Order Code RL32797
CRS Report for Congress
Received through the CRS Web
Drug Safety and Effectiveness:
Issues and Action Options After FDA Approval
March 8, 2005
Susan Thaul
Specialist in Social Legislation
Domestic Social Policy Division
Congressional Research Service ˜ The Library of Congress

---

Drug Safety and Effectiveness:
Issues and Action Options After FDA Approval
Summary
COX-2 inhibitors and SSRIs — the U.S. public has become more familiar with
these technical abbreviations for biochemical processes than one might expect from
our general level of science knowledge. Safety concerns about these drugs — used
primarily to treat pain and depression — have turned a spotlight on the Food and
Drug Administration (FDA) and its approach to protecting the public from drug risks
that had not been identified before FDA-approval allowed the drugs on the market.
Two regulatory frameworks exist for the review of prescription drugs. First, in
the pre-market approval process, FDA reviews the safety and effectiveness of new
drugs that manufacturers wish to market in the United States. A large part of this
review is FDA’s examining the manufacturer-provided data from clinical testing —
studies in which humans take the investigational new drug in carefully controlled,
and usually randomized, trials — from progressively larger Phases I, II, and III trials.
Second, after a manufacturer has sufficiently demonstrated a drug’s safety and
effectiveness for a defined population and specified conditions, and the drug is FDA-
approved, FDA acts through its postmarket regulatory procedures. Manufacturers
must report all serious and unexpected adverse reactions to FDA and clinicians and
patients may do so.
The law gives FDA authority to take limited action if it finds a drug’s post-
approval use presents an increased risk of an adverse event. However, many suggest
that not only does FDA need a broader range of enforcement tools, but that FDA also
is not taking full advantage of the authority it does have.
While critics of FDA differ in their assessment of what is wrong with FDA’s
approach to postmarket safety activities, there is broad agreement that it needs
significant change. Discussion of the problems and possible solutions revolves
around six areas: FDA organization, FDA budget, role of industry, opportunities to
use the drug approval process to enhance postmarket activities, insufficient
postmarket information, and lack of public access to available data. Some of the
proposed changes lie within the power of FDA to implement. Others would require
congressional action.
This report examines various options for strengthening FDA’s ability to protect
the public. It will be updated from time to time to reflect legislative action by
Congress.

---

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
FDA Approval of New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Legislative History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
The Current System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Investigational New Drug (IND) Application . . . . . . . . . . . . . . . . . . . . 5
Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
New Drug Application (NDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
FDA Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Funding of the Approval Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
FDA Postmarket Regulation of Approved Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 8
Legislative History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
The Current System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Office of Drug Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Enforcement Authority . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Off-Label Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Funding of Post-Approval Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Safety and Effectiveness Issues and Options Once a Drug Is FDA-Approved . . 11
FDA Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
FDA Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Put the Office of Drug Safety and the Office of New Drugs
under different supervisors . . . . . . . . . . . . . . . . . . . . . . . . . 14
Institute scientific dispute-resolution mechanisms . . . . . . . . . . . 14
Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Move safety oversight to another federal agency . . . . . . . . . . . . . 14
Provide whistleblower protection . . . . . . . . . . . . . . . . . . . . . . . . 15
FDA Budget . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Revise (or repeal) PDUFA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Increase FDA appropriations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Develop alternative funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Industry Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
FDA and Administration Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Fill vacant positions in FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Reassign conduct of pre-market studies away from
manufacturer to government . . . . . . . . . . . . . . . . . . . . . . . . 18
Diminish marketing role in study design . . . . . . . . . . . . . . . . . . . 18
Create transparency in funding of academic research . . . . . . . . . 19
Reduce conflicts of interest in consumer and physician e
ducation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Maintain tort claim option . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

---

Opportunities to Use the Drug Approval Process to Enhance
Postmarket Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Institute two-phase approval process that includes
mandatory reevaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Require specific postmarket surveillance and study commitments
for initial approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Require comparative effectiveness trial commitments for
initial approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Require commitment to study likely users not considered
in pre-approval trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Restrict use of newly approved drugs when first on the
market . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Insufficient Postmarket Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
FDA Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Reassess criteria qualifying as a “signal” . . . . . . . . . . . . . . . . . . . 23
Periodically assess the range of off-label use . . . . . . . . . . . . . . . 23
Design and conduct rigorous studies, including clinical trials,
to test the safety and effectiveness of drugs used off-label . 24
Use administrative, financial, and clinical databases . . . . . . . . . . 24
Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Mandate more activist surveillance . . . . . . . . . . . . . . . . . . . . . . . 24
Authorize FDA to require postmarket studies of situations
that had not been anticipated at the time of approval . . . . . 24
Require comparative effectiveness studies . . . . . . . . . . . . . . . . . 24
Increase funds to FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Explore alternative systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Existing Information Unavailable to All Groups . . . . . . . . . . . . . . . . . . . . . 25
FDA Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Enhance drug-information dissemination options . . . . . . . . . . . . 27
Transfer current information to prescribers . . . . . . . . . . . . . . . . . 27
Extend collaborative data collection and analysis activities . . . . 27
Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Require that labeling address off-label uses . . . . . . . . . . . . . . . . 28
Remove postmarket study responsibility from both manufacturers
and FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Require clinical trial registration . . . . . . . . . . . . . . . . . . . . . . . . . 28
Make data public . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Give FDA enhanced authority to regulate DTC advertisements . 29
Give FDA ability to institute penalties for misleading ads . . . . . 29
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
List of Tables
Table 1. Concerns and Options Raised by Observers . . . . . . . . . . . . . . . . . . . . . 31

---

Drug Safety and Effectiveness: Issues and
Action Options After FDA Approval
Introduction
On November 18, 2004, the Senate Finance Committee convened to hear
testimony sparked by concern over the popular Merck anti-inflammatory drug Vioxx.
A few weeks before, Merck had notified the Food and Drug Administration (FDA)
that it was withdrawing Vioxx from the market in response to recent study results
indicating an increased risk of heart attacks and sudden cardiac deaths among the
millions of patients who had been using Vioxx since its introduction in 1999.
Senators wanted to find out what had gone wrong and what could be done to prevent
it from happening again.
This was not the first time that this Congress had reacted to news about dangers
posed by drugs that had already reached the market. Just two months earlier, the
House Committee on Energy and Commerce’s Subcommittee on Oversight and
Investigations had held hearings because of controversy over the safety of
antidepressants when prescribed to children. In both cases, Members were worried
that neither the public nor FDA were sufficiently informed — or, in the case of FDA,
sufficiently forthcoming — about risks occurring after the drugs had been first
approved.
At the Finance Committee hearing, Dr. David Graham, Associate Director for
Science and Medicine in FDA’s Office of Drug Safety, was asked whether these
concerns were warranted in the case of Vioxx. He stated, “I would argue that the
FDA, as currently configured, is incapable of protecting America against another
Vioxx. We are virtually defenseless.”1 Pressed to name other marketed drugs he
thought troublesome, Graham named five.2
The furor after Dr. Graham’s testimony reawakened interest in a variety of
regulatory issues that have surfaced periodically ever since the storm of protest over
1 Testimony of David J. Graham, M.D., M.P.H., Associate Director for Science, Office of
Drug Safety, Center for Drug Evaluation and Research, U.S. Department of Health and
Human Services, Food and Drug Administration, Washington, D.C., before the U.S. Senate
Committee on Finance hearing, “FDA, Merck and Vioxx: Putting Patient Safety First?”
Nov. 18, 2004, at [http://finance.senate.gov/hearings/testimony/2004test/111804dgtest.pdf].
2 Marc Kaufman, “FDA Officer Suggests Strict Curbs on Five Drugs; Makers Dispute
Claims About Health Risks,” Washington Post, Nov. 19, 2004, p. A1. The five drugs named
were Accutane (to treat acne), Bextra (a COX-2 inhibitor used to treat pain), Crestor (a
statin used to lower cholesterol), Meridia (for weight loss), and Serevent (to treat asthma).

---

CRS-2
“filthy, decomposed or putrid” food and “worthless” medicines resulted in FDA’s
creation during Theodore Roosevelt’s presidency.3
The most recent example of intense public and regulatory attention: the meeting
of two FDA advisory committees on February 16-18, 2005, coming three months
after Dr. Graham’s testimony to the Senate Finance Committee and five months after
Merck withdrew Vioxx from the market. After weighing the evidence on the safety
and risk-to-benefit of Vioxx and similar drugs, the committees unanimously asserted
that the three COX-2 inhibitors currently licensed in the United States — Vioxx,
Celebrex, and Bextra — do increase the risk of heart attack and stroke. Illustrating
the complexity of decisions that FDA faces, a majority of the committee members
recommended to FDA that the benefits of the drugs outweigh the risks for certain
groups of people and that FDA should, therefore, permit their sale — with, however,
several severe limitations on advertising and strong warnings in consumer and
clinician labeling about cardiovascular risk that is likely associated with dose and
duration of use.4
Concerns about regulatory agencies’ abilities to protect the public are not unique
to FDA or public health.5 The life-and-death issues of medicine, however, strike
most closely to home for many Americans. There has not been a decade since FDA’s
creation without a highly publicized incident involving drug safety that has led to
legislation expanding and strengthening FDA’s authority to protect the public.
Examples include the scores of children killed by an untested antibiotic (elixir of
sulfanilamide) marketed by a company in Tennessee in 1937; the mistakes at a plant
manufacturing polio vaccine in 1954 that actually caused 260 cases of polio and 11
deaths; and, in 1962, thalidomide, the sleeping pill that eventually resulted in the
birth of at least 8,000 severely deformed babies and thousands of prenatal deaths,
mostly in Europe.6
In some of these episodes, FDA scientists have emerged as heros: thalidomide
would have caused many more birth defects had it not been for FDA researcher Dr.
Frances Kelsey, who refused to approve the manufacturer’s application to market the
drug in the United States. But in doing so, Kelsey had to fight both company threats
and the inaction of FDA’s commissioner.
3 Philip J. Hilts, Protecting America’s Health: The FDA, Business, and One Hundred Years
of Regulation (New York: Alfred A. Knopf, 2003), pp. xi and 54. (Hereafter cited as Hilts,
2003.)
4 FDA, Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk
Management Advisory Committee, Gaithersburg, Md., Feb. 16-18, 2005, Agenda, at
[http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.html], and
Discussion Points, at [http://www.fda.gov/ohrms/dockets/ac/05/questions/2005-4090Q1
_Final.pdf]; and Marc Kaufman, FDA Panel Opens Door for Return of Vioxx, Washington
Post, Feb. 19, 2005, p. A1.
5 Robert B. Reich, “A Suitable Remedy: When the FDA Is Weak,” Washington Post, Jan.
9, 2005, p. B5. (Hereafter cited as Reich, Jan. 9, 2005.)
6 Hilts, 2003, p. 158; and FDA, “Milestones in U.S. Food and Drug Law History,” FDA
Backgrounder, May 3, 1999, updated Aug. 5, 2002, at [http://www.fda.gov/opacom/
backgrounders/miles.html], visited Feb. 7, 2005.

---

CRS-3
In FY2005, FDA operates on a budget of $1.8 billion ($1.45 billion from tax
revenue and $350 million from user fees),7 almost $6 per U.S. citizen. With that
money, FDA is expected to oversee about $1 trillion of goods, which make up about
one-quarter of all U.S. consumer spending. Each month, FDA receives about 33,000
reports of threats to the public from possibly unsafe drugs.8
Congressional funding for FDA has increased at about half the rate as that of
industry user fees, established by Congress as a way to defray costs of new resources
to allow quicker progression through the approval process. Even though the user fees
account for somewhat less than 20% of the FDA total, their proportion within FDA’s
Center for Drug Evaluation and Research (CDER) is both larger and increasing more
rapidly: in 1992, user fees accounted for 53% of the CDER budget; they now make
up almost 80% of that budget.9
Two regulatory frameworks exist for the review of prescription drugs. First,
FDA reviews the safety and effectiveness of new drugs that manufacturers wish to
market in the United States; this process is called pre-market approval or pre-
approval review. Once a drug has passed that threshold and is FDA-approved, FDA
acts through its postmarket or post-approval regulatory procedures. Concerns about
postmarket safety involve many drugs. The Vioxx situation, however, has uniquely
sparked congressional and public attention because of the sheer numbers of
prescriptions filled — 93 million by some estimates. Dr. Graham’s analysis led him
to see a “7-fold increase in heart attack risk” resulting in, he calculated, between
88,000 and 139,000 Americans who suffered heart attack or stroke from the drug.
In addition, there have been a wide variety of recent books, editorials, and polls on
industry and FDA responsibilities for action, offering criticisms similar to those
Graham made in November. Both Senate and House leaders have made it clear that
the 109th Congress will see both hearings and legislation dealing with the safety and
effectiveness of drugs.
This report examines issues related to drug safety, specifically in the context of
the regulatory process that Congress and the FDA have established for ensuring that
drugs are safe and effective. It includes a primer on drug approval: how drugs are
approved and come to market, including FDA’s role in that process. It also describes
FDA and industry roles once drugs are on the pharmacy shelves, the postmarket or
post-approval period. It moves on to a discussion of the problems in identifying and
resolving postmarketing safety and effectiveness issues that are raised most
frequently in the debate. It outlines actions that a variety of analysts have suggested
to improve the situation, both ones that FDA could adopt on its own and others for
which legislation would be necessary.
7 HHS, Budget in Brief, Fiscal Year 2006, FDA table, p. 12.
8 FDA, Protecting Consumers, Promoting Public Health, at [http://www.fda.gov/oc/
opacom/fda101/fda101text.html], visited Jan. 7, 2005.
9 Gardiner Harris, “At FDA, Strong Drug Ties and Less Monitoring,” New York Times, Dec.
6, 2004. (Hereafter cited as Harris, Dec. 6, 2004.)

---

CRS-4
FDA Approval of New Drugs
Legislative History
Derived from the Dutch word meaning to boast (quacken), “quack” was the
word Americans commonly used to describe charlatans in medicine. Quacks peddled
adulterated and mislabeled medicines throughout the United States without penalty,
until 1906, when Congress passed the Food and Drugs Act, outlawing the practice.
It was the first of a series of laws intended to assure Americans that the medicines
they used did no harm and actually worked — that they are, in other words, safe and
effective.
Over the next half-century, Congress passed two major pieces of legislation
expanding FDA authority in pursuit of those goals. It passed the Federal Food, Drug,
and Cosmetic Act (FFDCA)10 in 1938, requiring that drugs be proven safe before
they could be sold in interstate commerce. Then, in 1962, in the wake of the
thalidomide tragedy, Congress amended the law to require that drugmakers prove the
effectiveness of their products as well.11
The process has not remained the same since 1962. The 1983 Orphan Drug Act
began a series of additional laws passed by Congress in recent decades to boost
pharmaceutical research and development, speed the approval of new medicines, or,
in some cases, both. The Orphan Drug Act provided incentives for pharmaceutical
manufacturers to develop drugs, biotechnology products, and medical devices for the
treatment of rare diseases and conditions. Other laws include the 1984 Hatch-
Waxman Act, the landmark compromise balancing greater patent protection of
manufacturers with quicker public access to lower-priced generic drugs; the 1992
Prescription Drug User Fee Act (PDUFA), which ushered in user fees and
performance goals for faster drug approvals; and the 1997 FDA Modernization Act
(FDAMA), which relaxed clinical testing requirements, eased access to experimental
therapies, and awarded drugmakers six more months of marketing protection for
testing drugs in pediatric patients. The 107th Congress reauthorized the FDAMA
pediatric testing provision within the 2002 Best Pharmaceuticals for Children Act,
and extended the drug user fee law for five more years under the Public Health
Security and Bioterrorism Preparedness and Response Act.12
All six pieces of legislation inform the U.S. drug approval process, which is
supervised by FDA in accordance with the laws from 1938 and 1962. In the
following section, we describe the drug approval process as it functions now.
10 The Federal Food, Drug, and Cosmetic Act, P.L. 75-717, 1938.
11 Kefauver-Harris Drug Amendments to the FFDCA, P.L. 87-781, 1962.
12 The Orphan Drug Act (P.L. 97-414), the Hatch-Waxman Act (the Drug Price Competition
and Patent Term Restoration Act of 1984, P.L. 98-417), PDUFA (P.L. 102-571), FDAMA
(P.L. 105-115), the Best Pharmaceuticals for Children Act (107-109), and the Public Health
Security and Bioterrorism Preparedness Act (P.L. 107-188).

---

CRS-5
The Current System
A drug cannot be marketed in the United States until three things occur: the
manufacturer demonstrates the drug’s safety and effectiveness to FDA’s satisfaction,
sees its manufacturing plant pass FDA inspection, and obtains FDA approval for the
drug’s labeling — a generic term for all written and electronic material about the
drug, including packaging, prescribing information for physicians, and patient
brochures.13 There are five steps leading to FDA approval of a drug for marketing
in the United States:14
Investigational New Drug (IND) Application. Before testing in humans
— referred to as clinical testing — the drug’s sponsor (usually its manufacturer) must
file an IND application with FDA. It includes information about the proposed study
protocol, completed animal test data, the lead investigator’s qualifications, and the
written approval of an Institutional Review Board based on its determination that the
study participants will be made aware of the drug’s investigative status and that any
risk of harm will be explained, minimized, and necessary. The manufacturer will
meet with FDA to discuss whether the clinical study design has sufficient statistical
power to enable the manufacturer to draw conclusions about the safety and
effectiveness of the drug.15 The application must include an Indication for Use
section that describes what the drug does and the clinical condition and population
for which drug use is intended. Trial subjects should be representative of those who
would receive the drug if it is approved. The FDA has 30 days to review an IND.
If there is no objection, a manufacturer may begin clinical testing after that time.
Clinical Trials. With IND status, researchers proceed to test in a small
number of human volunteers the safety they had demonstrated in animals. These
trials, called Phase I clinical trials, “try to determine dosing, document how a drug
is metabolized and excreted, and identify acute side effects.” If the product still
13 Labeling has become the focal point for much of the controversy involving safety and
effectiveness. Some contend that changes in prescribing information are not enough to
protect the public’s health because, as recent questions from consumers and Members of
Congress demonstrate, the labeling language, clear to those in the drug approval business,
can confuse lay readers. For example, “Effectiveness in children has not been
demonstrated” represents a different state of knowledge than “Studies in children have not
demonstrated effectiveness.” In the second sentence, we learn that researchers have looked
to see whether it was effective and were unable to find that evidence — although, the drug
still could be effective in children but the study design or analysis did not see that. The first
sentence, however, does not make clear whether any study had been done.
14 More detail on the drug approval process is in CRS Report RL30989, The U.S. Drug
Approval Process: A Primer, by Blanchard Randall IV.
15 A trial result may be considered positive if it demonstrates that the new drug has a
statistically significant benefit over a placebo or comparative drug. Accordingly, a result
could be called negative if, despite sufficient statistical power to demonstrate that the new
drug offers a benefit over placebo or comparative drug, the trial does not show a benefit.
A trial with insufficient statistical power to draw a conclusion regarding effectiveness, most
often due to inadequate sample size, that does not find an association is considered
inconclusive.

---

CRS-6
seems viable, the sponsor continues with Phase II and Phase III trials to gather
evidence of the drug’s efficacy and effectiveness in larger groups of individuals with
the particular characteristic, condition, or disease of interest, while continuing to
monitor safety.16
New Drug Application (NDA). Once the clinical trials are completed, the
sponsor submits an NDA to FDA’s Center for Drug Evaluation and Research
(CDER), containing not only the clinical trial results, but also information about the
manufacturing process and facilities, including quality control and assurance
procedures. During the review, CDER officials evaluate the drug’s safety and
effectiveness data, analyze samples, inspect the facilities where the finished product
will be made, and check the proposed labeling for accuracy.
FDA Review. The law requires “substantial evidence” of drug safety and
effectiveness. FDA has interpreted legislative intent to mean at least two adequate,
well-controlled, and convincing studies, although the agency exercises flexibility.17
As its regulations describe in detail, FDA can assess safety and effectiveness in a
variety of ways, relying on combinations of studies by the manufacturer and reports
of other studies in the medical literature.18
FDA has 180 days to review an NDA. If it finds deficiencies, such as missing
information, the clock stops until the manufacturer submits the additional
information. If the manufacturer cannot respond to FDA’s request (i.e., if a required
study had not been done, making it impossible to evaluate safety or effectiveness),
the manufacturer may voluntarily withdraw the application. If and when the
manufacturer is able to provide the information, the clock resumes and FDA
continues the review.
For many NDAs, FDA convenes advisory panels of experts to review the
clinical data. While not bound by an advisory panel’s recommendation regarding
approval, FDA usually accepts it. FDA makes the final determination: “approved,”
16 Safety tests, often referred to as toxicity testing, seek to determine the highest tolerable
dose or the optimal dose of the drug needed to achieve the desired benefit. Studies that look
at safety also seek to identify any potential adverse effects that may result from exposure to
the drug. Efficacy refers to whether a drug demonstrates a health benefit over a placebo or
other intervention when tested in an ideal situation, such as a tightly controlled clinical trial.
Effectiveness describes how the drug works in a real-world situation. Effectiveness is often
lower than efficacy because of interactions with other medications or health conditions of
the patient, sufficient dose or duration of use not prescribed by the physician or followed
by the patient, or use for a off-label condition that had not been tested. Also, see Carol
Rados, “Inside Clinical Trials: Testing Medical Products in People,” FDA Consumer, Sept.-
Oct. 2003, at [http://www.fda.gov/fdac/features/2003/503_trial.html]; and CRS Report
RL32478, Genetic Testing: Scientific Background and Nondiscrimination Legislation, by
Michele Schoonmaker and Erin Williams.
17 See FDA, “[DRAFT] Guidance for Industry: Providing Clinical Evidence of Effectiveness
for Human Drug and Biological Products,” CDER and CBER, May 1998, at
[http://www.fda.gov/cder/guidance/1397fnl.pdf].
18 The requirements for adequate and well-controlled studies are enumerated in 21 C.F.R.
§ 314.126.

---

CRS-7
“approvable” (if certain changes, such as more testing, are made), or “unapprovable.”
FDA can reject an NDA on two grounds: if the manufacturer failed to perform
adequate tests to demonstrate safety and effectiveness for its proposed use, or if the
clinical data were not sufficient to show a favorable benefit-to-risk profile. A
manufacturer may appeal FDA’s decision by filing a complaint with CDER’s
Ombudsman.
Finally, once drugs are marketed, manufacturers and FDA monitor their overall
safety using MedWatch, the agency’s postmarketing surveillance system [described
later in this report], and any Phase IV clinical trials that FDA required as a condition
of approval or for which the sponsor otherwise agreed with FDA and committed to
undertake.
Funding of the Approval Process
FDA funds its new drug approval reviews with appropriations provided by
Congress and fees paid by industry. The current funding arrangement grew out of the
long-standing tension between FDA and both industry and consumer groups over
how long the FDA reviews took.
In 1993, median review times for priority drugs averaged 16.3 months,19 a figure
FDA acknowledged could be lower with more FDA staff. The pressure for quicker
approvals came from two directions. First, manufacturers wanted it. Because the 20-
year patent protection begins with NDA submission, manufacturers see the time from
NDA submission to FDA approval decision as lost income. The Pharmaceutical
Research and Manufacturers of America (PhRMA) argues that because of the long
approval process and the Hatch-Waxman Act, encouraging generics, “the average
effective patent life for prescription medicines ... is 11-12 years, compared to an
average of 18.5 years for other products.”20 Meanwhile, consumer groups also
wanted quicker approvals to speed their access to promising drugs.
Congress reacted by looking for legislative ways to speed up the drug review
process without lowering approval standards, especially those that might compromise
patient safety. In 1992, it passed the Prescription Drug User Fee Act (PDUFA) and
five years later, in 1997, the Food and Drug Administration Modernization Act
(FDAMA). These laws created a system in which congressional appropriations only
partially fund new drug review; those monies are supplemented with “user fees” paid
by pharmaceutical companies.21 A third of the user fee money comes from an
application fee; the remaining two-thirds is unlinked to the application process, based
19 FDA, Approval Times for Priority and Standard NDAs; Calendar Years 1993-2003, at
[http://www.fda.gov/cder/rdmt/NDAapps93-03.htm], visited Jan. 29, 2005.
20 PhRMA, Fact Sheet: Pharmaceutical Patent Incentives, at
[http://www.phrma.org/publications/publications/17.06.2003.746.cfm], visited Jan. 29,
2005. Also, CRS Report RL30756, Patent Law and Its Application to the Pharmaceutical
Industry: An Examination of the Drug Price Competition and Patent Term Restoration Act
of 1984 (‘The Hatch-Waxman Act’), by Wendy H. Schacht and John R. Thomas.
21 See CRS Report RL31453, The Prescription Drug User Fee Act: Structure and
Reauthorization Issues, by Donna U. Vogt and Blanchard Randall IV.

---

CRS-8
instead on the type of manufacturing facility and product submitted for review. User
fees are paid at the start of the fiscal year. Following the introduction of user fees,
FDA quickly reduced its median approval time for priority new drugs from the 16.3
months of 1993. By 1995, it had fallen to six months, where it generally remained
until 2002 when it jumped to 13.8 months, coming down to 7.7 months in 2003.22
FDA has established and maintained detailed records tracking the PDUFA fees
collected.
FDA Postmarket Regulation of Approved Drugs
We now turn to a discussion of FDA’s role after a drug appears on the market.
First, we describe the current system. Then we present what critics have identified
as problems — and the solutions they propose.
Legislative History
The Federal Food, Drug, and Cosmetic Act gives the Secretary of Health and
Human Services (HHS) the authority to withdraw marketing approval of a drug.23
FDA-issued regulations regarding new drug approval require postmarketing reports
of adverse drug experiences and of other information produced or acquired by the
sponsor.24
The Current System
Office of Drug Safety. The webpage of FDA’s Office of Drug Safety (ODS)
describes its duties to include using reports of adverse events that consumers,
clinicians, or manufacturers believe might be drug-related to “identify drug safety
concerns and recommend actions to improve product safety and protect the public
health. Activities include updating drug labeling, providing more information to the
community, implementing or revising a risk management program, and, on rare
occasions, reevaluating approval or marketing decisions.”25
22 FDA, Approval Times for Priority and Standard NDAs; Calendar Years 1993-2003, at
[http://www.fda.gov/cder/rdmt/NDAapps93-03.htm], visited Jan. 29, 2005.
23 Section 505 of the FFDCA (21 U.S.C. § 355: New drugs.). In particular, 21 U.S.C.
§ 355(e): Withdrawal of approval; grounds; immediate suspension upon finding imminent
hazard to public health.
24 At 21 C.F.R. § 314. Applications for FDA approval to market a new drug, see, in
particular, Section 314.80. Postmarketing reporting of adverse drug experiences, Section
314.81. Other postmarketing reports, Section 314.150. Withdrawal of approval of an
application or abbreviated application, Section 314.200. Notice of opportunity for hearing;
notice of participation and request for hearing; grant or denial of hearing, and Section
314.126. Adequate and well-controlled studies.
25 FDA, Organizational Components: Office of Drug Safety, CDER, at [http://ww.fda.gov/
cder/Offices/ODS/default.htm], visited Feb. 9, 2005.

---

CRS-9
ODS, itself part of the Office of Pharmacoepidemiology and Statistical
Science,26 has three divisions. Staff in the Division of Drug Risk Evaluation works
to detect and evaluate safety data and published literature, and assess manufacturer-
provided plans for epidemiologic studies and surveillance tools. The Division of
Medication Errors and Technical Support assesses specific drug labeling questions.
The Division of Surveillance, Research, and Communication Support manages risk
communication activities that include research and patient materials, and MedWatch
and other epidemiologic data resources.27 A Drug Safety and Risk Management
Advisory Committee was established in 2002. Another FDA webpage, The
Enforcement Story: Fiscal Year 2003, presents the range of FDA-wide legal and
other enforcement activities.28
Reporting. Once FDA approves a drug, it monitors safety. Manufacturers
must report all serious and unexpected adverse reactions within 15 days of becoming
aware of them (21 C.F.R. § 310.305) to FDA’s Adverse Events Reporting System
(AERS). Health professionals or patients may report adverse reactions to FDA’s
MedWatch reporting system at any time. FDA can approve a drug even when it still
has questions about the drug’s longer- term effects; in such cases, FDA can require
formal postmarket studies and summary reports as conditions of approval. These
mechanisms of postmarket study are particularly important when it comes to
identifying rare adverse events. Often, these become clear only after many people
have taken the drug.
Some adverse events warrant regulatory actions such as labeling changes, letters
to health professionals, or, once in a great while, withdrawal from the market. FDA
does not need proof that a drug causes harm before ordering a labeling change. The
regulations require the company to make the label change as soon as there is
reasonable evidence of an association with serious hazard.29 The art and science of
these judgments result, at times, in different decisions by different reviewers. A
current example appeared on FDA’s website February 9, 2005, regarding Adderall,
a stimulant medication used to treat attention deficit disorder. On the basis of data
from U.S. reporting systems, Canadian authorities chose to stop sales, whereas U.S.
authorities chose to alert the public yet not restrict sales at this time.30
26 The Office of Pharmacoepidemiology and Statistical Science is parallel organizationally
to the Office of New Drugs.
27 FDA, Organizational Components: Office of Drug Safety, CDER, at [http://ww.fda.gov/
cder/Offices/ODS/default.htm], visited Feb. 9, 2005.
28 FDA, The Enforcement Story: Fiscal Year 2003, at [http://www.fda.gov/
ora/about/enf_story/]. One section offers statistics concerning agency actions including civil
money penalty, prosecution, seizures, injunctions, recalls, and warning letters, not all
relating to postmarketed drugs (at [http://www.fda.gov/ora/about/enf_story/
ch10/stats_charts.htm#1], visited Jan. 29, 2005).
29 21 C.F.R. § 201.57(e).
30 FDA, Statement on Adderall, FDA Statement, Feb. 9, 2005, at [http://www.fda.gov/
bbs/topics/news/2005/NEW01156.html], visited Feb. 9, 2005.

---

CRS-10
For certain categories of new drug approvals (those applications approved under
rules for accelerated approval, the animal efficacy rule, or the Pediatric Research
Equity Act), the manufacturer and FDA negotiate time-frames and study-topics of
required postmarket studies at the time of drug approval. Although not required for
an application that falls outside of those categories, postmarket study agreements
between manufacturer and FDA can be set at the time of approval.31
FDA can institute label changes on the basis of information it gathers from
mandatory industry reports to AERS and committed postmarket studies and from
voluntary adverse event reports from clinicians and patients. A manufacturer itself
can instigate a label change to support a new marketing claim. When it believes data
from original or published studies support a new use for a drug, a manufacturer may
submit a supplement to the original NDA including the new data, and request that
FDA allow it to modify the labeling. FDA must then review these supplemental
applications.
Enforcement Authority. At many recent congressional hearings, Members
have asked FDA officials about the agency’s enforcement authority. The responses
have not included the specificity for which the questioners were looking; this seems
to be unclear territory, and FDA’s authority is limited. The law authorizes FDA to
withdraw a drug’s approval. To get label changes and other most other actions, FDA
must couch its concerns as requests to the manufacturer.
Off-Label Use. The law prohibits manufacturers’ promoting or advertising
their drugs for any use not listed on the FDA-approved label: those claims for which
FDA has reviewed safety and effectiveness evidence. However, the FFDCA does not
give FDA authority to regulate the practice of medicine; that responsibility lies with
the states and medical professional associations. Once a drug is approved, a licensed
physician may prescribe it without restriction. A prescription to an individual whose
demographic or medical characteristics differ from those indicated in a drug’s FDA-
approved labeling is called off-label use and is accepted medical practice.
A drug that was tested in an eight-week trial may be prescribed for long-term
use; if it was tested at one dose it may be used at higher or lower doses; one tested
in adults may be prescribed to children; and a drug tested for the treatment of one
disease may be prescribed in an attempt to prevent another. Using drugs in these new
ways (for which researchers have not yet demonstrated safety and effectiveness) can
create problems that premarket studies did not address. Off-label use also presents
an evaluation problem to FDA safety reviewers. Manufacturers rarely design studies
to establish the safety and effectiveness of their drugs in off-label uses.
31 FDA, Draft Guidance for Industry: Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment, Center for Drug Evaluation and Research (CDER)
and Center for Biologics Evaluation and Research (CBER), May 2004, at
[http://www.fda.gov/cder/guidance/5767dft.pdf]; and FDA, Draft Guidance for Industry:
Reports on the Status of Postmarketing Studies — Implementation of Section 130 of the
Food and Drug Administration Modernization Act of 1997, CDER and CBER, Apr. 2001,
at [http://www.fda.gov/cber/gdlns/post040401.pdf].

---

CRS-11
Funding of Post-Approval Activities
The FY2005 program level budget for the Office of Drug Safety is $26.9
million, up from $15.4 million in FY2002. The FY2006 request is $33.4 million.
The growth comes primarily from the addition of PDUFA user fees beginning in
FY2003 following amendments known as PDUFA III in 2002.32 Staff full-time
equivalent (FTE) levels went from 77 in FY2002 to 109 in FY2005. The FY2006
budget request includes an additional 20 FTEs.33
Safety and Effectiveness Issues and Options Once
a Drug Is FDA-Approved
While critics of FDA differ in their assessment of what is wrong with FDA’s
approach to postmarket safety activities, there is broad agreement that it needs
significant change.34
The overall problem of postmarketing surveillance is similar to a house with
many windows. Consider, for example, the imbalance perceived by some between
FDA resources for new drug approval and postmarket activities: 80% to 20%. Do
we look at it through the window of Organization? Yes, if the solution is to add
more postmarket-review staff because that would change the FDA organizational
chart. And, yes, if the plan is to establish a separate entity with the aim of a more
independent staff. But to do those would require more or redirected money, which
means looking at it through the window of Budget.
32 PDUFA III is the popular name for Subtitle A of Title V of the Public Health Security and
Bioterrorism Preparedness and Response Act of 2002, P.L. 107-188. According to data
from the FDA Budget and Evaluation Office (FPC Spreadsheets/ODS figures FY96 to
FY2005, dated Jan. 31, 2004), FY2002: $15.4 million (BA only); FY2003: $20.2 million
total ($13.4 million BA, $6.6 million user fees); FY2004: $23.8 million total ($15.8 million
BA, $8.0 million user fees); FY2005 estimate: $26.9 million total ($17.9 million BA, $9.0
million user fees); and FY2006 estimate: $33.4 million total ($22.9 million BA, $10.5
million user fees).
33 FDA, FY 2006 Budget Summary and Budget in Brief, at [http://www.fda.gov/oc/oms/ofm/
budget/2006/PDFs/Summary/Pages28thru31.pdf].
34 In the last two years, several extremely reputable authors — historians, clinicians, and
editors — have published serious, popular books about what they see as problems with
government and industry’s handling of drug safety issues. These include: Marcia Angell,
The Truth About Drug Companies: How They Deceive Us and What to Do About It (New
York: Random House, 2004) (Hereafter cited as Angell, 2004, p. 124.); Jerry Avorn,
Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs (New York:
Alfred A. Knopf, 2004; and Philip J. Hilts, Protecting America’s Health: The FDA,
Business, and One Hundred Years of Regulation (New York: Alfred A. Knopf, 2003). Also,
an FDA task force proposed sweeping changes in its report Creating A Risk Management
Framework: Report to the FDA Commissioner from the Task Force on Risk Management,
May 1999, at [http://www.fda.gov/oc/tfrm/riskmanagement.pdf], visited Jan. 29, 2005.

---

CRS-12
Or maybe we should peer in through the window of Industry Role. After all,
PDUFA fees, among other factors, contribute to the perceived imbalance. Or,
because the goal of these organizational and budget shifts would be to obtain more
information about postmarket dangers, maybe we should look at it through the
window of Information.
Which window to choose depends on one’s perspective and ability to influence
the process. Someone skeptical of industry might want to repeal PDUFA and
increase federal appropriations for FDA. Someone unwilling to enlarge the budget
might preserve PDUFA but use it differently while keeping appropriations flat.
To make this paper useful to legislators, we organize this paper around the six
areas — windows, if you will — through which most analysts view the problems in
postmarketing surveillance, study, and regulatory action. We do this knowing that
the options we list in one section might not be possible without those from other
sections — especially Budget.
Most difficult to categorize is the influence of industry. To make the discussion
manageable, we limit the options listed under Industry Role to those that would
diminish what some analysts consider inappropriate industry behavior. The options
aimed at increasing postmarket information, many of which involve expanding
industry role, we put in the other procedure-defined sections.
That said, we turn to a discussion of the six areas around which most
recommendations revolve:
! FDA organization
! FDA budget
! Role of industry
! Opportunities to use the drug approval process to enhance
postmarket activities
! Insufficient postmarket information
! Lack of public access to available data
Some of the proposed changes lie within the power of FDA to implement. Others
would require congressional action. As an appendix, we provide a list of concerns,
FDA options, and congressional options.
FDA Organization
Some critics argue that FDA’s Office of Drug Safety (ODS) cannot be effective
because it has so much less influence than the Office of New Drugs (OND) in regard
to safety and effectiveness decisions. The FDA organization chart shows ODS as one
administrative level lower on the Center for Drug Evaluation and Research (CDER)
organizational chart, part of the Office of Pharmacoepidemiology and Statistical
Science, which is parallel to OND, both reporting directly to the CDER director.35
35 FDA, CDER [Center for Drug Evaluation and Research] Organization Charts and
(continued...)

---

CRS-13
In his November 18th testimony,36 Dr. Graham put it this way:
The organizational structure within CDER is entirely geared towards the review
and approval of new drugs. The same group that approved the drug is also
responsible for taking regulatory action against it postmarketing. This is an
inherent conflict of interest. At the same time, the Office of Drug Safety has no
regulatory power and must first convince the new drug reviewing division that
a problem exists before anything ... can be done. Often, the new drug reviewing
division is the single greatest obstacle to effectively protecting the public ... A
close second in my opinion is an ODS management that sees its mission as
pleasing the Office of New Drugs.
Dr. Graham is not alone in his belief. A related issue surfaced recently with the
revelation of an HHS Inspector General-conducted survey of FDA scientists.
Completed in 2002, the survey found that almost one-fifth of FDA scientists
sometimes felt pressured to ignore their safety reservations.37 A recent commentary
in the British medical journal The Lancet raises a more general point. It asks whether
bureaucratic or other constraints inhibit ODS from finding fault with a drug that its
sibling office, OND, had approved for marketing as safe and effective.38
Critics have recommended actions that address both whether ODS scientists feel
political pressure or are inhibited by a bureaucratic reluctance to restrict a drug that
OND had earlier approved. Although some have suggested legislation to compel
FDA to reorganize the agency, others suggest organizational solutions that FDA
already has the authority to implement. They have also recommended another way
to increase ODS power relative OND, more staff, for example. While this certainly
would be an organizational change, proponents point out that ODS also requires a
bigger budget. We therefore discuss that option in the section titled FDA Budget.
35 (...continued)
Directories, at [http://www.fda.gov/cder/cderorg.htm], visited Jan. 10, 2005. Inc., of Vioxx,
FDA Statement, Nov. 18, 2004, at [http://www.fda.gov/bbs/topics/news/2004/
NEW01138.html]. The current acting CDER director stated, however, “Both the Office of
New Drugs and the Office of Drug Safety report directly to me as the Director of the
Center” (Statement by Dr. Steven Galson, Acting Director, Center for Drug Evaluation and
Research (CDER), Regarding November 18, 2004, Committee on Finance of the U.S. Senate
Hearing on Drug Safety and the Worldwide Withdrawal by Merck & Co. (Hereafter cited
as Graham, Nov. 18, 2004.)
36 Graham, Nov. 18, 2004.
37 Marc Kaufman, “Many FDA Scientists Had Drug Concerns, 2002 Survey Shows,”
Washington Post, Dec. 16, 2004, p. A1. HHS had not released those survey findings; they
were obtained from FOIA material that public interest groups requested.
38 Richard Horton, “Vioxx, the Implosion of Merck, and Aftershocks at the FDA,” The
Lancet, vol. 364, no. 9450 (Dec. 4-10, 2004), p. 1995.

---

CRS-14
FDA Options.
Put the Office of Drug Safety and the Office of New Drugs under
different supervisors. Both now report to the Director of CDER. Some believe
that FDA should maintain that structure because a drug’s risks cannot be assessed
independently from its benefits. Others maintain that having the offices together may
create pressure to keep CDER-approved drugs on the market. In a November 5, 2004
statement, FDA announced that it is asking the Institute of Medicine (IOM) of the
National Academies to examine its post-approval safety program.39 Reports say that
IOM will also examine whether a separate entity is needed to oversee drug
postmarketing safety issues.40
Institute scientific dispute-resolution mechanisms. Right now, when
a scientist at FDA disagrees with the decisions of his supervisor, there is no
mechanism for resolving that disagreement except by discussion between the two of
them. This may silence reviewers who want to raise drug safety concerns. In
November 2004, FDA announced a one-year pilot program for “Documenting
Differing Professional Opinions and Dispute Resolution.”41 This internal dispute-
resolution process, under consideration during the last year, will use ad hoc panels
outside the direct supervisory chain to adjudicate cases involving scientific
disagreement among agency reviewers. According to the acting director of the drug
center, the intent is to formalize standard agency practices for resolving scientific
disagreements.42 Critics, though, argue that keeping a dispute within FDA, no matter
how the resolution is structured, makes scientific objectivity impossible. For
example, after someone requests a review through the CDER ombudsman, the
decision to proceed still involves the CDER director.
Congressional Options.
Move safety oversight to another federal agency. Supporters of this
option compare such a move to the National Transportation Safety Board’s
placement outside of the Department of Transportation, which separates it from the
Federal Aviation Administration. Harvard Medical School professor Dr. Jerry Avorn
suggests that assigning drug safety tasks to Centers for Disease Control and
Prevention, the Agency for Healthcare Research and Quality, the National Institutes
39 Food and Drug Administration, “FDA Acts to Strengthen the Safety Program for
Marketed Drugs,” FDA Statement, Nov. 5, 2004, at [http://www.fda.gov/bbs/topics/
news/2004/NEW01131.html].
40 “FDA Drug Safety Review Will Weigh Need for a Separate Safety Agency,” The Green
Sheet, Nov. 15, 2004, p. 1.
41 FDA, “Documenting Differing Professional Opinions and Dispute Resolution — Pilot
Program,” Office of the Center Director, CDER, Manual of Policies and Procedures, MAPP
4151.2, Nov. 4, 2004.
42 “CDER Dispute Resolution Policy Will Test ‘Ad Hoc’ Arbitration,” The Pink Sheet, Nov.
15, 2004, p. 10.

---

CRS-15
of Health, or a new unit in HHS could give safety reviewers the independence that
he believes they need.43
Provide whistleblower protection. Dr. Graham’s testimony has drawn
attention to the fact that the protection given corporate whistleblowers does not
extend to those in government. Congress may consider doing that in order to give
scientists recourse when they feel improper pressure to disregard safety concerns.
FDA Budget
Two aspects of FDA’s budget for post-approval activities attract criticism. One
is the overall program level, the amount that FDA can spend on safety issues after
drugs are on the market. The other is the presence of industry user fees, which can
be perceived — by both FDA reviewers and industry — as an influence on safety
judgments and FDA action.44 Total user fee contributions to FDA spending have
increased at a quicker rate than the contributions from congressional appropriations,
provoking further concern among those critics worried about undue industry
influence.45
Congressional Options. Those who see budgetary solutions to
postmarketing problems have offered solutions that are primarily legislative.
Revise (or repeal) PDUFA. Some critics maintain that FDA could keep the
current structure intact, but, by reducing the industry contribution proportion,
proportionally decrease industry influence. Others recommend using more of the
user fees to support post-marketing safety activities. Still others, such as Angell,
believe that no amount of industry support is acceptable and that the public would be
best served only when reviewers’ independence is rigorously maintained. They
propose that Congress repeal PDUFA and increase FDA appropriations to cover (or
exceed) current user fee levels.
Increase FDA appropriations. Independent of any action regarding
PDUFA, some analysts urge increases in congressional budget authority to FDA in
general and the Office of Drug Safety in particular.
Develop alternative funding. Avorn points out that there actually are a
wide variety of ways to conduct postmarket reviews other than government. Some
43 Jerry Avorn, Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs
(New York: Alfred A. Knopf, 2004), p. 213. (Hereafter cited as Avorn, 2004.)
44 A similar consideration occurred around Medicare inspection funding. Proposals to
require Medicare and Medicaid nursing homes to pay user fees for the inspections that
would determine their compliance with law and regulations have never been enacted, in part,
because of concern that inspectors might become too influenced by nursing home owners.
45 From FY1997 to proposed FY2005, FDA’s congressional appropriation just about
doubled. During the same period, PDUFA fees — FDA’s other source of income — almost
quadrupled. The change from FY2004 to FY2005 is especially dramatic: a 0.02% decrease
in congressional dollars, but a 12.5% increase in user fees (FDA, Justification of Estimates
for Appropriations Committees, Fiscal Years 1998-2005).

---

CRS-16
alternatives, all of which would require legislation to implement, include: research
by organizations such as HMOs, universities, or insurers. He suggests as possible
ways to fund such reviews: a 10-cent fee per filled prescription; a user fee by payers
on a per person-covered basis; or fees paid by manufacturers — although those
studies would need to be managed independently.
Industry Role
In some ways, criticism of the pharmaceutical industry is the most complicated
issue in this list. While it has drawn sharp criticism, and while the pharmaceutical
industry is at once immensely profitable and widely resented, making it an attractive
target, many of the specific criticisms of its role are passionately rebutted, not just by
industry spokespeople but by academics, and with substantive arguments.
Many observers believe that FDA’s dependency on industry user fees has
gradually worn away at the agency’s willingness to confront drug makers. More than
a funding issue, they say, the problems represent a cultural issue: FDA does not
exercise its tremendous moral authority and extraordinary public relations power to
combat corporations interested only in the bottom line, instead seeing its role as
pleasing industry.
Again, Dr. Graham’s testimony46 articulated this point, and, because he argues
from within FDA, his remarks attracted wide attention.
The corporate culture within CDER is also a barrier to effectively protecting the
American people. The culture is dominated by a world-view that believes only
randomized clinical trials provide useful and actionable information and that
postmarketing safety is an afterthought. This culture also views the
pharmaceutical industry it is supposed to regulate as its client, over-values the
benefits of the drugs it approves and seriously under-values, disregards and
disrespects drug safety.
The criticism of industry traditionally coalesces around one argument: that in
its zeal to market drugs, companies will overlook dangers evident to unbiased
researchers. Thus, Hilts writes that in the case of thalidomide, the “marketing
department, not the medical department, ran the ‘trial.’”47 Accounts of the Vioxx
controversy, four decades later, indicate that Merck scientists did argue for further
study of the drug but were met with objections from marketing divisions.48
46 Graham, Nov. 18, 2004.
47 Hilts, 2003, p. 151.
48 Anna Wilde Mathews and Barbara Martinez, “Warning Signs: E-Mails Suggest Merck
Knew Vioxx’s Dangers at Early Stage,” Wall Street Journal, Nov. 1, 2004, p. A1.
(Hereafter cited as Mathews and Martinez, Nov. 1, 2004.)

---

CRS-17
Certainly, industry makes its influence felt in many ways. For example:
Data. Information on which FDA approval is based comes from studies funded
by the manufacturer. While industry argues that its sense of social responsibility and
concerns about litigation keeps reporting honest, critics have found that difficult to
square with the events in cases like Vioxx for which data about increased risk were
available to the manufacturer four or five years before it withdrew the drug.
Funding. User fees have been mentioned elsewhere in this report because they
influence issues such as FDA organization and, of course, budget. But there are
those who are primarily interested in it as an example of inappropriate industry role.
User fees support new drug reviews. In 2005, industry paid FDA $200 million,
almost all of it directed to new drug reviews by law. This influx of money also
allows FDA to pay for staff conferences, travel, and training — but is limited
primarily, some say, to new-drug reviewers.
Independent research. Although this is changing, journals, conferences, and
researchers themselves do not always clearly identify their funding sources.
Researchers presumed to be independent often receive grants, vacations, status,
patients, or fees from industry that give the appearance of compromising objectivity.
At universities, traditionally perceived to be the bastion of unbiased research,
industry funding has become so pervasive that former Harvard University president
Derek Bok, pointing to research showing clinical trials supported by industry are
“more ... favorable to sponsors” than independent research, has warned, “the
dependence on corporate support has reached such a point that it will be difficult for
medical schools to free themselves of industry influence.”49 Whether researchers are
influenced by industry funding consciously, unconsciously, or not at all, the
perception of influence on both pre-market and post-approval research contributes
to some people’s lack of trust in findings.
Direct-to-consumer (DTC) advertising. The United States is one of only two
countries in the world that allow pharmaceutical companies to advertise directly to
consumers — the other is New Zealand.50 Industry argues this is a powerful tool for
informing consumers about diseases and the treatments available for them. Industry
critics agree that it is powerful tool — for misinforming consumers about the same
issues.
These concerns regarding industry influence are listed elsewhere in this paper.
The reason is that not everyone sees these problems in the same way. For example,
is it the fault of industry for supporting a solution, such as user fees, that could
compromise objectivity? Or does the fault lie with Congress because it has not
appropriated enough money for safety — forcing, as one writer put it, “a marriage
49 Avorn, 2004, p. 213.
50 Presentation by Dean G. Smith, Lynne Eagle, Kerry Chamberlain, and Lawrence C. Rose,
“The Views of Healthcare Professionals and Consumers on Direct-to-Consumer Promotion
of Prescription Drugs in New Zealand,” FDA Public Meeting, Washington, D.C., Sept. 23,
2003, at [http://www.fda.gov/cder/ddmac/p6smith/tsld001.htm]. See also CRS Report
RL31603, Direct-to-Consumer Advertising of Prescription Drugs, by Donna U. Vogt.

---

CRS-18
between the agency and industry years ago for the rich dowry that industry
offered?”51
Despite debate over detail, there seems to be widespread consensus that FDA
needs to be objective about the industry it regulates. Suggestions for revamping the
industry role to reduce postmarketing problems lie almost entirely within the
legislative arena.
FDA and Administration Options.
Fill vacant positions in FDA. Right now, FDA has acting directors of the
Center for Drug Development and Evaluation and its Office of Drug Safety. Acting
officials throughout government tend to act with caution, in part because they are not
perceived (even by themselves) as having the political backing to stand up to
industry, researcher, and consumer pressure.52 Many observers have urged the
President to move quickly to appoint a commissioner so that the agency could act to
fill its vacant science management slots.53 On February 15, 2005, the President
nominated Acting Commissioner Lester Crawford to be Commissioner of Food and
Drugs, three days after Michael Leavitt was sworn in as HHS Secretary.54
Congressional Options.
Reassign conduct of pre-market studies away from manufacturer
to government. Angell believes that marketing considerations unduly influence
even pre-market studies. She argues that government — whether FDA or NIH —
should control the clinical trials designed to test safety and effectiveness. One
drawback: right now, according to PhRMA, its member companies spent over $33
billion dollars in 2003 “on research to develop new treatments for diseases,55 an
expense Congress might find difficult to fund. Some observers have proposed
assessing industry for those costs but legislating ways to eliminate industry influence
in how the funds are spent.
Diminish marketing role in study design. As the Vioxx story makes
clear, marketing is where pharmaceutical employees have the sharpest conflict of
51 Harris, Dec. 6, 2004.
52 Marc Kaufman, “FDA’s Reliance on Unconfirmed Chiefs Is Faulted,” Washington Post,
Dec. 19, 2004, p. A1.
53 For example, see the letter, dated Feb. 1, 2005, from Senators Enzi, Kennedy, and 15 other
members of the Senate Committee on Health, Education, Labor and Pensions to the Hon.
George W. Bush.
54 The White House, Personnel Announcement, Office of the Press Secretary, Feb. 14, 2005,
at [http://www.whitehouse.gov/news/releases/2005/02/20050214-3.html]; and The White
House, President Thanks HHS Secretary Leavitt at Swearing-In Ceremony, Office of the
Press Secretary, Feb. 11, 2005, at [http://www.whitehouse.gov/news/releases/
2005/02/20050211-3.html].
55 PhRMA, Research & Development: Overview, at [http://www.phrma.org/issues/
researchdev/], visited Jan. 7, 2005.

---

CRS-19
interest when it comes to scientific decisions.56 With 93 million Vioxx prescriptions
having been written since its approval in 1999, with worldwide sales in 2003 of about
$2.5 billion, it is not surprising that, in the gray area where research is not crystal-
clear, marketers will clamor for more proof of safety or effectiveness concerns.
Greater available funding for independent research would mitigate the pressure that
marketing considerations place on research decisions.
Create transparency in funding of academic research. Congress could
mandate full and open disclosure of industry contributions to pre-market and post-
approval research in the same way it has mandated the disclosure of campaign
contributions.
Reduce conflicts of interest in consumer and physician education.
An essential ingredient in industry marketing efforts is its use of sales
representatives, conferences, and direct advertising. Pharmaceutical companies argue
that such efforts play a constructive role in educating consumers and doctors.
Suggestions for limiting direct-to-consumer advertising range from the minor to
outright banning it. Industry promotion to physicians, too, spurs a range of
suggestions. Some, such as Angell, say that these provide little health benefit and
those could be accomplished in other ways. She argues that the majority of Phase IV
clinical trials are marketing opportunities to introduce their products to clinicians and
the public. Some have proposed banning or limiting such practices as industry
sponsoring of conferences, gifts, and other practices compromising objectivity;
alternatively, sponsors could announce their support publicly and physicians could
declare receipt of the benefit. In particular, some recommend that members of the
advisory committees that review data and make recommendations to FDA should not
receive financial or other benefit from pharmaceutical companies.
The members of the FDA advisory committees that met in February 2005
regarding Vioxx, Celebrex, and Bextra addressed consumer and physician
advertising. They discussed a range of approaches, including a complete ban on
direct-to-consumer advertising, something FDA officials said was beyond their
authority. The committees also suggested various ways to restrict DTC ads, some of
them severely. One, for example, would require government-produced alternative
ads focused on a drug’s risks.57
Maintain tort claim option. Former Secretary of Labor Reich readily
acknowledges that both regulation and torts “can function far better than they do
now.” However, he went on to point out that when FDA is weak, “the tort liability
system is our only real defense against corporate negligence.”58 At a time when
Congress is exploring tort reform, it may consider what such action could do to
influence industry behavior when it comes to keeping drugs safe and effective.
56 Mathews and Martinez, Nov. 1. 2004.
57 Gardiner Harris, “FDA Is Advised to Let Pain Pills Stay on Market,” New York Times,
Feb. 19, 2005.
58 Reich, Jan. 9, 2005.

---

CRS-20
Opportunities to Use the Drug Approval Process to Enhance
Postmarket Activities
Aside from whether FDA is wholly independent, there is broad agreement
among those who have looked closely at FDA’s process for drug approval that a
number of specific changes in the evaluation process could make FDA more likely
to anticipate, identify, and handle problems in the safety and effectiveness of drugs.
FDA has the power now to implement these changes. Congress may choose to act,
however, if it appears that FDA is declining to act.
Is it possible to identify more problems during Phase III trials before a drug goes
to market? Not without slowing the process down. Pre-market trials assess the
safety and effectiveness of a drug when it is used for a specific purpose in a
specifically defined group of people. But some problems may occur in one user out
of a hundred thousand. Only when millions of people are using that drug can such
an effect become apparent. But that is not to say there can be no changes in process
for approving new drugs. Some problems, pointed to by a wide range of critics,
include the following:
Inability to attach strings to new drug approval. Some critics think that FDA
assesses safety disproportionately at the approval stage by providing close to a one-
time, all-or-nothing, approval. This severely restricts FDA’s ability to act once a
drug is on the market. Companies are under no obligation to continue research for
safety and effectiveness — even though some kinds of dangers take years to spot.
Inability to enforce postmarket research deadlines. Critics note that
manufacturers do not always complete the postmarket studies the law requires in
certain approval categories or that were otherwise agreed-to by the manufacturer.
FDA reports industry-committed study status annually in the Federal Register,59 but
many feel that not only does FDA not have adequate authority to compel compliance,
it does not sufficiently follow through with the tools it does have to enforce those
commitments.
Inability to stimulate comparative effectiveness analysis. Right now, pre-
market approval requires evidence of effectiveness and safety only in comparison to
a placebo treatment. Because most new drugs offer incremental changes to older
products, a comparison to placebo is not particularly relevant. Observers argue that
consumers and physicians need to know — from unbiased sources — whether it is
better than others on the market. The Vioxx controversy brought into sharp relief the
potential value of comparing one drug against other drugs used to treat the same
illness. Even if Vioxx had proven perfectly safe, consumers and physicians would
have wanted to know whether it was safer or more effective than ibuprofen. And was
59 See, for example, FDA, Federal Register Report and FDA website on Postmarketing
Studies, FDA Talk Paper, May 22, 2003, at [http://www.fda.gov/bbs/
topics/answers/2003/ans01223.html]; and HHS, FDA, Report on the Performance of Drug
and Biologics Firms in Conducting Postmarketing Commitment Studies; Availability; 69
Federal Register 12162, Mar. 15, 2004, at [http://www.fda.gov/cber/pstmrkt/
pstmrkperf0304.pdf].

---

CRS-21
it safer for everyone or just the tiny number of people for whom NSAIDs produce
gastric distress?
Inability to approximate anticipated circumstances of use. FDA accepts as
evidence of safety and effectiveness data from trials that do not include what some
critics see as a reasonable range of patient, disease, and care characteristics. That is,
clinical trials often limit study to people without problems other than the one being
studied. The initial trials of COX-2 inhibitors, such as Vioxx, therefore, excluded
patients likely to have heart attacks or strokes. Yet, once the drugs went on the
market, such patients became COX-2 users — as one might expect of a drug
prescribed for arthritis because both arthritis and increased cardiovascular risk are
associated with getting older. Excluding groups from clinical trials is a well-
established approach to drug research. If it is reasonable to expect that those groups
not represented in the trials will buy the drug, it is argued that there must be
alternative ways to make sure the drug is safe for them.
Reluctance to set limits on the use of approved drugs. Right now, physicians
can use any approved drug for any illness they deem appropriate. Such off-label use
has been particularly controversial recently in the issue of antidepressants and
children. An FDA Task Force noted that “[o]nce medical products are on the market,
however, ensuring safety is principally the responsibility of healthcare providers and
patients, who make risk decisions on an individual, rather than a population, basis.”60
No one recommends banning off-label use because it can offer relief not otherwise
available. Some urge that mechanisms be set up to monitor it.
Congressional Options. Drug approval requirements are set in law. So
most options to change the process would require legislation.
Institute two-phase approval process that includes mandatory
reevaluation. Abandoning the all-or-nothing approach means that FDA could re-
evaluate safety using postmarket data concerning prescribing patterns, use patterns,
adverse events, and effectiveness, for example. One approach could be to routinely
set license-renewal dates. FDA’s broader mission, supported by the FFDCA and
related regulations, is to protect the public from unsafe and ineffective drugs.
Require specific postmarket surveillance and study commitments
for initial approval. FDA has the authority now. With increased resources, FDA
could increase these requests, set due dates, and strengthen their enforcement.
Congress could also give FDA the authority to assess and enforce penalties for
noncompliance. As a condition of approval, FDA could require the postmarket
continuation of pre-approval clinical trials to assess, for example, the ramifications
of long-term use or latent safety risks that may become evident years after use. FDA
could require rigorous postmarket trials of samples of whatever off-label uses
become evident.
60 FDA, Managing the Risks From Medical Product Use: Creating a Risk Management
Framework, Executive Summary of the Report to the FDA Commissioner from the Task
Force on Risk Management, May 1999, at [http://www.fda.gov/oc/tfrm/1999report.html].

---

CRS-22
Require comparative effectiveness trial commitments for initial
approval. These trials would assess the comparative safety and effectiveness of a
new drug relative to other available drugs and treatments for the condition.
Require commitment to study likely users not considered in pre-
approval trials. FDA approval could require future studies that would be designed
to test safety and effectiveness across the range of people to whom and conditions for
which physicians will prescribe the drug.
Restrict use of newly approved drugs when first on the market.
There are a few critics who argue for banning all off-label prescribing. More
common are those who recommend limiting it and rigorously monitoring it.
So far, we have looked at problems that become apparent in the postmarket
period that may have been avoided by actions in the pre-approval process. But
whatever the limitations of the pre-market review and approval procedure, it
produces useful and peer-scrutinized data and analysis. The focus of postmarket data
collection and analysis dramatically shifts, with changed incentives and statutory and
regulatory requirements for both the manufacturer and the FDA. Critics and even
some supporters of the system find that postmarket information on safety and
effectiveness of FDA-approved drugs is insufficient to support the kinds of decisions
clinicians and patients need to make.
We divide these problems into two groups:
! insufficient postmarket information, and
! lack of access to existing information.
Insufficient Postmarket Information
Analysts of the current FDA system point out that it is one of passive
surveillance. Rather than reaching out to identify problems, FDA waits for
consumers and physicians to voluntarily report concerns with drugs; manufacturers
are required to pass on to FDA the reports they receive. Such reports are valuable
aids to researchers looking for potential risks. In its FY2003 Annual Report, the
ODS notes it received 369,839 reports that year.61 A 2000 study by the General
Accounting Office (GAO, renamed the Government Accountability Office in 2004)
estimated that FDA receives reports on no more than 10% of all adverse drug events.
The picture painted by the data, therefore, is “fragmentary and inconsistent.”62
What are the limitations of a passive approach? First, in relying on anecdotal
evidence, it provides an incomplete and distorted picture of actual problems. Second,
the system relies on a physician or consumer making the connection between an
adverse event with a drug. Physicians are much more likely to report rare conditions
61 FDA, Office of Drug Safety Annual Report FY 2003, created Dec. 28, 2004, at
[http://www.fda.gov/cder/Offices/ODS/AnnRep2003/default.htm#Adverse].
62 GAO, Adverse Drug Events: The Magnitude of Health Risk Is Uncertain Because of
Limited Incidence Data, GAO/HEHS-00-21, Jan. 18, 2000.

---

CRS-23
that follow drug use than more common conditions that could be expected in an older
user even without the drug. So, liver failure and anaphylactic shock get reported, but
fatigue and heart attacks do not.
There are other reasons that reports do not present a balanced picture. A 63-
year-old, weekend tennis player taking a COX-2 inhibitor for knee pain may not even
consider reporting a heart attack as a drug reaction. Meanwhile, consumers and
physicians report many events that occur immediately after a drug’s use that may
have nothing to do with that drug. Furthermore, the system relies on physicians or
consumers actually following through and reporting their concerns that adverse
events are related to the drug.
Finally, data from surveillance reports do not include sufficient information
about the medical, behavioral, and sociodemographic characteristics of the patient.
Scientists analyzing the data need that information to clarify what appear to be
associations between drugs and events. MedWatch provides a count of events but
does not provide the total number of people taking the drug. MedWatch may get 100
reports of adverse events. But, are 1000 people taking the drug or a million?
Without the denominator, a cluster of events reported to a system such as MedWatch
serves only as a red flag to prompt further investigation.
There is a second, more aggressive way to find postmarket drug effects.
Researchers can design studies to address the suspected association of the drug and
the adverse event by trying to hold constant other characteristics of the illness and the
patient. Researchers also can design studies to test hypotheses suggested by a drug’s
mechanism of action, or based on findings concerning other drugs in its class. They
may also measure a drug’s safety and effectiveness for known off-label uses; and to
comply with commitments made as part of the drug approval process.
Postmarket effort to identify safety and effectiveness problems requires a two-
pronged approach: first, an accurate assessment of what is happening to patients —
the warning signs that something may be wrong; and, second, carefully designed,
rigorously impartial research to see what is wrong.
FDA Options.
Reassess criteria qualifying as a “signal”. Whatever the surveillance
mechanism, FDA could reassess the criteria it uses to decide that there may be a
problem — called a signal — in surveillance data and clarify what steps it could then
take.
The next two postmarket activities also appear among pre-approval options.
There, the issue is commitment to do the studies. Here, in the postmarket options
section, the issue is actually doing them.
Periodically assess the range of off-label use. FDA could actively
collect prescribing or pharmacy data, by characteristics of patient and medical reason
for prescribing.

---

CRS-24
Design and conduct rigorous studies, including clinical trials, to
test the safety and effectiveness of drugs used off-label. FDA and the
manufacturer could design studies based on anticipation of likely off-label use and
postmarket data on off-label use.
Use administrative, financial, and clinical databases. FDA could
develop data collection and analysis procedures that validly capture necessary
information. In doing so, FDA would need to establish privacy and confidentiality
mechanisms that allow patient-level linkages among diagnostic, sociodemographic,
treatment, coverage, and outcome data. Other approaches might include the use of
automated databases and targeted medical record reviews or patient interviews when
necessary. The President’s budget submission for FY2006 refers to increases in these
kinds of activities.
Congressional Options.
Mandate more activist surveillance. Some critics urge a drug surveillance
system similar to FoodNet, which aggressively seeks food poisoning reports from
doctors and laboratories in nine states across the country. Others urge what GAO
calls a “proactive examination of a random sample of patient records.” The Institute
of Medicine urges a Center for Patient Safety to collect adverse drug event data.
Who would fund this system, and how? It is a question that applies to many of
the solutions presented in this paper. There are not an infinite series of choices:
increased federal appropriations, industry generated funds — with restrictions on
industry influence — are those mentioned most often by public health analysts.
Authorize FDA to require postmarket studies of situations that had
not been anticipated at the time of approval. Right now, FDA can only
request studies, using an implied or stated threat of action to withdraw a drug from
the market. Congress could authorize FDA to require them, avoiding the current
gamesmanship and asserting FDA’s role. There is another approach: Congress could
give FDA authority to take specific enforcement steps other than the current all-or-
nothing threat of revoking approval and, therefore, licensure.
Require comparative effectiveness studies. The clinical trials that
manufacturers field to support applications to FDA usually compare outcomes in two
groups: people with the disease who are given the new drug and people with the
disease who are given a placebo. What this approach does not provide, though, is
any comparison of the new drug with other available treatments. A clinician who is
deciding whether to prescribe drug A wants to know more than whether drug A is
better than nothing; the clinician also wants to know whether drug A is better —
more effective or safer — than drug B.
In part because FDA does not require comparative effectiveness studies,
manufacturers rarely mount them. And, in part, because comparative effectiveness
studies are expensive, neither do other researchers. In the 108th Congress, bills were

---

CRS-25
introduced bills to require — and fund — comparative effectiveness studies63 and in
its Medicare legislation, the 108th Congress directed the HHS Agency for Healthcare
Research and Quality (AHRQ) to “conduct and support research” dealing with “the
outcomes, comparative clinical effectiveness, and appropriateness of health care
items and services (including prescription drugs)....”64
Increase funds to FDA. A larger budget would enable intramural scientists
to analyze data and design and carry out follow-up studies based on data-suggested
hypotheses. Alternatively, or in addition, Congress could increase funds that FDA
can provide to extramural researchers for this work, as well as supporting training
programs.
Explore alternative systems. Congress may choose to examine some of the
systems adopted in other countries — the “pharmaco-vigilance centers” used by
doctors in France, or Great Britain’s “green card” requests that researchers send to
doctors asking for more information when they spot a possible problem.65
Existing Information Unavailable to All Groups
Lack of research into the kinds of safety and effectiveness questions that
clinicians and patients could use in treatment decisions is one problem. But there is
also significant research that exists — but is not available. The reasons are more
complicated than what some critics assert: that drug companies keep unfavorable
results secret. Among other reasons:
Publication bias. Medical journal editors have traditionally paid more attention
to positive findings — that a treatment works — than to reports of no differences or
statistically insignificant differences between new treatments and old or no
treatments. As a result, many researchers, whether industry-affiliated or not, often
decide not to submit negative studies for publication.
Insufficient FDA resources. We have already described FDA’s system for
collecting possible adverse drug event information. Whether because of budget
constraints or the unlikely prospect of identifying valid associations within
haphazardly collected and incomplete reports, FDA leaves much of these surveillance
data unanalyzed. In addition, the agency lacks enough trained pharmacologists,
epidemiologists, pharmacoeconomists and other researchers with the specialized
skills necessary for analysis. FDA’s budget justification of the FY2006 request
appears to recognize this by referring to “the wealth of data in its Adverse Event
63 For example, H.R. 2356, introduced by Rep. Allen on June 5, 2003, and S.Amdt. 1000 to
S. 1, introduced by Sen. Clinton on June 23, 2003.
64 Section 1013, P.L. 108-173.
65 Anna Wilde Mathews, “As Drug-Safety Worries Grow, Looking Overseas for Solutions,”
Wall Street Journal, Dec. 31, 2004, p. A1.

---

CRS-26
Reporting System (AERS) to assist medical officers involved in the review process
by providing a data mining tool to identify trends in adverse event data.”66
Industry use of information as marketing. Drug manufacturers do not release
all their findings to the public.67 Critics note that when manufacturers do publicize
their findings, in direct-to-consumer advertisements68 and marketing materials aimed
at physicians, they may provide an incomplete and distorted view of a drug’s
indications, safety, and effectiveness. Physicians — relying on information packaged
by the manufacturer or provided by its detailers — therefore may not have full safety
and effectiveness information.
Industry suppression of bad news. Researchers report that the companies
sometimes move to suppress the publication or presentation of findings when they
could harm a product’s sales. This raises complicated matters of policy and scientific
procedure. What should FDA do when researchers uncover a risk? What is FDA’s
duty to disclose industry data? Incorrect decisions can result from action taken too
quickly or action delayed from an excess of caution. The problem is that in scientific
research, chance, poor study design or analysis, or an unrelated event can imply that
a drug is risky when it is safe. Limiting or withdrawing a drug, in that case (based
on erroneous conclusions), protects no one — and hurts those who would have been
helped by it.
Labeling requirements. Labeling does not refer to the little sticker on a vial of
prescription drugs. It is the more detailed insert that comes with medicines to
drugstores. The law requires that pharmacists include them for patients, but that does
not always occur.
We have mentioned that once FDA approves a drug and the manufacturer puts
it on the market, physicians are mostly free to prescribe it as they wish. A doctor
may prescribe a drug approved for adults to a child; prescribe a lipid-lowering or
anti-inflammatory drug as a possible preventive measure against dementia; or
prescribe a drug that the manufacturer tested for six-week use at one dose to someone
at a higher or lower dose or for months, years, or a lifetime.69 Neither the clinician
nor the patient — nor FDA — can look up possible side effects of off-label use,
either because these uses have not been tested or results not been revealed.
66 FDA, Human Drugs, CDER, budget documents, at [http://www.fda.gov/oc/oms/ofm/
budget/2006/PDFs/Summary/Pages156thru193.pdf], visited Feb. 10, 2005.
67 Manufacturers must report all studies to FDA.
68 For a discussion of issues involved in the DTC advertising of prescription drugs, see CRS
Report RL31603, Direct-to-Consumer Advertising of Prescription Drugs, by Donna U.
Vogt.
69 For examples, see Shankar Vedantam, “FDA Links Antidepressants, Youth Suicide Risk,”
Washington Post, Feb. 3, 2004, p. A1; David Tuller, “Seeking A Fuller Picture Of Statins,”
New York Times, July 20, 2004, p. F5; or consider use of medication for chronic conditions,
such as diabetes or hypertension.

---

CRS-27
Why? The FDA’s passive system for picking up such problems certainly limits
it usefulness. In addition, industry is not likely to ask questions that might hurt the
drug’s financial prospects. The result: even when off-label uses are widely known
and suspected of being unsafe or ineffective, the labeling does not change.
FDA Options.
Enhance drug-information dissemination options. Especially with use
of the Internet, opportunities exist beyond traditional peer-reviewed professional
journals, while maintaining standards of scientific quality. For example, the not-for-
profit Public Library of Science (PLoS) established a Web-based public forum for
published research results.70 The National Library of Medicine announced that,
beginning in May 2005, NIH-funded researchers can voluntarily submit their reports
(after peer review and acceptance by a research journal) to its PubMed Central
database, which will be publicly accessible.71 Many applaud these types of actions.
Others worry that, while these two activities involve only published material, other
websites posting unpublished reports, thereby circumventing the current system of
anonymous peer review and editorial oversight, would weaken the protection and
integrity the traditional system of research publication provides.
Transfer current information to prescribers. FDA might explore
developing an education outreach program to physicians. Such a system might use
computer software; round-the-clock opportunities for telephone and e-mail
consultations; and visits to physician offices, a practice called “academic detailing”
in reference to the promotional visits, called “detailing,” of drug company
representatives.
Extend collaborative data collection and analysis activities.
Comparative effectiveness studies and safety monitoring need not await
government’s taking them on. Diverse groups have begun sharing data and results
and making them available to others. Examples of such work are the Cochrane
Collaboration,72 the British Medical Journal’s Clinical Evidence website,73 the
70 According to its website, the Public Library of Science is a “nonprofit organization of
scientists and physicians committed to making the world’s scientific and medical literature
a public resource” ([http://www.plos.org/about/index.html], visited Feb. 4, 2005).
71 National Institutes of Health, NIH Calls on Scientists to Speed Public Release of Research
Publications: Online Archive Will Make Articles Accessible to the Public, NIH News, Feb.
3, 2005, at [http://www.nih.gov/news/pr/feb2005/od-03.htm].
72 The Cochrane Collaboration, “an international non-profit and independent organisation,
dedicated to making up-to-date, accurate information about the effects of healthcare readily
available worldwide,” produces the Cochrane Database of Systematic Reviews; see website
at [http://www.cochrane.org/docs/descrip.htm], visited Feb. 11, 2005.
73 Clinical Evidence is a website owned by BMJ Publishing Group Limited, at
[http://www.clinicalevidence.com/ceweb/about/index.jsp], visited Jan. 10, 2005.

---

CRS-28
Oregon Drug Effectiveness Review Project,74 and the Centers for Education and
Research on Therapeutics (CERTs) program funded by the Agency for Healthcare
Research and Quality.75 Many urge that, with funding contributed by government,
as well as by foundations, healthcare payers, and industry, the information could —
and should — be made public and free.
Congressional Options.
Require that labeling address off-label uses. Right now, labeling
addresses the indications for which the manufacturer requested approval. When it
is apparent that clinicians are prescribing a drug for other purposes or to populations
other than those included in the approval application and supporting safety and
effectiveness data, FDA could require that the label include known information and
an assessment of hypothesized safety and likely effectiveness in the off-label use. A
less ambitious approach would be to require that the label clearly acknowledge that
the safety and effectiveness of the common off-label uses have not been studied with
the rigor (or at all) required by FDA for new drug approval. This information could
be updated regularly. After a drug has been used long enough or by enough people,
FDA could require formal assessment (with controlled clinical trials and well-
designed observational studies) of safety and effectiveness for those off-label uses.
Remove postmarket study responsibility from both manufacturers
and FDA. Avorn suggests that HMOs, academics, insurers, contract research
organizations, and other private groups should carry out postmarket studies under
government or industry contracts. He gives as examples a 10-cent fee for every filled
prescription, or user fees from payers on a per person-covered basis. If the funding
came from a line-item in the federal budget or from industry contributions, a
mechanism could be imposed to guarantee that the studies were managed
independently, without input from the government or industry. That way, the data
would not be owned by entities potentially reluctant to release them to the public.
Require clinical trial registration. Congress acted in 1997 to require
sponsors to publicly list any clinical trial at its outset to enable individuals to
participate.76 This public notice had a collateral effect: the public could follow-up,
years later, what the sponsor had found. Discussion in the 108th Congress focused
on registration as a way to compel openness. Incentives suggested to increase
74 The Oregon Evidence-based Practice Center, Oregon Health and Science University,
webpage describes the collaborative program, at [http://www.ohsu.edu/drugeffectiveness/
description/].
75 The CERTs fact sheet, at [http://www.ahrq.gov/clinic/certsovr.pdf].
76 The Food and Drug Administration Modernization Act. For more information about
clinical trial reporting, see CRS Report RS21944, Clinical Trials Reporting and Publication,
by Erin Williams and Susan Thaul.

---

CRS-29
compliance included linking registration either to permission to begin clinical studies
in humans77 or to publication of studies’ results.78
Make data public. This would avoid the potentially dangerous withholding
of data. It would present the opportunity to others to validate findings and
conclusions or to analyze the data differently. Making data public could cause
problems, too. If a proposed study might yield findings that would hurt a drug’s
sales, the manufacturer might choose not to pursue the research. If data were widely
disseminated before they were replicated, understood, or rejected, they could
prematurely form the basis of ill-informed treatment decisions. The enormity of data
collected would be unwieldy and difficult to analyze (or analyze within a useful
timeframe) without sophisticated statistical knowledge and computer software.
Give FDA enhanced authority to regulate DTC advertisements.
Much of the information available to physicians and the public about drugs comes
directly from the pharmaceutical industry. Although the law and regulations require
that material include description of risks as well as benefits, the DTC advertisements
are designed to sell the product, and some think that the balance of information is
distorted in favor of the product. Currently FDA reviews a DTC advertisement if it
becomes aware of a problem. Some would prefer a total ban on DTC advertising;
others urge stronger controls. Examples include requiring that FDA review and
approve advertising copy before it is published. This may require budget action;
according to Angell, in 2001 FDA had 30 reviewers for 34,000 direct-to-consumer
advertisements submitted.79
Give FDA ability to institute penalties for misleading ads. This may
require coordination with Federal Trade Commission regulations.
Conclusion
No drug is completely safe. In fact, the Federal Food, Drug, and Cosmetic Act
even defines a prescription drug as one with “toxicity or other potentiality for
harmful effect, or the method of its use, or the collateral measures necessary to its
use, is not safe for use except under the supervision of a practitioner licensed by law
to administer such drug.”80
Physicians have a responsibility to weigh benefits against risks when prescribing
drugs. To do so requires, in addition to their training and experience, available
information. Many ethicists say that the public, too, must have enough information
77 For example, H.R. 5252, introduced by Reps. Markey and Waxman on Oct. 7, 2004.
78 Catherine De Angelis et al., “Clinical Trial Registration: A Statement from the
International Committee of Medical Journal Editors,” New England Journal of Medicine,
vol. 351, no. 12, Sept. 16, 2004, p. 1250, at [http://content.nejm.org/cgi/content/full/351/
12/1250].
79 Angell, 2004, p. 124.
80 FFDCA Section 503(b)(1).

---

CRS-30
about risks to make up their own minds. However, in-depth analysis is often required
to assess the drug’s full effects. Some question whether individuals or even their
physicians can meaningfully interpret all relevant information.
The FDA’s task involves providing that in-depth analysis as it weighs benefits
against risks. For example, codeine provides pain relief but is addictive; Tamoxifen
keeps breast cancer at bay for those who have had a single mastectomy, but can cause
uterine cancer and blood clots; ibuprofen relieves inflammation but can cause
gastrointestinal distress; and statins lower cholesterol but may weaken muscle fibers.
Manufacturers and researchers should find new ways to diminish or mitigate risk.
If a drug is not effective, there is no potential benefit to counterbalance even the
smallest risk.
FDA’s advisory committees routinely tackle these tasks.81 But February’s joint
advisory committee meeting made clear how hard it is to assess the unique and
intertwined qualities of safety, benefit, and risk. The committees heard patients
testify that they would rather die than live without the COX-2 inhibitor that allows
them to function. They heard highly trained researchers present analyses of a drug’s
risk and come up with different conclusions. Finally, they sat for three days
surrounded by conversation and press releases carrying often sharply divergent views
from drug companies, consumers, academic researchers, the media, Members of
Congress, and the FDA itself.
While few question that FDA applies the necessary statutory, regulatory, and
procedural requirements for pre-market approval, there is broad criticism of its
postmarket enforcement activities. Many observers maintain that the law does not
provide sufficiently strong authority for FDA to act.
As we approach the FDA’s 100th year, Congress is clearly poised to examine
whether FDA needs more legal authority to do its job. It could also examine how
FDA can better use the legal — and moral — authority it already has to (1) encourage
and participate in developing, gathering, analyzing, and disseminating information;
(2) act on that information when necessary; and (3) by its powers to both offer
incentives and enforce penalties — and by its own example — encourage industry
cooperation.
There is broad agreement about what problems hamper postmarket activity. This
paper has summarized what observers point to as possible solutions. Congress now
has a much tougher job — picking the approaches that work best.
81 FDA, Human Drug Advisory Committees, at [http://www.fda.gov/cder/audiences/acspage/
index.htm#Introduction], visited Feb. 23, 2005.

---

CRS-31
Table 1. Concerns and Options Raised by Observers
Concerns
FDA options
Congressional options
FDA organization
— Political pressure
— Put Office of Drug Safety and Office of
— Move task of overseeing safety to
— Bureaucratic reluctance to restrict an
New Drugs under different supervisors
another federal agency
already approved drug
— Institute scientific dispute resolution
— Provide whistleblower protection
mechanisms
FDA budget
— Imbalance in funding
— Revise (or repeal) PDUFA
— Increase FDA appropriations
— Develop alternative funding
Industry role
— FDA dependency on industry
— Fill vacant positions in FDA
— Reassign pre-market study
— Cultural issue
responsibility from manufacturer to
— Influence over data
government
— Influence over funding
— Diminish marketing role in study
— Influence over research
design
— Direct-to-consumer advertising
— Create transparency in the funding of
academic research
— Reduce conflicts of interest in
consumer and physician education
— Maintain tort claim option
Opportunities to
— Inability to attach strings to new drug
— Institute two-phase approval process
use the drug
approval
that includes mandatory reevaluation
approval process
— Inability to enforce postmarket
— Require commitments to specific
to enhance
research deadlines
postmarket surveillance and studies for
postmarket
— Inability to stimulate comparative
initial approval
activities
effectiveness analysis
— Require commitments to comparative
— Inability to approximate anticipated
effectiveness trials for initial approval
circumstances of use
— Require commitments to study likely
— Reluctance to set limits on the use of
users not considered in pre-approval trials
approved drugs
— Restrict use of newly approved drugs
when first on the market

---

CRS-32
Concerns
FDA options
Congressional options
Insufficient
— Passive surveillance provides
— Reassess criteria qualifying as a
— Mandate more activist surveillance
postmarket
fragmentary and inconsistent picture
“signal”
— Authorize FDA to require postmarket
information
— Relies on physician or consumer to
— Periodically assess the range of off-
studies of situations that had not been
make event — drug connection and then
label use
anticipated at the time of approval
report it
— Design and conduct rigorous studies,
— Require comparative effectiveness
— Surveillance reports do not include
including clinical trials, to test the safety
studies
sufficient information about medical,
and effectiveness of drugs used off-label
— Increase funds to FDA
behavioral, and sociodemographic
— Use administrative, financial, and
— Explore alternative systems
characteristics of the patient
clinical databases
— Without denominators, reported
clusters of events serve only as red flags
— Researchers also can design studies to
test hypotheses
Existing
— Publication bias
— Enhance drug-information
— Require that labeling address off-label
information
— Insufficient FDA resources
dissemination options
uses
unavailable
— Industry use of information as
— Transfer current information to the
— Remove the responsibilities for
marketing
prescriber
postmarket studies from both the
— Industry suppression of bad news
— Extend collaborative data collection and
manufacturers and FDA
— Labeling requirements
analysis activities
— Require clinical trial registration
— Make data public
— Give FDA enhanced authority to
regulate DTC advertising
— Authorize FDA to institute penalties for
misleading ads

---