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.


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.


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.

FDA Public Docket for Technical Specifications

FDA Public Docket for Technical Specifications

By Mary Waters

Here’s Your Opportunity to be Heard

The Food and Drug Administration (FDA) has established a public docket so that anyone can share information, comments, and ideas on any matters related to the use of their technical specifications or technical specification guidance.

This is a great opportunity for those of you in the trenches to provide insight to the Agency about these specification/standards and if they are working or not for your organization.

What’s Behind Establishing a Public Docket

The Agency’s determined that it was not possible to describe and implement the electronic format(s) that could apply to every submission covered by section 745A(a) of the Federal Food, Drug, and Cosmetic Act in a single document. Instead, they created “standards” to explain their interpretations and to explain, clarify, and define the use of data standards used for certain submissions (new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and certain investigational new drug applications (INDs)).

By having established standards, the study data is uniform. This helps the Agency with being more effective and efficient in receiving, processing, reviewing and archiving submissions.

The Agency is interested in assisting sponsors in the submission of data in a standardized electronic format for NDAs, ANDAs, BLAs, and certain INDs. Both CBER and CDER have established technical specifications guidances which provide the thinking behind the established specifications, recommendations, and general considerations. These technical specifications explain, clarify, and define the specific use of data standards in regulatory submissions. In other words, the technical specifications break down the who, what, when, and where of the guidances.

Why You Should Comment

By providing your comments and viewpoints, this information gives the Agency insight into your (stakeholders’) experiences and views regarding the use of these technical specifications guidances and the data standards they contain. This may be a golden opportunity to make them easier to understand or apply to your data. And, that is a good thing in any industry!

Maybe you’ve found a specification or standard that is no longer relevant or just too complicated to use effectively. Or maybe you’re thinking about starting or have recently established your ESG account or secure email; this is where your input to the Agency is very valuable.

HartmannWillner Has Been There – Done That!

This link below will take you to the FDA’s Study Data Standards Resources web page that has all of the information, guidances, technical guides, position statements as well as business rules all listed in one place. You might want to bookmark this page for easy reference.


If after researching and reading, you still have questions and need answers, we can help you! We’ve been there and done that many, many times. Let us help you with any of your electronic publishing needs – we are just an email or phone call away!

Mary Waters

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.

Update to the eCTD “Mandate”

Update to the eCTD “Mandate”

By Mary Waters

The FDA had a mandate for submitting in eCTD format Drug Master Files (DMFs) (other than Type III – packaging material). Luckily for some, there was a reprieve as the FDA extended that date another year until 05 May 2019. That said, there are still other submissions types that now need to be submitted in eCTD.

Submission Types Required in eCTD Format

In section 745A(a) of the Food, Drug, & Cosmetic Act (FD&C Act), Congress granted explicit authorization to FDA to implement the statutory electronic submission requirements. This section also applies to all subsequent submissions, including amendments, supplements, and reports, to the submission types identified below:

  • New Drug Applications (NDA)
  • Abbreviated New Drug Applications (ANDA)
  • Biologics License Applications (BLA)
  • Commercial Investigational New Drug (IND) applications
  • Master files, such as DMFs

Implications for NOT using eCTD

Submissions not in electronic format(s) as described in the FDA guidance document will NOT be filed or received unless exempted from the electronic submission requirements (e.g., investigator-sponsored INDs: emergency use INDs and treatment INDs).

Electronic Submission Specifications and More

OMG, where to start…

  • Obtain a pre-assigned application number from the appropriate FDA Center.
  • Must follow the FDA eCTD technical specifications.
  • Must place each file in the appropriate main folder (m1 through m5) as well as the appropriate subfolder.
  • Must use the correct nomenclature for file names (only letters, numbers, hyphens or underscores), n-t-e 150 characters. No empty folders or subfolder are allowed.
  • Must use current portable document format (PDF) and version; documents must be submission-ready. FYI – PDF files have extensive rules to follow and validation criteria to pass.
  • Must use correct document lifecycle operator (new, replace, delete).
  • Clinical Efficacy and Safety Reports much adhere to the rules outlined in the guidance.
  • Datasets and Study Tagging Files (STF) are required when providing information in m4 or m5. STF are required for each study and are required for documents such as adverse event reports or change in principal investigators (PIs).
  • Submissions 10 gigs (GB) and under must use the ESG.
  • Submissions must include only FDA fillable forms, e.g., 1571 or 356h as well as an electronic signature to enable automated processing. Note: scanned images of the forms will not be accepted (i.e. rejected).
  • Don’t submit paper unless requested, e.g., meeting / briefing materials.
  • The FDA calculates the “receipt” date only after the submission has been through technical validation. The FDA sends an initial receipt and then two acknowledgments to the sender.

If you answer “yes” to any of these questions below, you may need us…

Is all of this information too much to digest or comprehend? Are you feeling overwhelmed with all of the steps involved in setting up a compliant system? Have you been designated the “IT” guru and really don’t want that title/responsibility? Do you have a submission or even several that need to be at the FDA in a matter of days and haven’t even started the process?

If you’ve answered YES to any of the above questions, it’s time to git’er-done! HartmannWillner is your answer forgetting, and then staying compliant with the FDA (and not missing deadlines).

Feel free to reach out to us so that we can help you! We’re just an email away!


FDA Guidance for Industry Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM333969.pdf

FDA Electronic Common Technical Document (eCTD) https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm




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.


How to Survive and Thrive in FDA Meetings on BsUFA Products: Key Differences Between the Original and Revised Guideline

How to Survive and Thrive in FDA Meetings on BsUFA Products: Key Differences Between the Original and Revised Guideline

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


Time is money, and to help you save both time and money the FDA recently released a revised version of their Guidance for Industry on Formal Meetings between the FDA and Biosimilar Biological Product Sponsors or Applicants (November 2015). Here are some of the major revisions to the document.

Major changes in the recently released Guidance for Industry “Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products” entail the addition of WRO meetings, precise details about paper submissions, a timeline of receiving preliminary comments from FDA, and the process of contacting the FDA project manager regarding disagreements about the meeting minutes.

Regarding potential meeting formats with the FDA, a new option is WRO, also known as Written Response Only. This variety of meeting is available to applicants interested in a Biosimilar Initial Advice (BIA) meeting in order to have an initial assessment on licensure through § 351 (k) of the Public Health Service (PHS) Act. A WRO is also an option for Biological Product Development (BPD) Type 2 meetings that intend to discuss a particular issue in an ongoing development program.

The new document also clarifies that paper submissions for meeting requests and packages are still an option as long as they are sent to the appropriate review division. Paper (desk copies) is still recommended for the Center for Drug Evaluation and Research (CDER), but not for the Center for Biologics Evaluation and Research (CBER).

According to the revised document, you should expect to receive preliminary responses to the questions asked two to five business days before the meeting, but note that these responses are not the final feedback. As in the previous version of this Guideline, if this feedback generates new ideas for the product or additional topics for the meetings, this information will not be reviewed by the FDA when you do meet since it was not presented in the initial application.

Furthermore, meetings are denied when they are not granted. Also, the revised document states that the FDA will record the meeting minutes that will serve as a general outline of the meeting. If there is a disagreement concerning these minutes, the requester should contact the FDA project manager to address these issues.

Additionally, there is more detail concerning the BSUFA fees related to the BPD program. These fees typically include both the initial and annual BPD fee as well as a reactivation payment. Remember, failing to pay these fees in the designated amount of time will result in the FDA canceling the BPD meeting.

All in all, this revised document is a lot more reader-friendly and should serve as your ultimate how-to guide when it comes to scheduling, preparing, and attending BsUFA meetings with the FDA. By following the FDA’s recommendations, you will surely be successful with your biosimilars!


We meet with the FDA to discuss biosimilar and interchangeable products on a regular basis. Do you need to have a BsUFA meeting with the FDA? Do you need help identifying the correct Review Division for your biosimilar or interchangeable product? Do you need help preparing your meeting materials? Contact us today to learn more about our services and how we can help you.


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