(ILLUSTRATION BY DAN WARD)
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As pharmaceutical companies face shortfalls in R&D productivity and increased generic-drug incursion, product lifecycle
management becomes increasingly important. Combination therapies provide an opportunity for innovator drug companies to extend
the lifecycle of a given API by developing a fixed-dose combination product that may offer improved and synergistic efficacy,
improved dosing regimes, and greater patient compliance. Combination drugs also allow specialty pharmaceutical companies to
use specialized drug-delivery and formulation strategies for product differentiation. Challenges, however, exist in developing
fixed-dose combination products compared with single API products, such as maintaining the physical and chemical stability
of the APIs and modulating drug release.
Regulatory framework
Combination products encompass a wide range of products, including drug–device combinations. By regulatory definition, a combination product is a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological
product; or a drug, device, and a biological product (1, 2). Under 21 CFR 3.2 (e), a combination product is defined to include:
- "A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic)
that are physically, chemically, or otherwise combined or mixed and produced as a single entity" (e.g., a monoclonal antibody
combined with a therapeutic drug, a device coated or impregnated with a drug or biologic, prefilled syringes, insulin injector
pens, metered dose inhalers, and transdermal patches).
- "Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products,
device and biological products, or biological and drug products" (e.g., drug or biological product packaged with a delivery
device).
- A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling
is intended for use only with an approved individually specified drug, device, or biological product where both are required
to achieve the intended use, indication, or effect and…the labeling of the approved product would need to be changed (e.g.,
to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose)."
- "Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for
use only with another individually specified investigational drug, device, or biological product where both are required to
achieve the intended use, indication, or effect" (e.g., photosensitizing drugs and activating laser/light sources and iontophoretic
drug delivery patches and controllers) (1–3).
Table I: Number and type of combination drug products for original applications for new drug applications (NDAs), biologics
license applications (BLAs), premarket approval applications (PMAs), premarket notifications (510(k)s, investigational new
drugs (INDs), investigational device exemptions (IDEs), and humanitarian-use exemptions (HDEs) received in fiscal year 2011
by FDA.
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In fiscal year 2011, FDA received 288 original applications classified into nine categories of combination products (see
Table I
). These applications included 26 new drug applications and 134 new investigational new drug applications, of which the majority
were drug–device combinations (see
Table I)
(2).
Combination products also include oral fixed-dose combination drugs of two or more APIs in a single product form (i.e., tablet
and capsule). According to 21 CFR 300.50, "two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed
effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective
for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug" (4).
