The FDA “Deemed to be a License” Provision of the BPCI Act changes “approved” biologics to “licensed” biologics

The FDA “Deemed to be a License” Provision of the BPCI Act changes “approved” biologics to “licensed” biologics

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


Biological products have historically been approved under two laws: The Public Health Service Act (PHS Act) through a Biologics License Application (BLA) and the Federal Food, Drug, and Cosmetic Act (FD&C Act) through a New Drug Application (NDA). Biological products are “licensed” under the PHS Act and “approved” under the FD&C Act. The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) mandated that biological products  previously submitted under  the FD&C Act be submitted under the PHS Act. March 23, 2020 is the transition date upon which this will occur.

Many of the applications for therapeutic biological products are licensed under the PHS ACct, but there are some protein products that have historically been  filed under the FD&C Act. The BPCI Act notes that protein products will be regulated by amending the definition of a biological product that was outlined in the PHS Act to also describe “a protein (except any chemically synthesized polypepetide).” Protein products that will transition from the FD&C Act to the PHS Act include insulin and insulin analogs, human growth hormone, and reproductive hormones.

With regard to proposed biological products, the BPCI ACT entails the potential approval pathways for submitting a marketing application that may be impacted by this transition in acts. After March 23, 2020, sponsors intending on submitting their biological products under section 505 in the FD&C Act will now need to be submitted under the PHS Act section 351. This needs to be filed as either a 351(a) BLA, which is known as a stand-alone BLA, or a 351 (k) BLA that is for a proposed biosimilar product or a proposed interchangeable product.

Conversely, for the approved products, the BPCI Act dictates that for a marketing application that was approved as a biological product based on section 505 of the FD&C Act will be considered as a license for the biological product, essentially an approved BLA following the section 351 of the PHS Act.

Beginning on March 23, 2020, the BPCI Act demands that an approved marketing application for a biological product filed under 505 section of the FD&C Act will be licensed as a biological product following the 351 section for the PHS Act. Additionally, the transition period of 10 years lasting from March 23, 2010 to March 23, 2020, allowed sponsors of biological products that are impacted by this change to prepare for these modifications and any applications for biological products filed under section 505 for the FD&C Act to be approved prior to March 23, 2020.

The FDA is attempting to be as accommodating as possible to ensure that this transition does not negatively impact any manufacturer or patient related to these biological products. Additional resources for specific situations can be consulted and reviewed:  Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009, The “Deemed to be a License” Provision of the BPCI Act: Questions and Answers, Definition of the Term “Biological Product,” Responsibility in OPQ for the Integrated Quality Assessment of Products Containing Drug Substances Composed of Amino Acid Polymers, and Preliminary List of Approved NDAs for Biological Products That Will Be Deemed to be BLAs on March 23, 2020.



At HartmannWillner LLC we understand the regulatory requirements for development of biological products through the BLA and NDA route. With our help, you can transition  your approved biologic to a licensed biologic. Contact us today to learn more about our services and how we can help you.

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

Smallpox (Variola Virus) Infection: Developing Drugs for Treatment or Prevention Guidance for Industry

Smallpox (Variola Virus) Infection: Developing Drugs for Treatment or Prevention Guidance for Industry

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


The purpose of the guidance: Smallpox (Variola Virus) Infection: Developing Drugs for Treatment or Prevention is to help sponsors involved in the clinical development of drugs for the treatment or prevention of smallpox (variola virus). Drugs relating to this disease need to be developed and approved following the Animal Rule regulations. All in all, the guidance is meant to address conversations between CDER Division of Antiviral Products (DAVP), pharmaceutical sponsors, academia, and the public.

Mainly, the guidance refers to drugs that are meant to inhibit variola virus replication. Variola major is the most severe form of smallpox, with a mortality ranging from five percent to fifty percent in various outbreak situations. This is the primary source of concern relating to possible bioterrorist uses of smallpox and is the most pertinent form addressed this guidance.

In 1980, the World Health Organization determined that smallpox was eradicated. There are variola virus stocks in Russia and the United States Center for Disease Control, which was approved by an international agreement. Regardless, there are concerns that the variola virus might be used as a weapon for bioterrorism.

Vaccination with the vaccinia virus is the first line of defense against smallpox infection.  However, routine vaccination in the United States was discontinued in the 1970s and there is no natural disease exposure, so a bioterrorist threat could be catastrophic.

Antiviral drugs could be a valuable asset for exposure situations when vaccination is not possible or inadequate. Drug development for the safety and efficacy of smallpox treatment and prevention is influenced by the absence of smallpox cases, lack of information about pathophysiology of smallpox, moral concerns, lack of variola virus samples, insufficient nonhuman models, etc.

These challenges with smallpox require a unique approach for drug development. The FDA recommends that active compounds in cell culture should be studied in lethal animal models through different non-variola orthopoxviruses, such as vaccinia virus.

Vaccinia virus needs to be studied due to its relationship to variola virus and the vaccinia virus should also be investigated relating to vaccination complications. Small animal models should be used in analyzing preliminary antiviral activity of the drug and serve as a means to evaluate drug doses, dosing regimens, evolution of disease, effects of viral species, and other characteristics. These studies could help with determining the effect of smallpox variations and determining the necessary resources to combat smallpox.

For the animal models, it is recommended that sponsors gain concurrence from DAVP for the animal models and study design. After numerous meetings with stakeholders, DAVP advises that drug efficacy should be based on information from at least two lethal animal models of non-variola orthopoxvirus infection. Also, non-variola animal models need to be well-characterized and generate reproducible results, and mortality.

In concordance with Product Development Under the Animal Rule, animal euthanasia criteria must be described and approved by DAVP before the study and include the necessary documentation (how animals met the euthanasia criteria and if there were any deviations from this criteria).

It is important that these animal studies are designed according to the general principles of human clinical trial design and past experience with characterization of animal models and results from the nonclinical natural history and exposure-response studies.

In order to pursue human dose selection for an investigational drug, sponsors need to create a pharmacokinetic profile of the drug for healthy humans and a pharmacokinetic profile and pharmacodynamics of the drug in surrogate orthopoxvirus animal models.

Additionally, study reports for the investigational drug should include data relating to the mechanism of action, antiviral activity in both cell culture and animal models, give data on development and possible mechanisms of viral drug resistance, and analyze cytotoxicity and mitochondrial toxicity.

The FDA recommends that sponsors evaluate the investigational drug’s antiviral activity against a variety of different orthopoxviruses. Sponsors should also submit data on sample collection, assays conducted, and validation on approaches for the assays.

Finally, the FDA performs independent assessments of virologic and resistance data. Sponsors should consult with DAVP before submitting virology data to help with future filing procedure.


At HartmannWillner LLC we understand the regulatory requirements for development of products through the Animal Rule. 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.


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

What’s It All About?—KASA

What’s It All About?—KASA

What’s it all about, KASA?

By Mary Waters

There’s been some buzzing about the FDA instituting a new review system called Knowledge-aided Assessment and Structured Application (KASA). In September 2018, the FDA met with the Pharmaceutical Science and Clinical Pharmacology (PSCP) Advisory Committee to explore the positive aspects of adopting this platform.

The goal of adopting KASA is to modernize generic drug reviews which are currently text-based into a data-based assessment. There have also been some discussions that KASA could also be applied to new drug applications as well as biologics license applications.

Some of the benefits of using a KASA system would capture and manage information about a drug product including:

• Identifying risks; mitigation and communication, and control strategy during product lifecycle,

• Using computer-aided analyses to compare regulatory standards and evaluate quality risks against approved applications and facilities;

• Improve the objectivity of regulatory actions, as well as to provide more consistency and better communication,

• Enable assessors to automatically retrieve historical data and facility information which equates to better evaluations and decisions,

• Reduce the subjectivity of documentation and time liabilities, and

• Improve the quality and efficiency of assessments.

The FDA also noted that the eCTD system currently used by the agency does not follow the development flow of the drug product and contains unstructured data in PDF files which leads to redundancy and lengthy assessments. Using KASA will structure submission data that could be pre-processed for reviewers to make it more uniform – which in turn should improve the efficiency and consistency of regulatory quality assessments.

The FDA has stated that this review method is still in development phase and doesn’t have a timeline established yet. Draft guidance is usually the first step for industry to comment on the proposal before anything is decided.

Further deciding factors involve other international regulators such as the European Medicines Agency (EMA) which is aware of the FDA’s potential changes. Other PSCP committee members suggest that the FDA also work the International Council for Harmonisation (ICH).

Please check back with us as more information is released about the KASA review system. To read more, please go to this link on the FDA website here.

Standards development and the use of standards in regulatory submissions reviewed in CBER

Standards development and the use of standards in regulatory submissions reviewed in CBER

By Nitisha Pyndiah, PhD

In a draft guidance document released on December 2017, FDA described CBER’s recommendations on the use of standards in product development and the use of such standards in CBER’s managed review process. Mainly, FDA promotes international harmonization of standards acceptable to FDA.

As the use of standards can greatly facilitate a sponsor’s product development and allow a more efficient evaluation of regulatory submissions, I propose to summarize the guidance for you.


How to describe standards?

Standards are described by FDA as integral to the execution of FDA’s mission. Standards are defined as common and repeated use of rules, conditions, guidelines etc, they also include the definition of terms, classification of components and delineation of procedures etc and terminology, symbols, labeling requirements as they apply to a product, process or product method. This means that activities that would need the use of standards are:

• The development of performance characteristics

• Testing methodology

• Manufacturing practices

• Product standards

• Scientific protocols

• Compliance criteria

• Ingredient specifications

• Labeling or

• Other technical or policy criteria

Standards are not regulations as they are voluntary unless mandated by regulation or statute. Standards are developed by organizations often outside of the federal government (those are called SDO: standard development organization). The United States Pharmacopeial Convention (USP), American Society for Testing and Materials International (ASTM) and International Organization on Standardization (ISO)) are examples of SDOs.

Voluntary Consensus Standards are on type of SDO, and are standards developed or adopted by a domestic or international voluntary consensus standards body. A voluntary consensus standard development includes the following attributes or elements:

• Openness

• Balance

• Due process (should include documented and publicly available=

• Appeals process (available for the impartial handling of procedural appeals)

• Consensus (general agreement)

Intellectual property policies may apply to voluntary consensus standards bodies.

SDOs development standards for the development of performance characteristics, testing methodology, manufacturing practices, product standards, scientific protocols, compliance criteria, ingredient specifications, labeling, and terminology.


The development of standards

SDOs use different methods to develop standards, but the process normally begins with the following:

• Identify the need for a written/documentary standard or a material/physical standard

• Gather experts to develop the standard

• Drafts of written standards are circulated for comment, voting, editing and publishing

CBER staff often take part in the development of standards but CBER clarifies that their participation in the development of a particular standard does not mean that they endorse the latter.


CBERs advice for sponsors and applicants using standards in support of their IND or BLA

Provide a complete reference for the standard used in the regulatory submission

• If CBER deemed that a version of a standard is acceptable, the sponsor should not use an updated version of the standard without discussing with the product office

• “A sponsor may use appropriate written/documentary standards that describe a process or assay used to assess a manufacturing intermediate or final product”

• “A sponsor may also utilize an appropriate physical standard or reference material in the development and testing of their product” e.g. reference standards obtained from reputable commercial source/ other materials of documented purity certified by an analytical laboratory. “CBER recommends providing the source and lot number, expiration date, certificates of analyses when available, and/or internally or externally generated evidence of identity and purity for each reference standard”

• Data standards may promote efficient review of regulatory submission (e.g. Structured Product Labeling (SPL)) see the FDA Data Standards Catalog, available here. 

Although standards are mostly voluntary, they may allow your drug development to be faster and more efficient reducing the need to develop unique methods and reference materials for individual products.


Communication between Sponsor and FDA – Best Practices

Communication between Sponsor and FDA – Best Practices

By Mary Waters

Anyone who deals with the FDA should become familiar with the FDA Guidance for Industry and Review Staff Best Practices for Communication Between IND Sponsors and FDA During Drug Development. This Guidance represents FDA’s current thinking on the topic; its purpose is to describe some best practices and procedures for timely and effective communications between you and the FDA.

With the 2012 Prescription Drug User Fee Amendments (PDUFA) ACT, the FDA agreed to develop a dedicated drug development communication and training staff. Within CDER, MATTB’s (Manufacturers Assistance and Technical Training Branch) focus was to enhance the communications between the FDA and Sponsors during product development. Both CBER and CBER agreed to jointly publish this Guidance for industry and FDA review staff, gathered review staff’s suggested best practices, and incorporated input from interested parties to create this Guidance.

FDA Terms to Remember

Shall, must, required: These words or terms convey a statute or regulatory requirement.

Advisable, should, critical, may be appropriate, discourage, encourage, prefer, recommend, suggest, urge: These words or terms mean that something is suggested or recommended, but not required.

Guidance: Not legally enforceable, represent Agency’s current thinking, viewed only as recommendations unless specific regulatory or statutory requirements are cited.

FDA Regulatory Project Managers (FDA RPMs): Collectively, review division RPMs and specific functional area RPMs are referred to as FDA RPMs.

Regulatory Project Managers (RPMs): These RPMs oversee projects, processes, and programs; primary contacts for facilitating timely resolution of technical, scientific, and regulatory questions, issues, or other challenges between you and review teams.

Review Division RPMs: Primary point of contact for communications between Sponsor and FDA during drug development life cycle.

Do’s and Don’ts

• Do obtain authorization from your Sponsor (in writing) if you are an independent consultant before initiating contact with the FDA.

• Do reach out to the next level supervisor (division chief or branch chief) if you encounter challenges in obtaining feedback.

• Do establish a mutually agreeable communication strategy early in the relationship. FDA suggests a preferred method(s) (email vs telephone) and frequency of communications, and/or how to manage information requests (singularly or bundled; daily or weekly).

• Do not contact the FDA reviewers, team leaders, and senior management directly; instead, direct inquiries to the assigned FDA RPM who ensures your requests are communicated to review team members.

• Do not delay in responding to FDA information requests as this can negatively affect you in later development.

Types of Advice that Sponsors Seek

FDA policy positions are typically documented in FDA Guidance’s, MAPPS (Manuals of Policies and Procedures), and SOPPs (Standard Operating Procedures and Policies). These topics include:

• Regulatory

• Clinical

• Safety

• Clinical pharmacology / pharmacokinetics

• Nonclinical pharmacology, pharmacokinetics, and toxicology

• Product quality

• Pediatric

The FDA has stated that complex scientific or technical drug development questions should be directed to the FDA RPMs via either a submission or through the formal meeting request process.

Note, however, the FDA has also stated that their resources are limited, and strongly encourage Sponsors to seek answers first from other resources; or employ an independent consultant for assistance. Using this approach allows for resource conservation involving more complex and/or challenging issues.

General Expectations of Communications

The FDA realizes that timely and effective communication during the IND phase of drug development gives Sponsors information they need to help design studies/trials, in addition to product quality data intended to support future approval of a marketing application.

Note: Safety-related questions will be prioritized higher than routine inquiries.

Sponsors should realize that questions posed as simple or needing clarifying can sometimes be more than “routine”. When questions turn out to be complex and require significant review before an answer can be provided, they end up demanding significant resources and response time. The FDA suggests that these types of questions be posed in more formal situations (meetings/submissions).

Meetings can be formal between the FDA and Sponsors, such as face-to-face, teleconference, or with written response only (WRO). The FDA has written feedback timelines outlined in the PDUFA and BsUFA, as well as the FDA meeting guidances. Feedback from the FDA includes preliminary comments, final meeting minutes, and questions posed in the WRO request.

Submissions made to an IND during its life cycle may involve hundreds of supporting documents which could require variable degrees of review for which communication is needed with the Sponsor. Other submissions have regulatory-mandated timelines (e.g. safety-related submissions) or drug development submissions without a regulatory clock but are critical and may require a new protocol or a protocol amendment. In these instances, communications between the FDA and Sponsor is critical.

Other inquiries received via telephone, email or through a submission without a specific timeline which ask specific questions, the FDA RPM will attempt to acknowledge the communication within three (3) business days of receipt via telephone or email. The acknowledgment will include:

• The response within the acknowledgment time frame;

• The estimated time frame for division response to question(s);

• If questions will involve consultation with other parties, for example, policy questions where legal input is necessary;

• Recommendations to submit a formal meeting request; or

• Recommend that you contact another functional area in the FDA.

You will need to acknowledge receipt of FDA’s request either in writing or in other ways and provide to the FDA RPM an estimated response time.

Best Practices FDA Buzz Words

• Shall, must, require or requirement – these words convey a statutory or regulatory requirement•

• Advisable, critical, important, may be appropriate should consider, discourage, encourage, prefer, recommend, suggest or urge – these words or phrases convey advice, comments, or current FDA thinking.

Communication Methods

Since the IND phase of drug development is typically a multiyear process, the FDA recognizes that new data will become available as well as new scientific and regulatory advances changes in clinical practice over time.

There are a number of ways to communicate with the FDA and this Guidance provides in-depth descriptions on each method.


The FDA website contains two pages that provide information for industry:

a) The FDA Basics for Industry web page can be found here:

 b) Investigator-Initiated Investigational New Drug (IND) Applications web page includes links to information for investigators about submitting INDs to FDA and can be found here:

Take Away

HartmannWillner is well versed in communicating with the FDA. In fact, we have completed hundreds of communications with FDA RPMs. If you need advice on how to write a question or want to set up a meeting, we are here to make that happen. Please contact us.

HW was at FDA for the Part 15 public hearing

HW was at FDA for the Part 15 public hearing

By Nitisha Pyndiah, PhD

HW reports

HW was at FDA for the Part 15 public hearing on facilitating competition and innovation in the biological products marketplace

 On September 4, 2018, FDA held a public hearing to hear comments from different stakeholders on FDA’s Biosimilar Action Plan (BAP).

HW was there and reports. This meeting was a great opportunity to listen to patients and patient advocacy groups express their concerns and reminding us all, why we work in the field. Industry leaders and physicians also talked about the gaps that they identified, and innovator drug manufacturers presented arguments against biosimilars.  

A major discussion topic was about interchangeable products; patient advocacy group explained their concerns over patients having to switch to different biosimilars after being stable on a treatment thus highlighting the need to increase patients and healthcare providers education about biosimilars. Speakers expressed their views on the changes that they would like to see including those to the purple book. Of no surprise, originator product developers questioned the safety of switching from one biosimilar to another, but FDA responded promptly and clarified that the risk was similar or greater when switching within the same drug class or when the originator drug manufacturer makes manufacturing changes, which is common practice. There were also still discussions about the use of random suffixes for non-proprietary names and the fact that they could mislead when it comes to pharmacovigilance and also make biosimilars look inferior to the reference product. Overall, an interesting meeting where participants called for “real-life data” on biosimilars. Commissioner Gottlieb intervened to express FDA’s strong support to biosimilar developers in an aim to reduce the high cost of biologics. He emphasized on the fact that he was not satisfied of the current state of biologics market and that half of the biosimilars approved are not on the market. Commissioner Gottlieb did mention that FDA was working with the Federal Trade Commission (FTC) to work on the gamic tactics to delay competition. Certain participants asked if FDA could collaborate with the US Patent and Trademark Office to resolve intellectual property issues related to originators preventing biosimilars to enter the marketplace. One of the features of the BAP is FDA’s initiative to reduce gaming of FDA requirements by working with legislators to close loopholes.

In this blog post, I propose to list FDA’s BAP key actions and discuss items covered during the Part 15 hearing:

“Developing and implementing new FDA review tools such as standardized review templates”

“Creating information resources and development tools for sponsors of biosimilar applications”

“Enhancing the purple book to include more information about approved biological products”

Most speakers commented on their wish to see the purple book improved. The Biosimilar Forum and an originator company explained that a new column to designate biosimilars or interchangeable products should be added for clarification purpose. The Biosimilar Forum also noted that adding the date of exclusivity expiration would be very useful to sponsors. An industry representative added that manufacturing changes such as the number and types of changes should be added to the purple book. Other speakers also expressed their wish to have patent information listed in the purple book such as in the orange book.

“Actively exploring the potential for entering into new data sharing agreements with foreign regulators to facilitate the increased use of non-US licensed comparator products in certain studies to support a biosimilar application”

A company on the biosimilar side, spoke about using non-US comparators for interchangeables, and, a nonprofit organization, spoke about using non-US comparators if FDA multinational data shows that they are within acceptable FDA ranges. FDA was also urged to define analytical requirements for non-US reference product, no more no less.

“Establishing a new Office of Therapeutic Biologics and Biosimilars (OTBB) to improve coordination and support of activities under the BsUFA program”

FDA already established the Therapeutic Biologics and Biosimilars Staff (TBBS) under the Office of New Drugs (OND) to coordinate with other offices at CDER to ensure consistent review. FDA is now in the process of transferring TBBS to the new OTBB. This transition will allow to improve coordination, accelerate response time to the different stakeholder and support policy development.

“Building on the FDA’s Biosimilar Education and Outreach Campaign”

Patient advocacy groups explained that they wanted to understand better how a biological product is biosimilar. They wish to understand the analytical characterization better.

Some mentioned that they needed education when the patient goes to the physician practice as not all patients will educate themselves online.

This week, FDA published a useful resource to help explain the biosimilar development process and the data required to demonstrate biosimilarity. Link

“Publishing final or revised draft guidance on biosimilar product labeling to assist sponsors in determining what data and information should be included in the labeling”

“Providing additional clarity for product developers on demonstrating interchangeability, including by publishing final or revised draft guidance”

Several stakeholders mentioned their concerns about interchangeability, mainly, patient advocacy groups explained that they do not wish for the pharmacist to change the treatment for an interchangeable product without approval of the physician or the patient specially when the patient is finally stable on a treatment after series of complications.

Industry representatives recommended to include the scope of interchangeability designations in product labeling. An industry representative recommended clarifying the guidance on interchangeability, including information on changes in formulation. Several industry speakers pushed for the inclusion of non-US comparator for interchangeables.

“Providing additional clarity and flexibility for product developers on analytical approaches to evaluating product structure and function to support a demonstration of biosimilarity”

“Providing additional support for product developers regarding product quality and manufacturing process, including by identifying physical product quality attributes that are most critical to evaluate, and by exploring ways to reduce the number of lots of the reference product required for testing”


HW experts can help you with the development of your biosimilar, we are on the forefront of biosimilar policies and regulations we’ve been developing biosimilars for 16 years – and can assist you from early to late stages whether it is to advise regarding your analytical and functional studies, your non clinical studies, your clinical studies, your manufacturing process, your IND and BLA preparation or to submit your regulatory submissions to FDA. HW can also assist you with any FDA communications and prepare your materials for meetings.