Robert Shapiro, chairman of Sonecon, LLC, and former advisor to U.S. President Bill Clinton and British Prime Minister Tony Blair, has published a study on the potential savings when generic biologic treatments (biogenerics) find a pathway in the U.S.   I say when and not if since the government is the largest consumer of medical care via medicare and medicaid and given the fact that sales of biotech drugs were $40.3 billion last year.

With such enormous amounts of money involved, Congress is seriously interested in creating a new regulatory pathway for the approval and marketing of generic or follow-on versions of biological treatments that no longer have patent protection. This is purely an economic (and political) issue, not one of health and safety.  Today, more than 150 biopharmaceuticals are available in the United States, including therapeutic serums, antitoxins, vaccines and biological therapeutics that induce immunity in infectious diseases, and the number of new biologics is growing at twice the rate of new small molecule pharmaceuticals.

Under the Hatch-Waxman Act, a pharmaceutical producer can secure FDA approval to market a generic version of an original drug no longer under patent protection without having to conduct lengthy and expensive safety and effectiveness studies and clinical trials, by demonstrating that the generic is the bioequivalent of the original drug. The process involves the approval of an Abbreviated New Drug Application (ANDA), which rests on a certification that the original patent has expired or is invalid, and that the dosage and active ingredients of a generic are identical to those in the original treatment.

However, the law covers only traditional, small-molecule pharmaceuticals. There is no mechanism for generic-drug makers to gain approval for generic biotech drugs or so-called follow-on biologics, sometimes called biosimilars or biogenerics.  The FDA evaluates and approves biologics mainly under the Public Health Safety Act, although a small number have been approved under the Food, Drugs and Cosmetic Act. The Center for Biologics Evaluation and Research (CBER) regulates biological products for safety. For the FDA to approve follow-on biologics, many difficult issues have to first be addressed such as safety, effectiveness and intellectual property rights have to be resolved.

The reason for the lack of a regulatory pathway for approval of biogenerics lies in the complexity of the biological products themselves. Biologics are large, complex, heterogeneous molecules for which the manufacturing process can be a determinant of the end product. Demonstrating that a generic version of the product is as safe and effective as the brand name product would be a difficult at best since, for example, establishing that immunogenicity had not been altered and that any undetected differences in the product would not impact safety and efficacy would be problematic without conducting extensive clinical trials.

Currently, the cost of conducting clinical studies from scratch keeps competitors out of the market. Biogeneric companies need an abbreviated approval pathway to avoid undertaking the same large scale clinical development process as the originator companies, and thus allow them to market their product at a discount to the brand while maintaining a profit margin.

It is likely that any follow-on biologic applicant would be required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. An applicant would need to provide evidence that its product has profound similarity — it is impractical to show identical biological products — and that these will produce the same clinical result as the brand product in any given patient and that it presents no additional safety risks or diminished efficacy if a patient alternates or is switched between products.

During a conference call this morning, Shapiro noted that the conventional wisdom held that the high cost of building the manufacturing infrastructure would be so high as to result in very little savings even if biogenerics are allowed. He argues that this is not the case given that there are plenty of other options in the marketplace. Shapiro pointed out the facilities currently available in Europe and Asia and the potential for partnerships.

According to the present study, the potential savings likely to follow from the introduction of these follow-on biologics over the next 10 and 20 years would be quite large. The study found that generic versions of the top 12 categories of biologic treatments with patent protections that have expired or are due to expire in the near future could save Americans, in net present value, $67 billion to $108 billion over the first 10 years and $236 billion to $378 billion over 20 years. Moreover, these estimates almost certainly understate the savings, because they could not take full account of a number of factors likely to reduce the price of biogenerics and further expand their use in the United States.

Currently, biogenerics are used in the European Union and the major countries of Asia. The study concludes that the United States has led the world in developing biologics, and when the U.S. Congress approves a regulatory pathway for biogenerics, the United States very likely will quickly become the world’s largest market for follow-on biologics.

See the entire report here.

See also:  Why are biogenerics so hard to regulate?

More from the Orange Book Blog and the BioJobBlog.

Posted February 19th, 2008 by Stephen Albainy-Jenei in Biogenerics, FDA, Biotech News
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It appears, for now at least, that the legislation creating an approval pathway for follow-on biologics will not be included in the FDA Revitalization Act (FDARA). FDARA would reauthorize the Prescription Drug User Fee Act or PDUFA (pronounced puh-doo-fuh), which expires Sept. 30.

PDUFA increases funding for the Food and Drug Administration through fees paid by the drug companies, which increase the speed of drug approval at the FDA. The FDA attempts to review and act on at least 90% of the New Drug Applications and Biologic License Applications within 10 months of the date of filing and within six months for drugs given priority review. User fees have gone from being 7 percent of the FDA’s budget to 59 percent.

Many of the new additions to the PDUFA involve the FDA’s ability to increase drug safety in the wake of Merck’s (NYSE: MRK) Vioxx withdrawal. The House bill gives the FDA power to order companies to run additional clinical trials after the drugs have been approved for marketing and requires drug companies to make much of their clinical trial data available to the public. It also gives the FDA the ability to levy up to $250,000 fines for false or misleading advertisements.

A bigger issue is whether the FDA should approve generic biotech drugs or so-called follow-on biologics, sometimes called biosimilars or biogenerics. Unlike with small-molecule drugs, there’s no mechanism for generic-drug makers to gain approval for follow-on biologics.

The two versions of the bills, S. 1082 and H.R. 2900, are currently pending before a conference committee. The Senate version of the bill contains a placeholder for follow-on biologics legislation, but the House has not yet discussed the issue.

The Public Health Service Act, under which biologics are licensed, does not contain an abbreviated approval pathway analogous to the process used under the Food, Drug, and Cosmetic Act for generic drug approvals, according to the FDA. However, the agency has approved some follow-on biologics under the FD&C Act, such as GlucaGen, Hydase, Fortical and Omnitrope.

The Senate Health, Education, Labor and Pensions Committee passed the Biologics Price Competition and Innovation Act, S. 1695, by unanimous voice vote earlier this summer, establishing a way for the FDA to approve products as biosimilar to existing biologics. S. 1695 would grant 12 years of data exclusivity to innovator biologic drugs.

Under the bill, a follow-on biologic applicant would be required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. The bill also allows the FDA to approve a follow-on biologic as interchangeable. However, the applicant must provide evidence that its product will produce the same clinical result as the brand product in any given patient and that it presents no additional safety risks or diminished efficacy if a patient alternates or is switched between products.

S. 1082 also includes language that prohibits the FDA from delaying approval of a generic drug on the basis of a citizen’s petition unless such a delay is necessary to protect the public health, according to a summary of the bill. In addition, it requires the FDA to take final action on a petition no later than 180 days after its submission unless such a delay is necessary.  The use of citizen petitions has been an effective tactic in delaying generic entrants to the market, such as with Wyeth’s injectable antibiotic Zosyn (piperacillin/tazobactam).

Recent news from Congress is it’s abandoning follow-on legislation and will address biogenerics in a separate bill. This will allow PDUFA IV to finally pass but, given the fact that sales of biotech drugs were $40.3 billion last year, this issue is far from dead.

Posted September 17th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA, Biotech News
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In a long-awaited — and some would say long-feared — update in the regulatory pathway for FDA approval of follow-on biologics, the Senate’s Senate Health, Education, Labor and Pensions HELP Committee gave the thumbs up to the Biologics Price Competition and Innovation Act of 2007 (S. 1695), which will address the scientific, regulatory and legal issues involved in bringing generic biologics to the marketplace.

Senators Kennedy, Hatch, Clinton, and Enzi introduced the legislation authorizing the FDA to approve a follow-on version of biologic therapies. The legislation includes standards for the FDA to approve follow-on biologics as well as a period of exclusivity for the brand name drug company. The Act amends section 351 of the Public Health Service Act to provide for an approval pathway for safe biosimilar and interchangeable biological products (relying in part on the previous approval of a brand product):

• A biosimilar applicant is required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. A demonstration of biosimilarity includes analytical data, animal testing and one or more clinical studies, unless such a requirement is determined by the FDA to be unnecessary.
• The Act provides incentives for the development of both new life-saving biological products and interchangeable biosimilar products: 12 years of data exclusivity for the brand company during which a biosimilar product may not be approved, and 1 year of exclusivity for the first interchangeable biological product.
• The biosimilar applicant must provide its application and information about its manufacturing process to the brand company. A series of informational exchanges then occur in which the biosimilar applicant and the brand company identify patents in question and explain their views as to their validity or infringement.

Senator Kennedy said the committee plans to attach the bill to the Prescription Drug User Fee Act (PDUFA) reauthorization bill. Sen. Sherrod Brown (Go Ohio!) had drafted an amendment that would have shortened the exclusivity period to seven years but withdrew the amendment without a vote.

Biotechnology Industry Organization (BIO) president Jim Greenwood stated that:

Senators Kennedy, Enzi, Clinton and Hatch deserve credit for their hard work in crafting this complex legislation, and for the bipartisan support they have achieved for the bill. Biotechnology innovators share the goal of ensuring all patients have access to life-enhancing and life-saving biologics. We support the development of a pathway for the approval of follow-on biologics.

Toward that goal, we will continue to work with Congress to make certain the legislation is improved to ensure it supports the principles we have outlined for a pathway to follow-on products, namely providing better protections for patient safety and the patient-doctor relationship.

In addition, the patent litigation rules included in the bill must be revised to improve protections for the intellectual property rights of innovators, ensure timely resolution of all patent disputes and maintain incentives to develop future medical breakthroughs.

Earlier, BIO released a set of principles to guide the development of a pathway for the approval of follow-on biologics. BIO also developed a detailed rationale supporting the need for substantial data exclusivity. Meanwhile, generic manufacturers expressed concern that a 12 year exclusivity for the brand company is too long.

The bill will still need to be passed by the full Senate and the House and then signed by the President.

Read the draft legislation here: Biologics Price Competition and Innovation Act of 2007 (S. 1695).

See lawmakers pat themselves on the back here.

Posted June 28th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA
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Senators Kennedy, Hatch, Clinton, and Enzi announced legislation authorizing the FDA to approve a follow-on version of biologic therapies. The legislation, the Biologics Price Competition and Innovation Act of 2007, includes standards for the FDA to approve follow-on biologics as well as a period of exclusivity for the brand name drug company.

The draft compromise bill tries to resolve some of the sticky issues surrounding the extent of trials a follow-on biologic would need prior to approval, whether a biosimilar could be deemed an interchangeable alternative to a brandname biologic, and the length of time an innovator biologic would be protected from competition.

A biologic is manufactured in a living system such as a microorganism, or plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules while a small molecule drug is typically manufactured through chemical synthesis. It is difficult to characterize a complex biologic by testing methods available in the laboratory. Therefore, for biologics, the product may be too closely tied to the process to separate the two.

Unlike small molecule drugs, which are approved under the FDCA, most biologics are approved under the Public Health Service Act (PHSA). The FDCA provides a framework for approving generic copies of small molecule drugs, but no commensurate legal framework is currently in place for approving follow-on biologics either under the FDCA or under the PHSA. The complexity of biologics makes it impossible to analyze them in a laboratory to the degree possible with chemical drugs, and to show without clinical trials that one biologic has the same safety and effectiveness profile as another.

To be approved as a generic, a drug must have the same active ingredient, strength, dosage form, and route of administration as the reference drug, and it must also be “bioequivalent.” This means that generic drugs are the same chemically as their innovator counterparts and that they act the same way in the body. The bioequivalence of the generic drug is demonstrated through relatively simple analyses such as blood level testing, without the need for human clinical trials. In approving a generic drug under 505(j) of the FDCA, FDA determines that the generic is “therapeutically equivalent” to the innovator drug, and is interchangeable with it.

FDA has stated that it has not determined how interchangeability can be established for complex proteins. Historically, FDA has permitted interchangeability only when two products are “therapeutic equivalents.” However, when the follow-on manufacturer establishes a new manufacturing process, beginning with new starting materials, it will produce a product that is different from and not therapeutically equivalent with that of the innovator. Because of the complexity of biologics, the only way to establish whether there are differences that affect the safety and effectiveness of the follow-on product is to conduct clinical trials.

Recent approvals of follow-on biologics by the FDA have been limited to those few biotechnologically derived products such as human growth hormone and certain insulin products approved under the New Drug Approval provisions of the Food, Drug, and Cosmetic Act, such as Novartis’ Sandoz approval of a 505(b)(2) NDA for its Omnitrope® version of Pfizer’s Genotropin® human growth hormone. While not a true generic application, a 505(b)(2) NDA allowed Sandoz to submit less than a full NDA. The FDA has previously taken the position that it lacks the authority to approve generic biologics under the PHSA.

The Act amends section 351 of the Public Health Service Act to provide for an approval pathway for safe biosimilar and interchangeable biological products (relying in part on the previous approval of a brand product) while preserving the incentives that have fueled the development of these life-saving medicines.

Approval Process

A biosimilar applicant is required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. A demonstration of biosimilarity includes analytical data, animal testing and one or more clinical studies, unless such a requirement is determined by the FDA to be unnecessary.

FDA may approve a biosimilar product as interchangeable, meaning it can be substituted for the brand product without the intervention of the health care provider who prescribed it. Showing interchangeability requires evidence that the biosimilar product will produce the same clinical result as the brand product in any given patient and that it presents no additional risk in terms of safety or diminished efficacy if a patient alternates or is switched between products.

The legislation allows, but does not require the FDA to issue guidance documents to inform with the public of the standards and criteria the agency will use in approving biosimilar and interchangeable products. Development of these guidance documents will require public input. Applications can be filed in the absence of guidance documents.

Exclusivities

The Act provides incentives for the development of both new life-saving biological products and interchangeable biosimilar products: 12 years of data exclusivity for the brand company during which a biosimilar product may not be approved, and 1 year of exclusivity for the first interchangeable biological product.

Patent Resolution

The legislation includes a multi-step process to identify and resolve patents that the biosimilar product may infringe. The biosimilar applicant must provide its application and information about its manufacturing process to the brand company. A series of informational exchanges then occur in which the biosimilar applicant and the brand company identify patents in question and explain their views as to their validity or infringement.

The two parties then either agree to a list of these patents to be litigated first or exchange lists when they can’t, and the brand company must then sue the biosimilar applicant within 30 days to defend them. If the brand company wins a final court decision that a patent is valid and infringed by the biosimilar product before the 12 year data exclusivity has run, the court must enjoin infringement of the patent until it expires. For identified patents not included in this initial litigation, the biosimilar applicant must give the brand company notice 180 days before it intends to launch its product, and the brand company may then seek a preliminary injunction to block the launch.

If the brand company fails to identify a patent, it can’t later enforce it against the biosimilar product. If it fails to defend a patent identified for initial litigation, the brand company may only later receive a reasonable royalty. If the biosimilar applicant fails at any step to do what it is required to do, the brand company may immediately defend its patents.

Legal Issues

The FDA has taken the position that each biologic is unique and inexorably linked to and inseparable from the manufacturing processes used in its creation. Complex operational and proprietary details of the manufacturing processes are central to and define the identity and unique molecular safety and effectiveness attributes of each biologic. Even if it were possible to establish “sameness” of biologics without clinical trials, it might be necessary for agency reviewers to examine trade secret data concerning the manufacturing processes of the innovator to perform a comparative assessment about “sameness.”

The bill is likely to be approved by the Senate Health, Education, Labor and Pensions Committee when it meets on June 27th.

Press statement: http://help.senate.gov/Maj_press/2007_06_22_a.pdf

Read the draft legislation here: Biologics Price Competition and Innovation Act

Posted June 26th, 2007 by Stephen Albainy-Jenei in Biogenerics
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As a follow-up on yesterday’s article on the road to biogenerics, Food and Drug Administration deputy commissioner Janet Woodcock testified before an Oversight Committee held to examine the prospects and need for a pathway that would allow the FDA to approve safe and affordable generic versions of biotech drugs. Witnesses included representatives of FDA, pharmaceutical manufacturers, scientists, and consumer groups.

During the House Oversight and Government Reform Committee hearing, Woodcock said that while the FDA can currently establish the safety between versions of simple protein-based drugs, it will likely “be a stepwise progression over a decade or so,” before the agency can scientifically verify that a generic version of a complex biotech drug can be substituted for the original. 

The issue comes down to a question of whether generic drug companies would have to conduct clinical trials (and to what extent) before gaining approval. Rep. Henry A. Waxman, D-Calif., along with Representatives Emerson, and Pallone and Senators Schumer and Clinton, have re-introduced H.R. 1038, the “Access to Life-Saving Medicine Act,” which would establish a process through which the FDA will be able to approve generic biologics or biopharmaceuticals.

In summary, H.R. 1038 “Amends section 351 of the Public Health Service (PHS) Act to authorize the Secretary of HHS to approve abbreviated applications for biological products that are ‘comparable’ to previously approved (reference) biological products.”

The current abbreviated pathway described in section 505(b)(2) of the FD&C Act permits an applicant to rely on published literature or on the FDA’s finding of safety and effectiveness for a referenced approved drug product to support approval of a proposed product. A 505(b)(2) applicant must demonstrate that reliance on the previous finding of safety and effectiveness is scientifically justified and must submit whatever additional nonclinical and clinical data are necessary to establish that the proposed product is safe and effective.

The FDA has used this pathway to approve some follow-on protein products including Hylenex (hyaluronidase recombinant human), Hydase (hyaluronidase), Fortical (calcitonin salmon recombinant) Nasal Spray, Amphadase (hyaluronidase), GlucaGen (glucagon recombinant for injection), and Omnitrope (somatropin [rDNA origin]).

However, Woodcock made clear that things won’t go easy absent a drastic change in the law stating that:

Because of the variability and complexity of protein molecules, current limitations of analytical methods, and the difficulties in manufacturing a consistent product, it is unlikely that, for most proteins, a manufacturer of a follow-on protein product could demonstrate that its product is identical to an already approved product. Therefore, the section 505 (j) generic drug approval pathway, which is predicated on a finding of the same active ingredient, will not ordinarily be available for protein products.

To establish that two protein products would be substitutable, the sponsor of a follow-on product would need to demonstrate through additional clinical data that repeated switches from the follow-on product to the referenced product (and vice versa) would have no negative effect on the safety and/or effectiveness of the products as a result of immunogenicity. For many follow-on protein products — and in particular, the more complex proteins – there is a significant potential for repeated switches between products to have a negative impact on the safety and/or effectiveness. Therefore, the ability to make determinations of substitutability for follow-on protein products may be limited.

Not that the FDA has been resting on it’s laurels. As evidence of progress on follow-on protein products, Woodcock noted that :

Because there are many challenging scientific and policy questions about follow-on protein products, FDA has actively promoted a public dialogue on these issues. FDA has held two public meetings (September 2004 and February 2005) and co-sponsored a workshop, in collaboration with the National Institute for Standards and Technology, and with the New York Academy of Sciences (December 2005), to gather input on scientific and technical issues related to follow-on protein products. These meetings resulted in a large number of comments and concerns from the interested parties that have informed our considerations of these issues.

Expect continued arguments over the process as well as the projects savings over current costs.

Posted March 27th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA
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Dr. Andrew von Eschenbach, the head of the Food and Drug Administration, addressed the issue of biogenerics at the annual meeting of the annual meeting of the Pharmaceutical Research and Manufacturers of America (PhRMA).  Eschenbach basically outlined that biogenerics would be considered only “similar” to brand-name drugs, not interchangeable or able to be substituted.

This is similar to the approach of the EU as used by the European Medicines Agency. “We recognize that the end point would be what could be best described as similarity,” von Eschenbach said. “Similarity in the sense that when a doctor gives you the product — delivered it to a patient — it will achieve an effect that is similar to the effect that we expected from” the brand-name drug.

The Generic Pharmaceutical Association maintains the FDA already has the scientific knowledge to approve knockoffs, just as it now can sign off on changes made by brand-name biotech companies in how they produce their drugs.

Recent approvals of follow-on biologics by the FDA have been limited to those few biotechnologically derived products such as human growth hormone and certain insulin products approved under the New Drug Approval provisions of the Food, Drug, and Cosmetic Act, such as Novartis’ Sandoz approval of a 505(b)(2) NDA for its Omnitrope® version of Pfizer’s Genotropin® human growth hormone. While not a true generic application, a 505(b)(2) NDA allowed Sandoz to submit less than a full NDA.

The problems currently faced stem from the fact that biologics are approved under the Public Health Service Act (PHSA) not under the FD&C Act like small molecule drugs. While the FD&C Act provides an abbreviated new drug application (ANDA) provision that allows for generic versions of chemical drugs, the PHSA lacks any statutory mechanism that allow filing an abbreviated license for a biologic. The agency itself has taken the position that it lacks the authority to approve generic biologics under the PHSA.

Using the existing mechanisms for approving generic versions of biogeneric drugs involves two problems: (a) proving that the generic drug is identical to the brand name active ingredient, dosage form, route of administration, conditions of use (i.e., labeling) and dosage strength; and (b) proving that it is bioequivalent to the brand-name drug. If these are proven for small molecule generic versions, the generic product can be substituted for the brand-name product.

With biogenerics, you would have to show that the two biologics, made using different processes, contain the same ingredient. Then, you would have to prove that the two products are bioequivalent, especially when analytical methodology often does not exist or is proprietary to the brand name product. This would be quite difficult absent clinical studies.

In the Omnitrope case, the European Medicines Agency (EMEA) concluded that, while Omnitrope was not identical to Genotropin, it was similar enough to warrant approval with labeling comparable to that of Genotropin. EMEA determined that the two products were comparable as to their effectiveness, it did not declare them as bioequivalent. Having reached those conclusions, EMEA was able to regard Omnitrope as a biosimilar to Genotropin.

Concurrently with endorsing Omnitrope, EMEA issued a number of guidelines on how biosimilar medicines should be regulated:

Comparability studies are required between the biosimilar and the reference brand medicine. The extent to which comparability can be proven impacts how many nonclinical and clinical studies the biosimilar applicant will be required to perform.

Nonclinical studies, usually less extensive that those for innovator applications, will be required for the biosimilar.

Clinical studies (rather than the classic bioequivalence studies used for chemical drugs) will be needed to support the biosimilar drug’s safety and effectiveness. In particular, the studies must address immunogenicity concerns.

Postmarket pharmacovigilance plans will be expected as part of approval commitments.

EMEA also issues drug-specific guidelines for developing biosimilars. EMEA has issued these annex guidelines on human growth hormone, recombinant erythropoietins, recombinant granulocyte-colony stimulating factor and recombinant human insulin.

After lots of pressure from the courts and lawmakers, the FDA approved Sandoz’s 505(b)(2) NDA for Omnitrope. In so doing, the agency made clear that the Omnitrope approval did not establish any distinct precedent for other follow-on biologics, stating:

Is this FDA’s first approval of a follow-on protein product?

No. FDA has approved other follow-on protein products under section 505 of the Food, Drug, and Cosmetic Act. These include GlucaGen (glucagon recombinant for injection), Hylenex (hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), and Fortical (calcitonin salmon recombinant) Nasal Spray.

Does today’s approval of Omnitrope create a new pathway for follow-on versions of all protein products?

No. The approval of Omnitrope in a 505(b)(2) application does not establish a pathway for approval of follow-on products for biological products licensed under section 351 of the Public Heath Service Act, nor does it mean that more complex and/or less well-understood proteins approved as drugs under the Food, Drug, and Cosmetic Act could be approved as follow-on products.

The FDA has classified Omnitrope as “BX” (insufficient data to determine therapeutic equivalence) in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).

Reps. Waxman, Clinton and Schumer have now introduced H.R. 6257, the Access to Life-Saving Medicine Act (ALMA).  The Act would establish the a path for follow-on biologic applications including:

An abbreviated process for biological licenses for products that is comparable to approved biologics by amending the PHSA

Comparability requirements based upon the follow-on product having no clinically meaningful differences from the approved reference product in terms of safety, purity or potency, based upon nonclinical or clinical studies, as needed

An approval process that includes a focus on correlating comparability to the reference product’s mechanism of action (If the mechanism of action is known, the follow-on applicant need only demonstrate comparability in one proposed condition of use. In contrast, if the mechanism is unknown, the applicant must show comparability for each proposed condition of use.)

Comparability requirements for the follow-on and reference products’ principal molecular structure features

Option for a comparable biologic product applicant to establish interchangeability with the reference product (if so established, the applicant may earn tax credits and an exclusive marketing period that would block other subsequent interchangeable versions of the reference product); to be interchangeable, a product must produce the same clinical results as the reference

Requirement that FDA approve or disapprove a follow-on biologic application at the earlier of eight months after submission or 180 days after the application is accepted for filing; this deadline would only be extendable by joint agreement of FDA and the applicant

The FDA says it will continue to develop guidelines required to consider applications on biogenerics.

Posted March 26th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA
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On March 8, a Senate committee will hold initial hearings on legislation that would establish a process for the U.S. Food and Drug Administration to approve biogenerics (generic versions of biologic drugs known as biosimilars).

On average, the FDA approves one new generic version of a conventional (small molecule-type) drug per day but it lacks the authority (it says) to approve biogenerics. Basically, the FDA has taken the position that approval of follow-on biologics are too complex to regulate under current rules. The Senate wants to make a path for the eventual approval process.

Representatives Waxman, Emerson, and Pallone, along with Senators Schumer and Clinton, have re-introduced H.R. 1038, the “Access to Life-Saving Medicine Act,” which will establish a process through which the FDA will be able to approve generic biologics or biopharmaceuticals. However, expect a continuance of the brand name companies trumpeting safety concerns while generic companies cry protectionism.

In summary, H.R. 1038 would amend section 351 of the Public Health Service (PHS) Act to authorize the Secretary of HHS to approve abbreviated applications for biological products that are “comparable” to previously approved (reference) biological products.  In addition, an application for a comparable biological product must demonstrate that there are no clinically meaningful differences between the two products with respect to safety or effectiveness.  The application must also show that the new product and the reference product contain highly similar “principal molecular structural features” and the same mechanism(s) of action, if known.

While some type of biogeneric process is likely to happen, it won’t be soon and it could add millions to the cost of developing generic biologics in the end.  In comparison, European regulators reviewing biogeneric applications have required companies to conduct a series of analytical studies, preclinical studies, and clinical trials comparing its product to branded versions to ensure safety. Don’t look for legislation that will skirt the extra layers of safety checks.

Posted March 7th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA
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Representatives Waxman, Emerson, and Pallone, along with Senators Schumer and Clinton, have re-introduced H.R. 1038, the “Access to Life-Saving Medicine Act,” which will establish a process through which the FDA will be able to approve generic biologics or biopharmaceuticals. While generic drugs have been extremely successful in bringing down the high cost of prescription drugs, there is currently no FDA pathway for getting approval for biogenerics.

It is estimated that generic drugs save about $10 billion a year and many would like to see this same result with expensive biotech drugs, many of which cost tens of thousands of dollars a year, even after patent expiration. Pharmacy benefit manager Express Scripts Inc., conducted a study showing that the average biotech drug costs $71,600 a year, compared with the annual average for a traditional drug of $1,200. It said that escalating biotech drug costs, which reached $40 billion in 2005, are expected to more than double in four years to a total of $90 billion in 2009, a rate three times faster than traditional drug costs. While they predict a savings of at least $71 billion over 10 years if there was a regulatory mechanism that allowed for the marketing of biogenerics, BIO cautioned against forecasting any savings from generic biotech drugs without knowing how much testing regulators would require.

In summary, H.R. 1038 provides for the following:

Amends section 351 of the Public Health Service (PHS) Act to authorize the Secretary of HHS to approve abbreviated applications for biological products that are “comparable” to previously approved (reference) biological products.

An application for a comparable biological product must demonstrate that there are no clinically meaningful differences between the two products with respect to safety or effectiveness. The application must also show that the new product and the reference product contain highly similar “principal molecular structural features” and the same mechanism(s) of action, if known.

The Secretary has discretion on a product-by-product basis to determine what studies are necessary to establish comparability. Unlike the sharply limited studies that can be required for traditional generic drugs, the Secretary is given authority to require one or more clinical studies in an application for a comparable biological product, if necessary to establish that the new product has comparable safety, purity, and potency to the reference product.

An application for a comparable biological product will be subject to user fees.

An applicant for a comparable biological product may elect, but is not required, to establish interchangeability. The Secretary is given discretion to determine what studies are required to establish interchangeability. The bill grants the first applicant to obtain approval of an interchangeable version of a biological product a period of exclusive marketing during which no other interchangeable version of the product may be approved.

Applicants for comparable biological products may elect to ask the holder of the reference product for a list of patents on the product and may elect to notify the reference product holder and owner of one or more of the patents identified that the applicant has filed a comparable biological product application. If the applicant sends such a notice, it must contain a detailed statement explaining why the identified patent(s) is invalid, unenforceable, or not infringed. If the reference product holder fails to disclose a relevant patent, it may not enforce that patent against that applicant. If no patent infringement action is brought within 45 days of notice of a challenge, the remedy in any later action to enforce that patent against that applicant is limited to a reasonable royalty.

While the FDA has approved Novartis AG’s Omnitrope hormone, there has not been a change in the stance taken by the FDA on generic biotechnology drugs. Omnitrope was approved only after a federal judge ordered the FDA to decide after a long delay. Also, Omnitrope is considered less complicated than most other biologics.Under both the Federal Food Drug and Cosmetic Act and the Food Prescription Drug User Fee Act, the FDA is required to either approve or reject new drug applications. However, no biogenerics (or follow-on proteins) have yet been approved in the US pharmaceutical market beyond Omnitrope.

The reason for the lack of a regulatory pathway for approval of biogenerics lies in the complexity of the biological products themselves. Biologics are large, complex, heterogeneous molecules for which the manufacturing process can be a determinant of the end product. Demonstrating that a generic version of the product is as safe and effective as the brand name product would be a difficult at best since, for example, establishing that immunogenicity had not been altered and that any undetected differences in the product would not impact safety and efficacy would be problematic without conducting extensive clinical trials.

With Omnitrope, the FDA, however, went out of its way to say that Omnitrope is not a generic biologic stating that “Omnitrope is not rated as therapeutically equivalent to (and therefore substitutable for) any of the other approved human growth hormone products. Omnitrope is more appropriately characterized as a “follow-on protein product.”

The FDA indicated that the approval of Omnitrope in a 505(b)(2) application does not establish a pathway for approval of follow-on products for biological products licensed under section 351 of the Public Heath Service Act, nor does it mean that more complex and/or less well understood proteins approved as drugs under the Food, Drug, and Cosmetic Act could be approved as follow-on products.

See the full text (pdf) of the bill here.

Posted February 16th, 2007 by Stephen Albainy-Jenei in Biogenerics, FDA
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