United States Regulatory Affairs

Question 1

What does FDA stand for and what is its primary mission?

Answer 1

The Food and Drug Administration. The FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, the nation’s food supply, cosmetics, and products that emit radiation.

Question 2

What does CFR stand for and what is its importance in medical device regulation?

Answer 2

Code of Federal Regulations. It’s a codification of the general and permanent rules published in the Federal Register by the executive departments and agencies of the Federal Government. Title 21 contains the regulations governing food and drugs, with medical devices regulated under 21 CFR Part 820 (Quality System Regulation).

Question 3

What is 21 CFR Part 820 and what does it govern?

Answer 3

21 CFR Part 820 is the Quality System Regulation (QSR) which defines the requirements for manufacturers’ quality management systems for medical devices sold in the US. It ensures that medical devices are safe and effective by requiring manufacturers to establish and follow quality systems.

Question 4

What are the three device classes in the US and how are they categorized?

Answer 4

• Class I: Low risk (e.g., bandages, examination gloves)
• Class II: Moderate risk (e.g., powered wheelchairs, infusion pumps)
• Class III: High risk (e.g., implantable pacemakers, heart valves)
  Devices are classified based on their risk level and the regulatory controls necessary to provide reasonable assurance of safety and effectiveness.

Question 5

What is a PMA and when is it required?

Answer 5

Premarket Approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. PMA is the most stringent type of device marketing application required by FDA. Class III devices that fail to meet PMA requirements are considered adulterated under section 501(f) of the FDCA.

Question 6

What is a 510(k) submission?

Answer 6

A 510(k) is a premarket submission made to FDA to demonstrate that a device is substantially equivalent to a legally marketed device (predicate device). If a device is found substantially equivalent, it can be marketed in the US. Approximately 98% of devices requiring premarket review go through the 510(k) process.

Question 7

Define “Substantial Equivalence” in the context of 510(k) submissions.

Answer 7

Substantial Equivalence means a device is at least as safe and effective as a legally marketed predicate device. A device is substantially equivalent if it: 1) has the same intended use AND same technological characteristics as the predicate, OR 2) has the same intended use but different technological characteristics that don’t raise new questions of safety and effectiveness.

Question 8

What is CAPA and why is it important?

Answer 8

Corrective Action and Preventive Action (CAPA) is a system focused on investigating, understanding, and correcting discrepancies while preventing their recurrence. It’s a core element of quality systems and one of the most frequently cited areas during FDA inspections. CAPA systems analyze quality data to identify, investigate, correct, and prevent product and quality problems.

Question 9

What is an MDR?

Answer 9

A Medical Device Report (MDR) is the mechanism by which manufacturers, importers, and healthcare facilities report adverse events and product problems to the FDA. MDR regulations (21 CFR Part 803) contain mandatory requirements for detecting and reporting device-related adverse events and certain malfunctions.

Question 10

What does IDE stand for and when is it needed?

Answer 10

Investigational Device Exemption (IDE) allows an investigational device to be used in a clinical study to collect safety and effectiveness data. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated. This exemption permits shipment of the device for investigational use without complying with other requirements that would apply to devices in commercial distribution.

Question 11

What is an FDA Form 483?

Answer 11

An FDA Form 483 is issued to firm management at the conclusion of an inspection when investigators observe conditions that may constitute violations of the Food, Drug, and Cosmetic Act. It notifies the company’s management of objectionable conditions, which require corrective action plans to be implemented expeditiously.

Question 12

What is an FDA Warning Letter?

Answer 12

When FDA finds that a manufacturer has significantly violated FDA regulations, it notifies the manufacturer through a Warning Letter. The letter identifies violations (such as poor manufacturing practices or improper claims) and makes clear that the company must correct the problem within a specific timeframe.

Question 13

What is the De Novo Classification process?

Answer 13

The De Novo process provides a pathway to classify novel medical devices for which general controls alone, or general and special controls, provide reasonable assurance of safety and effectiveness, but for which there is no legally marketed predicate device. It allows new, low to moderate risk devices to obtain marketing authorization as Class I or Class II instead of automatically being placed in Class III.

Question 14

What is UDI and why is it required?

Answer 14

Unique Device Identification (UDI) is a system to adequately identify medical devices through their distribution and use. The UDI system requires labels of medical devices to include a unique device identifier in human and machine-readable form. It improves patient safety, modernizes device postmarket surveillance, and facilitates medical device innovation.

Question 15

Which of the following devices would most likely be classified as Class III?
A) Dental floss
B) Blood glucose monitor
C) Implantable defibrillator
D) Surgical mask

Answer 15

C) Implantable defibrillator
Class III devices are high-risk devices that sustain or support life, are implanted, or present potential unreasonable risk of illness or injury.

Question 16

Which of the following is NOT a requirement for Quality System Regulations under 21 CFR Part 820?
A) Design controls
B) Process validation
C) Annual medical checkups for employees
D) CAPA procedures

Answer 16

C) Annual medical checkups for employees
QSR requires documented procedures for design controls, process validation, and CAPA, but does not mandate annual medical checkups for employees.

Question 17

Which type of 510(k) utilizes design control requirements of the Quality System Regulation for a modification to a previously cleared device?
A) Traditional 510(k)
B) Special 510(k)
C) Abbreviated 510(k)
D) De Novo 510(k)

Answer 17

B) Special 510(k)
The Special 510(k) allows the manufacturer to declare conformance to design controls for a modification to a device that has been previously cleared under the 510(k) process.

Question 18

Which FDA recall classification represents the most serious hazard?
A) Class I
B) Class II
C) Class III
D) Class IV

Answer 18

A) Class I
A Class I recall is a situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death.

Question 19

Outline the steps in the FDA’s 510(k) review process.

Answer 19

1. eCopy acceptance
2. Acknowledgement letter & 510(k) number designation
3. Acceptance Review (RTA)
4. Substantive Review (60 FDA days)
   
   • Including Interactive Review
   • Additional Information (AI) Request if needed
5. 510(k) Decision Letter (within 90 FDA days)
6. Possible outcomes:
   
   • Substantially Equivalent (SE) - clearance
   • Not Substantially Equivalent (NSE)
   • Additional Information needed

Question 20

What are the key steps in the PMA application process?

Answer 20

1. Pre-Submission meeting (recommended)
2. IDE approval and clinical trials (if needed)
3. PMA submission preparation
4. Filing Review and Decision
5. Substantive Review
   
   • Nonclinical studies review
   • Clinical studies review
   • Advisory Committee Panel Meeting (if needed)
6. QS/GMP inspection
7. Final decision by ODE (Office of Device Evaluation)

Question 21

A manufacturer receives three complaints about unexpected battery depletion in their implantable cardiac device. What regulatory actions should they take?

Answer 21

The manufacturer should:
1. Initiate complaint investigation under 21 CFR 820.198
2. Evaluate if the issue meets MDR reporting criteria (21 CFR 803)
3. If reportable, submit MDR within 30 days
4. Open a CAPA investigation
5. Perform risk analysis to determine if field action is warranted
6. If a correction or removal is necessary, submit report to FDA under 21 CFR 806
7. Monitor effectiveness of actions taken

Question 22

A company is developing a continuous glucose monitor with a smartphone app interface. How should design controls be applied?

Answer 22

Design controls should include:
1. Establish design inputs for both the device and software
2. Document user needs for both components
3. Create a risk management plan addressing hardware/software interactions
4. Develop verification protocols for the physical device and the app
5. Plan validation studies including human factors testing
6. Ensure cybersecurity considerations are addressed
7. Maintain traceability matrix linking requirements to verification/validation
8. Document all design reviews with cross-functional team

Question 23

What is the FDA’s Breakthrough Devices Program and what are its benefits?

Answer 23

The Breakthrough Devices Program is a voluntary program for certain medical devices that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases. Benefits include:
- Interactive and timely communication with FDA during development
- Priority review of marketing submissions
- Additional flexibility in clinical study design
- Potential for expedited CMS coverage determination

Question 24

What is a Pre-Submission (Q-Sub) meeting and when should it be used?

Answer 24

A Pre-Submission (Q-Sub) meeting is a formal process to obtain FDA feedback on specific questions prior to an intended premarket submission. It should be used when seeking:
- Input on testing protocols
- Feedback on clinical study design
- Guidance on appropriate regulatory pathway
- Advice on addressing specific regulatory challenges
Pre-Subs are especially valuable for novel devices or technologies with unclear regulatory paths.

Question 25

What is Real-World Evidence (RWE) and how can it be used in regulatory submissions?

Answer 25

Real-World Evidence is clinical evidence regarding the usage and potential benefits or risks of a medical device derived from analysis of real-world data (RWD). It can be used to: - Support expanded indications - Fulfill post-approval study requirements - Provide comparative effectiveness data - Support regulatory decision-making for certain modifications FDA now accepts RWE for certain regulatory decisions under the appropriate frameworks.

Question 26

What is the Least Burdensome Approach and how does it apply to regulatory strategy?

Answer 26

The Least Burdensome Approach is an FDA principle requiring the minimum amount of information necessary to adequately address a regulatory question or issue. It means: - Using the most efficient pathway to market - Accepting alternatives to clinical data when appropriate - Considering the total product lifecycle to minimize duplicate submissions - Focusing on relevant information rather than all possible information An effective regulatory strategy leverages this approach to optimize resources.

Question 27

Which FDA digital health policy would be most relevant for a mobile medical app that analyzes patient-generated data to predict disease progression? A) Software as a Medical Device (SaMD) framework B) Medical Device Data Systems (MDDS) guidance C) General Wellness Policy D) Enforcement Discretion for Device Functions

Answer 27

A) Software as a Medical Device (SaMD) framework The SaMD framework applies to software intended to diagnose, treat, mitigate, or prevent disease and operates independently from hardware medical devices. Prediction of disease progression would fall under diagnostic functionality that requires appropriate regulatory oversight.

Question 28

In developing a regulatory strategy for a novel device with no predicate, which pathway is LEAST appropriate? A) De Novo classification B) PMA C) Traditional 510(k) D) Humanitarian Device Exemption (HDE)

Answer 28

C) Traditional 510(k) The Traditional 510(k) pathway requires demonstration of substantial equivalence to a legally marketed predicate device. Without an appropriate predicate, this pathway cannot be used. A De Novo classification would be more appropriate for a novel, lower-risk device.

Question 29

When developing a regulatory strategy for a diagnostic test with multiple intended uses, which approach offers the most efficiency? A) Submit multiple 510(k)s simultaneously B) Submit one 510(k) for the primary indication, then add others through supplements C) Bundle all indications in a single 510(k) submission D) Submit a single De Novo for all indications

Answer 29

B) Submit one 510(k) for the primary indication, then add others through supplements Securing clearance for a primary indication establishes the device in the market, after which additional indications can be added through supplements. This staged approach allows for market entry while building evidence for additional indications.

Question 30

What factors should be considered when choosing between a 510(k) and De Novo pathway?

Answer 30

Key considerations include: 1. Availability of suitable predicates that share intended use and technological characteristics 2. Risk level of the device and ability to mitigate risks through general and special controls 3. Time to market considerations (510(k) typically faster than De Novo) 4. Cost considerations (De Novo has higher user fees) 5. Competitive landscape and strategic value of establishing a new device type 6. Long-term product development plans and potential for future device iterations 7. Potential for FDA to find no valid predicate during 510(k) review, resulting in NSE determination

Question 31

Outline a strategy for addressing FDA concerns during an interactive review process

Answer 31

An effective interactive review strategy includes: 1. Respond promptly to FDA questions within agreed timeframes 2. Schedule teleconferences when written responses may be insufficient 3. Prioritize understanding the underlying concerns, not just the specific questions 4. Provide complete responses that address both explicit and implicit questions 5. Include cross-references to previously submitted information when applicable 6. Present data in clear tables and graphs to facilitate reviewer understanding 7. Prepare alternative approaches or justifications if FDA is unlikely to accept original approach 8. Document all interactions thoroughly for future reference

Question 32

What US law provides the basic authority for FDA's regulation of medical devices?

Answer 32

The Federal Food, Drug and Cosmetic Act (FD&C Act), which was amended by the Medical Device Amendments of 1976 to create the framework for medical device regulation in the US.

Question 33

What is a 510(k) submission?

Answer 33

A premarket notification submission that demonstrates a device is substantially equivalent to a legally marketed device (predicate) that doesn't require a PMA. It's the most common pathway to market for most Class II and some Class I devices.

Question 34

Define substantial equivalence in the context of 510(k)

Answer 34

A device is substantially equivalent if it has the same intended use as the predicate and either has the same technological characteristics or has different technological characteristics but doesn't raise new questions of safety and effectiveness and is at least as safe and effective as the predicate.

Question 35

What does a Premarket Approval (PMA) application require?

Answer 35

A PMA requires valid scientific evidence demonstrating reasonable assurance that the device is safe and effective for its intended use. It typically includes clinical trial data, non-clinical laboratory studies, manufacturing information, proposed labeling, and post-approval requirements.

Question 36

What is the De Novo classification process?

Answer 36

A regulatory pathway for novel devices of low to moderate risk for which there is no legally marketed predicate device. It allows these devices to be classified into Class I or Class II instead of automatically being placed in Class III.

Question 37

What is the Humanitarian Device Exemption (HDE)?

Answer 37

A regulatory pathway that allows marketing of Humanitarian Use Devices (HUDs) that help diagnose or treat diseases affecting fewer than 8,000 individuals in the US per year. An HDE is exempt from effectiveness requirements of a PMA but must demonstrate safety and probable benefit.

Question 38

What is a medical device classification panel?

Answer 38

FDA classification panels are groups of medical specialists organized by medical specialty who provide advice to FDA regarding classification of devices, review of premarket submissions, and FDA's regulatory activities.

Question 39

What are the three device classes under FDA regulation?

Answer 39

Class I: Low risk, general controls Class II: Moderate risk, general and special controls Class III: High risk, general controls and premarket approval

Question 40

What is an Investigational Device Exemption (IDE)?

Answer 40

An IDE allows an investigational device to be used in a clinical study to collect safety and effectiveness data. Clinical studies with significant risk devices require both FDA and IRB approval before proceeding.

Question 41

What is included in Quality System Regulation (21 CFR 820)?

Answer 41

The QSR includes requirements for design controls, document controls, purchasing controls, production and process controls, corrective and preventive actions (CAPA), labeling and packaging controls, handling/storage/distribution, records, servicing, and statistical techniques.