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The information provided by analytical testing is important in determining whether additional clinical trails are necessary to bring a follow-on to market.
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.
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.
A related issue is whether a follow-on product could be rated therapeutically equivalent to an innovator biologic. Documenting comparability is quite challenging, said Siegel, but "ensuring interchangeability is essentially impossible." Even with the added studies, 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 switching between the innovator and the follow-on has no negative effects.
The prospect of reduced prices on expensive biotech therapies is the main force behind the push for follow-on biologics. A coalition of generics makers, payers, pharmacy benefit managers (PBMs), and patient advocates claim that new life-saving drugs are not worth much if patients can't afford them. The PBM Express Scripts unveiled a report in February projecting savings of $70 billion over ten years from biogenerics.
However, consulting firm Avalere Health estimates savings of only $3.6 billion over ten years. These analysts claim it will take years for manufacturers to develop and for FDA to approve new follow-ons, and these products will cost more to test and produce. If they're not interchangeable, moreover, physicians will be slow to prescribe them. But payers say that even prices only 10% less will save millions on drugs that cost more than $100,000 a year.
As the political pressure rises to legalize follow-ons, brands are seeking added patent protection. The Hatch-Waxman Act provides five years of exclusivity before generics can challenge a new drug's patent. In Europe, drugs and biologics essentially are protected for 11 years, which looks attractive to US innovators, especially small biotech companies. The high cost of developing new biologics—which the Tufts Center puts at $1.25 billion fully capitalized—and more expensive manufacturing processes warrant stronger protection from patent litigation, industry claims.
The lead biogeneric bill, which is sponsored by Rep. Henry Waxman (D-CA) and backed by Sen. Hillary Clinton (D-NY), doesn't address exclusivity. But generic industry leaders appear willing to negotiate patent issues and to pay user fees in order to move the legislation forward.
Dealing with such a wide range of complex biologics requires a flexible regulatory policy, says Woodcock. 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 developing a guidance to clarify what data it recommends for developing follow-ons of those biologics governed by the Food, Drug and Cosmetic Act. Additional guidances will address technical issues, beginning with immunogenicity and physical characterization methods for follow-ons. Establishing an approval pathway for this limited list of biotech therapies would support policies for approving a broader range of follow-ons.
More immediately, evaluation of these 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 towards 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 evaluating larger molecules.
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, firstname.lastname@example.org