Does this mean Biosimilars are delayed in the USA market?

Abbott filed a citizen petition with the U.S. Food and Drug Administration on 2 April 2012, asking the agency to refrain from accepting Biosimilars applications under the Biologics Price Competition and Innovation Act (BPCIA). The BPCIA, which provides an approval pathway for Biosimilars biological products and constitutes a portion of the Patient Protection and Affordable Care Act that was signed into law on March 23, 2010, allows the FDA to accept Biosimilars applications four years after a reference product has been licensed and to approve such applications twelve years after the reference product has been licensed. Abbotts’ patent on Humira® is set to expire in December 2016.

Abbott  has highlighted following points that "the reference product sponsor has invested massive amounts of capital . . . and has taken great risk to develop, test, and seek a license to market the reference product," Abbott argues that "an innovator's resulting license application typically reflects more than a decade of research and contains analytical, preclinical, and clinical data, as well as detailed manufacturing information, most of which qualifies as trade secrets," and contends that "these trade secrets are the private property of the reference product sponsor.  According to Abbott's Petition, "when FDA approves a Biosimilars biological product on the grounds that the reference product has been shown safe, pure, and potent, it uses these trade secrets."

Abbott also notes that when it submitted its BLA for Humira® in 2002, the company "had no notice, or reasonable expectation, that the agency would use its trade secrets to approve another company's product," and in fact, had "developed and submitted those trade secrets in reasonable reliance on FDA's lack of legal authority to approve Biosimilars, confirmed by years of agency statements that it lacked such authority."  The Petition suggests that other innovators who submitted pre-enactment BLAs also "reasonably expected -- on the basis of applicable law and agency statements -- that the trade secrets contained in their applications would not be used to benefit a competitor." 

Abbott also expresses a belief "that at least three companies have begun preclinical and/or clinical testing of Biosimilar adalimumab," but notes that it "does not know whether FDA is advising any companies about the contents of a Biosimilars application citing approval of Humira®.

The FDA continues to collect comments regarding Abbott's Citizen Petition, and has thus far received comments from the Generic Pharmaceutical Association (GPhA), Therapeutic Proteins International, LLC (a manufacturer and supplier of finished Biosimilars recombinant therapeutic proteins products), and Zuckerman Spaeder LLP (a litigation firm).  Each of these commenters has asked the FDA to deny Abbott's Petition.  Last month, the Washington Legal Foundation (WLF), a public interest law and policy centre, became the most recent group to submit comments on Abbott's Citizen Petition, but in contrast with the GPhA, TPI, and the Zuckerman firm, submitted its comments in support of Abbott's Petition.

The WLF's commented that any company that submitted a biologics license application (BLA) to FDA after adoption of the BPCIA in 2010 was on notice that FDA would be using information submitted in support of the application to evaluate the safety of Biosimilars.  But many if not all companies that submitted a BLA to FDA before adoption of the BPCIA (including Abbott, which submitted an application for Humira® in 2002) would very reasonably have believed that their trade secret information would not be used to assist their competitors in this manner and, on the basis of that belief, invested heavily in the development of their biological product. As a result, the WLF supports Abbott's request that the FDA not approve any application or any investigational new drug (IND) application for a Biosimilars that cites a reference product for which the BLA was submitted to the FDA prior to March 23, 2010.

FDA has held 21 Pre-IND sponsor meetings, has received 35 Pre-IND meeting requests for proposed Biosimilars to 11 reference products, and has received 9 INDs. FDA has not yet even approved (let alone filed) a Section 351(k) biosimilar application submitted pursuant to the procedures established by the BPCIA.

On the comments received from GPhA, FDA has stated that the 2010 law expressly states that an interchangeable biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. Substitutability helped spur the growth of the generic drug industry at an earlier time and is similarly essential to help foster competition in the biologic drug market. Ultimately, such competition will spur innovation, improve consumer choice and drive down medical costs. The high standards for approval of biosimilar and interchangeable products mean that patients and health care professionals can be assured that, when these products go to market, they will meet the standards of safety, efficacy and high quality that everyone expects and counts on. Efforts to undermine trust in these products are worrisome and represent a disservice to patients who could benefit from these lower cost treatments. FDA does not have a position on any particular state legislation, but it is important for everyone to approach these issues with an understanding of both FDA's expertise in this area and what the 2010 law requires for approval of biosimilar and interchangeable products.

 It is likely that the issues raised in Abbott’s Citizen Petition ultimately will have to be decided by the courts. The final outcome could impact the viability of the biosimilar framework, and have far-reaching effects on the biotechnology industry, as well as on healthcare costs and patient care. 

For more  information refer following links.

http://www.bloomberg.com/news/2013-08-27/california-assembly-passes-bill-on-biosimilar-drug-use.html

http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2013/09/biosimilars-state-legislation-scorecard.html

http://www.martindale.com/intellectual-property-law/article_Foley-Lardner-LLP_1541734.htm

Biosimilars: Twist and turn with a silver lining

I just came across, fantastic news about the first time Biosimilar versions of a monoclonal antibody (mAb) drug that have been recommended for approval in the European Union (EU), opening a new chapter in the developing market for cheaper copies of biologic medicines. CHMP has issued positive opinions on biosimilar versions of Johnson & Johnson's arthritis and Crohn's disease treatment Remicade (infliximab) filed by Celltrion Healthcare and Hospira. The reference product posted European sales of over $2bn last year.

To date a total of 12 medicines have been approved under the biosimilar regulatory pathway first laid out by the EMA in 2006, covering a range relatively small protein-based drugs including epoetins, filgrastims, growth hormones and recombinant human interferon alfa-2a.

The first time that the biosimilar concept has been successfully applied to such a complex molecule as the increased size and complexity of mAbs makes it more challenging to be able to demonstrate that their biosimilars do not have any meaningful differences from the reference medicine in terms of quality, safety or efficacy. So above news is fantastic in that sense.

It’s interesting to know some simple facts of biological drugs. But these simple cornerstones will help understand regulatory guidelines on biosimilars. Before understanding biological drugs let’s see them in comparison to chemical drugs.  It would help understand the difference in regulatory requirements of both.

Biological drugs (Bios) are different from small molecule medicines in many aspects first of it is they are made in living system such as microorganisms or animal cells. Small molecule medicines are typically manufactured by chemical synthesis. Both types of drugs differ in their manufacturing techniques, molecular size and complexity.

The production of biological medicines is a complex process which requires a very high level of technical expertise with typically about 250 in-process tests being conducted compared to about 50 tests for a small molecule medicine. The production of biological medicines involves processes such as fermentation and purification.

Size matters….....acetylsalicylic acid (ASA), aspirin's active ingredient with a molecular weight of about 180 g/mol or 180 Da and biologics molecule (protein) which are composed of more than 1,300 amino acids and can be as heavy as 150,000 g/mol (or 150 kDa).

Small molecule medicines generally have well-defined chemical structures. Bios have variability in the molecule (protein) as they are made in living systems and same protein exists in different forms.
For example enzyme Creatine kinase, the presence of which in the blood can be used as an aid in the diagnosis of heart attack, exists in 3 isoforms. Another source of variability is due to the type and length of sugar or carbohydrate group attached to the protein called glycosylation.

Due to the variability in structure of bios molecules it is more difficult to characterize it and exactly reproduce. Therefore batch to batch variation is controlled by manufacturers and regulators within accepted pre-defined limit.

Biological medicines have the potential to be recognized by the body as foreign due to their big size and therefore have the potential to induce immune reactions whereas chemical medicines are usually small molecule, to be recognized by immune system. This potential to induce immune reaction is called immunogenicity.

Biosimilar is a regulatory term used in the EU to denote the comparability between biosimilar and its reference medicinal product.  Biosimilar products are systematically developed and their comparability is performed in several steps.

1.       First step - quality comparability (physicochemical and biological comparability).

2.       Second step - non-clinical comparability (comparative non-clinical studies)

3.       Third step - clinical comparability (comparative clinical studies)

Comparability is an additional element to the normal requirement of the quality dossier. 
The exhaustive comparability exercise at quality level may allow reduction of the non-clinical and clinical data.

Differences in impurity profile and significant differences in product related substances may have consequences with regards to the amount of non-clinical and clinical data requirement in order to make satisfactory justification of the safety and efficacy of the biosimilar.

Quality comparability is established with regard to the molecular structure as well as with regard to the functionality.  Structural analysis is done using apt analytical methodology to deduce primary structures such as amino acid sequence; higher order structures including secondary, tertiary and quaternary structures, enzymatic post translational modifications such as glycosylation; other modifications such as protein deamidation, oxidation and intentional chemical modifications. 
Functional assays include bioassays, binding assays and enzyme kinetics. This information helps design clinical immunogenicity.

The non-clinical and clinical comparability then provides the confidence that any differences observed at the quality level have no impact on the safety and efficacy of the biosimilar medicinal product when compared to the reference medicinal product.

Animal data requires toxicity and PK PD profile. Immunogenicity studies are performed in animals when there is difference in impurity profile and excipients of biosimilar and reference medicinal product. Clinical studies include PK, PD studies and analysis of immunogenicity.

As a scientific matter, comparative safety and effectiveness data will be necessary to support a demonstration of biosimilarity if there are residual uncertainties about the biosimilarity of the two products based on structural and functional characterization, animal testing, human PK and PD data, and clinical immunogenicity assessment.

If interested refer following links.

http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144941.pdf
 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf
http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf