Establishing Parameters
Liposomal drugs are another example of complex products in which clear guidelines will be necessary to determine the safety
of generics. Liposomes are known to have a broad array of differing molecules, which vary in physiochemical properties. Some
examples, such as Doxil or Myocet, include marketed intravenous formulations of anthracyclines, or a class of drugs used in
cancer chemotherapy derived from a certain bacteria, encapsulated in liposomes. These types of compounds differ from one another
because of the many possibilities to vary the composition and characteristics including size, charge, bilayer fluidity, number
of bilayers, hydrophilicity of the external surface, and the attachment of hydrophilic polymers and/or targeting ligands to
the external surface. The main factor in determining the safety and efficacy of these products is through the rate and extent
of the drug release from the liposomal particles. For this reason, bioequivalence between generic liposomes and the reference
product should surround the release profile of the two therapies. Furthermore, the FDA has expressed concern that generic
versions of these types of drugs may, in fact, represent a completely new complex drug profile. As with all generics, a generic
liposome product should have the same characteristics as the innovative product; therefore, the parameters established for
these drugs need to be carefully addressed.
It has been argued that even if adequate technology is available to evaluate preclinical analytic data for products that demonstrate
interchangeability, it may still be difficult to ensure that the same dose of a generic product and its innovator are truly
equivalent. The EMA and other regulatory bodies have adopted a biosimilar approval pathway that requires clinical trials to
show therapeutic equivalence. However, for more complex drugs like glatiramoids, regulatory guidance is still undefined. The
FDA is currently working on guidance regarding the approval pathway for biosimilars and should take the EMA guidelines and
insights from industry experts into consideration. A single regulatory pathway meant to encompass all biologics and NBCDs
may be untenable. For example, some therapies may not require clinical trials to show substitutability while others may. To
protect patients, both the therapy and disease mechanism of action need to be considered.
The small-molecule generic approach should be limited to products that can be fully characterized, with established efficacy.
For highly complex products, like glatiramoids, where guidance does not exist, the biosimilar-like approach outlined by the
EMA should be applied, which includes full documentation of quality; inclusion of preclinical and clinical data; and a comparison
between the reference and generic product in terms of quality, safety, and efficacy. Special emphasis should also be given
to immunogenicity issues.
As US regulatory authorities grapple with the many considerations involved in developing guidance for the approval of follow-on
biologics, they should take into consideration the unique sensitivities associated with highly complex drugs, like NBCDs.
By referencing the EMA biosimilar pathway, the FDA has a foundation from which to build, as the agency works toward a US regulatory
process. Clinical data may be necessary for follow-on biologic and NBCD applications, but should not delay the approval process
if the reference product can be fully characterized.
Jill B. Conner, PhD, is Director of Medical Affairs and Medical Operations at Teva Neuroscience. She can be reached at Jill.Conner@tevapharm.com
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