Clarification of Roles and Responsibilities and Proposed Future Reviews of and Updates to the Coordinated Framework-Part 4

Clarification of Roles and Responsibilities and Proposed Future Reviews of and Updates to the Coordinated Framework-Part 4

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

Welcome to the fourth and final blog post in our mini-series focused on the 2017 Update to the Coordinated Framework for the Regulation of Biotechnology. In the three previous posts, we provided background relevant to this update, discussed the roles and responsibilities of the primary agencies that regulate biotechnology products, and then provided an overview of the interagency communication and coordination that exists between these primary agencies. In this post, we will discuss one case study provided within the update to help clarify the roles and responsibilities of the three major agencies (Food and Drug Administration [FDA], Environmental Protection Agency [EPA], and United States Department of Agriculture [USDA]) and proposed future reviews of and updates to the Coordinated Framework.

Case studies have been provided in this Update to the Coordinated Framework to aid developers in navigating the regulatory framework starting from research activities in the laboratory, to full commercialization of the product. Though these case studies provide examples, it is stressed that developers should contact agencies at the early stages of product development to help make the regulatory process more predictable. We will discuss one case study as presented in this Update, although the Update itself contains 8 different case studies.

Case study #7: A Hypothetical Genetically-Engineered Rabbit

A brief background of the product is provided: “The rabbit (Oryctolagus cuniculus) genome is genetically engineered to express recombinant human insulin (rh insulin) for use as a therapeutic protein in the treatment of human patients lacking adequate functional insulin. The human insulin coding sequence is controlled by 5’ bovine αS(1) casein promoter sequences direct expression of recombinant insulin protein in rabbit milk. The construct is microinjected into fertilized oocytes and the resulting embryos are transferred to the oviduct of a recipient dam. Once a germline GE animal is identified as a lineage progenitor, it is bred to establish a lineage of GE rabbits used in insulin expression in milk.”

Only the FDA has oversight over this product as the recombinant DNA construct encoding the recombinant human (rh) insulin protein integrated in the genome of the GE rabbits is regulated as a new animal drug by the FDA Center for Veterinary Medicine (CVM) and the rh insulin purified from the GE rabbit milk is regulated as a human drug by the FDA Center for Drug Evaluation and Research (CDER). Each product requires a separate approval.

The developer responsibilities during development (e.g., the laboratory, farm, and clinic) are such that the developer should initiate discussions with FDA/CVM once the lineage progenitor has been identified, upon which the FDA/CVM would open an investigational new animal drug file (INAD) leading to approval pertaining to this GE rabbit lineage.

Sponsors must meet all of the requirements for safety and effectiveness of the new animal drug prior to the approval of the rh insulin. For the rh insulin, the sponsor must submit an Investigational New Drug (IND) application to FDA/CDER prior to clinical trial activities. The developer may seek pre-IND advice as well. If FDA approves the rh insulin product, FDA posts a notice of the approval and provides a summary of the safety information relevant to the approval on its website.

Upon public engagement, the FDA codifies the approval of the new animal drug and publishes a Federal Register notice when the approval is codified. Further, the FDA posts on its website a summary of the information on which this approval was based.

A subsection exists within the Update detailing the timeline and mechanism for the review of and, if necessary, update to the Coordinated Framework. The Biotechnology Working Group will produce an annual report for at least five years on specific steps the agencies are taking to implement the Strategy produced by this Update to the Coordinated Framework and any other steps that are being taken to improve the transparency, coordination, predictability, and efficiency of the regulation of biotechnology products. The Biotechnology Working Group will continue to monitor scientific and technical developments in biotechnology and its applications, and to work with stakeholders to undertake future updates to the Coordinated Framework as warranted.

This concludes this mini-series on the 2017 Update to the Coordinated Framework for the Regulation of Biotechnology. For more information, you can read the 2017 Update to the Coordinated Framework for the Regulation of Biotechnology here:

2017_coordinated_framework_update

WE CAN HELP GET YOUR GE PRODUCTS APPROVED BY THE FDA

Are you in the process of developing a GE product? Do you need help preparing and submitting your INAD and IND to the FDA? We can help. Contact us today to learn more about our services and how we can help you obtain approval from the FDA.

 

Suzanne Sensabaugh

Suzanne M. Sensabaugh has advanced the development of over 130 biologics, biosimilars, and combination products since 2009. She can be reached at smsensabaugh@hw-fda.com

FDA Updated their Guidance Document about “Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues and Cellular and Tissue-Based Product”.

FDA Updated their Guidance Document about “Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues and Cellular and Tissue-Based Product”.

By Nitisha Pyndiah, PhD

Source: CDC/ Cynthia Goldsmith (2016).

This is a transmission electron microscopic (TEM) image of the Zika virus, which is a member of the family, Flaviviridae. Virus particles are 40nm in diameter, with an outer envelope, and an inner dense core. The arrow identifies a single virus particle.’

What is Zika Virus (ZIKV)?

ZIKV is an RNA virus from the Flaviviridae family, first isolated in 1947 from a rhesus monkey, and transmitted to human through infected Aedes species mosquitos. Most infected individuals are asymptomatic and even when symptoms are experienced, they are usually mild. Importantly, Zika infections have been associated with neurologic manifestations. The virus can be transmitted to a fetus during pregnancy including from asymptomatic mothers. Reports of congenital infections include microcephaly, ophthalmologic abnormalities and other neurologic abnormalities.

It has been reported that ZIKV can be transmitted through blood and blood products. There is also a theoretical risk for transmission of the virus by cellular and tissue-based products (HCT/Ps).

What is new in this guidance document?

The updated guidance document supersedes the version from March 2016 and provides ample details about results of more recent studies. Those studies include recent epidemiological studies and impact on public health, new data about the transmission of ZIKV, the current status of availability of ZIKV tests, sexual contact risk factors and deciding when an area is considered to have an increased risk for ZIKV transmission.

Furthermore, ZIKV is a virus that is still not well characterized and there are no appropriate testing measures to prevent the transmission of ZIKV through HCT/Ps.

Those updated results still highlight the importance of applying appropriate precautions and following recommendations when considering the eligibility of living donors and cadaveric donors of HCT/Ps.

Due, in part, to the reported presence of ZIKV in semen and umbilical cord blood and other gestational tissues long after viral RNA in plasma, and that ZIKV has been identified in hematopoietic stem/ progenitor cells (HPCs) from peripheral blood; FDA urges to follow recommendations to reduce the risk of transmission of ZIKV by HCT/Ps. HPCs recipients often being severely immunocompromised may affect the outcome of the viral infection as well and increase the risk for life threatening outcomes. ZIKV disease outcome in this population still needs to be studied further to allow for better understanding.

When is an area considered to have an increased risk for ZIKV transmission?

For an area to be considered at risk for ZIKV transmission, local transmission through mosquito-borne ZIKV should have been reported or the potential risk is based on epidemiological evidence.

FDA refers to the Centers for Disease Control and Prevention (CDC) website for areas of increased risk for ZIKV infection: https://www.cdc.gov/zika/areasatrisk.html.

What are FDA recommendations for HCT/Ps donor screening?

FDA considers ZIKV to be a relevant communicable disease agent or disease (RCDAD) under 21 CFR 1271.3(r)(2).

-For living donors of HCT/Ps to be considered ineligible:

  • Medical diagnosis of ZIVK in the past 6 months
  • Residence in, or travel to, an area with an increased risk for ZIKV transmission within the past 6 months
  • Sex within the past six months with a person who has either of the risk factors listed in items 1 or 2, above.

Additionally, donors of umbilical cord blood, placenta, or other gestational tissues should be considered ineligible if the donor has any of the following risk factors:

  • Medical diagnosis of ZIKV infection at any point during that pregnancy
  • Residence in, or travel to, an area with an increased risk for ZIKV transmission at any point during that pregnancy
  • Sex at any point during that pregnancy with a person who has either of the risk factors listed in items 1 or 2, above.

– For cadaveric donors of HCT/Ps to be considered ineligible:

  • Persons with a medical diagnosis of ZIKV infection in the past 6 months.

Finally, keep in mind that FDA is implementing this guidance document as soon as possible and within 4 weeks of the guidance issue date!

FDA Guidance for Industry. Updated May 2018. Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products.

Need any help with your blood product or HCT/P? Contact us now!

Suzanne Sensabaugh

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.

Interagency Communication and Coordination Between FDA, EPA, and USDA – Part 3

Interagency Communication and Coordination Between FDA, EPA, and USDA – Part 3

Part 3 – Interagency Communication and Coordination Between FDA, EPA, and USDA

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

Welcome to part three of this mini-series revolving around the recently-released 2017 Update to the Coordinated Framework for the Regulation of Biotechnology. In the previous two posts, we provided background relevant to this update and then discussed the roles and responsibilities of the primary agencies that regulate biotechnology products, respectively. In this post, we will discuss interagency communication and coordination that exists between the three major federal agencies, Food and Drug Administration (FDA), Environmental Protection Agency (EPA), and the U.S. Department of Agriculture (USDA).  The Update can be found at the following link.

Interagency communication is essential for the regulation of products that fall under the purview of more than one agency and may necessitate close coordination prior to final decision making. This communication is achieved through two mechanisms: Formal and Ad Hoc Interagency Working Groups and Memoranda of Understanding (MOU).

Formal and ad hoc working groups are established based on need, with one of the most recent examples of this being the formal development of the Biotechnology Working Group by the July 2015 Executive Office of the President Memorandum under the ETIPC committee. This working group developed this update and the accompanying Strategy and will continue the work initiated to fulfill the goals identified in the 2015 EOP memorandum.

Ad hoc groups are developed as necessary during agencies’ reviews of biotechnology products and are formed to facilitate discussions among relevant agencies. The update provides the following example: “…during the new animal drug review process, FDA may consult with other Federal agencies such as EPA, the U.S. Fish and Wildlife Service (FWS), National Marine Fisheries Service, and/or the U.S. Centers for Disease Control and Prevention (CDC). Similarly, other Federal agencies and departments, such as the National Institutes of Health, Department of Defense, Department of Homeland Security, Department of Commerce, Department of State, and others, are informed and consulted, as necessary and relevant.”

MOU are put in place by FDA, EPA, and USDA to enhance coordination and enable sharing of information among the agencies. The update lists three specific MOUs relevant to biotechnology products:

•    In July 2009, the EPA’s Office of Pesticide Programs’ Biopesticide and Pollution Prevention Division and USDA’s Animal and Plant Health Inspection Service’s Biotechnology Regulatory Services (BRS) entered into a science review work share MOU (09-2000-00520MU) for the purpose of sharing and utilizing science reviews of product characterization of plant incorporated protectants.

•   In February 2011, the EPA, FDA and USDA/APHIS BRS entered into an MOU (10-2000-0058-MU) to support and encourage cooperation and communication among the three agencies in the regulatory oversight over genetically engineered plants and the foods derived from such plants.

•   In October 2012, the EPA Office of Chemical Safety and Pollution Prevention (OCSPP) Office of Pesticide Programs (OPP), USDA/APHIS Plant Protection and Quarantine (PPQ), and USDA/APHIS BRS entered into the Microbial Pesticide Memorandum of Understanding, whereby the above offices agree to share, on a reciprocal basis, information of microbial pesticides related to their respective programs regulating microorganisms.

As a general matter, when FDA, EPA, or USDA need expertise from other agencies to assess fully the safety of a biotechnology product, that expertise can be accessed through interagency communication.

In the final post of this mini-series, we will discuss the roles and responsibilities of each major agency and proposed future reviews of and updates to the Coordinated Framework.

Suzanne Sensabaugh

Suzanne M. Sensabaugh has advanced the development of over 130 biologics, biosimilars, and combination products since 2009. She can be reached at smsensabaugh@hw-fda.com.

What do you need to know about immunogenicity?

What do you need to know about immunogenicity?

By Nitisha Pyndiah, PhD

One of the most challenging parts of your drug development is making sure that your drug does not elicit a detrimental immune response in the patient also known as immunogenicity. This immunogenic response can impact the efficacy and safety of the therapeutic product. There are ways to mitigate those immunogenicity risks and phase three clinical trials aim at directly looking at the response in patients and, according to FDA, resolve any ‘residual uncertainty’. But before reaching Phase 3, you should know enough about your product to avoid unforeseen events.

You will have to respond to regulatory bodies’ requirements, safeguard the safety of the patient and avoid loss of investment in your product development. Characterizing your biological product is crucial, understanding these complex products allows predicting whether a product is more, or less likely to induce immunogenicity in a patient based on previous studies and literature.

It is therefore of major importance to always keep in mind the immunogenicity risk during the development and have the appropriate tools to test and analyze this potential response.

We can help you navigate safely through your product development and mitigate the risk of immunogenicity to allow your product to benefit patients faster.

Let’s answer some of the most commonly asked questions about immunogenicity.

What to consider regarding immunogenicity when you are developing your product? 

A detrimental immune response to the therapeutic agent can be triggered in a patient through three ways:

  • The patient

Including genetic predisposition, the presence of already present antidrug antibodies from previous treatments, Fc receptors for IgG (FcγR)

The patient may develop anaphylactic reactions due to hypersensitivity to the therapeutic product, product neutralizing antibodies that may compromise the treatment, the immune response may alter pharmacokinetics/pharmacodynamics, the produced antidrug antibodies (ADA) may cross-react with endogenous proteins and trigger serious adverse reactions.

  • The therapeutic product

If is often thought that mainly protein drugs can elicit immunogenicity, but other biopharmaceuticals also can lead to an anti-drug antibody (ADA) response.

Drug-related factors that can affect immunogenicity include: Structure (amino acid sequence, tertiary structure), Post-translational modifications (glycosylation), Mode of action, Aggregates, Contaminants including process and product-related impurities.

  • The route of administration

Availability of immune cells and proteins at the site of entry will affect immunogenicity risk, indeed, it is broadly perceived that the subcutaneous route of administration poses a higher immunogenicity risk due to increased interactions of the therapeutic product with immune cells such as dendritic cells present at the site of injection, but it is still controversial whether this route is more immunogenic. This route is often preferred for the convenience offered to patients when it comes to home administration.

Click to enlarge figure 1

Mitigating immunogenicity risks is made on a case by case basis and relies on the characteristics of your therapeutic product. Want to learn more about how to mitigate the risks of immunogenicity? Contact us now. We can conduct an immunogenicity risk assessment for you.

What is the mechanism of immunogenicity? 

Immunogenicity involves both innate immunity and adaptive immunity. Innate immunity proteins and cells activate and enhance the response to the therapeutic agent. We describe here, in a simplified manner, the complex mechanism of immunogenicity.

Immunogenicity involves several mechanisms, including a wide range of cells and molecules that have recognized the therapeutic agent as an antigen. (see figure below for mechanism)

Want to learn more about the mechanism and if your product may place patients at risk? Contact us now.

Click to enlarge figure 2

How to assess immunogenicity?

The most common way and technically reasonable approach to evaluating immunogenicity are through antibodies that the patient generates against the therapeutic product. These antibodies are called anti-drug antibodies (ADA) and can be tested using several methods and assays can allow elucidating the effect and impact of the ADAs produced.

We can guide you in testing appropriately immunogenicity, understanding the requirements and help you save costs by making important decisions early in your product development as well as planning a smooth program. Contact us now.

Click to enlarge figure 3

Immunogenicity risk assessments are expected by the regulatory authorities. EMA expects an Integrated Summary of Immunogenicity in your Marketing Application. FDA accepts this summary in your BLA.

WE CAN HELP YOU ASSESS THE IMMUNOGENICITY RISKS FOR YOUR PRODUCT

Do you need to conduct an immunogenicity risk assessment? Do you need an Integrated Summary of Immunogenicity for the regulatory authorities? Are you in the process of developing a biological product? Do you need help preparing your IND or BLA? Contact us today to learn more about our services and how we can help you.

 

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 Interchangeability Guidance Part 2

FDA Interchangeability Guidance Part 2

 By Nitisha Pyndiah, PhD, Consultant

 

To follow up to our previous part 1 about the analytical data required to demonstrate interchangeability, let’s look into clinical studies required.

What clinical studies are required to demonstrate interchangeability?

To demonstrate interchangeability, FDA recommends using the residual uncertainty approach to identify the next steps to resolve the uncertainty. Once analytical characterization has been performed, non-clinical and clinical studies are conducted to address any specific residual uncertainty (for instance, immunogenicity that may arise in patients due to minor structural differences identified during the analytical characterization)

Postmarketing data from a licensed biosimilar will generally not be sufficient to demonstrate interchangeability without an appropriately designed, prospective, controlled switching study.

In FDA’s draft guidance about demonstration of interchangeability, FDA recommended switching studies with the aim to demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between use of the proposed interchangeable and the reference product is not greater than the risk of using the reference product without such alternation or switch.

Furthermore, in certain case scenarios, if there is residual uncertainty regarding interchangeability based on an immunogenicity-related adverse event, a sponsor may need to obtain licensure as a biosimilar product and collect postmarketing data before interchangeability can be demonstrated.

The draft guidance entitled, Considerations in Demonstrating Interchangeability with a Reference Product, also highlights that if a patient has an adverse reaction during the course of a switching study, the fact that the patient had been receiving both reference product and proposed interchangeable product may lead to carryover effects, thus determining which product was responsible for the reaction may be difficult. Differences identified between the non-switching and the switching arm would lead to the conclusion that the proposed product is not interchangeable regardless of which product either reference or proposed interchangeable product or switching from one product to the other was at the origin of this difference.

FDA highlighted that the agency would be flexible on the design of the switching studies and will address product-specific scientific matters on a case by case basis when sponsors/applicants sought advice from FDA. As for biosimilars, developers of interchangeable products are highly advised to contact FDA early in their development.

An interchangeable product developer has two main options regarding switching studies:

  • A dedicated switching study
  • An integrated study also referred to as ‘2 in 1’ studies (Figure 1)

The dedicated switching study design as its name suggests, is a study to demonstrate interchangeability once biosimilarity has been demonstrated using another clinical study. The integrated study, on the other hand, refers to a single study which is used to ‘support the demonstration of no clinically meaningful differences between the reference product and the proposed product for biosimilarity’ in a first part and incorporates a switching study in the second part (Figure 1 at bottom of the page).

For the switching study, the lead-in period with the reference product should be long enough to allow a steady state of pharmacokinetics before randomization to the switching part of the study. At least three switches are required for the switching arm, meaning that there should be at least two separate exposure periods to both the reference product and the proposed interchangeable product.

At the end of these switches, the last switching interval should be from the reference product to the proposed interchangeable product and be long enough to allow for the washout of the reference product corresponding to at least three or more half-lives of the product. Following this last step, the pharmacokinetics of the proposed interchangeable product will be assessed and compared in the switching arm and the non-switching arm.

There has been a lot of attention regarding switching studies and trying to understand whether switching studies may have a negative impact on patients. A recent publication (Cohen, H.P., et al. Drugs (2018)), analyzing the data from 90 studies that enrolled 14,225 unique patients, reported that in most of the studies, no immunogenicity, safety and efficacy differences were reported after switching from reference product to biosimilar. This recent report brings hope to patients and healthcare providers regarding unchanged safety and efficacy of the interchangeable products. Indeed, interchangeable products may have a major economical impact on healthcare costs as regulators, pharmacists, patients and payors work towards reducing the cost of biologics treatments.

We can assist in advancing the development of your Biosimilar or Interchangeable Biological Product

Are you in the process or developing a biosimilar or interchangeable product? Do you need help preparing and submitting your IND or BLA to the FDA? Or perhaps you need to request an Initial Biosimilar Advisory Meeting or a Biosimilar Product Development Meeting. We can help. Contact us today to learn more about our services and how we can help you advance our product with the FDA.

 

 

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.

May 5th Marks the Deadline for INDs and DMFs

May 5th Marks the Deadline for INDs and DMFs

By Mary Waters

Cinco de Mayo is widely interpreted as a celebration of Mexican culture and heritage. Today, celebrators mark the occasion with parades, parties, mariachi music, Mexican folk dancing and traditional foods such as tacos and mole poblano and consuming mucho cervesa.

Another widely celebrated event held on the first Saturday in May, this year being the 5th of May, is the Kentucky Derby. Thousands of horse racing enthusiasts will either be trackside or tuned in to see who will take home the blanket of roses and that valuable trophy!

This year however, there is also another very important event happening that you need to remember, and it’s closing in very quickly. It’s the upcoming deadline for the electronic Common Technical Document (eCTD) requirement for commercial Investigational New Drug Applications (INDs) and Master Files (DMFs) that MUST be submitted using eCTD format. After this date May 5, 2018 submission that do not use eCTD will NOT be filed or received. Whoa!

Also, note that ONLY FDA fillable forms (i.e., 1571, 356h) and electronic signatures to allow for automated processing will be accepted; scanned images of forms will NOT be accepted.

If you have not started down the road to obtain your WebTrader ESG account, or are not sure where to start, the FDA has provided a step-by-step list of what to do and when which can be found at the FDA ESG website, https://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm

Or, if you are overwhelmed with the prospect of starting from scratch, let us help you jump those hurdles. We are set up and ready to go – we can take the pressure off and have you compliant in no time!

Do you have an IND that needs to be put into eCTD format? Do you need to begin to submit your IND documents through the ESG? We can help you! Please contact us.

Mary is an expert provider of electronic Common Technical Documents  (eCTD) publishing services. Since joining HW in 2016, Mary has submitted over 225 electronic submissions through the FDA ESG.

Suzanne Sensabaugh

Mary is an expert provider of electronic Common Technical Documents  (eCTD) publishing services. Since joining HW in 2016, Mary has submitted over 225 electronic-submissions through the FDA ESG.