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In FDA’s draft guidance about demonstration of interchangeability, FDA recommended switching studies with the aim to demonstrate that the risk in terms of safety or diminished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The draft guidance entitled, Considerations in Demonstrating Interchangeability with a Reference Product, also highlights that if a patient has an adverse reaction during the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.

Regenerative Medicine Advanced Therapy Designation: Regulatory Shortcuts for Market Approval

Regenerative Medicine Advanced Therapy Designation: Regulatory Shortcuts for Market Approval

By Roushan Afroze and Suzanne M. Sensabaugh, MS, MBA

Near the end of 2016, the United States Congress enacted the 21st Century Cures Act to expedite the development and review of biologics that address unmet medical needs. This is to be accomplished by introducing a new designation process for regenerative advanced therapies, called Regenerative Medicine Advanced Therapies (RMATs). FDA’s Draft Guidance for Industry Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (November 2017) describes the Agency’s recommendations for the development and review of these therapies.

To obtain RMAT designation the product must meet the following criteria:

The biologic  must fall under the regenerative medicine therapy definition;

The biologic  must be intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and

The preliminary clinical evidence of the biologic must indicate that the biologic has the potential to address unmet medical needs for such disease or condition.

RMAT designation applies to cell therapies, therapeutic tissue engineering products, human cell and tissue products, or any combination product using any such therapies or products. Products regulated solely through the Public Health Service (PHS) Act §361 and 21 CFR Part 1271 do not qualify for RMAT designation. Products with the RMAT designation are also eligible for FDA’s other expedited programs, which include fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation, if they meet the criteria for such programs.

A request for RMAT designation must be made with or after the Investigational New  Drug (IND) application is submitted to the FDA. In most cases, the RMAT designation request is submitted as an amendment to an existing IND. As opposed to breakthrough designations, the RMAT designation does not require evidence to indicate that the biologic may offer a substantial improvement over available therapies – it must only have preliminary clinical evidence that the biologic has the potential to address an unmet medical need.

The designation request should include:

• A rationale that the biologic meets the definition of a regenerative medicine therapy;

• A discussion to support that the disease or condition, or the aspect of the disease or condition, that the product is intended to treat is serious;

• A summary of the risks and benefits associated with the therapies, if any, currently available for this condition;

• A description of the unmet medical need that the product has the potential to address; and

• The preliminary clinical evidence that the product has the potential to address the specified unmet medical need for this serious condition.

Upon receipt of the request, the FDA Center for Biologics Evaluation and Research (CBER) Office of Tissues and Advanced Therapies (OTAT) has 60 calendar days to determine if a RMAT designation can be granted. If the RMAT designation request does not meet the criteria for designation, the FDA sends a written explanation for its decision to the sponsor.

The draft guidance document Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (November 2017) is for comment purposes only. The document contrasts key features of the Breakthrough Therapy Designation and the RMAT Designation (see table below)

Source: FDA Draft Guidance document for Industry: Expedited Programs for Regenerative Medicine Therapies for Serious Conditions available at

https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm585414.pdf

For those therapies which receive RMAT designation and accelerated approval, post-approval requirements may be fulfilled through the submission of the following:

Clinical evidence, clinical studies, patient registries, or other sources of real world evidence such as electronic health records;

Collection of larger confirmatory clinical trials as agreed upon during product development; or

Post-approval monitoring of all patients treated with the therapy prior to approval of the therapy

CBER will determine what type of post-approval requirements will be necessary to confirm the clinical benefits of a RMAT that receives accelerated approval upon review of the BLA.

Finally, CBER encourages interested sponsors seeking accelerated approval for their RMAT to consult with the agency early in development. More information about RMATs and the application process can be found on the FDA website. https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm537670.htm

Suzanne M. Sensabaugh has advanced the development of over 130 biologics, biosimilars, and biologic/device combination products since 2009. She has successfully requested and received RMAT designation from the FDA. She can be reached at smsensabaugh@hw-fda,com.

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 Will Not Delay the Implementation of the eCTD DMF Mandate Again

FDA Will Not Delay the Implementation of the eCTD DMF Mandate Again

Mary Waters, Consultant 

At the DIA Regulatory, Submission and Information Management (RSIDM) conference held in Bethesda, MD, February 2018, the FDA directly stated that they would not delay the implementation of the eCTD DMF mandate again.

If your company/organization has taken a ‘wait and see’ approach to determine how they will comply with this mandate – maybe just hoping for another delay or even possibly a repeal – your time is just about up! If this your organization, you need to make something happen NOW!

Previously, the FDA allowed additional time to transition over from paper to electronic to allow DMF holders to prepare. That said, beginning on May 5, 2018, all new DMFs, as well as all documents submitted to existing DMFs, must be submitted using the electronic Common Technical Document (eCTD).

DMF submissions that are not submitted in eCTD format after this date will be rejected.

Need help preparing your documents? Have questions regarding this looming mandate?  Check out our website at  www.hw-fda.com or send an email to smsensabaugh@hw-fda.com !!!

WE ARE HERE TO HELP!

 

 

Mary Waters

eCTD Publishing Services.com

Part 2: Roles and Responsibilities of the Primary Agencies that Regulate the Products of Biotechnology.

Part 2: Roles and Responsibilities of the Primary Agencies that Regulate the Products of Biotechnology.

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

In part 1 of this mini-series discussing the newly-released 2017 Update to the Coordinate Framework for the Regulation of Biotechnology, we discussed some of the background relevant to understanding this document and how it came about., This second blog post will discuss the Roles and Responsibilities of the Primary Agencies that Regulate the Products of Biotechnology.

As mentioned in part 1, the “primary agencies” include the U.S. Food and Drug Administration (FDA), U.S. Environmental Protection Agency (EPA), and the U.S. Department of Agriculture (USDA). These three agencies act both independently and alongside each other to regulate various biotechnological products. Each agency overlooks several statutes that guide that specific agencies’ agenda, with each statute having a specific protection goal (not mentioned in this post). Briefly, the statutes for each agency are:

FDA – Federal Food, Drug, and Cosmetic (FD&C) Act; Public Health Service (PHS) Act

EPA – Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA); Federal Food, Drug, and Cosmetic Act; Toxic Substances Control Act (TSCA)

USDA – Animal Health Protection Act (AHPA); Plant Protection Act (PPA); Federal Meat Inspection Act (FMIA); Poultry Products Inspection Act (PPIA); Egg Products Inspection Act (EPIA); Virus-Serum-Toxin Act (VSTA)

The FDA regulates a wide variety of products, including human and animal foods (including dietary supplements), cosmetics, human and veterinary drugs, human biological products and medical devices. Some of the key regulatory framework associated with the FDA includes: human and animal foods derived from genetically-engineered (GE) plants; GE animals; human drugs; biologics; and medical devices derived from GE sources.

The EPA is responsible for protecting human health and the environment. Some of the key regulatory framework associated with the EPA includes: FIFRA FD&C Act, section 408, and TSCA. Under FIFRA, EPA regulates pesticides; under section 408 of the FD&C Act, EPA establishes the amount of pesticide chemical residues that may be present in foods; under the TSCA, EPA regulates biotechnology products that are new organisms not specifically excluded by the statute.

The USDA is responsible for developing and executing federal laws related to farming, agriculture, forestry, and food. Some of the key regulatory framework associated with the USDA includes: the Animal and Plant Health Inspection Service (APHIS) and the Food Safety and Inspection Service (FSIS). Under APHIS, USDA regulates products of biotechnology that may pose a risk to agricultural plant and animal health through the PPA and AHPA, respectively. Further, through the VSTA, again contained within APHIS, USDA oversees the regulation of products of biotechnology that are included in veterinary biologics, including the manufacturing and distribution and the purity, safety, potency, and effectiveness of these products. Under the FSIS, USDA ensures that the United States’ commercial supply of meat, poultry, egg products, and fish of the Order Siluriformes is safe, wholesome, and correctly labeled through the FMIA, PPA, and EPIA.

The 2017 Update to the Coordinated Framework contains a very descriptive table (Table 2) summarizing the current responsibilities and relevant coordination across EPA, FDA, and USDA for the regulatory oversight of biotechnology products, effectively identifying the responsible agency or agencies for different products and their applications. A list of the product areas and agencies involved for each product outlined in the table include:

 

Product Area
Agency(s) Involved
Specific Reason(s) for Agency Oversight

Food for humans

USDA

FDA

EPA

USDA: if plant/animal poses a plant pest risk or health risk to livestock

FDA

EPA: regulation of pesticide substance and related genetic material for human/environmental safety

Food for animals (i.e. pet and livestock food)

USDA

FDA

EPA

USDA: if plant/animal poses a plant pest risk or health risk to livestock

FDA

EPA: regulation of pesticide substance and related genetic material for human/environmental safety

Drug for humans

FDA

USDA

FDA

USDA: if plant poses a plant pest risk

 

Biologics for humans

FDA

USDA

FDA

USDA: if plant poses a plant pest risk

Medical device or medical diagnostic for humans

FDA

USDA

FDA

USDA: if plant poses a plant pest risk

Drug for animals (including farm animals and pets)

FDA

USDA

FDA

USDA: if plant poses a plant pest risk

Biologics for animals (veterinary biologics) (i.e. vaccines, etc.)

FDA

USDA

FDA: if rDNA construct itself does not meet veterinary biologic definition

USDA: if plant poses a plant pest risk

Medical device for animals

FDA

USDA

FDA

USDA: if plant poses a plant pest risk

Cosmetics

FDA

USDA

FDA

USDA: if plant poses a plant pest risk

Industrial or consumer chemicals, including pesticide intermediates

USDA

FDA

EPA

USDA: if plant poses a plant pest risk

FDA

EPA: if microbe is intergeneric and is manufactured/processed for commercial production purposes for a use that is not excluded under TSCA and is not otherwise exempt from reporting

Biomass conversion for chemical production, microbial fuel cells, mining and resource extraction, building materials, waste remediation and pollution control, non-pesticidal agriculture applications, and all other applications of intergeneric microbes not otherwise excluded under TSCA

EPA

EPA: if microbe is intergeneric and is manufactured/processed for commercial production purposes for a use that is not excluded under TSCA and is not otherwise exempt from reporting

Other (non-food, non-chemical producing, non-drug producing, non-biologic producing, non-pesticidal organisms)

 

USDA

FDA

EPA

USDA: for ornamental, silvicultural, or turfgrass crops, if plant poses a plant pest or noxious weed risk; if animal poses a plant pest risk or health risk to livestock; if plant-associated microorganism poses a plant pest risk

FDA

EPA: if microbe is intergeneric and is manufactured/processed for commercial production purposes for a use that is not excluded under TSCA and is not otherwise exempt from reporting

Pesticide

USDA

FDA

EPA

USDA: if plant/animal/microbe poses a plant pest risk

FDA: if human/animal food, FDA oversees non-EPA-regulated aspects of the food for safety of human/animal consumption

EPA: regulation of microbial pesticide, pesticide substance and related genetic material produced by plants/animals for human/environmental safety, including the safety of dietary exposure to pesticide residues in human/animal food

 

This concludes part 2 of our mini-series. In part 3, we will discuss interagency communication and coordination. Please contact us if you have any questions about this Update 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

Part 1: 2017 Update to the Coordinated Framework for the Regulation of Biotechnology

Part 1: 2017 Update to the Coordinated Framework for the Regulation of Biotechnology

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

In 2017, a joint effort between the U.S. Food and Drug Administration (FDA), U.S. Environmental Protection Agency (EPA), and the U.S. Department of Agriculture (USDA) produced the “2017 Update to the Coordinated Framework for the Regulation of Biotechnology.” This update represents a sequel to the 1986 Coordinated Framework for the Regulation of Biotechnology and the 1992 Update of the Coordinated Framework and is intended to clarify the current roles and responsibilities of the three above primary agencies involved in the regulation of biotechnology products, to develop a long-term strategy to ensure that the Federal biotechnology system is prepared for the future products of biotechnology, and to commission an expert analysis of the future landscape of biotechnology products to support these efforts. The below blog post is part 1 of 4 discussing this update. This post will detail the background necessary to understand this update.

As we are all aware, the landscape of biotechnology and biologics is rapidly changing with new advances in the science and technology, altering how the government regulates such products. Further, the complexity of the current regulatory is not conducive to a general public understanding of the regulation of biotechnology products and creates challenges for small and mid-sized businesses navigating the regulatory process for these products. The first Coordinated Framework was released in 1986 and explained the proper allocation and coordination of oversight responsibilities among relevant Federal agencies, including the FDA, EPA, and USDA. It was noted that this Framework was “expected to evolve in accord with the experiences of the industry and agencies…”

As such, the 1992 Update to the Coordinated Framework was released and described a risk-based, scientifically sound basis for the oversight of activities that introduce biotechnology products into the environment. Based on the original Coordinated Framework and the 1992 update, the FDA, EPA, and USDA have developed their own agency-specific regulations, rules, and policy documents and updated them as necessary.

Since the 1992 update, advances in science and technology have resulted in the development of products not previously possible. As such, an update to the aforementioned Coordinated Framework documents was necessary to facilitate appropriate Federal oversight by the regulatory agencies. On July 2, 2015, the Executive Office of the President (EOP) issued a memorandum to the FDA, EPA, and USDA to update the Coordinated Framework. The memorandum established a Biotechnology Working Group with representatives from the EOP, FDA, EPA, and USDA to implement the tasks in the memorandum. The memorandum stated that the following four objectives be accomplished:

  • clarifying which biotechnology product areas are within the authority and responsibility of each agency
  • clarifying the roles that each agency plays for different product areas, particularly for those product areas that fall within the responsibility of multiple agencies, and how those roles relate to each other in the course of a regulatory assessment
  • clarifying a standard mechanism for communication and, as appropriate, coordination among agencies, while they perform their respective regulatory functions, and for identifying agency designees responsible for this coordination functions; and
  • clarifying the mechanisms and timeline for regularly reviewing, and updating as appropriate, the Coordinated Framework to minimize delays, support innovation, protect health and the environment and promote the public trust in the regulatory systems for biotechnology products.

Over the next three posts, we will discuss the above four objectives and how they were accomplished in the 2017 Update to the Coordinated Framework.

Suzanne M. Sensabaugh

Suzanne M. Sensabaugh is President and Principal Consultant of Hartmann Willner, where she is a regulatory affairs consultant who provides professional advice to clients.