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Posts Tagged ‘Biosimilar’


RAbD Biotech Presents at 1st Pitch Life Sciences-Philadelphia-September 16, 2014

RAbD is a new biotechnology company founded by Fox  Chase Cancer Center investigators Gregory Adams, Ph.D., Matthew Robinson, Ph.D. and Roland Dunbrack, Ph.D. that is focused on the knowledge-based design of antibodies that bind to key functional, often highly conserved and difficult to target epitopes. We are using homology modeling, crystal structures, protein docking and design software and algorithms to drive combinatorial sampling of CDRs to computationally design new antibodies and then express, validate and perform further design in an iterative manner.Brian Smith, Ph.D., MBA is RAbD Biotech’s Business Development Lead.

Contact information for RAbD Biotech:

Website  http://rabdbiotech.com/

LinkedIn

Twitter @RAbDBiotech

The overall goal of RAbD is to

“drug the undruggable”

The company using in silico design methods to design to produce novel antibodies and biomimetics. The company is developing a first in class biomimetic, RaD-003, for the treatment of ovarian cancer.  Ovarian  cancer is one of the most deadly of all women’s cancers, with very low 5 year survival rates.  An expected 22,000 US women a year will be diagnosed and expected 16,000 will die every year.  Cisplatin/paclitaxel therapy is only approved and effective chemotherapy for ovarian cancer yet resistance develops quickly and is common. RaD-003  targets the MISII receptor (Mullerian Inhibiting Substance Type II Receptor), which is expressed on ovarian cancer cells but not on normal ovarian epithelium.

It has been shown that activation of this receptor by the Mullerian Inhibiting Substance (MIS) has antitumor activity in ovarian cancer.

The MISII receptor had been considered undruggable as

  • MIS is too expensive and difficult to produce
  • previous attempts to develop therapeutic antibodies ot MISIIR have proven difficult

Therefore, the company used their computational platform to produce a “first in class” chimeric biomimetic to more effectively target and activate MISIIR.

For  more information about this meeting and the Mid-Atlantic Bioangels and 1st Pitch please see posting on this site

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FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules. Author-Writer: Stephen J. Williams, Ph.D.

This posting is a follow-up on the Report on the Fall Mid-Atlantic Society of Toxicology Meeting “Reproductive Toxicology of Biologics: Challenges and Considerations post and gives a brief synopsis of the current state of FDA regulatory guidelines with respect to DART studies on small molecule (non-biological based) therapeutics.    The following is adapted from the book Principles and Methods of Toxicology by Dr. A Wallace Hayes (1) and is an excellent reference on reproductive toxicology and testing methods.

Chemical insult occurs to the human reproductive system at a multitude of stages in development and the life cycle, leading to the extensive testing which must be performed to diligently the reproductive and development toxicity of a chemical/drug.  Abnormalities and toxic manifestations in the offspring may result from insult to the adult reproductive (either female or male) and neuroendocrine systems, as well as damage to the embryo resulting in embryolethality, fetus at any period during organogenesis, juvenile development or, in the case of certain antibody therapies, immune system development.  The latter, toxic insult to the developing immune system could possibly be manifested as either an immune defect in the newborn or, later in life, as tolerance to said therapy.  It is estimated that exposure to the pregnant woman, of either environmental contaminants or drug, is significant.  It is estimated that a mother may be taking an average of 8-9 different drug preparations, mostly over the counter preparations such as antacids, vitamin preparations, cathartics etc. with the maximal drug intake occurring between 24 and 36 weeks of gestation.

Toxic insult to the developing embryo is dependent on

  • Fetal development stage during drug/chemical exposure
  • Maternal/placental xenobiotic metabolism
  • Pharmacokinetic parameters affecting bioavailability and fetal/maternal drug binding

The following table shows the dependency of developmental stage to teratogenicity: adapted from J. Manson, H. Zenick, and R.D. Costlow from Principles and Methods of Toxicology.

Developmental Stage Major Susceptibility
Preimplantation Embryolethality
Organogenesis Births defects; embryolethality
Fetal Growth retardation, fetal death, functional deficits
Neonatal Growth retardation, nervous system alterations, immune and endocrine systems

It is not generally accepted that there is a dose dependency of teratogenesis however most teratogens have specific mechanisms of action and teratogenic effects occur at much lower doses than result in maternal toxicity.   However, the developmental toxicity may be manifested later in life, including as reproductive toxicity affecting adult fertility and familial generations.

FDA Guidelines for DART Studies on Non-Biologics (Small Molecule Therapeutics)

The basic design for DART studies incorporate the aforementioned principles of tetralogy:

  • developmental stage of fetal exposure
  • parental effects on reproduction and development
  • toxicity may be manifested over multiple generations including fertility rates

Therefore two designs are generally used for DART studies

  1. exposure across several generations
  2. exposure during one generation

FDA requires one control group and two treatment groups, and evaluation of at least two species.  However, most studies will use two rodent and one nonrodent species.

Multigenerational Design

Multigenerational DART studies are conducted for compounds likely to concentrate in the body following long-term exposure.  Examples of types of compounds include pesticides and food additives.

Figure 1.  General Design of a Multigenerational DART study.  Weanlings (30-30 days of age) from the parental generation are treated for a period up to 60 days. At 100-120 days of parental generation, animals are mated.  Fx = filialx .

Three Segment, Single Generation Tests

The single generation design is more suitable for DART studies on drugs, as most therapeutic would be taken over short periods (during pregnancy) and have relatively short half-lives in the body.  FDA guidelines separate these studies in three phases:

I.            Phase I: evaluation of fertility and general reproductive performance

II.            Phase II: assessment of teratogenicity and embryotoxicity

III.            Phase III: peri- and postnatal evaluations.

All figures are adapted from Principles and Methods of Toxicology.(1)

FDA guidelines Guidance for Industry Reproductive and Developmental Toxicities —Integrating Study Results to Assess Concerns can be found at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079240.pdf

FDA Guideline for reproductive toxicity testing for small molecule therapeutics can be found at:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074950.pdf

1.            Hayes, A. W. (1986) Principles and Methods of Toxicology, Raven Press, New York

Other research papers on Pharmaceutical Intelligence and Reproductive Biology, Bio Insrumentation, Endocrinology Genetics were published on this Scientific Web site as follows

Non-small Cell Lung Cancer drugs – where does the Future lie?

Reboot evidence-based medicine and reconsider the randomized, placebo-controlled clinical trial

Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”

Leptin and Puberty

Gene Trap Mutagenesis in Reproductive Research

Genes involved in Male Fertility and Sperm-egg Binding

Hope for Male Contraception: A small molecule that inhibits a protein important for chromatin organization can cause reversible sterility in male mice

Pregnancy with a Leptin-Receptor Mutation

The contribution of comparative genomic hybridization in reproductive medicine

Sperm collide and crawl the walls in chaotic journey to the ovum

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

Biosimilars: CMC Issues and Regulatory Requirements

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Assisted Reproductive Technology Cycles and Cumulative Birth Rates

Innovations in Bio instrumentation in Reproductive Clinical and Male Fertility Labs in the US

Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)

Guidelines for the welfare and use of animals in cancer research

Every sperm is sacred: Sequencing DNA from individual cells vs “humans as a whole.”

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Reporter: Aviva Lev-Ari, PhD, RN

“A Synergistic Approach towards Biowaivers & Biosimilars”. Biosimilars-2012 is scheduled on September 10-12, 2012 at Hilton San Antonio Airport, USA.

Biosimilars or Follow-on biologics
http://en.wikipedia.org/wiki/Biologic_medical_product are terms used to describe officially-approved subsequent versions of innovator biopharmaceutical http://en.wikipedia.org/wiki/Biopharmaceutical  products made by a different sponsor following patent and exclusivity expiry on the innovator product.[1] http://en.wikipedia.org/wiki/Biosimilar#cite_note-biosimilars2012-0 Biosimilars are also referred to as subsequent entry biologics (SEBs) in Canada.[2] http://en.wikipedia.org/wiki/Biosimilar#cite_note-1 Reference to the innovator product is an integral component of the approval.
 
A Biowaiver is a waiver (exemption) of clinical bioequivalence studies given to a drug product.
 

Biowaivers and Biosimilars.

The main theme of the conference is “A Synergistic Approach towards Biowaivers & Biosimilars”.

Biosimilars-2012 is scheduled on September 10-12, 2012 at Hilton San Antonio Airport, USA.

 Click here to view the downloadable Preliminary Program 

 http://sm1.mailserv.in/omicsonlinebiz/lt.php?id=eR4DBVEEUA9UUksGBlMKAU4=UQMNDAgNSllRVQgECyUNWAodUg5C

This three day conference will cover the latest trends and challenges in Biowaivers and Biosimilars.   Biosimilars-2012 highlights the following topics:   

  • Biosimilars Pathway  
  • Immunogenicity   
  • Skill Set for Biosimilars Development  
  • Biosimilar Therapeutics      
  • Biomedical informatics  
  • BCS and IVIVC based biowaivers  
  • Transgenic animals & plants  
  • In vitro & In vivo Correlations  
  • Bioequivalence Testing  
  • BCS and IVIVC based biowaivers    
  • Oral drug delivery     

Conference assets are William Velander (University of Nebraska, USA), Lisa J. Murray (Absorption Systems, PA, USA), Leandro Mieravilla (Biosimilar-Biotech Global Expert, Canada) and David Goodall (Paraytec Limited, UK) who will discuss their novel research on Biosimilars & Biowaivers.

This conference is perfect for researchers and experts, as well as those who require in-depth analysis of the latest trends, technologies, and techniques.

Confirmed Speakers Including

Tentative Scientific Program18:00-19:00Registrations Sep-09-2012

Day 1

Sep-10-2012

07:00-08:00 Registrations

08:00-08:30 Breakfast

Breakout 1

08:30-09:00 Opening Ceremony

Keynote Forum

09:00-09:05 Introduction

09:05-09:30 Lisa J. Murray, Absorption Systems, USA

09:30-09:55 Yet to be Confirmed

09:55-10:20 Yet to be Confirmed

10:20-10:45 Yet to be Confirmed

Coffee Break 10:45-11:00

Track 1: Biosimilars : Innovator Pharmaceutical Products

Track 2: Biosimilars: Regulatory Approach

Session Introduction

11:00-11:20

Title: The role of scientific justification in the nascent us biosimilars approval pathway

Ben Kaspar, MMS Holdings Inc., USA

11:20-11:40

Title: The what million dollar question: Patent litigation and strategy under the biologics

price Competition and Innovation act

Bryan J. Vogel, Robins, Kaplan, Miller & Ciresi L.L.P., USA

11:40-12:00

Title: The role of patents in biosimilars and biobetters

Brian Dorn, Barnes & Thornburg LLP, USA

12:00-12:20

Title: New patent reform litigation options for biosimilars

Paul A. Calvo, Sterne, Kessler, Goldstein & Fox P.L.L.C., USA

12:20-12:40 Title: Regulatory consideration of the assessment of biosimilar products

Jun Wang, Duke University School of Medicine, USA

Lunch Break 12:40-13:20

13:20-13:40

Title: What hath FDA wrought: The February 2012 guidance and their implications for

securing biosimilar approval

Michal Swit, Duane Morris LLP, USA

13:40-14:00

Title: The role of clinical trials in demonstrating similarity of biological medicinal

products in the European Union

Cecil Nick, PARAXEL Consulting, UK

14:00-14:20

Title: Biosimilars panel: Opportunities and challenges to be overcome in the near term

Jennifer Brice, Frost & Sullivan, UK

14:20-14:40

Title: Graphical representation of the assessment of inventive step for patents using the

Problem-Solution-Approach (PSA)

Joachim Stellmach, European Patent Office, Germany

14:40-15:00

Title: IP strategies for the biosimilar arena

Ulrich Storz, Michalski Huettermann Patent Attorneys, Germany

15:00-15:20

Title: Biosimilars in emerging countries: Argentina

Gustavo Helguera, University of Buenos Aires, Argentina

15:20-15:40

Title: Developing biosimilars: Considerations, opportunities and challenges

Ming Wang, Gan & Lee Pharmaceuticals, China

Panel Discussion 15:40-15:55

Coffee Break 15:55-16:10

Track 3: Skill Set for Biosimilars Development

Track 4: Clinical Studies for Biosimilars

Session Introduction

16:10-16:30

Title: Strategies for development and validation of immunogenicity assays to support

preclinical and clinical biosimilar programs

Kelly S. Colletti, Charles River Preclinical Services, USA

16:30-16:50

Title: Transgenic blood proteins: An abundant source for next generation therapies with

worldwide availability

William Velander, University of Nebraska, USA

16:50-17:10

Title: The Danish HNPCC-system – Biomedical support to individual health care in

hereditary colon cancer families

Inge Thomsen Bernstein, Hvidovre University Hospital, Denmark

17:10-17:30

Title: Use of human protein transgenic animal models for immunogenicity testing and

their value for comparative studies of biosimilars

Melody Sauerborn, TNO Triskelion BV, The Netherlands

17:30-17:50

Title: Application of nanotechnology in drug delivery

Rawia Khalil, National Research Centre, Egypt

Panel Discussion 17:50-18:05

18:05-19:05 Cocktails: Sponsored by Journal of Bioequivalence & Bioavailability

Day 2

Sep-11-2012

Breakout 1

Track 5: Biosimilars Therapeutics

Track 6: Commercialization or Globalization of Biosimilars

Session Introduction

09:30-09:50

Title: Development of antibody arrays for measuring biosimilar conformational

comparability at molecular level

Xing Wang, Array Bridge Inc., USA

09:50-10:20

Title: Biosimilar market overview, present and future

Leandro Mieravilla, Biosimilar-Biotech Global Expert, Canada

10:20-10:40

Title: Modified biosimilars: Potential role in the emerging global biosimilar market

Pascal Bailon, Bailon Consultants, USA

Coffee Break 10:40-10:55

10:55-11:15

Title: The application of releasable pegylation linkers to improve the pharmaceutical

properties of biosimilars and biobetters

Hong Zhao, Enzon Pharmaceuticals, USA

11:15-11:35

Title: The clinical development of monoclonal biosimilars

Cecil Nick, PARAXEL Consulting, UK

11:35-11:55

Title: Ghrelin antagonist: Advantages and side-effects

Maria Vlasova, University of Eastern Finland, Finland

11:55-12:15

Title: Biosimilar market growth trends in emerging markets

Syamala Ariyanchira, Independent Consultant, Malaysia

12:15-12:35

Title: Developing of long acting glycoprotein hormones using gene fusion and gene

transfer: From bench to clinics

Fuad Fares, University of Haifa, Israel

Lunch Break 12:35-13:15

13:15-13:35

Title: Th1 immune response induced by Ipr1-PPE68 DNA vaccine in BALB/C mice model

Yang Chun, Chongqing Medical University, China

13:35-13:55

Title: Anticancer noscapinoids: Synthesis to nanomedicine

Ramesh Chandra, University of Delhi, India

Panel Discussion 13:55-14:10

Track 7: Plant Produ ced Biosimilar Products

Track 8: Aggregation and Immunogenicity of Biosimilars

Session Introduction

14:10-14:30

Title: Biosimilars: Lessons learned from development to commercial launch

Niranjan M. Kumar, ABS Inc. USA

14:30-14:50

Title: Plant-based production and preclinical analysis of biosimilar Trastuzumab

Michael D. McLean, PlantForm Corporation, Canada

Coffee Break 14:50-15:05

15:05-15:25

Title: Immunological aspects of formation of anti-drug antibodies against aggregated

protein drugs

Melody Sauerborn, TNO Triskelion BV, The Netherlands

15:25-15:45 Speech Opportunity Available

15:45-16:05 Speech Opportunity Available

Panel Discussion 16:05-16:20

Breakout 2

16:20-19:20

Editorial Board Meeting

Poster Presentations

Scientific Partnering

Cocktails: Sponsored by Pharmaceutica Analytica Acta

Day 3

Sep-12-2012

Breakout 1

Track 9: Biowaivers

Track 10: BCS & IVIVC Based Biowaivers

Track 11: Bioequivalence Assessment

Track 12: Analytical Strategies

Session Introduction

09:30-09:50

Title: Role of process controls in mitigating the risk associated with manufacturing of

biosimilars

Indu S. Javeri, CuriRx Inc., USA

09:50-10:20

Title: Current analytical techniques for analysis of carbohydrate containing biosimilars

Parastoo Azadi, University of Georgia, USA

10:20-10:40

Title: Improving outcomes: A decade of industry and regulatory experience with BCS

based biowaivers

Lisa J. Murray, Absorption Systems, USA

Coffee Break 10:40-10:55

10:55-11:15

Title: Approach for development of w-3 phospholipid dietary supplement to potential lipid

drug

Su Chen, Chainon Neurotrophin Biotechnology Inc., USA

11:15-11:35

Title: Bioanalytical challenges in development of biosimilars

Carmine Lanni, Bioanalytical Development Services, USA

11:35-11:55

Title: Some statistical issues on the evaluation of the similarity and interchangeability of

biologics

Laszlo Endrenyi, University of Toronto, Canada

11:55-12:15

Title: Rapid characterization of formulations: Protein size, aggregate levels and viscosity

David Goodall, Paraytec Limited, UK

12:15-12:35

Title: Taylor dispersion analysis, a rapid, nanolitre method to monitor protein aggregation

behavior

Wendy Louise Hulse, University of Bradford, UK

Lunch Break 12:35-13:15

13:15-13:35

Title: Effects of drying technology and polymers on integrity and biological activity of

proteins

Amal Ali Elkordy, University of Sunderland, UK

13:35-13:55

Title: A global perspective on the challenges of GLP/GCLP-bioanalysis for biosimilars

Aparna Kasinath, Clinigene International Limited, India

13:55-14:15 Speech Opportunity Available

14:15-14:35 Speech Opportunity Available

14:35-14:55 Speech Opportunity Available

14:55-15:15 Speech Opportunity Available

Panel Discussion 15:15-15:30

Editorial Board Meeting

For Biosimilars-2012 Organizing Committee 

OMICS Group Conferences
5716 Corsa Ave., Suite110
Westlake, Los Angeles
CA91362-7354, USA
Phone:+1-650-268-9744 <tel:%2B1-650-268-9744>
Fax:+1-650-618-1414 <tel:%2B1-650-618-1414>
Email: biosimilars2012@omicsgroup.com <mailto:biosimilars2012@omicsgroup.com>
     
         

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Curator: Aviva Lev-Ari, PhD, RN

 

For Financial Aspects of Biosimilars, go to:

Biosimilars: Financials 2012 vs. 2008

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-financials-2012-vs-2008/

 

For CMC and Regulatory Affairs of Biosimilars, go to:

Biosimilars: CMC Issues and Regulatory Requirements

https://pharmaceuticalintelligence.com/2012/07/29/biosimilars-cmc-issues-and-regulatory-requirements/

 

In this post we focus on the Legal Scene of Intellectual Property Creation & Protection by Pioneer & by Biosimilar Manufacturers.

The regulatory pathway for biosimilars has an impact on biopharma R&D, M&A and valuation of companies and products. Industry and investors were uncertain if biosimilar will be approved, the impact a new biosimilar will have on rate of return and sales of pioneer innovators which are big pharma with dedicated divisions to biosimilars as well as on new entrants as biosimilar manufacturers.

Biosimilars, aka biogeneric, biocomparable or follow-on biologic are different than traditional pharmaceuticals, aka small molecules produced by chemical reactions, subjected to generic competition. Biosimilars include proteins produced by genetically engineered organisms, have not been challenged by generic competion.The generic  competition provisions of the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) apply to products approved under the Food, Drug, and Cosmetic Act, which include small molecule pharmaceuticals, but not to products approved under the Public Health Service Act, which include biologics.

It is estimated that, within a few years, biologics will be half of the biopharmaceutical market. As a result there have been mounting calls for a biosimilar pathway for companies obtaining Food and Drug Administration (FDA) approval of generic versions of existing biologics based upon lesser showings of safety and efficacy than is required for a pioneer biologic.

Like Hatch-Waxman Act for generic drugs, The Biologics Price Competition and Innovation Act (BPCIA) aka Biosimilar Act of 2009  (1) establishes standards for application and approval; (2) provides a term of data exclusivity; and (3) establishes a scheme for handling patent disputes. The similarities, however, end with these broad constructs, as the details involved with each are quite different.

Patent Disclosure Requirements

The Biosimilar Act imposes completely new disclosure requirements for patents that are demanding and time-sensitive, and it imposes these requirements on both pioneer and biosimilar manufacturers. These requirements will be required after submission of a biosimilar application and will demand sophisticated legal counseling and planning. These requirements are as follows:

• The biosimilar applicant must provide a copy of the application to the pioneer manufacturer (reference product sponsor) within 20 days of being notified that its application has been accepted by the FDA.

• The pioneer manufacturer must provide the applicant with a list of patents that it believes “could reasonably be asserted” with respect to the pioneer product within 60 days of receiving a copy of the application. The list must identify which patents the pioneer manufacturer would be prepared to license to the biosimilar applicant.

• The biosimilar applicant must provide the pioneer manufacturer with a detailed statement describing its opinion that any patent listed is invalid, unenforceable, or will not be infringed by the commercial marketing of the biosimilar, or a statement that it does not intend to begin commercial marketing of the biosimilar before the expiration of the listed patent(s), within 60 days of receiving the list of patents.

• The pioneer manufacturer must provide the biosimilar applicant with a detailed statement describing its opinion that its patent(s) will be infringed by the biosimilar, as well as a response concerning the validity and enforceability of its patent(s) within 60 days of receiving the biosimilar applicant’s detailed statement.

• The biosimilar applicant must notify the pioneer manufacturer 180 days before the first commercial marketing of the biosimilar. The pioneer manufacturer may then seek a preliminary injunction.

After these required exchanges, the act requires good faith negotiations by the parties to agree on which patents will be the subject of any infringement action. Within 30 days of either agreeing on this list of patents, or exchanging each party’s final list of patents, the pioneer manufacturer must bring an infringement action. The pioneer manufacturer also has 30 days to amend this list after the issuance, or exclusive licensing, of a new patent that it believes is infringed by the biosimilar. If the pioneer manufacturer prevails in this action before approval of the biosimilar, the court must enter a permanent injunction prohibiting further infringement.

Failure to bring an infringement action within the 30-day mandate (or bringing an infringement action that was dismissed without prejudice or was not prosecuted to judgment in good faith) will result in the available remedy being limited to a reasonable royalty only. Finally, failure by the pioneer manufacturer to timely include a relevant patent in the exchanged list will preclude the pioneer manufacturer from later bringing an infringement action against the biosimilar applicant with respect to that undisclosed patent.

Intellectual Property Considerations

As a result, it is feasible that a biosimilar may be similar enough to qualify as a biosimilar under the Biosimilar Act but not similar enough to be covered by a patent claim. Accordingly, pioneer manufacturers should take care in obtaining valid claims that afford broad patent protection of their biologics. To do so, pioneer manufacturers should consider, for example, protecting not only the biologic itself but also, if possible, the target molecule(s) of the biologic, methods of use and methods of production. In addition, pioneer manufacturers should also contemplate how their biologics may be modified and consider obtaining patent protection for those modifications. While this is generally a common practice in patent law, it has been less important in pharamceuticals, where the focus has been on the patents that protect the drug itself rather than methods of its manufacture, and on obtaining protection from a generic (a bioequivalent drug, rather than a less equivalent drug that could treat the same condition).

Biosimilar manufacturers, on the other hand, should analyse how the pioneer’s biologic is protected by one or more patents and consider how they may be able to escape patent protection. Biosimilar manufacturers should also be careful of what admissions they make in regard to what is and is not equivalent in an application under the Biosimilar Act. Such admissions may be considered by manufacturers of the pioneer biologic for possible infringement positions. Under the Biosimilar Act, there is a certain amount of protection afforded through data exclusivity for a pioneer biologic. Pioneer biologic manufacturers, however, should not solely rely on this period of exclusivity for protection. Not only may patent protection go beyond the protection afforded by the data exclusivity period for a pioneer biologic, but an additional data exclusivity period may not be available under the Biosimilar Act. As a result, it is important for pioneer manufacturers to consider obtaining patent protection for improvements to their pioneer biologic.

Likewise, biosimilar manufacturers should also seek patent protection for their biosimilars and improvements to them, and consider the pioneer biologic and associated patents in doing so. Patent protection may be available for biosimilar biologics even when data exclusivity under the new act is not. In regard to the patent disclosure requirements, the scheme of the new act appears to avoid many of the problems that have arisen under the Hatch-Waxman Act for generic pharmaceuticals, such as the numerous issues regarding the requirement to list relevant patents in the Orange Book.

However, the completely new patent disclosure scheme for biosimilars will take years for the FDA and the courts to sort out. In the end, it may very well be more burdensome on the  parties than the Hatch-Waxman Act, which has spawned a tremendous amount of litigation. At the very least, the patent provisions of the Biosimilar Act establish demanding and time-sensitive disclosure requirements for both the pioneer and biosimilar applicant. Given the detail required and the complexity of the issues, both parties should conduct the necessary investigation and analysis well before a biosimilar application could be filed. Some steps that may be taken include: identifying all relevant patents, determining expiration dates and potential patent term extensions, and identifying patent owners and licenses. Based on the investigation and analysis, both parties should develop detailed infringement, validity, and enforceability positions before receiving the other party’s patent list or positions. Failing to take early action will likely result in a party rushing to prepare the very detailed statements required by the law for both parties, running the serious risk of making a potentially determinative mistake. Both parties also face penalties for failing to comply with the disclosure requirements.

In all, it will be important for pioneer and biosimilar manufacturers to fully understand their patent portfolios as well as those of their competitors and to review these portfolios regularly. The requirements of the Biosimilar Act will necessitate sophisticated and extensive legal counseling, active portfolio diligence, and time-sensitivity

http://www.wolfgreenfield.com/files/2426_biosimilars_2_final_pdf.pdf

http://www.managingip.com/Article/3047226/Search/An-overview-and-update-on-biosimilars.html?Home=true&Keywords=Biosimilars&Brand=Site&tabSelected=True

Greater clarity in the biopharma and pharma market place was achieved on June 28, 2012 when the US Supreme Court has upheld ObamaCare, ensuing that the pathway for biosimilars included with the law will remain intact.

The US paved the way for biosimilar approval in 2012 as part of the Patient Protection and Affordable Care Act (PPACA). A major element of the healthcare reform law is The Biologics Price Competition and Innovation Act (BPCIA) aka Biosimilar Act of 2009 provision of that bill said that biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product may be approved under an abbreviated pathway similar to the process for small molecule generics.

With the upheld ObamaCare, critical parts of the PPACA constitutional, and with it the BPCIA giving the FDA authority to approve biosimilars.

Had the PPACA been stricken in part or in its entirety, it would have presented obstacles to the BPCIA surviving in its present form. The US government has been critical of the 12-year data exclusivity period for Pioneer Innovators, calling for it to be shortened to 7 years (12 years is favorable to Pioneer Innovators and less favorable for Biosimilar manufacturers). The upheld ObamaCare, PPACA and BPCIA, constitutional, has prevented a multiyear delay in biosimilar approval. Thus, it was the best scenario for the biologics industry.

BPCIA provides the approval of biological products as biosimilar or interchangeable (BPCIA 351(k)). As part of the FDA’s approval process, biosimilar products would need to produce the same clinical effect and if a multi-dose product, not present any greater safety or efficacy risk to patients in switching from the reference product. There would have to be “clinically meaningful differences” between the pioneer biologic reference product and the biosimilar product in order to gain FDA approval.

Congress granted the FDA flexibility for approval standards for biosimilars, i.e., what type of clinical studies required, what differences in approval process from biologics license applications (BLA) are appropriate.

1. Pioneer inventors are granted 12 years of data exclusivity, barring FDA approval of a 351 (k) application from “the date on which the reference product was first licensed”

2. An application can’t be submitted to the FDA until 4 years after the date on which the BLA for the reference product was first granted.

3. FDA sets approval requirements unless FDA waives them: analytical studies demonstrating the biosimilar is highly similar to the reference product, animal studies, a clinical study sufficient to demonstrate safety, purity, potency, same mechanism of action, route of administration, dosage form and strength.

Hatch-Waxman Act for generic drugs patent challenge provisions are different from BPCIA‘s patent challenge provisions.

  • BPCIA require “negotiation” of patent disputes and exchanges of patent information between parties prior to instituting patent litigation.
  • BPCIA mandates risk evaluation and mitigation strategy (“REMS”) requirements, shall apply to biosimilars as they do to reference pioneer biologic.
  • Reimbursemwnt for biosimilars is set at Average  Sales Price (ASP) plus 6% of the amount determined for the amount determined for the reference pioneer biologic.
  • BPCIA allows for imposition of user fees to review biosimilars
  • Naming biosimilars: generic vs. proprietary naming requirements for drug safety and/or recalls, tracking adverse events,  as well as reimbursement
  • Unanswered, if a biosimilar applicant needs to provide data on al approved indications of the reference product, and can a biosimilar be better than a reference product (i.e., “biobetters”), if so in what way (e.g., safety or efficacy).

On 2/9/2012 – FDA issued 3 draft guidance documents intended to facilitate the submission of marketing applications for biosimilars

1.  Biosimilars Q&A: provide guidance on the content of 351(k) applications. Recommendations that sponsors meet early with FDA to discuss plans. Guidance sets out the FDA’s current view that comparative animal or clinical data developed using non-US-licensed product can provide evidence that proposed product is biosimilar to a US-licensed reference product.

2. Biosimilars Scientific Guidance – three approaches to establish demonstrated biosimilarity.

a.  “stepwise” approach comparison of proposed product with reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), cinical immunogenicity, and clinical safety and effectiveness.

b.  “totality-of-the-evidence” approach

c.  “general scientific principles” in conducting comparative structural and functional analysis, animal testing, human PK and PD studies, clinical immunogenicity assessment and clinicall safety and effectiveness studies (study design issues)

3.  Biosimilar Quality Guidance provides directions on analytical studies assessing if the proposed biosimilar protein product and the reference product are “highly similar” Guidance suggests that there may be an opportunity for pioneer innovators to argue that current technology does not permit for demonstration of  “biosimilarity” of a potentially competitive product in a manner adequate to gain approval under 351(k), thus necessitating the filing of full BLA.

Outstanding issues under BPCIA’s provisions related to marketing and development could affect biopharma investment:

1.  effects on coverage and reimbursement of the pioneer biologic based on approval of a biosimilar, reimbursement of biosimilars themselves

2. biosimilars and not expressly treated in the new act under Medicare Part B, Medicare Drug Pricing Program, Medicaid, 340B program.

3. non clear is biosimilars will constitute “multi-source drugs.”

Unlike the generic drugs market, the biosimilars market is likely to have a smaller number of entrants, greater costs of applications and testing, less reduction in price from that of a pioneer biologic and necessity of marketing staff.

It is unclear when the cost of the drug will become a switching factor in purchasing a biosimilar. purchaser resistance  note withstanding price advantage did occur in the past. There eexist potential purchaser/payor concerns regarding interchangeability, safety, efficacy (i.e., potency). There is concern over evergreening strategy by pioneer inventors to use drug modifications to extend the exclusivity period thus, deterring the entrance of biosimilars.

In June 2011, the European Medicines Agency (EMA) and FDA issued a joint report noting the interactions between the two agencies, when a biosimilar version of a mococlonal antibody, Remicade was filed in the EU.

Defining Protein Therapeutics

FDA promises a risk-based “totality-of-the-evidence” approach to reviewing biosimilars. Novo Nordisk and Pfizer urged FDA to rethink its definition of proteins as excluding alpha amino acid polymers with fewer than 41 amino acids. Jim Shehan, Novo Nordisk’s corporate vp, legal, government, and quality affairs, noted that the definition clashed with statutes defining biological products as including any polypeptide except for those that are chemically synthesized.

“We believe they have selected an arbitrary cutoff,” Shehan told GEN. “It can conflict with the statutory language and it really isn’t grounded in science either,” an exception, he said, to the guidance’s overall focus on respect for science and patient safety. “In broad strokes, they met the mark in seeming to have a healthy respect for the need to have data in order for biosimilars to come to market.”

F. Owen Fields, Ph.D., Pfizer vp, worldwide regulatory strategy, worldwide R&D, suggested a case-by-case review of proteins with 40 or fewer amino acids. He cited Nisin, a 37-amino-acid polypeptide derivative approved by FDA as a food preservative, as an example among natural peptides best treated as proteins because of their potential for use as substrates for new drug development. “There are structures less than 41 amino acids that present regulatory science issues that are more similar to biologically synthesized proteins than to chemically synthesized peptides,” Dr. Fields pointed out at the hearing.

Keeping Trade Secrets Secret

Abbott called for additional FDA efforts to protect trade secrets of reference drugs during agency review of biosimilar applications. “Safeguards are needed to ensure that the agency doesn’t unintentionally, inadvertently, but nevertheless impermissibly use or disclose to a biosimilar applicant an innovator’s trade secrets,” Neal Parker, an Abbott attorney, said at the hearing.

Among safeguards suggested by Parker were FDA developing IT systems tracking employee involvement with BLAs and biosimilar applications, creating policies and procedures and training employees in them, and preventing FDA reviewers “significantly” involved in reviewing specific U.S.-licensed innovator BLA products from any biosimilar application review activities or any communications with biosimilar applicants seeking to rely on those same reference products.

Abbott recently submitted a citizen’s petition requesting that the agency not consider any applications for biosimilars based on biologic reference products for which a BLA was submitted before March 23, 2010, the date that President Barack Obama signed the Biologics Price Competition and Innovation Act. The request would effectively shield Abbott’s mAb therapeutic and biggest-selling treatment Humira from biosimilar competition. The company is about to spin off its brand-name drug development operations, remaining as a maker of medical equipment and generic drugs.

Fine-Tuning Data Requirements

Kalyan R. Anumala, Ph.D., senior director of Therapeutic Proteins, suggests that the agency should only require Phase II and III trials where it establishes a need after reviewing a submission. He also said the agency should encourage new characterization methods rather than clinical trials.

Also calling for additional characterization methods is the only U.S. company marketing biosimilar drugs, Hospira. Its products include anemia treatment Retacrit in the EU and biosimilar filgrastim product Nivestim, sold in the EU and Australia for stimulating production of white blood cells in patients receiving cytotoxic chemotherapy.

Samant Ramachandra, M.D., Ph.D., Hospira’s senior vp, R&D and regulatory and medical affairs and CSO, also urged FDA to account for reference product variability and clarify the required approach to show clinical immunogenicity assessment.

Dr. Ramachandra and James M. Roach, M.D., svp and CMO of Momenta Pharmaceuticals, urged FDA to permit the use of bridging data in return for allowing non-U.S. reference products. “This is critical if the goal is to implement a global development program that is feasible to conduct,” Dr. Roach added. Eli Lilly’s Gregory C. Davis, Ph.D., pressed FDA for more guidance on the type and extent of bridging data that would be permissible.

Abbott, by contrast, said data from studies involving a foreign comparator product cannot be considered pivotal if the foreign comparator is different from the U.S. reference product. FDA has stated that clinical comparisons with a non-U.S. licensed product do not provide an adequate basis to support interchangeability.

Jay P. Siegel, M.D., chief biotechnology officer and head of global regulatory affairs for Janssen Pharmaceutical, echoed many brand-name drug developers by urging FDA to maintain the draft guidance’s standard for interchangeability. Applicants would have to demonstrate biosimilarity and the ability of the biological product to produce the same clinical result as the reference product in any given patient.

If biosimilarity is established, it should also be extrapolated to pediatric populations, said Karl Heinz Emmert, Ph.D., managing director for Merckle Biotec, a Teva Group member. Dr. Emmert contended that FDA need not require clinical studies of pediatric populations with a biosimilar product. That differs from the thinking of Pfizer, which while supportive of extrapolations between populations within an indication, suggested an exception: diseases where pediatric pathophysiology differs from that of adults.

With regard to manufacturing concerns, Paul Eisenberg, an Amgen svp, argued in part: “Requiring the maintenance of biosimilarity over time would inhibit manufacturing and quality improvements and unduly burden industry without benefiting patients.” Mark McCamish, M.D., Ph.D., head of global biopharmaceutical development for Sandoz Biopharmaceuticals, disagreed.

Determining Label Details

Amgen did not address manufacturing issues in testimony but focused instead, along with several other companies, on how biosimilars should be identified and labeled to ensure accurate tracking and tracing. Suggestions included biosimilar names sharing a common root but having a unique suffix and/or prefix to denote biosimilarity and interchangeability.

“Having unique names will avoid unintended substitution, minimize risk of medication errors, allow for essential elements of pharmacovigilance such as traceability and follow-up of adverse drug reactions, as well as facilitate prescriber-patient decision making,” commented Michelle Rohrer, Ph.D., vp, U.S. regulatory affairs at Genentech.

Teva’s Dr. Emmert and Ahaviah Diane Glaser, vp for policy and strategic alliances with the Generic Pharmaceutical Association (GPhA), noted, however, that while all biologics should be uniquely tracked, biosimilars should not require unique International Nonproprietary Names (INNs) from their reference products. Glaser said different INNs would impede market competition because it would likely require a different marketing campaign, thus raising costs, and would also complicate collection of global safety data and could increase medical errors.

Embracing Biosimilars

Further guidance on naming biosimilars and interchangeables was one point agreed upon by industry and patient groups, so it’s likely FDA will oblige. That’s the easy issue for the agency. Tougher will be how to balance shepherding biosimilars and interchangeable products to market without sacrificing patient safety.

“If FDA issues product-specific guidances with very clear mandates that to get a biosimilar approved, you need to run a Phase III-like trial of X size, evaluating X, Y, and Z, it takes away from the incentive to put that much more time and scientific thought into proving from a structural and functional basis that you have the same compound,” Dr. Roach of Momenta told GEN.

Years ago EMA developed solid scientific guidelines, then product-specific rules that succeeded in bringing biosimilars to Europe. Sandoz’ Dr. McCamish credited EMA’s consistent standards with health authorities embracing biosimilars. It’s a lesson the U.S. will have to learn as FDA builds the pathway for biosimilars to finally reach the American market. 

http://www.genengnews.com/insight-and-intelligenceand153/fda-s-hearing-for-biosimilars-showcased-issues-ranging-from-definitions-to-study-requirements-to/77899607/

On February 9, FDA issued long-awaited guidelines designed, according to FDA drug division director Janet Woodcock, M.D., “to help industry develop biosimilar versions of currently approved biological products.” Paul Calvo, Ph.D., a director at Sterne, Kessler, Goldstein & Fox, told GEN, “There were no major surprises” in the guidelines.

“It is clear that FDA wants to move forward with biosimilar approvals and they will be looking to a totality of the evidence as the standard for a determination of biosimilarity.” He also commented that FDA wants a constant dialog with biosimilar sponsors and all the structural and functional data up front. “Their goal for the up-front data is to be involved in design of the clinical trials in order to maximize the data provided.”

FDA’s new documents describe a step-wise approval pathway, starting with extensive analytical, physico-chemical, and biological characterization data that will have to demonstrate a high degree of similarity to the reference product. FDA will evaluate that data and then provide advice to the sponsor on the extent and scope of animal and human testing needed to show biosimilarity. The agency will consider multiple factors in making study determinations, including product complexity, formulation, stability, structure-function relationships, manufacturing process, and clinical experience with the reference product.

While the pathway to the agency’s decision making will be abbreviated, “it will depend on existing data,” Rachel Sherman, M.D., director of the Office of Medical Policy in FDA’s Center for Drug Evaluation and Research, said during a conference call. “We do not want companies repeating studies that do not need to be done.” As to whether most biosimilar applicants will be expected to carry out clinical trials, decisions will be made on a product by product basis.

Another topic of note is that the FDA has said that there could be extrapolation of clinical data to other diseases to give companies developing biosimilars approval for use in multiple indications for a given product. “But for therapeutics like Rituxan with two disparate indications, one for lymphoma and another for rheumatoid arthiritis, two sets of clinical trials will likely be required,” Dr. Calvo explained.

Interchangeability and Exclusivity

Importantly for the industry, the guidance documents indicate that the agency hasn’t settled some important biosimilars policy questions, including requirements for demonstrating interchangeability of a biosimilar with a reference product and terms for establishing the exclusivity period for pioneer biologics.

The Patient Protection and Affordable Care Act, signed into law by President Barack Obama on March 23, 2010, mandated the creation of an abbreviated approval pathway for biosimilars and proposed a 12-year data exclusivity period. The president’s budget proposal for fiscal 2013 released February 13, however, suggests that exclusivity should be lowered to seven years.

With regard to interchangeability, FDA states that it “is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.” Dr. Calvo explained that “interchangeability is important because it provides for a period of market exclusivity as well for automatic substitution of the interchangeable for the approved biologic without intervention from the prescribing physician.”

“However,” Dr. Calvo added, “given how new the whole process for biosimilar approval is, it would have been surprising if the FDA would have said there would not be any issues in determining interchangeability.” But, he noted, the agency has said that right now it doesn’t have the scientific ability to approve biosimilars as interchangeable.

An Amgen spokesperson commented that “FDA’s acknowledgement that determining interchangeability is scientifically difficult at this time is important. Patient safety does not stop at approval, and Amgen believes that post-approval activities including ongoing monitoring are essential to patient safety.”

Dr. Sherman believes that the hurdles for interchangeability would be high. Biologic drugs carry the added risk of prompting an immune response, she noted, and the FDA would “almost certainly” require clinical trials in which a patient is switched from the branded drug to the biosimilar and back to rule out the risk of triggering the immune system.

Potential Cost Savings

Dr. Calvo pointed out that “the ability to have a high level of FDA input will likely increase the chance that biosimilars will soon enter the U.S. market.” However, he added, the price erosion that occurs with small molecules “will not happen for biosimilars to even close to the extent that it occurs with small molecules, mainly because there will not be a mechanism for automatic substitution and because clinical studies will be required at least to some degree.”

For more complex products such as antibody conjugates or highly purified protein mixtures, “it is highly likely that more sophisticated manufacturing and analytical methods and possibly clinical trials will be required, therefore increasing costs for biosimilar entrants,” Jefferies analyst Biren Amin said in a note to clients. “This could apply to products like Seattle Genetics’ Adcetris or ImmunoGen and Roche’s T-DM1.”

The Congressional Budget Office still estimates that biosimilars would save the government $25 billion in healthcare spending during the coming decade. While generic chemical compounds like Norvasc and Metoprolol usually sell for less than 20% the cost of the brand product, biosimilars are expected to sell for 60% to 80% of the cost of branded biologics. The difficulty of producing and gaining approval for biosimilars will provide manufacturers increased pricing power and larger margins compared to traditional generic medications.

Biosimilars represent a tremendous opportunity for pharma and biotech companies that can successfully manufacture and market them. The global market for biosimilars will range between $11 billion and $25 billion by 2020, accounting for 4 to 10 percent of the total market for biotech drugs, according to IMS Health. Despite the potential hurdles to both interchangeability and exclusivity, patent expiries in the next two years put around $11 billion in biologic drug sales into play. That kind of potential along with the establishment of a designated approval pathway clears away some lingering doubts about the viability of generic competition.

As for the industry, potential biosimilar manufacturers continue to make deals. While there are no currently marketed biosimilars in the U.S., so-called innovator companies including Amgen, Pfizer, Novartis, and Eli Lilly have joined the ranks of generic firms such as Teva in developing biosimilars. Amgen told GEN that as a leading provider of high-quality biologic medicines, it understands the challenges of developing and manufacturing innovative and biosimilar medicines and appreciates the agency’s efforts on the guidelines, and encourages adoption of a thorough review and approval process.

While it remains to be seen whether approved biosimilars provide the savings in healthcare costs that the Congressional Budget Office optimistically predicted, both the FDA and the industry are moving toward making them a reality in the U.S. As per the three dozen or so requests for meetings, FDA staffers are holding pre-IND meetings with sponsors and encouraging all prospective biosimilar makers to seek early advice. Nine INDs for biosimilar have been filed so far, and the agency is anticipating a full 351(k) application soon.

http://www.genengnews.com/insight-and-intelligenceand153/what-will-fda-biosimilars-guidelines-mean-for-industry/77899555/

More than a year after launching a dialogue with industry regarding biosimilars, FDA is holding a morning-long public meeting today. The proposed approval pathway and fees drug developers must pay for the five fiscal years starting October 1, 2012, will be discussed. The agency is soliciting public comment through January 6, 2012

Those comments are expected to shape a final FDA recommendation on biosimilar user fees, which the agency plans to send to Congress by January 15, 2012. On December 7, the agency published “Biosimilar Biological Product Authorization Performance Goals and Procedures, Fiscal Years 2013 through 2017.”

The user fee program is expected to aid FDA in developing the final abbreviated approval pathway for biosimilars, which was required under the Biologics Price Competition and Innovation Act (BPCIA) of 2009. BPCIA was tucked into page 686 of the Patient Protection and Affordable Care Act enacted last year by President Obama. Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research co-authored a paper published this August in The New England Journal of Medicine that provided some clues on the overall approval pathway.

http://www.genengnews.com/insight-and-intelligenceand153/fda-holds-public-discussion-of-user-fee-program-for-biosimilars/77899515/

The initial fee would be 10% of the fee established for a drug application under PDUFA each year from FY 2013 through 2017. The agency would collect only one initial BPD fee per product, regardless of the number of proposed indications.

Sponsors that submit marketing applications would pay fees equal to those established for drug applications under PDUFA minus the cumulative amount of BPD fees. Under PDUFA, 2012 fees for drug products go up as high as $1.84 million.

“By providing FDA with these resources, they would be able to meet with sponsors, provide clear and established guidelines for regulatory action, and as a result that should reduce the barriers to market entry even more than what would be represented through a modest fee like this,” Emmett said. Since established biopharma companies are more likely to produce biosimilars than early-stage companies, “I wouldn’t anticipate that $180,000 would be a significant barrier to market,” Emmett added.

“FDA anticipates a modest level of funding from these sources initially because only biosimilar biological products that are approved for marketing would be subject to these fees,” the agency said.

http://www.genengnews.com/insight-and-intelligenceand153/fda-holds-public-discussion-of-user-fee-program-for-biosimilars/77899515/

Biosimilars and Follow-On Branded Biologics

Promoting Innovation and Access to Life-Saving Medicine Act (H.R.1427, a bill from the first session of the 111th Congress) and the FTC’s report titled Emerging Health Care Issues: Follow-on Biologic Drug Competition are intended to provide the rationale for moving access to biosimilars/follow-on biologics and driving the legislative compromise. Of particular interest is the FTC’s projection of what cost savings (10–30%) will actually be achieved, and that the originator biologic manufacturer may likely retain 90% of its market.

When a new human growth hormone (hGH) product tried to compete with  Genentech’s hGH, physicians hesitated to move patients on to it, so its market was just new patients. If there is only a 10–30% price differential for biosimilar/follow-on biologics and they lack an AB substitutability rating, one would anticipate the same reluctance to switch patients.

http://www.genengnews.com/gen-articles/biosimilars-and-follow-on-branded-biologics/2981/?page=2

FDA’s draft guidance for biosimilars drew mostly good marks from industry at the hearing held May 11. Executives from a dozen biopharma companies, however, pressed for greater flexibility in the definition of proteins, tighter standards in naming and labeling follow-on biologics, as well as more details on moving drugs through agency approvals.

Draft Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet and Related Injectors Intended for Use with Drugs and Biological Products, April 2009.) The Guidance recognizes that these are innovative approaches to deliver drugs or biologics products that may enhance accuracy and patient compliance.

One major significant issue of this Guidance lies in its application to biosimilars, facilitating their conversion into higher-value follow-on branded products. As an example, Novo Nordisk is now introducing its next-generation FlexPen, a prefilled insulin delivery device that the company reports has a 25–41% lower force than the existing SoloStar and KwikPen devices; diabetic patients prefer lower-force insulin injections since they are less painful.

After obtaining FDA approval to market in the U.S., a first-generation biologic may have little commercial value as a commodity product and have a BX rating (not substitutable), since most biopharma companies have developed a second- or third-generation biologic with an innovative delivery system—a specialty product. It is anticipated that specialty products will command prices near or only 10–20% less than that of the originator product, even though they will not have a BX rating. In this scenario, the initial approval of the first-generation biosimilar is really a strategy to rapidly enter the marketplace, then quickly evolve into a higher-value specialty, often called a follow-on branded product.

http://www.genengnews.com/gen-articles/biosimilars-and-follow-on-branded-biologics/2981/

CMC Issues and Regulatory Requirements for Biosimilars

Dr. Bao-Lu has exposed very important CMC Issues and Regulatory Requirements for Biosimilars in

http://www.tbiweb.org/tbi/file_dir/TBI2009/Bao-lu%20Chen.pdf

Chemistry, Manufacturing and Controls (CMC), preclinical and clinical are three critical pieces in biosimilars development. Unlike a small-molecule generic drug, which is approved based on “sameness” to the innovator’s drug; a biosimilar is approved based on high similarity to the original approved biologic drug. This is because biologics are large and complex molecules. Many functional-, safety- and efficacy-related characteristics of a biologic depend on its manufacturing process. A biosimilars manufacturer won’t be able to exactly replicate the innovator’s process. The traditional abbreviated pathway for generic drug approval through the Hatch- Waxman Act of 1984 doesn’t apply for biosimilars as drugs and biologics are regulated under different laws. New laws and regulations are needed for biosimilars approval in the US. The EU has issued biosimilars guidelines based on comparative testing against the reference biologic drug (the original approved biologic). A full scale CMC development is required including expression system, culture, purification, formulation, analytics and packaging. The manufacturing process needs to be developed and optimized using state-of-the-art technologies. Minor differences in structure and impurity profiles are acceptable but should be justified. Abbreviated clinical testing is required to evaluate surrogate markers for efficacy and demonstrate no immunogenic response to the product.

We anticipate the package for a biosimilars approval in the US will be similar to that in the EU and contain a full quality dossier with a comparability program including detailed product characterization comparison and reduced preclinical and clinical requirements.

Biosimilars Become Inevitable

Biologics developed through biotechnology constitute an essential part of the pipeline for medicines available to patients today. Biologic drugs are quite expensive and many of them are top-selling medicines (see Table 1). Since they come at extremely high prices to consumers, some patients may not be able to afford the use of biologics as the best-available treatments to their conditions. The patent protection on a large number of biologics has expired since 2001. These off-patent biologics include Neupogen, Novolin, Protropin, Activase, Epogen or Procrit, Nutropin, Humatrope, Avonex, Intron A, and Humulin. Traditionally, when a drug patent expires, a generic drug will be quickly developed and marketed. Similarly, generic version of off-patent biologic drugs (also referred to biosimilars or follow-on biologics or biogenerics) represents an extraordinary opportunity to companies that want to seize the potentially great commercial rewards in this unexploited territory. Biosimilars not only benefit the biosimilar manufacturers but also can save patients, and insurance companies, substantial cost and allow patients to gain access to more affordable biologics resulting in market expansion. The government can use biosimilars to reduce healthcare costs. Therefore, development and marketing of bosimilars are supported by both manufacturers and consumers.

Differences between Generic Drugs and Biosimilars

Enacted in 1984, the US Drug Price Competition and Patent Term Restoration Act, informally known as the “Hatch-Waxman Act of 1984” standardized US procedures for an abbreviated pathway for the approval of small-molecule generic drugs. The generic drug approval

is based on “sameness”. In comparison to the innovator’s drug, a generic drug is a product that has the same active ingredient, identical in dose, strength, route of administration, safety, efficacy, and intended use. For approval, the generic companies can go through the Abbreviated

New Drug Application (ANDA) process with reduced requirement in comparison to approval for a new drug entity. The generic drugs need to show bioequivalence to the innovator drugs typically based on pharmacokinetic parameters such as the rate of absorption or bioavailability in 24 to 36 healthy volunteers. No large clinical trials for safety and efficacy are required. The generic companies can rely on the FDA’s previous findings of safety and effectiveness of the innovator’s drugs.

However, the abbreviated pathway for generic drugs legally doesn’t apply to biologics as small-molecule drugs and biologics are regulated under different laws and approved through different pathways in the US (Table 2). Small-molecule drugs are regulated under the Food, Drug and Cosmetic Act (FD&C) and require submission of a New Drug Application (NDA) to FDA for drug review and approval. Biologics are regulated under the Public Health Service Act (PHS) and require submission of a Biologic License Application (BLA) to FDA for review and approval. The Hatch-Waxman Act of 1984 doesn’t apply for biosimilars. New laws are needed to establish a pathway for biosimilar approval.

There are some crucial differences between biologics and small-molecule drugs. Small-molecule drugs are made from chemical synthesis. They are not sensitive to process changes. The final product of a small-molecule drug can be fully characterized. The developmentand production of generic drugs are relatively straightforward. Biologics are made from living organisms so that its functional-, efficacy- and safety-related properties depend on its manufacturing and processing conditions. They are sensitive to process changes. Even minor modifications of the manufacturing process can cause variations in important properties of a biological product. Thus it is believed that a biologic product is defined by its manufacturing process. Biologics are 100- or 1,000-fold larger than small-molecule drugs, possess sophisticated three-dimensional structures, and contain mixtures of protein isoforms. A biological product is a heterogeneous mixture and the current analytical methods cannot characterize these complex molecules sufficiently to confirm structural equivalence with the reference biologics.

Laws and Regulatory Pathways for Drug Approval in the US

Law/Application             Small-molecule            Drug Biologics                     

Law             Food, Drug and Cosmetic Act (FD&C)             Public Health Service Act (PHS)

Drug application   New Drug Application (NDA)   Biologic License Application (BLA)

Generic application   Abbreviated New Drug Application(ANDA)   NEW pathways beyond BPCIA, 2009

Differences between small-molecule drugs and biologics

Product characteristics

Small-molecule generics Small, simple molecule

(Molecular weight: 100-1,000 Da)

Biosimilars   Large, complex molecules, Higher order structures, Post-translational, modifications

(Molecular weight: 15,000-150,000 Da)

Production

Small-molecule generics Produced by chemical synthesis

Biosimilars  Produced in living organisms

Analytical testing

Small-molecule  Well-defined chemical structure, all its various components in the finished drug can be determined

Biosimilars  Heterogeneous mixture, difficult to characterize, some of the components of a finished biologic may be unknown

Process dependence

Small-molecule   Not sensitive to manufacturing process changes. The finished product can be analyzed to establish the sameness.

Biosimilars   Sensitive to minor changes in manufacturing process. The product is defined by the process

Identity and purity

Small-molecule Often meeting pharmacopeia or other standards of identity (e.g., minimums for purity and potency)

Biosimilars   Most have no pharmacopeia monographs

immunogenicity issues prior to 1998. When J&J made a change in the Eprex formulation by replacing human serum albumin (HAS) with polysobate 80 and glycine in response to the

request from European health authorities, some patients developed pure red-cell aplasia (PRCA), a severe form of anemia. Eprex induced antibodies neutralize all the exogenous rHuEPO and cross-react with endogenous erythropoietic proteins. As a result, serum EPO is undetectable

and erythropoiesis becomes ineffective. Upon investigation, J&J found that polysorbate 80 might have caused uncoated rubber stoppers in single-use Eprex syringes to leach plasticizers, which stimulated an immune response that resulted in PRCA. Replacing with Teflon coated stoppers resulted in 90% decrease in PRCA by 2003 [3,4]. The effect of neutralizing antibodies has not always resulted in serious clinical consequences. Three interferon beta products, Betaseron, Rebif and Avonex, are marketed by three different companies. These products induce neutralizing antibodies in multiple sclerosis patients from 5 to 50% after one year treatment. Although these antibodies might be associated with loss of efficacy of treatment resulting in some patients to withdraw from the treatment, it seems no other severe adverse effects were detected [5,6].

Regulatory Landscape

The US, the EU and Japan are the three cornerstonemembers of the International Conference on Harmonization (ICH), which intends to harmonize the regulatory requirements for drug or biologic approval in these three regions. With the other two members, the EU and Japan, already have established biosimilar approval procedures (see below), the US lags behind in the biosimilar race. There are no formal approval pathways for biosimilars in the US. Congress needs to establish a legal framework in order for FDA to develop guidelines. Legislation has been under discussion in Congress since 2007. The legislative debate is centered on patient safety and preserving incentives to innovate with introduction of biosimilars. Two bills introduced in March 2009 deserve attentions [7,8]. The Waxman bill (H.R. 1427) proposes 5 years of market exclusivity to the innovator companies and requires no clinical trials for biosimilar development. The Eshoo bill (H.R. 1548) proposes 12 years of market exclusivity to the innovator companies and requires clinical trials for biosimilar development. Obama administration appears to favor a 7-year market exclusivity [9]. Once a legal framework is established for biosimilars, the FDA will likely take a conservative approach using the comparability as an approval principle. Clinical proof of efficacy and safety will be required, probably in reduced scale.

In the EU, the European Medicines Agency (EMEA) issued regulatory guidelines for approving biosimilars in 2005 (Figure 1) [10-16]. These include two general guidelines for quality issues [11] and non-clinical and clinical issues [12] and four class-specific annexes for specific data requirements for Granulocyte-Colony Stimulating factor (G-CSF) [13], Insulin [14], Growth hormone [15] and Erythropoietin [16]. In addition, a concept paper on interferon alpha [17] is also available. So far, there are eleven biosimilar products which received market authorization in the EU and they are biosimilar versions of human growth hormone, Epoetin and filgrastim. It is estimated six to eight years on average for a biosimilar to be developed [18].

The EMEA treats a biosimilar medicine as a medicine which is similar to a biological medicine that has already been authorized (the “biological reference medicine”) in the EU, The active substance of a biosimilar medicine is similar to the one of the biological reference medicine.

A biosimilar and the biological reference medicine are used in general at the same dose to treat the same disease. A biosimilar and the biological reference medicine are not automatically interchangeable because biosimilar and biological reference medicine are only similar but not identical. A physician or a qualified healthcare professional should make the decision to treat a patient with a reference or a biosimilar medicine. Since the biosimilar may contain different inactive ingredients, the name, appearance and packaging of a biosimilar medicine differ to those of the biological reference medicine. In addition, a pharmacovigilance plan must be in place for post-marketing safety monitoring.

Japan’s Ministry of Health, Labor and Welfare (MHLW) issued guidelines for follow-on proteins or biosimilars approval in March 2009. The first biosimilar, Sandoz’ growth hormone Somatropin, was approved in June 2009. The MHLW’s guidelines consider biosimilars drugs which are equivalent and homogeneous to the original biopharmaceuticals in terms of quality, efficacy and safety. Biosimilars are also requested to be developed with updated technologies and knowledge. Biosimilars need to demonstrate enough similarity to guarantee the safety and efficacy instead of absolute identity to the original biologics. Biosimilars’ regulatory approval applications will be categorized separately from conventional generic drugs. In general, the applications should be submitted, as the new drug applications, with data from clinical trials, manufacturing methods, long-term stability and information on overseas use. The MHLW will assess the data on absorption, distribution, metabolism and excretion (ADME) on a case-by-case basis. The applications do not need to provide data on accessory pharmacology, safety pharmacology and genotoxicity.

Biosmilars are already thriving in Eastern Europe and Asia, where regulatory and intellectual property (IP) standards for biosimilars are more liberal. Biosimilars developed in these regions are primarily sold domestically. These markets are considered less controlled. The quality of the biosimilars may not be in full compliance with ICH guidelines although they are often developed through comparative quality testing and clinical trials against the biologics which are already approved in Western countries

 Comparability Demonstration

 A comparability exercise based on the ICH guideline [22] needs to be performed to demonstrate that the biosimilar product and the reference biologic product have similar profiles with respect to product quality, safety, and efficacy. This is accomplished by comparative testing of the biosimilar product and the reference biologic product to demonstrate they have comparable molecular structure, in vitro and in vivo biological activities, pre-clinical safety and pharmacokinetics, and safety and efficacy in human patients. Comparison of quality attributes between the biosimilar and the reference biologic product employs physicochemical and biological characterization. Comparability on physical properties, amino acid sequence, high order structures, post-translationally modified forms are evaluated by physicochemical tests. In vitro receptor-binding or cell-based (binding) assays or even the in vivo potency studies in animals need to be performed to demonstrate comparable activity despite they are often imprecise. Levels of product related impurities (aggregates, oxidized forms, deamidated forms) and process related impurities and contaminants (host cell proteins, residual genomic DNA, reagents, downstream impurities) need to be assessed and quantified. Stability profiles of the biosimilar product and the reference biologic product also need to be studies by placing the products under stressed conditions. The rate of degradation and degradation profiles (oxidation, deamidation, aggregation and other degradation reactions) will be compared. If unknown degradation species are detected, they need to be studied to determine if they affect safety and efficacy. If differences on product purities and stability profiles are present between the biosimilar product and the reference biologic product, these differences need to be justified using scientific knowledge or preclinical or clinical studies. Changes in the impurity profile should be justified as well.

The demonstration of comparability in quality attributes does not necessarily mean that the biosimilars and the reference biologics are identical, but that they are highly similar. In many cases, the relationship between specific quality attributes and safety and efficacy has not been fully established. For example, physicochemical characterization cannot easily predict immunogenicity and slight changes in manufacturing processes or product composition can give rise to unpredicted changes in safety and efficacy. Changes in bioavailability, pharmacokinetics, bioactivity bioactivity, and immunogenicity are the main risks associated with the manufacturing of biosimilars. In vivo studies should be designed to measure the pharmacokinetics and pharmacodynamics relevant to clinical studies. Such in vivo studies should be designed to detect response differences between the biosimilar and the reference biologic not just responses per se. In vivo studies of the biosimilar’s safety in animals may be used to research any concerns into the safety of the biosimilar in human patients. Although extensive clinical testing is not necessary for biosimilars, some degree of clinical testing is needed to establish therapeutic comparability on efficacy and safety between the biosimilar and the reference biologic product [23,24]. This includes using surrogate markers of specific biologic activity as endpoints for demonstrating efficacy, and showing that patients didn’t develop immunogenic responses to the product. In general, the approval of biosimilars will be based on the demonstration of comparable efficacy and safety to an innovator reference product in a relevant patient population. Clinical data requirement for each individual product will be different and will be determined on a case-by-case basis.

Small-molecule Generics versus Biosimilars

 Small-molecule

  • Approval based on “sameness”

Biosimilars

  • Approval based on “high similarity”

Small-molecule

  • Replicate the innovator’s process and product and perform a bioavailability study demonstrating similar pharmacokinetic properties

Biosimilars

  • Full CMC development with comparative testing, conduct substantial clinical trials for efficacy and safety including immunogenicity

Small-molecule

  • Abbreviated registration procedures in Europe and US

Biosimilars

  • Regulatory pathway is defined in EU on “Comparability” status, no pathway yet in US under BLA

Small-molecule

  • Therapeutically equivalent, thus interchangeable

Biosimilars

  • Lack of automatic substitutability

Small-molecule

  • $1 to $5 million to develop

Biosimilars

  • $100-$200 million to develop

Small-molecule

  • Brand-to-generic competition

Biosimilars

  • Brand-to-Brand competition

Conclusion

The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approval and eventually biosimilar generic drugs.

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars. 2009 and 2012 represent milestones in the regulatory provisions for biosimilars in the US.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.

REFERENCES

1. Federal Trade Commission Report, June 2009.

2. Schellekens, H.; Nat. Rev. Drug Discov. 2002, 1: 457-462.

3. Van Regenmortel, M.H.V.; Boven, K. and F. Bader, BioPharm International, August 1, 2005, Vol 18, Issue 8.

4. Locatelli, F.; Del Vecchio, L. and P. Pozzoni, Peritoneal Dialysis International, 2007, 27(Supplement 2): S303-S307.

5. Hartung, H.P.; Munschauer, F. And Schellekens, H., Eur J. Neurol., 2005, 12, 588-601.

6. Malucchi, S. et al., Neurol. Sci., 2005, 26, suppl, 4:S213-S214.

7. Greb, E., Pharmaceutical technology, June 2009, pp. 36-42.

8. Del Buono, B.J., BioPharm International, July 2009, pp 46-53.

9. Usdin, S., Biocentury, July 20, 2009, 17(32): A1-A6.

10. “Guideline on Similar Biological Medicinal Products”, (Doc. Ref.: EMEA/CHMP/437/04, London, 30 October 2005).

11. “Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues”, (Doc. Ref.: EMEA/ CHMP/BWP/49348/2005, London, 22 February 2006).

12. “Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues”, (Doc. Ref.: EMEA/CHMP/BMWP/42832/2005, London, 22 February 2006).

13. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Granulocyte-Colony Stimulating Factor”, (Doc. Ref.: EMEA/CHMP/ BMWP/31329/2005, London, 22 February 2006).

14. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Human Soluble Insulin”,(Doc. Ref.: EMEA/CHMP/BMWP/32775/2005, London, 22 February 2006).

15. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Somatropin”, (Doc. Ref.: EMEA/ CHMP/BMWP/94528/2005, London, 22 February 2006).

16. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Non-Clinical and Clinical Issues – Guidance on Similar Medicinal Products Containing Recombinant Erythropoietins”, (Doc. Ref.: EMEA/CHMP/BMWP/94526/2005 Corr., London, 22 February 2006).

17. “Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: (Non) Clinical Issues – Concept paper on similar biological medicinal products containing recombinant alpha-interfero  (Doc. Ref.: CHMP/BMWP/7241/2006, London, 26 April 2006).

18. “EGA Handbook on Biosimilar Medicines”, European Generic Medicines Association, Received August 2009).

19. “Points to Consider in the Characterization of Cell Lines to Produce Biologicals”, FDA CBER, 1993.

20. Chirino, A.J. and A. Mire-Sluis, Nature Biotechnology, 2004, 22(11): 1383-1391.

21. Kendrick, B.S. et al., BioPharm International, 2009, August, pp 32-44.

22. “Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process”, ICH Harmonized Tripartite Guideline Q5E, 18 November 2004.

23. Mellstedt, H.; Niederwieser, D. and H. Ludwig, Annals of Oncology, September 14, 2007, pp. 1-9.

24 Schellekens, H., NDT Plus, 2009, 2 [suppl 1]: i27- i36.

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Curator: Aviva Lev-Ari, PhD, RN

For IP and Legal aspects of Biosimilars, go to:

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

For CMC and Regulatory Affairs of Biosimilars, go to:

Biosimilars: CMC Issues and Regulatory Requirements

https://pharmaceuticalintelligence.com/2012/07/29/biosimilars-cmc-issues-and-regulatory-requirements/

The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approval and eventually biosimilar generic drugs.

With the upheld ObamaCare, critical parts of the PPACA constitutional, and with it the BPCIA giving the FDA authority to approve biosimilars.

Had the PPACA been stricken in part or in its entirety, it would have presented obstacles to the BPCIA surviving in its present form. The US government has been critical of the 12-year data exclusivity period for Pioneer Innovators, calling for it to be shortened to 7 years (12 years is favorable to Pioneer Innovators and less favorable for Biosimilar manufacturers). The upheld ObamaCare, PPACA and BPCIA, constitutional, has prevented a multiyear delay in biosimilar approval. Thus, it was the best scenario for the biologics industry.

Thus, projection of Sales for Biosmilars as % of top 100 U.S. Pharmaceutical will receive a special meaning and an expected enhanced market share for 2012 year end and beyond 2012.

Biosimilars are occupying the Following ranking in the U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales: 10, 11, 12 13, 15, 24, 27, 29, 33, 35, 39, 57, 58, 62, 65, 70,  72, 74, 90, 98, 99. In addition the following biosimilars did not make the Top 100 list:

Biosimilar Drugs by US Sales – not included in the Top 100 Drug List 

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant) by Baxter 5.7 Billion in 2012

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease by Genzyme 200 millions in sales

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011 by Elan and Biogen

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk – $1.5Billion

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca  $570 millions

Humulin $1.1 1992 Insulin Human by Eli Lilly $ 1.2 Billion

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer $1.4 billion

U.S. Pharmacuetical Sales – 2012: Top 100 Drugs for Q1 2012 by Sales – Small Molecule Drugs (in green) and Biosimilars (in red)

The following is a list of the top 100 pharmaceutical drugs by retail sales in 2012, listed by U.S. sales value and drug name. Last updated: July 2012 (updated quarterly)

http://www.drugs.com/stats/top100/sales

Rank Drug

Sales ($000)

   
1 PlavixBristol-Myers Squibb Company

1,620,790

Stats

2 NexiumAstraZeneca Pharmaceuticals

1,395,981

Stats

3 AbilifyOtsuka Pharmaceutical Co.

1,340,200

Stats

4 SingulairMerck & Co., Inc.

1,238,134

Stats

5 SeroquelAstraZeneca Pharmaceuticals

1,161,141

Stats

6 Advair DiskusGlaxoSmithKline

1,139,182

Stats

7 CrestorAstraZeneca Pharmaceuticals

1,117,904

Stats

8 CymbaltaEli Lilly and Company

1,029,262

Stats

9 atorvastatinGeneric Drug

952,407

Stats

10 HumiraAbbott Laboratories

928,124

 

Stats

11 RemicadeCentocor Ortho Biotech, Inc

899,453

 

Stats

12 EnbrelAmgen Inc.

890,135

 

Stats

13 NeulastaAmgen Inc.

849,971

 

Stats

14 LipitorPfizer Inc

840,715

Stats

15 RituxanGenentech, Inc

756,875

 

Stats

16 CopaxoneTeva Pharmaceuticals

748,585

Stats

17 AtriplaGilead Sciences, Inc.

694,901

Stats

18 OxyContin

662,876

Stats

19 SpirivaBoehringer Ingelheim Pharmaceuticals, Inc

659,818

Stats

20 AvastinGenentech, Inc

632,183

Stats

21 ActosTakeda Pharmaceuticals North America, Inc

630,970

Stats

22 JanuviaMerck & Co., Inc.

583,603

Stats

23 TruvadaGilead Sciences, Inc.

546,098

Stats

24 LantusSanofi-Aventis

520,584

Stats

25 DiovanNovartis Corporation

509,615

Stats

26 LexaproForest Pharmaceuticals, Inc

491,053

Stats

27 EpogenAmgen Inc.

489,570

 

Stats

28 LyricaPfizer Inc

458,171

Stats

29 Lantus SolostarSanofi-Aventis

448,388

 

Stats

30 enoxaparinGeneric Drug

442,263

Stats

31 EloxatinSanofi-Aventis

431,928

Stats

32 CelebrexPfizer Inc

430,993

Stats

33 HerceptinGenentech, Inc

425,687

 

Stats

34 Diovan HCTNovartis Corporation

415,475

Stats

35 LucentisGenentech, Inc

409,547

 

Stats

36 SynagisMedImmune, Inc

396,556

Stats

37 NamendaForest Pharmaceuticals, Inc

391,638

Stats

38 GleevecNovartis Corporation

391,072

Stats

39 AvonexBiogen Idec

388,623

 

Stats

40 VyvanseShire US Inc

387,167

Stats

41 olanzapineGeneric Drug

385,867

Stats

42 IncivekVertex Pharmaceuticals

371,349

Stats

43 One Touch Ultra

366,294

Stats

44 SuboxoneReckitt Benckiser Pharmaceuticals Inc.

338,840

Stats

45 methylphenidateGeneric Drug

337,211

Stats

46 ZetiaMerck & Co., Inc.

328,653

Stats

47 AndroGelAbbott Laboratories

311,850

Stats

48 ProvigilCephalon, Inc.

303,029

Stats

49 LidodermEndo Pharmaceuticals

301,354

Stats

50 TriCorAbbott Laboratories

298,834

Stats

51 SymbicortAstraZeneca Pharmaceuticals

290,669

Stats

52 CombiventBoehringer Ingelheim Pharmaceuticals, Inc

285,487

Stats

53 ProAir HFATeva Pharmaceuticals

284,647

Stats

54 Seroquel XRAstraZeneca Pharmaceuticals

282,416

Stats

55 amphetamine/dextroamphetamineGeneric Drug

275,447

Stats

56 NasonexMerck & Co., Inc.

274,748

Stats

57 NovologNovo Nordisk Inc.

266,305

 

Stats

58 ProcritJanssen Pharmaceuticals, Inc

264,190

 

Stats

59 AlimtaEli Lilly and Company

263,024

Stats

60 ViagraPfizer Inc

260,678

Stats

61 GeodonPfizer Inc

260,514

Stats

62 Rebif

258,088

 

Stats

63 budesonideGeneric Drug

257,243

Stats

64 NiaspanAbbott Laboratories

255,383

Stats

65 HumalogEli Lilly and Company

244,587

 

Stats

66 Flovent HFAGlaxoSmithKline

241,552

Stats

67 LovazaGlaxoSmithKline

239,845

Stats

68 LevemirNovo Nordisk Inc.

239,576

Stats

69 Adderall XRShire US Inc

239,097

Stats

70 NeupogenAmgen Inc.

238,427

 

Stats

71 ReyatazBristol-Myers Squibb Company

238,151

Stats

72 AranespAmgen Inc.

231,643

 

Stats

73 metoprololGeneric Drug

231,395

Stats

74 NovoLog FlexPenNovo Nordisk Inc.

227,228

 

Stats

75 VytorinMerck & Co., Inc.

218,215

Stats

76 JanumetMerck & Co., Inc.

212,596

Stats

77 IsentressMerck & Co., Inc.

211,526

Stats

78 escitalopramGeneric Drug

210,171

Stats

79 CialisEli Lilly and Company

206,996

Stats

80 AciphexEisai Corporation

203,097

Stats

81 PradaxaBoehringer Ingelheim Pharmaceuticals, Inc

201,065

Stats

82 SolodynMedicis Pharmaceutical Corporation

198,909

Stats

83 fentanylGeneric Drug

197,350

Stats

84 ZyprexaEli Lilly and Company

194,460

Stats

85 VelcadeTakeda Pharmaceuticals North America, Inc

188,583

Stats

86 RestasisAllergan, Inc

188,501

Stats

87 LunestaSunovion Pharmaceuticals Inc.

187,941

Stats

88 acetaminophen/hydrocodoneGeneric Drug

185,374

Stats

89 PrezistaJanssen Pharmaceuticals, Inc

182,859

Stats

90 PegasysGenentech, Inc

181,693

 

Stats

91 ZyvoxPfizer Inc

179,523

Stats

92 Prevnar 13Wyeth

179,085

Stats

93 LovenoxSanofi-Aventis

178,957

Stats

94 BenicarDaiichi Sankyo

174,619

Stats

95 VESIcareAstellas Pharma US

174,524

Stats

96 Ventolin HFAGlaxoSmithKline

172,707

Stats

97 OrenciaBristol-Myers Squibb Company

172,202

Stats

98 BetaseronBayer Healthcare Pharmaceuticals

172,143

 

Stats

99 ErbituxBristol-Myers Squibb Company

171,513

 

Stats

100 DexilantTakeda Pharmaceuticals North America, Inc

171,179

Stats

Source: IMS Health (Midas).

Biosimilars Drugs by US Sales – not included in the Top 100 Drug List 

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant) by Baxter 5.7 Billion in 2012

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease by Genzyme 200 millions in sales

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011 by Elan and Biogen

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk – $1.5Billion

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca  $570 millions

Humulin $1.1 1992 Insulin Human by Eli Lilly $ 1.2 Billion

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer $1.4 billion

2011 US Sales vs. 2008 US Sales (in Billions) for Top Selling Biologics

Source for 2008 Sales

http://www.tbiweb.org/tbi/file_dir/TBI2009/Bao-lu%20Chen.pdf 

Source for 20011, Q1 2012 Sales

http://www.drugs.com/stats/top100/sales

Drug Name,  2008 Sales, Year approved , Indication

[i.e. Drug Name Enbrel,  2008 Sales $8.0B, Year approved 1998 , Indication RA]

Enbrel $8.0 1998 — RA, psoriatic arthritis, or ankylosing spondylitis indication

Q1 2012 12 (1) $890,135 1.92% 823 -4.63%
Q4 2011 11 (1) $873,343 1.67% 863 1.77%
Q3 2011 12 (1) $858,997 1.27% 848 -2.97%
Q2 2011 13 (2) $848,230 3.77% 874 3.19%
Q1 2011 11 $817,401 847

http://www.drugs.com/stats/enbrel

Remicade $7.9 1998 — RA & Chron’s Disease

Q1 2012 11 (2) $899,453 10.04% 1,556 10.04%
Q4 2011 13 (3) $817,365 -7.02% 1,414 -9.82%
Q3 2011 10 $879,054 1.52% 1,568 1.03%
Q2 2011 10 (2) $865,903 7.61% 1,552 7.11%
Q1 2011 12 $804,699 1,449

http://www.drugs.com/stats/remicade

Humira $7.3 2002  — treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis

Q1 2012 10 $928,124 2.50% 546 -2.85%
Q4 2011 10 (1) $905,527 3.18% 562 2.55%
Q3 2011 11 (3) $877,641 3.95% 548 3.01%
Q2 2011 14 $844,296 6.32% 532 2.31%
Q1 2011 14 $794,076 520

http://www.drugs.com/stats/humira

Rituxan $7.3 1997 — cancer medicines to treat non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.

Q1 2012 15 (1) $756,875 -1.91% 547 -0.91%
Q4 2011 14 (2) $771,622 6.96% 552 4.74%
Q3 2011 16 $721,408 -1.77% 527 -1.86%
Q2 2011 16 (4) $734,378 7.26% 537 5.09%
Q1 2011 20 $684,666

http://www.drugs.com/stats/rituxan

Second Quarter 2012 Highlights: RITUXAN(R) (rituximab) revenues from our unconsolidated joint business arrangement were $285 million for the quarter, an increase of 31% year-over-year. As previously disclosed, during the second quarter of 2011 our share of RITUXAN revenues from unconsolidated joint business was reduced by approximately $50 million to reflect our share of damages and interest that might be awarded in relation to an intermediate decision in Genentech, Inc.’s ongoing arbitration with Hoechst GmbH

http://www.marketwatch.com/story/correcting-and-replacing-biogen-idec-increases-revenue-18-to-14-billion-in-the-second-quarter-2012-07-24

Herceptin $5.7 1998 —  treat metastatic breast cancer that has progressed after treatment with other chemotherapy

Q1 2012 33 $425,687 -0.06% 155
Q4 2011 33 (2) $425,931 7.61% 155 4.73%
Q3 2011 31 (1) $395,804 -0.64% 148 -0.67%
Q2 2011 32 (4) $398,348 3.62% 149 1.36%
Q1 2011 36 $384,428 147

http://www.drugs.com/stats/herceptin

Lantus $5.1 2000 — long-acting form of the hormone insulin.

Q1 2012 29 (5) $448,388 9.81% 3,737 7.32%
Q4 2011 34 $408,336 8.54% 3,482 7.07%
Q3 2011 34 (2) $376,208 4.53% 3,252 6.00%
Q2 2011 36 (5) $359,907 7.80% 3,068 8.30%
Q1 2011 41 $333,878 2,833

http://www.drugs.com/stats/lantus-solostar

Epogen/Procrit $5.1 1989Anemia, low RBC

Worldwide, sales of the two drugs – sold under the brand names Epogen, Procrit and Aranesp – exceeded $9 billion in 2005 for Amgen and Johnson & Johnson, their makers.  Johnson & Johnson, which sells epoetin under the brand names Procrit in the United States and Eprex everywhere else, reported sales of $2.4 billion in the first nine months of 2006, down slightly from 2005.

Amgen Recalls Anemia Medications for Glass Fragments09/24/2010 – Drug-makers Amgen (AMGN) and Johnson & Johnson (JNJ) are voluntarily recalling two brandsof an injectable anemia medication because vials containing the drug may have tiny glass flakes. The drug, Epoetin alfa, is marketed under the brand names Epogen and Procrit.Known as lamellae, the glass fragments are created by the interaction of the drug with glass vials during storage, Amgen said in a statement announcing the recall. The recall is being conducted in cooperation with the Food and Drug Administration, Amgen said.

Latest study shows anemia drugs Epogen, Aranesp and Procrit cause strokes, says FDA

Posted on January 7, 2010

Anemia drugs sold by Amgen and Johnson & Johnson have been reported to cause strokes when prescribed in high doses, according to an article from the FDA, recently published in the The New England Journal of Medicine. The law firm of Aylstock, Witkin, Kreis & Overholtz is investigating the FDA’s recent announcement.

The FDA commentary said the latest study and previous studies “raise major concerns” about the use of these drugs to treat anemia caused by kidney disease. The drugs are also used to treat anemia caused by chemotherapy. Studies over the past several years have revealed a link between the drugs and heart attacks, strokes, and other problems.

Amgen’s anemia drugs include Epogen and Aranesp. Johnson & Johnson sells anemia drug Procrit, which is produced by Amgen. The drugs are designed to raise red blood cell levels, to promote delivery of oxygen to body tissues.

http://www.awkolaw.com/news/heart-attacks/anemia-drugs-epogen-aranesp-procrit-cause-strokes-says-fda/

Epogen / Procrit / Aranesp: The July 2012 News Report Which Tells Story Of Big Pharma Profits Over Patient Safety And Drug Efficacy

Once The FDA Started Paying Attention The Writing On The Wall Became Apparent, Albeit Too Late For Some

(Posted by  at DrugInjuryWatch.com)

This lengthy and well-presented news report, “Anemia drugs made billions, but at what cost?”, written by Peter Whoriskey and published July 19, 2012 by The Washington Post (free registration required), is a must-read for anyone with a concern or interest in how larger pharmaceutical companies might put corporate profits ahead of patient safety and drug efficacy.

Here is an excerpt from this Washington Post article which will give you a sense of what went on that, in hindsight, is so disturbing:

For years, a trio of anemia drugs known as Epogen, Procrit and Aranesp ranked among the best-selling prescription drugs in the United States, generating more than $8 billion a year for two companies, Amgen and Johnson & Johnson. Even compared with other pharmaceutical successes, they were superstars. For several years, Epogen ranked as the single costliest medicine under Medicare: U.S. taxpayers put up as much as $3 billion a year for the drugs.

The trouble, as a growing body of research has shown, is that for about two decades, the benefits of the drug — including “life satisfaction and happiness” according to the FDA-approved label — were wildly overstated, and potentially lethal side effects, such as cancer and strokes, were overlooked.

Last year, Medicare researchers issued an 84-page study declaring that among most kidney patients, the original and largest market for the drugs, there was no solid evidence that they made people feel better, improved their survival or had any “clinical benefit” besides elevating a statistic for red blood cell count.

As for some of the key events which led up to this revelation of sorts, we start with a June 24, 2011 FDA press release, “FDA modifies dosing recommendations for Erythropoiesis-Stimulating Agents — Cites increased risk of cardiovascular events when used to treat chronic kidney disease”, which included the following:

The U.S. Food and Drug Administration today recommended more conservative dosing guidelines for Erythropoiesis-Stimulating Agents (ESAs) when used to treat anemia in patients with chronic kidney disease (CKD) because of the increased risks of cardiovascular events such as stroke, thrombosis, and death….

Procrit —  (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Q1 2012 58 (3) $264,190 -2.13% 295 -4.22%
Q4 2011 55 (2) $269,937 3.58% 308 3.01%
Q3 2011 53 (12) $260,610 -21.61% 299 -21.32%
Q2 2011 41 (7) $332,466 7.04% 380 5.56%
Q1 2011 48 $310,606 360

http://www.drugs.com/stats/procrit

Epogen —  (epoetin alfa) is a man-made form of a protein that helps your body produce red blood cells

Q1 2012 27 (7) $489,570 -24.54% 555 -17.04%
Q4 2011 20 (2) $648,794 4.67% 669 3.40%
Q3 2011 22 (2) $619,828 -13.96% 647 -18.41%
Q2 2011 20 (1) $720,376 3.32% 793 4.48%
Q1 2011 19 $697,224 759

http://www.drugs.com/stats/epogen

Neulasta $4.2 2002 — used to prevent neutropenia, a lack of certain white blood cells caused by receiving chemotherapy. stimulates the bone marrow and promotes the growth of white blood cells called neutrophils

Q1 2012 13 (1) $849,971 3.33% 331 1.53%
Q4 2011 12 (2) $822,578 4.59% 326 3.49%
Q3 2011 14 (1) $786,464 -3.86% 315 -5.69%
Q2 2011 15 $818,068 4.04% 334 3.41%
Q1 2011 15 $786,288 323

http://www.drugs.com/stats/neulasta

Novolog $3.7 2000 —  Insulin aspart is a fast-acting form of insulin. NovoLog is used to treat type 1 (insulin-dependent) diabetes in adults and children who are at least 2 years old. It is usually given together with a long-acting insulin.

Q1 2012 57 (6) $266,305 5.67% 2,980 3.72%
Q4 2011 63 (3) $252,015 0.97% 2,873 -0.48%
Q3 2011 60 (1) $249,591 -0.96% 2,887 -2.66%
Q2 2011 61 (5) $252,010 3.16% 2,966 -0.70%
Q1 2011 66 $244,297 2,987

http://www.drugs.com/stats/novolog

Erbitux $3.6 2004 — used to treat cancers of the colon and rectum. It is also used to treat head and neck cancer.

Q1 2012 99 (2) $171,513 2.30% 266 3.91%
Q4 2011 97 (7) $167,657 -0.15% 256 0.79%
Q3 2011 90 (3) $167,909 -2.48% 254 -1.93%
Q2 2011 93 (2) $172,185 -0.89% 259 -0.38%
Q1 2011 95 $173,735 260

http://www.drugs.com/stats/erbitux

Aranesp $3.2 2001 — Anemia, low RBC,  (darbepoetin alfa) is a man-made form of a protein that helps your body produce red blood cells. 

Q1 2012 72 (6) $231,643 -5.86% 293 -7.86%
Q4 2011 66 (15) $246,056 -6.07% 318 -3.64%
Q3 2011 51 (3) $261,967 -10.25% 330 -11.29%
Q2 2011 48 (3) $291,873 -1.03% 372 -1.33%
Q1 2011 51 $294,912 377

http://www.drugs.com/stats/aranesp

The article reports on the decline of worldwide sales of Aranesp drug from Thousand Oaks, California-based Amgen Inc. as of the second quarter of 2007. According to Amgen, the 10% decrease of Aranesp worldwide sales was due to the reimbursement issues related to the anemia drug and the drop of U.S. demand for drug, in which the U.S. Aranesp reported sales in the second quarter of 2007 was only $578 million from $713 million in 2006.

http://connection.ebscohost.com/c/articles/26375335/amgen-posts-lower-aranesp-sales

1/24/2011, Amgen boosts prices to offset Aranesp sales

Amgen is hiking prices to make up for the shrinking sales volume of its anemia drug Aranesp. Bloomberg reports that Amgen raised the price tag on Aranesp itself by 4.4 percent, but also marked up the white-blood-cell-boosting meds Neulasta and Neupogen by 2.9 percent.

http://www.fiercepharma.com/story/amgen-boosts-prices-offset-aranesp-sales/2011-01-24

Recombinate $2.9 1998 — Antihemophilic Factor VIII (Recombinant)

BioScience core franchises include: Hemophilia, Biotherapeutics, BioSurgery and Vaccines. BioScience products represent approximately 45 percent of Baxter’s annual sales, totaling $5.7 billion in 2010.

2007 Outlook – Sales within Baxter’s BioScience business totaled $1.2 billion, an increase of 18 percent from the same period last year. This growth was driven by record sales of ADVATE, Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (rAHF-PFM) for the treatment of hemophilia A, antibody therapy products, including GAMMAGARD LIQUID(TM) [Immune Globulin Intravenous (Human)] (IVIG) 10% Solution for the treatment of primary immunodeficiencies, specialty plasma therapeutics and biosurgery products. Medication Delivery sales increased 7 percent to $1.0 billion, with increased sales of infusion systems, intraveneous solutions and parenteral nutrition products, along with accelerated growth in the company’s drug delivery business. Renal sales increased 6 percent to $537 million reflecting accelerating gains in peritoneal dialysis patients globally.

Lucentis $2.7 2006 intraocular injection. (ranibizumab injection) is a recombinant humanized IgG1 kappa isotype monoclonal antibody fragment designed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor A (VEGF-A).

Date Range Sales Rank Sales ($000) Units (000)
Q1 2012 35 (5) $409,547 -6.89% 224 -5.88%
Q4 2011 30 (2) $439,867 2.44% 238 2.59%
Q3 2011 28 (2) $429,393 1.13% 232 0.87%
Q2 2011 30 (3) $424,611 0.95% 230 1.32%
Q1 2011 33 $420,635 227

http://www.drugs.com/stats/lucentis

http://www.gene.com/gene/about/ir/historical/product-sales/lucentis.html

Lucentis brought in $1.7 billion for Roche last year, according to data compiled by Bloomberg.Alimera Sciences Inc. (ALIM), based in Alpharetta, Georgia, and Psivida Corp. (PSDV) also are developing a diabetic macular edema treatment known as Iluvien. The FDA has twice rejected Iluvien, most recently in November.

The FDA pooled results from two Roche clinical trials and found 39 percent of patients who used the 0.3 milligram dose were able to read three additional lines of letters on an eye chart after two years compared to 41 percent who had the same effect on the 0.5 milligram dose, according to an FDA staff report released July 24.

Genentech recommended approval of the 0.3 milligram dose in its application to the FDA since there isn’t evidence of additional benefit of the higher dose, Terence Hurley, a spokesman for the company, said in an e-mail.

Patients who received the monthly injection also were significantly more likely than those who received fake doses of the drug to achieve 20/40 vision, enough eyesight to drive.

http://www.bloomberg.com/news/2012-07-26/roche-s-lucentis-backed-by-fda-panel-for-diabetic-blindness-1-.html

Avonex $2.6 1996 —  Multiple Sclerosis, a form of protein called beta interferon that occurs naturally in the body. Interferons help the body fight viral infections. Avonex is used to treat patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability. This medication will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 39 (1) $388,623 2.22% 130 -3.70%
Q4 2011 38 (5) $380,189 0.19% 135 -2.17%
Q3 2011 33 $379,457 -0.05% 138 -1.43%
Q2 2011 33 (4) $379,639 2.45% 140 -1.41%
Q1 2011 37 $370,570 142

http://www.drugs.com/stats/avonex

Second-quarter net income surged 34 percent to $386.8 million, or $1.61 a share, from $288 million, or $1.18, a year earlier, the Weston, Massachusetts-based company said today in a statement. Earnings excluding some items of $1.82 topped by 26 cents the average of 21 analysts’ estimates (BIIB) compiled by Bloomberg. Revenue beat estimates by about $90 million.

Biogen said profit this year is expected to be more than $6.20 a share, 5 cents higher than its May 1 forecast (BIIB). The company has been increasing sales of Avonex, Rituxan and Tysabri, another MS therapy, while developing new medicines to introduce to the market.

http://www.businessweek.com/news/2012-07-24/biogen-second-quarter-profit-rises-as-avonex-sales-increase

AVONEX(R) (interferon beta-1a) revenues increased 16% year-over-year to $762 million.

Novolin $2.5 1991  —  Novolin R (insulin regular) is a short-acting form of human insulin, Diabetes, Type 1 Type 2

Date Range Sales Rank Sales ($000) Units (000)
Q1 2012 74 (2) $227,228 8.96% 2,489 13.81%
Q4 2011 76 (4) $208,552 10.19% 2,187 6.73%
Q3 2011 80 (6) $189,267 4.15% 2,049 4.92%
Q2 2011 86 (7) $181,733 3.71% 1,953 29.60%
Q1 2011 93 $175,235 1,507
http://www.drugs.com/stats/novolog-flexpen
Novo Nordisk launches iPhone app Posted 17th September 2010, 15:11:54
An iPhone app has been launched by Novo Nordisk in the US which lets healthcare staff check dosage guidelines for diabetes patients.

Novo Dose provides product-specific data for the company’s insulin analog agents Levemir (insulin detemir), NovoLog (insulin aspart) and NovoLog Mix (insulin aspart protamine/insulin aspart injectable).

Combined sales of the three medications increased by 24% last year, feeding a double-digit growth in Novo Nordisk sales and profits.

Novo Dose, the second diabetes app created by the industry, tells professionals when and how to dose the drugs, how to titrate and provides information on the blood glucose goals of patients.

Commenting on the new technology, Anup Kumar Sabharwal, an endocrinologist at the University of Miami Clinics’ Diabetes Research Institute, said: “This is where modern medicine is headed.”

Humalog $2.2 1996  Humalog is used to treat type 1 (insulin-dependent) diabetes in adults. Insulin lispro is a fast-acting form of insulin. It is usually given together with another long-acting insulin. It works by lowering levels of glucose in the blood. Humalog is also used together with oral (taken by mouth) medications to treat type 2 (non insulin-dependent) diabetes in adults.

Q1 2012 65 $244,587 -2.70% 2,570 -3.85%
Q4 2011 65 (2) $251,367 3.78% 2,673 2.81%
Q3 2011 63 (4) $242,208 -0.75% 2,600 -1.78%
Q2 2011 67 (5) $244,050 4.83% 2,647 1.15%
Q1 2011 72 $232,809 2,617

http://www.drugs.com/stats/humalog

Pegasys $2.0 2002 — (peginterferon alfa-2a) is made from human proteins that help the body fight viral infections. Pegasys is used to treat chronic hepatitis B or C. It is often used together with another medication called ribavirin (Copegus, Rebetol, RibaPak, Ribasphere, RibaTab).

Q1 2012 90 (1) $181,693 3.92% 87 3.57%
Q4 2011 91 () $174,833 84

http://www.drugs.com/stats/pegasys

Rebif $1.7 2002 — (interferon beta-1a) is a protein identical to one found in the body. Interferon beta-1a is made from human proteins. Interferons help the body fight viral infections. Rebif is used to treat relapsing multiple sclerosis (MS). This medication will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 62 (1) $258,088 -0.21% 540 -9.09%
Q4 2011 61 (7) $258,643 0.43% 594 -0.34%
Q3 2011 54 (5) $257,535 1.48% 596 -1.49%
Q2 2011 59 (2) $253,780 0.25% 605 -0.66%
Q1 2011 61 $253,143 609

http://www.drugs.com/stats/rebif

Cerezyme $1.5 1994 —  Gaucher disease and Fabrazyme for Fabry disease.

Last year Genzyme was forced to temporarily close its manufacturing plant in Boston due to a viral contamination. The interruption lead to shortages of two key drugs: Cerezyme for Gaucher disease and Fabrazyme for Fabry disease.

That crisis sent the company’s stock price plummeting from nearly $84 in 2008 to a low earlier this year of $45.39. Sanofi’s offer to acquire the company for $18.5 billion, or $69 a share — along with a 14 percent rise in the NYSE Arca Biotech Index since late July — have helped the shares rebound.

But Genzyme is now on a mission to prove to shareholders that it is worth more than Sanofi is offering, and executives told investors on a conference call that the third quarter marks the beginning of its financial turnaround.

Third-quarter sales of Cerezyme, the company’s top drug, rose to $179.8 million from $93.6 million a year earlier, beating analysts’ average forecast of $175 million.

“In the third quarter we saw our financial recovery start to take effect, and we expect that this will accelerate during the fourth quarter as Cerezyme patients are able to return to normal dosing levels and we begin to increase shipments of Fabrazyme,” Genzyme CEO Henri Termeer said in a statement.

Cerezyme is the principal drug for Gaucher patients. In the first quarter of 2012 Genzyme (now part of Sanofi (SNY))reported Cerezyme sales of 149 million euros (approx. $194 million), up 5.8% from the same quarter of the previous year. The other supplier Shire (SHPGY) reported $72 million in Vpriv sales, up 22%. There is now a third supplier, Pfizer (PFE), teamed up with the Israeli company Protalix Biotherapeutics (PLX), whose product was approved by the FDA in May 2012. Elelyso (taliglucerase alfa) is now available in the US.
Product Cerezyme
2009 2010 2011
 Total 793 720 885
 Ann. Growth Total -9% 23%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=15461&componentID=1002

Tysabri $1.4 2004 — Multiple Sclerosis by Elan and Biogen

Global in-market sales of TYSABRI in the second quarter of 2012 were $395 million, an increase of 2% over the second quarter of 2011. The total was comprised of $211 million in U.S. sales and $184 million in sales outside the U.S.

TYSABRI(R) (natalizumab) revenues were $280 million, in-line with the second quarter of 2011.
ITALIAN DISPUTE

Elan derives its revenue almost exclusively from Tysabri and it reported total sales for the three months to June 30 of $288 million, up 6 percent on a year ago once sales from its since-divested drug delivery business are omitted.

That compared to the $299 million forecast by four analysts surveyed by Reuters and was driven by in-market sales of Tysabri that rose 2 percent year-on-year to $395 million, also shy of the $419 million expected by analysts.

Biogen, which detailed the sales numbers when it reported second quarter results on Tuesday, attributed the softer-than-expected Tysabri sales to a dispute with the Italian government over pricing.

The number of patients on Tysabri rose 4 percent to 69,100, maintaining Elan and Biogen’s 10 to 12 percent share of the MS drug market in the face of competition from Swiss drugmaker Novartis AG’s Gilenya treatment, the first multiple sclerosis pill to come on the market.

The average addition of 185 new patients per week was the highest quarterly run-rate since the fourth quarter of 2009.

http://in.reuters.com/article/2012/07/25/elan-idINL6E8IP1VV20120725

NovoSeven $1.4 1999 —  Anti-fibrinolytics by Novo Nordisk —

Generic Name:   eptacog alfa
Product NovoSeven
2009 2010 2011
 Total 1,324 1,431 1,559
 Ann. Growth Total 8% 9%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&id=13483&lType=modData&componentID=1002

Synagis $1.3 1998 — Generic Name:  palivizumab     Anti-virals by AstraZeneca

Product Synagis
2009 2010 2011
 Total 1,042 906 570
 Ann. Growth Total -13% -37%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=91&componentID=1002

Neupogen $1.3 1991 —  (filgrastim) is a man-made form of a protein that stimulates the growth of whiteblood cells in your body. White blood cells help your body fight against infection. Neupogen is used to treat neutropenia, a lack of certain white blood cells caused by cancer,bone marrow transplant, receiving chemotherapy, or by other conditions.

Q1 2012 70 $238,427 0.06% 170 -2.86%
Q4 2011 70 (5) $238,289 0.16% 175 10.76%
Q3 2011 65 (5) $237,915 0.69% 158 0.64%
Q2 2011 70 (4) $236,294 2.51% 157 0.64%
Q1 2011 74 $230,515 156

http://www.drugs.com/stats/neupogen

Betaseron $1.2 1993 — (interferon) is made from human proteins. Interferons help the body fight viral infections. Betaseron is used to treat relapsing multiple sclerosis (MS). Betaseron will not cure MS, it will only decrease the frequency of relapse symptoms.

Q1 2012 98 (1) $172,143 2.93% 67 -10.67%
Q4 2011 99 (12) $167,236 -3.76% 75 -5.06%
Q3 2011 87 (2) $173,769 -2.89% 79 -2.47%
Q2 2011 89 (4) $178,938 -2.17% 81 -7.95%
Q1 2011 85 $182,908 88

http://www.drugs.com/stats/betaseron

Humulin $1.1 1992 Insulin Human by Eli Lilly 

Product Humulin R
2009 2010 2011
 Total 1,022 1,089 1,249
 Ann. Growth Total 7% 15%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=12399&componentID=1002

Kogenate FS $1.1 1993 — octocog alfa    Anti-fibrinolytics By Bayer

Product Kogenate
2009 2010 2011
 Total 1,238 1,332 1,496
 Ann. Growth Total 8% 12%

http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=11681&componentID=1002

Conclusion

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.

REFERENCES

http://www.wolfgreenfield.com/files/2426_biosimilars_2_final_pdf.pdf

Read Full Post »


Biosimilars: CMC Issues and Regulatory Requirements

Reporter: Aviva Lev-Ari, PhD, RN

Updated on 6/30/2015

Biosimilars in the US: How much can we learn from Europe?

http://www.xcenda.com/Insights-Library/HTA-Quarterly-Archive-Insights-to-Bridge-Science-and-Policy/HTA-Quarterly-Spring-2015/Biosimilars-in-the-US-How-much-can-we-learn-from-Europe/#.VY-99uehlRA.mailto

Updated on 2/10/2014

Cambridge Healthtech    Institute’s Fifth  Annual Biotherapeutics Analytical Summit
Hyatt Regency    Baltimore | Baltimore,  MD | BiotherapeuticsAnalyticalSummit.com

<http://wec.chi-lifescience.com/t/20344782/1039908871/3650297/1006/>

The    Science and  Regulation of Process Changes for Biologics (Comparability)
Thursday,  March 27, 2014 | 5:30 – 8:30 PM | More Information 

http://wec.chi-lifescience.com/t/20344782/1039908871/4704449/1007/?fb8dc108=YXZpdmFsZXYtYXJpQGFsdW0uYmVya2VsZXkuZWR1&x=9c418447

Manufacturing changes can impact on quality     attributes of biologics, and may affect efficacy and/or safety of the product.   For that reason, a thorough comparability exercise is required, to assess the   impact of the change and whether CMC data alone will suffice to support the     change. This interactive short course will consider comparability exercises     during development, as well as post-approval, addressing regulatory and     technical requirements. This should provide the attendee with the knowledge on   how to prepare a comparability package for discussion with regulatory  agencies,   towards acceptance of the proposed change to the process/product.  Attendees   will  be contacted before the event and asked about topics on which  they would   like to  focus.

Topics covered     include:

  • Ways that manufacturing changes can impact    on quality attributes
  • Features of a thorough comparability exercise
  • Critical evaluation of quality data
  • The comparability exercise during development
  • Post-approval comparability, ICH Q5E, Comparability Protocols (US) and Change Management Protocols (EU)
  • Regulatory requirements in the EU and US: guidelines, their interpretation and application
  • Discussion with Q&A


Course    Instructors:
       
Christopher J. Holloway, Ph.D., Group     Director, Regulatory Affairs &  CSO, ERA Consulting Group        
Kazumi Kobayashi, Ph.D., Director, Bioprocess Development, Biogen Idec,    Inc.       
Marjorie Shapiro, Ph.D., Chief, Laboratory of Molecular and Developmental  Immunology, Division of Monoclonal Antibodies,            FDA/CDER
 

Comparability and Developability conference program at Biotherapeutics Analytical Summit.

The third track of the Biotherapeutics Analytical    Summit focuses on the practical application of analytical characterization for    Comparability, Biosimilarity and Development purposes. It covers case studies    with a variety of products and a range of analytical technologies. We have    invited the FDA and regulatory experts to advise and to discuss regulatory    challenges being experienced by the industry. This conference also covers the    link between the process and analytical technologies for innovator products and   for biosimilars.

BiotherapeuticsAnalyticalSummit.com/Comparability

http://wec.chi-lifescience.com/t/20344782/1039908871/4665296/1009/?fb8dc108=YXZpdmFsZXYtYXJpQGFsdW0uYmVya2VsZXkuZWR1&x=833e704b>

SOURCE

From: Biotherapeutics Analytical Summit Short Course <lauran@healthtech.com>
Date: Mon, 10 Feb 2014 12:40:59 -0500
To: <avivalev-ari@alum.berkeley.edu>
Subject: The Science and Regulation of Process Changes for Biologics (Comparability)

Comparability: The Final Frontier of Protein Therapies

The rapid expansion of protein therapeutics has crossed into all major disease classes (cancer, metabolic disease, inflammatory disease, infectious disease, immune disorders, etc.).  Due to the lengthy learning curve and high cost of developing these complex products, the development of therapies has been traditionally limited to highly specialized companies.  As protein therapeutics become more mainstream, these products are finding new applications in disease treatment and commercial application beyond the range of the traditional biotech companies.  Unfortunately, the expansion of medical applications for these therapies is outpacing the rate of innovation in product development and, as a result, market availability is becoming constrained by the ability to characterize and control product characteristics.

The Future Opportunity:

The key to most effectively and efficiently developing a biopharmaceutical or biologic to marketing approval is to have a clear understanding of the unique properties of proteins and to use that knowledge to design appropriate manufacturing processes, preclinical pharmacology-toxicology and clinical programs.  It is essential in dealing with complex comparability issues related to the types of manufacturing processes or changes in manufacturing to understand the scientific reasons for requiring a demonstration of comparability and the relationships between bioanalytical differences or changes in a protein and potential alterations in protein functionality in terms of specificity, potency, pharmacological activity, pharmacokinetics, toxicity and ultimately clinical safety and efficacy.  This understanding requires in depth knowledge of protein chemistry, manufacturing processes, pharmacology, immunology and toxicology that comes with extensive training and experience.  The same scientific and regulatory expertise and experience that is required for a successful demonstration of comparability is also applicable to the development of a biosimilar. This type of experience and expertise should prove invaluable as the expansion in the area of protein therapies continues and the development of biosimilars grows in the coming years.

How to Get There from Here:

Product developers can begin today to capitalize on this opportunity.   A number of technology advancements are being explored that will enhance our understanding of relationships between process, product, and clinical safety and efficacy.   One must think through how to integrate the future product comparability into early stage product development.  For new product development, these issues will include more in-depth analysis of the product structure and relationship of various structural features to function andin vivo activity, increased knowledge about the effect of process conditions on the types and mix of final product variants, and careful choice of in vitro binding and functional assays that clearly relate to the proposed mechanism of action of the product and can often also be used as a potency assays.  New technologies are being developed for these assays, and appropriate in vitro functional assays as relates to pharmacological mechanism of action can be very useful for demonstrating comparability.

A careful determination of appropriate animal models of disease for demonstration of proof-of-concept pharmacology is also important early in development. Identification of appropriate biomarkers of efficacy or safety should also be examined in these early animal models for future use in clinical development as well as demonstration of comparability.  The discovery of appropriate biomarkers can sometimes be carried over to the clinic and used in clinical trials with the appropriate validation.  Finally, as the safety database for the various classes of biopharmaceuticals and biologics expands, the understanding of safety issues associated with each of these various product classes will make it easier to more efficiently demonstrate comparability as well as to develop biosimilar products.

For developers who are trying to bridge comparability on products that lack a complete process/product history due to legacy issues or as in the case for biosimilar development, companies must think about the pharmacology of the product as relates to the proposed indication of either the previous iteration of the product or the innovator product, depending on whether this is a comparability issue or development of a biosimilar. It is the pharmacological activity of a given protein product that determines the efficacy and to a great extent the toxicity of the product.   The pharmacological activity of a product is driven by protein structure, mix of product variants, binding kinetics, dose, dosing regimen, route of administration, and final product formulation, among others.

As the development of biopharmaceuticals and biologics continues to expand, more and more information accrues on potential safety issues related to each of the various product classes, and this information will also prove quite useful to demonstration of comparability and development of biosimilars.

Biologics Consulting Group can assist developers in designing and implementing each of their comparability programs with the greatest chance of rapid regulatory approval.  Our staff has both FDA and industry experience, with a track record of success in helping academic institutions, start-ups, and established biotech and pharma companies.  Our direct knowledge and contemporary experience with all possible regulatory pathways – and every associated nuance — and can provide the requisite preclinical, clinical, quality, analytical, and manufacturing support to increase your chances for success.

Contributors: T. CarrierD. BarngroverJ. JessopV. NarbutJ. HumphriesB. FraserR. WolffN. RitterL. Winberry 

SOURCE

http://www.biologicsconsulting.com/perspectives/comparability-protein-therapies/

For IP and Legal aspects of Biosimilars, go to:

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

For Financial Aspects of Biosimilars, go to:

Biosimilars: Financials 2012 vs. 2008

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-financials-2012-vs-2008/

Tr e n d s  i n  B i o / P h a r m a c e u t i c a l I n d u s t r y , 1 9 -26

Special Report on Biosimilars

About the Author: Dr. Bao-Lu has over 18 years of experience in product development, CMC regulatory, manufacturing management and quality oversight. He is currently the Director of Manufacturing and Process Development at Sangamo BioSciences. In this role, he oversees outsourced GMP production and testing of Sangamo’s gene therapy products and is responsible for the release and disposition of final drug product. He also provides CMC regulatory support and manages the in-house quality system by maintaining GMP database and implementing quality SOPs. Previously, Bao-Lu served as an Associate Director of Formulation at Xencor and Chiron and a Formulation Scientist at Amgen. Bao-Lu graduated with a BS degree from Fudan University and was selected as one of the forty chemistry students in the first year CGP Doering program. Bao-Lu earned his Ph.D. in Chemistry from University of Oregon and performed postdoctoral research in Biology at Massachusetts Institute of Technology.

http://www.tbiweb.org/tbi/file_dir/TBI2009/Bao-lu%20Chen.pdf

CMC Issues and Regulatory Requirements for Biosimilars

Abstract

Chemistry, Manufacturing and Controls (CMC), preclinical and clinical are three critical pieces in biosimilars development. Unlike a small-molecule generic drug, which is approved based on “sameness” to the innovator’s drug; a biosimilar is approved based on high similarity to the original approved biologic drug. This is because biologics are large and complex molecules. Many functional-, safety- and efficacy-related characteristics of a biologic depend on its manufacturing process. A biosimilars manufacturer won’t be able to exactly replicate the innovator’s process. The traditional abbreviated pathway for generic drug approval through the Hatch- Waxman Act of 1984 doesn’t apply for biosimilars as drugs and biologics are regulated under different laws. New laws and regulations are needed for biosimilars approval in the US. The EU has issued biosimilars guidelines based on comparative testing against the reference biologic drug (the original approved biologic). A full scale CMC development is required including expression system, culture, purification, formulation, analytics and packaging. The manufacturing process needs to be developed and optimized using state-of-the-art technologies. Minor differences in structure and impurity profiles are acceptable but should be justified. Abbreviated clinical testing is required to evaluate surrogate markers for efficacy and demonstrate no immunogenic response to the product.

We anticipate the package for a biosimilars approval in the US will be similar to that in the EU and contain a full quality dossier with a comparability program including detailed product characterization comparison and reduced preclinical and clinical requirements.

Biosimilars Become Inevitable

 Biologics developed through biotechnology constitute an essential part of the pipeline for medicines available to patients today. Biologic drugs are quite expensive and many of them are top-selling medicines (see Table 1). Since they come at extremely high prices to consumers, some patients may not be able to afford the use of biologics as the best-available treatments to their conditions. The patent protection on a large number of biologics has expired since 2001. These off-patent biologics include Neupogen, Novolin, Protropin, Activase, Epogen or Procrit, Nutropin, Humatrope, Avonex, Intron A, and Humulin. Traditionally, when a drug patent expires, a generic drug will be quickly developed and marketed. Similarly, generic version of off-patent biologic drugs (also referred to biosimilars or follow-on biologics or biogenerics) represents an extraordinary opportunity to companies that want to seize the potentially great commercial rewards in this unexploited territory. Biosimilars not only benefit the biosimilar manufacturers but also can save patients, and insurance companies, substantial cost and allow patients to gain access to more affordable biologics resulting in market expansion. The government can use biosimilars to reduce healthcare costs. Therefore, development and marketing of bosimilars are supported by both manufacturers and consumers.

Differences between Generic Drugs and Biosimilars

Enacted in 1984, the US Drug Price Competition and Patent Term Restoration Act, informally known as the “Hatch-Waxman Act of 1984” standardized US procedures for an abbreviated pathway for the approval of small-molecule generic drugs. The generic drug approval

is based on “sameness”. In comparison to the innovator’s drug, a generic drug is a product that has the same active ingredient, identical in dose, strength, route of administration, safety, efficacy, and intended use. For approval, the generic companies can go through the Abbreviated

New Drug Application (ANDA) process with reduced requirement in comparison to approval for a new drug entity. The generic drugs need to show bioequivalence to the innovator drugs typically based on pharmacokinetic parameters such as the rate of absorption or bioavailability in 24 to 36 healthy volunteers. No large clinical trials for safety and efficacy are required. The generic companies can rely on the FDA’s previous findings of safety and effectiveness of the innovator’s drugs.

However, the abbreviated pathway for generic drugs legally doesn’t apply to biologics as small-molecule drugs and biologics are regulated under different laws and approved through different pathways in the US (Table 2). Small-molecule drugs are regulated under the Food, Drug and Cosmetic Act (FD&C) and require submission of a New Drug Application (NDA) to FDA for drug review and approval. Biologics are regulated under the Public Health Service Act (PHS) and require submission of a Biologic License Application (BLA) to FDA for review and approval. The Hatch-Waxman Act of 1984 doesn’t apply for biosimilars. New laws are needed to establish a pathway for biosimilar approval.

There are some crucial differences between biologics and small-molecule drugs (Table 3). Small-molecule drugs are made from chemical synthesis. They are not sensitive to process changes. The final product of a small-molecule drug can be fully characterized. The developmentand production of generic drugs are relatively straightforward. Biologics are made from living organisms so that its functional-, efficacy- and safety-related properties depend on its manufacturing and processing conditions. They are sensitive to process changes. Even minor modifications of the manufacturing process can cause variations in important properties of a biological product. Thus it is believed that a biologic product is defined by its manufacturing process. Biologics are 100- or 1,000-fold larger than small-molecule drugs, possess sophisticated three-dimensional structures, and contain mixtures of protein isoforms. A biological product is a heterogeneous mixture and the current analytical methods cannot characterize these complex molecules sufficiently to confirm structural equivalence with the reference biologics.

Laws and Regulatory Pathways for Drug Approval in the US

Law/Application           Small-molecule            Drug Biologics                     

Law                     Food, Drug and Cosmetic Act (FD&C)             Public Health Service Act (PHS)

Drug application                 New Drug Application (NDA)   Biologic License Application (BLA)

Generic application   Abbreviated New Drug   Application(ANDA)   No pathway yet

 Immunogenicity Poses a Concern

One of the major complications that biologics can produce is immunogenicity as therapeutic proteins are inherently immunogenic [2]. Immunogenicity is related to biologics structure and formulation and is dependent on dose, route of administration and frequency of administration.

Clinical implications of immunogenicity are not always predictable. Formation of antibodies can result in harmless clinical effect or produce significant adverse events or severe disease. Examples are provided below. The Eprex (Erythropoietin, EPO) has been marketed by Johnson & Johnson (J&J) in the European Union (EU) countries for 10 years with no noticeable

Differences between small-molecule drugs and biologics

Product characteristics

Small-molecule generics Small, simple molecule

(Molecular weight: 100-1,000 Da)

Biosimilars   Large, complex molecules, Higher order structures, Post-translational, modifications

(Molecular weight: 15,000-150,000 Da)

Production

Small-molecule generics Produced by chemical synthesis

Biosimilars  Produced in living organisms

Analytical testing

Small-molecule  Well-defined chemical structure, all its various components in the finished drug can be determined

Biosimilars  Heterogeneous mixture, difficult to characterize, some of the components of a finished biologic may be unknown

Process dependence

Small-molecule   Not sensitive to manufacturing process changes. The finished product can be analyzed to establish the sameness.

Biosimilars   Sensitive to minor changes in manufacturing process. The product is defined by the process

Identity and purity

Small-molecule Often meeting pharmacopeia or other standards of identity (e.g., minimums for purity and potency)

Biosimilars   Most have no pharmacopeia monographs

immunogenicity issues prior to 1998. When J&J made a change in the Eprex formulation by replacing human serum albumin (HAS) with polysobate 80 and glycine in response to the

request from European health authorities, some patients developed pure red-cell aplasia (PRCA), a severe form of anemia. Eprex induced antibodies neutralize all the exogenous rHuEPO and cross-react with endogenous erythropoietic proteins. As a result, serum EPO is undetectable

and erythropoiesis becomes ineffective. Upon investigation, J&J found that polysorbate 80 might have caused uncoated rubber stoppers in single-use Eprex syringes to leach plasticizers, which stimulated an immune response that resulted in PRCA. Replacing with Teflon coated stoppers resulted in 90% decrease in PRCA by 2003 [3,4]. The effect of neutralizing antibodies has not always resulted in serious clinical consequences. Three interferon beta products, Betaseron, Rebif and Avonex, are marketed by three different companies. These products induce neutralizing antibodies in multiple sclerosis patients from 5 to 50% after one year treatment. Although these antibodies might be associated with loss of efficacy of treatment resulting in some patients to withdraw from the treatment, it seems no other severe adverse effects were detected [5,6].

Regulatory Landscape

The US, the EU and Japan are the three cornerstonemembers of the International Conference on Harmonization (ICH), which intends to harmonize the regulatory requirements for drug or biologic approval in these three regions. With the other two members, the EU and Japan, already have established biosimilar approval procedures (see below), the US lags behind in the biosimilar race. There are no formal approval pathways for biosimilars in the US. Congress needs to establish a legal framework in order for FDA to develop guidelines. Legislation has been under discussion in Congress since 2007. The legislative debate is centered on patient safety and preserving incentives to innovate with introduction of biosimilars. Two bills introduced in March 2009 deserve attentions [7,8]. The Waxman bill (H.R. 1427) proposes 5 years of market exclusivity to the innovator companies and requires no clinical trials for biosimilar development. The Eshoo bill (H.R. 1548) proposes 12 years of market exclusivity to the innovator companies and requires clinical trials for biosimilar development. Obama administration appears to favor a 7-year market exclusivity [9]. Once a legal framework is established for biosimilars, the FDA will likely take a conservative approach using the comparability as an approval principle. Clinical proof of efficacy and safety will be required, probably in reduced scale.

In the EU, the European Medicines Agency (EMEA) issued regulatory guidelines for approving biosimilars in 2005 (Figure 1) [10-16]. These include two general guidelines for quality issues [11] and non-clinical and clinical issues [12] and four class-specific annexes for specific data requirements for Granulocyte-Colony Stimulating factor (G-CSF) [13], Insulin [14], Growth hormone [15] and Erythropoietin [16]. In addition, a concept paper on interferon alpha [17] is also available. So far, there are eleven biosimilar products which received market authorization in the EU and they are biosimilar versions of human growth hormone, Epoetin and filgrastim. It is estimated six to eight years on average for a biosimilar to be developed [18].

The EMEA treats a biosimilar medicine as a medicine which is similar to a biological medicine that has already been authorized (the “biological reference medicine”) in the EU, The active substance of a biosimilar medicine is similar to the one of the biological reference medicine.

A biosimilar and the biological reference medicine are used in general at the same dose to treat the same disease. A biosimilar and the biological reference medicine are not automatically interchangeable because biosimilar and biological reference medicine are only similar but not identical. A physician or a qualified healthcare professional should make the decision to treat a patient with a reference or a biosimilar medicine. Since the biosimilar may contain different inactive ingredients, the name, appearance and packaging of a biosimilar medicine differ to those of the biological reference medicine. In addition, a pharmacovigilance plan must be in place for post-marketing safety monitoring.

Japan’s Ministry of Health, Labor and Welfare (MHLW) issued guidelines for follow-on proteins or biosimilars approval in March 2009. The first biosimilar, Sandoz’ growth hormone Somatropin, was approved in June 2009. The MHLW’s guidelines consider biosimilars drugs which are equivalent and homogeneous to the original biopharmaceuticals in terms of quality, efficacy and safety. Biosimilars are also requested to be developed with updated technologies and knowledge. Biosimilars need to demonstrate enough similarity to guarantee the safety and efficacy instead of absolute identity to the original biologics. Biosimilars’ regulatory approval applications will be categorized separately from conventional generic drugs. In general, the applications should be submitted, as the new drug applications, with data from clinical trials, manufacturing methods, long-term stability and information on overseas use. The MHLW will assess the data on absorption, distribution, metabolism and excretion (ADME) on a case-by-case basis. The applications do not need to provide data on accessory pharmacology, safety pharmacology and genotoxicity.

Biosmilars are already thriving in Eastern Europe and Asia, where regulatory and intellectual property (IP) standards for biosimilars are more liberal. Biosimilars developed in these regions are primarily sold domestically. These markets are considered less controlled. The quality of the biosimilars may not be in full compliance with ICH guidelines although they are often developed through comparative quality testing and clinical trials against the biologics which are already approved in Western countries

CMC Development

The CMC requirements for biosimilars in the EU are those described in the ICH Common Technical Document (CTD) Quality Module 3 with supplemental information demonstrating comparability or similarity on quality attributes to the reference medicine product.

Since the US is a member of ICH and encourages submission using CTD format, once the legal framework for approving biosimilars is established in the US, the CMC development will be similar to those in the EU.

Biosimilar manufacturers will have no access to the manufacturing process and product specifications of the innovator’s products because these are proprietary knowledges. To develop a biosimilar, a biosimilar manufacturer will need to first identify a marketed biologic product to serve as the reference biologic product. Then a detailed characterization of the reference biologic product will be performed. The information obtained from the characterization of the reference biologic product will be utilized to direct the process development of the biosimilar product and comparative testing to demonstrate bioequivalence between the biosimilar product and the reference biologic product. A biosimilar will be manufactured from a completely new process, which may be based on different host/vector system with different process steps, facilities and equipment.

A flow chart for a typical work flow from production to drug use is shown in Figure 2. The CMC development starts with establishment of the expression system. A cell-line will be selected among bacterial, yeast and mammalian host strains and then the correct DNA sequence will be inserted. Elaborate cell-screening and selection methods are then used to establish a master cell bank. Extensive characterization on the master cell bank needs to be carried out to provide microbiological purity or sterility and identity [19].

Bulk protein production involves developing robust and scalable fermentation and purification processes. The goals for fermentation are to increase the expression level and efficiency without compromising the correct amino acid sequence and post translational modification. Achieving high expression requires optimizing culture medium and growth conditions, and efficient extraction and recovery procedures. Correct amino acid sequence and post translati0nal modification will need to be verified.

Cell Bank

Fermentation

Purification

Drug Substance

Formulation

Fill/finish

Drug Product

Shipment

Administration

Typical flow chart for a biologics from production to drug use, above

Solubilization and refolding of insoluble proteins are sometimes necessary for proteins which have tendency to aggregate under the processing condition. Differences in the cell bank and production processes may create impurities that are different from the innovator’s product. The purification process needs to remove impurities such as host-cell proteins, DNA, medium constituents, viruses and metabolic by-products as much as possible. It is important for biosimilar manufacturers to accept appropriate yield losses to achieve high purity, because any increase in yield at the expense of purity is unacceptable and can have clinical consequences.

The final product is produced by going through formulation, sterile filtration and fill/finish into the final containers. Selection of formulation components starts from basic buffer species for proper pH control and salt for isotonicity adjustment. Surfactants may be needed to prevent proteins from being absorbed onto container surface or water-air interface or other hydrophobic surfaces. Stabilizers are required to inhibit aggregation, oxidation, deamidation and other degradations. The container and closure system can be glass vials, rubber stoppers and aluminum seals or pre-filled syringes or IV bags. The container and closure integrity needs to be verified by sterility or dyeleak test.

Biologics are not pure substances. They are heterogeneous mixtures. Each batch of a biologic product for clinical or commercial use needs to be produced in compliance with current Good Manufacturing Practice (cGMP) and is typically tested by a panel of assays to ensure the product meets pre-defined specifications for quality, purity, potency, strength, identity and safety. The product purity is often measured by multiple assays, which measure different product related variants (biologically active) or product related impurities (biologically inactive). Biologics are parenteral drugs and filled into the final containers through the aseptic process so that microbiological control is critical. It is advisable to set up product specifications for a biosimilar within the variation of the reference biologic product. Product characterization can be performed on selected batches for primary sequence, high order structures, isoform profiles, heterogeneity, product variants and impurities and process impurity profiles. Physicochemical characterization tests include IEF, CE, HIC, LCMS, carbohydrate analysis, N & C terminal sequencing, amino acid analysis, analytical ultracentrifugation, CD and DSC [20,21]. Biologics are highly sensitive to environmental influences during storage, shipment and handling. Temperature excursion, movement, and exposure to UV light can lead to protein degradation. Product expiry needs to be based on the real time stability data. Stability program should also include accelerated or stress studies to gain insight of the degradation profiles. In-use stability studies are carried out to verify shipping conditions or handling procedures cause no detrimental effect to the drug product.

 Comparability Demonstration

 A comparability exercise based on the ICH guideline [22] needs to be performed to demonstrate that the biosimilar product and the reference biologic product have similar profiles with respect to product quality, safety, and efficacy. This is accomplished by comparative testing of the biosimilar product and the reference biologic product to demonstrate they have comparable molecular structure, in vitro and in vivo biological activities, pre-clinical safety and pharmacokinetics, and safety and efficacy in human patients. Comparison of quality attributes between the biosimilar and the reference biologic product employs physicochemical

Product release assays for biologics

Type                         Assays

Quality              Appearance, particulates, pH, osmolality

Purity                 SDS-PAGE, SEC-HPLC, IEX-HPLC, RP-HPLC

Potency             In vitro or in vivo bioactivity assays

Strength             Protein concentration by A280

Identity               Western blot, peptide mapping, isoelectric focusing

Safety                  Endotoxin, sterility, residual DNA, host cell proteins

and biological characterization. Comparability on physical properties, amino acid sequence, high order structures, post-translationally modified forms are evaluated by physicochemical tests. In vitro receptor-binding or cell-based (binding) assays or even the in vivo potency studies in animals need to be performed to demonstrate comparable activity despite they are often imprecise. Levels of product related impurities (aggregates, oxidized forms, deamidated forms) and process related impurities and contaminants (host cell proteins, residual genomic DNA, reagents, downstream impurities) need to be assessed and quantified. Stability profiles of the biosimilar product and the reference biologic product also need to be studies by placing the products under stressed conditions. The rate of degradation and degradation profiles (oxidation, deamidation, aggregation and other degradation reactions) will be compared. If unknown degradation species are detected, they need to be studied to determine if they affect safety and efficacy. If differences on product purities and stability profiles are present between the biosimilar product and the reference biologic product, these differences need to be justified using scientific knowledge or preclinical or clinical studies. Changes in the impurity profile should be justified as well.

The demonstration of comparability in quality attributes does not necessarily mean that the biosimilars and the reference biologics are identical, but that they are highly similar. In many cases, the relationship between specific quality attributes and safety and efficacy has not been fully established. For example, physicochemical characterization cannot easily predict immunogenicity and slight changes in manufacturing processes or product composition can give rise to unpredicted changes in safety and efficacy. Changes in bioavailability, pharmacokinetics, bioactivity bioactivity, and immunogenicity are the main risks associated with the manufacturing of biosimilars. In vivo studies should be designed to measure the pharmacokinetics and pharmacodynamics relevant to clinical studies. Such in vivo studies should be designed to detect response differences between the biosimilar and the reference biologic not just responses per se. In vivo studies of the biosimilar’s safety in animals may be used to research any concerns into the safety of the biosimilar in human patients. Although extensive clinical testing is not necessary for biosimilars, some degree of clinical testing is needed to establish therapeutic comparability on efficacy and safety between the biosimilar and the reference biologic product [23,24]. This includes using surrogate markers of specific biologic activity as endpoints for demonstrating efficacy, and showing that patients didn’t develop immunogenic responses to the product. In general, the approval of biosimilars will be based on the demonstration of comparable efficacy and safety to an innovator reference product in a relevant patient population. Clinical data requirement for each individual product will be different and will be determined on a case-by-case basis.

Small-molecule Generics versus Biosimilars

 Small-molecule

  • Approval based on “sameness”

Biosimilars

  • Approval based on “high similarity”

Small-molecule

  • Replicate the innovator’s process and product and perform a bioavailability study demonstrating similar pharmacokinetic properties

Biosimilars

  • Full CMC development with comparative testing, conduct substantial clinical trials for efficacy and safety including immunogenicity

Small-molecule

  • Abbreviated registration procedures in Europe and US

Biosimilars

  • Regulatory pathway is defined in EU on “Comparability” status, no pathway yet in US under BLA

Small-molecule

  • Therapeutically equivalent, thus interchangeable

Biosimilars

  • Lack of automatic substitutability

Small-molecule

  • $1 to $5 million to develop

Biosimilars

  • $100-$200 million to develop

Small-molecule

  • Brand-to-generic competition

Biosimilars

  • Brand-to-Brand competition

Conclusion

The patent provisions of the Biosimilar Act, 2009 establish demanding and time-sensitive disclosure requirements. ObamaCare upheld by the Supreme Court is a victory for future development of pathways for biosimilar regulatory approvaland eventually biosimilar generic drugs.

Biosimilars are defined as biological products similar, but not identical, to the reference biological products that are submitted for separate marketing approval following patent expiration of the reference biological products. As one of the ICH members, the US needs to catch up with the EU and Japan as those two countries have already issued regulatory guidelines for biosimilars. 2009 and 2012 represent milestones in the regulatory provisions for biosimilars in the US.

Once Congress establishes a legal framework, FDA is expected to set up a biosimilar approval pathway which will be similar to those in the EU and Japan and harmonized under ICH. The biosimilar will need a full CMC development package plus demonstration of comparable quality attributes and comparable efficacy and safety to the innovator’s product. Table 5 provides a comparison summary between small-molecule generics and biosimilars. It will take a much bigger effort to develop a biosimilar than a generic drug. Automatic substitution between the innovator product and a biosimilar is not appropriate as a biosimilar is not a generic version of the innovator product and is approved based on comparability to the innovator product.

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