![“
”
“Any virus, therapeutic serum, toxin, antitoxin or analogous product
applicable to the prevention, treatment or cure of diseases or injuries of
man” (FDA)
“A medicinal product manufactured with one or more of the following
biotechnological techniques: recombinant DNA techniques, controlled
gene expression and antibody methods” (EMA)
“A product, the active substance of which is a biological substance. A
biological substance is a substance that is produced by or extracted from
a biological source […]” (AIFA)
Definitions by some regulatory authorities…](https://image.slidesharecdn.com/projectworkbiosimilars-160530205739/85/Biosimilars-assets-and-sustainability-between-regulation-and-information-4-320.jpg)
![“
”
“the absence of a significant difference in the rate and extent to which the active
ingredient or active moiety in pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug action when administered at the
same molar dose under similar conditions in an appropriately designed study.” (FDA)
“[bioequivalency occurs if two medicinal products are] pharmaceutically equivalent
or pharmaceutical alternatives and if their bioavailabilities after administration in
the same molar dose are similar to such a degree that their effects, with respect to
both efficacy and safety, will be essentially the same” (EMA)
“[bioequivalency occurs if two medicinal products], at the same dosage, present
blood concentration profiles depending on time so similar that it is improbable they
will have relevant differences in their efficacy and safety effects”. (AIFA)
Definitions by some regulatory authorities…
Biosimilars cannot be completely bioequivalent due to the batch-to-batch variability
and their intrinsic biological nature. They are only “highly similar”, considering
minor differences in clinically inactive components and no clinically meaningful
differences in terms of safety, purity and potency.](https://image.slidesharecdn.com/projectworkbiosimilars-160530205739/85/Biosimilars-assets-and-sustainability-between-regulation-and-information-14-320.jpg)
Biosimilars: assets and sustainability, between regulation and information
- 1. Biosimilars: assets and sustainability, between regulation and information Final Project Work, March 2016 Master in Pharmaceutical Marketing & Management Alma laboris S.r.l. Author: Jacopo Sacquegno
- 2. Index 1.1 What are biopharmaceuticals? 1.1.1 Some definitions and general features 1.1.2 Notable differences with traditional drugs 1.2 What are biosimilars? 1.2.1 Comparing generics and biosimilars 1.3 How are biosimilars authorized? 1.3.1 Bioequivalence and regulatory needs; 1.3.2 Interchangeability and substitutability for biosimilars; 1. A SCIENTIFIC APPROACH
- 3. 1.1 What are biopharmaceuticals? «Broad Biotech» Pharmaceuticals that are biological in nature and manufactured by biotechnology methods. This includes both products manufactured by recombinant DNA technology (e.g., monoclonal antibodies and recombinant proteins; involving genetic engineering) and products naturally present in living organisms and extracted (e.g., proteins and vaccines derived from non-engineered organisms as well as blood/plasma-derived products) 1.1.1 some definitions and examples «New Biotech» Only those pharmaceuticals biological in nature and manufactured using genetic engineering (hence, it includes only biological products such as monoclonal antibodies and recombinant proteins). • Been around for over 200 years; • Revenues reaching about 160$bn/yr
- 4. “ ” “Any virus, therapeutic serum, toxin, antitoxin or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man” (FDA) “A medicinal product manufactured with one or more of the following biotechnological techniques: recombinant DNA techniques, controlled gene expression and antibody methods” (EMA) “A product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source […]” (AIFA) Definitions by some regulatory authorities…
- 5. RECEPTOR CONSTRUCTS (fusion proteins), usually based on a naturally- occurring receptor fused to the immunoglobulin frame through DNA recombinant techniques. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology. Biosynthetically produced substances that are (nearly) identical to the body’s own key signalling proteins, including: Hormones, chemicals transfer information and instructions between cells in animals and plants (INSULIN, GLUCAGON, GROWTH HORMONE, GONADOTROPINS); Cytokines, hormone-like molecules that can control reactions between cells (INTERFERON, INTERLEUKINS, ERYTHROPOIETIN); Enzymes, complex proteins that catalyse organic reactions (INSULIN, GLUCAGON, GROWTH HORMONE, GONADOTROPINS); Various blood factor, involved in coagulation (FACTOR VIII, FACTOR IX) and thrombolysis (TISSUE PLASMINOGEN ACTIVATOR); MONOCLONAL ANTIBODIES. These are antibodies produced by using hybridoma technology (i.e. hybridizing antibody-producing spleen cells with immortalized cells) or other methods that allow to obtain antibodies made by identical immune cells all clones of an identical parent cells and bind the same target, in contrast to polyclonal antibodies which are made from several different immune cells. When used as biopharmaceuticals, they are designated with the stem -mab.
- 6. Technology Mechanism of action Indications 1. Adalimumab (Humira®) Monoclonal antibody TNF antagonist Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease 2. Etanercept (Enbrel®) Recombinant human TNF- receptor fusion protein TNF antagonist Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis 3. Infliximab (Remicade®) Monoclonal antibody TNF antagonist Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease 4. Insulin glargine (Lantus®) Recombinant insulin Insulin analogue Diabetes 5. Rituximab (Rituxan®, MabThera®) Monoclonal antibody CD20 binding and B-cell elimination Many lymphomas, leukemias, transplant rejection and autoimmune disorders. 6. Bevacizumab (Avastin®) Monoclonal antibody VEGF-A antagonist Colorectal, lung, breast, renal and brain cancer; several eye disease. 7. Trastuzumab (Herceptin®) Monoclonal antibody HER2/neu receptor antagonist Breast cancer 8. Pegfilgrastim (Neulasta®) PEGylated form of the Granulocyte colony stimulating factor (GCSF) Stimulates neutrophils blood concentration Fight infections in patients undergoing chemotherapy. 9. Ranibizumab (Lucentis®) Monoclonal antibody fragment VEGF-A antagonist Age-related web macular degeneration 10. Erythropoietin alfa (Epogen®, Procrit®, Eprex®, ESPO®) Recombinant human erythropoetin EPO analogue Anemia from chronic kidney disease, chemotherapy-induced anemia in patients with cancer, Crohn's disease and ulcerative colitis and myelodysplasia from the treatment of cancer Top-10 biologic active substances for global sales in 2014
- 7. 1.1.2 Notable differences with traditional drugs Traditional drugs Biopharmaceuticals Size Tens or hundreds of Da Hundreds of thousands of Da Complexity Relatively simple Much more complex Origins Standardized organic reactions Living Organisms Stability Stable Not so stable Production Synthesis is relatively cheap, can be standardised and is easily replicable. Synthesis is expensive and hardly reproducible (“product is the process”); purification is not standardisable. Treatment Used to treat “traditional” diseases. Used to treat otherwise untreatable pathologies. Adverse effects Predictable. Possible immunogenicity.
- 8. MCBs are under trade secret, hence no MCB is equal to the other and this influences the final product. Cell banks are constantly examined in order to avoid contamination from external agents. After scaling up in increasingly bigger volumes, culture is collected, active principle is extracted and goes through several steps of purification before being ready. The whole process is much more complex and expensive than what is usually required for traditional drugs. The complexity of the process makes the final product totally dependent from each step. The same molecule obtained by two different companies can be different at the end of the manufacturing process (e.g. in its tridimensional structure and post-translational modifications), leading to significant alterations in terms of effectiveness and safety. Even different batches of the same product display a certain degree of variability. After culture, the resulting product- producing cells are generally aliquoted and frozen, creating identical and ready to use “MASTER CELL BANKS” (MCB) that can be indefinitely preserved. Each “master cell bank” is then thawed and used up to create aliquoted “WORKING CELL BANKS” (WCB), which functions as viable source of cells for a production batch. This system allows to ensure an essentially indefinite supply of the originally developed production cells for manufacturing purposes. «The product is the process»
- 9. *Adverse effects A peculiar feature of biopharmaceuticals is their possible IMMUNOGENICITY, i.e. the capacity of inducing an immune reaction. Once in the body, these recombinant proteins can be recognized as “non-self” by the organism, which in response produces anti-drug-antibodies (ADAs) inactivating the therapeutic effects of the treatment and, in rare cases, inducing adverse effects. One example of this is the aplastic anemy that was associated with a particular form of recombinant erythropoietin (Eprex®). The prediction of the immunogenic potential of novel protein therapeutics is thus a challenge in biotherapy. *Molecular size Ibuprofen has only 13 carbon atoms and a molecular weight of about 206 Da; Simvastatin has 25 carbon atoms for about 418 Da; Vancomycin has 66 carbon atoms for about 1450 Da. Human growth hormone is a protein with 191 amino acids and a molecular weight of 22 kDa; Human erythropoietin is a glycoprotein with 165 amino acids in its mature form, weighing 34 kDa; Immunoglobulins have molecular weights in the range of 150kDa;
- 10. Biopharmaceuticals are designed to target precisely on a single structure (protein, receptor, DNA sequence), increasing the effectiveness of the therapy and reducing side effects at the same time. Biopharmaceuticals have had a profound impact on many medical fields, primarily rheumatology and oncology, but also cardiology, dermatology, gastroenterology, neurology and others, adding major therapeutic options for the treatment of many diseases, including some for which no effective therapies were available, and others where previously existing therapies were clearly inadequate. Autoimmune diseases (e.g. rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis). Many form of tumors (e.g. breast, renal, liver, lungs, brain, colorectal), including lymphomas and leukemias. Chronic inflammatory diseases (e.g. Chron’s disease, ulcerative cholitis). *Treatments
- 11. 1.2 What are biosimilars? The increasing development of sequencing technologies, molecular cloning processes and in vitro biological production has allowed the production of virtually any recombinant DNA-based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches. Since many of the first generation biopharmaceuticals have been developed in the 80’s, they are getting close to their patent’s expiration date; for some of them, this date is soon to come or has passed by already. This allows any biotech company other than the original creator of the expired biological product to develop and market the same product on its own. After years of debate, these products have been defined “BIOSIMILAR MEDICINES” by the EMA. The term clearly distinguish them from what generics (“bioequivalent”) are with respect to traditional drugs. 1.2.1 Comparing generics and biosimilars
- 12. Generics Biosimilars Structure Identical to the reference product. Most probably not identical. Production Manufacturing process is highly standardized and generally the same as the originator. Manufacturing process can be different from the one of the originator (possible patent). Analysis Analytical techniques can demonstrate identity with the originator. Analytical techniques cannot fully characterize complex molecules. Contaminants Detectable and quantifiable. Different depending on the substrate/organism used. Formulation Rarely influences bio-equivalency. May interfere with therapeutic effects. Safety & Efficacy variations Minimal. Cannot be inferred without supporting clinical trials.
- 13. Generic drugs are based on active substances, which are bioequivalent to another active substance already authorized, with the same quali- quantitative composition, pharmaceutical form and therapeutic indications. Mass spectrophotometry and nuclear magnetic resonance can safely identify the active substance and detect contaminants; manufacturing procedures, being highly standardised, are generally the same as those of the originator; different excipients and final formulations have minimal effects on the final safety and efficacy of the drug. A biosimilar and its reference product, on the other hand, are obtained through inevitably different manufacturing processes, which is due to the inherent variability of the biological expression system and the manufacturing process itself. Differences in the former determine differences in the contaminants, and replication of the latter can be even harder because the originator’s producer can hold patent rights on the production process itself. Moreover, analytic techniques cannot fully characterize complex biological molecules, which makes them insufficient to demonstrate that the biosimilar product is equal to its originator. An alternative final formulation can also alter the biosimilar’s properties.
- 14. “ ” “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” (FDA) “[bioequivalency occurs if two medicinal products are] pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same” (EMA) “[bioequivalency occurs if two medicinal products], at the same dosage, present blood concentration profiles depending on time so similar that it is improbable they will have relevant differences in their efficacy and safety effects”. (AIFA) Definitions by some regulatory authorities… Biosimilars cannot be completely bioequivalent due to the batch-to-batch variability and their intrinsic biological nature. They are only “highly similar”, considering minor differences in clinically inactive components and no clinically meaningful differences in terms of safety, purity and potency.
- 15. In short, bioequivalent drugs must show the same absorption, the same upstream and downstream blood levels, the same permanency in the blood circle and same excretion time. These parameters define a drug’s BIOAVAILABILITY The fraction of an administered dose of unchanged drug that reaches the systemic circulation and it is described by the plasma concentration time curve assessing the rate and extent of absorption. The area under the curve (AUC) reflects the extent of exposure. Cmax, the maximum plasma concentration or peak exposure, and the time to maximum plasma concentration, tmax, are pharmacokinetic parameters that are influenced by absorption rate. Most small molecule drugs are accepted as bioequivalent if their AUC and Cmax are within the range of a 90% Confidence Interval of 0,8-1,25.
- 16. Marketing authorization for biopharmaceuticals is released by the EMA through a Centralized Procedure. The COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) writes the EUROPEAN PUBLIC ASSESSMENT REPORT (EPAR), published on the EMA website, which includes the motivation for the favourable response to the authorization request and a section about presentation requirements (labelling, packaging, etc.). Attribution of a Community M.A. number. Registration in the Community Register of Medicinal Products (available on the European Commission website). 1.3 How biosimilars are approved? 1.3.1 Regulatory needs and marketing authorization
- 17. EMA has been the first regulatory authority to establish a specific set of rules for the approval of biosimilar products. This legislative framework later inspired several other countries (Australia, Canada, Japan, Turkey, Singapore, South Africa, Taiwan, the United States), as well as the World Health Organization. The authorization procedure follows EMA guidelines: General guidelines defining the concept of biosimilars and establish general requirements for authorization. Guidelines for biosimilars’ quality; Guidelines for preclinical and clinical studies; Guidelines specific for each biosimilar line (e.g., monoclonal antibodies, erythropoietins, GH, ecc.).
- 18. “COMPARABILITY EXERCISE” is the name for the overall process aiming to ensure that the quality, safety and efficacy of a biopharmaceutical produced by a changed manufacturing process overlap the originator’s ones. The exact requirements of Comparability Exercises are set by the EMA (in Europe) or the FDA (in the U.S.). A Comparability Exercise consist of a series of stepwise procedures starting with tests for quality (physical-chemical and biological comparability) and proceeding with non-clinical and clinical trials (evaluation of safety and efficacy). CTD modules Generic drugs Biosimilar drugs Module 1: Administrative informations Complete Complete Module 2: Summary of the next modules Complete Complete Module 3: Product quality Complete Complete + comparability exercise Module 4: Non-clinical reactions Omissis / bibliographic references Preclinical tests results + comparability exercise Module 5: Relations on clinical trials Bioequivalence study Clinical trials results + comparability exercise Requirements for the Common Technical Document (CTD)
- 19. Step 1 - Quality comparability: this involves a thorough characterisation program comparing the physicochemical and biological quality attributes, including the purity of the potential biosimilar medicine as compared with the reference product. Step 2 - Non-clinical comparability: As is the case with any biopharmaceutical, proposed biosimilars must undergo pre-clinical studies before trials in humans are conducted. Data for biosimilars are usually obtained via an abbreviated program of in vitro tests or studies in animals, as required by EU guidelines. The non-clinical studies usually comprise repeat dose toxicity, pharmacokinetic and pharmacodynamic studies in an appropriate animal model, together with local tolerance testing in some instances. Step 3 - Clinical comparability: A proposed biosimilar has to show that it is clinically comparable to its reference biologic in terms of both efficacy and safety (phase I and III clinical trials), including specific evaluation on immunogenicity. Specification of the clinical information required takes into account existing comparability data, such as physicochemical characteristics, receptor-binding assays and results from testing in animal models. The closer the profiles of a biosimilar and reference products and the higher the similarity that has been demonstrated through previous steps, the more an abbreviated clinical trial program can be accepted by regulators. Comparability exercise
- 20. 1.3.2 Interchangeability & substitability for biosimilars “An interchangeable pharmaceutical product is one which is therapeutically equivalent to a comparator product and can be interchanged with the comparator in clinical practice.” (WHO 300 technical report series, no. 937, 2006) “Interchangeability refers to the medical practice of replacing one drug with another equivalent one in a given clinical context on the initiative or with the agreement of the prescribing physician.” (European Generic Medicines Association, EGA) “Interchangeability refers to the medical practice of replacing one drug with another that has the same benefit-risk profile and is expected to have the same clinical effect in a given clinical context on the initiative or with the agreement of the prescribing physician.” (EFPIA/EBE-EuropaBIO)
- 21. Limits in the interchangeability of biosimilars 1. Manufacturing Process: reference biopharmaceuticals and their biosimilar are similar but not identical. Therefore, it cannot be assumed that they are automatically interchangeable. The switch must be carefully monitored. 2. Lack of phase II clinical trials aiming to identify proper dosage: clinical trials for the originator are taken into account. 3. Extension of indication: once the biosimilar’s effectiveness has been demonstrated for one indication, it gets extended to all others. In onchology, this could result inadequate, especially for monoclonal antibodies. Each new therapeutic indication should be tested with a specific registration process. 4. Immunogenicity risk: undetectable differences between biosimilars and originators could lead to unexpected immunogenicity.
- 22. SUBSTITUTABILITY, on the other hand, refers to the practice of replacing a drug with another drug, often at a lower cost for the Health Service or for the patient, which has the same qualitative and quantitative composition of active substances, the same pharmaceutical form and route of administration and is bioequivalent to the reference medicine on the basis of appropriate bioavailability studies. Automatic substitutability (of equivalents) by pharmacists refers to the practice by which the pharmacist may, or must, in accordance with national or local regulations, dispense a drug equivalent and interchangeable instead of the prescribed medicine, without consulting the prescriber. Finally, as regards substitutability, these differences should be noted: • primary substitutability refers to the medical practice of beginning a new treatment with a biosimilar product (or an equivalent) rather than with the originator reference product; • secondary substitutability, on the other hand, refers to the medical practice and/or of the pharmacist of modifying the treatment of a patient already being treated with a biologic drug with its biosimilar.
- 23. 2.1 How is the biopharmaceutical market? 2.1.1 The present-day global scenario 2.1.2 The lead actors on the biopharma market 2.2 How does biosimilars impact the market? 2.2.1 The past and the present of biosimilars 2.2.2 The future of biosimilars 2.3 How is the biosimilar situation in Italy? 2.3.1 The AIFA and the regional heterogeneity; 2.3.2 Interchangeability and substitutability for biosimilars; 2. A MARKETING APPROACH
- 24. 2.1 How is the biopharmaceutical market? 2.1.1 The present-day global scenario Sales from biotechnology products have grown from a share of 14% in 2006 to 23% in 2014, and they are expected to reach 27% of the global market by 2020. Top-100 blockbuster drugs in 2006 comprehended only 21% biophar- maceuticals; in 2014, this figure has much increased reaching 44%. The forecast for 2020 see the percentage to increase to 46%, lower than the 52% predicted in last year’s report (which would have meant a reversal in the major market share of top selling drugs between biological and conventional medicinal products).
- 25. Humira® (adalimumab) was the single most lucrative product in 2014 ($12 billion). Humira® generated $35 billion sales over the period 2010-2013. A total of 37 individual biopharmaceuticals recorded blockbuster sales (>$ billion). Taken together, the top ten generated $69.8 billion sales in 2013 (50% of total biopharmaceutical revenues) In terms of target indications, the majority of antibody and antibody-like products target inflammatory and/or autoimmune conditions (cumulative 2013 sales of $41bn) and cancer (2013 cumulative sales of $26bn). Among nonantibody–based products, insulins are the next most lucrative product class, collectively generating sales of $21.5bn in 2013.
- 26. Number of biopharmaceuticals approved for market: a. Approvals in the US and EU for each year from 2010 to 2013 period; b. Approval numbers over the indicated period. More than 250 biopharmaceutical products licensed in both markets over the considered period. In 2014, 150 biologics were marketed worldwide and more than 370 were in the pipeline. Product approvals as a percentage for each class over the total, in the 2010-2014 period and from 1982 to 2014 (cumulative). There has been a decrement in approval for some classes (such as interferon and interleukins) in the last period, likely reflective of market saturation. Monoclonal antibodies, on the other hand, have continuously grown in importance; from about 10% of all approvals by the end of the 1980s to 22% by 2014.
- 27. Promising research into synthetic biology and continuing computer-related progress in biotech areas: Many bioinformatics studies are carried out for gene sequencing, drug discovering, searching new drug receptors and producing tailored drugs which act specifically on the target. Unsatisfied therapeutic needs: biopharmaceuticals are the only known medications capable of being used for the treatment of diseases and disorders toward which other therapies are otherwise often ineffective. Vast research investments by major pharmaceuticals firms: many major Pharmaceutical companies are going to augment their biological portfolio and they have greatly increased their research investments or benefitted from their partnering or acquisition of biotechnology companies. Major Pharmaceutical firms went or will go off patent: Many major conventional drugs, including best-sellers like GSK’s Advair® (2010), Pfizer’s Lipitor® (2011), BMS’s Plavix® (2012), Novartis’ Diovan® (2012) and AstraZeneca’s Nexium® (2014) have recently gone off patent, or will do so in the near future, which means a significant boost to generic manufacturers that quickly issues their own low-priced versions. Reasons of this success
- 28. 2.1.2 The lead actors on the biopharma market
- 29. Roche can count on three of the most important anti-tumoral monoclonal antibody products in its pipeline (Avastin®, Herceptin®, Rituxan®), totalizing more than $20 billion revenues in 2014 taken all together. By 2014, Amgen had 12 approved biological medicines. Among these, the largest selling product lines were Neulasta® and Enbrel® (co-marketed with Pfizer in the U.S.) Novo Nordisk, a diabetes specialist, manufactures many recombinant insulin-based products (e.g. Novolog®/Novorapid®, Levemir®, Actrapid®/Novolin®). Sanofi has recently seen a slowdown in Lantus® sales, but it has enforced partnerships with the American biotechnology firm Regeneron to develop and launch monoclonal antibodies; four specialities are already at a critical stage. Originated in 2013 as a spin-off of Abbott Laboratories, Abbvie owes most of its fortune to its best-selling drug Humira® (almost 55% of total revenue in 2014).
- 30. Mergers & Acquisitions Pfizer acquired Wyeth Biotech in 2009. Producer of Enbrel®, co-marketed with Amgen. Roche acquired Genentech in 2009 Producer, among others, of Avastin®, Herceptin®, Rituxan® and Lucentis® ...and also Sanofi + Genzyme ($20.1bn), the world third-largest biotechnology firm; Pfizer + Hospira ($17bn), world's leading supplier of injectable drugs and infusion technologies; etc. Merck & Co. acquired Schering-Plough in 2009. Producer of several biologics, including Remicade® A wave of acquisition by Big Pharma toward successful biotech companies, in order to acquire biologic expertise and market. However, innovation in biopharmaceuticals have started to slow down with respect to late 1990s (saturation for therapeutic indication and more restrictive requests from regulatory agencies may be the cause) Entering biosimilar market may be an alternative way to create value with biologic for Big Pharma.
- 31. 2.2 How do biosimilars impact the market? 2.2.1 The past and the present of biosimilars March 23th, 2012: the Obama administration passed The Biologics Price Competition and Innovation Act (BPCI Act), an amendment to the Public Health Service Act to create an abbreviated approval pathway for biological products. July 24th, 2014: First biosimilar application to FDA. August 8th, 2014: First monoclonal antibody application to FDA. March 6th, 2015: Zarxio® by Sandoz is the first biosimilar approved by FDA. Its reference product is Amgen’s Filgrastim (originally licensed in 1991). July 1st, 2005: First biosimilar application to EMA. April 12th, 2006: Omnitrope® (somatropin) by Sandoz is the first biosimilar approved by EMA. 2010: By the end of the year, 14 biosimilars were approved in EU, establishing a market that reached about $172 million. March 1st, 2012: First monoclonal antibody application to EMA. September 10th, 2013: EMA authorizes sale of Remisma® (biosimilar of Remicade) by Celltrion Healthcare in the EU. Timeline In Europe In the U.S.
- 32. Drivers Growing pressure to reduce healthcare expenditure in developed countries; Increase in the number of patients that can afford prescription drugs in developing markets; Various blockbuster biologics going off patent; High prevalence of chronic diseases in ageing population; Regulatory initiatives (e.g. the EMA introduction of a licensing procedure; the BPCI act decided by the American government). Restraints High initial investment in research and development; Medical efficacy and patient safety. Stringent regulations in developed economies to restrict investments. COST The average R&D investment for a biopharmaceutical is $1.2bn. As a consequence, for example, Remicade costs almost $18.000 a year; Herceptin costs up to $40.000 a year per patient. The BGMA estimates that by 2020 biosimilars could shave up to €33bn off drug bills in eight EU countries. TIME It takes an average of 10-15 years to develop and market a new biopharmaceutical. Biosimilars may benefit from shortened licensing process and previous research studies. In this way, their marketing time is reduced to 7-8 years.
- 33. After an initial burst of approvals from 2006–2008, the EU approval rate has slowed. This is hardly the opening of the biosimilar’s floodgate that someone predicted. Market penetration was slow, although now biosimilar market in the EU stays at around $360mn, with global total sales reaching about $676mn (0.4% of the biological market) (IMS Health). On the positive side: • by the end of 2012, 41% of EU filgrastim market and 19% of short-acting EPO market were covered by biosimilars. • Biosimilar prices in the EU have an average 30% discount on the product relative to their originator. • No unexpected safety issues raised. The European experience
- 34. An increasing number of markets is developing their own biosimilar pathways, either based on EMA or WHO. Globally, by 2014 there were 280 biosimilars in the pipeline, and their clinical trials is increasing by 20% each year. Two big markets like Russia and China have still to develop their own pathway. As for biosimilar manufacturing, India is the third big player after EU and the US. The Asia-pacific region is the most promising market, with many biosimilars already in use. By 2020, it will become the highest revenue generating area. © 2016 - William Reed Business Media SAS - All Rights Reserved
- 35. Biopharma industry is in the middle of a “patent cliff” in Europe and US, which will put a market of more than $60bn (considering only the top 10 selling products) at risk. The most important patent expirations in the EU for the next future are represented by Neulasta® ($4.4bn) and, even more remarkable, Humira® ($12bn). Biosimilars developers will be using emerging markets with less intellectual property protection to quickly enter into established markets. Best example for this is the Asia-Pacific Region: • Collaboration between Mylan and Biocon to commercialize biosimilar of Herceptin® in India; • Cadilla Healthcare launched in India the first adalimumab biosimilar under the name Exemptia® in 2014. 2.2.2 The future of biosimilars © 2016 - William Reed Business Media SAS - All Rights Reserved
- 36. The challenge for biosimilar manufacturers is not only to implement a proper manufacturing process, but also to prove comparability through clinical trials in a cost-effective manner. The high upfront costs needed, both to manufacture and to execute clinical trials will, therefore, act as a strong barrier to entry into the biosimilars market regardless of the ”patent cliff”. The price drop for biosimilars will not be as pronounced as for generics, because companies entering the market need to overcome these barriers yet still make a financial return (at date, most biosimilars are sold at about 65%-85% of the originator’s price in the EU) The key capabilities necessary to entry and prevail into the biosimilar market can be identified in: • Research and Development: financial resources for basic research and clinical trials. • Manufacturing: access to specific biomanufacturing facilities. • Supporting activities: such as legal expertise and global distribution channels. • Marketing: scientific information and a global network of sales representatives. • Lobbying: with regulatory bodies, KOLs and governments.
- 37. 2.3 How is the biosimilar situation in Italy? 2.3.1 Biosimilars impact on the Italian market Therapeutic proteins (growth factors, interleukins, interferons, insulins, ecc.) cover almost all volumes of biopharmaceuticals used in Italy and more than half of the expenses. Monoclonal antibodies represent only 5% of the volumes, but this amount translates into 42% of the total expense for biopharmaceuticals. Cesbio Bocconi – secondo rapporto di ricerca sui farmaci biotech (2014)
- 38. Cesbio Bocconi – secondo rapporto di ricerca sui farmaci biotech (2014)
- 39. By the end of 2013, 9 on 14 biosimilars approved by the EMA were present on the Italian market: Omnitrope (somatropine) 29/10/07 Abseamed (EPOetin alfa) 03/11/08 Binocrit (EPOetin alfa) 29/10/07 Retacrit (EPOetin alfa) 03/11/08 Ratiograstim (filgrastim) 16/03/09 Tevagrastim (filgrastim) 01/11/09 Zarzio (filgrastim) 01/11/09 Nivestim (filgrastim) 08/06/10 Grastofil (filgrastim) 12/12/13 Italian market share of biosimilars has steadily grown. Use of filgrastim biosimilars has become higher than the reference product since 2012. EPO biosimilars has sensibly grown as well, while somatropine remained more or less stable. Cesbio Bocconi – secondo rapporto di ricerca sui farmaci biotech (2014)
- 40. 2.3.2 The AIFA and the regional heterogeneity To date, the EMA has not expressed an official opinion yet about biosimilars’ substitutability, leaving decisional and legislative autonomy on the matter to national authorities. Recommendations suggest a precautionary approach: In Italy, the AIFA makes it clear that biological medicines and biosimilars cannot be considered purely and simply the same as equivalent products, and thus excludes the mutual automatic substitutive therapy. “The decision about the choice of prescribing a particular drug to be used, rather than reference biosimilar, must be entrusted to qualified health workers” (Ref. EMEA/74562/2006 Rev.1)
- 41. Tuscany (Regional Resolution n.592/2010) In public purchase procedures for biosimilars, composition, route of administration, therapeutic indications and dosage must be indicated exclusively. In no circumstance substitution with drugs equal in composition, pharmaceutical form and dosage produced by a different pharmaceutical company is allowed. Choice by the medical specialist to prescribe a drug different from the one accepted by the public purchase procedure must be motivated to the people/person in charge of the institute of reference. Further costs deriving from prescription of drugs different from those object of the public procedure cannot be charged on the Regional Health System.
- 42. Molise (Regional Decree n.5/2010) Biosimilar drugs must be used as first choice with drug naïve patients, except for other therapeutic indication and/or clinical judgement, which will be object of a specific technical relation that must be sent to the Therapeutic Regional Committee (CTR). In patients already treated with biopharmaceuticals, it must be guaranteed the alternative use of a biosimilar, except for other clinical judgement or welfare complexity conditions, object of a specific technical relation that must be sent to the Therapeutic Regional Committee (CTR). Treatment with biopharmaceutical drug must be guaranteed to the patient in case of therapeutic inefficacy, non-sufficient therapeutic response or manifested non-tolerance to the biosimilar.
- 43. Campania (Regional Decree n.34/2012) (D.n.44/2010 – n.15/2009) All prescribing doctors, in the act of prescribing biopharmaceuticals, must show a preference to biosimilar drugs, with equal therapeutic indications and route of administration. Prescribers will motivate a different therapeutic choice with the specific patient card, which must be attached to the request and sent online, monthly, to the Nucleo di controllo dell’appropriatezza. Patient card does not have to be filled for those biopharmaceuticals of the same fifth level-ATC category that got their price reduced with respect to the one established at the release date of Commissioner’s Decrees n.15 of 30/11/2009 and n.44 of 14/07/2010, allowing achievement of the expected 40% discount. Concerning naïve patients, with equal therapeutic indication in the data sheet, the least expensive biosimilar must be used. In case of documented therapeutic inefficacy and/or non-tolerance, use of another biopharmaceutical must be guaranteed.
- 44. Lacking a national policy about biosimilar’s substitutability, every Italian region has expressed or could express its own set of rules and measures, which can be discordant on the matter and put the equality of the citizen’s right to healthcare over all national territory at risk. Tuscany, Molise and Campania are regions that have favoured biosimilar’s use, at least for naïve patients. For those being already treated with a biopharmaceutical, the principle of therapeutic continuity is generally held. Therapeutical switch toward a biosimilar must be carefully evaluated and decided only with the consent of prescribing doctor. Nevertheless, for example, therapeutic continuity and personalization is more stressed in Tuscany’s resolution, while Campania’s regulations aim primarily to cut expenses. These are two different approaches that could probably lead to different guarantees for the citizens of the two regions. Regions interested by resolutions on biosimilars and their relative number over the course of the 2009-2012 period Cesbio Bocconi – primo rapporto di ricerca sui farmaci biotech (2013)
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