Biosimilar Marketing Application CMC Deficiencies identified in the US and in Europe

Biosimilar Marketing Application CMC Deficiencies identified in the US and in Europe

By Nitisha Pyndiah, PhD

Regulatory agencies such as FDA and EMA require that biosimilars be highly similar and have no clinically meaningful differences with a reference product. In February 2018, EMA published in AAPS PharmSciTech, trends in deficiencies identified during the evaluation of the quality part of applications for marketing authorizations. Several of these deficiencies have also been observed in the US.

Here I propose to discuss common deficiencies that I found in biosimilar applications and use the list of common quality deficiencies in EMA marketing submission as a basis. By doing so, I wish to help biosimilar developers address or avoid deficiencies prior to submission to allow their product to reach market faster!

Part 1: What are the major deficiencies identified regarding the Drug Substance?

Biocomparability: Issues due to lack of supporting data when comparing reference product to proposed biosimilar. Differences in glycosylation not well elucidated, insufficient data regarding differences in potency assay results.

Analytical methods validation: All validation characteristics recommended for the type of test should be done. All validation data should be submitted to the regulatory body. I have often seen that there was insufficient validation of the analytical method used.

Reference standards or materials: Issues with calibration and qualification, lack of information about in-house reference material and how they were established.

Stability: Inadequate or insufficient stability data to support the proposed shelf life. No appropriate stability results using the proposed container closure system.

Processes: The manufacturing process and process controls should be described thoroughly.

Specifications: The lack of justification regarding the specification of DS. Specifications unmet due to insufficient validation of the analytical method used.

Drug substance comparability: Comparability of similar manufacturing processes not adequately shown.

Sourcing of reference product: To obtain licensure a sponsor has to demonstrate that the proposed product is biosimilar to a reference product that has been previously licensed by FDA or establish an acceptable bridge between the non-US reference product the US-licensed reference product and the biosimilar.

I have often seen sponsors using a non-US product prior to using a US-licensed reference product and carrying out bridging studies. Inconsistencies in the sourcing of the reference product for the comparability program for quality, safety and efficacy studies have been seen.

Characterization: A common deficiency is the inadequate elucidation of structure and characteristics of the DS, I have observed that the elucidation of the structure was often incomplete. Orthogonal physicochemical methods are important in confirming the structure and characteristics of the drug substance. FDA strongly recommends using multi-parameter approaches that are extremely sensitive in identifying analytical differences.

Mainly, I have often seen that glycosylation was not well characterized; differences in post translational modifications (PTM) between the reference product and the biosimilar may lead to immunogenicity (i.e detrimental immune response in the patients commonly measured using anti-drug antibodies). The most common PTM is glycosylation and should be well characterized to also ensure that not clinically meaningful differences are observed between a biosimilar and a reference product. The drug substance is produced in nonhuman tissues, therefore it is important to ensure that nonhuman glycosylation that could potentially induce a detrimental immune response are not present.

Do you need help with your biosimilar product?

Are you in the process of developing a biosimilar biological product? Do you need help preparing and submitting your IND or BLA to the FDA? Or perhaps you need to request a Biosimilar Initial Advisory Meeting or a Biosimilar Product Development (BPD) 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 andGMP. 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.

 

Biosimilar developer, what are your BsUFA fees for FY 2019? Let’s clarify those for you!

Biosimilar developer, what are your BsUFA fees for FY 2019? Let’s clarify those for you!

By Nitisha Pyndiah, Ph.D.

 

The BPD/Program Fee invoices for FY2019 were emailed on August 27, 2018. As a follow-up to my previous blog post on the BsUFA II fees, I will list the BsUFA fees since FY 2015 and use two case studies to help you understand the changes in your Biosimilar User Fees.

In our previous blog post, we described the user fee types for biosimilars: Biosimilar Biological Product Development (BPD) Fees, Application fees and Program fees. We highlighted a major change which eliminated the reduction of an application fee by the cumulative amount of fees paid by the applicant under the BPD program. For certain biosimilar developers that have been in the program for a long time it means an important budget change as there would be no deduction to their application fees. This increase in the fees will be used to expedite the review process for biosimilars, enhance review transparency and communication. According to the Agency, in the BsUFA II Five-year Financial Plan: “During BsUFA I, FDA received fewer original biosimilar biological product application submissions than the Agency had initially expected to receive, which resulted in the collection of relatively more BPD fees than expected and fewer application, establishment, and product fees […] FDA anticipates that many of the development programs started in BsUFA I will convert to original submissions early in BsUFA II, which would contribute to an increase in application review work relative to BsUFA I.”

As a biosimilar developer, you should be aware of these changes to plan appropriately your drug development and maybe realign your budget.

To understand better the change in fees, the user type fees from FY2015 to FY2019, have been listed in the table below.

In green, no reduction on the application fee.

Table 1: Overview of the BsUFA fees from FY 2015 to FY 2019.

Case Study 1

In June 2017, a company A submitted their BLA for their Biosimilar product. Company A had been in the program for three years and would have paid $ 891,660 in BPD fees ($ 216,910 initial BPD fees in 2014 and the annual fees until FY 2017, see table 1). Under BsUFA I, Company A was able to reduce their application fee by deducting the amount paid in BPD fees from the application fee due when the BLA was submitted on June 2017. This company A paid $1,146,440 at the time of the marketing application submission. ($2,038,100 – $891,660= $1,146,440)

•  The total amount of BsUFA fees paid until after submission of the application: $1,146,440

Please note that company A would have paid an establishment fee of $512,200 and a product fee of $ 97,750 once the submission was approved.

Case Study 2

Our second example is company B wishing to submit their BLA for their Biosimilar Product in December 2018. Company B has been in the program for over four years and has paid $ 1,304,282 in BPD fees ($ 216,910 initial BPD fees in 2014 and the annual fees until FY 2019, see table 1).

Company B, initially thought (when they entered the program) that they would be able to reduce their application fee with the amount paid in BPD fees but under BsUFA II they will have no reduction in their application fee at the time of marketing application submission.

Here is the economic impact on the product development of their biosimilar product:

If company B submits the application in December 2018, it means that company B would have to pay the full application fee (w/clinical data) $ 1,746,745 and would have also paid $ 1,304,282 in BPD fees. Although the company is submitting the application in December 2018, they will still have to pay the BPD fees for FY2019 as these are due on the first business day on or after October 1 of each fiscal year.

•  Total amount of BsUFA fees paid until after submission of the application: $1,304,282+$1,746,745=$ 3,051,027

Please note that company B would have to pay an annual program fee of $304,162 for each biosimilar biological product identified in the application (applicants will not be assessed more than 5 program fees per FY) once the product is approved.

for further information, please see “BsUFA II fees—are you aware of the major changes?” here.

 

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.

It’s NOT a Snowman, it’s SNOMED!

It’s NOT a Snowman, it’s SNOMED!

By Mary Waters, Senior Consultant, eCTD Publish Services

The FDA updated their Form FDA 1571 and Form FDA 356h in May 2018 to include a few new fields; 6B, 7B, and 15B. This change on the Form FDA 1571 now includes the SNOMED CT Indication Disease Term. SNOMED CT is the acronym for Systematized Nomenclature of Medicine Clinical Terms.

SNOMED International established in 2007 and is responsible for determining the global standard for healthcare terminology. SNOMED CT is considered the most comprehensive and multilingual terminology for clinical healthcare worldwide and is the basis and general core terminology for all electronic health records. There were more than 30 countries involved in contributing, developing, and maintaining SNOMED CT. The FDA has adopted this terminology standard for coding study indications for submissions such as IND, NDA, BLA, and ANDA.

The primary purpose of using SNOMED CT is to encode the meanings in health information, support effective clinical records, provide consistent information in data. Using SNOMED CT allows for a consistent manner to index, store, retrieve and aggregate clinical data across specialties and care sites. These consistent terms are also used in representing the medical conditions in Structured Product Labeling (SPL).

The SNOMED CT nomenclature includes clinical findings, symptoms, diagnoses, procedures, body structure, organisms and other etiologies, substances, pharmaceuticals, specimens, and devices.

To complete the Form FDA 1571, ensuring the completed form passes validation and is not rejected, it’s best to go directly to the SNOMED International website which is found at http://browser.ihtsdotools.org/.

There are currently nine editions to choose from, but for US FDA purposes, please select the United States Edition. Also, please note that the website states that Internet Explorer will not work and to use Google Chrome.

After you have chosen the US Edition, the next page will show you tab choices of Taxonomy, Search, Favorites, and Refset. The next set of tab choices are the Concept Details: Summary, Details, Diagram, Expression, Refset, Members and References.

Using the Search box, if you type in the term “migraine”, the program provides 156 matches for this term, which could be further grouped or filtered. The US National Library of Medicine (NLM) maintains a module of core metadata concepts which is indicated by a US Flag icon.

When completing the Form FDA 1571, the agency is looking for both the Concept Code (e.g. 37796009) and the Disorder (e.g. Migraine). This is the information needed to complete Field 7B.

The other notable change to the Form FDA 1571 is the addition of Field 6B. You now need to indicate if your submission is Commercial or Research. If you select Commercial, you are stating that the product(s) are under investigation that are intended to be commercialized at a later time; and Research is defined as products under investigation that will not or are not intended to be commercialized at a later time. With this change, the FDA is now requiring that commercial INDS will be formatted in eCTD.

The FDA is refining their processes for preparing electronic submissions. These changes should make doing business with them easier, especially for those who are new to this area. If, however you or your firm still need some help after reviewing the instructions, please reach out to us. We can help you not only interpret or choose the appropriate code(s) to use but can also help you properly complete the form. Remember, we are only just a phone call away!

 

 

 

Nitisha Pyndiah - Biotech Consulting Services

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.

 

FDA’s Thoughts on Adolescents in Adult Clinical Oncology Trials

FDA’s Thoughts on Adolescents in Adult Clinical Oncology Trials

By Rose Pagano and Suzanne M. Sensabaugh, MS, MBA

 

Pediatric cancer is frequently different than cancer found in adults and requires unique treatments. Conversely, certain cancers (soft tissue and bone sarcomas, central nervous system tumors, leukemias and lymphomas, and melanoma) in adolescents are similar to those found in adults.  Typically, age restrictions disqualify adolescents from participation in adult oncology trials. Also, drug trials for adolescents usually beginning after the drug is approved for adults. As a result, adolescent patients may have delayed access to potentially beneficial drugs.

The FDA recently released “Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials Guidance for Industry” to convey information regarding the incorporation of adolescent patients (ages 12 to 17) in adult oncology clinical trials to the pharmaceutical industry and clinical investigators. According to the document, the FDA recommends involving adolescents in the appropriate adult oncology trials to facilitate more preemptive examination and approval of drugs for adolescents with cancer. The guidance details ethical requirements, safety procedures, dosing and pharmacokinetic (PK) evaluations, and necessary conditions for the incorporation of adolescent patients in adult oncology trials in the numerous stages of drug development.

This guidance is intended to be a general overview for sponsors debating the use of this approach. Obviously, the specific elements of a drug development program in adult oncology that incorporates adolescent patients differs based on the drug and disease being analyzed. Due to this variability, it is recommended that sponsors contact the necessary FDA review division to discuss details before the program is initiated with patients.

Generally, the document states that adult oncology clinical trials at any stage in drug development should be accessible to adolescent patients when the histology and biologic behavior of the cancer being tested is the same in both patient groups. For both first-in-human and dose-escalation trials, adolescents can be involved with the trial once the initial adult PK and toxicity data has been collected. Sponsors should contact the FDA review division to decide if the data is sufficient enough to enroll adolescents.

If the adolescent patients are going to be early dose cohorts, the doses should satisfy 21 CFR 50.52 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects. Usually, adolescents involved in early phase trials should have cancers that have relapsed or are refractory to typical therapies. In activity estimating or confirmatory trials, adolescents are allowed to be admitted to the program concurrently with adults.

Additionally, the necessary drug doses for adolescents should be determined based on if the adult dosage is according to body size or fixed dose. For drugs that are given in a fixed dose, there should be a minimum body weight adolescents need to meet to receive the drug. Based on research conducted by the FDA, 40 kg is usually the safest minimum body weight.

For these clinical trials, a suggested dosage needs to be reinforced by PK characteristics of the drug in question. It is important to keep in mind how the adolescent patient’s size will influence the drug’s pharmacokinetics, therapeutic index of drug, and dose and exposure response relationships. PK analysis for adolescents should be conducted when adolescents become involved in the drug development program.

Safety monitoring was also mentioned in the document. Information gathered during the course of the trial concerning safety should be analyzed for age-related differences. Developmental toxicities, such as growth derangements and fertility issues, resulting from drug exposure should be analyzed in a longitudinal evaluation. Juvenile animal studies are not always required before including adolescents in oncology clinical trials unless data do not provide sufficient information on toxicity.

All in all, enrolling adolescents in relevant adult oncology trials with the necessary dose considerations and safety monitoring is justified by the life-threatening nature of their disease.

LET US HELP YOU TO GAIN FDA APPROVAL

At HartmannWillner LLC we understand the regulatory requirements for FDA approval, such as the requirements explained above for oncology studies. With our help, you can develop a realistic strategy that will move your product closer to approval as you reach each regulatory milestone.  Contact us today to learn more about our services and how we can help you.

 

 

 

Nitisha Pyndiah - Biotech Consulting Services

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 releases Q&A Guidance After Confusion Surrounding S9A Nonclinical Evaluation for Anticancer Pharmaceuticals Guidance

FDA releases Q&A Guidance After Confusion Surrounding S9A Nonclinical Evaluation for Anticancer Pharmaceuticals Guidance

By Rose Pagano and Suzanne M. Sensabaugh, MS, MBA

 

The S9 Nonclinical Evaluation for Anticancer Pharmaceuticals Guidance (ICH S9) has resulted in confusion and challenges amongst its users. S9 Nonclinical Evaluation for Anticancer Pharmaceuticals Questions and Answers Guidance for Industry is intended to aid in the implementation of ICH S9 and help with the reduction, refinement, and replacement of animals.

ICH S9 nonclinical program is applicable to the majority of initial development programs for both adult and pediatric patients suffering from diseases that are resistant and refractory to available therapies. For programs where the cancer is not considered to be resistant or refractory, ICH S9 can be used as a starting point and ICH M3 and S6 may serve as good references. Always consult with FDA if the development pathway remains unclear.

Many have interpreted the ICH S9 guidance as applying to people with life expectancies around three years. However, the guidance does not make reference to the number of years patients are expected to live and how that should dictate drug trials. Utilizing this guidance should not be dictated on life expectancy, but rather on the resistant and refractory nature of the cancer.

It is important to note that using the principles of ICH S9 for non-oncology therapies for diseases that are life-threatening and have limited drug treatments goes outside the scope of the document. ICH M3 would be a good guidance to reference for these situations.

Additionally, the Q&A clarifies that if an anticancer pharmaceutical is proven to extend survival of patients, then typically general toxicology studies are unnecessary. Clinical safety data are meant to assess human risks more so than those generated by further animal studies. Additional toxicology studies other than general toxicology may be required depending on the situation, and these studies should be submitted after approval of the anticancer drug.

Also, the document explains that additional toxicology studies are not warranted when moving therapeutic development from an approved indication in oncology or from an unapproved indication with a sufficient nonclinical and clinical safety database to an unapproved oncology indication that is serious but not life-threatening. Again, clinical safety data for a patient population for an approved indication are most beneficial in an unapproved indication.

Furthermore, clinical trials in the adjuvant or neo-adjuvant setting are also covered under ICH S9. This document is a good starting point for drugs used in these settings even when there is not a detectable residual disease.

The Q&A guidance goes on to state that scientific assessment of recovery potential should be given in general toxicology studies to support clinical development, but recovery groups do not need to be included in all general toxicology studies. These data can be generated through the understanding that a certain effect is seen as reversible or non-reversible or by having a recovery period in at least one study. Recovery in 3-month studies is only necessary if there is a concern in short-term toxicology or from clinical studies that recovery animals could answer.

If there is a situation where the only relevant species is a non-human primate (NHP), a weight-of-evidence assessment of reproductive risk should be given. If the weight-of-evidence assessment  indicates risk, then a NHP study is not necessary. An NHP study for analysis of a hazard to embryofetal development should not be a default approach.

Nonclinical studies on abuse liability are usually unnecessary to support clinical trials and the marketing of pharmaceuticals for patients with advanced cancer. Likewise, for biopharmaceuticals, tissue cross reactivity studies are not required for an initial first-in-human study or later in development,  unless there is specific cause for concern. If there is no pharmacologically relevant species, human tissue cross reactivity and other methods may be a potential route of investigation for the first-in-human study.

All things considered, this Q&A guidance answered many of the commonly asked questions concerning the initial ICH S9 guidance and is useful for applicants under these protocols.

WE CAN HELP GET YOUR NONCLINICAL PROGRAM ACCEPTED BY THE FDA

Are you in the process of developing an anticancer drug product? Do you need help preparing and submitting your 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.

 

Nitisha Pyndiah - Biotech Consulting Services

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

BsUFA II fees—are you aware of the major changes?

BsUFA II fees—are you aware of the major changes?

By Nitisha Pyndiah, PhD

The FDA guidance document Assessing User Fees Under the Biosimilar User Fee Amendments of 2017 explains the changes, but let’s review the most important items.

Quick introduction

The Biosimilar User Fee Act of 2012 (BsUFA I) added sections to the FD&C Act, authorizing FDA to collect user fees for a 5-year period from developers of biosimilar biological products. BsUFA was reauthorized in 2017 for a 5-year period under Title IV of the FDA Reauthorization Act of 2017 (BsUFA II) and fees have increased. Read on to understand those changes.

What are the main differences between BsUFA I and BsUFA II?

There are three types of fees under BsUFA II that are set each fiscal year:

  • Biosimilar biological product development program fees (BPD fees)
  • Biosimilar biological product application fees (application fees)
  • Biosimilar biological product program fees (program fees)

This means that the fees for supplements and for establishments have been eliminated.

A very important aspect is that BsUFA II also eliminates the reduction of an application fee by the cumulative amount of fees paid by the applicant under the BPD program meaning that the full application fee will be due at the time of submission for BLAs with clinical data required to support safety and efficacy.

For example, if an applicant submits their BLA in December 2018, the BPD annual fees for FY2019 will be due on October 1, 2018 and will not be refunded or deducted.

The fees for FY2019 (October 1, 2018 to September 30, 2019) will be published in August 2018.

 

Let’s describe further those BSUFA II fees

BPD fees

Initial BPD fee

One-time fee assessed to a sponsor to enter a BPD program (the sponsor enters the program by submitting a meeting request for a BPD meeting for a product or submits a clinical protocol for an investigational new drug application (IND) describing an investigation to support a biosimilar biological product application)

Annual BPD fee

An annual fee that the sponsor has to pay the next fiscal year after paying the initial BPD fee. This amount is due on or after October 1 of each fiscal year.

As this part can be confusing, some further clarifications: If a person submits a BLA for a biosimilar before October 1 of the fiscal year and the application is accepted for filling on or after October 1 of that fiscal year, the applicant may request a refund of the annual BPD fee paid.

A sponsor may also wish to discontinue the participation in a BPD program but need to keep in mind that to resume participation in the BPD program (by requesting a BPD meeting or submitting a clinical protocol to an IND) the sponsor will have to pay a reactivation fee within 5 calendar days of FDA granting a meeting or upon submission of the IND. That reactivation fee is twice the amount of the annual BPD fee established for that fiscal year.

Application fees

  • From FY 2018, each person that submits an application (BLA for biosimilar) is assessed an application fee:
    • Full application fees for a biosimilar BLA for which clinical data with respect to safety or effectiveness are required for approval
    • Half of the full application fees for a biosimilar BLA for which clinical data with respect to safety and effectiveness are not required for approval
  • Exception to the application fees
    • If a biosimilar BLA:
      • was submitted by a person that paid the fee for the application,
      • was accepted for filing, and
      • was not approved or was withdrawn (without a waiver)
    • Refund of the application fee
      • If an application is refused for filing or is withdrawn without a waiver before filing, FDA will refund 75% of the application fee paid. An application that was withdrawn before filing or refused for filing will be subject to the full application fee when resubmitted, unless a waiver applies.
    • Waiver of the application fees
      • Small business submitting its first biosimilar biological product application to the FDA and does not have another product that has been approved under a human drug application or a biosimilar.

Program fees

A fee for approved applications

Program fees are assessed to each person who is named as the applicant in a biosimilar biological product application for each biosimilar biological product identified in an approved biosimilar biological product application as of October 1 of the fiscal year.

Important note: Program fees for liquid parenteral biosimilar biological products. The definition of biosimilar biological product was reviewed under BsUFA II to mean a ‘specific strength of a biological product in final dosage form for which a biosimilar biological product application has been approved’. E.g an autoinjector with the same strength or potency in final dosage form as a prefilled syringe or vial will be assessed a separate program fee.

There is a limit of five program fees to be paid for biosimilar biological products identified in each approved application.

What happens if you fail to pay the fees?

  • A BPD meeting related to a product for which fees have not been paid, will not be granted by FDA
  • FDA will not consider an IND submitted for the product to have been received under section 505(i)(2) of the FD&C Act if FDA determines that the investigation is intended to support a biosimilar biological product application
  • FDA shall prohibit the sponsor of a clinical investigation from continuing the investigation (‘financial hold’) if FDA determines that the investigation is intended to support a biosimilar biological product application.

Stay tuned for our next blog post on this topic where we will provide you with the detailed costs for the development of a biosimilar biological product.

Do you need help with the development of your biosimilar product or determining what fees you have to pay?

Are you in the process of developing a biosimilar biological product? Do you need help preparing and submitting your IND or BLA to the FDA? Or perhaps you need to request a Biosimilar Initial Advisory Meeting or a Biosimilar Product Development (BPD) 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.