Related Web sites: BIOSIMILARS.com BIOPHARMA.com BIOPHARMACOPEIA.com

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1 Biosimilars and Biopharmaceuticals: Dealing with the Challenges Pharmaceutical and Health Technology (PHT) Division, Special Libraries Association (SLA), Spring Meeting March 18-20, 2012 Baltimore, MD. Ronald A. Rader President Biotechnology Information Institute 1700 Rockville Pike, Suite 400 Rockville, MD Phone: Related Web sites: BIOSIMILARS.com BIOPHARMA.com BIOPHARMACOPEIA.com

2 What is Biotechnology? Biotechnology = involving use of living organisms for product manufacture; organisms generally perform some type of biological transformation (bioprocessing) Other common uses of term: Anything involving life sciences research or technology (BIO definition) Anything involving hot/upbeat/sexy high tech life science (stock analysts; business and trade press) Anything involving biotech-like business model (small, entrepreneurial) companies (stock analysts; business and trade press) Biotechnology and biopharmaceutical information: today s common themes: complexity; anarchy; nothing is easy; inadequate information resources

3 What is Recombinant? Recombinant (adj.) = involving use of genetic engineering, gene splicing, in live organisms (for the purpose of product manufacture) Expression system = the host organism/ species transformed (desired gene inserted) by recombinant methods enabling it to express(produce) a desired protein product Genes (nucleic acid polymers) code for proteins (amino acid/peptide polymers)

4 What is Biopharmaceutical? : Many Definitions Terminology is a Mess Nearly all of the more comprehensive and authoritative English language and even sci-tech and medical dictionaries lack any entry for biopharmaceutical despite decades of widespread use. In a Google search, a good indicator of general usage, biopharmaceutical retrieves about 442,000 entries. [We are now at 1.1 million] Rader. R.A., What is a Biopharmaceutical?, 2-part series in BioExecutive, March 2005 Drug = pharmaceuticals manufactured by chemical means; involves small molecules and chemical substances [drawing/biopolymer test] Biopharmaceutical = involving use of living organisms (biotechnology/bioprocessing) for manufacture of pharmaceutical products [intersection of pharma and biotech] Most within the core industry itself use this definition. Biologics is the FDA/regulatory term for biopharmaceuticals

5 Examples: What is not Biopharmaceutical? Natural products = chemical substances derived from dead organisms/tissues = not Heparin, big complex biological molecule derived from dead pig intestines, boiled (no biotech) Collagen from dead rooster combs not; but yes if made by live bacteria (both types on market) Taxols from tree bark (dead tissue) = not Antibiotics, other small molecules, metabolites, from biotechnology processing = not Small molecule drugs = not

6 Biopharmaceutical Industry Perspectives US/EU Products Biopharmaceuticals (total) $150 billion 436 Recombinant Proteins $100 billion 167 Recombinant antibodies (mabs) $48 billion 54 Vaccines (few recombinant; many legacy) $25 billion 202 Blood/Plasma Products $20 billion 160 Biosimilars (EU; none in U.S. yet) $.3 billion 14 Companies in core industry 1,200 Product prices and profit margins High! Products in the Pipeline ~1,000 in trials Percent of Pipeline products 40% In top 10 by sales 8 Pharmaceutical industry is counting on biopharma to survive!

7 Multiple Vastly Different Definitions/Views of What is Biopharmaceutical

8 Implications of Different Definitions of Biopharmaceutical Always ask, What are you talking about? Library users, What do you really want? Nearly all, particularly the most prominent, industry data is trash, useless, misleading Incredibly common, even by high-tech professionals, to mix in small molecule drugs Analysts and study criteria almost always unfixed, manipulated, bogus

9 What is a Biopharmaceutical Product? Process = Product Paradigm Biological products - Because made in complex living organisms, with structures so complex (big; folding; cross-linking; glycosylation, etc.), each product is invariably fully unique, different! Process (bioprocessing) defines product! Common experience with biotech products Wine, cheese each same product is unique Yeast change yeast brand; cake/bread different

10 Implications of Process = Product Because biological systems are involved, biotechnology and biopharmaceutical products are highly complex, and often defy short, simple description and analytical characterization. Unlike chemical substances and drugs, biopharmaceuticals are rarely composed of single, readily describable chemical forms/structures. [mixtures of isoforms, range of molecular variants] Lots of information needed to fully define a product! A biopharmaceutical s description is dependent on its identity (source), manufacture (bioprocessing) and specifications. [Scary; how do we identify and name them?] The product=process paradigm is the basis for regulation of biopharmaceuticals ( biologics being the reg. term)

11 Implications: Biopharmaceuticals vs. Drugs Drugs Chemical structure + formulation defines finished product same active agents are presumed and treated as being the same Generic drug approvals common Generic drug often interchangeable (in Rx) and substitutable (by pharmacist) Manufacture outsourced China, India Structure patent is primary protection Chemical names OK for active agent Have trade associations Information orderly, predictable Biopharmaceuticals Bioprocessing (proprietary!) + formulation defines product same active agents/products are never the same; basis for regulations/approvals No generic biopharmaceutical approvals Not at all (officially) Manufactured in-house mostly Besides structure (gene/protein sequence) process, indications, formulation, reference standards, etc. also protect, often better Chemical and other names inadequate, inherently generic (not specific)! No trade trade association in U.S.! Absolute chaos, anarchy, no infrastructure

12 Some Best in Class (Only) Biopharmaceutical Information Resources [all authored by me] Concerning products, technologies, facilities and upcoming, biosimilars BIOPHARMA: Biopharmaceutical Products in the U.S. and European Market (BIOPHARMA.com) the only biopharmaceutical products (not pipeline) information resource/reference; >650 product records, 1.2 million words; in 11 th annual edition; published by Biotech. Info. Inst. Biopharmaceutical Expression Systems & Genetic Engineering Technologies a directory of 350+ technologies available for license; published by BioPlan Associates Top 1000 Global Biopharmaceutical Facilities Index (Top1000Bio.com) ranks 1,000 manufacturing facilities worldwide by capacity [BioPlan] Biosimilars and Biobetters in the Pipeline [no title yet]; discussed below; published by FirstWord, purchase from Biotech. Info. Inst.

13 And Now Come Biosimilars, Biobetters and Biogenerics! More Complications Until ~2 years ago, there was no U.S regulatory pathway for abbreviated (quicker, cheaper), comparisons-based, approval mechanisms for biologics, while there are multiple generic drug approval pathways Biologics Price Competition and Innovation Act (BPCIA) part of health care reform act (ObamaCare) Biosimilar approvals are based on comparisons, including trials vs. an approved reference product (much like generic drugs; think of as generic drug approvals but the product in no way treated as generic) Zero biosimilars approvals in U.S.; 14 marketed products in the European Union (EU)

14 Biosimilarity: The Basis for Biosimilar Approvals Active agent primary structure must be the same as reference product. If not, product must receive traditional full approval (presumed innovative). Approval is based on showing lack of clinically significant differences with reference product! With generic drugs, prove is the same [very different approach]. Analytical profiles (chemistry, biological activities) must be rather very similar Pharmacokinetics (uptake in body) must be very similar Safety and efficacy must be similar. If anything is significantly different (subjective), including better, it is not biosimilar and must go for full approval.

15 Biosimilars-Related Terminology Many Synonyms in Common Use Biosimilars Biocomparables Subsequent entry biologics - Canada Similar biological medicinal products EU Follow-on biologics Me-too biopharmaceuticals Generic biopharmaceuticals (improper) Off-patent biopharmaceuticls Use caution when searching!

16 Biopharmaceutical Nomenclature: None Chemical names, Reg. Nos. generic for agent, not product USANs/INNs purposely generic for agent; adding Greek letters, subscripts to help Trade names/trademarks for product; proprietary; easily gamed; advertising FDA Proper Names for biologics generic for active agent

17 Biosimilars Pipeline Project Background Goal comprehensive biosimilars (and biobetters) pipeline database for all protein products known or presumed on track for U.S. and/or EU approval Product published study (book) Coverage all approved proteins (90% recombinant); excluded vaccines, blood and cellular products includes products worldwide, including biogenerics Sources everything available to author not costing big $ BIOPHARMA ( - for reference product PhRMA Medicines in Development (901 entries; ADIS pipeline subset) Continuous competitive intelligence; monitoring news, trade literature Search engines; company directories; likely 1,000 co. sites No use of fee-based databases; no pipeline databases [where the library/ information center can add value]

18 Biosimilars Pipeline Study-Related Terminology Biosimilars - a similar/me-too/follow-on product relative to a reference product and known or presumed on track for biosimilar approval (all are biosimilars, unless presumed otherwise) Biobetters similar/me-too/follow-on relative to a reference product but presumed on track for full approval - too dissimilar to be a biosimilar (altered structure, delivery, etc.) [Note, not really better at all! Never compared]

19 Product Records (plus many tables) Generic/agent names INN/USAN; agent description Product Names trade names; company codes Product Class reference/biosimilar/biobetter Reference Product biosimilars and biobetters FDA class biologic, drug [505(b)(2)] Phase of development with annotations Companies involved with annotations Patent expiration - U.S. and EU expirations; with annotations Biosimilar Launchable Date U.S. and EU Biobetter Launchable Date U.S. and EU Patents notes/analysis in reference product records Indexing - 4,600 terms (mostly indications)

20 Snapshot of Patent Expiry Notes

21 Breakdown by Product Class Total 897 Reference 118 Biosimilars 417 Biobetters 359 Mark. - Ref. 202

22 Blockbusters Facing the Competition Product(s) Sales Biosimilars Biobetters Enbrel $ Avastin $ Rituxan $ Remicade $ Herceptin $ Humira $ Lantus $ Neulasta $ Lucentis $ Aranesp $ Insulins (all) TNF inhibitors G-CSF mabs/antibody-like Interferons alfa Interferons beta EPO/epoetins 60 25

23 Products By Phase of Development; Will Go from.$3 to >$40 billion in 5 years Blue = All Red = Biosimilars Green = Biobetters Preclinical Phase I Phase II Phase III Marketed (80% Intl. biogenerics)

24 Number of Companies by Region/Country (by total, biosimilar and biobetter involvement) Blue = All Red = Biosimilars Green = Biobetters

25 Biosimilars and Biobetters Launchable Dates US Biosimilars US Biobetters EU Biosimilars EU Biobetter

26 For Further Information: See me today. or Web sites: for products - for nomenclature and terminology