hot topic post-marketing surveillance and observational
TRANSCRIPT
01 HOT TOPIC Post-Marketing Surveillanceand Observational Prospective Cohort Studies
03 REGULATORYFRAMEWORK UPDATE
04 BIOSIMILARSAPPLICATIONS Approved & Under Review
HOT TOPICPost-Marketing Surveillance and Observational Prospective Cohort Studiesby Agnes RivailleScientific Affairs Director, Late Phase Services
A lthough referenc -controlled clinical trials are usually re-quired to demonstrate clin-
ical comparability of quality, efficacy and safety, biosimilars—due to their differences in term of manufactur-ing—may have rare characteristics different to originator reference prod-ucts that cannot be detected through pre-market testing (in particular, safe-ty risks like immunogenicity).
Even if extensive Phase III clinical trials are performed, the study popula-tion is too small to allow the detection of rare side effects. If this limitation is
valid for the indication explored, it is even more applicable when extrapo-lation to other indications is allowed.
For these reasons, manufacturers of biosimilars must have adequate post-marketing surveillance mechanisms in place to detect possible differenc-es between reference and biosimilar products and to compare the frequen-cy and severity of known side effects of the reference product with any differences or new side effects not yet observed with the reference product.In terms of post-marketing safety and risk management requirements, there
are no significant differences be-tween FDA (Food and Drug Admin-istration) and EMA (European Med-icines Agency) recommendations. As part of risk assessment, Marketing Authorization can be granted subject to the condition to conduct post-au-thorization safety study (PASS) and/or Drug Utilization Study (DUS). The aim of a PASS is to identify, charac-terize or quantify a safety hazard or to confirm the safety profile of the med-icine whereas DUS aim is to describe how an authorized medicinal product is prescribed and used in routine clin-ical practice.
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B I O S I M I L A R S N E W S L E T T E RVolume 3 , Ju ly 2014
Welcome
Welcome to the third edition of Biosimilars Newsletter, a quarterly publication dedicat-ed to keeping you updated on current biosimilars news, including the global regulatory landscape, biosimilars articles and reports and company news as reported by the com-pany press releases. The “hot topic” for this edition focuses on the essential role which pharmacovigilance plays in the development of a biosimilar product and in particular the need for strategic planning of post-marketing surveillance activities and the role of observational pro-spective cohort studies.
INSIDE THIS ISSUE:
01. Biosimilars Newsletter
Welcome
Hot Topic
03. Regulatory Framework Update
Europe
United States
04. Regulatory Framework Update
Rest of World
04. Approved & Under ReviewEuropeUnited StatesRest of World
04. Regulatory Meetings
05. Articles & Reports of Interest
06. Company News
06. Next Edition
02
Prospective PASS studies are frequently observational per design as they present an opportunity to evaluate the performance of a biosimilar over an extended period in a diverse group of patients. “Observational,” “non-inter-ventional,” “real-world” or “real-life project” are terms frequently used to refer to research where no interventions are carried out including treatments where assignments are up to patients and their physicians and the investigator sim-ply observes and reports existing data according to routine practice.
Among the different types of observational methods, prospective cohort studies are considered as the best method for PASS for producing valuable long-term data and determining the incidence of events. In addition to safety parameters, the PASS studies can also gather information on patients’ characteristics, effectiveness outcomes, pattern of utilization (indication, dose, physician knowledge and reason of choice) or measure the effectiveness of the risk management measures.
For PASS designed with single, double or multiple cohorts, a group of people treat-ed with each treatment of interest is observed over a period of time to see wheth-er they develop adverse events (AEs). For biosimilars AEs in all system organ classes are collected as required; for example, by European Union (EU) pharma-covigilance guidelines. In case of a single cohort, the people who do not develop the outcome of interest are used as internal controls. When two cohorts are used, the group not exposed to the treatment of interest is acting as an external control. If, however, cohort studies have the advantage to examine various outcome vari-ables, they have some inherent limitations. Cohorts permit calculation of relative risk, but any element that could affect the considered outcome (e.g., a study pop-ulation, rare condition or loss of follow-up for long term evaluation) can impact the conclusion. Similarly when a third factor (confounding variable) is associated to exposure, it could also affect the outcome and mix or blur the relation.
The results and findings of a prospective observational PASS depend on the rig-or with which it is conducted. Since the main objective is to guarantee patient protection and data quality, the following key components have to be ensured:
• Study Protocol: study purpose has to be clearly stated and structured and content needs to be aligned with recent guidelines (i.e., the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance [ENCePP]).
• Study Population: the source of the sample should be defined to optimize the represenativity of the study sample vs. the general population and ensure that each subject has the potential to develop outcomes. This process can include:– A random selection of participating physicians among prescribers of treat-ment(s) of interest to involve a variety of practice types– A streamlined approach in exclusion and inclusion criteria – An exposure definition integrating the specificity of biosimilars (INN, owner and batch number)– A consecutive enrollment of patients as soon they are seen and their consent is obtained
• Study Measurements and Outcomes: for avoiding missing confounding factors, a comprehensive review of the natural history of the disease and epidemiology is critical in order to define that all (and only relevant) infor-mation is collected. The limiting factors are: – Information about outcomes have to be obtained in the same way across sites and also for subjects exposed or not exposed to the treatment of in-terest– Measurement (clinical, patient reported outcomes) have to be regarded as valid by regulatory authorities and the scientific community– Variables studied have to be available according to routine practice, accu-rately evaluated and reported
• Data Completeness and Validity: missing data due to unreported informa-tion or loss of follow-up can significantly affect the validity of the results. For this reason it is critical: – To optimize site motivation with efficient support and attractive recognition and communication strategy– To minimize loss of follow-up with an appropriate strategy going from a simple reminder to a direct-patient contact – To monitor study progress based on initial risk assessment of the study with an on-going review of risk indicators associated with a robust escala-tion strategy
It is clear that gaining approval for biosimilars is not easy, but as biologic drug patents continue to expire, more biosimilars will be developed. Com-mitments for additional information on safety and product utilization based on real-world research will increase and the execution of observational PASS with a valid methodology will become part of the life cycle of biosimilars.
BIOSIMILARS NEWSLETTER | Volume 3, July 2014
Links to Further Information on PASS and Observational Studies
Guidance for Industry Postmarketing Studies and Clinical Trials-Implementation of Section 505(o)(3) of the Federal Food, Drug and Cosmetic Act | http://www.fda.gov
Post-Authorization Safety Studies (PASS) | http://www.ema.europa.eu
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance | http://www.encepp.eu/
Prospective Observational Studies to Assess Comparative Effectiveness: ISPOR Good Research Practices Task Force Re-port—Draft | http://www.ispor.org/
Registries for Evaluating Patient Outcomes: A User’s Guide Third Edition | http://www.ncbi.nlm.nih.gov
• Population includespeople typically excludedfrom RCTs
• Many outcomes
• Value for investigating casual relationships: Incidence, relative risk,temporality
• Duration and cost (but morecost-effective than RCT)
• Treatment to be used in care settings
• Risk of bias related to selection or loss-to-follow-up
• Confounding variables
PROSPECTIVE COHORT
STRENGTHS WEAKNESSES
EXPOSURE OUTCOME
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The EMA releases second draft revision on the guideline on recombinant human insulin and insulin analogues biosimilars.
Uhe EMA has released a second draft revision of the guidelines on non-clinical and clinical requirements for recombinant insulin-con-
taining biosimilars, EMEA/CHMP/BMWP/32775/2005_rev. 2. (end of con-sultation 31 July 2014).
The second revision includes—among other changes—extended sections on pharmacokinetic (PK) and pharmacodynamics (PD) that detail the different endpoints for short-, intermediate- and long-acting products.
With regard to clinical safety the revision states that safety studies should gener-
ally focus on immunogenicity; however, “There is no need to power the study to formally demonstrate non-inferiority regarding immunogenicity.”
Clarity is also provided on extrapolation of indications (e.g., from subcuta-neous to intravenous use and to other indications and patient populations licensed for the reference product).
Link to biosimilars insulin guideline http://www.ema.europa.eu/downloads
The FDA Looks to Close Loophole That Could Delay Approval of Biosimilars
U S regulators have indicated that they are moving to close a regu-
latory loophole identified by legislators in 2012 that could prevent a biosimilar product from obtaining timely approval.
In 2012, the Food and Drug Admin-istration Safety and Innovation Act (FDASIA) was passed into law. Sec-tion 1135 of the law directed the FDA to amend Section 505(q) of the FD&C Act to include an additional drug filing application: the 351(k) filing, otherwise known as the biosimilar application.
The section is intended to make sure biosimilar applications cannot be de-layed by unnecessary citizen petition filing, most likely by rival companies; however, given the inherent differ-ences between biologics and biosimi-lar products, companies will likely not be lacking for "valid scientific or reg-ulatory issues" to put a competitor's filing on hold. On 10 March 2014, the
As reported previously in Edition 2 (April) of PRA Health Sciences’ Bio-similars Newsletter, this draft guid-ance is one in a number of planned biosimilars guidance documents due to be released by the FDA in 2014.
The draft guidance pertains to those products - such as therapeutic biolog-ical products - for which pharmacoki-netic (PK) and pharmacodynamic (PD) data are required as part of a stepwise approach to developing the data and information necessary to support a demonstration of biosimilarity. The guidance discusses some of the overar-ching concepts related to clinical phar-macology testing for biosimilar prod-ucts, approaches for developing the appropriate clinical pharmacology da-tabase and the utility of modelling and simulation for designing clinical trials.
The agency also says that clinical pharmacology studies are normally a critical part of demonstrating biosim-ilarity by supporting a demonstration that there are no clinically meaningful differences between the proposed bio-similar and the reference product.The draft guidance states the useful-
FDA issued a Federal Register notice indicating that it is seeking Office of Management and Budget (OMB) ap-proval to amend its practices to pre-vent companies from unnecessarily delaying biosimilar applications.
Noting that it already has OMB ap-proval to collect information on Citi-zen Petitions, FDA's latest submission to OMB updates its procedures to in-clude 351(k) filings.
Link to Federal Register Notice 11 Mar 2014https://www.federalregister.gov/
The FDA issues new Guidance for Industry Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
T he FDA has issued new draft guidance for biosimilars (released
May 2014), which explains how to use clinical pharmacology data to show biosimilarity to a reference product.
ness of comparing the quality attri-butes of the proposed biosimilar prod-uct with those of the reference product with the results of comparative analyt-ical characterization leading to one of four assessments—not similar, similar, highly similar and highly similar with fingerprint-like similarity
The use of specific assays and analyt-ical methods and the design of phar-macological studies are explained at length in the guidance. In conclusion the FDA states that clinical pharma-cology studies are part of a stepwise process for demonstrating biosimi-larity between a proposed biosimilar product and the reference product and add to the totality of the evidence to support an overall demonstration of biosimilarity between the proposed biosimilar product and the reference product through the demonstration of no clinically meaningful differences.
Link to guidance documenthttp://www.fda.gov/downloads
Regulatory Framework Updates Europe The EMA issues a revised version of biosimilars quality guideline
The EMA has published the new version of its biosimilars quality guide-line EMA/CHMP/BWP/247713/2012 (Guideline on similar biological
medicinal products containing biotechnology-derived proteins as active sub-stance: quality issues (revision 1))
The guideline addresses the requirements regarding manufacturing processes, the biosimilar comparability exercise for quality, considering the choice of ref-erence biological, analytical methods, physicochemical characterization, bio-logical activity, purity and quality attributes for relevant specifications of the biosimilars and will come into effect on the 1st December 2014.
As previously reported the EMA is also in the process of revising two other overarching guidelines for biosimilars: · EMEA/CHMP/BMWP/42832/2005 Rev. 1: Guideline on similar biological me-dicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues· CHMP/437/04 Rev 1: Draft guideline on similar biological medicinal products
Link to biosimilars quality guideline http://www.ema.europa.eu/docs
Regulatory Framework Updates United States
BIOSIMILARS NEWSLETTER | Volume 3, July 2014
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Switzerland’s medicines agency, Swissmedic, has updated their Q&A document on the authorization of similar biological medicinal products (biosimilars) (10 Mar 2014). The Agency claims that it is following the example of
the EMA in requiring a Swiss or EU reference product for pivotal trials. Swissmedic claims it will accept comparative bridging studies to justify the use of a reference product authorized in the EU reference product but reference prod-ucts sourced from Japan and the US can only be used for supportive—rather than pivotal—studies.
The CHMP has recommended approval of a biosimilar version of insulin glargine (Abasria, Eli Lilly/Boehringer Ingelheim) for the treatment of type 1 or type 2 diabetes in adults and children as young as two years of age.
Abasria is the first biosimilar insulin to be recommended for marketing authorization in the European Union. Link to EMA news site dated 27 Jun 2014http://www.ema.europa.eu
Regulatory Framework Updates Rest of World Swissmedic accepts bridging to EU drug.
Link to Q&A documenthttps://www.swissmedic.ch/
Biosimilars Applications Approved & Under ReviewEurope
The European Committee for Medicinal Products for Human Use (CHMP) Recommends First Biosimilar Insulin
US / Rest of World
None reported
Regulatory MeetingsEurope/US/Rest of World
None reported
BIOSIMILARS NEWSLETTER | Volume 3, July 2014
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particular interest given its recent ap-proval for Remsima™ and Inflectra™ to a limited extrapolation to a subset of the indications held by the refer-ence product, Remicade®. Product interchangeability and post-market surveillance are also discuss.
Click here to read/locate the article http://onlinelibrary.wiley.com
Biosimilars in oncology: from development toclinical practice.
Tkaczuk KH, Jacobs IA.: Semin Oncol. 2014 Apr;41 Suppl 3:S3-S12
This review highlights critical factors involved with the inte-
gration of biosimilars into oncology treatment paradigms and practices. Topics covered include—among oth-ers—a review of the evolving regula-tory framework that provides guid-ance for development and approval of biosimilars and the potential role of scientific societies in providing help to clinicians, payers and providers in understanding key data relating to biosimilars. The importance of con-tinued education of physicians and other healthcare providers, payers and patients about biosimilars is also addressed.
Click here to read/locate the article http://www.ncbi.nlm.nih.gov/
Alternative statisticalstrategies for biosimilar drug development.
Combest AJ et al; GaBI Issue 1: 13-19, Volume 3 Year (2014)
This paper reports the outcome of the use of alternate statistical
approaches to practical case studies of bevacizumab, adalimumab and rituximab biosimilars to test wheth-er it is possible to reduce the sample
The challenge of indication extrapolation for infliximab biosimilars.
Feagan BG et al.; Bio-logicals. 2014 Jun 21. pii: S1045-1056(14)00045-1. doi: 10.1016/j.biologi-cals.2014.05.005. [Epub ahead of print]
This paper addresses the critical question, “Can clinical stud-
ies that satisfy concerns regarding safety and efficacy in one condition support ‘indication extrapolation’ to other conditions?” The authors re-view the factors to consider when evaluating indication extrapolation for biosimilars with a special focus on the biosimilar infliximab which was approved recently in South Korea, Europe, and Canada for multiple in-dications through extrapolation.
Click here to read/locate the article http://www.sciencedirect.com
Biosimilar monoclonal antibodies: A Canadian regulatory perspective on the assessment of clinically relevant differences and indication extrapolation.
Scott BJ, Klein AV and Wang J :J Clin Pharmacol. 2014 Jun 26. doi: 10.1002/jcph.339. [Epub ahead of print]
The purpose of this review is to discuss the Canadian regulatory
framework for the authorization of biosimilar mAbs with specific discus-sion around the clinical requirements for establishing (bio)-similarity and to present the principles that are used in the clinical assessment of New Drug Submissions for intended biosimilar monoclonal antibodies. Health Can-ada’s current views regarding indi-cation extrapolation are of interest
Articles & Reports of Interest
size of clinical biosimilar trials. Many regulatory authorities have published requirements for the approval of bio-similar medicinal products; however, there is no guidance on which quanti-tative standards should be used to de-fine how similar a follow-on product must be to be considered biosimilar. In conclusion, the paper encourages the use of non-traditional statistical approaches with the warning that discussions are required with the reg-ulatory authorities before using these methods during the clinical develop-ment of any biosimilar.
Click here to read/locate the article http://gabi-journal.net/
Biosimilar Primer: US Primary Care Physicians’ Attitudes, Beliefs, and Intentions (June, 2014)
This report features survey data concerning the perspectives of
US physicians (cardiologists, CNS/ neurologists, oncologists, PCP and re-spiratory/pulmonologists) regarding their familiarity and prescription pro-pensity for biosimilar products.
With the patent cliff approaching, the report aims to provide an overview of the familiarity with and use of bi-osimilars in the professional medical market, as well as what role biosimi-lars may play in the near future.
Click here to read/locate the article http://www.isrreports.com/
Factors Supporting a Sustainable European Biosimilar Medicines Market (June 2014)
The study undertaken by GfK Market Access on behalf of the
European Biosimilars Group (EBG), a sector group of the EGA, outlines a series of measures for the future sustainability of the biosimilar med-icines market based on interviews conducted across seven European countries. The conclusions are based on in-depth contributions from 71 experts and policy influencers at na-tional and regional levels and from multiple stakeholder groups—physi-cians, payers, pharmacists, patients and industry
Click here to read/locate the article http://www.egagenerics.com
BIOSIMILARS NEWSLETTER | Volume 3, July 2014
Series C Preferred investment round raising $55 million. New investors KKR & Co. L.P. (“KKR”), Venrock, RA Capi-tal Management, Rock Springs Capital and Fidelity Biosciences joined exist-ing investors Sofinnova Ventures, Lilly Ventures and Vivo Capital in the trans-action.
Company Press Release 19 May 2014http://www.coherus.com/
mAbxience acquires 100% of biopharmaceutical Genhelix
A s aglobal company specialised in biosimilar medicines that
belongs to Spanish-based Chemo Group, mAbxience has purchased 100% of the Genhelix biopharma-ceutical plant, located in Spain.
Genhelix received in July 2013 the GMP approval by the European Au-thorities as a manufacturer of Bio-logical APIs of its flexible and fully single use technology-based facility. They are one of only a few compa-nies to receive such authorization at the EU level and are pioneers in being validated for a plant based on the most advanced technology com-ponents for single use.
Company Press Release 12 Jun 2014http://www.mabxience.com/
Phase 3 Data Demonstrate Comparability of Epirus’ BOW015 to Remicade® for Treatment of Rheumatoid Arthritis
Epirus Switzerland GmbH, an-nounced clinical data from a
Phase III study of the efficacy and safety of BOW015, a biosimilar in-fliximab, in patients with active rheumatoid arthritis (RA).
The study, an equivalence trial de-
Polpharma expands its investment in biotechnology
P olpharma has signed an agree-ment to jointly develop and
commercialize biosimilar products. The company’s partner in the joint venture is Neuraxpharm Group owned by the Strüngmann family.
Within the framework of this col-laboration, both partners will share the costs and risks related to the de-velopment of biosimilars and have equal rights to future products.
Company Press Release 26 Mar 2014http://www.polpharma.pl/
UK court overturns two patents on Roche's Herceptin, following Hospira challenge
The UK High Court has over-turned two patents on Roche's
breast cancer drug Herceptin (tras-tuzumab) following a challenge by Hospira. The main patent on Her-ceptin expired on the 28th of July in Europe, while Hospira was seeking to invalidate two additional patents related to the dosages and composi-tion of the antibody. The successful challenge opens the door to launch-ing a biosimilars version of Ge-nentech’s Herceptin (trastuzumab) monoclonal in the UK.
Link to England and Wales High Court (Patents Court) Decisions http://www.bailii.org/
Coherus BioSciences Secures $55 million Series C Financing
C oherus BioSciences, Inc. (“Co-herus”), a leading biologics plat-
form company focused on biosimi-lars, announced today the closing of a
signed to compare BOW015 to Rem-icade in severe RA patients, met its pre-specified statistical endpoint (ACR20 response rate BOW015 89.8%: Remica 86.4%)
No meaningful differences were ob-served between BOW015 and Remi-cade for the key secondary objectives of the study—assessments of long-term efficacy, safety, tolerability and immunogenicity. Results of the open label phase are expected to be avail-able in the third quarter of 2014.
Company Press Release 11 Jun 2014http://www.epirusbiopharma.com/
Oncobiologics LaunchesPhase I Clinical Trial for ONS-3010 Biosimilar Version of Humira®
Oncobiologics, Inc. announced (12 Jun 2014) that it has received
approval to initiate a Phase I clinical trial in Europe for its first biosimilar molecule, ONS-3010, a highly bio-similar version of the marketed drug, Humira®.
Oncobiologics is developing several additional biosimilars, including a biosimilar version of Avastin®, which will be filed for its first clinical trial later in 2014 and biosimilar versions of Herceptin®, Rituxan® and Erbitux® with plans to initiate studies in 2015 and thereafter.
Company press release 12 Jun 2014http://oncobiologics.com/
Oncobiologics and IPCA create biosimilars alliance
Ipca Laboratories Ltd., India (Ipca) and Oncobiologics, Inc., US (Onco-
biologics) have announced a two-part alliance for the development, manu-facture and commercialization of bio-similar monoclonal antibody products.
Under the first part of the agreement, Ipca will in-license and commercial-ize biosimilar products—developed by Oncobiologics to US FDA and EU regulatory standards—for the India and associated markets. Under the second part of the agreement, On-cobiologics will replicate its Biolog-ics R&D and manufacturing facility in India to create capability for Ipca for further biosimilar commercial-ization. Oncobiologics states, in its press release, that the biosimilars it is considering “are among the most popular therapies in the world for immunology and oncology disease indications.”
Company Press Release 02 June 2014http://oncobiologics.com/
Company News(The information provided is sourced directly from the company websites)
Next EditionLook out for the next edition
of the Biosimilars Newsletter
due October 2014
Contact Rodeina Challand,
Executive Director Biosimilar Development, Scientific Affairs
Hazel Gorham,
Director Biosimilar Development, Scientific Affairs
PRA Health Sciences4130 ParkLake Avenue, Suite 400, Raleigh, NC 27612 U.S.A.
Phone: +1 (919) 786-8200 Email: [email protected]
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