welcome to the wcbp cmc strategy forum · 2018-04-02 · douglass mead, janssen r & d, llc...
TRANSCRIPT
Welcome to the WCBP CMC Strategy Forum
We are pleased to welcome you to the 26th
WCBP CMC Strategy Forum. The purpose of the CMC
Strategy Forum is to provide a venue for biotechnology/biological product discussion. The meetings
focus on relevant CMC issues throughout the lifecycle of a product and thereby foster collaborative
technical and regulatory interactions. The Forum strives to share information with the regulatory
agencies to assist them in merging good scientific and regulatory practices. Outcomes of the Forum
meetings are published in an appropriate peer-reviewed journal.
Each meeting will focus on a CMC related issue such as product characterization, comparability,
specifications, etc. The format of each meeting will consist of case studies and presentations by Industry
and/or FDA experts to introduce the topic and the key issues of concern. Breakout sessions will then be
conducted to allow for additional discussion on the technical and regulatory details of the topics. It is
envisioned that the final outcome of the workshop discussions will be the development of a document to
be submitted to the appropriate Regulatory Agency designees for their consideration in developing
and/or clarifying good regulatory practice guidelines for biotechnology derived products.
The success of the CMC Strategy Forum will depend on your active participation in discussing and
raising issues pertaining to development of biologics. We encourage you to participate wholeheartedly
in the workshops that have been designed to stimulate exchange of ideas and information.
We would like to thank the speakers who are giving generously of their time and resources, and to you,
for your attendance. We acknowledge the generosity of our sponsors: Amgen Inc.; Biogen Idec;
Biologics Consulting Group, Inc.; Eli Lilly and Company; Genentech, a Member of the Roche Group;
Janssen Research & Development, LLC; MedImmune; Novartis Pharma AG; Novo Nordisk A/S and
Pfizer, Inc. We are grateful for the expert management assistance of Karen Bertani and Stephanie Flores
at CASSS. Their experience, guidance and skill in the preparation of this meeting have been invaluable.
CMC STRATEGY FORUM ADVISORY COMMITTEE
Siddharth Advant, ImClone Systems Corporation
John Dougherty, Eli Lilly and Company
Christopher Joneckis, CBER, FDA
Rohin Mhatre, Biogen Idec Inc.
Anthony Mire-Sluis, Amgen, Inc.
Wassim Nashabeh, Genentech, a Member of the Roche Group
Anthony Ridgway, Health Canada
Nadine Ritter, Biologics Consulting Group, Inc.
Mark Schenerman, MedImmune
Keith Webber, CDER, FDA
The Organizing Committee gratefully acknowledges the
pharmaceutical and biotechnology industry for their generous
support of the WCBP CMC Strategy Forum series:
FORUM PROGRAM PARTNERS Amgen Inc.
Biogen Idec
Biologics Consulting Group, Inc.
Eli Lilly and Company
Genentech, a Member of the Roche Group
Janssen Pharmaceutical R & D, LLC
MedImmune
Novartis Pharma AG
Novo Nordisk A/S
Pfizer, Inc.
LEADING MEDIA PARTNER
BioProcess International
MEDIA PARTNERS
BioProcessing Journal
International Pharmaceutical Quality
Forum Abstract
Drug Product for Biological Medicines: Novel Delivery Devices, Challenging Formulations and
Combination Products
Program Planning Committee: Donna French, Genentech, a Member of the Roche Group, South San Francisco, CA USA
Jay Gerondale, Amgen Inc., Longmont, CO USA
Joel Goldstein, ImClone Systems Corporation, Branchburg, NJ USA
Suzanne Kiani, MedImmune, Gaithersburg, MD USA
Gerd Kleemann, Amgen Inc., Seattle, WA USA
Kathy Lee, CDER, FDA, Bethesda, MD USA
Mark Marley, Eli Lilly and Company, Indianapolis, IN USA
Douglas Nesta, GlaxoSmithKline, King of Prussia, PA USA
Lana Shiu, CDRH, FDA, Silver Spring, MD USA
Forum Co-Chairs: John Dougherty, Eli Lilly and Company, Indianapolis, IN USA
Anthony Mire-Sluis, Amgen Inc., Thousand Oaks, CA USA
Traditionally, the CMC Strategy Forum has provided more scientific focus on the development of
biotech drug substance and its manufacture and characterization, leaving the development of drug
product formulation and filing, understanding primary containers and considering novel delivery
systems somewhat out of scope. However, over recent years, the importance of investing more science
and technology into drug product development has become evident as different product types, higher
protein concentrations and doses and requirements for improved delivery of biological drug products
have increased. The need to give larger and more concentrated doses has challenged formulation
scientists, who now collaborate with early protein scientists to develop protein sequences at the earliest
stages of development with the final drug product in mind. Increasing such volumes and concentrations
of drug product now require alternative delivery systems rather than a simple vial or prefilled syringe -
which themselves are not without their own issues. Such delivery devices fall under the device
regulations and have vastly different design, development and validation requirements than the protein
drug product itself (e.g. upfront design requirements, human factor studies etc.). In addition, the
regulatory environment has changed whereby biological drug product, in even simple delivery systems,
are now considered combination products and thus also puts the development of such drug products
under new and different requirements.
The aim of this CMC Forum will be to explore these new challenges and discuss potential solutions, as
well as gain a better understanding in collaboration with FDA representatives of the current and future
regulatory landscape around devices and combination products.
WCBP CMC Strategy Forum Program Summary
Drug Product for Biological Medicines: Novel Delivery Systems, Challenging Formulations and
Combination Products
Forum Co-Chairs: John Dougherty, Eli Lilly and Company and Anthony Mire-Sluis, Amgen Inc.
MONDAY, JULY 16, 2012
07:30 – 08:30 Registration in the Lister Hill Auditorium Foyer
07:30 – 08:30 Breakfast in the Lister Hill Auditorium Foyer
08:30 – 08:45 Welcome and Introductory Comments to the WCBP CMC Strategy Forum
John Dougherty, Eli Lilly and Company, Indianapolis, IN USA
08:45 – 09:15 Combination Products: Challenges and Opportunities in Developing
Guidance and Regulations
Anthony Watson, CDRH, FDA, Silver Spring, MD USA
Session One: Developing Formulations for Biotechnology and Combination Products
Session Co-Chairs: Jay Gerondale, Amgen Inc., Joel Goldstein, ImClone Systems Corporation, Gerd
Kleemann, Amgen Inc., and Kathy Lee, CDER, FDA
09:15 – 09:40 Using Sequence Analysis and Design to Mitigate Formulation Concerns
During Pre-clinical Development
Margaret Ricci, Amgen Inc., Thousand Oaks, CA USA
09:40 – 10:05 High Dose Delivery of Biologics – Development of Hyaluronidase Co-
Formulations
Heiko Nalenz, F. Hoffmann – La Roche Ltd., Basel, Switzerland
10:05 – 10:30 Proteins at Interfaces: Formulation Approaches Minimizing Device
Interfaces Incompatibilities Mariana Dimitrova, MedImmune, Gaithersburg, MD USA
10:30 – 11:00 AM Break in the Lister Hill Auditorium Foyer
11:00 – 11:25 Formulation Considerations for Micro-needle Delivery Systems
Peter Johnson, 3M Drug Delivery Systems, St. Paul, MN USA
11:30- 12: 30 Roundtable Discussion:
Mariana Dimitrova, MedImmune
Peter Johnson, 3M Drug Delivery Systems
Heiko Nalenz, F. Hoffmann – La Roche Ltd.
Ed Patten, CBER, FDA
Margaret Ricci, Amgen Inc.
12:30 – 13:45 Lunch Break in the Lister Hill Auditorium Foyer
MONDAY, JULY 16 continued
Session Two: Combination Products for Biological Products: Early Design and Characterization
Session Co-Chairs: Andrew Donnelly, MedImmune, Jennifer Mercer, Genentech, a Member of the
Roche Group, and Lana Shiu, CDRH, FDA
13:45 – 14:10 Regulatory Expectations for the Characterization of Biotechnology Products
in Combination Products Kathy Lee, CDER, FDA, Bethesda, MD USA
14:10 – 14:35 An Industry Perspective on Design Controls
Jay Gerondale, Amgen Inc., Longmont, CO USA
14:35 – 15:00 Design Perspectives on Implantable Devices for Targeted Drug Delivery
Steve Christenson, Medtronic Neuromodulation, Fridley, MN USA
Deanna Lane, Medtronic Neuromodulation, Fridley, MN USA
15:00 – 15:30 PM Break in the Lister Hill Auditorium Foyer
15:30 – 15:55 Industry Perspectives of the Challenges with Developing Combination
Products for Biotechnology Products
Paul Jansen, Sanofi, Cambridge, MA USA
15:55 – 16:55 Roundtable Discussion:
Steve Christenson, Medtronic
Jay Gerondale, Amgen Inc.
Paul Jansen, Sanofi
Deanna Lane, Medtronic
Kathy Lee, CDER, FDA
John Towns, Eli Lilly and Company
17:15 – 17:30 Depart Lister Hill Auditorium
18:15 – 19:45 Networking Reception in the Concours Terrace at the Hyatt Regency Bethesda
TUESDAY, JULY 17, 2012
07:30 – 17:00 Registration in the Lister Hill Auditorium Foyer
07:30 – 08:30 Breakfast in the Lister Hill Auditorium Foyer
Session Three: Combination Products for Biologicals: Human Factor Validation Testing and
Clinical Studies Conducted for Combination Products
Session Co-Chairs: Mark Marley, Eli Lilly and Company and Jacqueline Ryan, CDRH, FDA
08:30 – 08:55 Human Factor Studies for Combination Products: Impact on Design and
Development of Combination Products Molly Story, CDRH, FDA, Silver Spring, MD USA
08:55 – 09:20 Regulatory Considerations for Developing a Human Factors Validation
Strategy: An Industry Perspective on the DRAFT FDA Guidance on Human
Factors Desiree Crisolo, Genentech, a Member of the Roche Group, South San Francisco,
CA USA
09:20 – 09:45 Lessons Learned from Adverse Events, Patient Feedback and Labeling of
Combination Products and their Influence on Existing and Developing
Guidance Carol Holquist, CDER, FDA, Bethesda, MD USA
9:45 – 10:10 An Industry Perspective on Clinical Trials for Combination Products
Mark Marley, Eli Lilly and Company, Indianapolis, IN USA
Jennifer Visich, Genentech, a Member of the Roche Group, South San Francisco,
CA USA
10:15 – 10:45 AM Break in the Lister Hill Auditorium Foyer
10:45 – 11:45 Roundtable Discussion:
Donna French, Genentech, a Member of the Roche Group
Carol Holquist, CDER, FDA
Mark Marley, Eli Lilly and Company
Molly Story, CDRH, FDA
Jennifer Visich, Genentech, a Member of the Roche Group
11:45 – 13:00 Lunch Break in the Lister Hill Auditorium Foyers
TUESDAY, JULY 17 continued
Session Four: Combination Products for Biological Products: Regulatory Pathways, Marketing
Applications and Post-licensure
Session Co-Chairs: Jeanmarie Sales, Medtronic Neuromodulation and Nikhil Thakur, CDRH, FDA
13:00 – 13:25 Navigating FDA Channels for the Approval of Combination Products
Lana Shiu, CDRH, FDA, Silver Spring, MD USA
13:25 – 13:50 Challenges with Applications for Combination Products
Jacqueline Ryan, CDRH, FDA, Silver Spring, MD USA
13:50 – 14:15 Putting Together the Marketing Application for a Combination Product
Suzanne Kiani, MedImmune, Gaithersburg, MD USA
Douglass Mead, Janssen R & D, LLC, King of Prussia, PA USA
14:15 – 14:45 PM Break in the Lister Hill Auditorium Foyer
14:45 – 15:45 Roundtable Discussion:
Desiree Crisolo, Genentech, a Member of the Roche Group
Suzanne Kiani, MedImmune
Kathy Lee, CDER, FDA
Douglass Mead, Janssen R & D, LLC
Jaqueline Ryan, CDRH, FDA
Lana Shiu, CDRH, FDA
Nancy Waites, CBER, FDA
15:45 – 16:30 Recap of Program
Summary Slide Presentation
Anthony Mire-Sluis, Amgen Inc., Thousand Oaks, CA USA
16:30 – 16:45 Invitation to CMC Strategy Forum January 2013
16:45 Adjournment
Presenter Abstracts
Combination Products: Challenges and Opportunities in Developing Guidance and Regulations
Anthony Watson
CDRH, FDA, Silver Spring, MD USA
Combination products hold the promise of innovative solutions to delivering complex therapies. The
process of regulating and creating guidance for combination products strives to balance the need to
provide clarity, ensure products are safe, effective and efficacious with the need to allow these
innovative products to the market as efficiently as possible. Incorporating the scientific and regulatory
needs of several centers poses several challenges that have to be addressed. The challenges to ensure
that guidances and regulations are timely and relevant are exacerbated by the unique issues associated
with combination products. The efforts to address these issues extend to recent and future regulations
and guidances, review practices, and design standards.
NOTES:
Using Sequence Analysis and Design to Mitigate Formulation Concerns During Pre-clinical
Development
Margaret Ricci; Riki Stevenson; Holly Huang; Francis Kinderman; Heather Franey; Stephen Brych;
Xichdao Nguyen; Jie Wen; Cynthia Li; Randal R. Ketchem; Guna Kannan; Nicolas Angell; Yijia Jiang;
Linda Narhi
Amgen Inc., Thousand Oaks, CA USA
Selecting the optimal therapeutic molecule candidate to progress into clinical development is critical to
proactively mitigate manufacturing, formulation, and delivery challenges. Several case studies are
presented that show the importance of leveraging pre-clinical molecule candidate assessment to mitigate
issues related to solubility, viscosity, and stability. Solubility limitations were encountered in
formulation and delivery of a human cytokine, and these limitations were overcome by using the murine
sequence as a blueprint for generating analogs of increased solubility. Within the antibody modality,
screening assays were implemented to select low viscosity molecules and molecular modeling was
applied to select favorable sequence attributes and to eliminate localized charge patches. We have
demonstrated that engineering the molecule for desired solution properties is a viable approach to
mitigate formulation and delivery concerns in pre-clinical development. Furthermore, molecule
candidate selection principles can be effectively applied in conjunction with formulation, process, and
delivery device strategies.
NOTES:
High Dose Delivery of Biologics—Development of Hyaluronidase Co-Formulations
Heiko Nalenz
F. Hoffmann - La Roche Ltd., Basel, Switzerland
The subcutaneous administration route provides patients with a convenient alternative to i.v. infusion.
Nevertheless, limitations with respect to the volume that can be administered have to be overcome for
efficient administration of biologics such as antibody (mAb) drugs. Increasing the concentration of the
mAb and/or increasing the interstitial space at the injection site are potential strategies to overcome this
hurdle. In particular, glycosaminoglycanase enzymes such as recombinant hyaluronidase (rHuPH20) are
being considered to transiently increase the subcutaneous tissue space.
This presentation highlights the scientific approaches used at Roche for the drug product development of
high dose antibody/rHuPH20 co-formulations. The presentation will focus on the particular challenges
of keeping two very different proteins in a stable and active state within one formulation. Additional
challenges of the co-formulation on specific drug product manufacturing processes will also be
discussed.
NOTES:
Proteins at Interfaces: Formulation Approaches Minimizing Device Interfaces Incompatibilities
Mariana Dimitrova
MedImmune, Gaithersburg, MD USA
Patient convenience, accurate dosing, and the need to deliver high concentration protein formulations
are driving the development of advanced drug delivery systems including large volume autoinjectors
and other drug delivery devices. The development of combination products, comprised of sensitive
biologics assembled with drug delivery devices is often associated with component compatibility
challenges. When exposed to incompatible interfaces, protein therapeutics may be susceptible to
structural perturbations, aggregation, particle formation, oxidation and other degradation pathways. This
talk will discuss formulation challenges developing combination products for high concentration protein
therapeutics. A case study will be presented highlighting the incompatibilities of a protein therapeutic to
components made of high-density polyethylene and certain types of polypropylene. Interface
incompatibility, manifested in the formation of visible and sub-visible particles as well as
conformational and colloidal destabilization of the protein, will be illustrated. Two formulation
approaches were successfully developed resolving protein structural and colloidal destabilization and
preventing particle formation at the incompatible interfaces. This talk will highlight the importance of
compatibility risk assessment input into the design of the device early in development as well as
balancing formulation compatibility requirements with device performance and user requirements
considerations.
NOTES:
Formulation Considerations for Micro-needle Delivery Systems
Peter R. Johnson; Scott Burton; Kris Hansen
3M Drug Delivery Systems, St. Paul, MN USA
Novel delivery systems, challenging formulations and combinations products…Yes, yes and yes. That
would describe 3M’s microneedle-based delivery technology, the Microstructured Transdermal System
(MTS) for intradermal delivery of biologicals. The hollow-microneedle and solid-microneedle systems
offer unique capabilities and present unique considerations for formulation. This presentation will
address: 1) the opportunities for drug delivery to the dermis (i.e. intradermal delivery); and 2)
formulation considerations for this route of delivery.
3M’s hollow Microstructured Transdermal System (hMTS) is a delivery technology for intradermal
delivery of liquid formulation through an array of small, hollow microneedles. hMTS has attributes of
an autoinjector and attributes of a transdermal patch. The hMTS device is adhered to the skin, while it
delivers up to 2mL of liquid formulation into the dermis (as opposed to a volume limit of 1mL
subcutaneous delivery for most autoinjectors). The hMTS device has an array of 16 hollow
microneedles covering an area of approximately 1 cm2 for distributing formulation into the dermis
approximately 0.5mm below the surface of the skin and over a broader area than a device based on a
single conventional needle. Delivery of formulation to the dermis enables rapid uptake of drug by the
lymphatic system and results in more rapid systemic availability (faster Tmax) than what is typically
observed when formulations are delivered subcutaneously, especially for macromolecules.
3M’s solid Microstructured Transdermal System (sMTS) targets the epidermis and upper dermis for
delivery of drug formulation that has been coated and dried onto the tips of microneedles. A patch that
contains an sMTS microneedle array is applied to the skin via an applicator. The microneedles in the
sMTS array are square pyramids, 250-700 microns tall, with approximately 1300-300 microneedles per
array (1 cm2), respectively. The sMTS API formulations utilize excipients that 1) facilitate the coating
process, 2) yield a coating that is even and reproducible, 3) enable rapid release into the skin, and 4) may
provide stabilizing capabilities to the final drug product, minimizing or eliminating the need for cold
storage.
NOTES:
Developing Formulations for Biotechnology and Combination Products
Questions:
1. What are the challenges with developing biopharmaceutical formulations for combination products?
a) What are current pinch points causing challenges in the regulatory filings of combination
products?
2. What technologies and strategies can be leveraged to overcome formulation challenges for biotech
combination products?
a) What technologies or strategies can be utilized to mitigate some of the limitations for high-
viscosity formulations?
b) What would be an effective but product quality-friendly sterilization technique?
c) What could be small-scale high-throughput methodologies with at-scale predictability of product
quality attributes?
3. How can biotherapeutics manufacturers influence the development of container and device materials
that are compatible with biotherapeutic combination products?
a) What is the motivation to the supplier to develop new solutions for biocompatible container
closure materials?
b) What do the manufacturers need in order to make the effort profitable? (Assuming that we know
who the manufacturers are)
c) What is the biopharmaceutical industry willing to pay/invest for new biocompatible container
closure materials?
d) What are the critical challenges with container closure systems and what new or next generation
container closure systems should be considered to overcome those challenges? (e.g., glass vs
plastic; silicone oil vs container coatings; needle vs needle-free vs micro-needles; etc.)
4. How do formulation attributes of biopharmaceutical combination products (such as high
concentration formulations and new container closure systems) challenge analytical characterization
strategies?
a) What are the current limitations and challenges of analytical technologies utilized for the
characterization of high concentration formulations?
b) What do new and innovative analytical technologies need to focus and deliver on to overcome
the current analytical limitation and challenges? (e.g., more quantitative and robust
methodologies for particle characterization; methodologies capable of analyzing neat
formulations without changing the protein concentration during analysis; etc.)
NOTES:
Presenter Abstracts
Regulatory Expectations for the Characterization of Biotechnology Products in Combination
Products
Kathy Lee
CDER, FDA, Bethesda, MD USA
Characterization of combination products present unique challenges compared with characterization of
traditional biotechnology products. This talk will center on the regulatory expectations for combination
products submitted in Investigational New Drug applications or Investigational Device Exemption
applications focusing on early phase product development.
NOTES:
An Industry Perspective on Design Controls
Jay Gerondale
Amgen Inc., Longmont, CO USA
When developing and manufacturing combination products, manufacturers must comply with two
quality system regulations, current Good Manufacturing Practices (CGMP) for drugs and biologics and
the Quality Systems Regulation (QSR) for medical devices. There are multiple aspects of the design
control process that will reduce risk for both the manufacturer and the end user to ensure that designs are
easy to use, robust and safe. Procedures must be established and maintained for validating production
units under use conditions and demonstrate that the intended use and user needs are satisfied.
This presentation will provide an overview of the processes used to design and develop the device
portion of a combination product, and the design control requirements that must be followed.
NOTES:
Design Perspectives on Implantable Devices for Targeted Drug Delivery
Steve Christenson and Deanna Lane
Medtronic Neuromodulation, Fridley, MN USA
Medtronic Neuromodulation manufactures chronic implantable devices for targeted drug delivery into
the central nervous system. This presentation will review design perspectives on chronic implantable
drug delivery systems, focusing on the considerations for characterizing interactions between the device
and the physiological environment, and between the device and the therapeutic agent being delivered.
NOTES:
Industry Perspectives of the Challenges with Developing Combination Products for Biotechnology
Products
Paul Jansen
Sanofi, Cambridge, MA USA
Development of combination products is a challenging business. Development of combination products
which include biotechnology products is even more challenging. Successful products result from
managing three key challenges and their interdependencies. It is critical to manage and balance
development cycle time, regulatory compliance and product stability requirements. As requirements in
these areas are continually changing it is essential that the Project Team determines appropriate
techniques to meet the challenges. Two key tools are the use of device platforms and establishment and
agreement of ‘equivalent devices’ for use in Phase 3 and Phase 2 clinical trials.
NOTES:
Combination Products for Biological Products: Early Design and
Characterization
Combination products pose many challenges, particularly with the technical and scientific issues that
may arise from a drug-device combination for novel and innovative delivery devices. Understanding
how to evaluate and assess the impact of the interaction between the drug/biologic and its constituent
parts is critical in developing a combination product that is safe and effective. Other unique challenges
include the development path and potentially divergent demands on developing a drug and its
constituent parts, as well as understanding the manufacturing and quality requirements for both a drug
and device combination. Often the device constituent is introduced late in development, shortening the
design and characterization time frame. The goal of this forum is to provide a general understanding of
the regulatory expectations for characterization of a combination product, as well as challenges that
Sponsors face when dealing with design and characterization of an innovative combination product with
a unique delivery system.
Questions:
1. What studies during development are required to characterize the combination product?
2. How are changes to the device managed during development of the combination product to
enable licensure of the combination product?
3. What are the expectations for the assessment of extractables/leachables during development of
the combination product?
4. Is it necessary to characterize the combination product using aspects of design controls for a
standard pre-filled syringe or delivery device (eg, autoinjector)?
5. What is defined as the “to be marketed product” or “final finished product” for a drug delivery
device? What are the implications for clinical development?
NOTES:
Presenter Abstracts
Human Factor Studies for Combination Products: Impact on Design and Development of
Combination Products
Molly Story
CDRH, FDA, Silver Spring, MD USA
Abstract was not available at the time of printing.
NOTES:
Regulatory Considerations for Developing a Human Factors Validation Strategy: An Industry
Perspective on the DRAFT FDA Guidance on Human Factors
Desiree Crisolo
Genentech, a Member of the Roche Group, South San Francisco, CA USA
In the last few years, human factors validation has proven to be a challenge for pharmaceutical
companies integrating drug delivery devices as part of their drug product configuration. A lack of
understanding of how to effectively apply human factors principles throughout the development process
and the inability to provide adequate human factors information as part of the dossier has led to delays in
approval.
With the release of the 2011 draft guidance from CDRH, titled “Applying Human Factors and Usability
Engineering to Optimize Medical Device Design”, the FDA provides information on how manufacturers
are to approach, execute and analyze human factors data to support use of the device. The regulatory
landscape continues to evolve and understanding how to successfully integrate human factors principles
within the device development process will be essential in the commercialization of medical devices.
The purpose of this presentation is to highlight the technical and regulatory considerations in developing
and documenting a human factors strategy. A case study of current experience gained with a drug
delivery device will be presented.
NOTES:
Lessons Learned from Adverse Events, Patient Feedback and Labeling of Combination Products
and their Influence on Existing and Developing Guidance
Carol Holquist
CDER, FDA, Bethesda, MD USA
This presentation provides an overview of human factors considerations for the design and development
of drug and drug/device combination products. The presentation will provide examples of medication
errors reported to CDER relating to poor product design describe current practices for human factors
submissions to CDER and describe the top five problems associated with these submissions.
NOTES:
An Industry Perspective on Clinical Trials for Combination Products
Mark Marley1; Jennifer Visich
2
1Eli Lilly and Company, Indianapolis, IN USA;
2Genentech, a Member of the Roche Group, South San
Francisco, CA USA
Abstract was not available at the time of printing.
NOTES:
Combination Products for Biologicals: Human Factor Validation Testing
and Clinical Studies Conducted for Combination Products
Questions:
1. What are key considerations for determining whether or not to conduct an “actual use” clinical
evaluation Human Factor study instead of “simulated” use for drug delivery devices?
2. If a device in development has been used commercially for other products and/or the same
patient population, are additional “ease of use” studies necessary? If a device has shown to be
bioequivalent with PFS for other drugs, and risk assessments do not indicate new risks to PK
with the introduction of a new drug, are additional PK studies necessary?
3. For simulated use human factors studies with and without drug product, is IRB approval needed
and is submission of an IDE or protocol to an IND needed?
4. What are the specific considerations one needs to take into account in the design of clinical
studies for combination products, including clinical bridging strategies can be considered to
support the safety and efficacy of a combination product?
5. Since it may not be practical to conduct a pivotal phase 3 clinical study using the final
commercial device/combination product; is it possible to use a risk-based assessment to
determine the level of clinical evidence or clinical data required, if any, for registration of the
combination product (eg, literature, BE study, Human Factors “actual use” study, post-market
data and technical evidence?
NOTES:
Presenter Abstracts
Navigating FDA Channels for the Approval of Combination Products
Lana Shiu
CDRH, FDA, Silver Spring, MD USA
Combination Product is a newly emerging area of interest as medical technology moves forward to
facilitate drug/biologic delivery into the body. As such, manufacturers and sponsors are facing new
challenges in the regulatory arena with submissions to FDA. This presentation will increase the
understanding of how the Agency regulates combination products and comprehend the various ways to
navigate the application process to avoid certain regulatory pitfalls.
NOTES:
Challenges with Applications for Combination Products
Jacqueline Ryan
CDRH, FDA, Silver Spring, MD USA
Combination product development may raise a number of challenges from novel concept to innovative
marketed product. This presentation will identify some of the regulatory challenges in early product
development, the pre-marketing application, Phase III device bridging, and post marketing device
changes in the context of pre-filled syringe delivery systems and will give advice on overcoming them.
NOTES:
Putting Together the Marketing Application for a Combination Product
Suzanne Kiani1; Douglass Mead
2
1MedImmune, Gaithersburg, MD USA;
2Janssen R & D, LLC, King of Prussia, PA USA
In preparing a NDA/BLA marketing application for a drug-device combination product, the sponsor
must consider the principles and content requirements of a device submission and apply these in the
development of a drug application. This presentation will review the 510(k) content requirements that
might apply to the device constituent part (alone) and discuss the challenges in merging this information
into the eCDT format. Depending on complexity of the device involved, this content may be included in
limited sections in the dossier (e.g., Container Closure sections), or may involve additional eCTD
modules. The format options may need to be based on the specific device characteristics, and also
consider whether to consolidate device information in a single section, or use a 510(k) reference or
master file strategy. Other device specific information, such as assembly information and control
strategies, specifications based on device design controls, or delivery device Instructions for Use may
pose unique questions or review timing challenges. The potential requirements and strategies for
handling post-approval changes will also be discussed.
NOTES:
Combination Products for Biological Products: Regulatory Pathways,
Marketing Applications and Post-licensure
The focus of this session is to discuss the various regulatory pathways for seeking regulatory approval
(clearance) for combination therapies through the different Centers within CDRH. The session will also
explain how and when sponsors should interact with the FDA when developing their combination
therapies. Lastly, the Session aims to highlight the premarket and post market challenges that impact
Sponsors during the regulatory life cycle of their combination product.
Questions:
1. What are the processes to appropriately file combination products through its approval lifecycle
since multiple Offices/Divisions may be involved in the ultimate combination product approval?
2. What are the top causes of delays to approval of combination product filings?
3. There are many types of submission strategies that a company could use for a kitted or single-
entity combination product (Single BLA/NDA, BLA/NDA and DMF/MAF, BLA/NDA and
510(k), etc...). Industry would like to be able to maintain as much flexibility in these options as
possible to allow for multiple types of combination products. Are there any filing strategies that
FDA would not accept?
4. What are the considerations for reporting of post market changes made to the device constituent
part of a combination product? If it has been submitted as part of the overall combination product
in a single marketing application, could the sponsor use guidance associated with changes to a
medical device to determine reportability of device specific changes?
5. Under what specific regulations does a manufacturer of a combination product need to comply to
assure approval of the product (pre-market, postmarket)?
6. Does the form of the submission and/or the lead review division affect the pre-and post-licensure
regulatory requirements for the constituents of a combination product? Or are the applicable
regulations determined by the nature of the constituents, regardless of submission form or lead
review division?
7. Under what circumstances would a companion IVD and therapeutic product (drug, biologic,
device, combo) be considered a combination product, and what are the consequences?
8. Can FDA provide guidance on how manufacturers should handle post-approval changes to their
product? What is the regulatory thought process? What are the relevant FDA guidance
documents associated with that thought process?
NOTES: