FDA Releases Draft Guidance on Statistical Approaches to Evaluate Analytical Similarity Between Biosimilars

FDA Releases Draft Guidance on Statistical Approaches to Evaluate Analytical Similarity Between Biosimilars

By Benjamin Policicchio, PhD and Suzanne M. Sensabaugh, MS, MBA

The Food and Drug Agency (FDA) released a guidance draft to aid sponsors interested in developing biosimilar products for licensure, titled: Statistical Approaches to Evaluate Analytical Similar. It describes the type of information a sponsor should obtain regarding the structural/physiochemical and functional attributes of their biosimilar product(s), how that information is used in the development of an analytical similarity assessment plan, and the statistical approaches recommended for evaluating analytical similarity.

This guidance draft complements a previously released guidance document: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product. As it stands, 15 pages are split into the following sections: general principles for evaluating analytical similarity, which encompasses an analytical similarity assessment plan and statistical methods for evaluation.

A biosimilar product is described by the FDA as “biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product notwithstanding minor differences in clinically inactive components.”  Sponsors wishing to submit a biosimilar product must submit a 351(k) application, including information demonstrating biosimilarity based on data derived from “analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components.”

The draft details the preferred methods of determining analytical similarity by first understanding the structural/physiochemical and functional attributes of the reference product and then developing an analytical similarity assessment plan. The draft first describes the “quantity and quality of both reference and biosimilar lots that we generally believe are scientifically necessary for evaluating analytical similarity,” and then describes “general principles for the evaluation of analytical similarity.”

The draft lists and describes several factors that should be considered when selecting lots:

  • Number of reference product lots – minimum 10 reference product lots should be sampled
  • Number of biosimilar product lots – minimum 10 biosimilar lots should be included
  • Variability in reference product lots – “Lots with remaining expiry spanning the reference product shelf life should be selected”
  • Accounting for reference product and biosimilar product lots – “Sponsors should account for all of the reference product lots available to them”
  • S.-licensed reference product and other comparators – “The analytical similarity acceptance criteria should be derived using data from an analysis of the U.S.-licensed reference product”
  • Biosimilar lots manufactured with different processes – Data may be combined from “proposed biosimilar product lots manufactured with different processes and/or at different scales”

The draft goes on to describe the most appropriate way to develop an analytical similarity assessment plan, which the FDA notes should be included when submitting a 351(k) biologics license application. The draft describes a list of factors to be considered when designing an analytical similarity assessment plan and should be developed in four stages. The factors include:

  • Differences in age of the lots produced at testing
  • Multiple testing results
  • Assay performance
  • Differences in attributes that will be considered acceptable

The four stages of the development of an analytical similarity assessment plan are:

  1. Development of risk ranking of attributes
  2. Determination of the statistical methods to be used
  3. Development of the statistical analysis plan
  4. Finalization of the analytical similarity assessment plan

Briefly, these stages encourage sponsors to thoroughly identify risks associated with their proposed biosimilar products; decide which statistical methods are best suited for the product based on the identified risks, split into three tiers (Tier 1 [equivalence testing] is for highest risk rankings; Tier 2 [quality ranges] is for lower risk rankings; Tier 3 [visual comparisons] is for lowest risk rankings); compile the work from the first two stages into a detailed statistical analysis plan; and produce the final analytical similarity assessment plan, which should “specify the anticipated availability of both proposed biosimilar and reference product lots for evaluation.” The draft then goes on to describe in detail the FDA’s current thinking on the statistical evaluation of analytical similarity for each tier.

The draft encourages sponsors to contact the FDA as early as possible to discuss the appropriate attributes/assays that should be evaluated in each tier. It should be noted that the final analytical similar assessment plan should be submitted to the FDA prior to initiating the final analytical assessments and that the “FDA’s final assessment as to whether a proposed biosimilar is highly similar to the reference product is made upon the totality of the evidence, rather than the passing or failing of the analytical similarity criteria.”

 

HW reports advice from FDA, CDER reviewers

HW reports advice from FDA, CDER reviewers

What are the benefit-risk considerations during the development of your drug and how to avoid clinical hold?

On September 27-28, the FDA SBIA REdI Fall Conference took place in Rockville, MD. HW was there and reports highlights of the drug track of the meeting.

FDA reviewers and administrators explained the process to prepare an Investigational New Drug (IND) Application and methods to communicate with FDA. They highlighted the importance of reaching out to FDA early on during the drug development.

Charu Mullick, MD, Medical Officer at the Center for Drug Evaluation and Research (CDER), division of antiviral products, presented the benefit-risk considerations in drug development. She emphasized that the regulatory decision relies on the benefits, risks and disease that the drug is intended to treat. Furthermore, using a consistent and systematic approach when considering the benefit-risk assessment is critical. The outcomes of regulatory decisions are affected by many considerations including: benefit of the drug, safety (e.g. human safety data, toxicology, other nonclinical data, class-related toxicity concern), nature and severity of the target condition, the medical need, the availability of alternative therapy, areas of data gap, specific information regarding the drug or intended indication. Case studies for the division of antiviral products were provided.

One case study involved safety concerns (i.e. drug-induced liver injury) during a phase 2 clinical trial of an ongoing Human Immunodeficiency Virus (HIV) clinical program. As the decision took in consideration the trial patients populations (naïve HIV-infected patients with other alternative treatment available and experienced HIV infected patients with limited options) the decision was to place the trial in partial hold to allow dosing in treatment-experienced HIV infected patients. In a second case study, toxicity was identified in a 39-week chronic toxicology study while the clinical program was ongoing. This case study related to a treatment of genital herpes in immunocompetent adults using a novel mechanism of action. The initial toxicology data submitted with the initial IND did not raise any concern but during the phase 2 clinical trial, severe drug-related toxicities in the chronic toxicology study resulted in unscheduled animal sacrifice. When toxicity is identified in animals, it is important to evaluate whether the toxicity was identified in one or more than one species and whether the target organ was involved together with the extent of the severity. In this case, it was determined that human subjects would be exposed to unreasonable and significant risk of illness or injury and the IND was placed on full clinical hold.

What are the options after a full clinical hold? The review division will communicate to the sponsor the reasons for the clinical hold and will provide information that would be required to resolve the hold issues. With serious toxicities, the options to resolve the hold issue are limited.

The sponsor could address the nonclinical toxicity findings by – demonstrating that the toxicity is specific to an animal species and not relevant to humans, – demonstrating a study specific issue explaining the toxicity, – identifying a patient population for which the benefit-risk assessment would be favorable. The latter is likely to be the most feasible approach. In this case scenario, the program is revised to target patients who are immunocompromised with resistant virus. Indeed, an investigational drug of new class and mechanism of action may help avoid common resistance pathways. But due to limited treatment options in this population, it will be important to carefully find the acceptable dose and the limit to the dose/duration based on data obtained in clinical trials to date. A boxed warning will be added to the labeling due to the considerable toxicity.

The take-home message was to remember that the context matters and the totality of data provided is taken into consideration when assessing the benefit-risk of a drug.

Maria Cecilia Tami, PhD, from the FDA CDER, Office of pharmaceutical quality (OPQ) and Office of Biotechnology Products (OBP) presented case studies for biologics regulated in CDER. Those include proteins greater than 40 amino acids and derived from living material. Dr Tami, provided an overview of how FDA reviewers review an IND application based on a drug’s safety and effectiveness. Also presented, were the requirements for testing of the cell bank, including revealing the identity of expected species, the purity with the potential type of contaminants and the testing for adventitious viruses. One of the case study presented was about a recombinant protein produced in CHO. In that case, the cumulative log10 reduction factor (LRF) did not meet the safety requirements to avoid potential patient exposure to viral particles. Furthermore, insufficient information was provided to demonstrate the appropriateness of the model used. Altogether, the data provided lead to a clinical hold as the sponsor was unable to determine robust viral clearance of the downstream manufacturing process and acceptable safety margin.

What were the sponsor’s options after the clinical hold? The sponsor repeated the viral clearance studies and also added an additional viral clearance step, demonstrated higher cumulative log10 reduction value (LRV), reached acceptable viral safety margin and finally demonstrated that the process parameters in the scale-down model was representative or at least compared to the at-scale process. Altogether, the additional data allowed the removal of the clinical hold.

Dr Tami also highlighted the importance to submit to FDA both tabular and primary data for the drug substance characterization. The release/characterization tests should cover safety, purity, impurities and characterization, identity, potency and protein content. It is important to note that early in the drug development the release specifications are broader and methods together with strategies should be discussed with FDA.

In a second case study for a recombinant protein, stability data for only the toxicology lot and not the proposed clinical lot was submitted in an original IND submission. The toxicology lots showed a time-dependent increase in impurities by Reverse-Phase HPLC through 6 months of storage under recommended storage conditions of -70°C leading to a clinical hold. This decision was made as there was no assurance that the proposed clinical lot would remain stable throughout the planned duration of clinical study. Once the sponsor was able to provide sufficient real-time stability data, including the primary data for the clinical lot to ensure stability during the clinical study, the clinical hold was removed.

A sponsor should keep in mind that the CMC information to support a phase 1 IND should be focused on the safety of the investigational product.

Overall, a good planning of the drug development and mitigating the risks will help the sponsor to avoid a clinical hold and if a clinical hold is issued, there are ways to overcome it. HW can assist you throughout your drug development including assisting you in planning of your regulatory strategy but also providing advice on the suitability of the method used and mitigating the risks t

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 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.