Erika Ruiz by pengtt

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									Erika Ruiz


             Off-Label Drug Prescribing by Physicians:

                   Its Origins and Ramifications

                     REDACTED VERSION




                 Third Year Paper/Course Paper


                Harvard Law School, Class of 2002

                            April 2002




                                1
Table of Contents

Introduction 3

I. What is Off-Label Drug Use? 4

  A. A Brief History of Food and Drug Regulation in the United
States 4

 B. The Process of Acquiring FDA Approval of a Drug 6

 C.     Off-Label Use Distinguished from Investigational Use 7

 D. The Legal Basis for Off-Label Drug Use 9

   1. Notice of Proposed Rule Making—1972 9

   2. Subsequent Statements 12

II. The Debate Over Off-Label Drug Use 14

 A. Arguments Supporting Off-Label Drug Use 14

   1. The Prohibitive Costs of Obtaining FDA Approval 14

   2.        Length of Time to Acquire Supplementary Approval 15

   3. Special Needs of Certain Patient Groups 20

                                 2
        a) Patients Suffering from AIDS and Cancer 20

        b)    Pediatric Patients 21

         i) In the United States 21
Introduction



   The Food and Drug Administration’s importance stems from the
fact that its policies affect the lives of every American on a daily
basis, unlike many of the other agencies of the federal government.
The widespread use of the products it regulates—food, drugs, cos-
metics, and medical devices—assures that its actions will not go
unnoticed by the public and often assures that its rules and regu-
lations will prove controversial. Physicians’ practice of prescribing
FDA-approved drugs for unapproved uses or in unapproved dosages
is a common occurrence which is affected by the FDA’s policies and
which is not always understood by the general populace.

 The first part of this paper provides a general introduction to the
regulation of prescription drugs by the U.S. Food and Drug Admin-
istration and to “off-label” uses of FDA-approved drugs. Part I.A.
provides a brief history of the development of what is today the
FDA. Part I.B. describes the standard process of acquiring FDA
approval for a drug. Part I.C. distinguishes off-label drug use from
investigational use. And finally, Part I.D. summarizes the legal
basis for physicians’ off-label prescribing practices.



Part II discusses the current debate over the desirability of off-label prescribing; Part II.A. describes some of the

main arguments for off-label use, and Part II.B. describes some of the main criticisms of and arguments against

off-label use. Part III discusses the off-label uses of specific drugs, including thalidomide, misoprostol and “fen-

phen,” and the results. Part IV describes some issues related to off-label drug use, such as insurance coverage for

off-label prescriptions and regulation of the marketing and promotion of off-label uses.


                                                         3
 I. What is Off-Label Drug Use?

  A. A Brief History of Food and Drug Regulation in the United
States.



In 1906, Congress passed the first law regulating food products and medicines, the federal Pure Food and Drugs

Act1 , also known as the Wiley Act. Although this first attempt at ensuring the safety of food and drugs lacked

the power and sophistication of the modern Food Drug & Cosmetic Act, “at the time . . . it was a dramatic step

forward in consumer protection and hailed as a social landmark.”2 While the 1906 Act suffered from serious

weaknesses, no one sought to thoroughly revise the Act and ameliorate its flaws until 1938.3



In that year, as a result of efforts by Senator Royal Copeland and of the elixir sulfanilamide incident4 , a drug

disaster that caused about 100 deaths, mostly of children, Congress enacted the Food Drug & Cosmetic Act of

19385 , which expanded considerably the Food and Drug Administration’s (FDA) enforcement power and also gave

the FDA authority to regulate cosmetics and devices.6 Under the 1938 Act, “drugs were required to undergo prior

screening by the FDA—a form of negative option power to reject proffered applications.”7 The supporters of the

new legislation were motivated by paternalism and felt that these additional powers would enable the government,

through the FDA, to protect Americans from dangerous foods and medicines from which they could not protect
   1 Act  of June 30, 1906, ch. 3915, 34 Stat. 768.
   21  James T. O’Reilly, Food and Drug Administration § 3.02 (2d ed. 2001).
   3 Id. at § 3.04.
   4 A “Report of the Secretary of Agriculture on Deaths Due to Elixir Sulfanilamide-Massengill” concluded that:

  The fatal “elixir” was rushed onto the market without adequate test to determine whether or not diethylene glycol may be safely
used as a solvent for sulfanilamide, despite previously published reports in scientific literature showing that diethylene glycol might be
dangerous when taken internally. A few simple and inexpensive tests on experimental animals would have quickly demonstrated the
toxic properties of . . . the “elixir.”
  The entire report can be found in Charles Wesley Dunn, Federal Food, Drug, and Cosmetic Act, 1316 et seq. (App. F) (1938).
   5 Act of June 25, 1938, ch. 675, 52 Stat. 1040.
   6 1 O’Reilly, supra note 2, at § 3.04.
   7 Id.




                                                                   4
themselves. As Justice Frankfurter recognized, “The purposes of this legislation thus touch phases of the lives

and health of people which, in the circumstances of modern industrialism, are largely beyond self-protection.”8




In 1962, new amendments, known as the Kefauver-Harris Amendments, enhanced the drug approval authority of

the FDA.9 Under the 1938 Act, the FDA “could act against drugs, but if it failed to act in a timely manner,” a

drug would make it onto the market without proof of its safety; in addition, the Act did not require proof that

a drug was effective, so the Act constrained the FDA into approving “drugs not shown to be unsafe even if they

were not effective for their intended use.”10 The efforts of Senator Estes Kefauver and another drug tragedy, the

thalidomide disaster,11 sparked awareness of the need for the revision, and the new amendments gave the FDA

drug review staff more time to consider new drug applications and required more thorough safety and efficacy

testing, in order to ensure that not only were drugs safe, but also effective in achieving their stated goal.12




B. The Process of Acquiring FDA Approval of a Drug.




“New drugs after 1962, including new uses for old drugs, must be approved through the new drug application

(NDA) process as safe and effective under conditions stated in their labeling.”13 Acquiring such approval requires
   8 United  States v. Dotterweich, 320 U.S. 277, 280 (1943).
   9 Act  of Oct. 10, 1962, Pub. L. No. 87-781, 76 Stat. 780.
  10 1 O’Reilly, supra note 2, at § 3.07.
  11 “The Merrell Co. had filed a New Drug Application for the drug with the FDA, and it had distributed over 2.5 million tablets. . . for

investigational use by physicians in the United States, who dispensed thalidomide to 20,771 patients.” Reports from Germany
concerning the drug’s horrible teratogenic effects were received before the NDA was approved. Comment, The Food and Drug
Administration: Law, Science and Politics in the Evaluation and Control of New Drug Technology, 67 Nw. U. L. Rev. 858, 867-68
n. 41 (1972). Thalidomide is discussed further in Part III.A of the paper.
  12 1 O’Reilly, supra note 2, at § 3.07.
  13 Id. at § 13.04; see also 21 U.S.C. § 355 (2001).




                                                                   5
an expensive and time-consuming process. First, the manufacturer of the potential new drug conducts laboratory

and animal testing, a step which can take up to three and a half years.14 After this pre-clinical testing, the

manufacturer files an Investigational New Drug (IND) application with the FDA, a necessary step before the

proposed drug can be tested in humans.15



During the IND process, the drug undergoes three phases of clinical testing in humans.16 If the tests on human

subjects demonstrate both the safety and effectiveness of the new drug, the manufacturer then submits a New

Drug Application (NDA), along with the clinical results, to the FDA for review.17 Once FDA approves the

application, the manufacturer is free to market and promote the drug for the uses for which FDA approved it,

and the manufacturer includes with the drug a package insert describing the indication and dosages for which the

FDA approved the drug.18 The FDA, of course, can later recall the drug if studies show it to be harmful.19




The following diagram20 is a graphic illustration of the time-consuming process of obtaining FDA approval for a

drug:


[REDACTED]




C. Off-Label Use Distinguished From Investigational Use.
 14 Veronica   Henry, Off-Label Prescribing Legal Implications, 20 J. Legal Med. 365, 367 (1999).
 15 Id.
  16 James M. Beck & Elizabeth D. Azari, FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions, 53

Food & Drug L.J. 71, 75 (1989).
  17 Id.
  18 Henry, supra note 14, at 365.
  19 Beck & Azari, supra note 16, at 75.
  20 Jeffrey L. Blumer, Off-Label Uses of Drugs in Children, 104 Pediatrics 598, 600 (Sept. 1999).




                                                                 6
Off-label use of a prescription drug entails use of a drug for a purpose or in a dosage that has not been approved

by the FDA. “Off-label prescribing occurs when a practitioner prescribes a drug for a use, or in a manner, not

authorized by the [FDA].”21 Such use should not be confused with experimental or investigational use. The main

distinction between off-label and experimental use becomes apparent when one considers the differing goals of

the two uses. Off-label use constitutes part of the “practice of medicine,” which strives to help individual patients

get better, and off-label uses are often widely accepted and used by the medical community.22 The American

Medical Association (AMA) estimates that about 40-60% of all prescriptions are off-label.23 Because off-label

uses are often so widespread, they are obviously not investigational, and in many instances, physicians would likely

be liable for malpractice if they did not prescribe an off-label use.24 For example, the best treatment for Lyme

disease entails use of either amoxicillin or doxycyline, two antibiotics that have not been approved for this use,

but “the drugs have become such standards of care that a doctor might be considered negligent for not using

them.”25



Experimental use, in contrast, aims to gain scientific knowledge and information, not necessarily to help an

individual patient.26


              Research is research, designed to test a hypothesis and performed based on the rules of the protocol;
              treatment is something else, designed to benefit a patient, and subject to change whenever change is
              seen in the patient’s best interest. Confusing research with treatment confuses both the researcher and
              subject and permits self-interested self-deception by both of them.27
 21 Henry,   supra note 14, at 365.
 22 Beck   & Azari, supra note 16, at 82.
  23 Emile L. Loza, Access to Pharmaceuticals Under Medicaid Managed Care: Federal Law Compiled and State Contracts Compared,

55 Food & Drug L.J. 449, 468 (2000).
  24 John      Berlau,      Overturn      FDA’s   “Off-Label     Use”     Policy     (visited  Sept.             15,    2001)
<http://www.consumeralert.org/issues/health/oflabbr.htm>.
  25 Christine Gorman, Double-Duty Drugs, Time (Sept. 18, 1995).
  26 Beck & Azari, supra note 16, at 81.




                                                             7
Because physicians prescribe off-label uses of approved drugs for the benefit of the patient and not to use the

patient as a “guinea pig” to further scientific knowledge, some commentators would oppose requiring physicians

to obtain informed consent before giving a patient an off-label prescription, as would be necessary in the event

that a physician desired to administer to a patient a drug undergoing experimental research.28

The FDA itself recognizes the distinction between off-label and experimental use and sanctions off-label prescribing

in its regulations. For example, the IND requirements that apply to drugs undergoing clinical studies do not apply

to off-label use of approved drugs.29



              D. The Legal Basis for Off-Label Drug Use.

              1. Notice of Proposed Rule Making—1972.


In 1972, a decade after the Kefauver-Harris Amendments of 1962, the FDA issued a Notice of Proposed Rule

Making to clarify its position on physician prescribing of approved drugs for unapproved uses.30 The agency was

prompted by “the widespread use of certain prescription drugs for conditions not named in the official labeling,”

which raised questions not only about the legal implications for medical practitioners prescribing such unapproved

uses but also about the agency’s policy concerning this practice.31 In the Notice, the FDA stated its opinion

that the federal Food, Drug, and Cosmetic Act, which prohibits a drug being delivered via interstate commerce

without filing an IND application or receiving approval through the NDA process, is not violated when a physician

prescribes a drug for an unapproved use:
  28 Beck  & Azari, supra note 16.
  29 21  C.F.R. § 312.2(d) (“Unlabeled indication. This part does not apply to the use in the practice of medicine for an unlabeled
indication of a new drug product approved under Part 314 or of a licensed biological product.”).
  30 Legal Status of Approved Labeling for Prescription Drugs; Prescribing for Uses Unapproved by the Food and Drug Administration:

Notice of Proposed Rule Making, 37 Fed. Reg. 16503 (1972) (to be codified at 21 C.F.R. pt. 130) (proposed Aug. 15, 1972).
  31 Id.




                                                                8
                If an approved new drug is shipped in interstate commerce with the approved package insert, and neither
                the shipper nor the recipient intends that it be used for an unapproved purpose, the requirements of
                section 505 of the Act are satisfied. Once the new drug is in a local pharmacy after interstate shipment,
                the physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patient,
                or may otherwise vary the conditions of use from those approved in the package insert, without informing
                or obtaining the approval of the Food and Drug Administration.32

The FDA clearly did not intend to interfere with the “practice of medicine” and envisioned a separate role for the

physician in the area of prescription drugs—the FDA’s purpose was to ensure that drug manufacturers conducted

the necessary research to prove that a drug was both safe and effective and properly labeled, but the physician

had the authority to make the determination of what drugs to prescribe and in what manner based not only on the

drug’s label but also on “other adequate scientific data available to him.”33 While the label contains important

information regarding a drug’s properties, physicians are not bound by it:


                Although labeling . . . may constitute evidence of the proper practice of medicine, it is not controlling on
                this issue. The labeling is not intended either to preclude the physician from using his best judgment in
                the interest of the patient, or to impose liability if he does not follow the package insert.34


The FDA did caution, however, that while physicians were not bound to file INDs before prescribing unapproved

uses, such uses could sometimes be investigational, and that in such cases, physicians should file INDs and/or

submit information about the benefits and side effects of such uses to the FDA.35 In the Notice, the agency also

exhorted physicians to “take account of the scientific principles, including the moral and ethical considerations,

applicable to the safe use of investigational drugs in human patients.”36

The Notice also stated that the FDA would not hesitate to take necessary steps to curtail detrimental uses of

approved drugs, such as requiring warnings to be placed on the labels, limiting the distribution of a drug, and

even withdrawing the drug’s approval.37 Also, the agency warned manufacturers and distributors of drugs that

communicating to either physicians or patients that an approved drug can be used for a purpose not included on
 33 Id.   at 16504.
 35 Id.
 36 Id.
 37 Id.




                                                             9
the labeling would be a violation of the Food, Drug, and Cosmetic Act.38

Part of the proposed new rule would have explicitly sanctioned off-label prescribing as part of the practice of

medicine:


                Once a prescription new drug has been shipped in interstate commerce intended for its approved use(s)
                under approved labeling, the Federal Food, Drug, and Cosmetic Act does not require a physician to file
                with the Food and Drug Administration an investigational new drug plan in order to lawfully prescribe
                the drug for an unapproved use, when such prescribing is done as part of the practice of medicine.39

This proposed rule was never codified, and no further steps have been taken by the FDA in connection with

the proposed rule.40 The FDA, however, has continuously adhered to the policy expressed in its 1972 Notice of

Proposed Rule Making and has frequently reiterated its position to allow off-label drug use and not interfere with

physicians’ practice of medicine.41




2.

                                                       Subsequent Statements.



The FDA has subsequently reiterated the position espoused in the 1972 Notice of Proposed Rule Making in

various instances. For example, a decade after the proposed rule, there remained confusion among medical

practitioners over the appropriateness of prescribing uses for drugs that were not included in the FDA-approved

label, and in response, to clarify its position on the matter to physicians and other concerned parties, the FDA

published a statement entitled “Use of Approved Drugs for Unlabeled Indications” in the FDA Drug Bulletin,

again emphasizing physicians’ freedom in prescribing off-label uses42 :
 38 Id.
 40 Peter   Barton Hutt & Richard A. Merrill, Food and Drug Law 621 (2d ed. 1991).
 41 Id.
 42 Use   of Approved Drugs for Unlabeled Indications, 12 FDA Drug Bull. 4-5 (April 1982).




                                                                10
             The Food, Drug and Cosmetic Act does not limit the manner in which a physician may use an approved
             drug. Once a product has been approved for marketing, a physician may prescribe it for uses or in
             treatment regimens or patient populations that are not included in approved labeling. Such “unapproved”
             or, more precisely, “unlabeled” uses may be appropriate and rational in certain circumstances, and may,
             in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.43

In 1996, the congressional Committee on Government Reform and Oversight held a hearing to discuss the implica-

tions of off-label drug use and the process by which the FDA reviews SNDAs.44 The Chairman of the committee,

Representative Shays, stated in his introduction that off-label drug use is “a perfectly legal and necessary part

of the healing arts.”45 Later in the hearing, Michael Friedman, Deputy Commissioner for Operations of the

FDA, delivered a statement in which he also spoke about the FDA’s policy to not interfere with the practice of

medicine: “A licensed physician can prescribe a drug for other uses . . . in keeping with appropriate standards of

medical practice.”46

William Schultz, Deputy Commissioner for Policy at the FDA, also maintained the legality of off-label drug pre-

scription in a statement at another congressional hearing.47 The FDA, Schultz stated, recognizes that off-label

uses of approved drugs serve an important function and “in certain circumstances . . . are appropriate, rational,

and accepted medical practice.”48 He also described the FDA’s limited authority over off-label uses:


             The legislative history of the Federal Food, Drug, and Cosmetic Act indicates that Congress did not
             intend FDA to interfere with the practice of medicine. Thus, once a drug is approved for marketing,
             FDA does not generally regulate how, and for what uses, physicians prescribe that drug. A physician
             may prescribe a drug for uses or in treatment regimens or patient populations that are not listed in the
             FDA-approved labeling. . . the FDC Act does not authorize FDA to regulate the practice of medicine.49

Thus, while no formal rule has been enacted prohibiting the FDA from interfering with physicians’ prescribing

practices, the FDA acknowledges that Congress, in enacting the FDC Act, wanted to strike a balance between
  44 Off-Label Drug Use and FDA Review of Supplemental Drug Applications: Hearing Before the Subcomm. on Human Resources

and Intergovernmental Relations of the House Comm. on Gov’t Reform and Oversight, 104th Cong. (1996) [hereinafter Off-Label
Drug Use Hearing].
  45 Id. at 1.
  46 Id. at 54 (statement of Michael Friedman, Deputy Commissioner for Operations at the FDA).
  47 More Information for Better Patient Care: Hearing Before the Senate Comm. on Labor and Human Resources, 104th Cong.

(1996) (statement of William B. Schultz, Deputy Commissioner for Policy at the FDA).
  48 Id. at 81.




                                                           11
the FDA’s authority to protect the public and physicians’ power to practice medicine. These statements made at

congressional hearings indicate an understanding that Congress never intended the FDA’s authority to regulate

prescription drugs to be absolute and specifically did not intend to allow the FDA to interfere with the practice

of medicine.



II. The Debate Over Off-Label Drug Use.


              A. Arguments Supporting Off-Label Drug Use.




1. The Prohibitive Costs of Obtaining FDA Approval.




If physicians and scientists later discover that a drug approved for one purpose also serves another purpose, the

manufacturer may seek FDA approval of the new use in order to include it in the drug’s labeling by submitting a

Supplemental New Drug Application.50 When considering a supplemental NDA, the FDA can require the same

level of proof of safety and efficacy as it requires for an original NDA.51



Because the process of gaining approval for a new use can be as expensive and time-consuming as gaining initial

approval for a drug, manufacturers often do not have the proper incentives to seek FDA approval for new uses.
  50 Henry,  supra note 14, at 368.
  51 See  American Cyanamid Co. v. Young, 770 F.2d 1213, 1214 (D.C. Cir. 1985) (involving an attempt to market over the counter
(OTC) a flea-control product for dogs):
  As we read the governing statute, the FDA may fully evaluate the safety and effectiveness of a product not only before approving
an initial new animal drug application (NADA), but also before approving a supplemental NADA when the proposed change (such as
prescription-only to OTC status) has a bearing on the product’s safety or effectiveness.
  See also In re Warner-Lambert/Parke-Davis & Co.; Benyline; Final Decision, 44 Fed. Reg. 51512 (1979) (rejecting SDNA seeking
OTC status for human drug after full review of safety and effectiveness data).




                                                               12
For example, G.D. Searle & Co., the manufacturer of Cytotec (misoprostol), a drug approved to treat and prevent

gastric ulcers, indicated in 2000 that it did not intend to seek FDA approval of the drug as a means to induce

labor, even though physicians frequently used it for that purpose.52 As one commentator pointed out, “Indeed,

why should [Searle seek such approval]? At 13 cents a dose, with women taking no more than three doses per

birth, the drug is too cost-effective to waste a heap of money on research . . . ”.53 In addition, if the patent on the

drug has already or is close to expiring, a manufacturer would be less able to recoup the investment of seeking

FDA approval.54

Because pharmaceutical companies often do not have sufficient financial incentives to seek FDA approval of new

uses for existing drugs, a great number of patients would be denied therapeutic drugs if off-label use were illegal.

As New Jersey has recognized,


          “Off-label” use of FDA-approved drugs provides efficacious drugs at a lower cost. To require that all
          appropriate uses of a drug undergo approval by the FDA may substantially increase the cost of drugs
          and delay or even deny patients’ ability to obtain medically effective treatment. FDA approval for each
          use would require substantial expenditure and time to undergo the clinical trials necessary to obtain FDA
          approval. 55




2. Length of Time to Acquire Supplementary Approval.




   52 Ina May Gaskin, Cytotec:       Dangerous Experiment or Panacea?             (July 11, 2000) (visited Sept.         15, 2001)
<http://www.salon.com/health/feature/2000/07/11/cytotec/print.html>. In a letter dated August 23, 2000 to physicians around
the country, the manufacturer stated, “Searle has not conducted research concerning the use of Cytotec for cervical ripening prior to
termination of pregnancy or for induction of labor, nor does Searle intend to study . . . these uses.” Ralph W. Hale, M.D. & Stanley
Zinberg, M.D., Editorial, Use of Misoprostol in Pregnancy, 344 New Eng. J. Med. 59 (2001). Cytotec is discussed further in Part
III.C.
   53 Gaskin, supra note 52.
   54 Henry, supra note 14, at 369.




                                                                 13
The existence of off-label prescribing can be attributed in large part to the long-standing tradition that frowns

upon FDA interference with the “practice of medicine.” Part of this tradition stems from the fact that medical

discovery invariably outpaces FDA regulation. New drugs tend to reach consumers in other sophisticated and

developed countries significantly sooner than they reach consumers in the United States, a phenomenon known

as “drug lag.”56

This delay in approval plagues not only new drugs but also new uses for already existing drugs. Because “the

regulatory process simply is not able to keep pace with innovation,” physicians frequently realize the benefits of

new uses and dosages long before they become included in a drug’s labeling.57 For example, one study claims

that “journal articles substantiating new uses for old drugs appeared in print years before FDA approval,” and

that “[o]n average the new uses were recognized in the U.S. Pharmacopoeia Drug Information (USP DI), an

authoritative compendium of prescription drug information, a full two and half years before FDA approval.”58

Ordinarily, one would expect that the time to review a supplemental NDA would be shorter than the time required

to approve the initial NDA for the drug, since studies concerning the drug’s properties, toxicity, etc. have already

                                                                                         59
been done and the chemical nature of the drug has already been researched.                    Studies undertaken by the Tufts

Center for the Study of Drug Development hypothesized that “supplemental indications would, on average, be

approved more quickly than the original uses,” but none of the studies supported this proposition.60 In fact,

an analysis of the review times from 1989 through 1994 revealed that “supplemental indication approval times

averaged 28.3 months, which was 3.7 months longer than the average for the original indications.”61
  56 John Patrick Dillman, Prescription Drug Approval and Terminal Diseases: Desperate Times Require Desperate Measures, 44
Vand. L. Rev. 925, 936 (1991).
  57 Henry, supra note 14, at 371. “Off-label uses of drugs and medical devices is very common since the FDA delays in processing

supplemental NDAs . . . make it impossible for the manufacturer to keep up with actual physician use patterns and learnings about
the drug or device.” 1 O’Reilly, supra note 2, at § 13.16.
  58 Alexander T. Tabarrok, Assessing the FDA Via the Anomaly of Off-Label Drug Prescribing, Independent Review 7 (Summer

2000).
  59 Off-Label Drug Use Hearing, supra note 44, at 21 (testimony of Joseph A. DiMasi, Ph.D., Director of Economic Analysis of Tufts

Center for the Study of Drug Development).
  60 Id.
  61 Id.




                                                               14
Figure 162 : A comparison of five-year periods illustrates that the length of time to approve both original and

supplemental indications increased steadily from 1969 through 1994, and that the length of time to approve

supplemental indications surpassed the time to approve original indications beginning in the 1984-1988 period.



[REDACTED]



Figure 263 : A closer look at the review times for each individual year, however, demonstrates that some progress

was made in 1993 and 1994; in those years, review times were down for both original and supplemental indications,

and supplemental indications were reviewed quicker than the original indications. The difference in review time,

however, is not greatly significant; in 1993 supplemental indications were reviewed only 2.8 months sooner and

still took 22.2 months to review, and in 1994 supplemental indications took 16.2 months to review (3.6 months

less than for original indications).



[REDACTED]



Figure 364 : New indications for existing drugs not only “offer significant advances in patient care,” but sometimes

“the follow-on indication is even more important than the original use.”65 The study thus also analyzed review

times for new indications that represented important advances in health care and were acknowledged as such by

the FDA. And although important new indications were generally reviewed and approved faster than other new

indications that were not considered significant, the approval time for significant new uses still took about 10

months longer than the times for original uses.66
 62 Id. at   32.
 63 Id. at   33.
 64 Id. at   34.
 65 Id. at   21.
 66 Id.




                                                       15
[REDACTED]




Thus, while improvements have been made in FDA approval times, more effort is needed to expedite the approval

process for supplemental uses.67 The FDA has recognized the need to encourage manufacturers to submit

supplemental NDAs so that a drug’s label reflects the latest in clinical knowledge: “The FDA is undertaking

initiatives to encourage and expedite still further efficacy supplements for these unapproved uses. . . Our goal is to

have the product’s label more completely and more accurately reflect clinical usage that is safe and effective.”68




 3. Special Needs of Certain Patient Groups.




a) Patients Suffering from AIDS and Cancer.

The delay in acquiring FDA approval for new uses of approved drugs mostly harms patients suffering from fatal

diseases with no effective cure or treatment. When such patients organize politically, they exert significant pressure

on the FDA to expedite drug approval and on physicians to prescribe off-label uses of existing drugs. The saga of

the political battle over AIDS drugs provides an example. AIDS patients were, and still are, in a different position

than most other patients for various reasons.
  67 Id. at 27. Part of the reason the FDA takes so long to approve supplemental indications, according to DiMasi, is because

approving new uses is not a priority for the FDA since the drug is already available on the marketplace and physicians have the ability
to prescribe it for any off-label uses for which it is beneficial. This would not be a problem, he continues, if physicians had complete
information regarding off-label uses. Since manufacturers are restricted in their ability to communicate information regarding off-label
uses, however, there is likely “some underuse or misuse of drugs.” Id.
  68 Off-Label Drug Use Hearing, supra note 44, at 55 (statement of Michael Friedman).




                                                                  16
          First, unlike virtually all of the diseases whose sufferers had been previously harmed by FDA drug-approval
          policies, AIDS was fatal. Second, because the disease was new, no existing drugs were available to treat
          it. Third, and most important, those who suffered from delays in the FDA’s approval of drugs to treat
          AIDS were vocal and politically powerful.69

Oncology patients also rely heavily on off-label uses; some experts claim that more than half of the drugs used to

treat oncology patients is off-label,70 and some even place the percentage of off-label use of oncology drugs as

high as 95%.71 Off-label use is particularly widespread in the field of oncology because it is a field in which the

problem of the speed of medical discovery surpassing the slower process of FDA approval is particularly acute.72

In a letter to the FDA, the American Society of Clinical Oncology wrote, “The labeling of anticancer products

frequently presents an incomplete or even inaccurate picture of the current state of medical knowledge. For

virtually every cancer drug, appropriate medical usage differs from the terms of the product labeling.”73




 b) Pediatric Patients.




i) In the United States.




For a drug to obtain FDA approval, the drug manufacturer must prove its safety and efficacy.74 However, proof

of safety and efficacy in one patient population cannot be carried over to a different population; just because a
  70 W.   Wayt Gibbs, What Are Obstacles to Ideal Care?, Scientific American (visited Feb.                           23, 2002)
<http://www.sciam.com/0996issue/0996gibbs.html>.
  71 Endpoints of Clinical Trials Discussed at Special Session, Asco Daily News (May 14, 2001) (visited Feb.          23, 2002)
<http://www.asco.org/prof/adn/2001/mon/endpts.html>.
  72 Daniel E. Troy, The FDA and Off-Label Uses of Drugs and Devices, Commercial Speech Digest (Fall 1997) (visited Feb. 23,

2002) <http://www.mediainstitute.org/digest/97fall/wlf.html>.
  73 Tabarrok, supra note 58, at 7 (citing Letter from John R. Durant, M.D., executive vice president of the American Society of

Clinical Oncology, to Michael A. Friedman, acting Commissioner of Food and Drugs, July 21, 1998).
  74 See supra note 13 and accompanying text.




                                                              17
drug is safe and efficacious for use in adults does not mean it is safe and efficacious for use in children.75 Thus,

in order for a drug to be FDA-approved for use in children and neonates, it must be tested and proved safe and

efficacious for those populations. Most drug companies, however, do not engage in clinical trials with patients

from those populations, and the main reasons for this are “perceived concerns over ethical issues, fears of harming

children, and perceived increased liability in testing drugs in children.”76 In addition, because children constitute

only a small percentage of the general patient population, drug companies lack the incentives to spend the time

and money to obtain FDA-approval for pediatric uses of their drugs.77 The FDA could require pharmaceutical

companies to conduct controlled studies in the pediatric population, but it is reluctant to do so except when the

drug will be prescribed primarily for pediatric patients78 , and there are not too many drugs that fit this category.

As a result, most drugs approved by the FDA are not approved for use in children or are restricted to use in older

children; in fact, “only five of the 80 most frequently used drugs have been approved for use in [children].”79

Some experts estimate that about 85% of all drugs physicians administer to pediatric patients are off-label.80 If

it were not for the option of off-label use of approved drugs, the absence of FDA-approved labeling for pediatric

use of many beneficial medicines would severely hamper physicians in their efforts to administer therapeutic drugs

to the younger patient population. “Without pediatric labeling, the rational selection and dosing of most drugs

have to be made by the clinician based on clinical studies published in the medical literature and on extrapolation

of adult labeling information.”81
  75 Michael  L. Christensen et al., Is Pediatric Labeling Really Necessary?, 104 Pediatrics 593 (Sept. 1999).
  76 Id. at 594.
  77 Id. See also Off-Label Drug Use Hearing, supra note 44 (testimony by the American Academy of Pediatrics.

   With the exception of antibiotics, medications for fever, vaccines, and a few other therapeutic categories, pediatric use represents
a relatively small segment of the total market for a drug. Companies frequently are reluctant to expend the additional time and
resources to do pediatric studies with little promise of additional market potential. . . [O]nce a drug is marketed for an adult indication,
the economic incentive to do additional studies to include pediatric labeling is markedly reduced because the drug may be prescribed
off label. In the case of drugs which are off patent, there is absolutely no economic incentive to invest in studies to expand labeling
because a single sponsor can no longer benefit form such an investment due to the lack of exclusivity protection of the drug.
  78 Off-Label Drug Use Hearing, supra note 44 (testimony by the American Academy of Pediatrics).
  79 Christensen et al., supra note 75, at 593.
  80 National Center for Policy Analysis, Speak No Good: The Tragedy of FDA Gag Rules, Brief Analysis No. 214 (Sept. 27, 1996)

<http://www.ncpa.org/ba/ba214.html>.
  81 Christensen et al., supra note 75, at 595-96.




                                                                    18
Extrapolation of information from adults to children is an inexact science, but without specific approval for

pediatric uses for most major drugs, such extrapolation and off-label use is often the only way that physicians can

effectively treat children. For example, in effectively managing seizure disorders in pediatric patients (0.5%-1%

of children suffer from epilepsy82 ) physicians often have to resort to off-label drug usage: “[M]uch of the current

[antiepileptic drug] use in children is off-label and based on safety and efficacy data derived from adult trials,

along with smaller, uncontrolled studies in children.”83

The following chart84 illustrates several common drugs administered to children. For these drugs, “there are

articles published in well known medical journals that describe the use of these drugs in children despite there

being no adequate tests of the drugs’ safety and effectiveness for children.85




  82 John M. Pellock, M.D., Managing Pediatric Epilepsy Syndromes With New Antiepileptic Drugs, 104 Pediatrics 1106 (November

1999).
  83 Id. at 1107. The article argues that a greater amount of “published data from controlled clinical trials in children to enable

specific labeling for use in the various syndromes of pediatric epilepsy” of the new AED (antiepileptic drugs) is desperately needed.
Id.
  84 Public Citizen, Doublespeak: Clinton Administration Announces New Testing Requirements on Medicine for Children but Supports

Legislation Allowing “Off-Label” Drug Promotion, <http://www.citizen.org/publications/release.cfm?ID=6619> (Aug. 13, 1997).
  85 Id.




                                                                19
DRUGS AND NUMBERS OF PRESCRIPTIONS IN WHICH NO INFORMATION WAS AVAILABLE IN THE
PROFESSIONAL PRODUCT INFORMATION FOR THE AGE GROUP BEING TREATED. DATA FROM 1994.1



              DRUG                  BRAND NAME                   TOTAL PRE-         AGE GROUP
              (PURPOSE)                                          SCRIPTIONS         TREATED
              albuterol             Proventil                    1,626,000          under
              (asthma)              or                                              12
                                    Ven-
                                    tolin
                                    In-
                                    hala-
                                    tion
                                    So-
                                    lu-
                                    tion
              cromolyn sodium       Intal Nebulizer Solution     109,000            under 2
              (asthma)
              cromolyn              Intal                        399,000            under
              sodium                In-                                             5
                                    hala-
                                    tion
                                    Aerosol
              fluoxetine             Prozac                       349,000            under 16
              (anti-depression)
              fluoxetine             Prozac                       3,000              under
                                                                                    1
              paroxetine (nausea    Paxil                        248,000            under 16
              and vomiting)
              promethazine          Phenergan Syrup              663,000            under 2
                                                      TOTAL      3,397,000


1
    Data from IMS America, Ltd.




ii) In Europe.

The widespread use of off-label prescribing for pediatric patients is not confined to the United States alone. A

study undertaken to determine the extent of unlicensed and off-label drug use in pediatric patients in the hospitals


                                                        20
of five European Union nations found that such use is also common in Europe.86


that is, at a different dose or frequency, in different clinical indications, in different age groups, administration by
an alternative route, or in a formulation not approved for use in children. Id. at 79-80. The results of the study,
which involved 624 pediatric patients who received 2,262 drug prescriptions during their hospital stays, indicated
that nearly half of the drug prescriptions (46%) were either unlicensed or off-label, and over two-thirds of the
pediatric patients (67%) were prescribed a drug in an unlicensed or off-label manner.87
Interestingly, the highest level of unlicensed drug use occurred in the hospital in Rotterdam, which was also the
hospital that had the largest number of pediatric patients suffering from “complex diseases.”88 The children at
the Rotterdam hospital were being treated with drugs that were not in a form that could be administered to
children, and had to be altered by the pharmacists, resulting in the use being unlicensed.89 The article also noted
that while off-label drug use is not inappropriate, the risks are often not well-documented because of a lack of
adequate research and information.90 The authors encouraged greater use of clinical trials in pediatric patients
to determine the best dosages for children at various ages and stages of development.91

       c) Pregnant Women.
Similar to the situation with children, pregnant women and women who are breast-feeding are frequently left
out of controlled studies for new drugs.92 According to one estimate, approximately 23% of drugs prescribed for
pregnant women are used off-label.93 The main reason is that physicians frequently use drugs off-label to prevent
premature labor and delivery, and the drugs approved for this purpose are not as effective as off-label uses of
drugs approved for other indications.94
The following diagram95 illustrates the amount of off-label versus approved drug use for certain medical specialties:


[REDACTED]


                     4. Superior Judgment of Physicians.

   86 Sharon Conroy et al., Survey of Unlicensed and Off Label Drug Use in Paediatric Wards in European Countries, 320 British Med.

J. 79 (Jan. 8, 2000). The study draws a distinction between “unlicensed” and “off label” use:
   Categories of unlicensed use were modification of licensed drugs (such as crushing tablets to prepare a suspension); drugs that are
licensed but the formulation is manufactured under a special licence (such as a liquid preparation of a drug that is licensed only in
tablet form); new drugs available under a special manufacturing licence (such as caffeine injections for apnoea of prematurity); use of
chemicals as drugs when no pharmaceutical grade preparation is available; drugs used before a licence has been granted; and imported
drugs (drugs imported from a country where they are licensed). Off label use included use of a drug in situations not covered by the
product licence or the summary of product characteristics
   87 Id. at 80.
   88 Id.
   89 Id. at 80-81.
   90 Id. at 81.
   91 Id.
   92 Off-Label Drug Use Hearing, supra note 44 (testimony by the American Academy of Pediatrics).
   93 National Center for Policy Analysis, supra note 80.
   94 Id.
   95 Id.




                                                                 21
Physicians are also more aware of their individual patients’ circumstances and needs, and may be in a better

position than the FDA to know what is best for them. States have long recognized the value of allowing physicians

flexibility to prescribe drugs in different dosages and for different purposes, not necessarily in accordance with the

labeled dosages and uses.

For example, the Massachusetts Supreme Judicial Court acknowledged this in a medical malpractice case.96 A

physician had prescribed a drug to a child and failed to monitor her blood, as suggested by the Physicians’ Desk

Reference, and, at the trial, the plaintiff’s attorney questioned the physician, “And that was a violation of what

the ‘PDR’ calls for, was it not, Doctor?”97 On appeal, the Massachusetts Supreme Judicial Court held that “the

question to Dr. Retik using the word ‘violated’ was improperly tendentious for the reason indicated by the judge:

it could be understood to imply that a physician who did not follow the PDR was by that token irretrievably guilty

of a breach of professional standards.”98


B. Arguments Against Off-Label Drug Use.


                   1. New Uses for Existing Drugs Should be Treated as New Drugs.



The FDA requires that a new drug be proven safe and efficacious. Once a drug is approved, however, a physician

can use the drug for an unapproved use. One argument against off-label use is that this discrepancy in the FDA’s

authority over new drugs and over new uses of existing drugs is not warranted; just as a manufacturer must prove

a drug’s safety and efficacy before acquiring FDA approval, new uses for old drugs should also be proven safe and

efficacious before they can be prescribed.99
 96 Grassis v. Retik, 521 N.E.2d 411, 414 (Mass. 1988).
 97 Id. at 413-14.
 98 Id. at 414.
 99 William L. Christopher, Off-Label Drug Prescription: Filling the Regulatory Vacuum, 48 Food & Drug L.J. 247, 261 (1993).




                                                             22
As one commentator has countered, “This logic runs up against medical reality.”100 The FDA simply cannot

keep up with medical innovation, and “could not review drugs in its lengthy testing process at a pace equal to

that at which physicians discover beneficial off-label uses.”101 For one thing, advocates of physicians’ power to

prescribe off-label uses can point to the fact that, since an existing drug has already undergone clinical trials and

been approved for at least one use, “it has passed at least the minimum level of safety and efficacy testing.”102

So using a drug off-label is not comparable to using a completely unapproved drug, which is far riskier. Also,

the benefits, in terms of proving that an existing drug is safe and efficacious for a new use, are probably greatly

outweighed by the costs imposed in obtaining such expanded approval from the FDA, which would entail great

delay in making the new use available to patients.103


                        2. Physicians’ Misplaced Reliance on Medical Articles.




Because physicians prescribing drugs for off-label uses are usually relying on studies published in medical and sci-

entific journals, one argument against off-label drug prescribing attacks the practice by attacking the informational

sources on which it is based. One critic claims that physicians are not adequately prepared to critically evaluate the

results published in medical journals.104 The ability to critically evaluate results which most physicians allegedly

lack is an indispensable tool to the physician prescribing drugs for off-label uses because


            [t]he reporting of clinical research in the medical literature is fraught with many deficiencies, which
            have been the topic of numerous reports. Common criticisms include poor study design, incomplete
            documentation, questionable data collection methods, inappropriate statistical analyses, and indefensible
            conclusions.105
The flawed studies are published, according to this argument, because journal editors lack the sufficient time,
100 Id.   at 261.
101 Id.
102 Id.
103 Id.
104 Christensen     et al., supra note 75, at 596.



                                                            23
knowledge and expertise to recognize the flaws in the studies and do not have all the data on hand with which to

review the results of the studies; and physicians’ subsequent reliance on such studies to prescribe off-label uses

can result in ineffective treatments or harmful results.106

This argument is overstated. First, there is unlikely to be only one single study on a new beneficial off-label use of

an approved drug. Once such a beneficial use is discovered, other physicians and/or scientists will likely conduct

new studies, and if the original study is flawed or deceptive, it will most likely be discovered. Even if there is only

one published article documenting such an off-label use, that is not likely to be enough to convince physicians

to start prescribing the drug for such a use. Physicians, when prescribing a drug for an off-label use, do not rely

on just one study, but prescribe such uses only when they are supported by numerous well-document studies.

The chance that each of a number of studies supporting a specific off-label use are significantly flawed is remote,

which is exactly why off-label uses are prescribed only when supported by a myriad of sources.



                      3. Adverse Consequences of Off-Label Drug Use in Children.




As discussed above, most drug use in children is off-label. Because of the lack of clinical studies on children and

the difficulties of extrapolating data from the adult population to children, drugs used off-label in children can be

ineffective and can sometimes even have detrimental effects. One study criticized the two methods of extrapolating

adult doses to children, one consisting of adjusting the dose based on weight, and the second involving scaling

weight to surface area.107 The study showed that extrapolating adult doses to children frequently overestimates

the dose for neonates and underestimates the dose for infants and children and concluded that “adult-extrapolated

dosing in children may lead to either toxic effects from excessive doses or ineffective therapy from underdosing.”108
106 Id.
107 Christensen   et al., supra note 75, at 595.
108 Id.




                                                         24
The reason for the difficulty of adult-extrapolation is because extrapolating dosing information rests on the

implicit assumption that children are small adults, but they are not; the “significant physical and maturation

changes that occur” as children grow, especially differences in “drug absorption, metabolism, and excretion,”

hinder the effectiveness of extrapolation.109

Sometimes, FDA-approved drugs do cause side effects in children that they do not cause in adults. This problem

can occur when the drug has not been tested on or approved for children, yet physicians prescribe the drug for

pediatric patients. For example, last year Wyeth-Ayerst Pharmaceuticals was compelled to issue warnings to

physicians about the possible consequences of using Cordarone, a heart medication manufactured by the company

(the generic name is amiodarone) in pediatric patients.110

Despite the fact that the drug had never been approved for use in children, and that the labeling indicated this fact,

physicians frequently prescribed the drug, which is used to treat ventricular arrhythmias, to pediatric patients.111

Then the company discovered potential risks associated with the intravenous form of the drug (the drug was also

available in tablet form, but the intravenous form was easier to administer to small children, and was the only

way to administer the drug to neonates).112 First, the drug could cause a syndrome called “gasping syndrome,”

which could be fatal, in neonates, and second, the drug could react with the plastic tubes used to administer the

drug intravenously, releasing chemicals shown in animal testing to detrimentally affect the development of the

male reproductive system.113

Off-label use consisting of the prescription of FDA-approved drugs for children even if the drugs have not been

approved for use in children, however, is not to blame for the adverse consequences that sometimes occur. Rather,

the problem stems from the fact that pharmaceutical companies, whether because of ethical or financial concerns,
109 Id.  at 594.
110 Paul   Ting, Amiodarone Not For Pediatric Use: Company Warns Against Off-Label Applications (visited Sept.   15, 2001)
<http://anesthesiology.about.com/library/weekly/aa062001a.htm>.
 111 Id.
 112 Id.
 113 Id.




                                                          25
do not engage in controlled clinical trials in the pediatric and neonatal populations, and the federal government

does not require such clinical trials:


          Lack of pediatric labeling does not mean that the drugs are necessarily harmful, ineffective, or contraindi-
          cated in children but simply that the clinical trials which satisfy the FDA requirements for labeling were
          not conducted in children. 114


The testifying physician found it ironic that the government does not require clinical trials to prove a drug’s safety

and efficacy for children, considering that the main food and drug laws were passed in response to medicinal

disasters affecting young children.115



Because of a lack of pediatric labeling, physicians treating these populations are usually confronted with the choice

of treating their patients with off-label uses or not treating them at all. Physicians, of course, choose to adopt

the former approach and prescribe drugs for children even if they lack pediatric labeling.116 As a result, “off-label

use of medications has, by default, become an established standard of care for children.”117 Some, however, do

not understand that off-label drug use is often the standard of care, and instead view it as administering drugs to

children that have not been tested or approved for use in children or in dosages suitable for them.118

Today, many practitioners recognize that the problem lies not in off-label drug use in children but in the lack

of data from controlled studies in pediatric patients. Because of this, many physicians and pharmacists have

become extremely vocal in calling for more published data and clinical studies of drugs’ effects in children. As

one practitioner wrote:
115 Id.
116 Id.
117 Id.
118 Id.




                                                         26
          The answer to the question, “Is pediatric labeling really necessary?” is most assuredly YES! Pediatric
          labeling is the only way to ensure the safe and effective use of drugs in infants, children, and adolescents.
          The child is not a small adult. The failure of the pharmaceutics industry to sponsor the necessary studies,
          the FDA to enforce its regulations, and the legislature to mandate that all drugs with potential use in
          children be evaluated appropriately has allowed the child to remain a therapeutic orphan some 30 years
          after the term was coined by Dr. Harry Shirkey.119

One physician even noted that because the pediatric population as a whole is not entirely homogenous, companies

may need to conduct controlled studies in the various subgroups that exist, such as neonates, infants, young

children and adolescents, “in order to determine drug efficacy, dosing, toxicity, and appropriate formulations for

each subpopulation.”120


III. Off-Label Uses of Specific Drugs and the Results.


          A. Thalidomide.



Half a century ago, European physicians routinely prescribed a drug called Thalidomide as a sedative, but the

FDA never approved the drug for use in the United States.121 Later it was discovered that thalidomide was

teratogenic and led to the serious disfigurement of newborns when taken by expectant mothers; these babies were

often “born with seal-like flippers instead of limbs.”122 Thirty-five years later, a pharmaceutical company named

Celgene Corp. sought FDA approval to use thalidomide as a treatment for leprosy.123 One of the FDA medical

officers reviewing the drug expressed concern over the potential for off-label use of thalidomide, pointing out that

the small number of patients with leprosy would not make approval of the drug for leprosy profitable, unless the

company expected a large amount of off-label use, such as in AIDS or cancer patients.124
 120 Off-Label Drug Use Hearing, supra note 44 (testimony by the American Academy of Pediatrics). In its testimony, the Academy

also noted that another problem is that medicines are not manufactured in appropriate dosages for children:
   For example, many medications are provided in capsule or tablet forms which cannot be swallowed by small children and are not
available in small enough dosage increments to give the proper dose to children. Id.
 121 David Willman, A Long-Feared Drug Gets the Green Light, L.A. Times, Dec. 20, 2000.
 122 1 O’Reilly, supra note 2, at § 3.07.
 123 Willman, supra note 121.
 124 Id.




                                                              27
After FDA approved the drug on July 16, 1998, officials alleged that the company immediately began promoting

the drug for uses other than the treatment of leprosy, for which it was approved, and even Celgene’s CEO,

John Jackson, stated that in approving the drug, FDA realized “there was a need for this drug in the AIDS

community.”125 He later maintained that the company did not promote any off-label uses of thalidomide and

that the company desired to follow all FDA rules and regulations.126

The initial evidence about thalidomide’s benefits in treating AIDS patients conflicted.127 Upon FDA approval,

the use of thalidomide to treat AIDS did not gain popularity, and Jackson says physicians now use the drug

mainly to treat various cancers.128 That thalidomide never attained widespread use among the AIDS community

proves that merely allowing off-label use does not generate harmful or nonefficacious use; if a drug does not help

a particular illness, physicians will not prescribe it, despite their power to do so.




B. Fen-Phen.

One recent pharmaceutical scandal added fuel to the controversy over the propriety of off-label drug use. The

FDA had approved three drugs to be used as short-term appetite suppressants: phentermine, approved in 1959;

fenfluramine, approved in 1973; and dexfenfluramine, approved in 1996.129 Fenfluramine and dexfenfluramine,

when used alone, often led to fatigue in many patients, but when physicians realized, around 1990, that this

side effect disappeared when the drugs were combined with phentermine, they began prescribing the drugs as a
 125 Id. In addition, thalidomide apparently also has antiangiogenic properties, which means it can inhibit the development of new
blood vessels and thus could inhibit tumor formation or development. See AI Minchinton et al., The Effect of Thalidomide on
Experimental Tumors and Metastases, 7(3) Anticancer Res. 339-343 (1996); RJ D’Amato et al., Thalidomide is an Inhibitor of
Angiogenesis, 91(9) Proc. of the Nat’l Acad. of Sci. 4082-4085 (1994).
 126 Willman, supra note 121.
 127 Id. (“A study published by the New England Journal of Medicine in May 1997 found that some AIDS patients’ underlying disease

worsened on thalidomide, compared with those who took a placebo”); Bob Leibowitz, M.D., Thalidomide, the Reversal of the Benedict
Arnold Reputation, (visited Sept. 15, 2001) <http:www.prostatepointers.org/prostate/leibowitz/leib21.html> (1998)(“. . . doses of
thalidomide of 100 milligrams a day seem to reverse the cachexia/anorexia (the Wasting Away Syndrome) of end stage AIDS.”).
 128 Willman, supra note 121.
 129 Tabarrok, supra note 58.




                                                               28
combination, and the number of “fen-phen prescriptions” increased dramatically.130 In addition, physicians began

prescribing the combination for long-term weight-loss in patients who were not really obese, while the drugs had

only been approved for short-term use in truly obese patients.131 Because the FDA had only approved the drugs

to be used separately, the prescription of the fen-phen combination was off-label.

On July 8, 1997, physicians from the Mayo Clinic reported that they had discovered a link between fen-phen

and heart valve disease in women, and the FDA quickly recalled fenfluramine and dexfenfluramine.132 Critics

of off-label drug use took advantage of the situation and immediately clamored for more regulation of off-label

prescribing. However, as some commentators point out, the critics of off-label drug use misconstrued the problem.

The FDA never recalled phentermine, and no instances of heart-valve problems have arisen from use of phentermine

alone.133 Thus, it was fenfluramine and dexfenfluramine, and not the fen-phen combo, that caused the heart-valve

disease, and the problem had come to light only because the fen-phen craze led to a sharp increase in prescriptions

and usage of the dangerous drug.134 As one commentator noted, “The fen-phen episode does not speak to any

problem with off-label prescribing, but it does remind us that no drug is perfectly safe, not even FDA-approved

drugs.”135



            C. Misoprostol.



In 1988, the FDA approved the drug misoprostol, originally developed by G.D. Searle & Co., for the prevention

and treatment of gastric ulcers associated with the use of nonsteroidal anti-inflammatory drugs.136 Because of

the drug’s uterotonic effects, however, physicians began using it for several unrelated purposes, such as “elective
130 Id.
131 Beck    & Azari, supra note 16, at 71.
132 Tabarrok,  supra note 58.
133 Id.
134 Id.
135 Id.
136 Alisa   B. Goldberg, M.D. et al., Misoprostol and Pregnancy, 344 New Eng. J. Med. 38 (2001).




                                                               29
medical abortion, cervical ripening before surgical abortion, evacuation of the uterus in cases of embryonic or

fetal death, and induction of labor.”137 Use of misoprostol was soon widespread in the obstetrical/gynecological

physician community. Two physicians recognized that, for one specific use, “cervical ripening as a prelude to

induction of labor, misoprostol has been used so frequently and effectively that it has become the treatment of

choice.”138 The drug was not only not approved for such uses by the FDA, but also was contraindicated for use in

pregnant women because of its abortifacient properties, making any use of the drug in pregnant women off-label.

Despite the medical community’s acceptance and praise of misoprostol, various reports surfaced of serious adverse

effects in women who had been administered misoprostol to induce labor. In some women, misoprostol caused

the uterus to rupture and also led to fetal distress, often with catastrophic results.139 Studies revealed that the

risk of uterine rupture was especially acute in women who had previously undergone cesarean sections, and the

American College of Obstetricians and Gynecologists (ACOG) issued guidelines discouraging use in such cases.140

In part based on these events, Searle sent a letter on August 23, 2000 to obstetricians and other physicians around

the country pointedly reminding health care providers that “Cytotec administration by any route is contraindicated

in women who are pregnant because it can cause abortion. Cytotec is not approved for the induction of labor

or abortion.”141 The Cytotec package insert already contained this warning and also warned physicians that the

drug could cause uterine rupture.142 A spokesman for Searle indicated that the company felt the need to send a

letter reminding physicians about these risks after it had been involved in discussions with the FDA concerning
 137 Id.
 138 Hale & Zinberg, supra note 52, at 59. “Misoprostol given vaginally or orally is superior to placebo for inducing cervical ripening

before induction of labor with oxytocin, and misoprostol itself is also effective for induction of labor.” Goldberg et al., supra note
136, at 43. Goldberg et al. went on to state that, despite the fact that FDA had not approved the drug for use in pregnant women,
“misoprostol is one of the most important medications in obstetrical practice.” Id. at 45. Hale & Zinberg also noted that misoprostol
was so popular that in 1999, the American College of Obstetricians and Gynecologists (ACOG) issued an opinion, Induction of Labor
with Misoprostol, to guide physicians in its use.
 139 See, e.g., Gaskin, supra note 52; David Goodman, Forced Labor, Mother Jones Mag. (Jan./Feb. 2001) (visited Sept. 15, 2001)

<http://www.motherjones.com/mother jones/JF01/labor.html>. Both articles attribute physicians’ ability to prescribe off-label uses
as an FDA “loophole.”
 140 Goodman, supra note 139.
 141 Hale & Zinberg, supra note 52, at 59.
 142 Cytotec r (misoprostol) Package Insert (Revised March 6, 2000). The insert states:

  UTERINE RUPTURE HAS BEEN REPORTED WHEN CYTOTEC WAS ADMINISTERED INTRAVAGINALLY IN PREGNANT
WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE FIRST TRIMESTER OF PREGNANCY.



                                                                  30
cases of uterine rupture resulting from the off-label use of Cytotec.143

Physicians around the country reacted angrily to Searle’s letter. They could not understand what had prompted

Searle’s action, in light of the large body of scientific evidence and the experience of many physicians demonstrating

the benefits of misoprostol.144 They blamed Searle for making access to misoprostol more difficult for physicians

because upon dissemination of the letter, “many hospital attorneys, administrators, and pharmacies . . . [refused]

to allow misoprostol to be dispensed or used.”145 As physicians saw it, a pharmaceutical company had just

interfered with their ability to prescribe the drug in a manner they thought would most benefit their patients.


          Many of our physician members have been able to convince their hospitals to continue to make misoprostol
          available for off-label use. The real victims in this scenario are pregnant women who receive treatment in
          hospitals that will not allow the use of misoprostol. Alternative medications are expensive and relatively
          ineffective. Even worse, in some instances no alternative treatments are available. Searle seems to have
          ignored these women.146

Physicians and scientists have conducted many studies and have found the drug remarkably effective at

inducing labor (usually within 24 hours147 ). In reviewing the results of several studies,148 a group of leading

physicians acknowledged, however, that “because there were so few serious adverse effects, the relative risk of

rare adverse outcomes with the use of misoprostol for induction of labor remains unknown.”149 Despite the cases

of uterine rupture that have occurred, misoprostol continues to be regarded by physicians as, for the most part,

safe. In October 2000, about two months after Searle’s letter, ACOG issued a newsletter reassuring its members

that off-label use of misoprostol is based on sound scientific evidence and that physicians should continue using it

for off-label purposes; another newsletter asserted that the drug is safe and effective for induction of labor when
 143 Michael  A. Friedman, M.D., on behalf of Searle, Letter to the Editor, Manufacturer’s Warning Regarding Unapproved Uses of
Misoprostol, 344 New Eng. J. Med. 61 (2001).
 144 Hale & Zinberg wrote, “It is a sad state of affairs when a pharmaceutical company attempts to restrict the use of a drug although

a large body of scientific evidence indicates that the drug has unique benefits and is safe for a large group of patients.” Supra note
52, at 60.
 145 Id. at 59.
 147 Goldberg et al., supra note 136, at 43.
 148 Goldberg et al. “identified more than 200 studies involving more than 16,000 women who received misoprostol.” Hale & Zinberg,

supra note 52, at 59.
 149 Goldberg et al., supra note 136, at 44 (emphasis added).




                                                                 31
used appropriately.150

The debate over misoprostol, and Searle’s drastic action in sending a letter to physicians around the country, can

be explained in part by lack of knowledge concerning the propriety of off-label drug use. Critics of off-label drug

use have lambasted use of misoprostol for induction of labor because it can have serious side effects and use these

side effects to buttress arguments that off-label use should be prohibited. Just because using a drug in a certain

way has adverse effects, however, does not mean that it should not be used in that manner; all drugs, even when

used for their FDA-approved purposes, have some adverse effects. People with little medical sophistication often

focus on FDA approval, rather than on what constitutes the standard of care, when judging a physician who

prescribes a drug for an off-label use.




IV. Issues Raised by Off-Label Prescribing.

A. Insurance Coverage of Off-Label Prescriptions.

As off-label prescribing became more common, such as in treating cancer and AIDS, getting off-label drugs paid

for became a huge concern for many patients. While the FDA views off-label drug use as appropriate and normal

medical practice, as recently as ten years ago many insurers and state programs frequently refused to reimburse

patients for off-label drug prescriptions.151 A 1991 study by the General Accounting Office (GAO) found that “62

percent of doctors had admitted patients to hospitals rather than treating them as outpatients solely in order to

circumvent [policies denying reimbursement of off-label prescriptions].”152



Many commentators advocate government-mandated insurance reimbursement of off-label drugs as essential in

order to ensure “that patients will receive the most medically appropriate therapy.”153 Others, however, oppose
150 Hale & Zinberg, supra note 52, at 60.
151 Henry, supra note 14, at 377.
152 Tabarrok, supra note 58.
153 Henry, supra note 14, at 378.




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such a policy. The Academy of Managed Care Pharmacy, for example, while generally supporting off-label drug

use, does not believe that the government should require coverage of such uses because it believes that “managed

care organizations must be given latitude to make decisions regarding drug coverage that are compassionate,

medically sound, and fiscally responsible.”154

Thanks to intense lobbying by the Association of Community Cancer Centers, AIDS activists and other interest

groups, legislatures around the country began dealing with the problem of insurance coverage for off-label drugs.155

California, one of the first states to attempt to deal with the problem, enacted a law in 1992 requiring third-party

payers to reimburse patients for any prescribed drug that met three conditions:156 (1) the FDA approved the

drug; and (2) the physician prescribed the drug for a “life-threatening condition” or the drug is prescribed by a

participating licensed health care professional for the treatment of a chronic and seriously debilitating condition

and the drug is medically necessary to treat that condition; and (3) the drug has been recognized by one of three

specific drug compendia or by two articles from peer reviewed medical journals that present data supporting the

proposed off-label use as generally safe and effective unless there is clear and convincing contradictory evidence

presented in a major peer reviewed medical journal.157

As of 1999, 27 states had similar laws requiring third-party payers to reimburse patients for off-label drugs

prescribed for life threatening diseases, although the actual content of the laws vary from state to state.158 New

Jersey also enacted such a law to prevent insurers from interfering with access to appropriate medical treatment

by refusing to pay for off-label drugs:159 “Reimbursement for ‘off-label’ uses of FDA-approved drugs is necessary

to conform to the way in which appropriate medical treatment is provided, to make needed drugs available to
 154 Academy   of Managed Care Pharmacy, Position Statement on Off-Label Use of Pharmaceuticals, (visited Sept. 15, 2001)
<http://www.amcp.org/professional res/position/012.asp>.
 155 Tabarrok, supra note 58.
 156 Marilyn McGregor, Getting Your “Off-Label” Drugs Paid For, Breast Cancer Action Newsletter #21, Dec. 1993, (visited Sept.

15, 2001) <http://www.bcaction.org/Pages/SearchablePages/1993Newsletters/Newsletter021I.html>.
 157 Cal. Health & Safety Code § 1367.21(a) (West 2000).
 158 Henry, supra note 14, at 378.
 159 N.J. Stat. Ann. § 26:1A-36.9 (West 2001).




                                                             33
patients, and may help to contain health care costs.”160

As for the federal government, “Congress requires Medicare to pay for the off-label use of anticancer drugs when

they are used for a ‘medically accepted indication’ but does not include drugs used for other conditions. A

medically accepted indication requires either a citation in one of the [main] medical compendia or support for its

effectiveness in peer-reviewed medical journals.”161



    B. Regulating the Marketing/Promotion of Off-Label Uses.

The FDA also imposes restrictions on the informational content of advertising/marketing or other promotional

activities of pharmaceutical companies.

This is an issue in physicians’ off-label drug prescriptions, since “official drug labeling cannot contain instructions

for off-label uses.”162 For example, despite the well-known beneficial effect of aspirin on the incidence of heart

attacks, pharmaceutical companies manufacturing aspirin can only include on the label that the drug relieves minor

aches and pains, fever, headache, etc. This is because in 1988, Frank Young, the current FDA Commissioner,

threatened that the FDA would pursue legal remedies against pharmaceutical companies that promoted their

aspirin products’ therapeutic benefit of decreasing the risk of heart attack.163 The FDA’s threat in this instance

was unusual, as the FDA has the authority to regulate the advertisement of prescription drugs, while the power to

regulate over-the-counter (OTC) drugs, such as aspirin, mainly lies with the Federal Trade Commission (FTC).164

Several generalizations can be made about the FDA’s regulation of pharmaceutical advertising. First, most of

the FDA’s power is extralegal.165 While FDA does have various means of enforcing compliance with its policies,

pharmaceutical companies generally obey suggestions made by the FDA. Because the FDA controls almost every
 160 Id. § 26:1A-36.9(h).
 161 Henry,  supra note 14, at 378.
 162 Id. at 372.
 163 Hazardous to Our Health? 29-30 (Robert Higgs ed., 1995). Higgs uses the case of the aspirin advertising to illustrate the main

aspects of FDA advertising regulation, which will be further discussed below.
 164 Id. at 49.
 165 Id. at 30.




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aspect of a pharmaceutical company, from the approval of new drugs to inspections of facilities, companies

generally want to stay on the FDA’s “good side.” Thus, when the FDA tells a company not to advertise a

specific use of a drug, the company most probably will comply. Second, because of the stringent regulations on

advertising, the FDA is denying consumers access to beneficial information.166 Consumers thus must acquire their

information from other sources, such as the media or their personal physician, means of acquiring information

which are wholly inadequate and cannot supply the information in the necessary detail.

Third, the FDA seems overly concerned with the risks/costs of advertising and does not give enough consideration

to the value of advertising.167 For example, in the case of aspirin, despite overwhelming evidence of the benefits

of aspirin for individuals at risk for heart attacks the FDA did not want to allow companies to promote such use

because aspirin poses risks to other individuals, such as a slender increase in the chance of stroke in some persons.

However, this risk of stroke is “not . . . statistically significant,” and “the reduction in risk of heart attack from

taking aspirin for the middle-aged males tremendously outweighs the slightly increased risk of stroke. Moreover,

advertising and promotion could easily indicate that aspirin is not a suitable drug for . . . [any group] for whom

the risks might outweigh the benefits.”168



The reasons for this are simple, and parallel the reasons why the FDA approval process for new drugs is so long

and difficult. The FDA, like any other political entity, would want to minimize adverse publicity. Approving a new

drug or approving advertising of a new use for an existing drug that results in harmful consequences would likely

result in much adverse publicity. On the other hand, blocking approval of a new drug or prohibiting advertising of

a new use of an existing drug, even though it deprives the consuming public from beneficial effects, would probably

remain quiet and not receive much adverse publicity. This causes the scales weighing risks versus benefits to be

uneven, as any risk placed in the risk column will greatly overshadow even large benefits to the public.
166 Id.   at 31.
167 Id.   at 32.
168 Id.




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FDA’s stringent control over advertising of pharmaceutical drugs has special implications in the area of off-label

use because the FDA prohibits companies from advertising off-label uses. The FDA also has greatly restricted

non-advertising means of informing physicians of new uses for existing drugs. For example, the FDA had taken the

position that pharmaceutical companies could not send physicians copies of scientific articles or other information

respecting research on new unapproved uses. Drug companies could “send reprints if there [was] an unsolicited

request for the information.”169 No representative of the company could suggest to the physician that he request

such information from the company, because the FDA would consider those actions to be promotional.170

Those who supported distribution of articles describing off-label uses said that it would be irrational and overly

stringent for the FDA to refuse to allow distribution of an article that has been published in a medical journal

and thus is already in the public domain.171 Opponents of such distribution expressed concern that physicians

would be influenced by misleading information, producing detrimental effects, and also worried that by allowing

companies to promote off-label uses would diminish incentives to conduct the trials necessary to ensure the uses’

safety and perhaps obtain approval for the uses.172 Supporters of off-label article dissemination maintained that

distributing such information to physicians is essential to better patient care, and noted that restricting the flow

of information to physicians created “an unfair impact on non-teaching hospitals, which disproportionately serve

people in poorer economic classes than do teaching hospitals.”173

A case was brought in federal court in the District of Columbia challenging the FDA rules in the Food and Drug

Modernization Act that restricted manufacturers of prescription drugs from disseminating articles discussing off-

label uses of approved drugs.174 The court held that the restrictions were unconstitutional because they violated

the First Amendment and granted the plaintiff an injunction.175 On appeal to the Court of Appeals for the D.C.
169 Id.   at 36.
170 Id.
 171 Karen Young Kreeger, Off-Label Reprints Still a Hot Issue in FDA Reform,       The Scientist,   <http://www.the-
scientist.com/yr1997/jan/kreeger pl 970120.html> (Jan. 20, 1997).
 172 Id.
 173 Id.
 174 Washington Legal Foundation v. Henney, 56 F. Supp. 2d (D.D.C. 1999).
 175 Id.




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Circuit, however, the FDA claimed that the statute did not provide the agency with independent authority to

restrict speech.176 The appellate court thus found no constitutional issue and vacated the lower court’s holding

and injunction.177

Despite the anticlimactic end to the Washington Legal Foundation struggle, the issue of the scope of FDA’s

authority to regulate dissemination of information by drug manufacturers will likely continue to be a hot topic

of debate in the years to come. Especially due to the advent and booming popularity of the Internet, drug

manufacturers and physicians can communicate even easier with each other and with patients. The FDA has

had a hard time keeping up. For the most part, FDA has targeted specific websites with false and/or misleading

information in its enforcement actions, but has been relatively incapable of widespread regulation of material on

the internet.178

These enforcement proceedings typically target websites promoting products without clearance, promoting ap-

proved products for unapproved uses, or otherwise employing misleading or unsupported claims. In general, this

approach by the FDA has proven effective at least in deterring the specific parties against whom actions are

brought.179

But the FDA, in general, completely lacks control over information posted on the Internet, especially via electronic

mail and in Internet chat rooms. Thus, its restrictions on distribution of articles to physicians, while not a resolved

issue, may become an obsolete issue unless the FDA can keep up with the vast amounts of information moving

on the Internet every day.



Conclusion



176 Washington    Legal Foundation v. Henney, 202 F.3d 331 (2000).
177 Id.
178 Leah    Brannon, Regulating Drug Promotion on the Internet, 54 Food & Drug L.J. 599 (1999).
179 Id.   at 601.



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In the end, what position one takes on government regulation in general will likely affect one’s position on the

desirability of the freedom given to physicians to prescribe approved drugs for unapproved uses. I believe the

benefits greatly outweigh the costs with respect to off-label drug prescribing, and believe such decisions should

be left to the judgment of the physician. Further, drug manufacturers should be free to send articles and

other information to physicians. As long as the articles are from reputable sources, opening such avenues of

communication can only lead to better patient care, as doctors in remote areas or with limited resources would

become aware of medical innovations and scientific discoveries.




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