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Product characterization and production challenges are key issues in developing a pathway for biosimilar therapies.
The ability of modern analytical techniques to ensure that generic or follow-on versions of biotechnology therapies are comparable to innovator products is a central issue in establishing a legal process for bringing these products to market. Generic drug makers, as well as some biotechnology companies, want Congress to authorize the US Food and Drug Administration to approve similar biologics based on an abbreviated testing-and-application system.
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. Difficulties in assessing comparability and "sameness" has inhibited FDA from approving follow-on versions of those biologics regulated under the Food, Drug, and Cosmetic Act (FDCA). Now many manufacturers 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 ensure the safety and efficacy of follow-ons while also protecting markets and preserving research and development incentives, brand manufacturers insist that all follow-on biologics require additional preclinical and clinical testing. Even then, follow-ons might not be interchangeable with brands, a situation that would limit patient access and product sales. The debate is heating up as momentum builds for authorizing follow-on biologics or follow-on proteins (as FDA prefers) as a way to reduce spending on costly biotechnology therapies. Innovator companies want to keep the issue from blocking the speedy reauthorization of the prescription-drug user fee program and may be willing to compromise on a measure addressing biotechnology development and regulation.
The status of the science
All sides agree that science should determine the scope of follow-on testing, but they disagree about where the science stands. Generics makers maintain that advances in analytical testing can ensure the comparability and safety of follow-on products. "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, Education, Labor, and Pensions (HELP) Committee in early March 2007.
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Small biotechnology and testing companies, moreover, are creating new technical methods to develop follow-ons. One such method is a protein-characterization platform described by Insmed President Geoffrey Allan at a hearing held by the House Oversight and Government Reform Committee. Seattle-based Cell Therapeutics recently announced plans to use its genetic polymer technology to facilitate follow-on development.
These and other manufacturers believe that comparability protocols provide a model for follow-on development and evaluation. FDA allows innovator firms to use mass spectroscopy and other technologies to demonstrate that significant manufacturing changes—such as product reformulation or a move to a new plant—yield new products that are essentially the same as the original treatment.
In fact, FDA is encouraging manufacturers to adopt sophisticated quality-by-design production techniques that can limit the volume of data and testing needed to document comparability following manufacturing changes. The aim is to spur pharmaceutical companies to make continuous improvements in their manufacturing processes, explained FDA Deputy Commissioner Janet Woodcock at the House hearing.
But she also noted the need for comprehensive information about the structural aspects of a protein, as well as for 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 pointed out, and would bear the burden of demonstrating that a similar therapy from a different company works the same as the reference product.
FDA issued a white paper in April 2007 describing the agency's experience in evaluating and approving second-generation products and manufacturing changes for biologics. The white paper provided evidence of FDA's technical and legal ability to assess such products. The differences between producing protein products and small-molecule drugs, the paper explained, has produced a range of testing and regulatory approaches. FDA says the crucial issue in determining the extent of safety and efficacy studies the agency requests to support approval of follow-on protein products is how much structural similarity exists between the new drug and the original product. The agency weighs the robustness of the manufacturing process; the degree to which structural similarity can be assessed; the extent to which the mechanism of action is understood; the existence of valid, mechanistically related pharmacodynamic (PD) assays; comparative pharmacokinetics (PK); comparative immunogenicity; the amount of clinical data available; and the range of experience with the original product.
Conventional drugs can be verified analytically, making it fairly easy for generic makers to produce duplicate drugs with the same active ingredient, strength, dosage form, and route of administration as the innovator drug, the agency explains. Under the Hatch–Waxman Act, generic drugs can be approved generally if they contain the same active ingredient, document bioequivalence, and demonstrate adherence to good manufacturing practices. Even though small-molecule drugs can be produced by multiple pathways, they usually can be characterized sufficiently to demonstrate homogeneity and purity.
Because protein products are typically much larger, more complex, and often heterogeneous mixtures, many cannot be fully characterized using available analytical techniques, FDA states, and even well-characterized and highly purified proteins exhibit slight differences in structure. Recombinant products can vary slightly from lot to lot even from the same manufacturer, and product quality can vary depending on source material and the processes used to extract and purify the product.
At the Senate hearing in March, former FDA official Jay Siegel, now at Johnson & Johnson, described how a seemingly minor formulation change involving the stabilizer for "Eprex" (epoetin alfa) increased immunogenicity and led to serious red-cell aplasia in patients. Apparently, the new stabilizer, polysorbate 80, leached organic chemical compounds from uncoated rubber stoppers used in certain prefilled syringes, thereby causing the change in immunogenicity.
A white paper the Biotechnology Industry Organization (BIO) released in April 2007 similarly described the structural and physical characteristics of large molecules, claiming that they make it difficult to show the comparability or similarity of follow-ons. Proteins are based on four different structural characteristics and may also be glycosylated, factors that are critical to product safety and effectiveness. Even a small variation such as the substitution of a single amino acid or the alteration of a pattern of sugar residues, said BIO, "can dramatically alter the biological activity of the protein." Manufacturing changes also may affect the safety or efficacy profile in ways not easily detected by standard chemical and molecular-biology characterization techniques.
Unlike small molecules, biologics are "particularly sensitive to manufacturing-process issues," the paper pointed out. Chemistry, manufacturing, and controls information, including product specifications, analytical-testing procedures, equipment, purification, and fermentation processes, is "extremely important" for ensuring that a biological product is safe, pure, and effective. The development of reliable, consistent manufacturing processes that use cell cultures or other living organisms is "substantially more demanding" than developing the chemical synthesis and purification steps for a conventional drug. Today's biotechnology production processes are "incapable of yielding compositions that are homogeneous and objectively characterized," BIO stated.
The information provided by analytical testing is important in determining whether additional clinical trails are necessary to bring a follow-on to market. Biotechnology manufacturers maintain that only extensive comparison studies can rule out clinically significant differences. FDA officials observe, however, that the extent of additional studies should be based on the complexity of the product, its clinical use, and experience as a treatment. "Some degree of clinical assessment of a new product's immunogenic potential will ordinarily be needed," said Woodcock. But this could range from small PK studies to larger randomized trials.
Last year, FDA approved a follow-on version of human growth hormone, Sandoz's "Omnitrope," under its 505(b)(2) process, but only after years of testing and review. The agency implemented a case-by-case approach that called for Sandoz to conduct considerable physicochemical testing to demonstrate structural similarity to the innovator drug, Pfizer's "Genotropin." Sandoz had to provide pharmacology, toxicology, and bioavailability data. Clinical efficacy and safety data from comparative controlled trials were needed to establish that the active ingredients in Omnitrope and Genotropin have highly similar structures and analogous PK and PD parameters. FDA also required long-term trials of the new product, but they were less extensive clinical studies than those conducted by the innovator.
Similarly, Biogen (now Biogen Idec) used peptide maps and glycoform characterizations to demonstrate that its follow-on "Avonex" (interferon β1a) had a similar structure to the original product. Multiple bioassays were needed to demonstrate comparable bioactivity, and PK data was required to show comparable product distribution and clearance. Positive results from these tests allowed Biogen to rely on data from an earlier efficacy study.
For assessing structural changes in biotechnology products, clinical trials are not always the best approach, according to some experts. While FDA may ask for additional PK studies to evaluate differences following manufacturing changes, the agency seldom demands large outcomes studies. And if trials are not needed, Woodcock commented, it may be unethical to require them.
Similar or equivalent?
A related issue is whether preclinical and clinical testing can demonstrate that a follow-on biologic should be rated therapeutically equivalent to an innovator product. Conventional generic drugs that demonstrate bioequivalence and "sameness" do not require a physician's intervention for substitution at the pharmacy. But FDA officials have found that while a new biologic may be similar to the innovator, they are not sufficiently the same to be substitutable. The European Union talks only of "biosimilars," emphasizing that these products are not generic copies.
Documenting the comparability of biologics is quite challenging, said Siegel at the March Senate hearing, 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 said that the follow-on sponsor may need studies showing that repeated switches between the innovator and the follow-on have no negative effects. Such hurdles to documenting substitutability are prompting generics makers to talk of biotechnology "interchangeability." This less-precise term implies similarity that falls short of therapeutic equivalence and may require a physician's prescription for substitution.
Whether a follow-on can be rated equivalent or substitutable is an important issue because it can have a significant impact on the sales and prices of follow-ons. And, it is the prospect of reduced prices on expensive biotechnology therapies that is driving the push for legislation authorizing FDA approvals of follow-ons. The pharmacy benefit manager (PBM) Express Scripts unveiled a report in February 2007 projecting savings of some $70 billion over 10 years from biogenerics. Another study put the savings for Medicare at $14 billion. A coalition of generics makers, payers, PBMs and patient advocates claim that follow-ons can save lives by making new life-saving drugs affordable for many patients.
Consulting firm Avalere Health, however, estimates savings of only $3.6 billion over 10 years. This analyst claims 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% lower will save millions of dollars on drugs that cost more than $100,000 per year. The United States spends more than $3 billion a year on insulin, and state Medicaid agencies are searching for any savings they can find.
Facing strong political pressure to legalize follow-ons, brands are seeking added patent protection from any new legislation. 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 biotechnology 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 Sen. Hillary Clinton (D-NY), would make it possible to approve a follow-on with minimal clinical testing. Another House bill would require clinical trials and rule out therapeutic equivalence. Senate HELP Committee Chairman Edward Kennedy (D-MA) is working with other panel members on a compromise measure that addresses clinical-research and exclusivity issues with an eye to moving legislation forward this year.
Let FDA decide
Dealing with such a wide range of complex issues requires a flexible regulatory policy, said Woodcock. Like EU regulators, FDA envisions a case-by-case approach to testing and evaluating the comparability of follow-ons. One issue is to what extent follow-on sponsors can refer to innovator data in establishing abbreviated testing processes. BIO noted in its white paper that manufacturer information on product formula and production process is considered a trade secret, and that it is illegal for FDA to rely on such innovator information when evaluating follow-ons.
To assist manufacturers, FDA says it will develop its white paper into further guidance on what data it recommends for developing follow-ons of those biologics regulated as drugs under the FDCA such as human growth hormone and insulin. Additional guidances will address technical issues such as immunogenicity and physical characterization methods for follow-ons. Establishing an approval pathway for an initially limited group of biotechnology therapies would set the stage for expanding these approaches to a broader range of biotech therapies.
FDA evaluation of such products will be complex and time-consuming, but Woodcock said agency staffers have 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 the comparability of small peptides, Woodcock explained, it may take a decade to develop similarly precise methods for evaluating larger molecules. In its white paper, FDA notes that it expects to be able to evaluate structural similarity for various products as analytical technology continues to improve.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org