The European approach
Many American makers of biologic drugs view the European approach to approving follow-on drugs favorably. To date, EMEA has
approved 13 follow-on biologics, or about 67% of all applications (9). The European path is reasoned, scientifically balanced,
and would be a good basis for an American approval process, says Jim Green, senior vice-president of preclinical and clinical
development sciences at Biogen Idec (Cambridge, MA). Indeed, FDA and EMEA have included follow-on biologics on the agenda
for upcoming joint discussions.
EMEA developed guidelines about quality, nonclinical considerations, and clinical considerations for biologicals. The agency
also published guidances for particular classes and products. Product-specific guidances describe specific proteins such as
insulin, growth hormone, and erythropoietin. These proteins are relatively small and easy to characterize.
Makers of follow-on biologics must demonstrate to EMEA that their products have comparable biophysical and chemical characteristics
to the reference products, says Ahmed. To do this, an applicant must compile a data set (i.e., a full quality dossier) by
characterizing its product (e.g., performing biochemical analysis and bioactivity analysis) at each stage of production and
comparing it with the innovator product.
EMEA usually evaluates bioequivalence with a case-by-case approach, rather than according to a standard. This method provides
regulatory flexibility because the drugs' inherent variability and the lack of alternative therapies sometimes persuade regulators
to accept wide margins of equivalence, says Schneider. But margins should be justified adequately during discussions between
applicants and regulators, he adds.
Acceptable differences between drugs depend on the inherent risk that the bio-similar poses. "Biosimilars that simulate an
endogenous protein, such as erythropoietins, are usually perceived as higher-risk biosimilars, thus reducing the regulatory
tolerance to differences in side effects or immunogenicity," Schneider says.
In addition to analytical testing, nonclinical and clinical data are usually required, says Schneider. The guidance documents
list the standards for clinical-trial requirements for various classes and products. These requirements vary, however, according
to the product and the availability of acute and reproducible characterization methods. Other factors that affect clinical-trial
requirements include the drug's molecular complexity, therapeutic window, safety profile, and indications. Overall, European
clinical requirements for follow-on biologicals are usually much less onerous than for new biologicals, says Schneider.
EMEA also requires postapproval monitoring for follow-on biologicals that are administered for long periods. This requirement
is intended to provide additional confirmation that the follow-on's safety and immunogenicity profiles are similar to those
of the reference product. "I think that's important to maintain within the context of a US approval system," says Green.
The American way
The Public Health Service Act provides a framework for the approval of innovative biological drugs, but no US law explicitly
enables FDA to approve follow-on biopharmaceuticals. The Hatch–Waxman Act of 1984 established an abbreviated pathway for the
approval of small-molecule generic drugs, and regulators have used it to approve follow-on versions of small protein drugs
that are well understood (e.g., human growth hormone and insulin). Larger proteins such as antibodies are more complex and
seem to require an entirely new approach. In March 2009, legislators introduced two bills to Congress that would provide a
method for FDA to evaluate and approve follow-on biologics.
The Waxman bill.
Rep. Henry Waxman (D-CA) introduced the first of the two bills, "Promoting Innovation and Access to Life-Saving Medicine
Act." This bill is similar to the Hatch–Waxman Act in many ways. The Waxman bill would not require new clinical trials for
follow-on biologics. Instead, an applicant could use the innovator's safety and efficacy data as long as these data showed
that the follow-on product and the reference product had highly similar molecular structures; that the follow-on would not
exhibit clinically meaningful differences in safety, purity, and potency with the reference product; that the follow-on and
the reference product had the same mechanism of action; and that the follow-on and the reference biologic product had the
same use, method of administration, dosage, and strength.
The Waxman bill would also allow FDA to determine that an approved follow-on biologic was interchangeable with its reference
drug. This designation would let pharmacists substitute a follow-on for a branded biological as long as the prescription did
not forbid it.
Finally, the Waxman bill also grants patent protection for innovators' biologic drugs. New biopharmaceutical products would
receive five years of exclusivity, and products with new indications would receive three years of protection. If a manufacturer
undertook pediatric studies of its drug, the bill would grant the company six additional months of exclusivity (10).
The Eshoo bill.
Less than a week after the Waxman bill was introduced, Rep. Anna Eshoo (D-CA) introduced the "Pathway for Biosimilars Act."
The Eshoo bill would require the maker of a follow-on biologic to submit data from clinical trials that compared the product's
immunogenicity with that of the innovator's product. FDA could only waive the requirement for clinical trials after it published
a guidance that described what data would justify a determination about the immunogenicity of a follow-on product in a particular
Unlike the Waxman bill, the Eshoo bill would only allow FDA to determine that a follow-on product was interchangeable with
an innovative biological after the agency published a final guidance that described what data would justify a determination
The Eshoo bill would grant more patent protection for innovators' products than would the Waxman bill. New biopharmaceuticals
would receive 12 years of market exclusivity under the Eshoo bill. If a new indication were approved for an existing biological
within eight years of the product's approval, the product would receive 14 years of exclusivity. Like the Waxman bill, the
Eshoo bill would grant six additional months of exclusivity to innovators that undertook pediatric studies of a biopharmaceutical