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Biosimilar Risk Minimization Concerns
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Biosimilar Risk Minimization Concerns
- 글 Ghadeer Qawasimi
- GPKOL위원
경력사항
- 2012-현재 JFDA Pharmacovigilance department & Rational Drug Use department
- 2009-2012 JFDA Drug registration department
- 2008-2009 JFDA Research and Development LaboratoriesM
- 2005-2008 Al-Wafi Drug Store Drug registration department
세부 전문분야 및 컨설팅 내용
- 임상, 인허가
Introduction:
Biosimilars cannot be justified based on the similar requirements that apply to other medicines. Although the fact that a biosimilar can be “highly similar” to an already-approved innovative biologic product and that “there are no clinically meaningful differences” between it and the reference product “in terms of the safety, purity, and potency of the product”, it can show similarity in efficacy, and may show different safety profile in terms of nature, seriousness or prevalence of adverse reactions. However, the information from pre-authorization clinical studies generally are insufficient to identify all potential differences. Therefore, clinical safety of similar biological medicinal products must be monitored closely based on continued assessment of drug’s risk-benefit profile. The biosimilar applicant must provide the authority with a risk management plan and pharmacovigilance programme with its application, including a detailed description of the safety specifications associated with the biosimilar medicinal product. The risk management plan for biosimilars should construct methodologies to identify, assess and evaluate, communicate and minimize immunogenicity risks, the most critical safety concern relating to biopharmaceuticals and implement special post-marketing observation, besides, their unique source constituents and complex manufacturing and purification processes make them extremely expensive, thus limiting their availability to patients, and in public healthcare systems.
Pharmacovigilance Risk Management of Biosimilars:
Post-approval PV is critical for all biologics, and principally so for biosimilars. Primarily, patients taking biologics are often seriously ill and receive multiple medications at the same time making safety data analysis from patients difficult to evaluate. Additionally, biologics are proteins that persist in the body and undergo variations through biological pathways; safety concerns may only become deceptive outside the timeframes of controlled clinical trials. The probability of detecting a safety profile different from the innovator is low, this makes post-approval safety monitoring even more significant to construct a more relevant safety profile and to detect additional safety issues.
Biosimilar Major Safety Issue:
There is concern that biosimilar may induce an immune response, resulting in either loss of efficacy, development of neutralizing antibodies to the native endogenous hormone, or, less likely, increased potency. This risk of immunogenicity is of paramount concern, and relates to route, duration and frequency of administration as well as the patient’s underlying disease process and concurrent medication.
The followings are some important concerns and challenges with regard to for the safety and risk management of biosimilars:
1-Traceability and Accuracy in Product Identification
For PV teams When an adverse event is reported in relation to the use of a biosimilar, it should be clearly identified the specific product associated with the adverse event. Therefore, product naming is an important consideration in the case of biologic/biosimilar for traceability or accurate product identification (brand name, manufacturer’s name, and the batch number).
2-Adverse Events Associated with Immunogenicity:
Biologics being complex proteins possess the ability to evoke an immune response that may be humoral or cellular and that could become obvious in different ways, as hypersensitivity ,anaphylaxis, infusion reactions, cross-reactivity to endogenous proteins, transformed pharmacokinetics of the molecule, loss or lack of therapeutic efficacy which can appear after a long period post-administration, necessitating long-term safety monitoring.
The nature and severity of immunogenic reactions may differ from those observed for the reference biologic product and immunogenicity data from the innovator product cannot be directly extrapolated to the biosimilar since data from pre-authorization clinical studies of biosimilars are insufficient for identifying all potential differences between a biosimilar and its reference innovator product.
Since biologics may continue in the body over a longer timeframe, this could result in a long-lasting and variable period between intake of the drug and appearance of the reaction, thereby interpreting causality assessment difficult. Due to the small number/size of clinical trials of biosimilars, full clear immunogenicity profile may not be well-known at the time of regulatory approval…Consequently, there is need for additional post-approval studies to establish efficacy in indications not studied during the approval process, and long-term safety studies to establish the immunogenic potential and other safety issues that may be different from those of the reference product.
3-Labeling
Accurate and complete labeling is critical to the safe and effective use of a medicinal product because the safety data of the innovator product cannot be implicitly and completely applied to the biosimilar even if efficacy is shown to be comparable. Therefore, all post-marketing reported ADRs should be evaluated carefully in order to identify potential risks and detect missing information and linking each piece of information to the source product.
4-Non-substitutability:
A biosimilar is not necessarily interchangeable with its original biologic.
5- Manufacturing methods.
The manufacturing process for biopharmaceuticals is more complex than for conventional small-molecule drugs. Small differences between manufacturing methods can significantly impact a biosimilar’s biological properties, purity and clinical activity. Thus, there is no guarantee that the resulting biosimilar will be comparable to its reference product.
Some of the approaches to address these issues could be:
- Having a unique name/identification code for the product
- Structuring label information to identify sources of data in the label (reference or biosimilar product)
- Collecting detailed information on the product (including its brand name/international non-proprietary name (INN), manufacturer’s name and batch details at the time when an adverse reaction is received
- Careful medical assessment of all potential immunogenicity reactions
- Frequent review of safety data to compare safety profile of the biosimilar with its reference product
- Setting up mechanisms /registries for cohort event monitoring for early identification of safety issues, a
- Building a customized Risk Management Plan to address and mitigate potential safety issues in an effective manner
Proposed solutions to meet the challenges:
- Maintenance of a data source on all available biologics products.
- Development of special scripts that would allow for the collection of detailed information on the product associated with the AE.
- Careful medical assessment of all suspected immunogenicity reports.
- Understanding of the “at risk window”.
- Implementation of frequent cumulative reviews of safety data and comparison with the safety profile of the reference product.
- Creation of an RMP with additional measures to detect potential and unknown safety issues.
- Setup of special product/patient registries for cohort event monitoring,
- Undertaking adequately powered post-approval efficacy and safety studies in all indications and target populations.
- Product labeling with efficacy and safety information related to both the reference product and biosimilar identified by source.
References :
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Growth of Biosimilars: Implications for Safety and Risk Management
By Suhasini Sharma, Sciformix Corporation | September 11, 2015.
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Pharmacoepidemiol Drug Saf. 2010 Jul;19(7):661-9. doi: 10.1002/pds.1948.
Biosimilars: pharmacovigilance and risk management.
Zuñiga L1, Calvo B.
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Safety and Risk Management for Biosimilars :
April 29th, 2015 Safety & Risk Management Blog
Dr. Suhasini Sharma
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Biosimilars and Pharmacovigilance: 5 Key Challenges
April 7th, 2016 by Betsy Davis in Pharmacovigilance
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The challenge of biosimilars
H. Mellstedt D. Niederwieser H. Ludwig
Ann.Oncol-(2007)19(3):411-419.DOI: https://doi.org/10.1093/annonc/mdm345
Published: 14 September 2007
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Pharmacovigilance of Biosimilars
Lipika Chablani,Wegmans School of Pharmacy, St. John Fisher College, 3690 East Ave, Rochester, NY 14618, USA
Corresponding Author :Dr. Lipika Chablani
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