1. FDA Regulation of Bioengineered
Products for Human Use
Getting Cutting-Edge
Innovations to Patients
NIH Biotechnology Seminar Series
Institute of Biosciences and Bioengineering
Rice University
Jason E Moore, MS, MBA, RAC
Vice President, PLx Pharma Inc.

2. Improving and Extending Life
• Bioengineers and life scientists ultimately
want to positively affect human life
– Safely and effectively treat diseases
– Restore lost function from disease or injury
– Diagnose or prevent disease (or determine genetic
predisposition for disease)
– Extend life, improve quality of life
• And are developing a wide range
of biotechnologies to accomplish
this

3. Innovations Include
• Proteins, including
– Monoclonal antibodies
– Novel engineered
proteins (including
synthetic and
recombinant versions)
– Cytokines, growth
factors, enzymes,
immuno‐modulators,
and thrombolytics
– Proteins extracted from
animals or
microorganisms
• Stem cells and highly
manipulated cells
• Vaccines, including
therapeutic vaccines
• Bioengineered tissues
and matrices
• Gene therapies
• Cellular extracts

4. Pervasis Therapeutics ‐‐ VascugelTM
• Confluent monolayers of allogeneic
endothelial cells established by seeding cells
in culture onto “well‐characterized polymer
matrix” (gelatin)
• Cells in the matrix, placed on the adventitia,
secrete inhibitory products including:
• transforming growth factor beta‐1
(TGFβ‐1)
• heparan sulfate
• nitric oxide
• tissue inhibitors of matrix
metalloproteinases (TIMPs)
• Compounds inhibit thrombosis,
inflammation and proliferation of
the cell layer underlying the endothelium
• Gelatin is absorbed

5. To Improve Human Life…
• We have to get our products into the clinic
• And to do that, we have to understand the
regulatory context and the steps to getting
there
• Products described herein are regulated by
FDA as…
– Biologics
– Drugs
– Medical Devices

6. Biologics are Regulated by FDA
• Food and Drug Administration
– Center for Biologics Evaluation and Research
(CBER)
– Center for Drug Evaluation and Research (CDER)
– Center for Devices and Radiological Health (CDRH)

7. Ambiguity and Complexity of Biologics
• Regulatory definitions of
“biologic” can be
counterintuitive
• No simple, all
encompassing definition
exists
• Often defined by
– Sources
– Chemical properties
– Immunogenicity
– Macromolecular size or
structure
– How they function
• Complicated by historical
designations (eg, insulin
regulated as a drug)
• Requires a regulatory
analysis to be sure

8. Some (Legal) Definitions
Biologic1,2
• Drug products derived from
living sources1
• “…any virus, therapeutic
serum, toxin, antitoxin,
vaccine, blood, blood
component or derivative,
allergenic product or
analogous product…
• “that is intended for use in the
diagnosis cure, mitigation,
treatment or prevention of
disease.”
Drug3 (partial definition)
• “…articles intended for use in
the diagnosis, cure, mitigation,
treatment, or prevention of
disease in man or other
animals
• “articles (other than food)
intended to affect the
structure or any function of
the body of man or other
animals
• “articles intended for use as a
component
[of any of these]…”
1 Public Health Service Act (42 USC 262)
2 Ropp, KL. “Just What is a Biologic Anyway?” FDA Consumer, Apr 2003.
3 Federal Food, Drug and Cosmetic Act of 1938 (21 USC 321)

9. Some Definitions (cont)
• Note that source does not fully define
whether or not a product is a biologic1
• But note that a biologic can also be a drug as
defined under the FDCA2, which carries
certain implications
• Defining the regulatory categorization of a
given biologic can be complex and
ambiguous
1 For example, although antibiotics and hormones such as insulin and hGH are traditionally
obtained from living organisms, they are not regulated as biologics.
2 See FDCA , 21 USC 321, SEC 201 (g)(1)(B-D); CareToLive v. von Eschenbach, 525 F. Supp.
2d 952, 957 (S.D. Ohio 2007), for case law example.

10. Some Definitions (cont)
Medical Device1 (partial definition)
• “…an instrument,
apparatus, implement,
machine, contrivance,
implant, in vitro reagent, or
other similar or related
article, including any
component, part, or
accessory, which is…
– “intended for use in the
diagnosis of disease or other
conditions, or in the cure,
mitigation, treatment, or…
…prevention of disease, in man or
other animals, or
– “intended to affect the structure
or any function of the body of
man or other animals,
– “and which does not achieve its
primary intended purposes
through chemical action within or
on the body of man or other
animals
– “and which is not dependent
upon being
metabolized for
the achievement of
its primary intended purposes.”1 Federal Food, Drug and Cosmetic Act of 1938 (21 USC 321)

11. “Combination Products”
• A combination product is comprised of any combination of a
drug and a device (21 CFR 3.2(e))
• There are four definitions of combination products defined in the
regulations:
– A product comprised of two or more regulated components (eg, drug/device,
biologic/device, drug/biologic, or drug/device/biologic)
– Two or more separate products packaged together in a single package or as a
unit and comprised of drug and device products, device and biological
products, or biological and drug products
– A drug, device, or biological product packaged separately that according to its
investigational plan or proposed labeling, is intended only with an approved,
individually specified drug, device or biological product where both are
required to achieve the intended use, indication or effect…
– Any investigational drug, device, or biological product packaged separately
that, according to its propose labeling, is only for use with another individually
specified investigational drug, device, or biological product where both are
required to achieve the intended use, indication or effect…

12. Biologics are Regulated by FDA
• Food and Drug Administration
– Center for Biologics Evaluation and Research
(CBER)
– Center for Drug Evaluation and Research (CDER)
– Center for Devices and Radiological Health (CDRH)

13. CBER‐Regulated Biological Products
• Gene therapy (viral vectored
gene insertions)
• Cell therapy (products composed
of human or animal cells)
• Monoclonal antibodies, growth
factors, or other proteins when
used solely as ex vivo reagents
• Vaccines, including therapeutic
vaccines
• In vitro diagnostics used to screen
donor blood, blood components
and cellular products, and to
diagnose treat and monitor
people with infectious diseases
• Blood, blood components and
related products (eg, clotting
factors)
• Devices used in collection,
processing, testing, manufacture
and administration of licensed
blood, blood components, and
cellular components
• Antitoxins, antivenins and
venoms; toxins and toxoids
intended for immunization
• Plasma expanders
• Allergen patch tests; allergenics
(extracts used for the diagnosis,
prevention or treatment of
allergies)

14. CBER‐Regulated Biological Products
• Tissues: human cells or tissues
intended for implantation,
transplantation, infusion or
transfer into a human
recipient
• Xenotransplantation:
transplantation, implantation
or infusion into a human
recipient of:
– Live cells, tissues or organs from
a nonhuman animal source; or
– Human body fluids, cells, tissues,
cells, tissues or organs that have
had ex vivo contact with live,
nonhuman animal cells, tissues
or components
• But, note: CBER does NOT
regulate vascularized human
organs for transplantation (eg,
liver, kidney, pancreas)
– The Health Resources Services
Administration (HRSA) oversees
the transplantation of
vascularized human organs

15. CDER‐Regulated Biological Products
“Specified”, “well characterized”, and “therapeutic”
biological products
• Monoclonal antibodies for in vivo use (monoclonals
for in vitro use are with CBER)
• Cytokines, growth factors, enzymes,
immunomodulators and thrombolytics
• Proteins intended for therapeutic use that are
extracted from animals or microorganisms, including
recombinant versions (except clotting factors)
• Other non‐vaccine therapeutic immunotherapies

16. New Biologic/Drug Development
2 4 6 8 10 12 14 160
Development Year
DISCOVERY
NONCLINICAL
TESTING
FDA REVIEW
& APPROVAL
PHASE 4
PHASE 1 20-30 Healthy Volunteers
PHASE 2 100-500 Patient Volunteers
PHASE 3 500-10,000 Patient
Volunteers
NONCLINICAL TESTING
MANUFACTURING‐RELATED
Investigational
New Drug
Application (IND)
Pre-IND Activities

17. To Get to an IND
• You must be able to
– Define the product
– Show that you know the
identity, strength, quality,
purity, and potency of the
product
– Show that the product has
sufficient stability for initial
clinical trials
– Demonstrate that the product
is reasonably safe via a
package of nonclinical
(animal) studies
– Define at least one initial
clinical trial design (protocol)
– If autologous, address logistics
• And submit an IND to the
lead FDA center, per 21 CFR
312
• Key manufacturing, stability
and nonclinical studies must
be conducted under GMP
and GLP quality standards,
respectively

18. Selected Product‐Development Activities
• “CMC”
– Formulation development
– Process development
– GMP manufacturing
– Analytical methods development
– Product stability
• Preclinical/Nonclinical
– Pharmacology
• In vitro profiling
• In vivo animal models
• Safety pharmacology
• Combination Pharmacology/
Toxicology Studies
– PK/ADME
• In vitro metabolism
• In vivo pharmacokinetics
• Tissue distribution/mass balance
– Toxicology
• In vitro screening
• General Toxicology
• Genetic Toxicology
• Reproductive Toxicology
• Clinical
– Protocol design and
development
– Clinical trial management
• Regulatory
– Strategy development
– IND Submission and
Amendments
– Milestone and ad hoc FDA
meetings; other
communications
– Compliance

19. 19
Chemistry,
Manufacturing &
Controls --
“CMC”

20. Key Terms of Art
“DRUG SUBSTANCE”
• The active ingredient
– Biologically active moiety,
molecule, or prodrug
• Monoclonal antibody
• BRM, cytokine, other
therapeutic protein
• Protein‐peptide complex
• miRNA, siRNA
• Oncolytic immunotherapy
• Gene therapy (viral vector +
genetic material)
• Cell therapy
“DRUG PRODUCT”
• The formulated (and
packaged) product that is
actually used in the clinic,
studied under an IND, the
subject of a BLA (or NDA),
intended for sale
– Capsule
– Vial
– Pre‐filled syringe
– Inhaler
– Dropper bottle
– Ointment

21. GMP Manufacturing
• Current Good Manufacturing Practices (cGMP)
requirements apply to biologics if the biologic
is also a drug
• Those regulations cover virtually all aspects of
drug manufacturing
– Organization and personnel
– Buildings and facilities
– Equipment
– Control of product
components
– Control of containers and
closures
– Production and controls
– Packaging and label control
– Holding and distribution
– Laboratory controls
– Records and reports
– Returned and
salvaged drug
products

22. “ISQPP”1
• Identity: Must to be able to describe what is in your
product; “fully” characterize
• Strength: How much of a dose or unit of therapy are
you delivering?
• Quality: Must be manufactured under GMP quality
standards in a registered facility
• Purity: Must be free of contaminants or material
with unwanted characteristics
• Potency: What measure/assay describes potency/
biological activity?
1 Or “safe, pure, and potent”; All biological products must meet prescribed requirements of safety, purity and potency for
BLA approval (42 U.S.C. 262, Federal Food, Drug and Cosmetic Act, (FDC Act) (21 U.S.C. 321 et seq.); 21 CFR 601.2).

23. Manufacturing/Production Issues
• Biologics are frequently…
– Complex macromolecules or
mixtures
– Labile/unstable (vulnerable to
heat)
– Difficult to fully characterize
– Susceptible to contamination,
difficult to sterilize
– Tight control over production
processes and facilities is
essential for the product’s
identity and consistency from
batch to batch
– Autologous products that are
processed and returned have
logistical challenges
• Consider early
– What are the sources of
“active” materials (cells,
proteins, tissues) and their
controls?
– What other raw materials,
reagents are used in
production?
– What methods are available to
assure potency and activity?
– Who will produce materials for
clinical trials?
– In what form will the product be
delivered to the clinic?
– Are special tracking
tools needed?

24. Manufacturing/Production Issues (cont)
• Define Source Controls
• Manufacturing Process
Controls
• Establish sensitive analytical
methods to detect [cells,
proteins] with undesired
characteristics
• Ensure sterility (bacterial,
fungal, mycoplasma)
• Can protein, miRNA, siRNA
be completely sequenced/
conformationally defined?
• Cell Issues
– Morphologic evaluation
– Unique biochemical markers
– Gene and protein expression
analysis
– Cellular impurities profile
– Identity: HLA, other unique
marker
• Potency…

25. Strength/Potency1
• “Potency, that is, the therapeutic activity of the drug
product as indicated by appropriate laboratory tests
or by adequately developed and controlled clinical
data. . . .” (21 CFR 210.3(b)(16)(ii)).
• Regulations stipulate that “[t]ests for potency shall
consist of either in vitro or in vivo tests, or both,
which have been specifically designed for each
product so as to indicate its potency in a manner
adequate to satisfy the interpretation of potency
given by definition in § 600.3(s) of this chapter.” (21
CFR 610.10).

26. Strength/Potency (cont)
• “Strength” and “potency” are sometimes used
synonymously by regulators with respect to biologics1
• “The specific ability or capacity of the product, as
indicated by appropriate laboratory tests or by
adequately controlled clinical data obtained through
the administration of the product in the manner
intended, to effect a given result.”2
• The accuracy, sensitivity, specificity, and
reproducibility of the potency assay must
demonstrate lot‐to‐lot consistency and stability of the
product.3
1 See, for example, “Potency Tests for Cellular and Gene Therapy Products”, Draft Guidance for Industry, Oct 2008.
2 21 CFR 600.3(s).
3 21 CFR 211.165(a), (d), and (e); see section 351(a)(2)(C) of the Public Health Service Act (42 U.S.C. 262(a)(2)(C)).

27. For Cell Therapies…
• You will need to be able to:
– Provide a detailed description of where and how the cell
therapy product is manufactured
– Include all of the components and materials used during
the manufacture of the cellular product, such as cells, cell
bank systems, and any reagents or excipients
– Describe all procedures used during the manufacturing
process
Examples of these procedures may include recovery
and processing of tissues or cells, purification, and
other preparation of cells, donor screening and
testing, including final formulation of the product.

28. Some Useful Guidance Documents
• “Assay Development for Immunogenicity Testing of
Therapeutic Proteins” – DRAFT Guidance for Industry
(Dec 2009)
• “Potency Tests for Cellular and Gene Therapy Products”
DRAFT Guidance for Industry (Oct 2008)
• “Considerations for Allogeneic Pancreatic Islet Cell Products” –
Guidance for Industry (Sep 2009)
• “Guidance for Human Somatic Cell Therapy and Gene
Therapy” – Guidance for Industry (March 1998)
• “Content and Review of Chemistry, Manufacturing, and
Control (CMC) Information for Human Somatic Cell Therapy
Investigational New Drug Applications (INDs)” – Guidance for
FDA Reviewers and Sponsors (April 2008)

29. 29
Nonclinical Testing

30. Why is Toxicology Testing for Any New
Biologic Important?
• Provides information regarding the safety of
single and/or repeated exposure
– Toxicities related to the dose of product given
– Toxicities related to the duration of product
administration
– Identification of target organs for toxicities
– Reversibility of toxicities
• after clearance of the biologic product
• after development of neutralizing antibodies

31. Why is Toxicology Testing for Any New
Biologic Important? (cont)
• Provides supportive data for an initial safe
starting dose and subsequent dose‐escalation
scheme
• Aids in determining a risk/benefit assessment
for the proposed clinical studies
• Identifies potential endpoints for detecting
toxicity and the clinical monitoring of those
toxicities
• Guide in designing appropriate clinical trials

32. Nonclinical Testing – Types
• Nonclinical toxicity
studies fall into six
areas:
– Single‐dose acute
toxicity testing
– Repeated‐dose toxicity
testing
– Reproductive toxicity
testing
– Genotoxicity testing
– Carcinogenicity testing
– Special studies
• Traditionally, some are part
of initial IND submission,
some are completed during
clinical phase

33. Biologics are Different
• Traditional toxicology packages for a new
chemical entity can be quite different for
biologicals
– Animal model/system may be irrelevant
– Immunogenicity is a major issue, as individual
clinical responses can vary widely (including risk of
death)

34. Immunogenicity
• Clinical effects of patient immune responses
to biologics can range from no effect to
extreme, harmful effects
• Development of valid, sensitive immune
assays is a key aspect of product development
• IND applicants should implement preliminary
validated assays early (preclinical and phase 1)

35. Immunogenicity (cont)
• Animal models of immunogenicity:
– Therapeutic proteins are frequently immunogenic
in animals, but immunogenicity in animal models
is not predictive of immunogenicity in humans
– However, such assessment may be useful to
interpret nonclinical toxicology and pharmacology
data
– And, these data may reveal potential antibody‐
related toxicities that could be monitored in
clinical trials
• Banking clinical samples may be wise during assay
development

36. More Nonclinical Testing Goals
• Proof‐of‐concept
– Potential MOA
– Establish pharmacologically
effective dose(s)
– Optimize ROA/dosing
regimen
– Rationale for species/model
selection for further testing
• POC is part of regulatory
benefit‐risk calculus for IND
• Safety of conducting clinical
trial (benefit/ risk)
– Dose and dosing
– Potential target tissue(s) of
toxicity/activity
– Immunogenicity
– Mutagenicity, teratogenicity,
reproductive toxicity
– Parameters to monitor
clinically
– Eligible patient population
• Clinically relevant
product and
study design

37. Nonclinical Studies
• Reflect the proposed clinical indication as closely as
possible
• Detect site‐dependent toxicities
• Provide evidence to support therapeutic rationale
• Considerations for choice of Animal Models
– Immunosuppressed/immunodeficient animals
– Site of administration
– Absolute number of cells, percentage in the final product
– Number of animals for statistically valid evaluation of
potentially rare adverse events
– Duration of study
– Appropriate monitoring 37

38. Some Useful Guidance Documents
• ICH Guidances
– ICH S6: Preclinical Studies for Biotechnological Products
– ICH M3: Timing of Pre‐clinical Studies in Relation to Clinical Trials
– ICH S5a: Detection of Toxicity to Reproduction for Medicinal Products
– ICH S2b: Standard Battery of Genotoxicity Testing
• “Nonclinical Safety Evaluation of Drug or Biologic
Combinations” – Guidance for Industry (March 2006)

39. Some Further Resources
• Points to Consider
– Points to Consider in the Manufacture and Testing
of Monoclonal Antibody Products for Human Use ‐
2/28/97
• www.fda.gov/cber/gdlns/ptc_mab.pdf
– Points to Consider in the Manufacture and Testing
of Therapeutic Products for Human Use Derived
from Transgenic Animals – 1995
• www.fda.gov/cber/gdlns/ptc_tga.txt

40. 40
Early Clinical
Development

41. Clinical Questions/Issues
• What general indications
might be sought?
• What is the standard of
care?
• What target population?
• What clinical setting?
• What likely duration of use?
• What starting dose/dose
escalation?
• What endpoints are
clinically relevant for clinical
POC?
• What endpoints are
clinically relevant for
approval?
• How will endpoint(s) be
measured? (biomarkers,
surrogates)
• What comparator/control is
relevant? (placebo, active)
• What size trial (enrollment)
can show significant effect?
• Are effects likely to be
clinically relevant?

42. Objectives of Phase 1 Studies
• Traditional
– Safety/tolerability
– Pharmacokinetics
– Dose selection (MTD)
• Biologics trials
– Product characterization
– Product delivery/
dosing/safety
– Proof of concept/
mechanism of action
– Patient selection
(include biomarkers)
– Assessment parameters
for toxicity
– Effectiveness parameters
(early surrogates and
modeling of
relationships)
– Timing of assessments
– Duration of observation
42

43. Investigational Studies
• Study must be reasonably safe
– Risk vs. benefits
– First‐time‐in‐humans—most attention of all by FDA
– Consider other trials, indications, similar products, risks of
procedure;
• Assess drug exposure; duration of therapy; number of patients
exposed; stopping rules and expected/acceptable toxicity;
potential benefits; type of patients treated; minimization of
risks to subjects; plans for later phases; supporting animal
data, clinical data, in vitro data, manufacturing issues (e.g.,
product sterility, lot release data, etc.)
43

44. [Some] Cell Therapy Questions to Ask
• What cell type(s) will be used?
• What is the source of the cell(s)?
• How many cells are needed?
• Are the cells implanted alone?...with a scaffold?
• Are the cells modified?...now a ‘gene therapy’?
• What is the proposed therapeutic action?
• What is/are the biologically relevant animal species
for your product ?
• Are there potentially relevant animals models of
disease/injury that can be used?
44

45. [Some More] Cell Therapy Questions to Ask
• What is the optimal method/route to deliver the
product?
• What is the optimal timing for product
administration relative to the onset of disease/
injury?
• What happens to the cells in vivo following delivery?
• Will repeat administration be needed?
• What is the risk/benefit ratio for the intended
patient population?
45

46. 46
Clinical Trial Design
• Rationale
– Contrast established risk (teratoma) vs. intended
clinical benefit (little experience)
– For first in man studies, justified by particularly
strong preclinical proof‐of concept
• Appropriate trial design
• Doses/dose escalation
• Patient monitoring
• Follow‐up

47. Jason E. Moore, MS, MBA, RAC
jason.moore@plxpharma.com
713‐842‐1249
Thank you!!