The ability of modern analytical techniques to ensure that generic or follow-on versions of biotech therapies are comparable
to the innovator product is emerging as a key issue for shaping a legal pathway to bring these products to market. Generic
drug makers, as well as some biotech firms, want Congress to authorize the US Food and Drug Administration to approve similar
biologics based on an abbreviated application that draws on test data developed by the innovator firm. The Hatch-Waxman Act
established such a process for conventional drugs in 1984, but it does not apply to biologics regulated by the Public Health
Service Act. Now many companies claim they have the science and the skill to document the comparability and safety of large
molecules and are pressing to overcome the legal obstacles.
To protect markets and preserve R&D incentives, brand manufacturers insist that all follow-on biologics require additional
testing to assess immunogenicity and ensure product safety. Even then, follow-ons might not be interchangeable with brands,
making them harder for patients to obtain. The debate is heating up as momentum builds for authorizing follow-on biologics
or proteins (as FDA prefers) in order to reduce spending on costly biotech therapies. Innovator companies want to keep the
issue from blocking speedy reauthorization of the prescription drug user fee program, making compromise more likely.
STRESS ON SCIENCE
All sides agree that science should determine the scope of follow-on testing, but there is considerable dispute over where
the science stands. Generics makers maintain that advances in analytical testing can ensure follow-on comparability and safety.
"Our ability to make and characterize protein products and other complex biologics has progressed rapidly in the last few
decades," said Ajaz Hussain, a vice president at Sandoz and a former FDA official, in testimony before the Senate Health committee
in early March.
Small biotech and testing companies, moreover, are developing new scientific approaches for developing biogenerics, such as
a protein characterization platform described by Insmed resident Geoffrey Allan at a subsequent hearing held by the House
Oversight and Government Reform Committee. These manufacturers believe that comparability protocols provide a model for follow-on
development and evaluation. FDA allows innovators to use mass spectroscopy and other technologies to demonstrate that significant
manufacturing changes and moves to new plants yield revised products that are essentially the same as the original therapy.
At the House hearing, FDA Deputy Commissioner Janet Woodcock explained that the agency has been limiting the range of data
needed to document comparability following manufacturing changes in order to encourage companies to make continuous improvements
in manufacturing processes. But she also noted a need for full information on structural aspects of a protein as well as a
full understanding of the product's mode of action to predict clinical comparability. A new manufacturer would not have all
the information about the innovator's intermediate manufacturing steps, Woodcock explained, and would bear the burden of demonstrating
that a similar therapy from a different company works the same as the reference product.
The information provided by analytical testing is important in determining whether additional clinical trails are necessary
to bring a follow-on to market. Biotech manufacturers maintain that only extensive comparison studies can rule out clinically
significant differences, but FDA says the extent of additional studies should be based on the complexity of the product and
its clinical use and experience. At the Senate hearing, former FDA official Jay Siegel, now at Johnson & Johnson, described
how a seemingly minor formulation change involving the stabilizer for Eprex (erythropoietin) increased immunogenicity and
led to a serious red cell aplasia in patients.
"Some degree of clinical assessment of a new product's immunogenic potential will ordinarily be needed," said Woodcock. But
this could range from small pharmacokinetic (PK) studies to larger randomized trials. FDA required additional clinical testing
for Sandoz' Omnitrope follow-on, but not as much as for the innovator.
Moreover, clinical trials are not always the best way to assess product structural changes, according to some experts. While
FDA may ask for additional PK studies to evaluate differences following manufacturing changes, the agency seldom requires
large outcomes studies. And if trials are not needed, Woodcock commented, it may be unethical to require them.