Washington Report: Pathways for Proteins - Pharmaceutical Executive

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Washington Report: Pathways for Proteins
Innovators want exclusivity and clinical studies for follow-on biologics, but visions of billion-dollar savings may short-circuit the scientific debate


Pharmaceutical Executive


Can analytical techniques 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, vice president of Sandoz and former FDA official, in testimony before the Senate health committee in early March. Small biotechs are developing new scientific approaches for developing biogenerics, such as a protein-characterization platform described by Insmed president Geoffrey Allan at the House hearing. Seattle-based Cell Therapeutics recently announced it is developing a genetic polymer technology that would speed follow-on development.

Can comparability protocols support follow-ons? FDA allows innovators to use mass spectroscopy and other technologies to demonstrate that their products are unaltered after a change in a manufacturing process or a move to a new plant. At the House hearing, FDA Deputy Commissioner Janet Woodcock noted that if the agency is to predict clinical comparability of a follow-on, it needs full information on the structure of a protein and the product's mode of action. FDA wants to encourage companies to continuously improve manufacturing processes; as a result, it tries to limit how much data it requires to document comparability following manufacturing changes. But, Woodcock explained, a new manufacturer would not have all the information about the innovator's intermediate manufacturing steps and would bear the burden of demonstrating that the new therapy works exactly as the original product.

Are clinical trials necessary to bring a follow-on to market? Innovators say always; generics makers, seldom; and FDA, sometimes (based on the complexity of the product and its clinical use and experience). "Some degree of clinical assessment of a new product's immunogenic potential will ordinarily be needed," said Woodcock. But it's unclear if this means small pharmacokinetic studies or large randomized clinical trials. FDA required considerable additional clinical testing for Sandoz's Omnitrope follow-on, but not as much as for the innovator.

Innovators say that seemingly minor changes in a drug's formulation can increase immunogenicity and harm patients. At the Senate hearing, former FDA official Jay Siegel, now at Johnson & Johnson, described how a change in stabilizer for Eprex (erythropoietin) increased immunogenicity and led to serious red-cell aplasia in patients.

But some experts argue that clinical trials are not always the best way to assess structural changes to products. 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 added, it may be unethical to require them.

Can follow-ons be equivalent? Documenting comparability is quite challenging, said J&J's Siegel, but "ensuring interchangeability is essentially impossible." Only extensive comparison studies can rule out clinically significant differences, he said, noting that even with extensive testing, Omnitrope did not get a therapeutically equivalent rating from FDA. To demonstrate substitutability, Woodcock says that the follow-on sponsor may need studies showing that repeated switches between the innovator and the follow-on has no negative effects. The European Union talks only of "biosimilars," emphasizing that these products are not generic copies.

Let FDA Decide

Woodcock emphasized the need for a flexible policy for regulating the wide range of complex biologics. As with EU regulators, FDA envisions a case-by-case approach to testing and evaluating comparability of follow-ons.

To assist manufacturers, the agency is preparing long-awaited guidance to clarify what data it recommends for developing follow-on proteins governed by the Food, Drug, and Cosmetic Act, such as human growth hormone and insulin. Additional guidances will address technical issues such as immunogenicity and physical-characterization methods. Establishing an approval pathway for this limited list of biotech therapies would support subsequent policies for approving a broader range of follow-ons.

Evaluation of such products will be complex and time-consuming, but Woodcock says FDA has the expertise to make the hard decisions that will arise. Overall, agency officials anticipate a gradual evolution toward follow-ons. While FDA now has the tools to assess comparability of small peptides, Woodcock explained, it may take a decade to develop similarly precise methods for larger molecules.

Patents will expire in the next few years on important biotech therapies, so follow-on advocates are eager to offer them in more affordable versions. Generics makers also appear willing to pay user fees for FDA to process the applications, which could provide a rationale for including Waxman's biogeneric bill in a PDUFA package.

Jill Wechsler is Pharm Exec's Washington correspondent. She can be reached at


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