This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`m
`
`Off-Label Dermatologic Therapies
`
`Usage, Risks, and Mechanisms
`
`Vincent W. Li, MD; Michael P. Jaffe; William W. Li, MD; Harley A. Haynes, MD
`
`ff—label refers to the prescribing ofFood and Drug Administration—approved drugs for a
`use not indicated on the package insert. The prescribing of off-label drugs may benefit
`patients with many dermatologic diseases including angiogenesis—related conditions. We
`surveyed 55 dermatologists from a single large academic program to assess their use of
`particular drugs for specific skin conditions, their perception of such use as being for Food and Drug
`Administration—approved or for off—labelindications, and their attitudes towards off-label therapies. The
`practice of prescribing off-label drugs was common among the respondents, many of whom had mis-
`perceptions about which conditions are Food and Drug Administration—approved indications and about
`the legal ramifications of off-label therapies. We suggest that understanding the principles of off—label
`prescribing in conjunction with the mechanisms of drug action in diseases may help clinicians exercise
`their judgment in finding innovative therapies for their patients. Arch Dermatol. 1998;134:1449—1454
`
`A prescription is considered off-label when
`the condition being treated is not listed
`on the package insert or in the Physicians’
`Desk Reference1 as an indication for the
`drug being used. Off—label prescribing is
`sometimes referred to as unconventional
`medicine because it does not conform to
`convention as established under the rigid
`standards of the Food and Drug Adminis-
`tration (FDA), or as innovative therapy, the
`term used by a congressionally appointed
`commission to describe a clinician’s depar—
`ture “in a significant way from standard or
`accepted practice.”2 While many clini-
`cians are aware of anecdotes or case stud-
`ies regarding the off-label use of medi—
`cines and while off-label prescribing is being
`increasingly acknowledged,3 the scope and
`significance of this phenomenon is only
`now beginning to receive systematic study.
`A representative national survey was taken
`of oncologists on off—label prescribing and
`FDA policies toward information dissemi-
`nation (J. E. Calfee, L. McGinness, unpub—
`lished data, September 1997). We postu-
`late that off-label prescribing is common in
`the field of dermatology in which thera-
`peutic options are often numerous and rela-
`tively benign. Of special interest is the ap-
`plication of this practice in angiotherapies
`(angiogeneeis-based therapies), a group of
`
`ARCH DERMATOL/VOL 134, NOV 1998
`
`From the Division of
`Dermatology, Department
`of Medicine, Brigham and
`Women’s Hospital, and the
`Department of Dermatology,
`Harvard Medical School,
`(Drs V. W. Li and Haynes)
`Boston, Mass; and the
`Angiogenesis Foundation Inc,
`Cambridge, Mass (Drs V. W. Li,
`and W. W. Li and Mrjaffe).
`Information presented herein
`is intendedfor educational
`purposes and does not
`constitute medical or
`legal advice.
`
`treatment modalities that modulate the gen—
`eration of new blood vessels. According to "
`a recent market study by the Angiogenesis
`Foundation, Cambridge, Mass, a non-
`profit information clearinghouse and think
`tank, up to 1 10 million people in the United
`States have some type of angiogenesis-
`dependent skin disease.4
`To study the perception and practice of
`off—label prescribing, we surveyed the affili-
`ated dermatologists at a large medical cen—
`ter encompassing 12 hospitals (academic
`attending dermatologists, private practitionj
`ers, and residents and fellows-in—training).
`Our objectives were to determine the fre—
`quency, sources and motivation ofprescrib—
`ing off-label medicinesand to identify the per—
`ceived role ofthe FDA in restricting off—label
`uses. In addition, we considered whether a
`knowledge ofdrug mechanisms might affect
`off-label prescribing. The subjects completed
`an anonymous questionnaire addressing their
`use ofspecific drugs for specific diseases and
`were asked their opinion about whether the
`indications were approved or off-label.
`
`
`This article is also available on our
`
`
`
`Web site: www.ama—assn. org/derm.
`
`1449
`©1998 American Medicai Association. All rights reserved
`Downloaded From: http://archderm.jamanetwork.com/ by a University of Wisconsin -Madison User on 06/11/2013
`
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`|PR2013-00371
`
`

`

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`
`PARTICIPANTS, MATERIALS,
`AND METHODS -
`
`A close-ended questionnaire was developed to evalu—
`ate the use and perception of FDA—approved drugs
`for approved and off—label indications.
`
`SURVEY TOOL
`
`Respondents were instructed to refrain from con-
`sulting references, to indicate Whether they had pre—
`scribed a particular drug for a particular condition
`during the past 3 years, and to evaluate only the drug’s
`use, not its efficacy. In addition, the respondents were,
`asked whether they perceived the drug’s use in treat—3
`ing the condition for which it was prescribed to be
`approved by the FDA or off—label. If the disease was
`not seen in a given respondent’s practice, the ques-
`tion was left unanswered. Fifteen systemic thera—
`pies and 7 topical therapies representing treatments
`for a range of dermatologic conditions were listed.
`Of the 21 drugs, 10 had angiogenesis—modulating
`activity.
`Other questions addressed the importance that
`respondents placed on a physician’s responsibility to
`use a drug only for its approved indications, their per-
`ception of the legal risk of prescribing off—label, the
`sources from which they learned about FDA-
`approved disease indications, and their reasons for
`prescribing drugs off—label. All questions were yes/no
`or multiple choice.
`
`STUDY SAMPLE
`
`Fifty—nine questionnaires were distributed to affili—
`ated dermatologists in Harvard Medical School’s De—
`partment of Dermatology, that includes faculty and
`house officers from Massachusetts General Hospi-
`tal, Brigham and Women’s Hospital, Beth Israel-
`Deaconess Medieal Center, Boston Children’s Hos-
`pital, Dana—Farber Cancer Institute, Joslin Diabetes
`Center, Cambridge City Hospital, Cambridge, Mass,
`Lahey—Hitchcock Clinic, Burlington, Mass, Harvard
`Pilgrim Health Plan, and the Brockton/West Veter—
`ans Administration Medical Centers in Brockton and
`West Roxbury, Mass (all places are located in Bos-
`ton, Mass, exceptwhere noted). No attempt was made
`to identify persons completing the questionnaire, but
`respondents were queried about their type of prac—
`tice (academic, private, in—training). Forty—two of the
`55 respondents were board-certified dermatolo—
`gists. Only 4 had less than 1 year (9 months) of resi-
`dency training in dermatology.
`
`,
`
`
`
`
`
`
`
`OFF-LABEL USE
`
`All 55 respondents used drugs for off-label indications.
`All 15 systemic therapies and all 7 topical therapies listed
`in the questionnaire were used by at least some of the
`dennatologists. Table 'I shows data on the use ofall drugs
`listed. For some questions, certain respondents left an-
`swers blank, indicating that they did not see the disease
`or were unsure of the answer; in such cases, their an-
`swer was not coded.
`
`PERCEPTION OF DRUG APPROVAL
`
`Twenty-one of the 22 drug/indication pairs listed repre-
`sented off-label use but were incorrectly believed by some
`dermatologists to be FDA approved. Nine off—label treat—
`ments were believed by more than 25% of respondents
`to be approved and 5 were believed by at least half of re—
`spondents to be approved: azathioprine (Imuran, Glaxo—
`Welcome Inc, Research Triangle Park, NC), for bullous
`pemphigoid; cyclosporine (Sandimmune, not Neoral,
`Novartis Pharmaceuticals Corp, East Hanover, NJ), for
`psoriasis; itraconazole, (Sporanox,Janssen Pharmaceu-
`tica, Titusville, NJ), for onychomycosis in human im-
`munodeficiency virus (HIV); psoralen for vitiligo; and
`betamethasone dipropionate (Diprolene, Schering Corp,
`Kenilworth, NJ) under occlusion for palmar—plantar pso-
`riasis. The only drug listed for an approved purpose was
`hydroxychloroquine sulfate (Plaquenil, Sanofi Pharma-
`ceuticals Inc, New York, NY) for lupus erythematosus;
`12 (22%) of 55 respondents incorrectly believed that this
`was an off-label indication.
`
`PERCEPTION OF LEGAL RISK
`FROM THE FDA IN OFF-LABEL USE
`
`Twenty-eight (53%) of 53 respondents believed that when
`they prescribed a drug for off-label use they were plac-
`ing themselves “at risk for legal action by the FDA”
`(Figure 'l ). This figure was slightly lower (9 [41%] of
`22 respondents) among academic dermatologists than
`among private practitioners or physicians—in-training.
`
`PHYSICIAN’S RESPONSIBILITY
`FOR RESTRICTING DRUG USE
`TO APPROVED INDICATIONS
`
`Only 8 (15%) of 55 respondents believed that it was im-
`portant to use a drug only within its FDA—approved in-
`dications; these respondents answered 1 or 2 on a scale
`of 1 to 5. Half of respondents (27 [49%]) did not feel it
`was important, answering 4 or 5 on a scale of l to 5, while
`the remainder were undecided (Figure 2).
`
`SOURCES OF INFORMATION
`ON APPROVED AND OFF-LABEL USE
`
`lw T
`
`he 55 surveys completed represented a 93% response rate.
`Of the respondents, 21 (38%) were in academic practice,
`15 (27%) were in private practice, and 19 (35%) were in-
`training (dermatology residents and fellows). A compara-
`tive analysis revealed little behavioral discrepancy among
`these subgroups.
`
`When respondents were asked to name the single source
`from which they learned most about FDA—approved uses
`for drugs, 27 (49%) identified the Physicians’ Desk Ref—
`erence, 11 (20%) identified drug representatives, and 8
`(15%) cited package label inserts.
`
`ARCH DERMATOL/VOL 134, NOV 1998
`1450
`
`©1998 American Medicai Association. All rights reserved.
`Downloaded From: http:l/arcbderm.jamanetwork.com/ by a University of Wisconsin -Madison User on 06/11/2013
`
`

`

`
`
`
`
`Table 1. Data of Prescription Drug Use and Perception of FDA Approval*
`
`5D
`
`rug Use,
`No.
`
`Perception of FDA-Approval
`Status, No.
`
`r—
`l
`Do Not
`Believe
`Believe
`Believe
`
`Drug
`Disease
`Use
`Use
`Approved
`Off-Label
`Use, %
`Approved, %
`Systemic
`3
`
`
`
`1'—
`
`52
`
`Lupus
`
`Hydroxychloroquine
`(Plaquenil)
`Psoralen
`Cetirizine (Zyrtec)
`Azathioprine (lmvran)
`ltraconazole (Sporanox}
`Niacinamide
`lsotretinoin (Accutane)
`Supersaturated potassium
`iodide
`
`\htiligo
`Atopic dermatitis
`Bullous pemphigoid
`Onycliomycosis in HIV
`Bullous pemphigoid
`Eosinophilic folliculitis
`Erythema nodosum
`
`43
`46
`38
`33
`31
`29
`30
`
`8
`9
`16
`17
`23
`23
`25
`
`28
`25
`28
`36
`4
`2
`18
`
`19
`26
`17
`6
`4O
`43
`25
`
`40
`
`12
`
`95
`
`73
`
`84
`84
`7D
`66
`57
`56
`55
`
`55
`45
`52
`72
`7
`4
`33
`
`0
`47
`46
`O
`29
`. 26
`Warts
`Cimetidine
`50
`46
`11
`27
`29
`25
`Psoriasis
`Cyclosporine (Sandimmune)
`42
`38
`17
`21
`31
`19
`Hemangioma of infancy
`Prednisone
`2
`38
`40
`1
`33
`20
`Pyoderma gangrenosum
`Minocycline
`15
`34
`28
`8
`35
`18
`Pemphigus vulgaris
`Dapsone
`Griseofulvin
`Lichen planus
`16
`37
`1
`34
`30
`2
`
`Stanozolol (Stanazol)
`Lipodermatosclerosis
`13
`38
`6
`29
`25
`12
`Topical
`
`Tretinoin (Retin-A)
`Tretinoin (Retin-A)
`Betamethasone dipropionate
`(Diprolene) (under
`occlusion)
`
`Flat warts
`Mild actinic keratoses
`Palmer—plantar psoriasis
`
`47
`46
`44
`
`8
`9
`1O
`
`2
`6
`31
`
`50
`43
`19
`
`Dermatoheliosis
`
`31
`
`23
`
`5
`
`40
`
`85
`84
`81
`
`4
`11
`57
`
`57
`
`9
`
`Ammonium lactate
`(LacHydrin)
`32
`57
`26
`17
`23
`30
`Hyperpigmentation
`Azelaic acid (Azelex)
`23
`43
`25
`12
`30
`23
`Hand eczema
`Mupirocin (Bactroban)
`17
`26
`33
`9
`39
`14
`Common warts
`lmiquimod (Aldara)
`
`*FDA indicates Food and Drug Administration; hydroig/chloro
`quine for lupus erythematosus is the only Food and Drug Administration—approved drug/disease
`pair herein. H/Vindicates human immunodeficiency virus.
`
`
`-
`
`
`
`__l
`
`47% of
`Respondents
`Perceived
`No Legal Risk
`From the FDA
`
`53% of Respondents
`Perceived Off-Label
`Prescribing Placed
`Them at Risk for Legal
`Action by the FDA
`
`a
`Z.
`:3)
`‘5%
`
`2
`
`
`
`Figure 1. Perception oflegal risk from the Food and Drug Administration
`(FDA). Respondents were queried if they perceived that prescribing in an
`off-label fashion placed them at risk for legal action from the FDA.
`
`No moorlant
`
`important
`
`Figure 2. Importance placed on following Food and Drug Administration—
`approved indications. Important is defined as number of respondents
`answering 1 or2 on a scale of 1 to 5; not important, number answering 4
`or 5. Not shown are the respondents who answered 3 (undecided).
`
`Of the 4- options listed, case reports in the litera—
`ture were the most frequently cited information source
`on the prescribing of drugs for off-label uses, selected by
`40% of respondents. The other 3 options were personal
`experience, anecdotal experience of colleagues, and frus-
`tration with approved alternatives.
`
`w U
`
`nderstanding the practice of off-label prescribing is im-
`portant for several reasons. First, physicians are increas-
`
`ingly concerned about minimizing their perceived risk. Sec-
`ond, the lay media have recently focused on the possible
`risks associated with off-label use of high-profile drugs,
`such as sildenafil citrate (Viagra, Pfizer Pharmaceuticals,
`New York, NY), to increase sexual performance in men
`and fenfluramine hydrochloride and and phentermine
`hydrochloride, a combination drug product also known
`
`ARCH DERMATOL/VOL 134, NOV 1998
`14-51
`
`@1998 American Medicat Association. A11 rights reserved.
`Downloaded From: http://archdern1.jamanetwork.com/ by a University of Wisconsin -Madison User on 06/11/2013
`
`

`

`r
` onc:
`Hydmxychloroquine
`§
`itraconazole
`I Systemic Therapies
`.
`(Lupus)I
`‘
`(Onychomycosis in a Patient With
`
`
`
`0 Topical Therapies
`Human immunodeficiency \firus)
`I
`
`Azathioprine
`(Builous Pemphigoid)
`-._l
`.......
`
`Betamethasone Dipropionate
`Under Occlusion
`(Palmer-Plantar Psoriasis)
`o
`l Psoraien (\fitfligo)
`Cetirizine
`(Atopic Dermatitis)
`I
`
`\iD
`
`a)o _|_
`01o
`
`_|
`
`r
`
`.4
`r
`
`o.)o
`
`ND
`
`
`
`I
`RespondentsBelievingDrugIsFDAApproved,“la 8
`
`
`
`Dapsone
`Aldara (Common Warts)
`(Pemphigus
`O
`Vulgaris)
`I
`Ammonium Lactate
`l Stanuzoloi (Lipodermatuscierosis)
`(Dermatoheliosis)
`.1 c)
`Griseofirlvin
`Minocycline
`o Tretinoin (Aotinic Keratoses)
`Cimeiidine
`(Lichen Pianos)
`(Pyoderma Gangrenosum)
`I
`I
`(-3 Niacinamide (Bullous Pemphigoid)
`(Wars)
`.1—
`r—
`" lsotretinoin (Eos Foliicuiitis)
`
` 0 Tretinoin (Flat Warts) c)
`r—
`1—
`—"i—
`—I'
`1—
`MDi
`60
`30
`40
`50
`70
`80
`90
`Respondents Prescribing Drug, %
`
`CyciospprinelSandimmufne
`(Psoriasis)
`‘
`_
`--—~
`.
`I
`
`Ftednisone
`(Hemangioma of infancy)
`I
`
`5
`5
`
`Mupirucin
`(Hand Eczema)
`
`-...
`Supersaturated
`Potassium Iodide
`(Erythema Nodosum)
`i mentation
`e
`'
`DAzelaicAcid H
`( yp reg
`
`)
`
`—r
`100
`
`Figure 3. Prescription use plotted against perception of Food and Drug Administration (FDA)-approved status for a particular indication. Data points in the lower
`right quadrant represent drugs perceived most often to be FDA approved. Data points in the lower right quadrant represent drugs perceived to have been used
`in an off-label fashion. As might be expected, most dermatologists did not use drugs for conditions that they did not believe to be FDA—approved indications
`(data points in lower left quadrant).
`
`as fen-phen, to combat obesity. The cover story for the
`May 11, 1998 issue of Business Week, whose headline
`reads “Danger: Read the Label. .
`.
`. Doctors Are Prescrib-
`ing Drugs for Unapproved Uses and Patients Are at Risk,”
`further catapulted this issue into the mainstream. A third
`concern is that as physicians become restricted by managed—
`care formularies treatments that are not approved by the
`FDA may fall by the wayside. Any of these factors can have
`a negative impact on patients by limiting their access to
`potentially effective off-label therapies.
`Our study suggests that the practice of prescribing
`drugs for off-label uses is common in dermatology. In
`fact, 100% of the dermatologists surveyed prescribed one
`or more of the topical and systemic therapies listed in
`our questionnaire for off-label use.
`Our analysis reveals a positive correlation (R = 0.69)
`between use and beliefin FDA approval for systemic drugs
`(Figure 3). In practical terms, the importance of this
`relationship is not clear because belief in FDA approval
`is often different than actual approval. Dermatologists in
`this study misidentified many of the off-label therapy/
`disease pairs as approved by the FDA.
`
`THE ROLE OF THE FDA IN DRUG APPROVAL
`
`What is the FDA’s role in guiding a physician’s use ofdrugs?
`The FDA has jurisdiction over pharmaceutical manufac—
`turers but cannot regulate how and to whom physicians
`prescribe drugs after their approval. For the physician, the
`legal implications of using FDA-approved medications for
`unlabeled uses are clear.5 The concept of off-label pre-
`scribing was first described to the FDA in 1972 and was
`regarded as being in line with laws passed by Congress to
`guide the FDA, principally the 1938 Federal Food, Drug,
`and Cosmetic Act and its 1962 amendments. According
`to these laws, physicians make the final judgment about
`the appropriate use of any FDA-approved drug by weigh-
`ing the available scientific and clinical informalion, the facts
`presented in the package insert, and their own experi-
`ence (and that oftheir colleagues) in prescribing the drug.
`As long as neither the manufacturer nor the pharmacy to
`which a drug is shipped intends for the drug to be used
`for an unlabeled purpose when it is shipped, federal laws
`
`governing interstate commerce are fulfilled. A physician
`may lawfully prescribe a drug at a different dosage or for
`conditions not described in the package insert without in-
`forming or obtaining the consent of the FDA. Federal courts
`have continued to uphold this autonomy, stating that Con—
`gress does not want to interfere with physicians’ treat—
`ment of their patients.6 Although a patient has a right to
`seek civil damages in court if there is evidence of malprac-
`tice, off-label prescribing does not itself constitute liabil—
`ity. If a physician uses a drug for an off-label indication to
`benefit a patient while simultaneously using it as part of a
`research investigation, they are subject to appropriate in—
`ternal review board and informed consent requirements.
`On the other hand, if innovative therapy is used solely to
`benefit a patient, no specific type of consent is required
`although the risks should be disclosed to the patient.5
`Drug development and regulatory issues are not un-
`derstood by all clinicians. There is a perception among
`some that if a therapy were truly effective and safe for a
`particular indication, it would have received FDA ap—
`proval for that condition. In reality, the lack of mention
`ofan indication on the package insert does not imply that
`a drug is unapproved for that indication. In fact, there is
`no legal definition of the term unapproved use. A disease
`indication is simply a condition that the manufacturer
`has submitted to the FDA to consider for approval. The
`U5 Pharmacopoeia Drug Information, the PDR Compan-
`ion Guide, and the American Medical Association’s Drug
`Evaluations books are annually published resources that
`describe uses of drugs in accepted and common clinical
`practice, regardless of their official labeling status. It is
`unclear how many physicians actually use this resource
`and whether they understand the implications and risks
`associated with applying such information to patients.
`The approved indications for a drug can be driven
`as much by politics and business as by medicine. The av—
`erage duration and cost of drug development are more
`than 15 years and more than $300 million, respec-
`tively.7 Drug developers want their indications to en-
`compass the largest possible market so that they can at
`least recoup their initial investment. Once a drug is ap—
`proved, its approval for another indication is a costly and
`lengthy process that few pharmaceutical firms can jus—
`
`ARCH DERMATOL/VOL 134-, NOV 1998
`1452
`
`©1998 American Medicai Association. Ali rights reserved.
`Downloaded From: http://archderm.jamanetworkcom/ by a University of Wisconsin -Madison User on 06/11/2013
`
`

`

`
`
`Table 2. Dermatologic Therapies With an Angiogenesis—Based Mechanism
`
`m A
`
`impact on
`Angiogenesis
`
`Disease
`Warts
`
`Psoriasis
`
`Rosacea
`Kaposi25 sarcoma
`
`Hemangioma of infancy
`
`Chronic ulcer
`
`
`
`Reference No.
`Drug
`12
`Cimetidine
`13
`Tretinoin
`14,15
`imiquimod
`_ 16
`Caicipotriene
`17
`Cyclosporine
`18
`Acitretin
`Inhibitor
`1 9
`Minocycl ine
`.
`.
`20
`Thalidomide
`inhibitor
`:l
`21
`Capt0prii
`.
`.
`22
`Corticosteroids
`'"h'b't‘"
`:l
`23
`interferon aifa—Za
`.
`10
`Becapiermin
`Stimulator
`:l
`24
`Sucraifate
`
`
`ngiogenesis
`Level
`Excessive
`
`Excessive
`
`Excessive
`Excessive
`
`Excessive
`
`insufficient
`
`’
`
`inhibitor
`
`inhibitor
`
`_|
`
`
`
`In the current environment of competing therapies,
`what motivates dermatologists to choose one therapy
`over another? Clearly, belief in efficacy is an important
`factor. But how do physicians conclude that a drug
`works when no clinical trial results are available? Our
`
`tify as the clock on their patent protection winds down.
`A few dermatologic drugs have undergone this capital-
`intensive process. As an example, cyclosporine under the
`trade name Neoral, (Novartis Pharmaceuticals Corp, East
`Hanover, NJ) was recently approved for the treatment of
`psoriasis. Some drug manufacturers may never choose
`to apply for certain indications if there is no clear finan-
`cial gain. For example, diflorasone diacetate (Psorcon,
`Dermik Laboratories Inc, Collegeville, Pa) is the only class
`I topical steroid approved for use under occlusion, but
`dermatologists already routinely prescribe other non—
`diflorasone steroids for use in this fashion. In addition,
`the use of itraconazole (Sporanox) is indicated for use
`in patients with onychomycosis Who do not have HIV
`but many dermatologists already routinely prescribe this
`drug for their patients infected with HIV.
`
`DRUG MECHANISMS
`AND OFF—LABEL PRESCRIBING
`
`riasis, for example, the tortuous vessels in the papillary
`dermis support the proliferation of the diseased epider-
`mis. In other diseases, such as chronic ulcer diseases, there
`is insufficient vascularity to provide the appropriate granu—
`lation tissue for wound healing.Theref0re, the pharma-
`cological manipulation of angiogenesis may be useful in
`treating many derrnatologic diseases. More than 100 drug
`candidates are being developed for the control of angio—
`genesis, but most are not expected to be on the market
`for another 2 to 5 years. Only 1 drug has obtained FDA
`approval for an angiogenic skin condition: recombinant
`human platelet—derived growth factor, becaplermin, (Re-
`granex, Ortho—McNeil Pharmaceutical Inc, Raritan, NJ)
`for the treatment of diabetic foot ulcers .11 In the mean-
`time, dermatologists are learning from the scientific lit-
`erature that a number of existing formulary medicines
`have been rediscovered by researchers as agents possess-
`ing angiogenesis—modulating properties. Table 2 lists
`common angiogenic skin disorders and therapies that have
`been used to treat them. The inhibition or stimulation
`of angiogenesis may contribute to the efficacy of these
`drugs_ 10,12-24
`Modulating angiogenesis is only one of many mecha-
`nisms by which drugs may affect the dermatologic dis-
`eases listed in our survey. For example, topical mupiro-
`survey indicates that case reports of efficacy in the lit—
`cin (Bactroban, SmithKline Beecham Pharmaceuticals,
`erature often influence situations in which drugs are
`Philadelphia, Pa), and oral antibiotics may alleviate atopic
`prescribed. Nevertheless, half the responding derma-
`dermatitis by suppressing staphylococcal superantigen
`tologists felt uncomfortable about prescribing off-label
`on the skin of colonized patients.11 Although the gen-
`drugs, even though they believed such drugs might
`eral use of antihistamines in eczema is controversial, ce—
`benefit their patients.
`tirizine hydrochloride (Zyrtec, Pfizer Pharmaceuticals Inc,
`Another factor that may influence prescribing of
`New York, NY) may relieve inflammation by inhibiting
`drugs is an understanding of the scientific basis for a drug’s
`eosinophil chemotaxis.25 Niacinamide, also known as
`activity in a given disease. This point is well illustrated
`nicotinamide, may constitute a useful steroid-sparing
`in evolving angiogenesis-based therapies. Although the
`therapy for certain inflammatory disorders because it can
`field of angiogenesis has recently received intense me—
`inhibit nitric oxide synthesis in macrophages and sup-
`dia attention in terms of a “cure” for cancer, angiothera—
`press the antigen-presenting function of the class II ma-
`pies have tremendous potential to treat diseases in many
`j or histocompatibility complex on endothelial cells and
`other fields including dermatology.8 Angiogenesis, or neo-
`fibroblasts at sites of tissue inflammation.”27 The anti-
`vascularization, underlies many conditions in which ei-
`malarial chloroquine may be effective in lupus partly be-
`ther excessive or insufficient blood vessel growth leads
`cause of its action on endothelial cell apoptosis.28 Az—
`to disease development or progression}10 Certain skin
`elaic acid cream, although indicated for acne, may be
`diseases are characterized by excessive vascularity; in pso-
`helpful in pigmentary disorders since it inhibits tyrosi-
`
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`©1998 American Medical Association~ Ail rights reserved.
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`

`

`Market Study of Angiogenesis—Dependent Diseases: Classification and Sizing ofthe
`Potential Market forthe Pharmaceutical lndustry in the U.S. and the European Union.
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`unlabeled (off—label) uses. Arch Dermatol. 1994;130:32—36.
`Chaney v Heckler, 7128 F211 1174 (1983).
`ooNICD
`. The Angiogenesis Foundation industry Database, 1998.
`. Gorman C. Curing cancer: how to tell the hype from the hope. Time. May 18,
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`Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat
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`Campbell DE, Kemp AS. Proliferation and production of interferon-gamma (lFN-
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`
`nase and disrupts melanin biosynthesis.29 Lastly, antibi-
`otics of the tetracycline class are well known to have anti-
`inflammatory as well as antimicrobial activity, possibly
`because of the inhibition of complement-driven neutro—
`phil migration and suppression of matrix metallopro-
`teinases associated with inflammation.”31
`
`In summary, this study underscores 3 important
`points. First, FDA—approved drugs are frequently pre-
`scribed for off-label dermatologic indications, but mis-
`understanding exists about the indications for which drugs
`are approved. Second, physicians appear to be inad-
`equately informed about the FDA’s regulatory role and
`the perceived legal risks involved in the prescribing of
`drugs. Third, knowledge ofmechanisms of action of drugs
`used in dermatology (eg, modulation of angiogenesis) is
`an important factor in the choice of therapy.
`Although clinical trials remain the criterion stan-
`dard for FDA approval of a drug, a knowledge of off—label
`drug use broadens the clinician’s ability to relieve the symp—
`toms of patients with diseases that are refractory to stan-
`dard therapy or for which there is no effective standard
`therapy. Fortunately, the accessing of information about
`off-label use is becoming easier for the clinician. The fed-
`eral government recently eased its restrictions barring drug
`manufacturers from telling physicians about off-label uses
`for their products. The FDA Modernization Act passed by
`Congress in 1997 allows companies to distribute pub-
`lished studies about their products for off—label indica-
`tions, although manufacturers still cannot market their
`drugs for off—label use. Under these new guidelines, manu—
`facturers must still submit a copy of the information to the
`FDA 60 days before distributing it; after a review, the agency
`can regulate this distribution of information.
`
`Accepted for publication August 31, 1998.
`We thank Andrew Jay Lee, MHS, and the staff of the
`Angiogenesis Foundation, Cambridge, Mass, an interna—
`tional nonprofit Clearinghousefor information, research, and
`education in angiogenesis, for their assistance with regula-
`tory documents and database reviews.
`Reprints: Dermatology Division, Brigham and Wom—
`en’s Hospital, 75 Francis St, Boston, MA 02115.
`
`w 1
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`©1998 American Medical Association. A11 rights reserved.
`Downloaded From: http:l/archderm.jamanetwork.com/ by a University of Wisconsin -Madison User on 06/11/2013
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