GTC Biotherapeutics (fka GTCB)

[MTB]

Hello All,

A colleague at work has just published an excellent review, overview, and roadmap for the inevitable changes in legislation surrounding 'follow on biologics' in the N. Engl. J. Medicine.

In very lucid prose, he lays out the historic reasons why 'biologics' are considered separately than small molecule drugs, and goes on to describe the inevitability of the increasing importance of generic forms of 'biologics' (such as Novo 7, epo, etc) being adopted as a means of cost control for the government and hospitals.

Overall, they describe a reasonable course for the adoption of FOB's, and one that is very favorable for companies like GTCB.

The FOB's are a hugely important market in the new 1-7+ years. Given their strengths in low-cost production of difficult to express protein, GTCB is unique situated to exploit this market.

Even with the god-awful placement like that earlier in the month, GTCB will be exploding shortly (like ENCY) as Big Pharma folks come to read the writing on the wall. For long term investors, this is not unalloyed good news (a quick double vs a more gradual 10-bagger).

Best,
MTB

NEJM 358:843-849 February 21, 2008 Number 8




Scientific and Legal Viability of Follow-on Protein Drugs

David M. Dudzinski, M.D., J.D., and Aaron S. Kesselheim, M.D., J.D.


Since recombinant human insulin (Humulin) became the first recombinant-protein drug approved by the Food and Drug Administration (FDA) 25 years ago, nearly 100 recombinant-protein therapeutics, including other hormones and monoclonal antibodies, have become part of clinical practice (Table 1).1 Though small-molecule drugs are more common than recombinant-protein drugs — only 1 of the top 200 prescribed drugs of 2006 (on the basis of prescription volume) was a recombinant protein — protein-based therapeutics have been used to treat diabetes and anemia, as well as relatively rarer conditions, such as rheumatoid arthritis, Gaucher's disease, and multiple sclerosis.2,3

Table 1. Classes of Approved Recombinant-Protein Drugs.



Recently, the protein-based–therapeutics market has become a growing source of controversy in the health care system. These products cost anywhere from $15,000 to $150,000 per year, prices that are far in excess of those charged for traditional small-molecule products.1,4,5 Manufacturers charge these prices, in part, because the complex molecular structure of proteins contributes to substantial development and manufacturing costs.6,7 Between 2002 and 2005, just four classes of protein-based therapeutics represented on average 13% of total hospital pharmaceutical costs (Figure 1).8,9,10,11 In 2006, the recombinant proteins darbepoetin alfa (Aranesp), epoetin alfa (Epogen, Procrit), and etanercept (Enbrel) were among the year's top 10–selling pharmaceuticals on the basis of dollar value and accounted for almost 4% of the $275 billion annual U.S. pharmaceutical market.12,13 At the same time, drug-related expenses for government insurance programs have risen, leading to restrictions on services or changes in eligibility requirements,14 which have been linked to worse health outcomes.15


Figure 1. Total Spending by Nonfederal Hospitals and Percent Annual Expenditures for the Four Most Popular Classes of Protein Therapeutic Products, 2002–2005.
The bars represent the aggregated annual hospital pharmaceutical spending on erythropoietins (epoetin alfa [Procrit, Epogen] and darbepoetin alfa [Aranesp]), granulocyte colony-stimulating factors (pegfilgrastim [Neulasta] and filgrastim [Neupogen]), the anti–tumor necrosis factor antibody infliximab (Remicade), and the anti-CD20 antibody rituximab (Rituxan). The solid line represents the percent annual hospital pharmaceutical expenditures arising from these four drug classes.8,9,10,11


Although generic alternatives to small-molecule drugs can be marketed at vastly reduced cost after the expiration of the original product's patent protection, in the case of protein therapeutics, manufacturers have been able to sustain high prices even after the expiration of their patents, because no general mechanism exists under current federal law for approval of "follow-on" protein products. (The term "follow-on" is often used in this context because some follow-on proteins may not be both biologically and functionally equivalent, which is the definition of a generic drug.16) In the United States alone, patents have already expired on protein therapeutics representing more than $15 billion in costs annually; alternative versions of these products could be available for savings of at least 10 to 30%.17,18 Such savings could be realized by payers as well as patients, since many patients often bear a substantial portion of the costs of these products through higher copayments or gaps in their insurance coverage.19 Reductions in medication costs for patients can also improve adherence to plans of care.20 However, representatives of the biotechnology industry argue that follow-on products in the protein-therapeutics market can jeopardize the safety of patients and undermine intellectual-property protections.21,22

In part because expenditures in the protein-therapeutics market are predicted to continue to expand by 15 to 20% annually, Congress is considering various systems for approval of follow-on protein products. In this article, we review the regulatory distinction between small-molecule drugs and protein-based drugs and evaluate the scientific and policy considerations behind the promotion of competition in the protein-therapeutics market while maintaining high standards of safety.

Historical Distinction between "Biologics" and "Drugs"

The current debate over follow-on protein products has its origins in the fact that the FDA considers most recombinant-protein products to fall under the ill-defined term "biologics," which are regulated under a federal law that is separate from the one regulating small-molecule drugs. These two federal pharmaceutical laws arose in close proximity. In 1902, after outbreaks of tetanus from contaminated vaccines, Congress passed the Biologics Control Act to regulate the manufacturing of "viruses, therapeutic serums, toxins, antitoxins, or analogous products" as biologics intended for the "prevention and cure of diseases."23 The act regulated the manufacturing process, as opposed to the end product, because in 1902 methods of protein purification were primitive, and neither qualitative nor quantitative means of product characterization had been developed.1 A few years later, the Pure Food and Drug Act of 1906 provided basic standards for drugs by focusing on end-product quality and purity.24 The dichotomy was maintained as each statute was revised — the Biologics Control Act was merged into the Public Health Services Act (PHSA) of 1944,25 whereas the Pure Food and Drug Act ultimately became the Federal Food, Drug, and Cosmetic Act (FFDCA) when the requirement for ensuring drug safety was added in 1938.26

Today, most protein-based products still fall under the PHSA. For example, interferon is classified as analogous to blood products and therefore is legally a biologic because interferon products were first isolated from leukocytes.1 The approval pathway for biologic products, which involves filing a biologics licensing application, is evaluated separately from new-drug applications for small-molecule products. However, because of historical vagaries, a few select recombinant-protein products — such as insulin, glucagon, human growth hormone, and thyrotropin alfa — are governed under the FFDCA and were approved under new-drug applications.1

The drugs–biologics dichotomy was in place in the 1980s, when Congress attempted to address growing national pharmaceutical expenditures by promoting generic drugs. Before that time, most manufacturers that wanted to distribute generic versions of brand-name drugs had to undertake a full set of clinical trials proving the safety and efficacy of their products, and as a result, few generic products were available on the U.S. market. In 1984, Congress enacted the Hatch–Waxman Act, which established two routes for approval of generics — abbreviated new-drug applications and applications submitted under section 505(b)(2) of the FFDCA — both of which allowed manufacturers of generic drugs to rely on results from the original new-drug applications.27 The process for abbreviated new-drug applications applies if the products are bioequivalent, and the 505(b)(2) process might apply, for example, for slight differences in dose or formulation, changes in route of administration, or combination products.28,29 However, the Hatch–Waxman Act explicitly amended only the FFDCA — not the PHSA. Congress probably did not intend to include the PHSA because, by 1984, Humulin was the only approved recombinant protein and the modern biotechnology industry did not yet exist.1 As a result, there is no streamlined process to approve a follow-on version of a protein product under the PHSA.

Past Experience with Follow-on Proteins

Follow-on recombinant proteins may arise from separate manufacturing processes and differ in master cell line, processing and purification, inert ingredients, and packaging. Opponents of accelerated approval mechanisms for follow-on protein products believe, regardless of rigorous physicochemical characterization of the protein, that the "process is the product," because even small and seemingly insignificant manufacturing changes could theoretically contribute to differences in protein folding, aggregates, and glycosylation, which might manifest clinically as decreased efficacy, altered pharmacokinetics, or increased immunogenicity.22,30

Nevertheless, in a few cases, follow-on protein products have been reviewed and approved under the Hatch–Waxman Act. In July 2003, Sandoz sought approval under section 505(b)(2) for Omnitrope, a recombinant human growth hormone (somatropin) that is structurally identical to Pfizer's Genotropin, which itself was approved under a 1995 new-drug application. As part of its application, Sandoz submitted chemical data, bioassays in hypophysectomized rats, safety studies in rats and rabbits, human pharmacokinetic studies, and results of phase III studies.31 After a year of deliberations, the FDA decided it was unable "to reach a decision on the approvability of the application because of unresolved scientific and legal issues."32 Sandoz sued, and in 2006, a District Court instructed the FDA to end its "marathon round of keep-away" and make a decision about the product.33

The FDA ultimately approved Omnitrope, allowing an abbreviated pathway only because human growth hormone had been historically regulated under the FFDCA.34 The FDA also acknowledged that a comparison of "end products of different manufacturing processes" was possible in select cases because of "improvements in the availability and sophistication of analytical techniques."31 Specifically, Omnitrope was approvable because it had numerous favorable scientific characteristics: for example, it had a well-characterized protein structure (including primary, secondary, and tertiary structures), a known mechanism of action, a lack of glycosylation, and a "long and well-documented history of clinical use" with a "safety and efficacy profile . . . thoroughly described in the literature."31,34

The FDA made clear that its decision applied only to follow-on versions of reference proteins approved under the FFDCA; the agency did not comment on "more complex and less well understood" proteins or those approved under the PHSA.31 In 2005, the FDA approved two more follow-on recombinant versions of nonrecombinant-protein products that were originally approved under the FFDCA: recombinant salmon calcitonin (Fortical)35,36 and recombinant hyaluronidase (Hylenex).37,38 Fortical was approved because its protein structure was identical to that of synthetic salmon calcitonin, the two drugs shared similar pharmacokinetics and pharmacodynamics, and the immunogenicity of Fortical had been studied in a 6-month trial. Hylenex was approved because its potency was similar to that of the original bovine hyaluronidase, even though the two drugs had different protein structures.39

At the same time that Sandoz was involved in legal wrangling in the United States, the European Agency for the Evaluation of Medicinal Products (EMEA) and Australia's Therapeutic Goods Administration had already approved follow-on versions of human growth hormone by 2006. Australia was able to avoid the drugs-versus-biologics issue in approving Omnitrope because its laws do not segregate therapeutic products into various regulatory statutes.40,41 EMEA had already invested years working on guidance documents42,43,44,45 for follow-on proteins (including human growth hormone, erythropoietin, interferon, and insulin) and had approved two follow-on versions of human growth hormone by April 2006.46,47 However, the EMEA requirements are substantial in that even the simplest recombinant proteins require phase II study.45 For more complex agents, such as erythropoietin, the recommendation is closer to a phase III study.48 In these regards, the proposed EMEA approval processes are not abbreviated and may not have a marked effect on lowering costs.49

New Mechanisms for Approving Follow-on Protein Products

In 2007, four bills were introduced in Congress with the goal of creating a viable abbreviated approval scheme for follow-on protein products. In February, Representative Henry Waxman (D-CA), along with Senator Charles Schumer (D-NY), offered the Access to Life-Saving Medicine Act (ALSMA).50,51 In April, Representative Jay Inslee (D-WA) introduced the Patient Protection and Innovative Biologic Medicines Act,52 followed by the Affordable Biologics for Consumers Act, sponsored by Senator Judd Gregg (R-NH).53 In June, Senator Edward Kennedy (D-MA) introduced yet a fourth follow-on protein bill, the Biologics Price Competition and Innovation Act.54 Although there was some talk that one of the bills would be included in the recently passed FDA Amendments Act,55 none reached a floor vote.

In each of the proposed abbreviated mechanisms of the four bills, the ultimate scientific and clinical standard hinges on an assessment of the safety, purity, and potency of a candidate follow-on that shares the same mechanism and indication as a reference protein. Only ALSMA, by discussing "principal molecular structural features," made explicit the protein structural criteria required for consideration.56 However, one potential loophole in ALSMA was its listing of five categories that could automatically meet the comparability standard despite differences from the reference protein structure. Key differences between the bills included the evidence required to support a follow-on application. ALSMA appeared to discourage duplicate clinical investigations, though it suggested that the applicant must provide necessary clinical studies and can discuss with the FDA the "design and size of studies needed for approval of such application."56 The Inslee bill was a reaction to this supposed "short circuiting [of] the clinical trial process"57 and advocated (as did the Gregg bill) a regime similar to that of EMEA whereby the FDA would create product-specific guidelines that outline the necessary comparative clinical trials and postmarketing surveillance required for approval.58,59 Yet if all potential follow-on manufacturers were held to a strict clinical-trial standard or the same standard that was required of Sandoz for Omnitrope (which, as the FDA stated, was the simplest possible case), the cost and time investments for clinical investigation might be prohibitive for potential manufacturers. Such restrictions could limit the number of potential entrants into the market and reduce potential cost savings.16,18

In the realm of follow-on protein therapeutics, the optimal system should encompass scientific and legal flexibility to adjust the regulatory burden to the lowest and most appropriate level that will ensure approval of effective and safe follow-on products. Given advances in analytical chemistry and protein science, it can no longer be said for every recombinant protein that the "product is the process." In some cases, direct comparison of follow-on protein products with original protein products may now be feasible, as it was for Omnitrope. Thoroughness of characterization of the protein, nonclinical and clinical experience with the protein, purity, similarity of bioassay and potency results, and similar pharmacokinetics all represent favorable features of a product that might allow the FDA to rely on findings of safety and efficacy of the reference drug and thus lower the regulatory burden on the follow-on manufacturer in terms of required clinical investigation. The FDA should also be able to rely on studies and analyses done to secure EMEA or Australian approval.

Nevertheless, some scientific issues do remain unresolved — most notably, the potential for complex effects in protein quaternary structure, pharmacodynamics, and immunogenicity owing to changes in manufacturer, inert ingredients, and packaging.6,60,61 For example, in the case of Eprex, a recombinant human erythropoietin, when the stabilizer in the manufacturing process was changed from albumin to sorbitol, antierythropoietin antibodies were formed, and pure red-cell aplasia developed as a side effect.22,61 Thus, the clinical investigation of safety and efficacy and postmarketing pharmacovigilance studies will probably be required for all except the simplest follow-on protein products for the foreseeable future. The exact requirements should be set for each class of follow-on proteins.

In addition to appropriate scientific and clinical standards, follow-on proteins raise other regulatory issues, including intellectual-property rights as well as product branding and exchangeability. The Hatch–Waxman Act set a standard period of 5 years for data exclusivity for small molecules, and many observers believe that this framework has been effective in maintaining incentives to innovate in the small-molecule setting while promoting the production of generic drugs after the period of data exclusivity or the expiration of the patent (although some manufacturers have exploited the system to delay the approval of generic drugs).62 Even though a patent can protect a drug's basic chemical composition, the period of data exclusivity differs in that a competing manufacturer cannot use a pioneer manufacturer's clinical studies during that time to meet FDA regulatory requirements, making approval of a generic product impossible without independent investigation.63

Some data-exclusivity protections for pioneer recombinant proteins may be justified on the basis of higher fixed costs for protein manufacturing or the fact that patents for complex proteins tend to be more narrow and therefore easier to design around in creating similar follow-on products.64,65 The Kennedy bill set out a base exclusivity period of 12 years, but it did not define the level of innovation required to earn subsequent data-exclusivity periods on the same molecule. As a result, manufacturers could apply for and receive exclusivity extensions for slight changes in the molecular structure, which could inappropriately delay entry of a follow-on product. Given that the average research-and-development cost for a biopharmaceutical product may not be far different from that of a small-molecule drug,66 in our opinion the optimal period of exclusivity should equitably balance price competition and health care savings with incentives for investment in pioneer protein products.

The name of the follow-on product is another contested subject. The ALSMA bill suggests assignment of the same nonproprietary name to a follow-on protein, as is done with small-molecule drugs, which implies therapeutic interchangeability with the reference protein. Opponents of the legislation argue that this could obscure the tracking and reporting of outcome and safety data that should be attributed specifically to the follow-on protein.67 On the other hand, insurance payers such as Medicaid rely on regulations permitting therapeutic substitution of equivalent generic products to promote cost savings. One potential solution would be to mark prescriptions with unique identifiers so that the manufacturer and even specific manufacturing facility could be traced to assist in the reporting of this data.

Ultimately, if a compromise on these issues cannot be reached, one alternative solution would be a government-mandated price cut for protein therapeutic products after a certain period of time on the market. This discount could approximate the cost savings anticipated from development of follow-on proteins. Though the government has the authority under the principle of eminent domain to assume control of intellectual property for the public good,68 this authority would not need to be invoked if the action is done after the time when the patents on the products have already expired.

Conclusions

Despite the failures of the bills sponsored by Waxman, Inslee, Gregg, and Kennedy to reach floor votes, these bills collectively represent important first steps that should help to stimulate further discourse on salient scientific issues and signal an end to the de facto permanent patent that a recombinant-protein therapeutic currently enjoys unless substantial clinical trial data are accrued. Anticipating that the legal issues in the United States will soon be resolved, the worldwide generics industry is preparing for product launches of follow-on types of insulin, growth hormone, interferon, erythropoietin, and colony-stimulating factor, with up to 10 companies working on generic versions in each category.1,4,17,69 While the FDA waits for its congressional mandate on the follow-on issue, EMEA continues to work on product-specific guidelines and in September 2007 approved three new drugs that are biosimilar to erythropoietin (Binocrit, Abseamed, and Epoetin alfa Hexal).70

Meanwhile, the medical community, in part through collective efforts of professional societies, can help identify and address the important scientific issues of follow-on protein products relevant to their specialties. The role of physicians is critical, because in the near future physicians will be tasked by governments, hospitals, and health-management enterprises to support the use of follow-on products. It will be essential that physicians feel confident about their safety and efficacy. Physicians will also be intimately involved in long-term pharmacovigilance programs. To complete these tasks, physicians must be aware of the salient scientific and legal issues underlying the approval of follow-on protein products to ensure that their patients' interests in safety and efficacy are adequately represented in a system that promotes lower cost and expanded access to protein therapeutics.



Dr. Dudzinski reports receiving consulting fees from the Blue Cross and Blue Shield Association. No other potential conflict of interest relevant to this article was reported.

We thank Kevin Outterson and William Shrank for their comments on earlier versions of the manuscript.


Source Information

From the Department of Medicine, Massachusetts General Hospital (D.M.D.); and the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital (A.S.K.) — both in Boston.

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