incomplete. It is, therefore, possible that prescription drug advertising in medical
journals is responsible for some inappropriate prescribing of medications.

Medical journals, which play important roles in informing and educating physicians,
should guard against this possibility. These journals, which devote considerable effort
to scrutinizing the adequacy of articles submitted for publication, could similarly review
the content of advertisements.

Assuming responsibility for advertising content raises some difficulties for medical
journals. Yet this role is one that some journals already are performing and that
many others can perform without an extensive commitment of resources.” We
suggest that the leadership of medical journals address the issue and identify specific
ways in which their journals can best review the prescription drug advertisements they
receive.

13


FIGURE 2

Educational Value of Prescription Drug Advertisements

Little Value (38%)

No Value (12%)

Some Value (21%)

No Agreement (28%)
Great Deal of Value (1%)

Source: OIG/UCLA Solicited Assessments of Medical Journal Advertisements, Winter 1991

contraindications and information on the effectiveness of the drug, and 2) the
advertisement must not be false or misleading with respect to side effects,
contraindications, or effectiveness. The FDA regulations specify 33 criteria for judging
whether an advertisement makes a "true statement." Twenty of these criteria indicate
that an advertisement is false, lacking in fair balance, or otherwise misleading, while
13 criteria indicate that an advertisement may be false, unbalanced, or misleading.
These 33 criteria are summarized in appendix C. Our questions walked the reviewers
through statements related to these guidelines, asking them to evaluate the
advertisements based on the statements. While our reviewers made determinations
based on their own scientific knowledge and not on FDA law or FDA-approved
labeling, the questions allowed our reviewers to cite specific examples of potential
violations of FDA regulations. The FDA bases its determinations of actual violations
only on comparisons to approved labeling.”

On average, the reviewers cited 4.3 specific examples of potential violations of FDA
regulations per advertisement.” For 92 percent of the advertisements, two or more
reviewers answered in agreement on at least one of our questions indicating a
potential violation of FDA’s guidelines. For 38 percent, our reviewers cited five or
more examples of potential violations. For 7 of the 109 advertisements, our reviewers
cited more than ten examples.


TABLE A-1

Characteristics of Physician and Pharmacist Reviewers

Characteristic Physicians (n=108) Pharmacists (n=53)
Age (mean + standard 52 +10 3446
deviation)
Sex (percent male) 98% 51%
Academic rank (physicians
only):
Lecturer 2% -
Assistant Professor 10% -
Associate Professor 19% -
Professor 56% -
Other Academic 12% -
Highest degree in pharmacy:
Doctorate - 75%
Masters - 6%
Bachelor - 19%
Articles authored in peer- 15 + 16 243
reviewed journal in past
three years (mean +
standard deviation)
Articles peer-reviewed in 1124 0
past three years (mean +
standard deviation)
Percentage who received 1% 26%
payments from
pharmaceutical
manufacturers in the past
two years
Less than $200 3% 23%
More than $5000 53% 0%

Source: OIG/UCLA Records on Physician and Pharmacist Reviewers, Winter 1991



We have worked extensively with FDA in developing our findings and conclusions.
The FDA has indicated to us its interest and concern in the issues presented in this

report.

FINDINGS

The reviewers found many deficiencies with the prescription drug advertisements they

reviewed.

> The reviewers noted the following major deficiencies: the advertisements lacked
needed references and information on efficacy, appropriate populations, safety,
and side effects or contraindications.

> The reviewers rated 60 percent of the advertisements poor or unacceptable in
terms of scientific references.

> Using criteria similar to those used for reviewing scientific articles, the

reviewers would have rejected for publication 17 percent of the advertisements
and would have required major revisions for another 24 percent.

The reviewers rated half of the advertisements as having little or no educational value.

>

The reviewers found that 50 percent of the advertisements had little or no
educational value.

The reviewers concluded that 59 percent of the advertisements would not lead
to proper prescribing if the physician had no other information.

The reviewers frequently found the advertisements to be lacking in comparison to the
principles stated in FDA regulations on prescription drug advertising.

>

On average, the reviewers cited 4.3 examples of inadequate, misleading, or
inappropriate information per advertisement. These examples indicate
potential violations of FDA regulations.

The reviewers frequently found the advertisements to be inadequate in the
: y . . . . .
areas of presentation of side effect information, referencing, use of headlines,

and presentation of comparative claims.

The FDA has used a variety of regulatory responses to remedy violations or correct
misleading or false advertising, but it has rarely taken formal action against violators.

>

After monitoring over 19,000 prescription drug advertisements in print media in
fiscal year 1991, FDA took formal regulatory action against an advertiser 217
times. The FDA’s actions consisted of issuing notice of violation and warning

ii


25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

Conversation on September 5, 1990, with the acting director of the FDA’s
Division of Drug Advertising and Labeling.

D.A. Kessler and W.L. Pines, "The Federal Regulation of Prescription Drug
Advertising and Promotion," Journal of the American Medical Association 264,
no. 18 (November 14, 1990): 2409-2415.

Formerly, there were two stages of letters instead of warning letters. One was
a notice of adverse findings letter, the other was a more severe measure, known
as a regulatory letter.

Kessler and Pines, "Federal Regulation." In addition, FDA usually requires that
manufacturers submit introductory campaign material prior to publication. The
FDA believes that advertising is a prime source of information about new
products and therefore new product advertising is more important to review
than established product advertising.

Ibid, The authors note that "in recent years criminal cases have been pursued,
though none to completion, and none has been disclosed publicly." It is also
important to note that legal action generally requires the cooperation of the
Department of Justice. Initiation of cases is not, therefore, the sole
responsibility of FDA.

D.L. Breo, "Sidney Wolfe, MD--Healing the System or Just Raising Hell?"
Journal of the American Medical Association; 266, no. 8 (August 28, 1991): 1133.

Personal communication with the Acting Director of FDA’s Division of Drug
Marketing, Advertising and Communications, October 16, 1991.

M. Gladwell, "Firm to Recant Drug Claims," Washington Post, October 11,
1991, Al, A4.

We conducted interviews with several lawyers specializing in FDA law for our
report on "Prescription Drug Promotion Involving Payments and Gifts"
(OEI-01-90-00480). At that time, we asked several questions about FDA
enforcement activity. In addition, we conducted interviews with FDA officials
who did not refute these statements.

"Tough Talk from Ann Witt, New FDA Drug Advertising Chief," PMA
Newsletter 33, no. 19 (May 13, 1991): 1.

At the time our reviews were conducted only one journal (Obstetrics and
Gynecology) reviewed advertisements according to the editors of the journals.
At least one additional journal now conducts reviews of advertisements.

In addition, Wade et. al. (V.A. Wade, P.R. Mansfield, and P.J. McDonald,
"Drug Marketing: Drug Companies’ Evidence to Justify Advertising,” Lancet


APPENDIX A

Methodology
Selection of Advertisements

We selected advertisements from 10 peer-reviewed medical journals. Nine were
specialty medical journals and one was a general medical journal. The specialty
journals were American Journal of Psychiatry, Annals of Emergency Medicine, Annals of
Internal Medicine, Annals of Surgery, Archives of Neurology, Archives of Surgery, Journal
of Family Practice, Obstetrics and Gynecology, and Pediatrics. The general medical
journal was the New England Journal of Medicine. For each journal, we used the first
issue of 1990 (with the exception of the Annals of Surgery for which copies of the
second issue were obtained, because original copies of the first issue were
unavailable).

From each journal, we selected all pharmaceutical drug advertisements of at least one
page length. If identical advertisements appeared more than once in the 10 journal
issues, duplicate advertisements were eliminated. If a drug product had two different
advertisements, then both remained in the study. We finally selected 109 unique
advertisements as our sample. We then attempted to obtain all material referenced in
each advertisement. When references were not available in the Regional National
Library of Medicine Reference Library, we contacted the pharmaceutical
manufacturer and requested reprints. Of the 149 references cited in the
advertisements, we were able to obtain copies of 64 percent. The process by which we
attempted to obtain references was thorough and exhaustive, but many of the
references were made to unpublished papers, confidential reports, or studies from
journals that could not be obtained. Requests to the manufacturers were returned
with written comments claiming that the reference was confidential or that they could
not find it in their files.”

Physician Reviewers

The editors of three specialty journals provided us with lists of experienced peer
reviewers who covered the range of medical expertise required for this study. These
journals were the Archives of General Psychiatry, Annals of Internal Medicine, and
Obstetrics and Gynecology. We sent the nominated peer reviewers a cover letter
describing the study and asking whether they wished to participate. We enclosed a
letter from the editor of the journal for which they were the reviewer, encouraging
them to participate. We then systematically telephoned the nominated until 125
agreed to act as reviewers. Only about 15 percent of those contacted declined to
participate. We sent 113 of these physicians (91 percent) advertisements to review,
basing their selection on areas of expertise. For example, infectious disease specialists
reviewed only antibiotic advertisements, and psychiatrists reviewed only psychiatric
medicines. This constituted a sample large enough to send each advertisement to two

A-l


15. use "no statistically significant difference" to demonstrate that two therapies are
similarly effective;

16. use statements that the drug differs from or does not contain another drug to
misleadingly represent that the advertised drug is safer or more effective than
another drug;

17. use data from studies that provide subjects with dosages of the drug that are
different than those recommended in labeling;

18. use headline, subheadline, or pictorial or other graphic matter in a way that is
misleading;

19. represent that because drug dosages are proper for certain types of patients
they are safe for other types of patients; and

20. lump together specific side effects into one general condition.
Advertisements that may be false, Jacking in fair balance, or otherwise misleading:
21. contain information from an inadequate study;

22. use statistical significance to support a statement that is not clinically relevant
or significant; -

23. use analyses of data to cite findings not supported by the study;
24. use graphs or tables to distort relationships, trends, and so on;
25. use reports claiming to be using sound scientific methods but do not;

26. contain claims related to the mechanism or site of drug action that are contrary
to established scientific evidence;

27. fail to give sufficient emphasis to information on side effects and
contraindications in comparison to claims of effectiveness;

28. fail to present information on side effects and contraindications with a
prominence and readability comparable to information on effectiveness;

29. fail to provide adequate emphasis for the fact that two facing pages are part of
the same advertisement;

30. in promotion directed to a certain class of patients, fail to adequately
emphasize specific side effects for that class of patients;


They were also asked to rate how much educational value, rather than promotional
value, the advertisement has on a scale of 1 to 4 with 1 being none and 4 being a
great deal.

Finally, each reviewer was asked what his or her overall suggestion to a journal editor
of a leading medical journal would be regarding publication using review criteria for a
scientific article. The reviewer was asked whether he or she would accept the
advertisement in its present form, accept it contingent upon minor revisions, accept it
contingent upon major revisions or reject it. He or she was then asked what revisions
were necessary.

Analysis of Data

Most of the analyses are presented in terms of percentage of advertisements. We
usually reported only about advertisements which at least two reviewers evaluated.
Except when noted, we reported only opinions agreed on by at least two reviewers.
When there were three reviews for the advertisement, it was possible that we reported
an opinion that only two of the three reviewers agreed on. When there were only two
reviews for the advertisement, both of the reviewers had to agree. We call this
technique the majority rules criteria. In some cases, the percentage of advertisements
on which no agreement was reached is a relevant statistic. In these cases, we report
this also.

When summarizing the questions on FDA regulations, we grouped the strongly agree
and somewhat agree categories into an agree category and the strongly disagree and
somewhat disagree categories into a disagree category.

To evaluate the pattern of responses, we assessed agreement within one category on
the question about acceptability. For each group of reviewers, we compared
agreement with one category on the four category reject/major revisions/minor
revisions/accept scale (e.g. if one reviewer recommended rejection, the other reviewer
agreed within one category if he or she recommended rejection or major revision).
The concordance rates among reviewers, using pairwise kappas were fair to good:

2 for each of the 3 reviewer pairs in advertisements with three

reviewers.


37.

38.

39,

40.

(November 25, 1989): 1261-1264.) have noted the positive effects physician
review and interaction with pharmaceutical manufacturers can have on
improving the quality of advertising. The Australian Medical Lobby for
Appropriate Marketing reviews marketing material of pharmaceutical
manufacturers and uses the influence of physicians to improve its quality.

Unpublished data from a study entitled, "Journal Editors and the News Media,”
conducted by M. Wilkes from UCLA.

Journal editors argue that reviewing editorial content of prescription drug
advertising could lead to the perception of collusion between the editor and the
advertiser. One writer has said that it would require "setting up an FDA for
each journal." (D. Rennie, "Editors and Advertisements: What Responsibility
Do Editors Have for the Advertisements in Their Journals?" Journal of the
American Medical Association 265, no. 18 (May 8, 1991): 2394-2395.)

Our consultants conducted: thorough peer reviews of advertising within a quick
timeframe without many of the resources journal editors have (such as editorial
staff, working procedures for handling peer review, and a peer review panel
used to working with the journal). Although there was variability, the reviews
in our study were conducted in an average of 20 minutes. Medical journals,
unlike our consultants, have a ready source of experienced peer reviewers who
could screen advertisements. ‘

The written comments we received from manufacturers we sought references
from include: "we have not been able to locate the study as yet. However, we
believe it is a worthwhile study ... if you come across it please let us know,"
"The information is part of confidential research report of a study
commissioned by us," and "unfortunately, the department which maintains these
documents has been unable to locate the document."


CONCLUSION

Our review looks at the overall quality, truthfulness, accuracy, and educational value of
prescription drug advertisements in leading medical journals from the perspective of
highly respected clinical reviewers. The sharp criticisms these reviewers made, based
on criteria relevant to prescribers’ interpretations of advertisements, indicate
significant problems with prescription drug advertisements and their potential effects
on prescribing. While the Public Health Service (PHS), through FDA, is the
government agency responsible for oversight of prescription drug advertisements, it
cannot alone assure their truthfulness and value. The pharmaceutical industry is first
and foremost responsible for the quality of prescription drug advertising. Medical
journals also have clear responsibilities in this regard. Below we offer several options
to strengthen pharmaceutical advertising.

OPTIONS

The Public Health Service (PHS), through FDA, could conduct periodic review of a
sample of prescription drug advertisements in medical journals. It could use pharmacist
and physician consultants to conduct the reviews.

Although FDA has recently increased the staff allocated to review prescription drug
advertising, it is still not likely to be able to review prescription drug advertisements
adequately. The volume of advertisements is simply too large. But if FDA were able
to solicit the expertise of physician and pharmacist reviewers, it could at the very least
identify advertisements needing more detailed review.

Furthermore, this group of reviewers would give FDA the advantage of having
prescribers’ perspectives on drug advertisements. This unique viewpoint would be
helpful in validating claims of impropriety and would certainly bolster legal efforts.

Finally, educating physicians and pharmacists who act as reviewers in FDA regulations
and having them carefully evaluate prescription drug advertisements would make them
much more aware of the potential problems with advertisements. Since physician and
pharmacist reviewers could potentially be important and respected leaders in the
clinical community, their increased awareness could encourage others to be more
attentive to the limitations of advertising.

The PHS could seek congressional approval to strengthen FDA’s authority to deal with
violators of prescription drug advertising regulations. This could include authority to
impose civil monetary penalties and to require violators to publish corrective or
educational advertisements to remedy the violations.

Civil Monetary Penalties. Although FDA has used regulatory means to change and

cancel advertisements they have found to be in violation, these means are effective
only after advertisements have been published. These means do not appear to have

11


Our instrument led each reviewer through 30 specific statements about the
advertisement with which they could agree or disagree. It then asked the reviewers to
rate the quality of the advertisement on four criteria. The instrument then asked the
reviewers to rate how much educational value, rather than promotional value the
advertisement had. Each reviewer was then asked what his or her overall suggestion
to a journal editor of a leading medical journal would be regarding publication using
review criteria similar to those used in reviewing a scientific article. If the reviewer
felt the advertisement needed to be revised or rejected the advertisement, he or she
was asked what deficiencies the advertisement had.

The UCLA researchers selected all advertisements in early 1990 editions of 10 leading
peer-reviewed medical journals for inclusion in the study.!* After eliminating
duplicates, they were able to evaluate 109 pharmaceutical advertisements. In addition
to the advertisements themselves, they provided each reviewer with all the available
references cited in the advertisements. Their intent was to have two physician-
reviewers and one pharmacist-reviewer evaluate each advertisement. They
accomplished that goal for 84 percent of the advertisements. For 15 percent, they
received 2 reviews and for 1 advertisement, they received 1 review. A total of 309
reviews were conducted.

We report results using advertisements as the unit of analysis, unless otherwise noted.
To summarize the two or three reviews we had for each advertisement we use a
majority rules criteria. In other words, we report opinions on which at least two
reviewers agreed. Appendix A provides detail on the methods used and on the
credentials and demographic profiles of the reviewers.

In addition to the reviews of the advertisements, we used literature, interviews, and
other data gathered from research for another Office of Inspector General report.
That report was the first of three (of which this is the third) which discuss prescription
drug promotion. Entitled "Promotion of Prescription Drugs through Payments and
Gifts" (OEI-01-90-00480), it was released in August 1991. The second report, released
in draft in March 1992, presents the results of a national survey of physicians on
prescription drug promotion practices involving payments and gifts. It is entitled
"Promotion of Prescription Drugs through Payments and Gifts: Physicians’
Perspectives" (OEI-01-90-00481).

Our review was conducted in accordance with the Interim Standards for Inspections
issued by the President’s Council on Integrity and Efficiency.


10.
11.

12.
13.

14.

15.

a=
an

17.

It should be noted that some observers of the pharmaceutical industry have
held a much more cynical view of why pharmaceutical manufacturers spend so
much money on journal advertising, namely, that advertising dollars buy
influence on the editorial content of medical journals. See M. Silverman and
P.R. Lee, Pills, Profits and Politics (Berkeley: University of California Press,
1974), p. 56, and M. Wilkes and M. Shuchman, "Pitching Doctors," New York
Times Magazine, November 5, 1989, p. 88.

Formerly known as the Division of Drug Advertising and Labeling.

The current acting Director of the division estimated that at the time the
advertisements reviewed in our study were published, the division had only four
full-time professionals reviewing advertisements.

P. Mansfield, "Drug Advertising," Lancet, May 20, 1989, p. 1137.

For examples of the commissioner’s interest, see "Drug Advertising Regulatory
Action by FDA Appears Likely: FDA Collecting Records on Repeat Offenders
in Preparation for Setting Object Lesson," F-D-C Reports, February 18, 1991; p.
6, D.A. Kessler and W.L. Pines, "The Federal Regulation of Prescription Drug
Advertising and Promotion," Journal of the American Medical Association 264,
no. 18 (November 14, 1990): 2409-2415; and "FDA Must Clarify Promotion
Rules--And Soon, Kessler Tells Kennedy," PMA Newsletter 33, no. 10 (March
11, 1991): 1.

American Journal of Psychiatry, Annals of Emergency Medicine, Annals of
Internal Medicine, Annals of Surgery, Archives of Neurology, Archives of Surgery,
Journal of Family Practice, New England Journal of Medicine, Obstetrics and
Gynecology, and Pediatrics.

We used a majority rules criterion. If the advertisement was reviewed by three
people and two agreed, that was the judgment we used. If the advertisement
was reviewed by only two people, both had to agree on the judgment.

These figures represent conservative estimates of percent of advertisements
with deficiencies, since for many advertisements there was not agreement. For
example, for only 10 percent of the advertisements was there agreement that
36 percent of the advertisements, two reviewers had different opinions about
the advertisement on this point.

Some observers of the peer review process have noted the propensity of
reviewers to find at least minor problems with almost all articles. It therefore
may be wise to focus less on the minor revisions category as being meaningful.
However, the large number of advertisements that would have required major
revisions or would have been rejected should raise a great deal of concern.


Statement

Number of
Advertisements for
Which At Least Two
Reviewers Answered
the Question

Number of
Advertisements in
Which At Least Two
Reviewers Cited a
Violation

Percentage of
Advertisements in
Which At Least Two
Reviewers Cited a
Violation

Not adequately
referenced

23

7

30%

Likely to lead the
reader to a misleading
conclusion

23

30%

Misleads the reader
about efficacy

16

37%

Promotes appropriate
use of the drug

16

25%

Supported by written
text

16

6%

Citation of Studies and
Use of Statistics:

Statistics are derived
from inconclusive,
dissimilar, or poorly
designed studies

27

30%

Uses "statistical
significance” to
support a claim that
has not been
demonstrated to have
clinical relevance or
validity

26

4%

Contains favorable
information or
conclusions from a
study or studies that
isfare adequate in
design, scope, or
methodology to justify
its application in
practice

39

11

28%

Makes claims based on
| studies whose subjects
are substantially
different from the
population of patients
for whom this
advertisement is
directed

55

13%



TABLE OF CONTENTS

EXECUTIVE SUMMARY
INTRODUCTION . 2.0.6 cece nent eens 1
FINDINGS 2.0... ccc eee enn e een ene e nets ene e eee 4

The reviewers found many deficiencies with the prescription drug advertisements they
TEVIEWED Lc cece center eee teen eee t teen ete neeee 4

The reviewers rated half of the advertisements as having little or no educational
The reviewers frequently found the advertisements to be lacking in comparison to the
principles stated in FDA regulations on prescription drug advertising. .........-- 6

The FDA has used a variety of regulatory responses to remedy violations or correct
misleading or false advertising, but it has rarely taken formal action against violators. 8

Although journal review can improve the quality of published prescription drug
advertising, many medical journals do not review the content of the advertisements

they publish. . 6.6... ee cee eee ee eee ee eee ete ee een eens 10
CONCLUSION 2.0... cece ence ence nen nents 11
APPENDIX A

Methodology .... 0... cece ccc cee eee teen eee e teens A-1
APPENDIX B

Deficiencies noted by reviewers in advertisements not acceptable in their

poet) 1c Cct6 ib Ce) 61: na B-1
APPENDIX C

FDA prescription drug advertisement regulations .........---.+2-0e 05> C-1
APPENDIX D

Reviewers’ opinions of prescription drug advertisements: adherence to FDA

regulations . 6.6... eee cee eee eee eee eee teen eee D-1
APPENDIX E

NOtes cece erence eee e eee ene ene e ene E-1


letters and requesting that manufacturers publish corrective advertisements or
send letters to pharmacists and physicians correcting advertisements.

The FDA took formal legal action (injunction) against only two false or
misleading advertisers since June 1991.

Although journal review prior to publication can improve the quality of published
prescription drug advertising, many medical journals do not review the content of the
advertisements they publish.

»

Our reviewers rejected no advertisements in the one journal selected for our
study that reviewed advertisements prior to publication.

> According to a survey of 221 medical journal editors, 37 percent of medical
journals review advertising prior to publication and only 13 percent do any sort
of peer review of advertising.

CONCLUSION

While the Public Health Service (PHS), through FDA, is the government agency
responsible for oversight of prescription drug advertisements, it cannot alone assure
their truthfulness and value. The pharmaceutical industry is first and foremost °
responsible for the quality of prescription drug advertising. Medical journals also have
clear responsibilities in this regard. Below we offer several options to improve
pharmaceutical advertising.

Options for improving pharmaceutical advertising:

>

The Public Health Service (PHS), through FDA, could conduct periodic review
of a sample of prescription drug advertisements in medical journals. It could
use pharmacist and physician consultants to conduct the reviews.

The PHS could seek congressional approval to strengthen FDA’s authority to
deal with violators of prescription drug advertising regulations. This could
include authority to impose civil monetary penalties and to require violators to
publish corrective or educational advertisements to remedy the violations.

The Pharmaceutical Manufacturers Association could emphasize to its members
the importance of accuracy and truthfulness in advertising and could assist them

in improving procedures for reviewing advertisements prior to publication.

Medical journals could identify specific ways to assure the truthfulness and
accuracy of the pharmaceutical advertisements they publish.

iti


acted as significant deterrents to keep some pharmaceutical companies from
publishing false or misleading advertising. Currently available legal and civil actions
have rarely been taken and thus likely are not seen as a deterrent. Many violators of
FDA regulations who are cited by FDA are not penalized.

The PHS might benefit from having a new tool to deter and punish violative
advertisers. The currently available legal actions can be either too difficult to pursue
or inappropriately matched to the violations. The possibility of proving criminal intent
in the case of false or misleading advertising seems remote. On the other hand,
seizure of a company’s product seems ill matched to the offense. A company may
have a fine product which has been inappropriately advertised; if FDA seized the
product, it could negatively affect the public health.

Civil monetary penalty (CMP) authority would allow PHS to pursue financial damages
suits against violative pharmaceutical manufacturers without having to prove criminal
intent. Substantial CMPs could help deter pharmaceutical companies from producing
false and misleading advertising.

Authority to Require Corrective or Educational Advertisements. Although FDA has
occasionally requested that advertisers publish corrective or educational
advertisements to remedy violations, pharmaceutical companies do not have to comply
with the requests. The authority to require publication of corrective or educational
advertisements would allow FDA to assure that violators of their regulations, at the
very least, produce information that corrects false or misleading advertisements. It
could also deter advertisers from producing improper advertisements.

The Pharmaceutical Manufacturers Association (PMA) could emphasize to its members
the importance of accuracy and truthfulness in advertising and could assist them in
improving procedures for review of advertisements prior to publication.

As we stated earlier, the pharmaceutical industry is first and foremost responsible for
the quality of prescription drug advertising. It is important for the PMA to make clear
to its members how vital the quality of advertisements is to the medical community

Individual manufacturers’ procedures for reviewing advertisements prior to publication
may vary significantly. The PMA could help coordinate information about how best to
conduct pre-publication review. For example, they could foster communication among
companies through panels, seminars, and newsletters.

Medical journals could identify specific ways to assure the truthfulness and accuracy of
the pharmaceutical advertisements they publish.

Studies have shown that prescription drug advertisements have some influence on

physicians’ prescribing decisions. In this study, our expert reviewers found that
advertisements in leading medical journals are often misleading, inaccurate, and

12


The very fact that pharmaceutical companies commit huge sums of money to
advertising further speaks to its effectiveness in changing medication use. It is unlikely
that given the deep understanding pharmaceutical manufacturers have of the market
for prescription drugs, they would spend such large amounts on ineffective
advertising?

The Food and Drug Administration (FDA) is charged with regulating promotion of
prescription drugs. It has the authority to penalize pharmaceutical manufacturers who
sponsor false or misleading advertisements through criminal and civil actions. It can
also use its influence to alter or cancel inappropriate advertising. But until recently,
FDA’s Division of Drug Marketing, Advertising, and Communication” had a staff of
less than 10 full-time professionals to review tens of thousands of advertisements in
medical journals and promotional activities." One FDA official estimated that this
scarcity of resources made it possible to act on only about five percent of the
advertisements that are false or misleading.’* In response to these problems, the
Commissioner of FDA has focused much attention on prescription drug advertising
and promotion, and has doubled the staff for the division.

Our objective is to discover the level of inaccurate, low quality, or otherwise unsuitable
prescription drug advertising in medical journals. We evaluate advertisements in three
general areas: (1) whether there were major deficiencies with the advertisements; (2)
the educational value of the advertisements; and (3) whether the advertisements
appear to adhere to FDA regulations concerning false and misleading advertising. In
addition, we describe current responses to false or misleading advertising. We
conclude with suggestions for the Public Health Service (including FDA) and others on
how to improve regulatory and other responses to false and misleading advertising.

We have worked extensively with FDA in developing our findings and conclusions.
The FDA has indicated to us its interest and concern in the issues presented in this
report.

METHODS

This project was conceptualized and designed by a group of Robert Wood Johnson
clinical scholars at the University of California at Los Angeles (UCLA) working under
contract for us. They gathered assessments of prescription drug advertising and
presented the results to us. They enrolled physicians who had acted as peer reviewers
for medical journals as well as pharmacists who had been involved in physician
education about pharmaceutical drugs to review the advertisements. A total of 161
reviewers participated in the study, 108 of whom were physicians and 53 of whom
were pharmacists. Each reviewer was asked to complete a review form for each of
two advertisements. The form allowed reviewers: to evaluate the acceptability of the
advertisements for publication in leading journals using criteria similar to those used in
reviewing scientific articles; to judge the educational value of the advertisements; and
to evaluate specific aspects of the advertisements, such as images, claims, balance, and
use of statistics, all of which relate to FDA guidelines and regulations.


APPENDIX B

Deficiencies Noted by Reviewers in Advertisements
Not Acceptable in Their Published Form

Deficiency Type Advertisements for Advertisements for Advertisements for
Which at Least One Which at Least One Which at Least One
Reviewer Reviewer Reviewer
Recommended Minor | Recommended Major | Recommended
Revisions, Major Revisions or Rejection | Rejection (N=24
Revisions, or (N=59 advertisements) | advertisements)
Rejection (N=104
advertisements)

| Lacked information on | 60% 15% 1%

efficacy

Lacked needed 54% 56% 1%

references

Lacked information on | 43% 59% 87%

appropriate

populations

Lacked information on | 38% 41% 11%

safety

Lacked information on | 28% 36% 42%

side effects and

contraindications

Contained misleading | 14% 24% 33%

j, statements in the text i

Contained misleading | 7% 12% 12%

images

Contained misleading | 5% 8% 4%

references

Con isleading 4% 1% 8%

graphs or tables

Other correction 4% 2% 0%

| needed

Note: Figures are percent of advertisements on which two or more reviewers cited the listed deficiency

Source: OIG/UCLA Solicited Assessments of Medical Journal Advertisements, Winter 1991


Department of Health and Human Services

OFFICE OF
INSPECTOR GENERAL

PRESCRIPTION DRUG ADVERTISEMENTS
IN MEDICAL JOURNALS

s sete
e Richard P. Kusserow
5 ( INSPECTOR GENERAL
“neg

JUNE 1992



> The reviewers rated 60 percent of the advertisements poor or unacceptable in
terms of scientific references.

In addition to asking our reviewers to decide what deficiencies advertisements had, we
asked them to evaluate each advertisement’s overall quality in terms of four criteria:
factual accuracy, scientific references, clarity, and honesty of claims. The
advertisements were generally poorly rated on scientific references, with the reviewers
agreeing that 60 percent of the advertisements were poor or unacceptable on this
measure. On factual accuracy, clarity, and honesty of claims, the advertisements fared
better, but still 18 percent of the advertisements were rated poor or unacceptable on
accuracy, 16 percent poor or unacceptable on honesty of claims, and 12 percent poor
or unacceptable on clarity.

> Using criteria similar to those used for reviewing scientific articles, the
reviewers would have rejected for publication 17 percent of the advertisements
and would have required major revisions for another 24 percent.

We asked each reviewer to evaluate whether he or she would have accepted the
advertisement for publication, accepted it contingent upon minor revisions, accepted it
contingent upon major revisions, or rejected it. The reviewers were asked to use
criteria consistent with those they would use for a scientific article. The reviewers
agreed that 17 percent of the 109 advertisements would have been rejected, 24
percent would have required major revision, 26 percent would have required minor
revision, and only 3 percent would have been accepted without change (figure 127
The reviewers did not agree on 31 percent of the advertisements. For the 34
advertisements on which there was no agreement, we used reviews as the unit of
analysis and similar patterns emerged.’

These ratings are validated by the deficiencies cited by the reviewers. Deficiencies
were proportionally more prevalent when the reviewers judged that the advertisement
required major revision or rejected the advertisement. Appendix B shows this in
detail.

half of the advertisements as having little or no educational value.

> The reviewers found that 50 percent of the advertisements had little or no
educational value.

We asked our reviewers to evaluate each advertisement on the basis of how much
educational value, as opposed to promotional value, the advertisement had. For only
one advertisement did two or more reviewers agree the advertisement had a great
deal of educational value. For 21 percent of the 109 advertisements, the reviewers
agreed that the advertisement had some educational value; for 38 percent, the
reviewers agreed the advertisement had little educational value, and for 12 percent of
the advertisements, the reviewers agreed the advertisement had no educational value
(figure 2). The reviewers did not agree on 28 percent of the advertisements.


FINDINGS

The reviewers found many deficiencies with the prescription drug advertisements they

reviewed.

> The reviewers noted the following major deficiencies: the advertisements lacked
needed references and information on efficacy, appropriate populations, safety,

and side effects or contraindications.

For 53 percent of the 109 advertisements reviewed, two or more of the reviewers

agreed?

that the advertisement lacked information on efficacy; for 50 percent, that

the advertisement lacked needed references; for 40 percent, that the advertisement
lacked information on appropriate populations; for 38 percent, that the advertisement
lacked information on safety; and for 28 percent, that the advertisement lacked
information on side effects or contraindications. Table 1 lists all the deficiencies
mentioned and the percentage of advertisements in which the reviewers agreed

revisions were needed to correct them.

TABLE 1

Deficiencies in Advertisements in Leading Medical Journal

Deficiency Type

| Percent of Advertisements on Which

Two or More Reviewers Agreed on the |
Deficiency (N=109 advertisements)’®

Lacked information on efficacy

53

Lacked needed references 50

Lacked information on appropriate populations 40

Lacked information on safety 38

Lacked information on side effects and contraindications | 28

Contained misleading statements in the text 14

Contained misleading images 7

Contained misleading references 5

Contained misleading graphs or tables 5

Other correction needed 4 |

Source: OIG/UCLA Solicited Assessments of Medical Journal Advertisements, Winter 1991


APPENDIX E

Notes

An October 1990 report by the majority staff of the U.S. Senate Special
Committee on Aging presented evidence on the extent and sources of
mismedication as well as the effects mismedication has on health care and its
costs. The report listed physicians’ prescribing errors as one of three major
reasons for adverse drug reactions and cited studies that have estimated that up
to 7.3 percent of prescriptions have potentially serious errors. The report
noted that adverse drug reactions account for three to eight percent of all
hospital admissions in the United States and may have accounted for $5 billion
to $13 billion in hospital expenses in 1987.

See D. Christensen and A. Wertheimer, "Sources of Information and Influence
on New Drug Prescribing among Physicians in an HMO," Social Science and
Medicine 13A (1979): 313-322, and M. Peay and E. Peay, "Differences among
Practitioners in Patterns of Preference for Information Sources in the Adoption
of New Drugs," Social Science and Medicine 18, no. 12 (1984): 1019-1025. Both
articles detail research that shows that physicians often receive the first news of
a drug from advertising. :

J. Avorn, and S.B. Soumerai, "Improving Drug-Therapy Decisions through
Education Outreach: A Randomized Controlled Trial of Academically Based
Detailing," New England Journal of Medicine 16, no. 308 (1983): 1457-1463.

B.R. Meyer and the Health and Public Policy Committee of the American
College of Physicians, "Improving Medical Education in Therapeutics," Annals
of Internal Medicine 108 (1988): 145-147.

Food, Drug, and Cosmetic Act, 21 U.S.C. 331, 352.

M.C. Smith, "Drug Product Advertising and Prescribing: A Review of the
Evidence," American Journal of Hospital Pharmacy 34 (November 1977): 1208-
1224.

Healthcare Communications, Inc., "The Effect of Journal Advertising on
Market Shares of New Prescriptions," 1989.

J. Avorn, M. Chen, and R. Hartley, "Scientific versus Commercial Sources of
Influence on the Prescribing Behavior of Physicians," American Journal of
Medicine 73 (1982): 4-8.


Statement

Number of
Advertisements for
Which At Least Two
Reviewers Answered
the Question

Number of
Advertisements in
Which At Least Two
Reviewers Cited a
Violation

Percentage of
Advertisements in
Which At Least Two
Reviewers Cited a
Violation

Images:

Promote use in the
appropriate
populations

87

27

31%

Promote drug use in a
manner consistent
with the written text

90

19

21%

Minimize concerns
about, or awareness of,
side effects or adverse
drug reactions

85

27

32%

Are used in a manner
that misleads the
reader about the
efficacy of the drug

22

24%

Medical illustration is
in agreement with
current scientific
knowledge

17%

Overall:

Presents a fair balance
between information
on efficacy and on side
effects/
contraindications

104

42

40%

Presents information
on side effects and
contraindications with
a prominence and
readability that is
reasonably comparable
to the presentation of
information on
effectiveness

95

54

57%

Appropriately
highlights side effects
| and contraindications
in special patient

| populations

49

23

4T%

Source: OIG/UCLA Solicited Assessments of Medical Journal Advertisements, Winter 1991.



INTRODUCTION

PURPOSE

The purpose of this study is to assess the accuracy, truthfulness, educational value, and
quality of prescription drug advertisements in leading medical journals. It is intended
to assist the Food and Drug Administration in its oversight of prescription drug
advertisements.

Many researchers and marketing professionals have noted the substantial influence
advertising has on prescribing decisions. Misleading pharmaceutical advertising has
serious implications for society because it can lead to inappropriate prescribing.

BACKGROUND

Inappropriate prescribing can cause deaths, illnesses, and injuries, and can add to the
overall health care bill of the United States.’ Physicians frequently learn about
medications from information supplied by drug companies. Particularly in the case of
new products, journal advertising has become the most readily available and succinct
source of information for physicians.” In one study, Avorn and Soumerai found that
physicians were unable to distinguish between information they received from drug
advertising and that obtained from a journal text.? Because physicians have limited
formal education in pharmacology,‘ their reliance on advertising as an information
source is particularly important.

In its obligation to help promote public health and to administer Medicare, Medicaid,
and other health care programs, the Department of Health and Human Services has a
broad responsibility for promoting the proper prescribing of medications. Through the
Food and Drug Administration (FDA), it has a precise statutory mandate to oversee
the truthfulness and accuracy of prescription drug advertising.”

Many researchers and marketing professionals have noted the influence advertising
has on prescribing decisions. In a 1977 article, Smith cited numerous studies that
measured the effect of journal advertising on prescribing decisions. The evidence was
mixed.® However, many studies done since 1977 bolster the evidence that advertising
affects prescribing decisions. For example, a 1989 study sponsored by the Association
of Independent Medical Publications and five pharmaceutical manufacturers addressed
the issue of whether journal advertising increases market shares. The study concluded
that an effective sales theme will raise a product’s share of new prescriptions in a
predictable way.’ Avorn and colleagues showed that doctors believed in the
superiority of two heavily promoted drugs over alternative forms of therapy, despite
overwhelming scientific evidence to the contrary. They concluded that these doctors
must have been relying on promotional information (such as journal advertising)
rather than scientific material in forming their opinions.®


physician reviewers, while sending each reviewer two advertisements. Of the 113
physicians we asked to act as reviewers, 96 percent or 108 returned reviews. Table A-
1 lists the characteristics of the physician reviewers.

Clinical Pharmacist Reviewers

We contacted seven university medical centers with established and well-respected
drug information programs (two from Connecticut and five from California). The
director of each program was informed about the research project and asked to
participate in the study by providing a list of experienced clinical pharmacists at their
institution who were involved in physician education concerning pharmaceuticals. All
seven programs agreed to participate and supplied the names of 54 clinical
pharmacists. Of those contacted, 100 percent agreed to participate in this study.
Each clinical pharmacist was asked to review two advertisements. Of the 54 clinical
pharmacists we asked to act as reviewers, 98 percent or 53 returned reviews. Table
A-1 lists the characteristics of the pharmacist reviewers.

Instrument

Our instrument lead the reviewers through 30 specific statements regarding the
advertisements. Twenty-eight of these related to FDA regulations, while one related
to whether or not the advertisement was offensive and one asked whether the
advertisement would lead to proper prescribing if it were the only source of
information about the drug. Reviewers were asked whether they strongly agreed,
somewhat agreed, somewhat disagreed, or strongly disagreed with the statement.
Depending on the statement, agreement either meant the reviewer thought the
advertisement was in violation with an aspect of the FDA regulations or it was not.
For example, one statement was "This advertisement presents a fair balance between
information relating to efficacy and to side effects/contraindications." If the reviewer
agreed with the statement, he or she was saying that the advertisement was not in
violation of an FDA regulation on fair balance. However, another statement was,
"This advertisement uses statistics derived from inconclusive, dissimilar, or poorly
designed studies." If the reviewer agreed with this statement, he or she was citing an
ey of a of an FDA regulation. While our reviewers made
determinations based on their own scientific knowledge and not on FDA law or FDA-
approved labeling, the questions allowed our reviewers to cite specific examples of
potential violations of FDA regulations. The FDA bases its determinations of actual
violations only on comparisons to approved labeling. Appendix C summarizes all of
the statements relating to FDA regulations, as well as the reviewers’ assessments about
these statements.

In addition to these statements, reviewers were asked to rate the overall quality of
advertisements regarding several criteria: factual accuracy, scientific references, clarity,
and honesty of claims. They were asked to use a scale of 1 to 5 with one being
unacceptable and 5 being excellent to make these ratings.


31. fail to present on a page facing another page (or on another full page) of an
advertisement on more than one page, information relating to side effects and
contraindications when such information is in a distinct part of the
advertisement;

32. fail to provide information or at least a reference that information is on
another page on side effects and contraindications; and

33. contain information from reports or opinions falsely or misleadingly represented
or suggested to be authentic or authoritative.

Source: FDA Regulation, Part 202-Prescription Drug Advertisements - CFR
_ 202.1(e)(6) and CFR 202.1(e)(7)


EXECUTIVE SUMMARY

PURPOSE

The purpose of this study is to assess the accuracy, truthfulness, educational value, and
quality of prescription drug advertisements in leading medical journals. It is intended
to assist the Food and Drug Administration in its oversight of prescription drug
advertisements.

Many researchers and marketing professionals have noted the substantial influence
advertising has on prescribing decisions. Misleading pharmaceutical advertising has
serious implications for society because it can lead to inappropriate prescribing.

BACKGROUND

In its obligation to help promote public health and to administer Medicare, Medicaid,
and other health care programs, the Department of Health and Human Services has a
broad responsibility for promoting the proper prescribing of medications. Through the
Food and Drug Administration (FDA), it has a precise statutory mandate to oversee
the truthfulness and accuracy of prescription drug advertising.

We focus in this report on evaluating the overall quality of prescription drug
advertisements in leading medical journals. We also assess the educational value of
the advertisements. Finally, we evaluate them in terms of criteria based on FDA
regulations governing truth and accuracy in prescription drug advertising.

Our data were gathered by a group of Robert Wood Johnson clinical scholars at the
University of California at Los Angeles. They recruited physicians and pharmacists to
review the advertisements. The physicians have acted as peer reviewers for leading
medical journals. The pharmacists have worked at medical centers with established
and well-respected drug information programs and have been involved in educating
physicians about prescription drugs. These expert reviewers were asked to complete a
review form for each of two advertisements. The form allowed reviewers: to evaluate
the acceptability of the advertisements for publication in leading journals using criteria
similar to those used in reviewing scientific articles; to judge the educational value of
the advertisements; and to evaluate specific aspects of the advertisements, such as
images, claims, balance, and use of statistics, all of which relate to FDA guidelines and
regulations. A total of 109 advertisements from early 1990 issues of leading medical
journals were reviewed by 108 physician reviewers and 53 pharmacist reviewers.

We report results using advertisements as the unit of analysis, unless otherwise noted.
To summarize the two or three reviews we had for each advertisement we use a
majority rules criteria. In other words, we report opinions on which at least two
reviewers agreed.


> The reviewers frequently found the advertisements to be inadequate in the
areas of presentation of side effect information, referencing, use of headlines,
and presentation of comparative claims.

We asked reviewers to respond to a series of statements about each advertisement
they were reviewing. For each question, we analyzed data only for advertisements on
which at least two reviewers responded.

For 58 percent of the 85 advertisements for which at least two reviewers responded to
the question, the reviewers agreed that images minimized concerns about, or
awareness of, side effects or adverse drug reactions. For 57 percent of the 95
applicable” advertisements, the reviewers agreed that information presented on side
effects and contraindications was not comparable in prominence and readability to
information presented on effectiveness. The reviewers agreed that the headlines were
not adequately supported by the references given for 48 percent of the 64 applicable
advertisements. For 47 percent of the 49 applicable advertisements, the reviewers
found that the advertisement did not appropriately highlight side effects and
contraindications in special patient populations. The reviewers found that the
headlines were not supported by the written text for 42 percent of the 92 applicable
advertisements. For 40 percent of the 104 applicable advertisements, the reviewers
agreed that the advertisement did not present a fair balance between information on
efficacy and on side effects and contraindications. The reviewers disagreed with a
claim about the drug being more effective than another for 39 percent of the 23
applicable advertisements. Appendix D summarizes reviewers’ opinions relating to
FDA guidelines.

The FDA has used a variety of regulatory responses to remedy violations or correct
misleading or false advertising, but it has rarely taken formal action against violators.

> After monitoring over 19,000 prescription drug advertisements in print media in
fiscal year 1991, FDA took formal regulatory action against an advertiser 217
times. The FDA’s actions consisted of issuing notice of violation and warning
letters and requesting that manufacturers publish corrective advertisements or
send letters to pharmacists and physicians correcting advertisements.

The FDA Division of Drug Marketing, Advertising, and Communication’s small staff
monitored 19,161 advertisements in print media in FY 1991 (October 1990-September
1991). The division chose to review 227 advertisements in more depth.4 The

FDA identified most of the advertisements to review through complaints from outside
parties, including physicians, consumer groups, and other pharmaceutical

manufacturers.’

The FDA’s formal regulatory action takes several forms. The FDA can issue two
levels of letters. One is a notice of violation letter, which specifies how an
advertisement is in violation of FDA guidelines and proposes or demands a
remedy.”® This is usually sent if more informal means fail to induce the


yourselves for much more serious penalties. All traditional methods--seizures,
injunctions, prosecutions--as well as preclearance" will be considered.TM

Although journal review prior to publication can improve the quality of published
prescription drug advertising, many medical journals do not review the content of the
advertisements they publish.

> Our reviewers rejected no advertisements in the one journal selected for our
study that reviewed advertisements prior to publication.

Only one of the 10 journals selected for our study reviewed the advertisements prior
to publication.*> None of the advertisements in this journal on which reviewers’
judgements agreed were rejected. In comparison, the other journals had an average
rejection rate of 19 percent.

> According to a survey of 221 medical journal editors, 37 percent of medical
journals review advertising prior to publication and only 13 percent do any sort
of peer review of advertising.

In a recent study, researchers found from a survey of 221 medical journal editors that
only 37 percent of journals use editorial staff to review prescription drug
advertisements. In addition, peer review of advertising is conducted by 13 percent of
the journals.>”

Only 32 percent of the journal editors in the survey agreed with a statement that

medical journals should be responsible for the truthfulness of prescription drug
advertisements in their journals.

10


Department of Health and Human Services

OFFICE OF
INSPECTOR GENERAL

PRESCRIPTION DRUG ADVERTISEMENTS
IN MEDICAL JOURNALS

ca sts
e Richard P. Kusserow
5 (4 INSPECTOR GENERAL

OEI-01-90-00482



APPENDIX C

FDA Prescription Drug Advertisement Regulations

Advertisements that are false, lacking in fair balance, or otherwise misleading:

1.

ka

12.

13.

14,

—)

contain statements of being "better, more effective, useful in a broader range of
conditions, safer, having fewer side effects" that have not been demonstrated
adequately;

contain claims comparing to another drug that have not been demonstrated
adequately;

contain information or opinions that are not in agreement with current
scientific knowledge;

contain claims of safety that have not been demonstrated adequately;

present information from a study in a way that implies the study is more
representative than it really is;

use references that do not adequately control for concomitant therapy or
placebo effect;

contain information from nonclinical studies in a way that suggests the
information is from clinical studies;

contain a statement from a recognized authority that has been superseded by
other statements or information from the same authority;

use a quote or paraphrase out of context to convey a false or misleading idea;

promote the drug for an unapproved use;

offer a combination of drugs as treatment when one of the drugs in the
combination adequately treats the condition;

use a study based on healthy subjects when the treatment is not for healthy
individuals;

use statistics based on pooled data from inconclusive studies;


OFFICE OF INSPECTOR GENERAL

The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, as
amended, is to protect the integrity of the Department of Health and Human Services’ (HHS)
programs as well as the health and welfare of beneficiaries served by those programs. This
statutory mission is carried out through a nationwide network of audits, investigations, and
inspections conducted by three OIG operating components: the Office of Audit Services, the
Office of Investigations, and the Office of Evaluation and Inspections. The OIG also informs
the Secretary of HHS of program, and management problems, and recommends courses to
correct them,

OFFICE OF AUDIT SERVICES

The OIG’s Office of Audit Services (OAS) provides all auditing services for HHS, either by
conducting audits with its own audit resources or by overseeing audit work done by others.
Audits examine the performance of HHS programs and/or its grantees and contractors in
carrying out their respective responsibilities and are intended to provide independent
assessments of HHS programs and operations in order to reduce waste, abuse, and
mismanagement and to promote economy and efficiency throughout the Department.

OFFICE OF INVESTIGATIONS

The OIG’s Office of Investigations (OI) conducts criminal, civil, and administrative
investigations of allegations of wrongdoing in HHS programs or to HHS beneficiaries and of
unjust enrichment by providers. The investigative efforts of OI lead to criminal convictions,
administrative sanctions, or civil money penalties. The OI also oversees State Medicaid fraud
control units which investigate and prosecute fraud and patient abuse in the Medicaid program.

OFFICE OF EVALUATION AND INSPECTIONS

The OIG’s Office of Evaluation and Inspections (OEI) conducts short-term management and
program evaluations (called inspections) that focus on issues of concern to the Department,
the Congress, and the public. The findings and recommendations contained in these inspection
reports generate rapid, accurate, and up-to-date information on the efficiency, vulnerability,
and effectiveness of departmental programs.

This report was prepared in the Boston Regional Office under the direction of Regional
Inspector General Mark R. Yessian, Ph.D., and Deputy Regional Inspector General Martha B.
Kvaal. Project staff inciude:

David Veroff, Project Leader Penny Thompson, Headquarters
David Schrag, Analyst Mary Beth Clarke, Headquarters
Michael Wilkes, M.D., Consultant

Bruce Doblin, M.D., Consultant

Martin Shapiro, M.D., Consultant

To obtain a copy of this report, call the Boston Regional Office at (617) 565-1050.


18.

19,

20.

21.
22.
23.

24.

In 28 percent of the reviews for these 34 advertisements, our experts favored
rejecting the advertisement; in 32 percent of the reviews, major revisions were
called for; in 28 percent, minor revisions were recommended; and in 12
percent, the experts favored acceptance without change.

Christensen and Wertheimer, "Sources of Information" and Peay and Peay
"Differences among Practitioners".

Because our reviewers are not experts in FDA regulations, we do not know
with certainty that the examples they cite are indeed violations. Furthermore,
FDA, in practice, compares the claims and statements made in advertisements
to approved labeling (package inserts). The criteria our reviewers were asked
to use was often "current scientific knowledge." Although, in theory, approved
labeling should be in agreement with current scientific knowledge, FDA officials
assure us that labeling occasionally lags behind scientific knowledge. The FDA
regulations specify that "advertisements cannot contain favorable information or
opinions about a drug previously regarded as valid but which have been
rendered invalid by contrary and more credible recent information" among
other things. Our interpretation was that this implied advertisements should
agree with current scientific knowledge, but examples of this type may not be
cited by FDA as violations.

For each violation, at least two reviewers cited the example.
"Applicable" means that at least two reviewérs responded to the question.

The FDA monitored 19,161 advertisements, but many of these were duplicates
of one another (i.e. printed in more than one journal or more than one
publication date of the same journal). The FDA actions are based on unique
advertisements. We were not able to ascertain how many unique
advertisements FDA monitored.

The FDA has a number of methods it uses, both prior to and after a drug
advertisement is published, to improve advertisements. These methods are
informal efforts that usually require the cooperation of the sponsor of the
advertisement. For example, it often sends letters to manufacturers giving them
advisory opinions in response to a request to prescreen a proposed promotion;
it did this 417 times in FY 1991. It also rendered advisory opinions in meetings
and telephone conferences 158 times. The FDA reviewed introductory
campaign materials 62 times in FY 1991. Occasionally (77 times in FY 1991),
FDA will deliver informal ad critiques to manufacturers in response to
complaints or a problem noted in an in-house review.

FDA files: FY 1991 Annual, Quarterly, and Monthly Report of Activities of the
Division of Drug Marketing, Advertising, and Communication.


APPENDIX D

Reviewers’ Opinions of Prescription Drug Advertisements:
Adherence to FDA Regulations

Statement Number of Number of Percentage of
Advertisements for Advertisements in Advertisements in
Which At Least Two Which At Least Two Which At Least Two
Reviewers Answered Reviewers Cited a Reviewers Cited a
the Question Violation Violation

Claims:

Drug is useful in a 20 3 15%

broad range of

conditions or diseases

Drug is effective in a 44 6 14%

broad range of

patients

Drug is “the drug of Si 16 31%

choice” for at least one

condition

Drug is more effective | 23 9 39%

than another drug

Drug is safe 59 4 1%

Use of Headlines:

Promotes appropriate | 90 23 26%

use of the drug

Misleads the reader 94 30 32%

about efficacy

Are supported by the 92 39 42%

written text of the

advertisement

Are adequately 64 31 48%

supported by the

references given

| Misleads the reader 95 18 19%
about side effects and
! contraindications

Use of Graphs and

Tables:

Misrepresent the 23 2 9%

conclusions of clinical

studies



FIGURE 1
Acceptability of Prescription Drug Advertisments in Medical Journals

Major Revisions (24%)

Reject (17%)

Minor Revisions (26%)

Accept (3%) No Agreement (31%)

Source: OIG/UCLA Solicited Assessments of Medical Journal Advertisements, Winter 1991.

> The reviewers concluded that 59 percent of the advertisements would not lead
to proper prescribing if the physician had no other information.

According to several studies, advertisements are a primary source of prescribing
information for physicians, particularly for new drugs.’? As a secondary measure of
the educational value of the advertisement, we asked the reviewers whether the
advertisement would lead to proper prescribing if a physician had no other
information about the medication. The reviewers found that 59 percent of the
advertisements would not lead physicians to proper prescribing, while 35 percent
would. There was no agreement on six percent of the advertisements.

The reviewers frequently found the advertisements to be lacking in comparison to the
principles stated in FDA regulations on prescription drug advertising.

> On average, the reviewers cited 4.3 examples of inadequate, misleading, or
inappropriate information per advertisement. These examples indicate
potential violations of FDA regulations.

The FDA regulations specify that prescription drug advertisements must make a "true
statement" of information. The FDA has two basic criteria for this statement: 1) the
advertisement must present a fair balance between information on side effects and


manufacturer to withdraw or alter the advertisement. A more severe step is a warning
letter,” which notifies the advertiser it should take remedial or corrective action and
warns of impending legal action if the advertisement is not revoked. This letter is
more strongly worded than the other and is released publicly. The FDA can request
two types of remedial or corrective action. It can ask the manufacturer (1) to send a
letter to physicians and pharmacists explaining how the advertisement was false,
unbalanced, or misleading, or (2) to publish advertisements in the publications in
which the original advertisements appeared that correct the faulty information.
Manufacturers almost always comply because they wish to maintain positive
relationships with FDA. Recently FDA has requested repeat, offenders to submit
advertising and promotional material prior to public release.

The FDA sent 215 letters in FY 1991 -- 211 notices of violation and 4 warning letters.
It requested corrective or remedial action twice -- both times with "Dear Doctor"
letters.

The FDA’s efforts resulted in 39 advertisements being canceled by the manufacturers
in FY 1991.

> The FDA took formal legal action (injunction) against only two false or
misleading advertisers since June 1991.

The FDA can take a range of civil and criminal actions against violative advertisers.
Possible criminal penalties include prison terms of up to three years and fines of up to
$10,000. In addition, FDA can seize the firm’s products or file an injunction against
the manufacturer to force it to stop the violative action.

The FDA did not begin the process of taking legal action against any violator in FY
1989 or 1990.7 It had not successfully prosecuted a violative drug advertiser in 23
years.” However, in June 1991, FDA successfully filed an injunction against ICN
Corporation, prohibiting promotion of its drugs for unapproved uses.*!_In October
1991, FDA also successfully filed an injunction against Syntex Laboratories in reaction
to misleading promotion of Naprosyn® (naproxen). Syntex signed a decree of
permanent injunction agreeing to a massive remedial campaign to correct the
misleading claims the company made in promotional material and print advertising.”
The FDA’s reluctance to prosecute a drug company may have to do with the difficulty
of proving criminal intent. If criminal intent is not proven, there is only a slim chance
that a conviction will result in imprisonment, especially if no injury or death is linked
to the advertisement. Seizure is not pursued apparently because FDA is concerned it

might seize a medically useful product.

Personnel at FDA, however, have indicated an intent to pursue legal action more
actively against violators. Last year, the acting Director of FDA’s Division of Drug
Marketing, Advertising, and Communications told pharmaceutical executives, "Prepare