The European Medicines Agency has released a simplified version of its guideline on bioequivalence that focuses on quality issues, instead of clinical efficacy and safety perspectives.
EMA noted that some EU member countries preferred this quality approach to begin with, while others "have a more clinical relevance approach." The unwanted result has been that since the draft guideline came out in July 2008, many applications have had to be referred to the EMA's Committee for Medicinal Products for Human Use or the Co-ordination Group for Mutual Recognition and Decentralized Procedures.
The final guideline, which was released in January 2010, focuses on the easiest-to-quantify products: immediate-release formulations with systemic action. The document illustrates that even as European governments seek ways to boost generic utilization, the science behind them can often still be the subject of controversy.
Simpler, But No Less Stringent
The European Generic Medicines Association argued that the draft guideline was "very demanding in light of the prescriptive requirements it contains and of the number of new acceptance criteria it introduces," according to a summary published on the EMA Web site.
But while it did try to make the final guideline easier to interpret, EMA was reluctant to budge on industry requests to significantly loosen the requirements in various key areas. For example, commenters wanted individual packaging to be optional, but EMA rejected that suggestion, arguing that "it is of utmost importance that it is possible to identify unequivocally the identity of the product administered to each subject at each trial period. ... The aim of the requirement for individual packaging is not only to prevent fraud, but also to limit the risk of mistakes and to improve the traceability of the identity of the product administered to each subject at each trial period."
Another key area where EMA did not change its mind has to do with analytical methods and conditions. One commenter wanted the final guideline to say that any scientifically justified dissolution method, including volumes and choice of media and paddle speeds, would be acceptable. But the agency feels its more restrictive specifications are in line with the Biopharmaceutics Classification System-based biowaiver concept comparing different products with regard to bioequivalence, in contrast to quality control or other issues.
Changes To The Final Guideline
In other areas, EMA did make changes in response to comments. For example, commenters questioned whether performing a steady-state study in patients, as opposed to doing a single-dose study with a lower strength, would really reduce consumer risk.
"Contrary to other initiatives in the world, European regulators are moving in the introduction of additional requirements for steady-state studies in the case of immediate-release dosage forms," EGA argued. "This does not contribute significantly to better proof of bioequivalence. This move must have its roots in an overestimation of the added value of steady-state studies in those cases."
"The revised guideline focuses on strength and not dose," EMA responded. "In cases where evaluation of the highest strength is recommended and this is not tolerated in healthy volunteers, the highest tolerated strength may be selected."
In another instance, EGA suggested that bio-analytical requirements be addressed in a separate guideline, a suggestion EMA accepted.
As a supra-national institution, there are some areas EMA could not address. For example, several companies asked when the scientific principles of bioequivalence described in the guideline apply to generic substitution, but the agency said that it is a national legal issue that an EU guideline cannot deal with.
Many aspects remained virtually unchanged between the draft and final guidelines. EMA wants sponsors to justify the number and design of bioequivalence studies they plan to conduct based on the physico-chemical characteristics of the substance, its pharmacokinetic properties and proportionality in composition, according to the guideline. They may need to address linearity in pharmacokinetics, the need for studies in both fed and fasting states, the need for enantioselective analysis and the possibility of waiver for additional strengths.
Studies should be designed so that the formulation effect can be distinguished from other effects, according to the guideline. If two formulations are compared, a randomized, two-period, two-sequence, single-dose crossover design is preferable. However, under certain circumstances, well-established alternative designs could be considered, such as parallel design for substances with a very long half-life and replicate designs for substances with highly variable pharmacokinetic characteristics. Sponsors may conduct a multiple-dose study in patients rather than healthy volunteers if the latter cannot take the drug for tolerability reasons and the patients cannot participate in a single-dose study.
- Martin Berman-Gorvine (2 m.berman-gorvine@elsevier.com)
This article also appeared in "The Pink Sheet" – Feb 15, 2010
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