Post-Market Immunogenicity Monitoring
RAPID IMMUNOGENICITY TESTS FOR POST-MARKET MONITORING OF BIOSIMILARS
The exceptional growth of biotherapeutics to a $125 billion industry has brought the great benefit of targeted therapy to patients. However, these large molecules cannot be employed without the possibility of toxicity or rejection due to the patient’s immune response. All the currently available innovator biotherapeutics have been shown during their development to possess acceptably low risk of immunogenicity. As these pioneering biotherapeutics lose their patent exclusivity, a large wave of potentially lower-cost biotherapeutic “generics” are in multiple development pipelines. These copies are not equivalent to the original drugs but are considered “biosimilars”, with structures that can be sufficiently different to raise uncertainties about their immunogenicity.
Requirements/Recommendations on Post-Market Immunogenicity Testing by Regulatory Agencies
Both the US FDA and the European Medicines Agency (EMA) have issued definitive guidance documents on the need to establish the risk of biotherapeutic immunogenicity. The EMA issued their guidelines several years ahead of the FDA which released its draft guidance documents in February 2012. The two agencies have very similar approaches to this safety issue.
EMA Guidance on Immunogenicity
We quote the following sections (emphases added) from the EMA “Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins” EMEA/CHMP/BMWP/14327/2006 adopted in 2007 and effective in 2008 (emphases added):
“…unwanted immunogenicity can occur at a level, which will not be detected by such studies when conducted at a pre-approval stage, due to the restricted number of patients normally available for study. In view of this, it is often necessary to continue assessment of unwanted immunogenicity and its clinical significance post-approval, usually as part of pharmacovigilance surveillance. In some cases, post-approval clinical studies may be needed to establish the risk associated with unwanted immune response.”
“The extent of data on immunogenicity that can be obtained during the clinical development programme of a biotechnology-derived product before approval depends on the event rate, driven both by the immunogenic potential of the protein and the rarity of the disease. Therefore, further systematic immunogenicity testing might become necessary after marketing authorization, and may be included in the Risk management Plan.
The extent of immunogenicity data to be collected in the post-marketing setting will depend on various factors including:
- Disease-related factors like its prevalence, the vulnerability of the patients, availability of alternative therapies, duration of treatment, etc.
- Pre-authorization immunogenicity findings including impact on efficacy and safety
- Experience on immunogenicity with similar proteins or related members from that class of proteins, including proteins manufactured with similar production processes.
- Seriousness of the immune reaction.
However, biotechnology-derived proteins should be considered individually, and therefore the possibility for extrapolation from other related proteins is limited and needs to be fully justified.
Immunogenicity can be further studied in a post-marketing setting e.g. by enhanced reporting of possibly immune-related adverse events (including loss of efficacy), or by pharmacoepidemiological studies.”
The EMA has also released the “Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use” EMA/CHMP/BMWP/86289/2010, currently in its consultation phase. From it we quote (emphasis added):
“In many cases, the incidence of immune response is too low to be fully identified during Phase III clinical studies. Therefore systematic post-authorization monitoring may be necessary and should be adequately organized to capture clinical signs that could be related to immunogenicity. The involvement of antibodies in this should be established by conducting appropriate assays.”
FDA Draft Guidance on Immunogenicity
The latest draft guidance on Biosimilars released by the FDA in February 2012, “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product” states that, at the very least, two separate immunogenicity studies should be conducted to compare any biosimilar to its reference product:
“(1) a premarket study powered to detect major differences in immune responses between the two products and (2) a postmarket study designed to detect more subtle differences in immunogenicity.”(see lines 548-559)
In addition, the draft guidance goes on to state the following:
“The follow-up period should be determined based on (1) the time course for the generation of immune responses (such as the development of neutralizing antibodies, cell-mediated immune responses), and expected clinical sequelae (informed by experience with the reference product), (2) the time course of disappearance of the immune responses and clinical sequelae following cessation of therapy, and (3) the length of administration of the product. For example, the minimal follow-up period for chronically administered agents should be one year, unless a shorter duration can be justified by the sponsor.” (See lines 592-599)
Centralized Pre-Market Immunogenicity Tests vs. Decentralized Post-Market Testing
Pre-market immunogenicity studies are carried out in a centralized manner using well-organized collection procedures and schedules from properly defined and traceable donor cohorts under a defined and controlled study plan. In these studies, samples can be gathered centrally and tested using equipment-based laboratory methods such as ELISA or ECL immunogenicity assays controlled and performed by the drug developer. However, in order to carry out post-market immunogenicity surveillance, immunogenicity test methods have to be made available wherever patients live. These test methods are not high volume assays that can economically be included as part of a local clinical laboratory’s menu. The dissemination of these tests to and acceptance by local hospital and commercial centralized laboratories will be challenging if usage is sparse and sporadic.
Furthermore, patients may not be hospitalized and may in fact be ambulatory and continue to live normal lives while undergoing treatment. Patients will be found in urban areas and in remote rural settings with no predictability for their geographical demographics. Patient testing cannot be undertaken within a controlled study plan similar to Phase III safety evaluations but will be disperse and unpredictable.
Post-market immunogenicity testing resembles in great degree personalized medicine tests that need to be available in point of care (POC) settings. The classic example of a personalized medicine test is the blood glucose monitoring that diabetics perform daily. Ideally, any patient undergoing biotherapeutic treatment should be able to test for his or her individual tolerance of the administered drug under the guidance of a primary care physician in the similar manner that diabetics monitor their blood glucose levels. Interpretation and intervention can be made immediately without the need to send blood samples to a remote central laboratory which may not even offer an immunogenicity test method for that particular drug.
Whether performed by a physician or the patient, personalized immunogenicity testing can take its place within the evolving personalized medicine procedures used in patient care for cancer and metabolic diseases. Personalized immunogenicity testing should be performed before and during biotherapeutic treatment. A pre-treatment evaluation will serve to uncover pre-existing antibodies and enable a physician to evaluate the risk and rationale for using the specific biotherapeutic drug.
Need for Post-Market Point of Care Immunogenicity Tests on a Common Platform
In the end, the discussion devolves to the availability of tools for immunogenicity testing for patient care and compliance for post-market surveillance. Currently there are no such tools. Rapid immunogenicity tests that can be performed by a primary care physician or ideally, by the patient himself, are the best solutions. Since these tests are not broadly applicable and are specific to each biotherapeutic, innovator or biosimilar, they may be too esoteric and are therefore not attractive opportunities for large diagnostic businesses which depend on high volume and high-throughput tests.
Alliances between biopharmaceutical companies and specialized diagnostic companies are the keys to delivering these necessary post-market surveillance tools. A drug company can make its biotherapeutic available to the diagnostic entity to develop the rapid POC immunogenicity test. Although target drugs will originate from multiple companies, it is important to develop these tests on a common platform in order to simplify POC testing for physician’s offices and remote clinics.
ANP Technologies, Inc. has successfully developed rapid immunogenicity tests for both innovator and biosimilar biotherapeutics for established biopharmaceutical companies using its handheld reader-based NIDS® technology. Its PEG Rapid Immunogenicity test kit can be used universally in a POC setting to detect PEG-specific anti-drug antibodies in patients undergoing treatment with any of the large number of PEGylated drugs. ANP’s successful collaboration with biopharmaceutical companies has created an opportunity to develop its NIDS® handheld technology as the common platform for future POC immunogenicity tests for post-market surveillance and patient monitoring.
- European Medicines Agency: “Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins” EMEA/CHMP/BMWP/14327/2006
- European Medicines Agency “Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use” EMA/CHMP/BMWP/86289/2010
- US Food and Drug Administration , “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product” February 2012
- Pan J, Small T, Qin D, Li S ,Wang L, Chen D, Pauley C, Verch T, Kaplanski C, Bakhtiar R, Vallejo YR, Yin R. Comparison of the NIDS® rapid assay with ELISA methods in immunogenicity testing of two biotherapeutics. J. Pharm. Tox. Methods 63: 150-159 (2011)
- Pan J, Small T, Qin D, Pauley C, Kaplanski C, Verch T, Chen D, Bakhtiar R, Naling Y, Vallejo YR, Yin R. NIDS® Rapid Assays for the Detection of Anti-Drug Antibodies to Various Polyethylene Glycol (PEG) Polymers. American Association of Pharmaceutical Scientists National Biotechnology Conference, San Francisco, CA May 2010 (Abstract)
- Pan J, Small T, Qin D, Vallejo YR, Yin R. NIDS® Rapid Assays for the Detection of Anti-Drug Antibodies to Peptide Drugs. American Association of Pharmaceutical Scientists National Biotechnology Conference, San Francisco, CA May 2010 (Abstract, received the “Excellence in Ligand Binding Assays” award)