Maricopa Community Colleges Rio Salado Community College Health & Medical Question

1. Discuss the ramifications of off-label use of drugs.

2. Find and discuss two examples of off-label uses of drugs that have been successful. Find one example where a manufacturer has promoted an off-label use of a drug in a manner that was not in compliance with the law.  Don’t use the examples from the powerpoint!

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3. Discuss the influence of globalization of drug production and clinical trials on the availability and safety of drugs (hint, think of the aftermath of Hurricane Maria and the effects it had, or the effect that the COVID pandemic has had, on availability of drugs). One drug that became difficult to get for a while is tacrolimus, used to prevent organ transplant rejection.  You might want to investigate a drug shortage and discuss what you think the reasons were.

Week 5, Lecture 9
Off-Label Use of Drugs
HCR 555
©PE Potter/ASU 2022
Drug Labeling Defined
The FDA considers a drug label to be
◦ The display of written, printed or graphic
matter upon the immediate container of
any article
◦ This also includes the wrapping or any
other article that may accompany the drug
◦ Accompany means anything that
supplements or explains the product
Drug Labeling
The FDA includes:
◦ Brochures, booklets, mailers, letters
◦ Detailing pieces, house publications
◦ Bulletins, calendars, file cards
◦ Catalogs, price lists
◦ Films, film strips, slides, sound recordings, exhibits
◦ Literature and reprints, published references for use
by medical practitioners, nurses, or pharmacists
Drug Labeling
According to the US Supreme Court,
“accompanying” means
◦Any matter that explains or supplements
the product
◦Whether or not that material is attached
◦Includes anything disseminated by the
manufacturer and reaches customers,
doctors or patients before, with, or after,
the product
Drug Labeling
Cannot contain instructions for “off-label”
Manufacturers can be prosecuted for
illegally “misbranding” a drug if the label
contains information regarding “off-label”
The Federal Food, Drug and Cosmetic Act of
1938 made misbranding illegal
Drug Labeling
Misbranding occurs if the label contains false
or misleading information
Misbranding may include:
◦Information on the label
◦Information omitted from the label
◦ If every intended use is not included
◦ If adequate instructions for each use are not there
What is Off-Label Use?
Once a drug is approved for a specific
purpose, it can be used for other purposes,
even if not approved for it
An unapproved use is off-label whether:
◦Prescribed by a physician
◦Used by a patient
◦Marketed by the manufacturer
Off-Label Use
The 1997 Modernization Act stated
◦“nothing in this act shall be construed to limit or
interfere with the authority of a health care
practitioner to prescribe or administer any legally
marketed device to a patient for any condition or
disease within a legitimate health-care-practitionerpatient relationship
This limits the FDA’s ability to control off-label
use of drugs
Off-Label Use
An FDA Drug Bulletin states that
◦ Once a drug has been approved for marketing, a
physician may prescribe it for uses or in treatment
regimens or patient populations that are not
included in the approved labeling
◦ “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 reviewed
in the literature
FDA Role
The FDA cannot regulate a doctor’s off-label
prescription of a medicine
The FDA can also not regulate the ways in which
a patient uses medication that was prescribed by
a doctor
The FDA CAN regulate a manufacturer’s
marketing of a drug
FDA Role- the 1997 Law
Before, 1997, a manufacturer could promote a
drug ONLY for its FDA approved purpose
It was argued that these rules violated the rights
of free speech for the drug manufacturers
The manufacturers were given more leeway
regarding disseminating information regarding
unapproved uses for their drugs
FDA Role- the 1997 Law
The 1997 Act states a manufacturer
◦Is allowed to distribute written information concerning
the safety, effectiveness, or benefit of a use not
described in the approved labeling of a drug
The 1997 law allowed manufacturers to give less than complete
information to a doctor
Doctors could request information about off-label use from the
FDA Role- the 1997 Law
DIRECT promotion was not allowed
But INDIRECT means could be employed to inform
doctors about off-label uses
◦ Research published in journal articles could be used
◦ Some of this was sponsored by the pharmaceutical
◦ Textbooks could be used
◦ Education programs for doctors also
Off-label information
Manufacturers were allowed to provide financial
support for these “educational programs” where
speakers discussed off-label uses
BUT- the programs had to be organized by an
independent entity
The manufacturers were required to disclose their
financial interests and that these were unapproved
Off-Label Information
Information for off-label use could be disseminated if:
◦ A new drug application had been filed
◦ Information did not pose a significant risk to public health and was
not abridged, false, or misleading
◦ It is not from another manufacturers research unless permission
was obtained
◦ A copy of the information was sent to the FDA 60 days prior to
sending to doctors
◦ A supplemental application or exception had been filed
◦ It must contain a statement that it was NOT an approved use
Off-Label Information
This information can be given to
◦ A health care provider
◦ A pharmacy benefit manager
◦ A health insurance issuer
◦ A group health plan
◦ A Federal or State government agency
There must be a fair balance of information regarding
effectiveness and risks of the drug, as well as any
significant limitations to its use
What about The Information?
Manufacturers may design the studies, control data
analysis, and publication
Researchers supported by industry are likely to find positive
results and publish them
Unfavorable studies may not be published
Physicians may receive financial benefits for finding the
drug “useful”
The 2009 Guidelines
In 2009, new guidelines were posted regarding off-label
promotion of drugs to physicians, health care professionals,
health plans, and pharmacy benefit managers
It allowed manufacturers to disseminate “truthful and nonmisleading medical and scientific information on unapproved
uses of approved drugs” if “Good Reprint Practices” are
Good Reprint Practices
Retained from before:
•False, misleading info
•Poses risk to public health
◦Letters to the editor
◦Phase I reports in healthy subjects
◦“reference publications” with little or no
discussion of the relevant data
◦Publications funded by manufacturers or
anyone with a financial interest
◦Clinical investigations previously ruled as
not adequate or well-controlled by FDA
Even with Peer-Review..
Selective publication
◦Body of literature is still incomplete and may be
biased, as many studies showing negative results
may not be published
◦This was shown for antidepressants, where only
the positive clinical trials were published
Even with Peer-Review..
Ghost authorship
◦The literature can be manipulated by having authors
put their names on material written by ghost-writers
from the pharmaceutical industry
◦Ghost management of the study may eliminate
critical or unfavorable
◦Inadequate off-label supervision may encourage
NDAs for the easiest use and avoid better clinical
trials showing real risk-benefit relationships
Why Not Get Approval?
Drug is already on the market- physicians are allowed to
prescribe it
Approval will have little effect on sales
Testing process is very expensive
The patent may expire too soon to allow much profit
This is especially true for orphan diseases
The Learned Intermediary
Pharmaceutical companies have an exception to the
law requiring that consumers be warned of dangers
associated with a product
This is the learned intermediary doctrine, which
allows them to disseminate this information to
health care providers, instead.
This discharges the manufacturer from liability, and
puts it on the doctor
What About the Physicians?
Physicians are allowed to prescribe drugs off-label
◦ “It is the physician’s duty to weight the risks
and rewards of a particular course of treatment
when prescribing medication”
This assumes the physician has adequate
knowledge regarding the drug and its use
The court believes that doctors are best able to
evaluate and treat their patients
Physicians Become Liable
If the physician knows the risks of a drug, he or she,
not the manufacturer, becomes liable for problems
The patient then can only sue the doctor, not the
This is true whether the drug is prescribed according
to the label or off-label
Off-Label Prescribing
Widespread in the medical community
Estimated that from 40-60% of drugs prescribed for off-label uses
Off-label use accounts for 40-50% of prescription drug spending
Doctors are frequently unaware that the use is off-label
◦ Only half correctly identified whether uses of certain drugs
were approved or off-label
Off-Label Prescribing
◦Science often moves faster than regulation
◦May provide state of the art treatment
◦Necessary for “orphan diseases”
◦Many groups would not have any treatments,
as few drugs are approved for them, e.g.
◦May save hundreds of thousands of lives per
Off-Label Prescribing
90% of people with rare diseases have to use drugs off-label
Most diseases affecting less than 200,000 Americans have no
approved treatment
Many cancer treatments must be off-label, especially if they
are rare
33% of all cancer treatment is off label
Three of the most common cancer drugs are used off-label
85% of the time
Off-Label Prescribing
Drugs are generally approved in adults, not children
Very few drugs are approved for use in children
95% of the drugs used in neonatology are off-label
80% of drugs in children are off-label uses
80-90% of pediatric patients are treated with off-label drugs
Standard of Care
For many conditions, off-label use of drugs is
considered “standard of care”
Physicians would be considered to commit malpractice
if they DIDN’T use these drugs
This is true in many serious and life-threatening
Example: Dexamethasone for COVID-19
The Down Side
Drugs prescribed off-label did not go through testing for that
condition or in that population
A disease state may change the way that a drug acts in the body
Side effects may not be monitored as closely, although the drug
companies are required to monitor side effects EVEN if used off-label
Over 125,000 patients die every year from adverse drug reactions
Are They Effective?
Many drugs are prescribed for off-label uses because
they work well
Others are not effective, but used anyway
Many are just used in a different patient population
Some are just used for a different period of time, but for
a similar purpose
Antihistamines are approved for seasonal allergies
What if you have allergies all year?
They are used chronically by many people, with no
harm done
In these cases, the underlying condition is the same, the
mechanism is the same, but the duration is different
Scientific Basis
Sometimes, large randomized clinical trials are conducted for offlabel uses of drugs, to determine if they are effective
Case studies, cohort studies and clinical experience may also
provide useful information
Drugs approved for one indication may be used for more or less
serious forms of that condition, or one caused by a similar
mechanism, or with similar symptoms
Scientific Support
There is good scientific support for many off-label uses
BUT- for many drugs, the level of scientific support of
effectiveness is low
Data is hard to obtain for many of these uses
Often, prescribing is done based on anecdotal information, not
scientific evidence
Side Effects and Other concerns
A recent article in JAMA Internal Medicine (Jan 2016) discussed the concern of
unexpected side effects with off-label use of drugs. This led to commentaries
and discussion regarding off-label prescribing
Other Issues
Health insurers, especially Medicare and Medicaid, only cover offlabel prescriptions some of the time
They will cover indications supported by scientific research and in
major drug compendia
The regulations change, which is confusing for physicians and
Not allowing reimbursement for off-label prescriptions may be
quite expensive for patients, and sometimes the rules change
Bevacizumab (Avastin)
Monoclonal antibody, which inhibits VEGF, and decreases
Was developed as a chemotherapy agent for some cancers
There were several FDA approvals following clinical trials
◦ 2004 – colorectal cancer
◦ 2006 – non-small cell lung cancer
◦ 2008 – HER2 negative breast cancer
◦ 2010 – FDA recommended removal for this purpose after examining further
◦ 2009 – glioblastoma
Bevacizumab (Avastin)
Accelerated approval was granted for metastatic HER2 negative
breast cancer in 2008
◦ Based on open-label study where progression-free time was increased by
5.5 months, but overall survival was unchanged
FDA Oncology Drug Advisory Committee (ODAC) voted 5/4
AGAINST it- but the drug was still approved
◦ Concerns included open-label design of clinical trial, toxicity of the drug,
missing data, uncertain sample size, shortcomings in safety data, and
whether the measured endpoint in the trial was meaningful
Bevacizumab (Avastin)
In 2010, ODAC voted 12/1 against keeping it on the market for use in HER2negative breast cancer
◦ Based on 3 new clinical trials designed to convert accelerated
approval to regular approval and increase the number of
applications for the drug
There was a slight increase in progression-free survival (~1 month)
The committee felt that this not a viable endpoint- although FDA had
approved it in 2008
There was NO change in overall survival, and there was considerable
Bevacizumab (Avastin)
Based on this, FDA recommended withdrawing its approval for breast
However, it worked in some women; off-label use is possible
Insurance companies and Medicare are less likely to cover it off-label
for HER2-negative breast cancer, and although private payers follow
clinical compendia, not FDA regulations, many will not cover it for this
Each treatment costs about $5000
Bevacizumab (Avastin)
Because it decreases angiogenesis, it has some utility in treating
macular degeneration by decreasing vascularity in the retina
It was used off-label for age-related macular degeneration (AMD) for
several years
It was considered effective by most ophthalmologists
Thus, it became the standard of care for AMD
It was made in compounding pharmacies for about $27 per dose
Medicare/Medicaid reimbursed the doctor $50 per dose
It was cost effective for the patient and for the opthalmologist
Bevacizumab (Avastin)
Then, a new drug, ranibizumab (Lucentis), was approved for AMD
It has the same mechanism of action, is also an antibody, but is a
little smaller, and penetrates into the eye a bit better
An NIH clinical trial to compare the two was proposed, but the
manufacturer would not cooperate with the idea
The effectiveness of the two drugs appears similar
Cost of ranibizumab is about $2000/dose
Bevacizumab (Avastin)
Once it was approved, Medicare reimbursement to doctors changed
◦ Ranibizumab- $2039/treatment
◦ Bevacizumab- decreased to $7/treatment (but it costs them >$25)
Doctors now penalized for off-label use of bevacizumab
This change increased Medicare costs about $3 billion to cover
ranibizumab instead of bevacizumab
After protest, the decrease in reimbursement was overturned and
doctors now receive $55 for bevacizumab
◦ Some patients then filed a complaint that Medicare allowed bevacizumab
because they were motivated by cost rather than patient care!
◦ Patients are responsible for a fair proportion of cost on Medicare….
Money, money, money…
Fraud can occur in the prescription drug arena
There is big money to be made
Pharmaceutical spending was $327 billion in 2017
Post-marketing approval for new uses is very expensive
Fraudulent marketing has occurred
Kick-backs were once common
Off-Label Law Suits (some examples)
2017: Bristol Myers Squibb- $19.5 million for promoting Abilify in children and
adults with dementia
2013: Johnson& Johnson- $1.4 billion because they marketed Risperdal for
2012: Abbott- $800 million because they marketed Depakote to control
aggression in the elderly
2010: Astra Zeneca-$520 million for illegal marketing of Seroquel (they made
$4.9 billion in sales in 2009 from Seroquel)
2009: Eli Lilly- $1.415 billion for illegal marketing of Zyprexa in children and
Gabapentin (Neurontin)
Gabapentin was approved by the FDA in 1993 as adjunct treatment
for partial seizures
It has subsequently been approved for post-herpetic neuralgia and
for restless legs syndrome
It is widely used for many off-label purposes
It is very effective for neuropathic pain
It is effective for reduction in hot flashes
It is not very effective for its original approved use- seizures
Uses Promoted by Manufacturer
Gabapentin was agressively marketed for off-label use
Off-label use of this drug for pain increased from 1% in 1995,
to 41% of use of the drug in 2000
Overall, 83% of gabapentin use is off-label
95% of Medicare prescriptions for gabapentin are off-label
In 2000, sales of gabapentin were $1.3 billion- most of it offlabel
A “whistle-blower” who had been a salesman claimed that the
manufacturer illegally promoted the use of gabapentin for off-label
purposes to doctors
The company was reported to have
◦ Given false and misleading statements to health care providers regarding
◦ Given false statements regarding FDA approval
◦ Paying doctors to attend meetings to hear presentations regarding off-label use
◦ Sponsoring and providing input to medical education events that were supposed
to be “independent”
◦ Misleading physicians about these events
About of ½ of physicians received marketing appeals between 1995 and 1998 from
drug company salesman for off-label uses of gabapentin
Pfizer bought the drug, and said they would comply with the law in future
Parke-Davis/Warner Lambert/Pfizer was fined $430 million in 2004 (sales in 20013
were $2.7 billion)
Theywere fined $142 M in Canada in 2010 for fraudulent marketing
Pfizer was hit with more fines for Neurontin in 2014
There were 46 million prescriptions for gabapentin in 2017 (its generic now though)
Gabapentin- the evidence
Bipolar disorder
◦ 8 trials
◦ Ranged from1 or 2 patients, 8-37
◦ All were short term
◦ Mania improved slightly in some patients
◦ Depression improved slightly in some
Overall, not considered effective over the long term
Gabapentin- the evidence
◦ No clinical trials- anecdotes
◦ No evidence of effectiveness
◦ ADHD should be treated with stimulants and other
◦ Some effectiveness, but there are better
◦ Considered if nothing else has worked
Gabapentin- the evidence
Neuropathic Pain
◦Now approved for post-herpetic neuralgia
◦Used for diabetic neuropathy, has shown effectiveness
◦Effective for other types of neuropathic pain
◦Pregabalin (Lyrica) is also approved
◦Tricyclic antidepressants, old and cheap, are also useful for
this type of pain
◦Gabapentin is now also quite cheap now
Gabapentin- the evidence
Restless legs syndrome
◦Inconclusive data, only 2 case studies
◦Limited effectiveness
◦Has received FDA approval for this purpose
Drug/alcohol withdrawal
◦No evidence for effectiveness
Overall, gabapentin fairly safe, now generic, and may
be useful in many situations
Drugs Off-Label
Antipsychotics were
originally approved for
treatment of schizophrenia
The use of the newer drugs
has increased markedly,
much of it originally offlabel
Psychiatric Drug Off-Label
Astra Zeneca fined for off-label marketing of quetiapine
Quetiapine an effective antipsychotic
Originally approved for schizophrenia
Manufacturer pushed for use in bipolar disorder, now
approved for this purpose
Now being used as an antidepressant
Approved only for refractory depression, but
doctors are prescribing as initial treatment
Used as anti-anxiety agent
◦One clinical study suggested effectiveness,
improved sleep
Highly sedating, used for sleep disorders
A Few of the Side Effects
◦ Sleepiness
◦ Increased blood glucose
◦ Weight gain
◦ Increased cholesterol
◦ Cardiac problems
◦ Gastric problems
◦ Postural Hypotension
◦ Increased risk of death in elderly with dementia
Olanzapine (Zyprexa)
Approved for schizophrenia and bipolar disorder
◦ Subsequently approved for adjunct treatment of depression
Eli Lilly fined for promoting its use in agitation, depression, dementia,
sleep disorders
◦ “Viva Zyprexa!” campaign to expand use into primary care
◦ “5 at 5” marketing campaign- 5 mg at 5 pm to promote sleep
Side effects include weight gain, hyperglycemia, Type II
diabetes, increased death
◦ Manufacturer suggested weight gain could be beneficial in some
This is an anti-psychotic that was used off-label for treatment
resistant depression- This is a BIG market
The manufacturer has obtained FDA approval for adjunct
treatment of depression to be a labelled use for this drug now
It has also obtained FDA approval for a monthly maintenance
dose to treat bipolar disorder
 Ketamine, an anesthetic, is now being used off-label for
treatment-resistant depression
Antipsychotics in Dementia
Patients with Alzheimer’s disease sometimes have
hallucinations or are psychotic/hard to manage
Few therapeutic options for these patients
Newer antipsychotics became popular as off-label
Risperidone, olanzapine were most frequently used,
but older, conventional drugs have been used as well
All of the antipsychotics increased mortality in these
patients and are not recommended for use in patients
with Alzheimer’s disease
Mortality in older patients with
dementia treated with atypical or
typical antipsychotics
Black Box Warning
17 clinical trials were eventually
conducted, using most of the newer
Risk of death increased 1.6-1.7
The FDA has issued a Black Box
Warning for ALL Antipsychotics
Antipsychotics in Dementia
Prior to the Black Box warning,
prescriptions for antipsychotics in
elderly with dementia were increasing
by 16% per year
◦ Now, the rate of prescriptions for these
drugs in nursing homes for elderly went
down some (but not entirely)
So- the post-marketing system worked
New guidelines have been released
Antipsychotics in Other Populations
A recent study of VA patients showed that 60% of 279,778 patients
taking antipsychotics had no diagnosis for which their use was
◦ PTSD- 40%
◦ Minor Depression- 40%
◦ Major Depression- 23%
◦ Anxiety- 20%
◦ Alcohol dependence- 15%
◦ Drug abuse- 13%
Antipsychotics in Parkinson’s Dementia
Patients with Parkinson’s disease also get dementia
They may hallucinations and delusions
Atypical antipsychotics have been used in this population but are not
A new drug, pimavanserin, was approved by the FDA although it was
only slightly more effective than placebo
There have been concerns about the safety of this drug
Look at the FDA FAERS for reports on pimavanserin…..
Antipsychotics in Other Populations
In a Georgia Medicaid study
◦ Off-label use 64%
Cost of antipsychotic drugs about $13.1 billion/year in
the US
At least $4-5 billion for off-label use
◦ Lower doses used makes it a bit cheaper…
Little evidence for effectiveness in most of these
So, What Have We Learned?
Off-label use of drugs is very common
Doctors often do not know that the use of the drug is off-label
It is legal to use the drug off-label
◦ Unless manufacturer promotes incorrectly
It allows treatment of many groups who would be untreated (eg children,
since most drugs are not approved for them)
Adverse effects may be tracked and labeling changes made for off-label uses
Independent evidence is important in deciding whether drug is effective
Unexpected side effects can be a concern

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