firms reported that FDA was timely in responding to 
their inquiries and following up with them. 
Discrepancies between headquarters and district office data 
on warning letters are extensive 
We found significant differences between the headquarters warning letter database and the 
files we reviewed in the district offices.  Almost 20 percent of the warning letters that we 
reviewed in the district offices were not accounted for in the headquarters database. 
These warning letters did not appear in the 1995 or 1997 warning letter databases either. 
Warning Letters--Timeliness and Effectiveness  16  OEI-09-97-00381  In addition, district offices were unable to provide us with all of the warning letters that 
appeared in the 1996 headquarters database.  Approximately 16 percent of the warning 
letters in the headquarters database did not appear in the district offices files. 
To corroborate our on-site findings, we asked the 15 other district offices to provide us 
with the number of warning letters that they issued from 1994 to 1997 and compared their 
responses to the headquarters database.  The numbers matched less than 10 percent of the 
time. 
Warning Letters--Timeliness and Effectiveness  17  OEI-09-97-00381  R E C O M M E N D A T I O N  
Despite questions about annual decreases in warning letters, discrepancies in district office 
warning letter volume, and the overall effectiveness of warning letters, the findings in both 
of our reports indicate that the warning letter is one of several effective tools that district 
offices use to achieve compliance with Federal laws and regulations.  In our companion 
report, we recommend that FDA continue to improve relations and communication with 
industry and consider issuing guidance that would authorize district offices to use FDA-
483s and meetings to achieve compliance in lieu of warning letters.  Based on the findings 
in this report, FDA should increase its effectiveness by: 
<	 improving the timeliness of the warning letter process and follow-up activities 
and 
<  revamping its warning letter data collection system to ensure accuracy. 
The delay between completing a firms inspection and issuing a warning letter--which can 
be months or more than a year--lessens the effectiveness of the warning letter.  The 
inaccuracy of FDAs warning letter database may contribute to poor communication 
between the centers and districts, or it could be a sign that communication is already a 
problem.  Also, since FDA is required to make warning letters available through the 
Freedom of Information Act and posts them on the Internet, correct warning letter data is 
of primary concern. 
We received comments on the draft report from FDA in which the agency concurred with 
our recommendation.  Where appropriate, we have made revisions in the report in 
response to these comments.  We also have responded to several of FDAs comments in 
the appendix. 
Warning Letters--Timeliness and Effectiveness  18  OEI-09-97-00381  APPENDIX A 
AGENCY COMMENTS

Warning Letters--Timeliness and Effectiveness  19  OEI-09-97-00381  Warning Letters--Timeliness and Effectiveness  20  OEI-09-97-00381  Warning Letters--Timeliness and Effectiveness  21  OEI-09-97-00381  Warning Letters--Timeliness and Effectiveness  22  OEI-09-97-00381  Warning Letters--Timeliness and Effectiveness  23  OEI-09-97-00381  APPENDIX B 
OIG RESPONSE TO AGENCY COMMENTS 
We offer the following additional analysis based on FDAs comments. 
At the time that this inspection began, there were six regional offices and 21 district 
offices as we stated in the draft report.  The Mid-Atlantic and Midwest regional offices 
have since merged into the Central regional office, and the Buffalo district office has 
merged with the Brooklyn district office. 
The seafood industry was the only industry in our sample that has a seasonal component. 
Analysis of the firms in our sample that market seafood shows that either there was no 
follow-up inspection conducted (most often because it was a failure-to-hold violation) 
or that reinspection was actually more timely than the average.  Hence, reinspection delays 
resulting from the seasonal nature of the industry had either no effect or a diminishing 
effect on the 278-day average that we reported. 
We did not intend to place any value judgments on the number of warning letters 
produced by a district. Our purpose in identifying these extremes is merely to indicate the 
wide variation in warning letter production that exists among the districts. 
Analysis of FDA data indicates that while both the numbers of inspections and warning 
letters decreased from 1994 to 1997 (the range used for our statements in the reports), 
inspections decreased by 3.6 percent while warning letters fell 39 percent.  In other terms, 
in 1994, about 9.1 inspections conducted yielded 1 warning letter.  In 1997, the rate was 
12.2 inspections per warning letter. 
We agree that the prevalence of importers in a district could contribute to the variation in 
number of warning letters issued and have clarified their importance in the companion 
report entitled FDA Warning Letters: Trends and Perspectives. 
The FDAs opinion that firms will voluntarily correct violations is highlighted in the 
background section of this report. 
Several districts indicated that increased familiarity with FDA regulations leads to better 
industry compliance.  We have clarified this point in the companion report. 
Our recommendation was not intended to discourage the use of warning letters, but rather 
to encourage FDA to issue guidance which would allow a district office to select the tools 
it feels are most effective in achieving compliance in a given situation. 
Warning Letters--Timeliness and Effectiveness  24  OEI-09-97-00381  The medical device Warning Letter Pilot will allow FDA to use a firms response to an 
FDA-483 or an untitled letter to preempt a warning letter for certain segments of the 
device industry.  More information can be found on FDAs website or in the Federal 
Register for August 27, 1998. 
With respect to FDAs comment on Page 11, last paragraph after table of the draft 
report (the table and paragraph now appear on page 12), we note that the paragraph 
below the pie chart on page 13 shows that despite the discovery of repeat or new 
violations on reinspection, the warning letter was still effective.  As stated there, 
investigators believed that the violations found on reinspection were minor and that firms 
had made satisfactory progress towards compliance. 
Warning Letters--Timeliness and Effectiveness  25  OEI-09-97-00381