BME DESIGN II

LECTURE SEVEN
Dr. Daniel Akwei Addo

CRITICAL LENSES: STANDARDS, REGULATIONS, AND ETHICS

In the next few sections you will learn about three perspectives that are important in all design processes
but are especially critical in the design of a medical device. Each of these perspectives present
unique requirements that impact the design process.

Initial sections describe standards as widely accepted agreements that ensure medical products and
processes are safe, effective, and of high quality. There are standards for how to perform tests, determine
the interactions between materials and living systems, and guide the entire design process (known
as Design Controls). Standards have been mentioned in other previous lectures, but you will learn how standards
are created, accelerate innovation, encourage acceptance of new products, help gain regulatory
clearance, and save you time and effort.

The next few sections describe the complex regulatory review processes, mandated by law in most countries,
for protecting the well-being of the public. Although regulatory review is often viewed as a barrier to
commercializing a medical device, it provides a helpful framework for thinking more broadly about the
design process. You will learn about device classifications, the clearance and approval processes, proper
labeling and warnings, and recalls.

Later sections describe the ethical implications of bringing new healthcare technologies into the
world. The focus is on applied ethics as a lens through which you can view design decisions. Case studies
are used to illustrate ethical principles and demonstrate how many laws and policies arise due to
product failures that resulted from lack of oversight, conflicts of interest, violations of confidentiality,
negligence, and even malicious intent. The ultimate aim is for you to develop habits of mind that will
allow you recognize, dissect, and navigate ethical dilemmas that will inevitably arise during your

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career.

By the end of this lecture you will be able to:

• Create a list of standards that are relevant to your design project and will help you navigate the various
phases of your design process.
• Use one or more standards to design tests relevant to design verification.
• Create a plan for both domestic and international regulatory clearance.
• Perform a thorough assessment of ethical implications of your solution and how they might intersect, and
potentially conflict with, legal, social, political, and economic systems.

Medical Device Standards and Design Controls

As indicated by the biblical quote, standards have existed since at least ancient times. That standards
have played a role in every other chapter and is a clue to the significance of current standards in biomedical
engineering design. The general purpose of an internationally or regionally accepted standard is to
establish a universally or regionally accepted measurement, material composition, method, procedure,
or process. Standards also guide design activities including material selection and composition, the design of
experiments, test procedures and acceptance criteria, and packaging and design documentation.

In addition, standards can help reduce costs, increase productivity, generate economic growth,
improve quality, and promote fair comparisons with competitive products. When a medical device is
certified as having met a standard, it accelerates ultimate regulatory approval. Many stakeholders only
accept or pay for a medical device if it can be demonstrated that it complies with applicable
standards.

The formal definition of a medical device standard is provided by the International Organization for
Standardization (ISO) and the International Electrotechnical Commission (IEC):

A document, established by consensus and approved by a recognized body, that provides, for common
and repeated use, rules, guidelines or characteristics for activities or their results, aimed at the
achievement of the optimum degree of order in a given context.

In brief, for engineering applications, a standard is a technical guideline to ensure that materials, processes,
representations, and services are fit for their purpose. Standards are prominent in medical device
design to ensure safety, quality, and effectiveness.

In this lecture, we present more about how standards are created, how they are used in making design decisions,
and how to control the design process.

Need For and Types of Standards

As indicated in earlier lectures, standards are used to guide design activities including material selection
and composition, experimentation, design characteristics, packaging, and design documentation. They
define standard terminology to prevent confusion when communicating technical information. These
standards also address quality and safety; for that reason, most regulatory bodies, including the US
Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals
and Medical Devices Agency (PMDA) in Japan more readily approve healthcare products for clinical
use that satisfy a specific set of standards related to developing technology.

Standards build confidence and trust among various stakeholders in the healthcare ecosystem,
including users and customers, regulatory bodies, manufacturers, insurers, and healthcare providers.
Regulatory agencies only clear a medical device for sale if it can be proven it met applicable standards.
Doing so is one way to ensure safety and effectiveness. In this way, compliance with standards eases

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the pathway to regulatory approval, commercialization, and adoption of a product by the wider healthcare
ecosystem. In addition, standards can help reduce costs, increase productivity, generate economic
growth, improve quality, and promote fair comparisons with competitive products. One example is the
Luer lock presented above, which creates a leak-free connection between a male-taper
connection and a female counterpart.

This design of a locking mechanism is ubiquitous in medical applications. ISO

594 is a standard that describes characteristics of Luer taper connectors while ISO 80369-1
Specifies dimensions for all small-bore connectors to be used in intravascular or hypodermic applications.
Because virtually all healthcare product manufacturers comply with these standards, all of their products
are compatible with one another, thus enhancing safety, saving time, and promoting commerce
across brands and borders.

Types of Standards
There are a number of different classes of standards; seven primary classifications are summarized in
Table below.

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Standards Organizations and Standards Generation
Standards originate through a variety of means that vary across the globe. Often a technical need or new
technology warrants a new standard. At times, standards build upon and supplement one another. In this
section, we explore the various types of standards-generating bodies and how they generate and encourage
adoption of a standard.

Standards Development Organization

Standards Development Organizations (SDOs) create and publish standards (Table below).

Some SDOs are independent and not-for- profit, such as the ISO and ASTM International (ASTM
is the acronym for the former American Society of Testing Materials). Other standards are a part De facto
standards sometimes end up being sponsored by an SDO. For example, the Hypertext
Markup Language (HTML) used for webpages was first developed in 1991. After its fourth revision,
it became an internationally recognized standard nearly a decade later (ISO/IEC 15445
Information technology—Document description and processing languages—Hypertext Markup
Language [HTML]). There are also organizations that attempt to bring together other SDOs. For
example, the American National Standards Institute (ANSI) does not generate its own standards
but is a private nonprofit organization that brings together other SDOs to reach consensus (e.g., ANSI/AAMI/ISO
5840-1: 2015). ANSI is the only United States representative that is permitted to
serve as a member of ISO. The vast majority of standards in the United States are voluntary consensus

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standards, meaning that compliance is not mandatory. However, customers or companies
will often choose not to purchase a product that does not comply with specific standards. This
potential impact on sales often provides an incentive for companies to comply with relevant
standards.

Finding Medical Device Standards

There are thousands of standards that have been created specifically for medical devices and many
more cited in these standards. Due to the dynamic nature of health care, there are new standards being
released almost every week. For example, recent technical advances in computer-assisted
and robotic surgery, implantable “smart” sensors, nanotechnology, personal protective equipment, and improved
healing of injury through tissue engineering are prompting new standards to be created. It is not always
easy to find the standards that are relevant to your specific design project. A combination
of search methods is suggested for use as described below.

A powerful and robust way to find standards is to search the FDA 510(k) database for similar products.
As shown in Figure Below, a good place to start is with the 510(k) database and enter the product
name.

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Screenshots of FDA’s websites to determine tests and standards associated with a product. Using endosseous
dental implants in this case leads to (a) FDA’s 510(k) database, (b) companies that make the product, (c) a
product code and registration number, (d) testing requirements, and (e) relevant standards.

Although not recommended, one option for finding relevant standards is to use a generic search
engine. For example, you may be looking for testing methods that apply to an initial search term such
as “endosseous dental implant standards”; ISO standard 14801: Dentistry—Implants—Dynamic loading
test for endosseous dental implants appears on the first page. A limitation from a generic search is
that results do not indicate whether or not the standards found are recognized by regulatory agencies.

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Examples of Medical Device Standards

Design Controls and ISO 13485

Standards exist not only for guidance on design decisions (e.g., material choice, testing procedures) but also
for guidance of the design process itself. A design process that allows for detection and correction of technical
and nontechnical errors throughout the process results in less time needed for design, lower manufacturing
costs, and higher quality parts. One way to achieve that is through a Quality Management System (QMS).

A QMS is defined as being a formalized system that documents processes, procedures, and responsibilities
for achieving quality policies and objectives. In practical terms for the design process, the
purpose of a QMS is to ensure each time a process is completed, the same type of information, methods, skills, and
controls are applied in a consistent manner. In design, these are called Design Controls.

Design controls are part of part of ISO 9001, Quality Management Systems—Requirements, and
part of ISO 13485 Medical devices—Quality management systems—Requirements for regulatory purposes.
This set of practices and requirements aims to reduce risk and increase the probability that a
design meets customer needs. ISO 13485 includes requirements that help companies provide medical
devices and services that consistently meet customer and regulatory requirements. These are not product
standards; rather, they are quality management standards focused on the customer. As shown in
Figure below, more than 60% of recent FDA recalls were due to design defects or material problems.

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Many of these could have been prevented if effective design controls had been implemented, thereby
leading to better design decisions. In this section we outline the components of design controls.

§ Design Control Requirements

Design control requirements do not specify the exact methods to be used, but rather outline a generic
process. Each company and design team determines how they meet these requirements. At the most
general level, ISO 9001 describes the seven principles of a QMS and the basic rationale for each. In
alphabetic order, these are:

• Continuous Improvement—to maintain current levels of performance, to react to changes in internal and
external conditions, and to create new opportunities
• Customer Focus—to meet customer requirements and strive to exceed customer expectations
• Engagement of People—to empower competent people to enhance their capability to create and deliver
value
• Evidence-Based Decision Making—to understand cause-and- effect relationships and potential unintended
consequences
• Leadership—to establish unity of purpose and direction, and to create conditions in which people are
engaged in achieving the organization’s quality objectives
• Process Approach—to consistently achieve effective and efficient results when activities are understood
and managed as interrelated processes functioning as a cohesive system
• Relationship Management—to achieve sustained success, the organization must manage relationships with
all interested parties (employees, partners, and suppliers) to optimize their impact on the organization’s
performance.

In the context of biomedical engineering design, ISO 13485 specifies requirements for a QMS that
consistently meets customer and applicable regulatory requirements. ISO 13485 includes sections on
quality management systems, management responsibility, resource management, product realization,
and measurement, analysis, and improvement. A Section of the standard describes nine parts of design
controls. The FDA’s Design Control sections are included in the Quality System Regulation (QSR),
which is modeled after the ISO standard. A comparison of the titles in each are found in Table below.

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 § Design and Development Planning
Design and development planning requires design teams and manufacturers to establish and maintain
plans that describe all required design and development activities and identifies the person or group
responsible for their implementation. The plan includes who will be involved and which activities are
needed to provide input into the design and development process. Specific methods for design and development
planning are not part of the design control requirements; each design team or company develops its own plan.

§ Design Input
Design inputs include performance and technical requirements, specifications, applicable standards,
and regulatory requirements. These serve as the basis for the design of a device. Generally, these
make up the list of quantified and testable specifications. These specifications were based upon the methods of
discovery

§ Design Output
Design output consists of the deliverables of a design process that include product and process documentation
needed to transform a design into a prototype or finished product (final specifications, drawings,
and assembly instructions). They also include test procedures, test results, and risk analyses to
verify that a product meets the design input requirements.

§ Design Reviews
Design reviews are a required component of design control and are common in industry and academic
design projects. ISO 13485 Section 7.3.5 states, in part, the following requirements of design
reviews:

At suitable stages, systematic reviews of design and development shall be performed in accordance
with planned and documented arrangements to:

a) evaluate the ability of the results of design and development to meet requirements, and
b) to identify and propose corrective actions (if any) or improvements or both.

In academic design projects, design reviews enable a panel of experts outside the design team to
review and critique both the process and progress of a design project. Participants in such reviews usually
include faculty and advisors; they may also include representatives of the government or a company
comprised of technical experts on a product or prototype under consideration. In academia, design
reviews are usually part of a course grade.

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 § Design Verification
Design verification answers the question, “did we make the prototype right?” Verification involves
creating a formal testing plan (guidelines can be found in Section 9.6) demonstrating that design output
meets the design input requirements. Examples of verification testing standards include biocompatibility
testing (ISO 10993), software testing (ISO 62304), and electrical safety testing (ISO/ IEC 60601).

§ Design Validation
Design validation answers the question, “did we make the right product?” It aims to determine if the solution meets
the users’ needs, even if it meets all technical specifications. While design verification generally starts with the
testing of specifications using laboratory tests, at the heart of validation testing is the perspective of the user.

§ Design Changes
As indicated throughout this text, design is an iterative process in which new information is gained and the
project and design solutions are reevaluated on an ongoing basis. Design control requirements call for a
robust method of tracking these changes to ensure that the evolution of the design is transparent. This
includes documents, drawings, and prototypes. When more than one prototype can be made, it is critical
to capture the advantages and drawbacks of each iteration.

§ Design Transfer
Design transfer is the handoff of a completed design and tested prototype to manufacturing. This is
considered to be the last formal step in the engineering design process. Design transfer is most often done through a
Device Master Record (DMR) that contains all documentation needed to produce a
finished medical device. The DMR is divided into five categories of information:

• device specifications,
• product process specifications,
• quality assurance procedures,
• packaging and labeling specifications, and
• installation, maintenance, and servicing procedures.

§ Design History File

The DHF was introduced earlier in this lecture. In the context of design controls, the DHF is a compilation of the
entire design history of a finished medical device. The design controls used, and standards employed, must be
documented. Included in the DHF are reference records necessary to demonstrate that the design was developed in
accordance with proper design controls. This includes user needs and design inputs, design outputs, design
verification and validation results, design reviews, and design transfer materials related to manufacturing. For
commercialized products, additional components of the DHF likely include approved labeling, sterilization
procedures, design transfer documentation, and design change procedures.

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Regulatory Requirements
Introduction

Medical device regulations and regulatory bodies exist to protect the health and safety of the public.
Medical devices sold around the world typically require review and approval by a governmental or
sanctioning organization (regulatory body) confirming the devices to be safe (will not cause harm) and
effective (do what they are claimed to do). The type and level of review depend on the classification of
a medical device, which is based on its level of risk or potential to cause harm (death or severe injury)
to a patient. Classifying a medical device is the first step in determining its regulatory pathway, which
will impact the planned market introduction date and design of the device. Regulatory review requires
manufacturers to submit different types of information and supporting data, typically generated during
the design process, to demonstrate the safety and efficacy of the device. This includes data from verification
and validation tests.

Regulatory bodies also require evidence that procedures are in place to ensure that quality is maintained
throughout various aspects of the business (such as design, manufacturing, and distribution) and that procedures
exist for monitoring safety and efficacy of the device after market introduction. If problems are reported by users or
customers, regulatory bodies often oversee corrective actions that may include a product recall.
In this chapter, you will become familiar with regulatory terminology and requirements, device classifications,
pathways to market, post market surveillance activities, and reasons and procedures for product recalls.

Regulatory Considerations in Academic and Industry Design Projects

In an established medical device company, dedicated regulatory affairs personnel will be part of your
project team. They will be responsible for determining the regulatory strategy for a new product, managing
submissions to regulatory bodies, preparing for and guiding the company through audits and
inspections, and managing post market surveillance of safety and efficacy.

Design engineers, although not responsible for regulatory oversight, are often in close communication
with regulatory affairs personnel as they consider the impact of regulatory requirements on design decisions and
project timelines. For example, regulatory requirements are considered when narrowing
and refining design solutions, analyzing risk, designing and executing, and conducting clinical trials. The Design
History File (DHF) maintained throughout your project will be part of regulatory submissions. As discussed in this
lecture, design engineers may be involved in post market surveillance and product recalls. For these
reasons, you will need to understand regulatory terminology and requirements, approval processes and
pathways to market, risk management, and ethical obligations to the public.

In an academic design project, you are unlikely to have the time and resources needed to submit
documentation to regulatory bodies. An understanding of regulatory requirements and approval processes
can serve as a framework for guiding you through the design process and will help prepare you
for a career in the medical device industry.

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History of FDA Legislation and Regulation

Product Classifications: Device, Drug, Biologic, or Combination Product?

A new medical product can be classified by the FDA as a device, drug, biologic, or combination product.
Some products are classified as combination products with characteristics of more than one classification.
For example, a drug-eluting stent is classified as a combination product because it is comprised of both a drug and
device. Its primary intended use is to restore the diameter of an artery, which is considered a medical device
function. As a secondary intended use, the stent acts as a drug delivery product because it releases a controlled dose
of medication. This medication is classified as a drug. Thus, this type of device is a combination product.
Classifications are guided by the definitions presented in the following sections and are used to determine the
regulatory pathway for a new medical device.

Medical Devices

Medical devices cover a range of applications, medical specialties, risk, complexity, invasiveness, and
cost. Examples include tongue depressors, CT scanners, heart valve replacements, and endoscopes.
Medical devices also include in vitro diagnostic products, (e.g., general-purpose lab equipment,
reagents, test kits), combination products (e.g., drug-eluting stents, birth control implants), companion diagnostics
(tests used with a therapeutic drug to determine its applicability to a specific patient), software (depending on the
specific application), mobile medical apps, and some accessories. Products emitting electronic radiation, such as
diagnostic ultrasound products, x-ray machines, and medical lasers, may also meet the definition of a medical
device.

In the United States, if a product is labeled, promoted, or used in a manner that meets the following
definition found in section 201(h) of the Federal Food, Drug, and Cosmetic (FD&C) Act, it will be
regulated by the FDA as a medical device and will be subject to premarketing and post marketing regulatory

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controls:

A medical device is “an instrument, apparatus, implement, machine, contrivance, implant, in vitro
reagent, or other similar or related article, including a component part, or accessory which is
(1) recognized in the official National Formulary, or the United States Pharmacopoeia, or any
supplement to them, (2) 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 (3) 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.

This definition helps distinguish between medical devices and other FDA regulated products such
as drugs and biologics. Software functions that meet this definition may be regulated as medical devices.

Drugs

If the primary intended use of a product is achieved through chemical action or metabolism, the
product is typically classified as a drug. According to the FD&C Act, a drug is:

• a substance recognized by an official pharmacopoeia or formulary;

• a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease;
• a substance (other than food) intended to affect the structure or any function of the body; or
• a substance intended for use as a component of a medicine but not as a device or a component, part, or
accessory of a device.

Human drugs are regulated by FDA’s Center for Drug Evaluation and Research (CDER).

Biological Products

Per the FDA, a biological product is defined as:

…a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic
product, protein (except any chemically synthesized polypeptide), or analogous product, or
arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound),
applicable to the prevention, treatment, or cure of a disease or condition of human beings.
Biological products, including blood and blood products, and blood banking equipment, are regulated
by FDA’s Center for Biologics Evaluation and Research (CBER).

Combination Products

According to the FDA, combination products include:

• a product comprised of two or more regulated components (i.e., drug/device, biologic/device,

drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed
and produced as a single entity;
• 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 for use only with an approved individually specified drug, device, or
biological product where both are required to achieve the intended use, indication, or effect, and where
upon approval of the proposed product, the labeling of the approved product would need to be changed
(e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant
change in dose);

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 • or any investigational drug, device, or biological product packaged separately that, according to its
proposed labeling, is for use only with another individually specified investigational drug, device, or
biological product where both are required to achieve the intended use, indication, or effect.

Combination products are regulated depending on their primary intended use. For the drug eluting
stent example presented earlier, the primary intended use is to mechanically restore the diameter of an
artery, which is the function of a medical device. For this reason, it would be regulated as a medical
device—not a drug—and would follow one of the regulatory pathways presented in Section 12.6. Other
examples of combination products include hormone releasing intrauterine devices, prefilled syringes
containing medication, and dermal patches filled with drugs.

Software

The FDA regulates certain mobile medical apps, software embedded in medical devices, and certain
clinical decision support software. This section focuses on mobile medical apps. According to the FDA
website:

Mobile apps are software programs that run on smartphones and other mobile communication
devices. They can also be accessories that attach to a smartphone or other mobile communication
devices, or a combination of accessories and software. Mobile apps span a wide range of health functions.
Many mobile apps carry minimal risk; those that can pose a greater risk to patients (if the device
were to not function as intended) require FDA review.

Mobile medical apps are mobile apps that meet the definition of a medical device and are an accessory
to a regulated medical device or transform a mobile platform into a regulated medical device. The
FDA is taking a tailored, risk-based approach that focuses on the small subset of mobile apps that meet
the regulatory definition of “device” (mobile medical apps) and that are intended to be used as an accessory
to a regulated medical device or transform a mobile platform into a regulated medical device.

Other apps regulated by the FDA aim to help healthcare professionals improve and facilitate patient
care. For example, the Radiation Emergency Medical Management (REMM) app gives healthcare providers
guidance on diagnosing and treating radiation injuries. Some mobile medical apps can help
physicians diagnose cancer or heart rhythm abnormalities, or function as the “central command” for a
glucose meter used by an insulin-dependent
diabetic patient.

Device Classifications and Controls

In the US, medical devices are classified as Class I, II, or III. This classification is based on (1) the level
of control needed to provide reasonable assurance of safety and efficacy, (2) design complexity and
potential risk, (3) intended use of the device, and (4) indications for use. Intended use and indications
for use can be found in the device’s labeling and are also conveyed orally during product sale.

The main pathways for FDA review of a new device include the 510(k), Premarket Approval (PMA)
application, and others. These pathways and associated submissions for devices in each classification
are discussed in detail in this lecture.

Descriptions, submission requirements, applicable regulatory controls, and examples of Class I,

II, and III medical devices are presented in Table below. All classifications require compliance with general
controls. Class I devices are exempt from the 510(k) process if they are similar to products
sold prior to 1976, when the Medical Device Amendments were established. Devices sold prior to
1976 are pre-amendment devices and are “grandfathered” into the approval process (exempt from
new requirements). Class II devices generally require compliance with special controls, a premarket
notification (510[k]), and may require clinical study data to demonstrate substantial equivalence to a

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predicate device. Class III devices require PMA including clinical study data to prove safety and
effectiveness.

§ General Controls
General controls are requirements that apply to all classifications of medical devices. They require
manufacturers to:

• Register each manufacturing location with the FDA.

• List all marketed medical devices with the FDA.
• Manufacture devices in compliance with FDA Quality System Regulations (QSRs).
• Label devices in compliance with applicable regulations.
• Submit Premarket Notification, 510(k), unless device is exempt or subject to additional requirements

§ Special Controls
Special controls apply to Class II medical devices for which General Controls alone are inadequate to ensure
safety and efficacy. This is due to the potential health risk associated with the device. Special controls will
vary among Class II devices but may include special labeling requirements, conformance with FDA guidance
documents and mandatory performance standards, clinical trials, and post market surveillance.

Quality Requirements
FDA requirements are based on a quality systems approach that affects design and development activities.
For this reason, design engineers need to understand quality systems and quality-related regulatory requirements.
The term “quality,” as it relates to medical device design, refers to how well a design meets customer needs and
performs as expected. Quality does not refer to high-end products with many features and “bells and whistles,” nor
is a simpler design considered to be of low quality. For example, a Foley catheter with multiple lumens, check

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valves, and irrigation ports may be considered a low quality product if it does not meet customer needs. A simple
rubber intermittent catheter with a single lumen and no additional features may be considered a high-quality
product if it meets customer needs and expectations. Additional quality-related terms defined in ISO 9000 and used
in ISO 13485 are described below:

• Quality management refers to those aspects of a company’s overall management function (including upper
management) that determine and implement quality policy, which outlines a company’s goals as they relate
to product and process excellence.

• Quality system (or quality management system) refers to a company’s structure, procedures, processes,
and resources for implementing quality management, with the goal of ensuring that devices remain safe
and efficacious. Medical device companies create and maintain a quality manual that describes their
quality system. This system also standardizes activities and should provide efficiency in how a business is
run.

• Quality assurance is achieved through the systematic and planned actions that are needed to provide an
acceptable level of confidence that a product will meet the requirements for quality (will meet customer
needs).

• Quality control is a specific component of quality assurance and refers to the operational methods,
techniques, and activities used by an organization to meet quality requirements. This includes incoming
inspection procedures, vendor quality audits, and other activities.

§ Good Manufacturing Practice

Medical device manufacturers are required to design and build quality into their products. This means
that they must have processes and procedures in place to ensure that products meet customer needs and
performance requirements. Companies must document their quality processes and procedures and
prove that these are being followed during product development and after market introduction. Without this
documentation, devices will not be approved or cleared in the US and thus will not be allowed for
sale in major international markets.

Federal regulations require drugs and devices to be manufactured in accordance with current good
manufacturing practice (cGMP, sometimes referred to as GMP). These GMP’s provide minimum
requirements for what companies must do regarding methods, facilities, and controls used in the
manufacturing, processing, packaging, and storage of products, and provides significant flexibility as
to how the company accomplishes this.

§ Design History File

As emphasized in almost every chapter, the DHF is a critical component of the medical device design
process. It is required and contains or references the records needed to prove that the device was developed
per the approved design and development plan and design control requirements of the QSR. The
DHF documents the team’s progress and the evolution of the design and provides useful information
for future academic or industry design teams working on projects started by previous design teams. It
contains information that is part of the DMR, which is needed to begin production of a medical device.
In an academic design project, the DHF may be in the form of a project notebook that includes
meeting minutes, design input and output documents, design changes, results of design reviews, drawings,
sketches, calculations, test procedures, assembly procedures, design verification and validation
results, and evidence that design input = design output. Project definition documents, project schedules,
customer interview questions and responses, customer needs, and target product specifications are
often also included.

In industry, the DHF includes additional items such as manufacturing work instructions, labeling,

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packaging and shipping information, sterilization procedures, shelf life test results, maintenance and
disposal instructions, and information on accessories and components. This information will also be a
part of the DMR.

§ Registration of Medical Device Manufacturers

In the United States, there are more than 1700 categories of medical devices among 16 medical specialties
produced by more than 10,000 medical device manufacturers. These companies, along with new startup medical
device manufacturers, must register with the FDA to notify them of their intent to manufacture medical devices. This
makes the FDA aware of the new manufacturer and allows them to audit the production facilities of the company to
ensure that cGMPs are being followed and that requirements of the QSRs are being met. This is often accomplished
through careful review of the documentation contained in the manufacturer’s DHF. If violations are found during
an audit, the FDA has the legal authority to force manufacturers to correct the violation or shut down a
manufacturing facility until violations have been corrected.

Pathways to Market in the United States

The design of a new product can impact its regulatory pathway to market. Use of new materials not
previously used in medical applications—or new features not part of existing medical devices—can
present concerns to the FDA regarding device performance independent of device class and can trigger
requirements for costly additional material safety tests and clinical studies, respectively. It is important
for engineers to understand how their design can influence the required regulatory pathway. If speed to
market is a high priority, then the design may need to be revised so that no unplanned additional testing
will be required.

Most medical device companies employ experts in regulatory affairs to develop the regulatory strategy
for each new product. It is their responsibility to identify the shortest path to allow the company to
begin sales of a new product and determine the quickest appropriate pathway to market. Companies
initially determine the regulatory pathway that they feel is appropriate; however, the FDA makes the
ultimate decision regarding which path will be required. Regulatory personnel from medical device
companies often meet with FDA representatives to get a better idea of which regulatory path the FDA
will require. In some situations, it may be possible for academic design teams to contact FDA personnel
for advice on the appropriate path for their devices.

In this lecture we discuss the main pathways for FDA review of a new device which include the
510(k), PMA, De Novo classification request, Breakthrough Device Designation, and Humanitarian
Device Exemption (HDE). Each has a different impact on the project schedule, total project cost, and
required testing, and has different requirements to qualify for the pathway.

§ 510(k)

The 510(k) pathway gets its name from section 510, paragraph (k), of the FD&C Act that directs the
FDA to clear medical devices for marketing. It allows manufacturers to market their devices if they can
demonstrate substantial equivalence to a predicate device that is currently sold through interstate commerce
through submission of a 510(k) premarket notification. This pathway is generally applicable to
Class I and II devices where the specific classification regulation states that a 510(k) is required. To
demonstrate substantial equivalence, manufacturers must show that the new device performs the same
function(s) as the predicate device, is intended for the same use as the predicate device, and that any
differences between the two devices do not raise any new safety or efficacy concerns. Once a manufacturer
submits a 510(k) notification of its intent to market the device, the FDA has 90 calendar days to review the
premarket notification (depending on the 510[k] used), and the company has 6 months to

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resolve any questions asked by FDA. A 510(k) submission includes:
• a description of the device,
• the indications for use,
• a discussion of the predicate device and how the new device is similar in design and function, and
• labels and labeling (including full operator manuals).
It also includes, as applicable:
• protocols and reports for shelf life, biocompatibility, reprocessing validation, and performance
testing,
• protocols and reports for design verification and validation testing (with a specific focus on software
documentation),
• cybersecurity information,
• results of clinical trials (when necessary),
• evidence of compliance with applicable standards, and
• other information.

§ Premarket Approval

Class III devices are generally subject to PMA. This process involves a submission by the manufacturer and a
scientific review of safety and efficacy data by an FDA Advisory Committee. If a device is not yet classified
(completely new/novel device or significant change to an existing device), the device is automatically considered
Class III and may be subject to PMA unless it is down classified via the De Novo process (based on risk). A PMA
submission usually requires the submission of clinical study protocols and reports. If they present a significant risk
(which most PMA devices would), the clinical study requires a separate FDA review prior to study initiation. An
Investigational Device Exemption (IDE) is required before the study can begin and allows an investigational device
to be used in a clinical trial to support a PMA application. It also allows manufacturers to ship their unapproved
devices across state lines for purposes of conducting a clinical study. The PMA process takes an average of 250
days to receive approval. The PMA is a license granted to market the device, which prevents competitors from
selling their similar devices without obtaining their own PMA license. This serves as a barrier to entry
for competitors.

The PMA application contains scientific and regulatory documentation that demonstrates safety and
efficacy of a Class III device. It includes indications for use, a device description, nonclinical study data
(bench testing, animal studies, biocompatibility tests, shelf life studies, sterilization validations, software
validations), clinical studies, manufacturing processes and validations, and labeling. PMAs have
the strictest post approval requirements, meaning the level of required reporting and FDA scrutiny after
approval is higher than that of other device classifications.

§ Humanitarian Device Exemption

The Humanitarian Use Device (HUD) classification was created in 1990 as part of the Safe Medical
Devices Act to establish an alternate, expedited pathway to market in order to benefit patients with a
disease or condition affecting fewer than 8000 people per year in the United States. It provides a financial
incentive to manufacturers to develop devices for small populations in which, due to limited sales,
the expected returns on investment would not exceed the required research and development costs.
Examples of devices granted an HDE include a patient-specific talus spacer, pediatric esophageal atresia device,
and an aneurism neck reconstruction device. Many academic design projects involve devices for people with
disabilities. These projects often impact a small number of users and might qualify for the HDE.

To obtain approval for a HUD, an HDE application is submitted to the FDA. The application
includes similar information to what is included in a PMA application but is not required to include
results of scientifically valid clinical studies that prove efficacy for the device’s intended use. The application
must contain information to show that, in comparison to available devices or existing alternate
forms of treatment, the device does not present an unreasonable or significant risk of illness or injury,

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and that the health benefits outweigh the risk of injury or illness due to use of the device. The case must
also be made that there are no comparable devices available to diagnose or treat the disease or condition.
Once approved by the FDA, a HUD is limited to use in facilities with an established local IRB
that has granted approval to use the device to treat or diagnose the specific
disease or condition.

§ Breakthrough Device Designation

A breakthrough device is one that provides for more effective treatment or diagnosis of life-threatening
or irreversibly debilitating diseases or conditions compared to what is available. The goal of the
Breakthrough Devices Program is to provide patients and healthcare providers with timely access to
these medical devices by speeding up their development, assessment, and review, while still using the
PMA, 510(k) clearance, and other established pathways to market, consistent with the FDA’s mission
to protect and promote public health. Breakthrough devices (or combination products) qualify
for expedited review and a faster approval path if they meet all of the following criteria:

• intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition,

• represents a breakthrough technology that provides a clinically meaningful advantage over existing
technologies; leads to clinical improvement in diagnosis or treatment of a life-threatening or irreversibly
debilitating disease or condition, no approved alternative treatment or means of diagnosis exists,
• offers significant, clinically meaningful advantages over existing approved alternative treatments (if they
exist), and
• device availability is in the patient’s best interest; provides a specific public health benefit or meets the
needs of a well-defined patient population.

§ De Novo Classification

The De Novo classification applies to novel devices that have not been previously classified. These devices are
automatically classified as class III (high risk) when first reviewed by the FDA. These devices did not exist
prior to the 1976 Medical Device Amendments and no predicate devices exist to allow the 510(k) pathway to
be pursued. The De Novo classification process provides a pathway for manufacturers to request that a device
which was automatically classified as class III to be down classified to class I or class II, based on risk.

De Novo requests include information such as:

• the device’s intended use designation, prescription or over-the- counter use designation,
• device description, including technology, proposed conditions of use, accessories, and components,
• discussion of why general controls or general and special controls provide reasonable assurance of the
safety and effectiveness of the device, and, if proposing a class II designation, what special controls would
allow the FDA to conclude there is reasonable assurance the device is safe and effective for its intended
use,
• clinical data (if applicable) to support reasonable assurance of the safety and effectiveness of the device,
• results of animal studies (if applicable),
• nonclinical data including bench performance testing,
• information on reprocessing and sterilization, shelf life, biocompatibility, software, electrical
• safety, and electromagnetic compatibility, and

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Ethics in Medical Device Design
Introduction

A code of ethics is a set of rules that helps make decisions that impact others. You likely have developed
your own internal code of ethics that guides how you behave in the real world. These deeply personal
principles are intertwined with your background and experience. Professional fields and organizations
also have ethical principles to ensure that the field and its members act responsibly. In some cases,
global ethical declarations have been written about how all humans should treat one another.
As the designer of a medical device, you are making decisions that could impact others as you navigate
the design process. Just as practicing and encouraging preventive medicine is an important
approach to health care, so is developing your own personal and professional ethical compass before
you encounter an ethical dilemma. The purpose of this chapter is to provide you with a way of thinking
that can help you navigate the ethical issues that arise in developing a new medical device.

Applied Ethics

Ethics is one of the oldest academic disciplines, has origins in philosophy, and dates back to be beginning
of recorded history. Our main purpose, however, is to focus on applied ethics as a rational way to
resolve conflicts that arises when one or more “rules” conflict with one another. In this section we
discuss the origins of applied ethics as well as an ethical reasoning framework.

§ An Ethical Reasoning Framework

Applied ethics emerges when philosophical perspectives meet the real world. In the most difficult situations,
there is no “right thing to do” in an absolute sense. Rather a decision must be made that has
considered as many perspectives and dimensions as possible. The underlying idea of ethical reasoning
is that a process has been followed such that a difficult decision is justified.
Aarne Vesilind has proposed the following eight steps for ethical decision making in his book The
Right Thing to Do: An Ethics Guide for Engineering Students. They are:
1. What are the relevant facts?
2. What are the moral issues?
3. Who is affected by the decision you have to make?
4. What are your options?
5. What are the expected outcomes of each possible action?
6. What are the personal costs associated with each possible action?
7. Given the issues, alternatives, and costs, where can you get help in thinking through the problem?
8. Considering the moral issues, practical constraints, possible costs and expected outcomes, what is
the best right action to take?

Engineering Ethics
Almost all professional disciplines abide by self-imposed
ethical guidelines, which are social contracts
as applied to the relationship between a field and its members. As engineers, we should be proud of our
technological accomplishments but must keep in mind that medical technologies are meant to make
human life better. Ethical dilemmas that can arise in biomedical engineering range from beginning and
end of life issues to the balance between quality of life and extended life to changes in healthcare coverage
and policy. Although not always at the forefront, ethical principles are incorporated into almost all
decisions made during a design process. In this section, we discuss applied engineering ethics along
with two professional codes of engineering ethics.

§ Applied Engineering Ethics

Ethical decisions are encountered in every design process, from the sources of information you use

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to how you test devices to ensure that they are safe and effective. There are many competing demands
to consider. Hospitals and insurance companies need to make enough money to stay in business.
Technologies cost money and often add cost to the healthcare system. What is best for an individual
(or some select group of individuals) may not be best for a company, which also may not be best for
the population at large. For example, a product that is only available to a small segment of the population
can lead to inequities and institutionalized discrimination against already marginalized populations.
The most obvious example is when the cost of a product means that it is only available to
upper socioeconomic classes. Through your current project and your career, you should revisit the
quote at the start of this chapter from the movie Jurassic Park, substituting “engineers” for
“scientists.”

To make this more personal, would you consider allowing a device you have created to be used for
a loved one? If not, then it would stand to reason that it should not be allowed to be used for anyone.
The scenario in Breakout Below is one example of where ethical issues may arise in the context of a
design project. This hypothetical scenario is followed by two codes of ethics that are most applicable
to medical device design.

§ National Society of Professional Engineers Code of Ethics

The National Society of Professional Engineers (NSPE) was founded in the United States in 1934 as an
association representing licensed professional engineers. All members must abide by the NSPE code of
ethics, which outlines six professional duties engineers must fulfill:
1. Hold paramount the safety, health, and welfare of the public.
2. Perform services only in areas of their competence.
3. Issue public statements only in an objective and truthful manner.
4. Act for each employer or client as faithful agents or trustees.
5. Avoid deceptive acts.
6. Conduct themselves honorably, responsibly, ethically, and lawfully so as to enhance the honor,
reputation, and usefulness of the profession.
The full code expands upon these fundamental tenants to include statements on confidentiality,
conflicts of interest, giving credit where it is due, and accepting personal responsibility for professional
actions.

§ Biomedical Engineering Society (BMES) Code of Ethics

The NSPE code of ethics applies to all engineering professionals, but many subspecialties have developed
additional ethical guidelines. The BMES code of ethics outlines four areas for its members:
Professional, Health Care, Research, and Training. The professional tenants largely mirror those from
the NSPE code. Likewise, the healthcare obligations mirror many of the tenets of medical ethics and

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the Research obligations follow the tenets of research ethics, both outlined below. A somewhat unique
aspect of the code is the responsibility to train “biomedical engineering students in proper professional
conduct” as well as to “model such conduct” and to keep this training free from “inappropriate influence
from special interests.”

Legal and Ethical Duties of Medical Device Designers

The two codes of engineering ethics in the preceding sections are professional guidelines. In some
engineering disciplines, a professional license can be obtained; through this license, the engineer is
bound by the NSPE Code of Ethics. In the United States, becoming a licensed professional engineer
(PE) requires passing two exams that demonstrate an ability to apply the fundamentals of engineering
as well as specific disciplinary expertise. A PE can approve designs in their area of licensure. For
example, a PE in civil engineering can sign off on plans for new construction. Ethical violations, which
include negligence or lack of oversight, can result in the revocation of a professional license. In some
cases, the PE assumes legal liability should a design fail. Breakout Box 13.3 explores a specific case of
the ethical obligations of a PE.

In the United States, there is no professional license exam specific to medical device design. Though
the industry exemption allowed by many states, engineers designing medical devices for medical device
companies are not required to be licensed. As discussed in this lectures, all medical devices must demonstrate
safety and effectiveness to pass through the proper regulatory pathway of regulatory bodies
(e.g., The Food and Drug Administration (FDA) in the United States). Medical device companies typically
assume liability for design failures.

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