Challenges Facing Biosimilar Entries into US Markets by Sarfaraz K. Niazi
Series 2018 Challenges Facing Biosimilar Entries into US Markets
by Sarfaraz K. Niazi
Introduction page 3
Mistakes Made By Developers page 3
Regulatory Compliance page 7
Analytical Similarity Testing page 9
The Development Master Plan page 10
Outsourcing page 11
References page 12
About the Author page 13
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© 2017 BD. BD and the BD Logo are trademarks of Becton, Dickinson and Company. MC7501 © 2017 BD. BD and the BD Logo are trademarks of Becton, Dickinson and Company. MC7501 23–19581-00 23–19581-00 ince the 2009 enactment of the Biologics Price Competition and Back to Contents Innovation Act (BPCIA) (1), the US Food and Drug Administration (FDA) has licensed six products under PHS S 351(k) and approved one product under FD&C 505 (b)(2). It also provided complete response letters (CRLs) to four biologics license application (BLA) filings (Table 1) (2). By comparison, the European Medicines Agency (EMA) has approved 31 biosimilar products (3) and refused or withdrawn about five.
Table 1: FDA-approved biosimilars as of late 2017 Approval Date Biosimilar Product (Trade Name) Original Product (Trade Name) 6 March 2015 filgrastim-sndz (Zarxio) filgrastim (Neupogen) 5 April 2016 infliximab-dyyb (Inflectra) infliximab (Remicade) 30 August 2016 etanercept-szzs (Erelzi) etanercept (Enbrel) 23 September 2016 adalimumab-atto (Amjevita) adalimumab (Humira) 21 April 2017 infliximab-abda (Renflexis) infliximab (Remicade) 25 August 2017 adalimumab-adbm (Cyltezo) adalimumab (Humira) 14 September, 2017 bevacizumab-awwb (Mvasi) bevacizumab (Avastin)
There is no doubt that US market entry of biosimilars remains a slow process. Based on my first-hand experience in developing biosimilars for market and teaching about biosimilars over several years, I address herein the most critical questions about the fate of such products in the United States: • What key mistakes are biosimilar developers repeating? • What are some cost-effective approaches for development of new biosimilars? • Is the situation likely to change on the US market for biosimilars in 2018 and beyond?
Mistakes Made By Developers Back to Contents Litigation Delays: Most products listed in Table 1 are under litigation (4), which delays market entry for biosimilars. The peculiar nature of 351(k) filing requirements and the complexity of biomanufacturing opens wide the possibilities of intellectual property (IP) protection and litigation. Recently the 351(k) filing provisions were reviewed by the US Supreme Court, which held that a federal injunction cannot be used to compel biosimilar applicants to disclose application and manufacturing information as was anticipated by the BPCIA. Biosimilar applicants may provide statutory 180-day notice of commercial marketing either after or before receiving FDA approval (5). Although removal of the 180-day notice requirement certainly eases biosimilar entry, an optional “patent dance” does not necessarily help a developer, as has been widely suggested (Figure 1). Participating in that dance limits the scope of litigation, as pointed out in the Supreme Court decision, so it is an option provided to biosimilar developers. The risk involved in participating in the patent dance is that an originator may select two patents to litigate based on the specific process used to give the originator a better chance of sustaining its claim in the two rounds allowed for litigation. So for example, Sandoz refused to engage in the
patent dance with Amgen, but it 3is not BioProcess known International whether 16(1)Amgene January chose 2018 to E-B ook Sharp Elution Profile Easy and Reproducible Packing Decreased Manufacturing Costs Superior Binding Capacity High Purity Excellent Alkali Resistance Flow Rate Compatibility
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AmsphereTM is a global trademark of JSR Corporation ©2016 JSR Life Sciences – All rights reserved Figure 1: The so-called patent dance provides an option for biosimilar developers to limit the scope of litigation, but it comes with the risk of sharing details with an originator (reprinted with permission from Niazi SK. Biosimilars and Interchangeable Products: Strategic Elements. CRC Press: Boca Raton, FL. 2015; ISBN 9781498743471).
Process Detail: The Patent Dance • Within 20 days of application acceptance, applicant provides application and manufacturing information to the reference-product sponsor (RPS) 30 days 20 days Provide info to P • Within 60 days, RPS provides a list of owned/exclusively licensed patents File File Accepted and patents for licensing • Within 60 days applicant may provide a patent list; must provide factual and legal bases as well as a response regarding the license Provide list 0 days of patents • Within 60 days the RPS provides the basis for infringement and a response to the applicant about validity and enforceability • Parties negotiate patents to litigate 0 days Provide esponse If no agreement is reached after 15 days, applicant gives notice of patents it will designate for litigation; ve days later, the parties simultaneously exchange Basis for lists of patents to be included in the suit; RPS must then bring suit within 30 days Infringement 0 days If there is agreement, RPS must bring suit for agreed patents within 30 days • The applicant copies FDA on any lawsuit within 30 days
For more information, refer to BPCIA (42 U.S.C. §262(l)) at www.fda.gov/downloads/ 15 days drugs/guidancecomplianceregulatoryinformation/ucm216146.pdf Negotiate patents to 3030 days days P eference litigate Product ponsor es Bring uit 30 days P Bring uit FDA Agreement? 30 days opy FDA 5 days Applicant No on lawsuit Patents imultaneous designated e change of for litigation patents to include do so with Abbvie. Those risks can be minimized by conducting an From the BPI Archives: in-depth freedom-to-operate (FTO) analysis that requires great expertise The Patent Dance and continuous dialog between scientists and lawyers — a requirement Siekman MT, Johnstone OM. Impact that may have been underestimated by biosimilar developers, as has of Post-Grant Proceedings on Biologics and Biosimilars. BioProcess been demonstrated by the course of every biosimilar approved by the Int. January 2017: www. FDA thus far. bioprocessintl.com/business/ One way to prevent litigation and thus lower the costs of biosimilar intellectual-property/impact-of-post- development — as well as speeding market entry — is first to select the grant-proceedings-biologics- biosimilars. right product for development. Although more than 120 products with Angulo C. A Turning Point for US current markets of over US$120 billion are available as potential Biosimilars. BioProcess Int. May 2016: biosimilar candidates (see the “Biological Drug” patent boxes on the www.bioprocessintl.com/business/ next two pages), most developers are focusing on only about a dozen regulatory-affairs/turning-point-us- products, many of which have high litigation risks. biosimilars. As of the end of 2015, 41 biosimilars were under development for just four molecules: adalimumab, rituximab, infliximab, and etanercept. Other popular biosimilar candidates include erythropoietin, filgrastim, pegfilgrastim, insulin glargine, trastuzumab, somatropin, and alpha and beta interferons (6). The current choices have been driven mainly by market potential, whereas better choices could be made by considering the litigation risk first — then addressing the difficulty of manufacture and other scientific issues. Another safer strategy is to be the second rather than the first developer to file a biosimilar application for a given biomolecule — while fully anticipating and preparing for possible litigation.
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Activase: alteplase Lantus: insulin glargine Pediarix: DTP, hepatitis B and polio vaccine Avonex: interferon beta-1a Lemtrada: alemtuzumab PEGIntron: peginterferon alfa-2b BeneFIX: nonacog alfa Luveris: lutropin alfa Prevnar: pneumococcal vaccine Betaseron: interferon beta-1b Macugen: pegaptanib sodium Procrit: epoetin alfa Bexxar: tositumomab Natrecor: nesiritide Proleukin: aldesleukin Cerezyme: imiglucerase Neulasta: pegfilgrastim Provenge: sipuleucel-T Epogen: epoetin alfa Neumega: oprelvekin Puregon/Follistim: follitropin beta Fabrazyme: agalsidase beta Neupogen: filgrastim Rebif: interferon beta-1a Genotropin: somatropin Norditropin SimpleXx: somatropin Recothrom: thrombin alfa Gonal-F: follitropin alfa/beta NovoMix 30: insulin aspart ReFacto AF /Xyntha: moroctocog alfa Helixate: octocog alfa NovoRapid: insulin aspart ReoPro: abciximab Humalog: insulin lispro NovoSeven: eptacog alfa Replagal: agalsidase alfa Humatrope: somatropin Nutropin: somatropin Serostim: somatropin Humira: adalimumab Oncaspar: pegaspargase Somavert: pegvisomant Humulin R: insulin (human) Ontak: denileukin diftitox Synagis: palivizumab Increlex: mecasermin [rDNA origin] Orgalutran/Antagon: ganirelix acetate Thyrogen: thyrotropin alfa Insulin Analogs: insulin Orthoclone OKT-3: muromonab-CD3 Kogenate: octocog alfa Ovidrel: choriogonadotropin alfa
Regulatory Compliance FDA guidance on biosimilars (7) has been slow in coming, but the agency has been forthcoming in providing specific guidance in meetings related to biological product deviations (BPDs). However, a lack of developer understanding regarding FDA expectations remains the single largest cause of delays in the market approval of biosimilars. According to the statute, a 351(k) application must include analytical similarity, animal toxicology, pharmacokinetics/pharmacodynamics (PK/PD), and immunogenicity testing. Any “clinically meaningful” differences could require clinical studies. That simple statement has been misunderstood greatly by most developers, both small and large. A clinical study involving patients is not anticipated by the FDA, however, so one is needed only if so determined by the agency. Most developers less experienced with either new or generic drug development fail to understand the nuances of that requirement. For example, the FDA uses “phase 1,” “phase 2,” or “phase 3” labels to define the scope and limitations of classical phase-defined trials involving humans — but such terms normally do not apply to clinical studies in biosimilar development. Many biosimilar developers misinterpret their requirements and end up repeating much of the work. Every study conducted in the development of biosimilars has a focus on comparison, and investigations may cease once a product is proven to be biosimilar. So the FDA requires all clinical trials (including early PK/PD studies) to be conducted on at-scale good manufacturing practice (GMP) compliant lots and all analytical testing to be performed in a CFR 21 Part 11 compliant environment. Although human testing protocols are cleared by the FDA, nonclinical testing may be undertaken without consultation with the agency. But many companies have chosen the wrong animal species, the wrong dosing (intended to show toxicity), and incorrect protocols — only to end up repeating those studies to get them right. The focus 7 BioProcess International 16(1)e January 2018 E-Book 68 Biological Drugs Are Coming Off Patent 2018–2024 (Registered name: generic)
Advate: factor VIII (procoagulant) Ilaris: canakinumab Prochymal: remestemcel-L Afrezza®: insulin (human) Imvamune: smallpox vaccine Prolia: denosumab Aldurazyme: laronidase Intron A: interferon alfa-2b Recombivax HB: hepatitis B vaccine Apidra: insulin glulisine Ixiaro: Japanese encephalitis vaccine Remicade: infliximab Aranesp: darbepoetin alfa Jetrea: ocriplasmin Rituxan: rituximab Arcalyst: rilonacept Kadcyla: ado-trastuzumab emtansine RotaTeq: rotavirus vaccine Avastin: bevacizumab Kalbitor: ecallantide Saxenda: liraglutide [rDNA origin] Benlysta: belimumab Kepivance: palifermin Simponi: golimumab Blincyto: blinatumomab Kineret: anakinra Simulect: basiliximab Botox: onabotulinumtoxinA Levemir: insulin detemir Soliris: eculizumab Cervarix: human papillomavirus (HPV) Lucentis: ranibizumab Stelara: ustekinumab vaccine Mircera: methoxy polyethylene glycol- Tanzeum: albiglutide ChondroCelect: autologous cultured epoetin beta Trulicity: dulaglutide chondrocytes Myalept: metreleptin Tysabri: natalizumab Cimzia: certolizumab pegol Myozyme: alglucosidase alfa V419: DTP, hepatitis B, Hib and polio vaccine Cyramza: ramucirumab Natpara: parathyroid hormone Vectibix: panitumumab Elaprase: idursulfase NovoThirteen: catridecacog Victoza: liraglutide [rDNA origin] Elelyso: taliglucerase alfa Nplate: romiplostim Voraxaze: glucarpidase Elonva: corifollitropin alfa Nulojix: belatacept Vpriv: velaglucerase alfa Entyvio: vedolizumab Obizur: susoctocog alfa Xgeva: denosumab Erbitux: cetuximab Orencia SC: abatacept Xolair: omalizumab Forteo: teriparatide Orencia: abatacept Yervoy: ipilimumabZaltrap: Ziv-aflibercept Herceptin: trastuzumab Pegasys: peginterferon alfa-2a Zevalin: ibritumomab tiuxet of nonclinical studies is to demonstrate noninferiority at a dose level that is intended to show toxicity. Such studies are not conducted by an If a product is said to have originator, so there is little to refer to when designing them. The FDA “no clinically meaningful cannot help because there is no basis to support one protocol over difference,” then WHAT another. The solution is to engage statisticians and experts in ADDITIONAL pharmacology to assure that a protocol meets the requirement toward VALIDITY can be demonstrating noninferiority. achieved in the studies Whereas biosimilar developers need to improve their understanding intended to establish an and implementation of the FDA guidance, the agency needs to revisit interchangeable status? existing guidances that are logically and scientifically challenged. Establishment of biosimilarity comes when the FDA concludes that no clinically meaningful differences exist between a biosimilar candidate and a reference-listed drug (RLD) when developing under 505(b)(2)) or reference product (RP) when developing under 311(k)). However, if you are seeking interchangeability status, biosimilarity is not enough. The statute for this requires a study in patients during which switching and alternating with the reference product produces no lesser efficacy and no higher side effects. But if a product is said to have “no clinically meaningful difference,” then what additional validity can be achieved through studies intended to establish an interchangeable status? In fact, this requirement could be said to contradict our confidence in the safety and efficacy of a product. Therefore, the protocols for establishing interchangeability contradict the FDA’s position on clinical testing of biosimilars in the first place. Back to Contents The roots of this caution lie in the statutory declaration in CRF 320.25 (a) that “no unnecessary human research should be done.” When
8 BioProcess International 16(1)e January 2018 E-Book that statute was established for bioequivalence testing of chemical drugs, the prospect of highly potent biosimilar antibodies was not envisioned. The aim of FDA Today, the declaration applies more accurately to biosimilars because we biosimilar guidance have developed highly potent and immunogenic products for which should be to eliminate the testing in humans can be more risky. In addition, we now face a new need for studies involving conundrum in which it has become more difficult to find patient patients wherever an populations for drug testing (8). That also causes delays and escalates ALTERNATIVE costs of biosimilar development. The aim of FDA biosimilar guidance method of demonstrating should be to eliminate the need for studies involving patients wherever similarity is available. an alternative method of demonstrating similarity is available. “Fingerprint-like” characterization is least likely to invoke any need for studies involving patients as long as there is no need to categorize a biosimilar as interchangeable.
Analytical Similarity Testing Another area of difficulty in complying with the FDA guidance is in the statistical modeling of analytical similarity testing, the most critical part of 351(k) submissions. A developer identifies critical quality attributes (CQAs) and tests them on a tier 1, tier 2, or tier 3 level, depending on the nature of data output and the importance of an attribute to safety and efficacy of a biosimilar product. For CQAs in Tier 1, we test for equivalence by the following interval (null) hypothesis: σ H0:μT − μR ≤ −∂ or μT − μR ≥ where ∂ > 0 is the equivalence limit (or similarity margin), and μT and
μR are the mean responses of the test (the proposed biosimilar) product and the reference product lots, respectively. Analytical equivalence (similarity) is concluded if the null hypothesis of nonequivalence (dissimilarity) is rejected. The FDA further recommended that the equivalence acceptance σ σ criterion (EAC) — ∂ = EAC = 1.5 * R, where R is the variability of the reference product — be used based on extensive simulation studies and internal scientific input. A statistical justification for the factor 1.5 (9) follows the idea of a scaled average bioequivalence (SABE) criterion for highly variable drug products proposed by the agency. To achieve a desired power of the similarity test, the FDA further recommends that an appropriate sample size be selected by evaluating the power under the σ alternative hypothesis at μT − μR = ⅛ R. These assumptions are debatable: that μ − μ is proportional to σ , T R σR the selection of c = 1.5, and the allowed mean shift of μT − μR = ⅛ R. They already have generated much discussion among FDA, biosimilar sponsors, and academia. Here is one situation that confounds the tier 1 σ treatment of CQAs: What if R is closer to zero, but μT is not? The test would fail inevitably in that case, without any relevance to being clinically meaningful. If the attribute is protein content, the release criteria allow for variability, yet a much smaller variability will cause the test to fail. For CQAs in Tier 2, the FDA suggests that analytical similarity be σ σ performed based on the concept of quality ranges: ± x * R, where R is the standard deviation of the reference product and x is a constant that 9 BioProcess International 16(1)e January 2018 E-Book should be appropriately justified. Thus, the quality range of the reference σ σ product for a specific quality attribute is defined as (μR− x R, μR + x R). The analytical similarity will be accepted for a quality attribute if a sufficiently large percentage of test-lot values falls within the quality range. Under the normality assumption, we would expect in practice that ~95% of data would fall below and above 2 (x = 2) standard deviations (SD) of the mean, and ~99.7% of data would fall within ±3 SD (x = 3) Back to Contents of the mean. Under the normality assumption, the FDA-recommended quality range approach is considered to be reasonable only under the σ σ assumption that μT ≈ μR and T ≈ R. In this case, it could be expected that a majority of test-lot values would fall within ±x SD of the range established based on reference-lot test values. Although debate is ongoing regarding the chosen value of x, a product with a more desirable range of a CQA such as aggregation will fail a tier 2 test because it is not a noninferiority test. A biosimilar product with better CQAs should be rewarded rather than punished for that (10). A great deal of scientific discussion is required when submitting analytical similarity data to FDA. Developers and the agency both are learning With a new molecule, you how to bring a true scientific justification to satisfy the FDA mantra of work with whatever you “no clinically meaningful difference.” have to prove its safety Cost-Effective Approaches: The legal requirements of approval and efficacy; in the case pathways, together with the costly biomanufacturing processes, escalate of biosimilars, you need developing costs for biosimilars to as much as $75–250 million per to replicate a innovator’s molecule (11). Although it generally is believed that the price of molecule, even if a feature biosimilars will remain within 60–70% of their originators and allow for is not CLINICALLY large profit margins, the high cost of development makes entry prospects RELEVANT. poor so far. Fortunately, many things can be done to achieve a cost- effective approach.
A Development Master Plan Biosimilar development requires a deep understanding of a chosen molecule to replicate all imitations of its reference product. With a new therapeutic candidate, you work with whatever you have to prove its safety and efficacy; in the case of biosimilars, you need to replicate a innovator’s molecule even if a feature has not shown itself to be clinically relevant. Such scientific constraints are addressed more effectively when a developer begins with a comprehensive master plan. Related expertise is difficult to find because the current pool of experts in the industry either have experience in the generic drug industry or in development of new biological entities - neither of which have anything in common with what is required to write a biosimilar development master plan. Here are a few pieces of advice. Make the best use of FDA advisory committee meeting minutes. These represent a goldmine of information and advice. Instead of relying on freedom of information (FoI) requests, you can read between Back to Contents the lines to determine which approval documents are associated with a given posting. Craft BPD meetings with the agency to clarify uncertainties for finalizing your testing protocols. You no longer need to ask the FDA 10 BioProcess International 16(1)e January 2018 E-Book how to conduct analytical similarity testing; you should know that already. The goal of a Type 2 meeting is to come out ready for a Type 3 meeting, not to go back for another Type 2 (as most developers have done recently). Create a realistic timeline. This must come first because a timeline determines the “cost line.” Plan to perform as few human studies as possible to support commercialization of your product. Address the unique requirements of biosimilars. All testing must use at-scale lots in a GMP environment and be performed in CFR21 Part 11–compliant laboratories. No mandatory patient trial is anticipated to establish product safety and efficacy. Plan for early FDA inspection. The FDA guidance on GMP for investigational drugs (12) is interpreted differently for biosimilars. The agency can audit your facility for full GMP compliance in response to Back to Contents an investigational new drug (IND) filing, an aspect that many new biosimilar developers fail to realize.
Outsourcing A decade ago, there was a dearth of qualified contract research and manufacturing organizations (CROs, CMOs) that could boast the required expertise in manufacturing and testing to conduct necessary studies for development of biosimilars. That is no longer the case. Now a biosimilar developer can find dozens of qualified sources to engage in shortening the timeline to complete product development. Unlike the development of new molecules for testing, biosimilars require an upfront investment in a facility capable of at-scale GMP production and CFR21 Part 11–compliant testing, both of which add substantial costs that can inhibit smaller business entities from entering the market. Given the increased availability of outsourcing options, I believe that it is no longer necessary to create a fully integrated facility to produce biosimilars. Regardless of the size of facility, every integrated facility has capacity limitations that can be obviated by outsourcing the supply chain. Currently practiced by Karyo Biologics, this model opens up the possibility for many companies to take on the roles of biosimilar developers and marketers if they are able to engage qualified planning teams.
Biosimilars in 2018 and Beyond In my first book on biosimilars (13), I made several predictions that were highly criticized at the time. Later I wrote more books on the topic and remain convinced of my prediction that sooner or later, biosimilars will become generic biologics. But how long that takes will depend more on payers than prescribers, as we have begun to note happening in Europe and the United States. The FDA always has led in the realm of scientific proof, having established biosimilar approvals long before the BPCIA came into being. As the agency becomes more confident of the safety of biosimilars, and once speculation on this subject is no longer necessary, then I anticipate faster biosimilar approvals given the long history of their use in Europe and elsewhere. But that can happen only if sponsors improve 11 BioProcess International 16(1)e January 2018 E-Book their practices in development as discussed above. With much of the Back to Contents litigation questions taken care of through Supreme Court rulings, I foresee FDA approvals rising gradually over the next five years as new entrants to the field become successful on the market. I also foresee a substantial drop in the price of biosimilars: With decreased cost of goods (CoG), there is no reason why prices cannot be lowered from what they are currently. I can foresee competition in the market decreasing prices to <50% of the originator price, a level at which originators will start to exit the biosimilars market. And that will bring a major change to development opportunities available. I also anticipate that originators will change their products — such as by introducing higher-concentration formulations — and thereby protect them through IP to prevent them from being used as reference standards. New indications for many products will create a problem for biosimilar developers, who themselves eventually will need to extrapolate to new indications. But then, clinicians will have the freedom to prescribe these drugs, and I do not expect that strategy to slow down the market penetration of biosimilars. The first eight years since implementation of the BPCIA have brought slow progress, but we all have learned a great deal. As more developers and regulators work to speed biosimilar approvals, the industry will benefit from greater confidence in the future of these important products.
References 1 HR 3590. Title VII: Improving Access to Innovative Medical Therapies, Subtitle A - Biologics Price Competition and Innovation. Patient Protection and Affordable Care Act. 111th United States Congress: Washington, DC, 2010: 686–703; www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ ucm216146.pdf. 2 Drugs: Biosimilars. US Food and Drug Administration: Rockville, MD, 2017; www. fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm. 3 European Medicines Agency: London, UK; www.ema.europa.eu. 4 Stewart K. Approved and Pending Biosimilar Applications from Status of Biosimilar Applications. Mintz Levin Health Law & Policy Matters (blog) August 2016; www.healthlawpolicymatters.com/wp-content/uploads/sites/8/2016/08/Status-of- Biosimilar-Applications-August-2016.pdf. 5 Sandoz Inc. v Amgen Inc. United States Supreme Court, 2016; www. supremecourt.gov/opinions/16pdf/15-1039_1b8e.pdf. Back to Contents 6 Keshavan M. IMS Infographic: How Many Biosimilars Are in the Pipeline? MedCityNews. 29 March 2016; www.medcitynews.com/2016/03/ims-report-what- biosimilars-are-in-the-pipeline. 7 CDER/CBER. Considerations in Demonstrating Interchangeability with a Reference Product: Guidance for Industry (Draft Guidance). US Food and Drug Administration: Rockville, MD, January 2017; www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf. 8 Kolata G. A Cancer Conundrum: Too Many Drug Trials, Too Few Patients. The New York Times 12 August 2017; www.nytimes.com/2017/08/12/health/cancer- drug-trials-encounter-a-problem-too-few-patients.html?_r=0. 9 Chow S-C, Song F, Bai H. Analytical Similarity Assessment in Biosimilar Studies. AAPS J. 18(3) 2016: 670–677; doi:10.1208/s12248-016-9882-5. 12 BioProcess International 16(1)e January 2018 E-Book 10 Liao JJ, Darken PF. Comparability of Critical Quality Attributes for Back to Contents Establishing Biosimilarity. Stat. Med. 32(3) 2013: 462–469; doi:10.1002/sim.5564. 11 Biosimilar. Wikipedia; www.wikipedia.org/wiki/Biosimilar#cite_note- biosimilars-288. 12 CDER/CBER. Guidance for Industry: CGMP for Phase 1 Investigational Drugs. US Food and Drug Administration: Rockville, MD, July 2008; www.fda.gov/ downloads/drugs/guidances/ucm070273.pdf. 13 Niazi SK. Handbook of Biogeneric Therapeutic Proteins: Regulatory, Manufacturing, Testing, and Patent Issues. CRC Press: Boca Raton, FL, 2002. c
About the Author Sarfaraz K. Niazi, PhD, SI, FRSB, FPAMS, FACB, is the founder of Karyo Biologics, LLC and an adjunct professor at the University of Illinois; and patent agent for the USPTO. He has over two decades of hands-on experience in developing and taking biosimilars to market around the world, particularly in the United States. He has written about biosimilars, bioprocessing, pharmaceutical formulations, and regulatory management and is the most prolific solo inventor of bioprocessing technology. www.niazi.com; [email protected]; 1-312-297-0000.
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