Multiple-dose, comparative, parallel arm steady state PK studies are required for a similar biologic that is used in a multiple dose regimen, where markedly higher or lower concentrations are expected at steady state than that expected from single dose data PK measurements, and where time-dependence and dose-dependence of PK parameters cannot be ruled out.
Similarly, the India Guidelines require human pharmacodynamic studies:
Comparative, parallel arm or cross-over, PD study in most relevant population (patients or healthy volunteers) is required for detecting differences … If PD marker is available in healthy volunteers, PD in healthy volunteers can be done. … The relationship between dose/exposure, the relevant PD marker(s) and response/efficacy of the reference biologic should be well established and used to justify the design. The acceptance ranges for the demonstration of similarity in PD parameters should be predefined and appropriately justified.
Such PD studies are “recommended” when “the PD properties of the reference biologic are well characterized with at least one PD marker being linked to the efficacy of the molecule.”
The India Guidelines appear to mandate at least some additional human clinical trials “to demonstrate the similarity in safety and efficacy profiles between the similar biologic and reference biologic.” To establish similarity, “equivalence trials with equivalence designs (requiring lower and upper comparability margins) are preferred.” Hence, in India, unlike the US, it would seem to be possible, in some circumstances, to employ non-inferiority tests to establish efficacy and aspects of safety in addition toimmunogenicity.
As in the US and EU, assessment of adverse events occasioned by administration of a biosimilar product is a critical component of human clinical testing. Hence, the India Guidelines state that the “nature, severity and frequency of adverse events should be compared between the similar biologic and reference biologic and should be based on safety data from a sufficient number of patients treated for an acceptable period of time.” These guidelines add that [e]fforts should be made to ensure that comparative clinical studies have a sufficient number of patients treated for acceptable period of time in order to allow detection of significant differences in safety between similar biologic and reference biologic.”
The India Guidelines add specific post-market surveillance requirements that seemingly will augment or, perhaps, substitute for extensive pre-approval human clinical testing requirements. First, the guidelines require institution of a post-approval Risk Management Plan, designed to monitor and detect both known inherent safety concerns and potential unknown safety signals that may arise from the similar biologics. Such a risk management plan must be submitted along with a biosimilar sponsor’s Market Authorization Application. The Plan must include at least one non-comparative post-marketing clinical study with focus on safety and immunogenicity, designed to confirm that the similar biologic does not have any concerns with regards to the therapeutic consequences of unwanted immunogenicity. However, the India Guidelines provide, “[i]f immunogenicity is evaluated in clinical studies, it is not mandatory to carryout additional non-comparative immunogenicity studies in post-marketing studies.”
The importance of shifting human clinical testing requirements to the speed of approval of a biosimilar may be demonstrated by the experience of Dr. Reddy’s Laboratories (DRL) in approval of its Reditux® (rituximab) biosimilar product. During the November 2010 pre-guidance FDA hearing, a speaker for DRL reported that pre-approval testing of DRL’s rituximab biosimilar required administration of the proposed product to a mere 67 patients, with many more reported in post-market surveillance. Post market surveillance did not show “a single case of immunogenic response in any patient,” with more than 1000 patients treated with DRL’s Reditux after market approval, by the time of the presentation.
Extrapolation
The FDA guidances indicate that data derived from a clinical study sufficient to demonstrate safety, purity, and potency in an appropriate condition of use, potentially may be extrapolated to allow the biosimilar to be licensed for one or more additional indications for which the reference product is licensed. For example, relying on clinical testing of a Humira® or Remicade® biosimilars in patients with rheumatoid arthritis, it may theoretically be possible to obtain licensing for sale and use of such biosimilars in patients suffering from psoriasis or Crohn’s disease, which, like rheumatoid arthritis, are thought to be conditions associated with inflammation caused by the production of TNFα (tumor necrosis factor-α) in humans, without substantial or any additional clinical testing.
The India Guidelines state that “[i]n case the reference biologic is used for more than one indication, the efficacy and safety of the similar biologic has to be justified and if necessary demonstrated separately for each of the claimed indications.” They add that [j]ustification will depend on clinical experience, available literature data and whether or not the same mechanism of action is involved in specific indications.” The guidelines thus state that, in India, “extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible,” if certain conditions are met. The list of conditions for consideration of extrapolation is not as long as the list in US guidances, but it is similar in content.
Reference Product
The India Guidelines define a “reference biologic” as “the comparator [used] for head-to-head comparability studies with the similar biologic in order to show similarity in terms of safety, efficacy and quality.” The definition requires that “[o]nly a product that was licensed on the basis of a full registration dossier can serve as reference biologic.” Under the guidelines the reference biologic must be used in all “comparability exercise[s] with respect to quality, preclinical and clinical considerations.”
Under the India Guidelines, the reference biologic “should be licensed in India and should be innovator product.” It should be “licensed based on a full safety, efficacy and quality data.” Hence, “another similar biologic cannot be considered as a choice for reference biologic.”
While the reference biologic must be licensedin India and should be innovator product, it is not necessary, under the India Guidelines for the reference product even to be sold or marketed in India. The India Guidelines may simply recognize that some foreign manufactured biologic products are simply not yet available in India, if only for economic reasons. The India Guidelines appear to permit use of foreign reference biologic products in a comparability exercise, whether or not the reference product is marketed or, under some circumstances, even licensedin India. The critical issue will be whether Indian biosimilar developers and manufacturers are able to obtain sufficient quantities of a foreign reference product to enable all of the required analytical, animal and human clinical testing required by Indian regulators. While this seemingly has not been an extraordinary impediment to date, legal developments may make acquisition of reference product more difficult in the future.
Manufacturing
The India Guidelines set forth a series of quality considerations applicable to manufacturing of biosimilar products. Among other things, these guidelines state that the “manufacturing process for similar biologic should be highly consistent and robust.” They set standards for cell lines used in the biosimilar manufacturing process, as well as standards for fermentation and downstream process development, analytical methods, product characterization, stability and specifications. The guidelines generally require that “three consecutive standardized batches which have been used to demonstrate consistency of the manufacturing process should be used” in the quality comparability study. The guidelines mandate that “[h]ead-to-head characterization studies are required to compare the similar biologic and the reference biologic at both levels of drug substance and drug product,” adding that “[d]ifferences … should be evaluated for their potential impact on safety and efficacy of the similar biologic and additional characterization studies may be necessary.” The India Guidelines provide that such a “quality comparison … should employ state-of-the-art analytical techniques, including the analytical methods that are sensitive enough to detect the possibilities of changes to the product,” providing a list of routine analytical tests to be included in the quality comparability exercise.
Concluding Comments
The India Guidelines represent a major step forward in establishing a rigorous, science-based regime for approval of biosimilars pharmaceutical products, especially for sale and therapeutic use in India. The guidelines mirror similar efforts in the US and EU and, like those “regulated market” guidances, consciously rely upon other guidance documents issued by the International Conference on Harmonization, with a view toward encouraging the manufacture of safe and effective biologic products in India, perhaps at lowered costs, to ensure access to life-saving drugs for many.
Like their counterparts in the US, EU and perhaps elsewhere, the India Guidelines will contribute to harmonization efforts, perhaps ultimately resulting in a globally consistent approach to biologic development and manufacture, reducing the need for redundant clinical trials. The guidelines will likely also contribute enabling certainty to the efforts of both Indian drug manufacturers and others who may enter the burgeoning Indian market, that contemplate significant investment in research, manufacturing facilities, and new means of product marketing.
All of this may well lead Indian manufacturers to become effective competitors in the global market for biologic medicines, both as suppliers of biosimilar products and, soon thereafter, of “biobetters” and innovative new medicines. That contribution to global health, whether encumbered or unencumbered by disputes over exclusivities and patent protection, will be welcomed by all.