Fda biosimilar guidelines review


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Fda biosimilar guidelines review

  1. 1. FOCUS ON... the regsLooking at the RecentFDA Biosimilar GuidelinesImmunogenicity Concerns andExtension to Other Classes of Drugsby Vera WeinsteinS mall-molecule treatments are (www.photos.com) invaluable in providing symptomatic benefits for an array of illnesses. However,many serious conditions — rangingfrom cancer to autoimmune disorders— respond better to moresophisticated complex drugs such astherapeutic biologics and nonbiologiccomplex drugs (NBCDs). The latterare medicinal, nonbiological productsin which the active substance is not ahomomolecular structure, but ratherconsists of a number of different(closely related) structures that cannotbe fully characterized. The US Foodand Drug Administration (FDA)defines a therapeutic biologic as “aprotein derived from living material(such as cells or tissues) used to treat outlining necessary steps for for biosimilars two years ago, whenor cure disease” (1). submitting biosimilar drug President Barack Obama signed the Until recently, pharmaceutical applications. The agency’s attention to Patient Protection and Affordablecompanies in the United States had detail came about as a result of past Care Act (PPAC Act) into law on 23no procedure to follow when issues seen with complex therapies March 2010, amending the Publicsubmitting applications for “generic” such as interferons, which produced Health Service Act (PHS Act) .Theor follow-on versions of biologic drugs immunogenicity issues (neutralizing relevant statutory provisions are also(now called biosimilars). And still, no antibodies) in multiple sclerosis (MS) referred to as the Biologics Priceclear guidelines are available for patients (2). The guidelines address Competition and Innovation ActNBCDs. Despite expiring patents on issues often associated with complex (BPCI Act) of 2009 (3). Similar to thebiologics, this was a complicated issue products — such as immunogenicity Hatch–Waxman Act, which definedbecause even slight changes in protein concerns — by defining specific safety an approval pathway for small-structure (such as small differences in and efficacy testing requirements that molecule generics, the BPCI Act wasamino-acid sequence) could cause will be expected with submissions. aimed at a parallel objective forserious side effects (e.g., immunogenic biosimilars.reactions) in patients. Pathway to a Biosimilar Guidance In one recently released draft On 9 February 2012, the FDA The FDA began its process of guidance, the FDA defines biosimilarsreleased three draft guidelines developing regulatory requirements or biosimilarity as “highly similar to10 BioProcess International 10(6) J une 2012
  2. 2. the reference product, notwithstanding Alliance Urges a Cautious Approach for Patient Safetyminor differences in clinically inactive In response to the US Food and Drug when it comes to the requirement ofcomponents . . . and there are no Administration’s (FDA) draft guidance on clinical studies and pharmacovigilance.clinically meaningful differences approving biosimilar medicines, the There can be no grey area when it comesbetween the biological product and the Alliance for Safe Biologic Medicines to patient safety.reference product in terms of the (ASBM, www.safebiologics.org) “Unwanted immunogenicity is thesafety, purity, and potency of the submitted comments to the agency in preeminent safety challenge associatedproduct” (4). The FDA notes the April 2012 outlining recommendations with biological therapeutics and canimportance of ensuring similarity for ensuring that patient safety is at the result in unexpected or sometimesbetween a reference product and a forefront of the biosimilars pathway. severe adverse effects. The predictive ASBM states that effective value of animal studies is oftenbiosimilar by taking into account the implementation must incorporate insufficient to characterize“structure, function, animal toxicity, prudent measures, includingand human pharmacokinetics and immunogenicity in humans. Clinical • analytical data and clinical studies to studies, in addition to analyticalpharmacodynamics” of the reference fully characterize biosimilarity and methods, are necessary to weed outproduct (4). Additionally, “the nature immunogenicity ineffective and unsafe drugs —and complexity of the reference innovator biologics and biosimilars — • traceability measures including uniqueproduct will be considered along with before they are ever a risk to patients. nonproprietary names for all biologicthe degree of characterization of the therapies, transparent product labels, “In the unfortunate situation thatmechanism of action (MOA) of the and notification to patients and problems arise, measures must be inreference product, the extent to which physicians for clinical assessment and place to accurately and promptly connectpharmacokinetic and adverse event reporting. a specific patient to a specific product.pharmacodynamic tests predict clinical Before designating a biosimilar to be Our current pharmacovigilance system isoutcomes, the extent of clinical “interchangeable” with its reference not equipped to distinguish a biologicexperience and appropriate endpoints product, ASBM says, US regulators must reference product from its biosimilars.and biomarkers, and the extent of any recognize and address that the similarity Unique nonproprietary names forclinical experience with the proposed between reference and biolosimilar biosimilar and innovator compoundsproduct” (4). products may change over time due to ensure we will be able to effectively track manufacturing or environmental and trace a product to an adverse event. Similar criteria are seen in the variations. This must be implemented prior toEuropean Union’s regulatory pathway biosimilar market entry.for biosimilars, which was released by The organization outlined clear, concrete, and achievable ways to manage risk and The Alliance for Safe Biologic Medicinesthe European Medicines Agency thereby prioritize patient safety. Richard (ASBM) is an organization composed of(EMA) in 2005. In Europe, diverse healthcare groups andcompanies submitting applications for Dolinar (ASBM chair) released the following statement as he submitted the individuals from patients to physicians,biosimilars must show that their innovative medical biotechnology coalition’s comments to the docket:generic products are closely related to companies, and others working togetherreference medicines and do not have “We are pleased with the FDA biosimilar to ensure that patient safety is at the draft guidance, but it leaves a lot ofany meaningful differences in quality, forefront of biosimilar policy discussions. questions unanswered — particularlysafety, or efficacy (5). Additional guidelines are neededfor NBCDs that fall outside the realm of the reference products being generic manufacturers could notof both small molecules and biologics, reproduced. Such highly complex demonstrate that their productsbut the FDA biosimilar guidelines are drugs will require research into the contained the same active ingredient asan important first step in defining specificities of their make-up — e.g., the reference product. Althoughregulatory considerations for ensuring characterizing method of action sodium estrone sulfate and sodiumaffordable patient access to safe and (MoA) — and proper testing needed equilin sulfate were thought to be theeffective therapies. to demonstrate similarity to their only active Premarin ingredients, Because biosimilars are projected to reference products. laboratory and clinical studiesbe a multibillion dollar industry, they suggested that other active ingredientswill have implications for the Expanding the Guidelines could not be identified. In the FDApharmaceutical industry and patients to Other Complex Drugs statement, Center for Drug Evaluationoverall. Integrating affordable Although they are not biological drugs, and Research (CDER) director Janetbiologics into the market will provide NBCDs can be just as complicated to Woodcock stated, “Based on currentlymore patients with access to life- characterize as biologics, warranting available data, there is at this time nosaving drugs, and companies will be the need for their own generic way to assure that synthetic genericcompeting to supply them as soon as guidelines (6). For example, in 1997 the forms of Premarin have the same activepossible. Additional data may need to FDA refused to approve generic ingredients as the brand-name drug.be provided with biosimilar versions of Premarin tablets (an NBCD This is essential for determining theyapplications, depending on the nature used for estrogen replacement) because are equivalent to the brand drug, and is12 BioProcess International 10(6) J une 2012
  3. 3. • 3 Implementation of the Biologics Pricealso a legal requirement for their Competition and Innovation Act of 2009. USapproval” (7). Food and Drug Administration: Rockville, Fortunately, a lot of groundwork for MD, 10 March 2011; www.fda.gov/Drugs/the NBCD guidelines now has been GuidanceComplianceRegulatoryInformation/ All classes of ucm215089.htm.established by the biosimilar pathway 4 CDER. Guidance for Industry: Scientific— including the need for a stepwise complex drugs must Considerations for Demonstrating Biosimilarity toapproach to address immunogenicity be held to at a Reference Product. US Food and Drugissues that can arise with these drugs. Administration: 9 February 2012; www.fda.NBCDs would also need to be least the same gov/downloads/Drugs/GuidanceComplianceevaluated case by case to determine strict standards as RegulatoryInformation/Guidances/ UCM291128.pdf.whether clinical trials are necessary if biosimilars to ensure 5 Guideline on Similar Biological Medicinalinadvertent chemical and physical that the follow-on Products. European Medicines Agency:changes (such as aggregation) can London, UK, 30 October 2005; www.emea.greatly affect their immunogenicity versions are safe for europa.eu/docs/en_GB/document_library/profile. Already, a generic version of patient consumption. Scientific_guideline/2009/09/WC500003517.one NBCD has caused pdf.immunogenicity effects that were seen 6 Immunogenicity of biosimilar Low Molecular Weight Heparins. Generics andonly in longer-term clinical trials. Biosimilars Initiative: Mol, Belgium, 22 April Copaxone injection is an 2011; www.gabionline.net/Biosimilars/glatiramoid-class NBCD therapy for changes to biologics and NBCDs can Research/Immunogenicity-of-biosimilar-low-multiple sclerosis that produces extreme cause for patients. In a 2009 article, molecular-weight-heparins.immunogenicity effects when altered. It Eva-Maria Jahn of the University of 7 CDER. FDA Statement on Genericis a safe and efficacious MS drug Duisburg-Essen and Christian Premarin. US Food and Drug Administration: Rockville, MD, 25 June 2009; www.fda.gov/produced by Teva Pharmaceuticals as a Schneider of the Max Planck Institute Drugs/DrugSafety/PostmarketDrugSafetymixture of polypeptide sequences with noted that “as the consequences of InformationforPatientsandProviders/immunomodulating activity. Teva such immune reactions to a bio- DrugSafetyInformationforHeathcarepursued development of a follow-on therapeutic drug may lead to Professionals/PublicHealthAdvisories/glatiramoid (Protiramer) by introducing potentially serious side effects and/or ucm169045.htm.slight changes to the Copaxone loss of efficacy, it is essential to adopt 8 Data on File. Teva Neuroscience, Inc.: Petach Tikva, Israel.downstream synthesis procedure. an appropriate strategy for the 9 Jahn E, Schneider C. How toDespite similarity in the basic assessment of immunogenicity that Systematically Evaluate Immunogenicity ofpolypeptide characteristics, and involves assay development, and Therapeutic Proteins: Regulatoryalthough Teva did not initially detect bridging of results to and from clinical 280–286. • Considerations. New Biotechnol. 25(5) 2009:those in short-term preclinical testing, development from early on” (9).chronic Protiramer treatment in animal Immunogenicity is clearly antrials over time led to a number of important component for Vera Weinstein, PhD, is director ofsevere side effects: systemic toxicity, consideration, and all complex drug scientific affairs, CMC Israel, and Europeextensive fibrosis, organ damage, and applications should be assessed case by GBP R&D at Teva Pharmaceuticals,eosinophilia. Those results were case. All classes of complex drugs 5 Basel Street, Petach Tikva, 49131 Israel;drastically different from what was seen must be held to at least the same strict 972-3-9267267, fax 972-3-9234050;with the original drug, which has over standards as biosimilars to ensure that vera.weinstein@teva.co.il.one million patient years of success (8). the follow-on versions are safe forNo tests exist that can characterize and patient consumption. By formingquantitate the active ingredients of regulatory pathways based on a To order reprints of this article, contactglatiramer (the drug’s generic name). totality-of-the-evidence approach for Rhonda Brown (rhondab@fosterprinting.com) 1-800-382-0808. Download a low-resolutionBecause of that — and Teva’s inability highly complex drugs, the FDA and PDF online at www.bioprocessintl.com.to characterize the product’s MoA — EMA will ensure that patients getcreating a safe and effective follow-on access to the best care possible whileversion could prove to be extremely continuing to ensure that safetydifficult. A lack of similarity in remains a top priority.complex drugs can lead to severeconsequences, evident only when tested Referencesin long-term nonclinical or adequate 1 Drugs@FDA Glossary of Terms. US Food and Drug Administration: Rockville, MD, 2clinical trials. February 2012; www.fda.gov/Drugs/ informationondrugs/ucm079436.htm.Safety Cannot Be Compromised 2 Immunogenicity of Therapeutic BiologicalThe above examples illustrate Products, Volume 112. Brown F, Mire-Sluissignificant consequences that minor AR, Eds. S Karger: Basel, Switzerland, April 2003: 3–11.14 BioProcess International 10(6) J une 2012