n the United States, "unlabeled uses" (namely
"off-label drug use") are defined as drug uses that not included in the
indications or dosage regimens listed in the US Food and Drug
Administration (FDA)-approved labeling. Unlabeled use includes the use
of a drug product in doses, patient populations, indications, or routes
of administration that are not reflected in FDA-approved product
labeling [1]. Off-label drug use is common in many clinical areas such
as psychiatry, pediatrics, oncology and intensive care unit [2-5].
Sometimes off-label drug use is the only option for the patient’s
treatment. For example, methotrexate is the current gold standard
for rheumatoid arthritis treatment, which is off-label use in China.
However, off-label drug use is not uniformly regulated across the globe.
The Indian Medical Association had launched a campaign to permit
off-label drug use in India [6], but its legality still remains
disputed.
Although off-label drug use is legal in many
countries, its safety has attracted much attention. No law prohibits
off-label drug use in the United States and Canada [7,8]. Off-label drug
promotion is not allowed in many countries, but it is also not
absolutely prohibited. In the United States, the legislation governing
insurance reimbursement for off-label drug use varies from state to
state [9]. The Canadian Agency for Drugs and Technologies in Health
(CADTH) conducts cost-benefit assessments of drugs for their approved
indications through its Common Drug Review (CDR) process, and then
issues a recommendation to provinces and territories as to whether the
drug should be reimbursed by public programs. In Germany, the off-label
drug use is regulated by either the Medicines Law or the Social Law
[10]. Physicians are permitted to prescribe drugs outside the labels
within their therapeutic flexibility [11]. However, drugs can only be
prescribed at the expense of the statutory health insurance if they are
used for the treatment of a disease for which the pharmaceutical company
has obtained a marketing authorization from the relevant authority [12].
According to the British General Medical Council (GMC), off-label
prescriptions must better serve patient needs than alternatives and must
be supported by evidence or experience to demonstrate safety and
efficacy [13]. In special circumstances, National Institute for Health
and Clinical Excellence (NICE) provides advice on the use of unlicensed
and off-label uses of drugs [14]. Pharmaceutical companies operating in
the European Union need to collect and report information on the
off-label use of their drugs under new obligations making its way from
draft to final form at the European Medicines Agency (EMA) in the summer
of 2016 [15].
There is no legislation on off-label drug use in
China. Some public media in China once raised the issue of off-label
drug use being illegal, bringing a big headache to Chinese healthcare
professionals. The Guangdong Province Pharmaceutical Association (GDPA)
issued the consensuses on off-label drug use in 2010 and 2014, the first
set of standards for off-label drug use in China, and has done a lot of
work that changed the perspective of off-label drug use in China
[16,17]. In both China and India, the demand for healthcare is
increasing speedily with the rapid economic development. Therefore, our
working idea on off-label drug use may provide a reference to Indian
healthcare professionals.
Ethics is the framework of guiding principles that
brings order and purpose into what would otherwise be a void between
laws, and goes beyond law. India has medical ethical guidelines, but no
item refers to off-label drug use [18]. However, we can find the basis
of off-label drug use from the principles of medical ethics, which is a
system of moral principles that apply values and judgments to the
practice of medicine. In our opinion, it is unethical not to treat a
patient just because the necessary drug use is not in the label, and a
law preventing patients from the suitable treatment is not a good law.
Making off-label drug use illegal makes the best available therapy for
some patients impossible. For example, special populations, such as
children, pregnant women and elderly people, are often excluded from
drug trials. Thus many of their medications are off-label, but we must
try our best to treat them if they are ill. Off-label drug use is common
in children in Indian healthcare system. In neonatal intensive care
units of two institutions in Chandigarh, India, half of the
prescriptions in neonates were off-label [19]. In the
pediatric intensive care unit at a tertiary care hospital in another
Indian metropolitan city, 71% of the prescriptions were off-label in
nature [20]. Similar experience is available from other parts of the
country [21,22].
Human physiological pathways are always interlaced,
thus a drug effective for one disease may be effective for another.
However, it is impossible to include all the information in the drug
label. For example, both bevacizumab and ranibizumab are targeted
biological drugs that inhibit vascular endothelial growth factor, an
angiogenic cytokine that promotes vascular leakage and growth, thereby
preventing pathological angiogenesis. Ranibizumab is indicated for the
treatment of patients with neovascular age-related macular degeneration
(AMD), but bevacizumab was initially approved for the treatment of
colorectal cancer. The off-label use of bevacizumab and the approved use
of ranibizumab have equivalent efficacy for neovascular AMD [23].
However, it is much cheaper to use bevacizumab than ranibizumab to treat
neovascular AMD. If treating neovascular AMD with bevacizumab is banned,
some neovascular AMD patients who cannot afford ranibizumab will
therefore not get the treatment. Reducing the price would still not
fundamentally solve the affordability problem, the subcommittee of the
National List of Essential Medicines of Thailand (NLEM) listed
bevacizumab in the NLEM for AMD and diabetic macular edema in 2012 [24],
making Thailand the first country to officially endorse bevacizumab for
macular treatment.
As clinical situations are constantly changing, we
need to establish a strict but flexible management mechanism for
off-label drug use. The four principles of medical ethics are: respect
for autonomy, beneficence, non-maleficence and justice. In order to meet
these principles, we have the following consideration:
(i) The off-label use must not be for
research purposes.
(ii) If there is no reasonably replaceable
drug to treat the patient’s condition, the benefits of the off-label
use outweigh its risks, and the use is the best choice for the
patient.
(iii) The off-label use must be based on
reasonable medical practice evidence. In order to be more objective
and avoid medication and medical errors, the pharmacy department of
the hospital should verify the evidence of off-label use, and expert
advice should be sought. It will be better that the advice comes
from the drug control society of a country, but this practice cannot
adapt to rapid clinical change. Thus we propose that the hospital’s
pharmacotherapy and hospital ethics committees are good choices,
which is similar to the practice in some countries [25-27]. If the
risk is low, the off-label drug use just needs to be approved by the
hospital’s pharmacotherapy committee. However, the off-label drug
use should also be approved by the hospital ethics committee in case
the use poses high risk to the patients. Previously, hospital ethics
committees in China mainly looked after research ethics by reviewing
and approving research projects, but they are now involved in
various ethical aspects of clinical practice, as clinical ethical
committees do in the US and the United Kingdom [28]. However, the
off-label drug use may be exempted from application for approval in
an emergency situation.
(iv) As the off-label drug use may not
have been formally evaluated, the risk should be fully realized and
the contingency plan must be ready. The use must be monitored
continuously, and then the progress note must be written in detail.
(v) As the drug knowledge is developing
and the label may change, the off-label drug use should be improved
continuously.
The above five items meet the principles of
beneficence and non-maleficence. The principle of respect for autonomy
means that patients have the right to refuse the treatment [29]. Thus,
consent should be obtained from the patient or guardian. Although some
items above could be considered as imposed requirements [30], we hold
the opinion that these requirements make the off-label use more
reasonable, especially against the backdrop of already existing
physician-patient disharmony. The above consideration is also consistent
with Article 37 of the Declaration of Helsinki 2013 on Unproven
Interventions in Clinical Practice, and can be deemed as the embodiment
of duty of care in law.
Legal justice originates from ethical justice;
therefore, ethical off-label drug use can be considered legal. In 2012,
the China Ministry of Health (MOH) issued the GDPA consensus in its
working document. In 2015, the key points of the GDPA consensus have
been put into the clinical pharmacy textbook of the China National
Health and Family Planning Commission (Formerly MOH) [31]. More and more
hospitals in China have established regulations to manage off-label drug
use according to the GDPA consensuses. Indian medical professionals
should develop a common executable standard on off-label drug use, which
can be applied to evaluate such use in clinical practice. It is better
that the center for drug control of a country issues a list of off-label
drug uses with high-level of evidence.
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