Transcript 30_Patricia Khu

OFF-LABEL DRUG USE: ITS
ETHICAL IMPLICATIONS &
NEED FOR FURTHER RESEARCH
PATRICIA M KHU, MD,MS
UNIVERSITY OF THE PHILIPPINES MANILA
RESEARCH ETHICS BOARD (UPMREB)
CARDINAL SANTOS MEDICAL CENTER
RESEARCH ETHICS REVIEW COMMITTEE (CSMC-RERC)
OUTLINE
• What is “off-label drug use (OLDU)”
• Frequency of OLDU
• Regulations regarding OLDU
• Researches on OLDU
• Ethical issues on OLDU
Off-Label Drug Use
• Use of pharmaceutical drugs in following conditions:
– Unapproved indication: use for different condition
– Unapproved age group: use in children & neonates
– Unapproved dosage: given in different dose
– Unapproved form of administration: given by different
route
Factors Affecting OLDU
• Medication not studied & approved for
specific population (pediatric, geriatric,
pregnant patients)
• Life-threatening or terminal medical
condition may motivate physician to give
treatment that is logical & available, whether
approved by FDA or not
Factors Affecting OLDU
• If one condition from class of drugs has FDA
approval, physicians commonly use other
medications in the same class without specific
FDA approval for use for same medication
• If pathologic or physiologic features of 2
conditions are similar, physician may use a
medication approved for 1 of these conditions
for both (e.g. diabetes & metabolic synd,
anxiety & posttraumatic stress disorder)
Frequency of Off-Label Use
• Up to one-fifth of drugs prescribed are offlabel
• 31% in psychiatric drugs
• 62% of US pediatric office visits included offlabel prescribing; younger children at higher
risk (2009); 78.9% children discharged from
pediatric hospitals (Shah, et al; 2007)
Regulations of Off-Label Use
• Food, Drug, & Cosmetic Act of 1938: new
medication is safe
• Kefauver-Harris Amendment of 1962: new drugs
with evidence of effectiveness
• US: no law prohibits physician from prescribing
approved medication for other uses than specific
FDA-approved indications
• FDA Modernization Act of 1997: incentives for
pharma companies to test drugs on children
• Pharma companies not allowed to promote drug
for any other purpose without formal FDA
approval
Regulations of Off-Label Use
• Once drug approved for sale for a purpose, physicians
free to prescribe for any other purpose in their
professional judgment is safe & effective
• FDA approves a drug for prescription use & regulates
pharma industry’s promotional practices
• FDA does not have legal authority to regulate the
practice of medicine
• Manufacturers allowed provide providers with
publications on off-label uses of drug in response to
unsolicited request (FDA Modernization Act 2007)
Off-Label Use in Children & Neonates
• Risks in children & neonates: developmental
growth; fetal programming effect
• Belmont Report: special protection for
research involving vulnerable population;
prospect of direct benefit; risk benefit
analyses
Off-label Use in Psychiatric Disorders
• Patients with psychiatric disorders often
excluded from clinical trials and
inherently difficult to study
• Crossover in symptoms from different
psychiatric disorders
If Efficacious, Why FDA Approval not
Obtained to Convert Off-Label to OnLabel Uses?
• Obtaining new FDA approval for a drug can
be costly & time-consuming
• To add additional indications for an already
approved drug requires filing a supplemental
application; the approval of which may not
offset the expense and effort
• Generic meds may not have requisite funding
Ethical Issues
• Ethical issues arising from research design
• Ethical issues with enrollment of subjects
• Ethical issues with consent process
• Ethical issues with data analyses
Ethical Issues Arising from
Research Design
• “Equipoise” in RCT
• Design a trial minimizing risk while maximizing
benefits to specific subjects
• Placebo-controlled trial vs active-controlled trial:
PCT ethically justified if no standard treatment
exists; if standard therapy exists, PCT may be
justified if efficacy or safety of standard therapy
has not been established.
Placebo-controlled (PCT) vs Activecontrolled (ACT) Clinical Trial
• When standard therapy considered effective but associated
with degree of toxicity such that parents/participants
routinely refuse therapy, may justify use of placebo.
• When standard therapy effective & not associated with any
serious side effects, certain conditions to be evaluated to
determine whether PCT is ethical (Declaration of Helsinki):
PCT vs ACT
– Risk of placebo limited to minor & temporary
discomfort & proper informed consent is obtained
– Compelling scientific justification exists to conduct
study using placebo
– Valuable knowledge can be gained and investigators
have disclosed administration of a placebo
Clinical Equipoise vs Individual Equipoise
• Ethical dilemma in Grade II or III evidence for efficacy
of drug: clinical equipoise may exist but individual
(theoretical) equipoise may not exist: trade-off bet
risks to subjects and potential benefit to society
• Declaration of Helsinki: emphasizes concern for
interests of subject must come before interests of
science and society & every subject participating in
study should be assured of best proven diagnostic &
therapeutic management
Ethical Issues with Enrollment of Subjects
• An ethical dilemma may arise when
physicians consider enrolling their patients in
a RCT: view of physician on “equipoise” issue
(individual equipoise) may or may not
coincide with prevailing clinical equipoise of
medical community
Ethical Issues with Consent Process
• In context of emergency research: adequate
understanding of nature and purpose of
research not possible with time constraint
and stress (principle of autonomy)
Ethical Issues with Data Analyses
• When trials are stopped prematurely based
on interim data analyses: ethical rationale for
reasons of efficacy (principle that equipoise
has been disturbed) vs valuable info about
risks of treatment to research subjects (longterm adverse effects)
References
• Amin SB, McDermott MP, Sshamoo A. Clinical trials of ldrugs
used off-label in neonates:ethical issues and alternative study
designs. Account Res 2008; 15: 168-187.
• Eguale T, Buckeridge DL, Winslade NE, et al. Drug, patient, &
physician characteristics associated with off-label prescribing
in primary care FREE. Arch Intern Med 2012; 172: 781-788.
• Wittich CM, Burkle CM, Lanier WL. Ten common questions
(and their answers) about off-label drug use. Mayo Clin Proc
2012; 87: 982-990.
• Ventola CL. FDA policy: Off-label drug information:
regulation, distribution, evaluation, & related controversies.
P & T 2009: 34: 428-449.
References
• Saiyed MM, Prajapati A, Shah G. Parents’ awareness and
perspective on off-label medicines use in children. J
Pharmacol Pharmacother 2015; 6: 88-91.
• Elger CR, Hoppe C. Informed consent in off-label use and
incapacitated persons. Epilepsia 2009; 50 (Suppl): 79-80.
• Conti RM, Bernstein AC, Villaflor VM, et al. Prevalence of offlabel use and spending in 2010 among patent-protected
chemotherapies in a population-based cohort of medical
oncologists. J Clin Oncol 2013; 31: 1134-1139.
• Largent EA, Miller FG, Pearson SD. Going off-label without
venturing off-course: Evidence and ethical off-label
prescribing. Arch Intern Med 2009; 169: 1745-1747.
References
• Corny J, Lebel D, Bailey B, Bussieres JF. Unlicensed and offlabel drug use in children before and after pediatric
governmental initiatives. J Pediatr PharmacolTher 2015; 20:
316-328.
• Richey RH, Shah UU, Peak M, et al. Manipulation of drugs to
achieve the required dose is intrinsic to paediatric practice
but is not supported by guidelines or evidence. BMC
Pediatrics 2013; 81.
• Saiyed MM, Lalwani T, Rana D. Off-label medicine use in
pediatric inpatients: a prospective observational study at a
tertiary care hospital in India. Int J Pediatrics 2014;
• Bellis JR, Kirkham JJ, Pirmohamed, et al. Adverse drug
reactions and off-label and unlicensed medicines in children”
a nested case-control study of inpatients in a pediatric
hospital. BMC Med 2013; 11: 238.
Thank You