DIABETES CARE
As diabetes has become endemic in South Asia, we, as health care professionals, have
to reassess our strategy to tackle the condition. One way in which this is done is
by encouraging development, and rational usage, of modern pharmaceuticals. Such drugs
are expected to be effective, safe and well-tolerated. In a chronic condition such
as diabetes, it is imperative to be aware not only of short-term side effects, but
of the potential for long-term adverse consequences as well.
EVOLUTION OF INSULIN
The glucose-lowering drug in existence for the longest period of time is insulin.
For almost a century now, insulin has helped save the lives of millions of people
with diabetes. Over the decades, however, the type and quality of insulin has changed
significantly. Newer methods of manufacturing have allowed production of larger amounts
of effective, pure drug forms. This has been achieved by using recombinant deoxyribonucleic
acid technology, with either bacteria (Escherichia coli) or yeast (Saccharomyces cerevisiae,
Pichia pastoris) as host.[1] The use of these living organisms, as vectors for insulin
synthesis, classifies insulin, along with other hormones, like a biological product
[Table 1]. Enhanced awareness about the “therapeutic triad” (efficacy, safety, and
tolerability) has prompted stringent regulatory processes, which ensure that no innovator
biological molecule reaches the customer without going through a robust preclinical
and clinical development program.
Table 1
Definitions
BIOSIMILARS
At the same time, however, copies of such innovator biological products are being
produced. These copies, termed as biosimilars, are marketed in regulated countries
after expiry of patent production, but have been made available in less regulated
markets (e.g.China) even prior to this. Biosimilars may be similar to, but are not
exactly the same as, generics, or originator/innovator biological products [Tables
2 and 3].[2
3]
Table 2
Comparison of biosimilar and generic drugs
Table 3
Comparison of biosimilars and innovator molecules
Analogies to biosimilars can be drawn from the scientific world. To explain the concept,
biosimilar products may be compared with water vapor, water, and ice: All have the
same chemical formula (H2O) but have totally different structures. Similarly, diamond,
coal, and graphite are the same carbon atom, but totally dissimilar in appearance.
To take a typically South Asian analogy, various varieties of mango, rice, or fish,
may be biosimilar to each other, but are in no way the same. The average South Asian
can easily distinguish between farm-grown and wild catch fish; various types of mango;
or different types of rice. In a similar fashion, the diabetes care professional understands
the subtle defining characteristics of an original biologic and its follow-ons on
copies.
SOUTH ASIAN SCENARIO
South Asia is known as the drug factory of the world. Large pharmaceutical manufacturers,
in Bangladesh, India, and Pakistan, meet both domestic and international demand. While
no biosimilar insulin is approved in USA as of date August 2015, the European Medicines
Agency and Japanese drug regulatory authorities have given approval to only one insulin-a
biosimilar insulin glargine produced by Eli Lilly (Abasria).[4
5] The number of biosimilar insulin approvals in some South Asian countries is more,
however [Table 4].
Table 4
Biosimilar insulins and insulin analogs marketed in South Asia
Most South Asian countries have well laid out regulatory pathways for biosimilar approval.
India, for example, expects a biosimilar to prove efficacy for each indication that
it is approved in.[6] Sri Lanka is one nation which has applied strict World Health
Organization (WHO) good manufacturing practice rules.[7] Sri Lanka now requires all
biosimilars applying for approval to demonstrate safety and efficacy through a locally
conducted randomized controlled trial. This has resulted in many poorly studied biosimilars
losing their license. The Organization of Pharmaceutical Producers of India, in its
position paper on biosimilars, has also called for national regulatory guidelines
to conform to those of the WHO.[8]
PATIENT'S PERSPECTIVE
Studies have been carried out in the West to assess public opinion regarding biosimilars.
In an American study of 3214 patients with diabetes, 27% replied that they would “definitely
use” biosimilar while 13% and 4% stated they would be “unlikely to use” and “definitely
not use” biosimilars, respectively. Participants mentioned that they would consider
the delivery device, brand quality, and trust as significant factors in their decision
not to take biosimilars. While many respondents appeared to favor biosimilars because
of low cost, there were a few who were hesitant to switch for precisely the same reason:
They equated low cost with low quality.[9]
In another survey of 629 Americans, only 9% persons with Type 2 diabetes and 27% of
Type 1 diabetes were familiar with the term “biosimilar.” Though 30% prescribers and
12% pharmacists said, they used biosimilars, almost all of them identified biosimilars
wrongly. Awareness about regulatory pathways for approval of biosimilars was poor.[10]
The studies mentioned above reflect the need for aggressive public and health provider
education before biosimilars can be used safely.
CHALLENGES WITH BIOSIMILARS
The approval and use of biosimilars is associated with novel challenges, which must
be met by sustained awareness and education campaigns.[10] All stakeholders in diabetes
care, including regulatory authorities, prescribers, counselors, pharmacists, and
patients, should be aware of the distinction between biosimilars and innovator products
[Table 5].[11
12]
Table 5
Clinical issues with biosimilar use
Efficacy and safety
Health cost payers, whether governmental authorities or insurance companies, are faced
with the challenge of achieving “health for all” within a limited budget. Therefore,
they tend to prefer economical drugs.[11]
Insulin, however, is different from other pharmaceutical compounds. Insulin potency
can be affected by variations in the raw material source, production process, and
factory equipment. The presence of host-related, process-related, and product-related
impurities may cause differences in pharmacokinetic and pharmacodynamic properties.
There is a theoretical risk of formation of insulin-neutralizing antibodies, and “iatrogenic”
insulin resistance, if frequent switching of insulin preparations is done.[11]
Labeling
Labeling of marketed products must clearly mention the name of the biological molecule,
its method of production, and whether it is an originator or biosimilar drug. As all
preparations of aspart insulin or glargine insulin, for example, cannot be equated
with each other, the trade name, or unique identifying name must be used. Biological
product usage is different from generic prescription in this regard. The product insert
should clarify which indications the molecule has been studied in, as opposed to which
indications it is approved for.[13]
Substitution
Substitution of biological products carries potential for harm. No insulin preparation
should be substituted unless clinically indicated. The substitution must be informed
to the patient, and frequency of clinical as well as glycemic monitoring stepped up
in such cases. The need to avoid insulin substitution is an integral part of insulin
technique guidelines.[14]
Pharmacovigilance
Pharmacovigilance data must reflect the actual product being described, whether biosimilar
or innovator. A recent report of hypersensitivity to biosimilar glargine is an exemplar
of this concern.[15] Just as the safety of biosimilars is of paramount importance,
so is efficacy. There is evidence that higher doses of biosimilar insulin are needed
to achieve glycemic control.[16]
PATIENT-CENTRED APPROACH
Modern diabetes care prides itself upon a patient-centered approach, which respects
the patient's attitudes, wishes, and needs. Such an attitude is evident in Ayurveda
teachings from India and is exemplified by the behavior and work of great pioneers
such as National Professor Mohammed Ibrahim of Bangladesh.[17
18] To achieve optimal therapeutic outcomes, we practice informed, shared decision
making with the patients in every sphere of diabetes management.
Such combined decision making should extend to choice of insulin preparations. Patients
should be able to make an informed choice regarding the choice of originator or biosimilar
molecules, based upon available evidence, and socioeconomic reality. All factors which
may influence this decision, including robustness of clinical data, quality of cold
chain maintenance, and availability of postmarketing pharmacovigilance activities,
should be made public.[19
20]
Our call for shared decision-making, based upon informed choices, is not in contradiction
to earlier recommendations for prescriber-based choice (as suggested by the American
College of Rheumatology).[21] The prescriber, too, is an integral part of shared decision
making. In a chronic disease such as diabetes, the choice of therapy cannot be dictated
by a single shareholder, whether physician, pharmacist or payer. The patient has the
right to participate in management-related decisions and choose the best available
(or optimal product for himself or herself).
CONCLUSION
As the diabetes pharmacotherapeutic arena expands, more debate and discussion will
be needed to decide appropriate, patient-friendly means of using newer insulins. Regulatory
authorities will need to apply stringent mechanisms to ensure that only scientifically
rational molecules, with robust preclinical and clinical development programs, are
approved for use. Once and biosimilar are required to conform to stringent rule as
applied to innovators, quality will be assured.
Postapproval pharmacovigilance must be maintained, in order to ensure safety and tolerability.
The patient, along with prescriber, (and payer, if relevant) should be allowed to
take shared, informed decisions regarding the insulin they wish to use. This will
be “patient-centeredness” in its true spirit.