©2009 Law Offices of Albert Wai-Kit Chan, PLLC 1 Biogenerics * a/k/a Follow-on biologics or biosimilars* or biopharmaceuticals **** *Term to refer

©2009 Law Offices of Albert Wai-Kit Chan, PLLC1

Biogenerics*

a/k/a Follow-on biologics** or biosimilars*** or biopharmaceuticals****

*Term to refer to interchangeable biosimilars

**Term used by Biotechnology Industries Organization

***Term used to determine the comparability and similarity of a medicinal biological product alternative to a reference product.

****Term preferred by GPhA to refer to non-interchangeable biosimilars

Albert Wai-Kit Chan, Ph.DLaw Offices of Albert Wai-Kit Chan, PLLC


History: Regulation of Biologics in the U.S.

• Biologics have been around since the development of vaccines.

• Biologics were first regulated in 1902 by the Biologics Act when the diphtheria vaccine was being produced.

• Public Health Service Act (PHSA) was passed in 1912 to regulate biologics. The Act was revised in 1944 to require licensure and the criteria for license approval was established.

• The definition of drug was expanded to include biologics under the FDCA (Food, Drug & Cosmetic Act); which mostly governs chemical drug development.

• The PHSA primarily governs biologics and requires a biologics license application (BLA).

• The BLA is the equivalent of a NDA for chemical drugs.

History taken from Michael E. Clark et. al, Pharmaceutical Law: Regulation of Research, Development, and Marketing, 56-60 (2007).


History: Development of the Biotechnology Industry in the U.S.

• The development of the biotechnology industry began in the 1970s with advancement in technology.

• There was no patent approval process for biotechnology because the biological components were considered to have been found in nature.

• In 1980, the Supreme Court approved the principal of patenting genetically engineered life forms in Diamond v. Chakrabarty, 447 U.S. 303 (1980).

• This landmark decision paved the way for patenting biotechnology that resulted in the growth of the industry.

Information from History of Biotechnology – Time available at www.biotechinstitute.org/what_is/timeline.html and http://bio.org/speeches/pubs/er/statistics.asp.


History: Biotechnology Industry in the U.S.

• In 1982, Humulin, an insulin produced by genetically engineered bacteria, developed by Genentech, became the first biotech drug to be approved by the FDA (Food & Drug Administration) for treatment of diabetes.*

• Today, there are approximately 1500 biotechnology companies in the U.S.**

• The total GDP of these companies are over $60 billion dollars.**

*Information from History of Biotechnology – Time available at www.biotechinstitute.org/what_is/timeline.html.

**Information from Bio at http://bio.org/speeches/pubs/er/statistics.asp.

http://www.biotechinstitute.org/what_is/timeline.html

http://bio.org/speeches/pubs/er/statistics.asp


Today

• According to the California Public Employees Retirement System, its average cost for chemically based prescription drugs are $2 per day while biopharmaceutical drugs cost $55 per day.

• Biotech drugs are being used increasingly to treat diseases such as diabetes, cardiovascular diseases and cancer.

Taken from GPhA at http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&TEMPLATE=/CM/HTMLDisplay.cfm&CONTENTID=1948

http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&TEMPLATE=/CM/HTMLDisplay.cfm&CONTENTID=1948

http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&TEMPLATE=/CM/HTMLDisplay.cfm&CONTENTID=1948


Hatch-Waxman Act

• In 1984, Congress passed the Hatch-Waxman Act, (PL 98-417).

– Created the Abbreviated New Drug Application (ANDA) that streamlined the approval process if the chemical agent used is shown to be a bioequivalent of the original patented drug.

– Created a process for challenging a Patented chemical drug.

– To date, there is no equivalent legislation for biologics.


Requirements for Biologics License Application (BLA)

• 42 U.S.C. §262 requires:

– The biological product that is subject of the application is safe, pure and potent;

– The facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure and potent;

– Applicant consents to the inspection of the facility that is the subject of the application.

From Michael E. Clark et. al, Pharmaceutical Law: Regulation of Research, Development, and Marketing, 60-62 (2007).


Requirements for Biologics License Application

The BLA must also contain:

1. a full description of manufacturing methods;

2. data establishing stability of the product through the dating period;

3. sample(s) representative of the product for introduction or delivery for introduction into interstate commerce;

4. summaries of results of tests performed on the lot(s) represented by the submitted sample(s);

5. specimens of the labels, enclosures, and containers;

6. any medication guide proposed in the use of the product; and

7. the address of each location involved in the manufacturing of the biological product.



Requirements for “well-characterized therapeutic recombinant DNA-derived and monoclonal antibody”

well-characterized means:

• Products with definable, measurable, and controllable identity, purity, impurities, potency/biological activity, and quantity;

• Recombinant DNA biotechnology products with known amino acid sequence, known secondary structure (including disulfide bonds), and post-translational modifications (such as glycosylation); or

• Monoclonal antibodies with an identity that could be determined by rigorous physicochemical and immunological tests without full knowledge of chemical structure.



BLA Approval

Must demonstrate:

– No microbial or viral contamination;– No endotoxin, exotoxins, pyrogens; and– No nucleic acids (which were thought capable of

delivering oncogenes and transforming the DNA of a potential patient.

• Once BLA approved, then Clinical trial phases begin.



Biogenerics Debate

• The debate between the innovator companies and generic companies on whether or not a biosimilar developed would have the same result as the innovator drug, have been going on for more than a decade.

• Is it a question of science or politics?


Biogenerics Debate

• Bio (Biotechnology Industry Organization), the leading lobby organization of innovator companies’ position:

– Safety: Biologics are much more complex in structure than small molecule drugs and therefore it is not possible to have a “generic” of the branded drug.

– Immunogenicity: Occurs when our bodies treat a protein as if it is a foreign substance and produces antibodies to attack it. All biologics have the potential to stimulate antibody production in patients. Switching back and forth between products could trigger an immunogenic reaction.

– Initially wanted at least 14 years of exclusivity to protect incentive for innovation.

Taken from Bio at http://bio.org/healthcare/followonbkg/.

http://bio.org/healthcare/followonbkg/


Biogenerics Debate

• Bio’s position, continued.:

– Science not available to adequately review biogenerics without clinical studies.

– Biopharmaceuticals cannot be properly and completely characterized.

– “Even if it were possible to establish the ‘sameness’ of a follow-on biologic without clinical trials, agency reviewers would be unable to perform the rigorous scientific assessment necessary to reach legitimate conclusions about ‘sameness’ without first examining trade secret data concerning the manufacturing processes of the innovator, which is prohibited by law.”

– Cites the EMEA (European Medicines Agency) which requires case-by-case review that includes clinical trials.

Taken from Bio at http://bio.org/healthcare/followonbkg/.

http://bio.org/healthcare/followonbkg/


Biogenerics Debate

This is Genentech’s illustration of the difference between This is Genentech’s illustration of the difference between biologics and small molecule drugs and why it is not biologics and small molecule drugs and why it is not possible to have a “biosimilar,” it’s too complex.possible to have a “biosimilar,” it’s too complex.


Biogenerics Debate

• Generic Pharmaceutical Association’s (GPhA) positions:

– Terminology/Nomenclature – what the drugs are called is important to the effects it has on consumers.

• Non-interchangeable entities should be called “biopharmaceuticals.”

• Interchangeable entities should be called “biogenerics.”

– A streamlined or abbreviated review process should include the following criteria:

• Extent of Characterization• Comparability of biopharmaceutical product to reference

product• Observed variability in the reference product• Available data linking analytical test parameters and clinical

effects

Taken from GPhA’s White Paper on Generic Biopharmaceuticals (2004) at http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&Template=/CM/ContentDisplay.cfm&ContentID=1573.

http://www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs&Template=/CM/ContentDisplay.cfm&ContentID=1573


Biogenerics Debate

GPhA’s positions:

– Characterization – modern advances in technology enables current analytical methods to completely characterize certain proteins, albeit not all complex proteins. Proposes the following criteria:

• Observed variability in the reference product – measuring lot-to-lot variability of the reference drug for a baseline assessment.

• Clinically tested range of variation and product changes – the range of variation in the reference product used in clinical studies be used as the boundaries to compare in terms of compositions, processes and/or formulations.




Biogenerics Debate

• Characterization continued:

– Available data linking analytical test parameters and clinical effects – use publicly available information of in vivo – in vitro correlation, if they are available.

– Interchangeability versus approvability – characterization acceptance criteria should be designed with a few toward whether a determination of interchangeability or approvability is sought.

– Biological activity assays – allow the development of similar biological activity assays or employ some combination of tests that yield the same information as the reference’s biological activity assays so long as the results show comparability I identity, purity, potency, quality and safety.




Biogenerics Debate

GPhA positions continued:

• Manufacturing – should ensure the identity, potency, purity, quality and safety of the final product rather than whether the process is the same as the original (reference product) process

– Full CMC (Chemistry, Manufacturing and Controls) should be submitted

• Pre-Clinical Studies – should depend on whether there remains unanswered questions after review of the analytical characterization studies.

• Pharmacokinetic/Pharmacodynamic Studies – only if the reference product necessitates a PK/PD study then the “generic” would be required.




Biogenerics Debate

GPhA positions continued:

• Clinical Studies – only when necessary and required when other comparative analytical data is inadequate.

– Criteria for determining if clinical studies are necessary should be a rational, scientifically sound decision.

– Characterization of reference product should be the baseline for comparison

– Study should be on a smaller patient population and should not exceed the size of the study population of the reference product.



Biogenerics DebateGPhA positions continued:

• Immunogenicity

– not unique to only biopharmaceuticals but also known to occur in chemical drugs;

– Evaluations should focus on whether or not the antibodies are harmful and detrimental vs. transient;

– Consider taking a risk management approaching which resources are focused on assessing product factors with the greatest risk of immunogenicity, i.e. aggregation;

– Clinical trials do not necessarily detect all incidents of immunogenicity, particularly in rare incidences, including the reference product. Chiefly, clinical trials done solely to evaluate differences in immunogenicity in a limited patient population would be of limited utility.

• Exclusivity period should be the same as Hatch-Waxman Act, five years.



Most Recent Legislation

H.R. 5629 introduced by Rep. Anna Eshoo on March 13, 2008 with 43 co-sponsors in the House of Representatives. (mostly supports Bio’s positions) [has not been reintroduced as of 2/2/2009]

Highlights of differences

Approval Requirements

• Similarity to reference product with respect to each condition of use for which reference product was approved for, including clinical studies

• Clinical studies may be waived at discretion of the Secretary only after a draft guidance has been published for the product class to which that product belongs and public comments have been taken into consideration.

S. 1695 – introduced by Sen. Ted Kennedy with four co-sponsors, including Sen. Hatch on June 26, 2007 in the Senate; [mostly supports GPhA’s positions [has not been reintroduced as of 2/2/2009]

Highlights of differences

Approval Requirements

• Biological product is biosimilar to a reference product based upon data derived from studies; where clinical studies may be waived by the Secretary if deemed unnecessary for an application.

• Whether or not a final guidance is published is not a hindrance for review and approval of the application.



H.R. 5629

Interchangeability:

• Same as S. 1695, except:

– Requires the Secretary to issue a draft guidance of the product class that the application’s product belongs to for public comment and then after consideration of the public comments, can publish a final guidance determining that the product is interchangeable with the reference product.

S. 1695

• Requires Secretary to license if the information submitted is sufficient to show that the biological product is biosimilar or interchangeable with the reference product.

• Product is interchangeable if:– Product is biosimilar to reference

product and can be expected to produce the same clinical result in any given patient;

– For a product that is administered more than once, the risk of safety or efficacy of switching between the biological and reference product is not greater than the risk of using the reference product without switching.



H.R. 5629

• Requirement for application consideration:

– The Secretary may not accept an application until proceedings have been initiated for the issuance of guidance.

– The Secretary may not approve an application until process for issuance of the guidance has been completed.

S. 1695

• Requirement for application consideration

– No requirements of the issuance or non-issuance of a guidance is required for review or action on the application.



H.R. 5629

• Exclusivity of “generic”

– Cannot approve a second “generic” before 24 months.

• Naming

– Name must uniquely indentify the “generic” and distinguishes from the reference product.

S. 1695

• Exclusivity of “generic”

– Sets different time period that takes into consideration the possibility of on-going litigation; but minimum is 12 months.

• Naming

– Not addressed.



H.R. 5629

• Exclusivity of the reference product

– Same as S. 1695, but if a supplement to the reference product is approved, then exclusivity is extended to 14 years from when licensed.

– Allows application to be submitted 4 years after license issued, OR after the date of proceedings commenced for issuance of guidance, whichever is later.

S. 1695

• Exclusivity of the reference product

– No approval of a “generic” until 12 years after the reference product was first licensed regardless of whether a supplement was subsequently approved.

– Allows application to be submitted 4 years after the reference product has been licensed.


Most recent legislation: Infringement

H.R. 1695

Process as proposed:

1. Within 30 days of acceptance of application the Secretary shall publish a notice identifying the reference product and name and address of designated agent.

2. Within the same 30 days, Applicant shall provide reference product sponsor with a copy of the

application including: – Detailed description of the

“generic” product– Method of manufacture– Materials used in

manufacturing

S. 1695Process as proposed:

1. Application submitted for review

2. Applicant informed that the application has been accepted for review

3. Applicant shall provide a copy of the application to reference product Sponsor within 20 days.

4. Applicant may provide additional information requested by Sponsor

5. Within 60 days of receipt of application, Sponsor shall provide a list of patents Sponsor believes a claim of infringement could reasonably be asserted.

6. Sponsor can provide a list of patents Sponsor would be willing to license to Applicant.


Most Recent Legislation: InfringementH.R. 5629

3. Within 60 days of receipt of the information from Applicant, Sponsor shall provide a list of relevant patents owned by the Sponsor.

4. Within 45 days of receipt of Sponsor’s patent list, Applicant shall either:• State that Applicant will not

commence marketing and has requested the Secretary not to grant final approval; OR

• Provide a detailed written explanation as to why Applicant believes the making, use, sale or importation of the “generic” will not infringe Sponsor’s patent(s); OR

• State that the patent is invalid or unenforceable

5. Sponsor has 60 days to file an infringement suit; if Sponsor prevails, application can only be approved after the patent expires.

S. 1695

7. Within 60 days of receipt of list by Sponsor, Applicant may provide a list of patents that the Sponsor may assert a patent infringement claim;

8. Applicant shall provide either:

• provide a detailed statement, on a claim by claim basis, the factual and legal basis of why such patent is invalid, unenforceable, or will not be infringed by the commercial marketing of the

“generic” product; or • a statement that the applicant

does not intend to begin commercial marketing of the “generic” product before such patent expires; and

• Shall provide to reference product sponsor a response regarding each patent identified Sponsor is willing to license.


Most Recent Legislation: Infringement

H.R. 5629

6. If Sponsor does not file suit, then Applicant can only file a Declaratory Judgment action three (3) years prior to the expiration of the 12 year exclusivity of the issued license.

7. This bill also provides for an interested third-party to file suit if the third-party deems that the application may infringe upon one or more of its patents.

S. 1695

• Not later than 60 days of Applicant’s statement of why the patent is invalid, unenforceable or will not be infringed, Sponsor shall provide a response, on a claim by claim basis, the factual and legal basis of the opinion of the Reference Product Sponsor that such patent will be infringed by the commercial marketing of the biological product.

10. Both parties must then engage in “good-faith” negotiations on which patents both can agree shall be the subject of an action for patent infringement.

11. Failure to reach an agreement within 15 days of beginning negotiations, both sides will submit a list of potential patent infringements.

12. Sponsor has 30 days of agreement or no agreement of the list of patents, to file a patent infringement action.


Assessment/Realistic Assumptions

• Under the House bill, at minimum, it would take 195 days or 6½ months before an infringement suit is filed.

• But if the Sponsor does not file a suit, a declaratory judgment could not be filed until at least 5 years later. [assuming that an application is filed 4 years after the issuance of the Sponsor’s license and Applicant must wait until 3 years prior to the expiration of the 12 exclusivity period.]

• Under the Senate bill, at minimum, it would take 245 days or 8½ months before an infringement lawsuit would be filed.

• The Senate emphasizes negotiation and even if an infringement suit is filed, both sides would have already presented their legal arguments which potentially makes it easier for a summary judgment motion on either side ending litigation much sooner.

• The average length of litigations under Hatch-Waxman takes 3 ½ years.



• What was highlighted were the differences in the two competing bills.

• As you have seen, the differences appears to be more “political” than “scientific.”

• The purpose of the Hatch-Waxman Act was to enable generic companies to file an abbreviated application to be approved by the FDA that is streamlined and does not require the extensive clinical trials as that of the “patented” application.

• The application can be filed after the patent has expired OR by challenging the validity of the patent 5 years after its NDA was approved.



• Therefore, based upon the purpose and intent of Hatch-Waxman, it would appear that Congress would pass a bill that would be closer to the Senate’s version with some compromise with the House’s version.

• The Obama administration has signaled its support for a biogenerics bill and it is believed that legislation could pass within the next 4 years.


European Union: EMEA guidelines

• In 2004, the European Union passed Directive 2004/24/EC and 2004/27/EC to provide for approvals of biosimilars for drugs once the patents expires.

• Since this Directive and its subsequent guidelines, there are 7 biosimilars that have been approved by the EMEA for sale after patent expirations.

• Two for human growth hormone somatropin*, three for epoetin alfa*, a treatment for anemia and most recently one for sifrol**, a treatment for Parkinson’s disease and rebetol**, a treatment for hepatitis C.

*Sean Milmo, Report from:Europe, PharmTech.com, October 2, 2008 at *Sean Milmo, Report from:Europe, PharmTech.com, October 2, 2008 at http://pharmtech.findpharma.com/pharmtech/Article/Report-From-Europe/ArticleStandard/Article/detail/558009?http://pharmtech.findpharma.com/pharmtech/Article/Report-From-Europe/ArticleStandard/Article/detail/558009?contextCategoryId=35556&searchString=biosimilars .contextCategoryId=35556&searchString=biosimilars .

**EMEA Summaries of Opinions at http://www.emea.europa.eu/pdfs/human/opinion/RibavirinTeva_3449309en.pdf. and **EMEA Summaries of Opinions at http://www.emea.europa.eu/pdfs/human/opinion/RibavirinTeva_3449309en.pdf. and http://www.emea.europa.eu/pdfs/human/opinion/PramipexoleTeva_54961708en.pdf.http://www.emea.europa.eu/pdfs/human/opinion/PramipexoleTeva_54961708en.pdf.


Opportunity for Indian pharmaceuticals

• Indian pharmaceutical companies have been one of the leaders in providing generic drugs in the U.S. market.

• Indian biotech companies are already selling biogenerics in its home market and therefore have already developed the technology required.

• The new legislation may cut down litigation costs enabling Indian companies, including smaller pharmaceuticals to play a significant role.

• According to GPhA, more and more biotechnology drugs are relying on the chemical make-up of the biologics, which is within the expertise of current small molecule generic drug companies.

Documents

©2009 Law Offices of Albert Wai-Kit Chan, PLLC 1 Biogenerics * a/k/a Follow-on biologics** or biosimilars*** or biopharmaceuticals **** *Term to refer

©2009 Law Offices of Albert Wai-Kit Chan, PLLC 1 Biogenerics * a/k/a Follow-on biologics or biosimilars* or biopharmaceuticals **** *Term to refer