BN5208

Biomedical Quality and Regulatory Systems

FDA classification of medical

devices and Tissue Engineering
products/devices
 Schedule for today…

• Practice questions from previous lecture 

• Discussion on project/schedule
• History of FDA
• FDA’s risk based classification of Med dev.
• What is 510k and PMA
• FDA mantra for TE products
• TE product regulation
• Bench to bedside
• TE endpoints
 But First…

• Lets go over the schedule, grading scheme and

project details and answer any questions/
concerns that you may have
• Practice questions to ensure we have learnt and
retained well from last weeks lecture  and we
all are on same page
FDA : Food and Drug
Administration
 Birth of FDA and US regulatory framework

1906; The pure 1938; The 1976; The med

food and drug food, drug and device amendment 1990; Safe 2002; Med dev
1997; FDA
act enacted cosmetic act act granting FDA a med devices user fee and
modernization
(concerned with replaces the statutory mandate act modernization
act.
product labelling 1906 act on regulating devices act allowing FDA
and habit Post market to charge
Regulation on
forming drugs; Devices previously surveillance processing/appl
biologicals and
Birth of FDA marketed don’t need reviewing fees
combination
resubmissions products
(preamendment
devices)

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Risk based classification

Class I: No FDA approval documentation required

Class II: FDA premarket notification 510K required
Class III: FDA premarket approval (PMA) required
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Class I medical devices

General controls:
• Registration of facility required (online)
• Device listing with FDA
• Appropriate labelling
• Approval documents are usually exempt

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 General controls
Failure poses no risk to life
– no performance standards
– requires no clinical testing

• Must not be adulterated or misbranded

• Requires:
– Establishment registration
– Device listing
– Labelling

• Requires (but may be waived):

– premarket notification
– GMP
– Design control
 Class II devices

General controls and special controls:

• Approval documentation required
Premarket notification
510k substantially equivalence to predicate device
• Quality system regulations

A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is
at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR
807.92(a)(3)) that is not subject to PMA
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 Classes III

• Class III – high or unknown risk;

• If fails may cause serious injury or even
death
• require pre-market approval (PMA);
complete evaluations from design, bench,
animal and human testing (clinical trials)

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 PMA
• Approval of a product for marketing by FDA;
• Reasonable assurance of safety and effectiveness
based on design and testing
• Clinical data that provides valid scientific evidence
of S&E; controlled trials to case histories but not
anecdotes on use
• Changes to PMA products require submission,
review and approval; called amendments

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Areas of concern when developing
Class II and III products
• Design controls
• Animal trials
• Clinical trials
• Quality systems regulations

Why design control

requirements?
Many product failures in the 1980s and
1990s were linked to flaws in the
device design
 Significant Risk Device

Device may be:

– an implant

– used in supporting or sustaining human life

– of substantial importance in diagnosing, curing, mitigating or

treating disease or preventing impairment of human health
How should this be classified ?
15
 De Novo
• Products without a class but understood to be
moderate risk
• Process to obtain classification – based on data;
engineering, animal, some clinical to support risk
category
• Pre-submission and risk guidance documents
• About 120 day review of complete application

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 predicate
In a nutshell

Manufacturer completes FDA judges

tests & submits results to if product is
FDA as premarket “substantially
notification (510k) equivalent”
510(k)
(Class II)
The drawing board

Yes
No
Product goes
go to market

PMA Yes
(Class III)

Manufacturer completes
most tests & submits
results to FDA for
permission to conduct
clinical trial
Clinical trial(s)
FDA judges
if product is
“safe and
Manufacturer submits all effective”
results (clinical & non-
clinical) to FDA as premarket
application (PMA)
 Issues and approaches in TE,
Translational and regulatory challenges

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 In this part we will discuss …

• TE product as a medical device…

• TE market dynamics and capitalization
• FDA classification of TE products…
• Regulation of TE products
• TE product development considerations

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 FDA TE products

Human cells, tissues, and tissue based

products (including biomaterials for
various TE applications) are regulated as
medical devices

Biomaterials for TE applications are approved but devices are regulated

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 Classification of Medical Devices I, II or III
TE products TE products

I. General controls II. Special controls III .Premarket

approval (PMA)

No FDA approval needed Equivalent to marketed Human trial,

prior to marketing, only device ? Investigational device
registration Premarket notification exemption (IDE)

Good manufacturing practices/good lab practices

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 What are combination products?
• Combination products are made of multiple
constituents: drug-device, drug-biologic, device-
biologic or drug-device-biologic that are physically or
chemically combined, co-packaged in a kit or
separate cross-labeled products.
• All components work as a system and are critical to
achieve the eventual desired effect/function.

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 Examples

Medical Devices: Collagen, hyaluronic acid and synthetic

implants:
• Focalseal L: PEG solutions modified to photo-
polymerize in-situ
• Emdogain: porcine enamel matrix proteins

Combination products:
• Apligraf: cells on bovine collagen

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Structure Procedures/Year
Skin 4,750,000
Cartilage 1,132,100
Blood Vessels 1,100,000
Pancreas 728,000
Kidney 600,000
Breast 261,000
Liver 155,000
Tendon & Ligament 123,000
Intestine 100,000
Ureter & Urethra 81,900
Heart Valves 65,000
Bladder 57,200

Potential U.S. Organ and Tissue Markets

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 Concept/Discovery Research
to Successful TE Product (bench to bedside)
Public/Private
Funding

Post
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Discovery
Clinical Trials Market Successful market
Research (unmet consider
(safety/efficacy) (profitability) Product ations ?
clinical need)

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Intellectual Property Regulatory Evaluation Public(s) Perception

& Patent Protection & Product Approval & Market Acceptance

SCIENCE
Talent/People
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Market dynamics is the propeller…
 FDA Mission Statement

 The FDA is responsible for protecting the public health by assuring

the safety, efficacy, and security of human and veterinary drugs,
biological products, medical devices

 The FDA is also responsible for advancing the public health by

helping to speed innovations that make medicines and foods more
effective, safer, and more affordable; and helping the public get the
accurate, science-based information they need to use medicines
and foods to improve their health

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 FDA Organization
• CBER (Center for Biologics Evaluation and Research): vaccines, blood and blood
products, human tissue/tissue products for transplantation, cells, gene therapy
– Office of Cellular, Tissue, and Gene Therapies
– Office of Vaccines Research and Review
– Office of Blood Research and Review
• CDER (Center for Drug Evaluation and Research): drugs, some biological products
• CDRH (Center for Devices and Radiological Health): devices for treatment, implants,
diagnostic devices
• Center for Drug Evaluation and Research (CDER)
• Center for Food Safety and Applied Nutrition (CFSAN) Center for Veterinary
Medicine (CVM)
• National Center for Toxicological Research (NCTR)
• Office of the Commissioner (OC)
• Office of Regulatory Affairs (ORA)

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 Regulations vs. Standards

• Regulations
– Government implementation of statues that have the force of law
– Define specific requirements for safety
– Provide accurate information to health professionals and consumers
• Standards
– Voluntary
– Frequently developed outside of the government
– Written standards describe how manufacturers might meet regulatory
requirements
– Physical standards provide accepted “benchmark” materials

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ISO 10993: Evaluation criteria for TE products/devices

Start Biological evaluation not

applicable

no
Does the
device contact
the
blood/tissue?

Final
assessment
Material characterization
yes
yes

Is the material Does the device

same as in Sufficient
have properties
existing justification
similar to a
commercial yes yes and/or data
commercial
product? available?
product?

no no no

Perform biological evaluation as per ISO 10993

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 FDA mantra on TE products

Efficacy
– Does it function for the intended purpose?
– Does it function better than current clinical products?

Safety
Is the device safe (particularly for II and III products)

Clinical End-points
– What is measurable to supply a statistically relevant
observation to support safety and/or efficacy?

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 Design Idea

• R&D
• Do not harm
• Improvement over current products
• Can it be manufactured?
• End user friendly
• Will someone pay?
• FDA approvable?

Pointers for your final presentation as well…

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 Functional Product
GMP:
Control of:
– Facility
– Equipment (validation)
– Personnel
– Raw materials (audit)
– Production
– Storage
– Documents
– Final Product

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Safety and effectiveness considerations for a cell–scaffold combination product.
GMP, good manufacturing practice; MCB, master cell bank; QSR, quality systems
regulation;WCB, working cell bank.
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 FDA New Approach

Proposed Approach to the Regulation of

Cellular and Tissue-based Products”
– Tiered system of regulation
– Provides firm structure to regulations
– Reduces restrictions on new technology development
– Technology representing higher level of risk concerns
receive greater level of review

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Facilitate dialogue with the FDA regarding
regulation of tissue engineered products

Products utilizing tissue engineering strategies continue to

move towards clinical application with some products
already in trials and/or on the market. Many of these
products have multiple components, which can complicate
the regulatory pathway.

It is important for the field to maintain an understanding of

the current regulatory process and a ongoing dialogue with
the FDA.

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Additional factors that contribute to the
commercial success (or failure) of TE products

TE products can present unique challenges to successful

therapeutic development, not only from a scientific
standpoint but also because their development, delivery and
market profile is somewhat different from conventional
medical devices or even pharmaceuticals.

Several factors that impact therapeutic success of TE

products, including gaining insurance acceptance, meeting
market expectations and clinical need profiles

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Regulatory considerations that contribute to
the success of TE products

• Tissue engineering shares with other aspects of the regenerative

medicine field the regulatory challenge that some clinical indications
do not have adequate preclinical models to prove the safety and
efficacy of a product.
• Clinical trials and commercialization plans should be designed
bearing the regulatory environment in mind.
• Investigators must work closely with the FDA and patients to develop
an acceptable risk-tolerance profile and an achievable regulatory
path to approval if these products are to be successful.

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 Regulatory consideration for TE products
• Regulatory barriers are considered as major challenges for TE product
commercialization
• Both FDA and EMA (European Medicines Agency) have recognized the
regulatory challenges presented by TE product technologies, raw
materials, pre-clinical testing, and clinical assessment.
• TE product pipeline is broad and deep presenting unique challenges for
regulators such that the EMA and FDA Pre-Submission Meetings allow
sponsors to obtain specific guidance on their respective technology (cells,
genes, combinations, etc).
• TE products are complex presenting unique manufacturing, pre-/non-
clinical and clinical challenges for regulation
 Regulatory consideration for TE products

Both EMA and FDA:

– Take a risk-based approaches to evaluate the specific risks unique to each TE
product submission.
– Have identified special pathways (e.g. orphan, accelerated assessments, etc) to
encourage TE therapies reaching the market most expeditiously and are safe and
effective for the intended patient population.
– Promote long-term follow-up on safety, efficacy and durability of TE products
– Have entered into agreement for parallel advice and collaborations with
industrial organizations on regulation of TE product development
– Offer specific guidance to industry in key technological areas of concern:
scientific advise being sought by sponsors has focused on non-clinical challenges
although clinical trial design have also served as a topic of industrial interest.
– Accept international studies for marketing applications if they meet specific
requirements for data validity, good clinical practices and supporting information
 Regulatory consideration for TE products

• The way forward for TE technologies and products includes:

– Raise awareness of unique safety challenges and efficacy opportunities
– Learn from experience as these new technologies advance to
commercialization and become standards of care.
– Promoting industrial-regulatory and regulatory-regulatory dialog to
promote the commercialization of safe and effective TE technologies for
unmet medical needs
Steps in TE product development
Analysis of Raw Materials/Supplies
– Purity, Identity, Strength, Sterility, Stability
– By-products and Interaction of all Components

Documentation Process
- SOP (standard operating procedures)
- GMP (good manufacturing practices)
- GLP (good lab practices)

Toxicology and Pre-clinical Testing (Animal

Efficacy/Safety)
– Define Human Protocol/End-points
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Biological evaluation of medical devices is performed
to determine the potential toxicity resulting from
contact of the component materials of the device with
the system. The device material should not, directly or
indirectly or through release of their material
constituents

Evaluation of any new device intended for human use requires data from
systemic testing to ensure that the benefits provided by the final product
will exceed any potential risk produced by the device materials

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When selecting appropriate tests for biological evaluation
of a medical device, one must consider the chemical
characteristics of the device material and the nature,
degree, frequency and exposure duration

The tests may include:

• Acute, sub-chronic and chronic toxicity
• Irritation to skin, eyes and mucosal surfaces
• Genotoxicity
• Carcinogenicity

Additional organ specific tests may also be required

The specific clinical application and the material constituents may also dictate
need for specific tests

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 Tissue Engineering Endpoints

Morphological/Histological/Biochemical
– Match the composition and architecture of the tissue.
– Problem: Is it really feasible?

Functional
– Achieve certain functions; display certain properties (e.g.,
mechanical properties).
– Problem: Difficult to measure all properties; which properties are
the most important?

Clinical
– Pain relief.
– Problems: Can only be evaluated in human subjects and the
mechanisms (including the placebo effect) and kinetics of pain relief
(e.g., how long it will last) are unknown.

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Suggested tests to be performed on device materials
and/or extracts from materials for FDA approval
Irritation tests: potential to cause skin/tissue irritation (animal or human)
Sensitization assay: potential for sensitization to a material (animal or human)
Cytotoxicity: cell growth inhibition or death (cell cultures) Acute systemic toxicity:
harmful effects of single or multiple exposures in < 24 hr period (animal)
Hemocompatibility: evaluation of hemolysis (red blood cell lysis), thrombosis,
coagulation, platelet and immunological response
• Limited contact (in vitro)
• Extended contact with circulating blood (in vitro + animal model)
Pyrogenicity: material-mediated febrile response (animal)
Implantation tests: toxic effects on tissue at implant site (animal)
Mutagenicity: potential for gene mutations (cell cultures)
Subchronic toxicity: harmful effects of multiple exposures over short-term (1 day to
10% of animal lifetime e.g., 90 days for rat) (animal)
Chronic toxicity: harmful effects of multiple exposures over long-term (>10% of animal
lifetime)
Carcinogenesis bioassay: tumorigenic potential over lifetime (2 yrs for rat)

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Testing must follow Good Laboratory Practices Regulations
All preclinical safety studies must be conducted with:
• well-defined written protocol (standard operating procedures, SOP)
• trained personnel supervised by study director
• independent review by a quality assurance unit (QAU)

Animal Welfare Act (1989)

• All protocols involving animals must be reviewed
• minimum number of animals
• least invasive and traumatic procedures

Data from previous research can be submitted in support of an application, to reduce

cost and time of evaluation

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Clinical Studies
To perform clinical studies on an unapproved product, applicants file for an
Investigational Device Exemption (IDE)

- Based on data from biocompatibility testing

- Must follow Good Clinical Practices (GCP) Regulations
- well-defined study plan/protocol
- informed consent of patients
- participating investigators must disclose financial interests
- requires a “control” population: randomized trials w/ no treatment, placebo,
conventional treatment; or historical control (amassed data)
- foreign clinical trials may be included
- investigators recognized as competent, data validity can be verified

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 Approval of protocol pre- and
clinical trials

IRB: Institutional review board

IACUC: Institutional animal care and use committee

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Some concerns bringing TE products to market…

• Average time to market of 10-15 years,

• Average development and production costs of $1 billion,
• Failure rate of 90% by the clinical-trial stage,
• Less than 30% chance that an approved product will generate
enough revenue to recoup its own development costs.
• TE products have a limited track record in the medical industry,
and the financial rewards involved in developing new products
are not as certain as they are for developing a second or third
generation of an existing pharmaceutical
• Since each TE product is unique the regulatory pathway may not
be clear and are therefore considered risky.

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 Some concerns bringing TE products to market…

• The manufacturing and scale-up of TE products can be complicated and

potentially expensive. For complex TE products, scale-up might be
applicable to only a portion of the product, or will require developing
procedures that allow products to be made at the clinical site. Complex
products may also require training of doctors on the implantation
and/or utilization of the TE product.
• The business model is less clear for TE products and ability to secure
insurance reimbursement is less certain than for small molecule
pharmaceuticals.
• There are few options for funding the manufacturing of TE products, for
instance. As a consequence, many academic research projects remain
stuck at an early stage of therapeutic development

Such challenges explain why venture capitalists (VCs) are increasingly unlikely to invest in TE
products prior to Phase III clinical trials, when the product has passed enough functional and
regulatory hurdles to have a reasonable chance of success.

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Several potential strategies to increase the success
rate of new TE products:
• Keeping a focused product line,
• Positioning the product as a first-line treatment to increase market
penetration and improve the likelihood of insurance reimbursement,
• Avoiding large infrastructure and personnel costs,
• Keeping product development through early stage clinical trials in
academia,
• Acquiring seed funding from people with a personal stake in the
product’s success,
• Outsourcing
• Lightening the regulatory burden by using already approved products
or procedures

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The choice of cells and materials for tissue engineering is
often done without the human clinical endpoint in mind.
Why? How it may be addressed…
Translating discoveries in the laboratory into a tissue-engineered product,
however, faces not only technical challenges with the tissue construct itself but
business challenges including scale-up and manufacturing issues, navigating FDA
approval, addressing the appropriate market needs, and raising funds needed to
bring the product to market. Translation of discoveries from the bench to the
bedside would be greatly eased if these non-scientific challenges were identified
and addressed up front

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Outcomes: advancing TE approaches to the clinic
• Support basic research using stem cells for tissue engineering and studying cell-material
interactions: TE-directed research will focus on areas such as the differentiation of stem
cells, their aggregation into 3D structures or tissues in vivo or in vitro, the immune response
and foreign body response, and the development of adequate analytical tools test the
safety and efficacy of TE products in either preclinical animal models (where adequate) or
first-in-man studies. Increase effort to fund basic research that will elucidate the interaction
of cells with synthetic and biologically derived materials, by targeting groups that combine
strong bioengineering and stem cell experience.

• Promote collaborations between stakeholders in TE therapies, particularly basic scientists,

surgeons, and industry. TE products must be developed with the clinical goal in mind, so
early communication between all collaborators is essential to increasing a product’s
potential. In its more translational funding initiatives, we should aim to improve therapeutic
success of TE products by insisting upon collaborative projects that have concrete avenues
for early and regular communication between varied stakeholders.

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Outcomes: advancing TE approaches to the clinic
• Regulatory transparency for TE products. The FDA is in the position of needing to
regulate TE products that are heterogeneous in their composition and intended
uses. The challenge can make the regulatory process treacherous for both
regulators and product developers. As a dual advocate for patients and stem cell
scientists, there should be interest in making regulatory processes as transparent
and effective as possible.

• Highlighting non-scientific factors that impact commercial success. Many TE

products are intended for a clinical market. Researchers should consider non-
scientific factors that will contribute to their products’ future success. In designing
its grant applications and educational outreach activities for therapeutic TE
products, participants should prioritize clinical need, develop measures to both
evaluate the market and provide insurance coverage for the product being
developed, and ensure that products will be well accepted among medical
practitioners who will be the end-users of the technology.

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 Take home points:
• Medical devices have been regulated by federal agencies since 1938 and due
to rapid changes in technology regulation is still evolving
• The FDA assigns certain levels of risk to each device, which corresponds to the
class level
• Class I devices pose the least risk while class III pose the most risk
• There are more class I devices in the market than class III devices
• Low risk class I devices are subject to significantly less oversight than the
highest risk class III devices
• A predicate device is a legally marketed device to which equivalence is drawn
for the approval of new class II devices
• Class III medical devices require premarket approval, which typically involves
clinical trials
• Technological innovation can be expected to impact medical device
classification and approval pathways
• FDA approves different categories of health care products

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Reference
www.fda.gov

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