FDA released a guidance on interchangeability earlier this year, is your company ready?

FDA released a guidance on interchangeability earlier this year, is your company ready?

Part 1: Introduction to interchangeable products and the analytical data required

Introduction

In the last decade, there has been an emergence of cutting-edge technologies used to discover or create promising biological products. This ever-evolving field requires rapidly adapting measures to allow new therapies to reach patients while ensuring safety and efficacy.

Biologics are complex bodies and this complexity is at the origin of the cost of biological treatments. To reduce such cost, products qualified as biosimilar to an already approved product can be placed on the market upon expiration of the 12-year exclusivity. The FDA defines a biosimilar as a biological product ‘highly similar’ to an already approved biological product with no demonstrated clinical differences in terms of safety and efficacy from the reference product notwithstanding minor differences in clinically inactive components. The type of data needed to demonstrate the safety and efficacy of a biosimilar differ from an originator product. Whereas a reference product marketing application is evaluated based on a full profile of non-clinical and clinical data, the data for a biosimilar application is comparative and focuses on intensive analytical and functional studies.

Six biosimilars have now been approved in the US.

What is the main implication of an interchangeable product?

Under section 351(k) of the PHS Act, an interchangeable product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. So in January 2017, FDA released the long-awaited draft guidance document about the demonstration of Interchangeability for therapeutic proteins. An interchangeable product is required to meet the biosimilarity criteria but with additional aspects to consider as the implications are greater. The interchangeable product ‘can be expected to produce the same clinical result as the reference product in any given patient’.

In this part 1 of our Blog’s Interchangeability series, we will cover the type of analytical data and information required to demonstrate interchangeability.

‘Fingerprint-like characterization’

What factors may affect the analytical data required to demonstrate interchangeability?

 FDA highlighted evaluating the complexity of your product to understand the data required. FDA will evaluate the totality of data on a case by case basis. Hence, demonstrating the flexibility of the agency about interchangeable products. For a product to be an interchangeable product, biosimilarity is one of the criteria that needs to be met.

To demonstrate biosimilarity, sponsors need to use a stepwise approach meaning that at each step, the level of residual uncertainty should be reduced. The agency reiterated the importance of evaluating any uncertainty left between the reference product and the interchangeable product and identify the methods required to resolve the uncertainty.

As the pharmacist is able to substitute for the reference product making sure that the patient will not develop an immune response to the therapeutic product, that can be fatal, is crucial.

Structural differences between the reference product and an interchangeable product may be at the origin of such a negative effect. To mitigate such events, appropriate analytical data from protein primary structure and higher order structure to impurities is required. For instance, post-translational modifications such as glycosylation can vary greatly according to the system of expression used. Glycosylation patterns that are not present endogenously in humans may elicit a reaction in patients and sponsors should provide appropriate data to support that the interchangeable product can be expected to produce the same clinical result as the reference product in any given patient. Several analytical methods will allow pinpointing the differences, for instance in glycosylation patterns (from methods to identify differences at the level of your intact glycoproteins to the monosaccharide composition), between the reference product and the interchangeable product. FDA recommends using a fingerprint-like analysis as they will consider the ‘totality of the data and information submitted’. This fingerprint-like characterization will allow for targeted clinical studies necessary to demonstrate interchangeability if residual uncertainty remains.

A protein with a lower structural complexity or binding a single target may require less characterization to resolve the residual uncertainty regarding interchangeability compared to other proteins part of not well-established pathways or with a pleiotropic activity.

The impact on Immunogenicity

As mentioned earlier, minor changes in the structure or characteristic of the protein may elicit an immune response to the therapeutic protein in the patient. The fact that an interchangeable product may be substituted for the reference product without the intervention of the healthcare provider means that it is necessary to make sure that there is no risk associated with alternating or switching products. The agency also highlighted that when reference products have a documented history of eliciting detrimental immune responses, further intensive analytical data will need to be provided for the interchangeable product.

Because of the complexity of biologics, the amount of data required will vary from one product to the other according to its characteristics. It is therefore highly recommended to meet with FDA early during the drug development process to discuss your product.

 

Nitisha Pyndiah - Biotech Consulting Services

Nitisha Pyndiah, PhD, is a Consultant where she provides advice for the development of biological, biotechnological, and biosimilar products.

Nitisha provides expertise in the areas of virology, molecular biology, microbiology, immunology, immunogenicity, quality control, GLP and GMP. She prepares and evaluates CMC sections, including FDA meeting documents; and conducts scientific and regulatory gap analyses. She supports technical, strategic, and operational regulatory affairs for recombinant proteins, monoclonal antibodies, and vaccines.

The FDA and Scientific Experts Discuss Infectious Disease Risk

The FDA and Scientific Experts Discuss Infectious Disease Risk

On February 8-9, 2017 the Food and Drug Administration (FDA) organized a public workshop entitled ‘Identification and Characterization of the Infectious Disease Risks of Human Cells, Tissues, and Cellular and Tissue-based Products’. The purpose of this workshop was to gather scientific experts to discuss the methods available to identify and characterize infectious disease risks associated with human cells, tissues, and cellular and tissue-based products (HCT/Ps).

Experts from the FDA, the Centers for Disease Control and Prevention, the industry and several academic institutions discussed the challenges associated with preventing infectious disease transmission in the HCT/P donor population, and the complexity associated with assessing the risks and benefits. Discussions about emerging diseases and testing methods currently used brought light into what improvements should be made.

The global ease of human movement is at the origin of a rapid spread of zoonotic infections and other emerging diseases. Indeed, an epidemic can easily spread and requires a global response to identify the causing agent, the reservoir and determine ways to produce vaccines for global supply.

Another factor affecting the spread of emerging diseases is when herd immunity is compromised. Infectious diseases such as measles can predictably re-emerge, an example provided during the workshop was the 2014 measles epidemic in the US. Experts also discussed the widespread of yellow fever, Zika and other vector-borne diseases and the threat caused by the presence of their vectors such as Aedes albopictus and Aedes aegypti mosquitos on the US territory. Presenters have particularly stressed the need for a global supply of yellow fever vaccine.

Modeling methods are now available and allow to simulate and predict the potential impact of emerging diseases in specific populations, as those can be influenced by various factors including vaccination and resistance to antibiotics. It has been shown that statistical analysis of the incidence and prevalence of these diseases can be influenced by the population, the vector, the geography and surveillance methods used. These parameters can be used for scaling to estimate the potential risk.

Estimating the disease incidence in the blood donor population using recently developed assays to identify recent and long-standing infections can allow the prevention of transmission to occur. Nucleic acid tests allow a determination of early infections when antibodies are not yet detected and serological assays allow a determination in older infections. But these frames vary according to the virus and test used. Experts at the workshop have discussed the importance of improving the data collection and making the use of a confirmatory test for positive results consistent to facilitate modeling. Reliability of the data, specificity, and sensitivity of the assays used together with a consistency of the methods used across the US would improve the incidence estimation. Challenges associated with emerging infections such as Ebola are the uncertain period of time of asymptomatic viremia which can have brutal consequences. Ebola had a 90% mortality in some outbreaks.

The data obtained from blood donors can be used to estimate the incidence and prevalence in the HCT/P donor population. However, variables such as the diseases tested, the gathering of donor medical behavior history from interview information, which is not possible with deceased donors, and the lack of follow-up testing of most donors will affect this estimation. An integrated approach to monitor zoonotic diseases in the US may be beneficial to identifying emerging diseases. The modeling of incidence and prevalence is also challenged by the donor types such as reproductive HCT/Ps or conventional tissues from deceased patients. There are many challenges associated with post-mortem detection of infectious diseases which can make the detection unreliable such a changes in plasma samples that can interfere with the nucleic acid amplification process.

Nevertheless, without close surveillance data, the risk for the donor population is difficult to quantify. Experts have discussed the presence of Ebola in aqueous humor of patients who have survived even nine weeks after clearance of the viremia. Zika RNA was found by RT-PCR in aqueous humor although the corneal tissue is avascular and less prone to disease transmission. Scientists also discussed fungal contamination of ocular tissue and the possibility of potentially adding antifungals to corneal storage media.

Many pathogens can be transmitted through HCT/Ps and the risk of transmission is variable according to the pathogen tropism, tissue type, tissue processing and preservation.

Furthermore, to follow-up on sample storage and treatment, past experience have shown that freeze-drying of Factor VIII for hemophiliacs did not stop HCV and HIV transmissions. Regarding repeat sperm donors, storage of the samples can allow a timeframe to test for infectious diseases but the storage treatment itself does not prevent transmission. However, for other types of transplant such as Bone grafts, presenters gave an example of recipients of irradiated bone from an HCV-positive donor not being infected, showing that tissue processing can affect transmission.

Experts also discussed risks and benefits, that varies for different types of tissues. For instance, when a patient requires a transplantation for survival, the options to mitigate infectious disease are limited leading to a life and death decision.

Although rare, transmission of disease to HCT/P recipients have occurred.

To reduce the risk, a multistep process is recommended to select a safe donor and reduce the bioburden. For instance, by the time a tissue is tested for CJD (brain biopsy processed etc), the tissue would have already been transplanted. Better surveillance is key for organ transplant.

Challenges of traditional screening and testing approaches for donors of HCT/Ps, correlation of positive and negative serology and nucleic acid test results with the medical history interview is affected by a number of influences including the interviewee relationship to the deceased donor. Testing needs to HCT/P donors differs from testing performed for blood donors and participants highlighted the importance of the collaboration needed between tissue bank and test kit manufacturers to advance the scientific knowledge. Finally, to model better the benefit-risk assessment of a medical product, the FDA pointed out two aspects: the risk management and risk communication. The risk management consists of ways to decide if the used of the product affect the benefit-risk and risk communication makes sure that people are aware of the scientific base of knowledge on how to use a product effectively.

This FDA workshop allowed to have an insight into the methods currently used but also those being developed to prepare for emerging diseases in the donor population.

In the recent years, scientists have also studied the importance of innate immunity in the tolerance and rejection of transplants, the emergence of diseases in the recipient following transplantation and the outcome of viral infection in patients with active infections. New methods such as CRISPR for gene editing allow an insight into personalized therapeutic transplant and potential applications to introduce or edit genes to prevent viral infections. For instance, CCR5-Δ32 mutation provides resistance to HIV infection after transplantation with CCR5Δ32/Δ32 stem cells. These new methods evolve rapidly and will hopefully help prevent the emergence of infectious diseases in the donor population.

Nitisha Pyndiah - Biotech Consulting Services

Nitisha Pyndiah, PhD, is a Consultant where she provides advice for the development of biological, biotechnological, and biosimilar products.

Nitisha provides expertise in the areas of virology, molecular biology, microbiology, immunology, immunogenicity, quality control, GLP and GMP. She prepares and evaluates CMC sections, including FDA meeting documents; and conducts scientific and regulatory gap analyses. She supports technical, strategic, and operational regulatory affairs for recombinant proteins, monoclonal antibodies, and vaccines.

FDA is making biological products more easily distinguishable

FDA is making biological products more easily distinguishable

The US Food and Drug Administration (FDA) recently released the final version of the guidance document about nonproprietary naming of biological products. This long awaited document applies to originator biological products, related biological products and biosimilars previously licensed and newly licensed.

The aim of this new naming convention is to enhance pharmacovigilance and allow healthcare practitioners and patients to easily identify and distinguish the biological products. The high complexity of biological products means that similar biologics may have different immunological impact on patients. FDA hopes to help prevent inadvertent substitution of biological products that were not found to be interchangeable in order to ensure the safe use of biologics.

In 2015, the Agency called for companies to submit no more than three four-letters randomly selected suffixes and in the order of the applicant’s preference in a draft guidance document.
In 2016, a guidance document calling for ten randomly selected suffixes was withdrawn two weeks after being published.
These changes reflect the rapidly evolving approach of the agency to biologics based on comments from pharmaceutical companies and healthcare providers. As more biological products are being approved, the agency is seeking to reduce the risk of medication error and make sure that safe and effective biological products reach patients.

In the final guidance document published this year, FDA announced that up to ten suffixes should be submitted during the IND or at the time of BLA submission. These should be composed of four lowercase letters, ‘devoid of meaning’, and attached to the core name with a hyphen. Out of these four letters, at least three should be distinct. The suffixes can be submitted in the order of the applicant’s preference and should be unique. The agency also recommends to applicants to include any supporting analyses of the proposed suffixes to demonstrate that they meet the required criteria.

Finally, the FDA also went over the retrospective naming of biological product which will, according to the agency, help with medication error, ease manufacturer-specific pharmacovigilance, encourage routine use of these suffixes and finally advance accurate perception of these biological products. Also, applying this naming convention to already-approved products is to prevent misinterpretation that biosimilars are inferior to their reference products.

Reference:  Nonproprietary Naming of Biological Products. FDA Guidance for Industry. (January 2017)

Nitisha Pyndiah - Biotech Consulting Services

Nitisha Pyndiah, PhD, is a Consultant where she provides advice for the development of biological, biotechnological, and biosimilar products.

Nitisha provides expertise in the areas of virology, molecular biology, microbiology, immunology, immunogenicity, quality control, GLP and GMP. She prepares and evaluates CMC sections, including FDA meeting documents; and conducts scientific and regulatory gap analyses. She supports technical, strategic, and operational regulatory affairs for recombinant proteins, monoclonal antibodies, and vaccines.