BN5208

Biomedical Quality and Regulatory Systems

Product Recall and

Revision of previous lectures

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 What we will learn today…

• Practice questions 
• Further info on Unique Device Identifier (UDI)
• Recall and Field Safety Corrective Action (FSCA)
• Off label usage and medical device reporting
• Recall classification
• Flow in adverse event reporting and maintaining global databases
• Product life cycle and new product development
• Post market clinical follow up (phase IV clinical trials)
• Contributors to safe and effective products
• Revision of previous lectures for forthcoming CA Quiz

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 Group feedback session on
Tuesday, 25th
Following the midterm feedback, I noted many of you found the earlier feedback
session to be very helpful. To further help and guide you, I plan to have another
feedback session. This is not compulsory but I will have dedicated time for all groups,
in case they have any question. The purpose are many fold;

• To ensure, all your questions/queries are answered that relates to any aspect of the
concept/understanding on medical device regulation
• Any question that relates to the final report and presentation (I have already
shared the rubric previously)
• Ensure you are in right direction and that all groups are working coherently to
attain the best learning outcomes
• Opportunities for the shy students to be able to talk and discuss with me on any
relevant issues

I care for all of you and want to make sure all the activities including the various
brainstorming sessions, numerous case discussions, external guest lecture and
postlecture presentations attain their intended outcomes and you all are enjoying
the learning journey and benefiting from such endeavours.
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Team Allocated time
Team 1 1-1.15pm

Team 2 1.15-1.30pm
1. This session is not compulsory but
Team 3 1.30-1.45pm encouraged, if you have any
Team 4 1.45-2pm questions on ANY aspect of the
Team 5 2-2.15pm module. All is fair game.
Team 6 2.15-2.30pm 2. Please log in during your session
3. This session is supposed to further
Team 7 3-3.15pm
help your understanding of the
Team 8 3.15-3.30pm
materials covered as well as any
Team 9 3.30-3.45pm questions on final report and
Team 10 3.45-4pm presentations.
Team 11 4-4.15pm 4. If any group prefers a different
Team 12 4.15-4.30pm day/time, please let me know.
Team 13 4.30-4.45pm

Team 14 4.45-5pm

Team 15 5-5.15pm

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 Unique Device Identifier (UDI)

Additional Info on UDI:

• Medical devices (more relevant to Class III), needs to be tracked
in cases of recall and FSCA. This requires manufacturers to put a
UDI to device labels.
• To be in manually readable plain text and machine readable bar
code
• Consist of 2 parts:
• Device Identifier (DI or static part): labeller and device version
• Product Identifier (PI or dynamic part): Lot and batch#, expiration date
and date of manufacture etc

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 FSCA vs Recall

Recall (USA)
Adverse
event
= =
FSCA (ASIA)

Explanation: Recall is generally the ‘final outcome’ of FSCA, where product is called back by
manufacturer to ensure public safety and decrease specific product related risks. FSCA involves
diverse steps to decrease scope of specific product inflicted health risks and thus enhance public
confidence and also to adhere to product conformity and regulatory requirements. 6
 FSCA

Any action taken by a product owner to reduce a risk of

death or serious deterioration of the health associated
with the use of a medical device and may include:

• Return of device product owner

• Device modification
• Device exchange
• Device destruction
• Label change/modification
• Software upgrades
• Advice given by product owner regarding the use of the device

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Health Hazard Evaluation (HHE, basis for recall)

For initiation of Recall, manufacturers (particularly upper

management), prepare a HHE, in consultation with
Regulatory agency. The following considerations are at
play:

• Whether injuries have already occurred

• Whether existing conditions may predispose humans or animals to the
hazard
• Assessment of the hazard (particularly vulnerable populations)
• Degree of seriousness
• Likelihood
• Consequences

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 Who initiates FSCA/Recall

• Legal manufacturer (voluntary)

• Regulatory agency (forced or
mandatory)

Majority of recalls are voluntary as manufacturers recognize and realize their

social responsibility and don’t want to take unintended risks on patients
health and safety. Its ethical as well!

Field Safety Notice (FSN): Communication send to public in relation to FSCA

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 Why should companies recall
voluntarily ???)

As we have learnt from the various post-lecture presentations,

many of the controversies relating to recall are caused by notion of
continuous and uninterrupted financial gain, resulting in patient
harm, right! Thus to prevent such occurrences, both the medical
device manufacturers as well as regulatory agency should initiate
timely recall, if need be. This prevents damage to company image,
lawsuits, ethical and financial repercussions as well.

This is the right thing to do…

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Company initiated voluntary recall !

• Identify the product (product batch and lot#)

• Reason for recall, conveyed to FDA (AE already happened or
potential based on trending)
• Risk evaluation associated to the recall (cost-benefit
evaluation, availability of replacement product)
• Amount of such products (volume of recall)
• Distribution of the product (Market penetration and access of
the device in question)
• Recall strategy (how to do it??)
 Medical Device Reporting (MDR)

• One of the tools used by regulatory agencies to detect product

deficiencies, perform risk-benefit analysis and identify any potential
future events (data may be used in FSCA)
• Its mandatory for manufacturers but is voluntary for customers and
end users (although strongly encouraged)
• Such information eventually becomes available for use to predict any
future adverse event that necessitates recall
• The eventual objective is to protect public health and thus prevent risk
• Manufacturer needs to report to FDA within 10 working days under 21
CFR

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 Recall Classification

Designated Class I, II or III, depending on the degree of

risk presented to individuals or community in general
(opposite of risk classification class )
• Class III: Use of the device has minimal scope for causing serious health
hazard (usually some CAPA, following which the product may be approved
fit for reuse)

• Class II: Possibility of serious health consequences is not significant or the

health issues caused is temporary/reversible

• Class I: Has already resulted in serious (including death)/non reversible

health consequences or has potential to cause as such, either to individuals
or has implication on the community in general

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 Recall vs removal vs CAPA

• Recall (aka FSCA in some cases) are initiated over concerns that
relate to safety and performance of a particular medical device
• Removal refers to physical removal from the market to prevent
patients from using the device
• CAPA is change/modification that don’t affect the
safety/performance of medical device, like change in label,
instructions, training etc

Case study for brainstorming: A medical device has been making loss financially
for XYZ company and the company decided to discontinue the product. Should the
company ‘Recall’ the device ?

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 Product recall handling work flow (in a
nutshell)

Initiate Manufacturer
Manufacturer Perform CAPA,
investigation, advise to local Submission of
report product review design
manufacturer distributors and report to local Management
recall to control,
will issue a recall hospitals: return regulatory control
Regulatory production &
advise letter to all relevant requirement
agency process control
customers products

Overall responsibility lies with the Management to develop and follow an

appropriate, approved and predetermined strategy for Recall if need arises. The
considerations are gathered data (may even be competitors product data) as
well as negative trends on product performance/response on patients
 Schematic of Information flow during FSCA or Side
effects of Medical Devices
Patients
MI / RA Team

F2F
Medical
Director
Verbal/written/
e-response Medical
Medicovigilance Medical Safety
HCP Information MSL
Officer Advisor(s) Officer
Specialist

F2F

MSR/MSL/Manager
Global database of
Std. response medicovigilance
How Global databases are maintained (sharing my
own experience)

• HCP Name • who responded

• Contact details
• Date responded
• Which TA
• Who approved
• Query
• Response
• Who documented
• Communicated, how
• Mode of communication
• Documentation
• Date responded

PMV/ Dedicated
hotline
AE Call Center
PharmD PhD Complicated question
Qualified
MD person
BPharm Response
Bachelors
with few
Global MS year exp.
database
HCP/
PMV: post market vigilance
• Std responses customer
HCP: healthcare provider
AE: adverse event • FAQ’s
 Case study for brainstorming (Real
example from industry)

Would a medical device manufacturer submit a new PMA

or a PMA ‘supplement’ if

• Label of the medical device needs to be modified

• A ‘new’ ‘better’ biomaterial would be used to replace components
of the device
• When would FSCA be initiated

Hint: A PMA or ‘supplement’ is needed if CAPA is not enough and the new
change/modification affects the safety and performance of the device

18
Medical Device Life cycle and
Global strategy/process

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 Continuous, ongoing clinical trial data
collection
• To ensure long-term success of medical devices,
manufacturers engage in continuous monitoring and
gather of clinical, patient data
• This becomes part of device history record and
facilitates future improvement of the device
• May be required based on
– Long term (i.e. lifetime) results are still unknown
– High risk (population, disease, location, design)
– Innovative (unknown risks)
– Residual risks unaccounted for in Clinical Investigation
– Changes to product or intended use

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 Post Market Clinical Follow up/data collection
• Not required if:
– Well known or established mode of treatment
– Adequate data already exists for device (e.g. moving from
high risk indication to lower risk one)
– Other parts of Post Market Surveillance can cover the risks
• Can include
– Extended follow up review of original clinical investigation
– New clinical investigation
– Literature review (data registry or retrospective review)

Did you know: Risks arising from use of a medical device

• 20% due to the device itself – design and manufacture
• 80% due to how the device is used
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 Ongoing Event Reporting

• Slippery Ground (may not report under certain

circumstances or depends on the product or at times use
common sense)
– did not result in a Field Safety Corrective Action
– Event is already “common” and a part of product’s risk
management file and included as a precaution in the patient
information and included in a updates to a Periodic Summary
Report
• If rate of incidents is high than predetermined expected levels (“trigger
level”), then event reporting occurs (Trend Reporting)
– Device deficiency is found before harm is caused
– Patient conditions were the cause of event
– Device was used improperly (outside shelf life, off label)
– Alarm stops procedure under correct conditions
– Risk Severity of Death is Negligible (BE CAREFUL!)

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Revision of previous
lectures/contents

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 Our journey thus far…

• In this portion, we will revisit and focus on some core concepts keeping in mind
the holistic learning efforts as well as keeping the CA quiz next week in mind.
• In the last many weeks we have covered much ground and learnt about the
various steps that a ‘potential’ medical device has to take to reach the patients.
The emphasis is always on ‘safety’, ‘quality’ and ‘performance’
• Each week we covered a specific stage or step of the process, to ensure the
information was in bite-sized chunks and not overwhelming
• The numerous case studies, interaction with expert from the industry made the
learning more industry-relevant
• Hope you enjoyed the brainstorming sessions and my inputs from my own
experience working for JnJ, now you have a better idea how ‘things’ actually
happen in the industry. It’s a very ‘happening’ industry, if any one of you later
choose it as a career 
 Whole process in a Nutshell

Feedback
Loop
Premarket On market Postmarket

User need
identification
Design and
attributes
Prototyping and
manufacturing
Preclinical and
clinical trials Approval Packaging and
labelling
Advertisement
and sales
Post-market
obligations
Use and disposal

Initiation of Risk Verification Validation Surveillance/vigilance

identification and planning and QMS and Recall (if necessary)

Stage Premarket Placing on market Post market

Responsibility Manufacturer Manufacturer and regulator Manufacturer, regulator and
end user
Attributes/activities Device attributes Labelling Surveillance/vigilance
• Safety and performance • Packaging and instructions for • Adverse events reporting
• Assays and tests use • Alerts and updates
Manufacturing Approval • Monitoring safety and
• Quality • Agency/ regulator performance
• Maintaining FAQ databases
• Training of clinicians and
patients (if needed)
Which of these are (not) medical devices…

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Why regulate medical devices ?...The
Billion ($$$) dollar question…

Medical Devices are regulated to

ensure:
1. Safety
2. Quality
3. Performance

Intended to safeguard the health and safety of:

• Patients
• Medical professionals
• Manufacturers

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 Medical Devices Medicinal/medicines
Product nature Pure molecules; based on pharmacology and
Physical objects; complex components and chemistry; now encompassing biotechnology,
assemblages; generally based on mechanical, genetic engineering, etc.
electrical, and materials engineering
Most act through physical interaction with body Administered by mouth, skin, eyes, lungs, or by
or body part injection; act through metabolic, pharmacologic,
or immunologic means
Localised “site of action” treatment effect Typically systemic effect

Duration and nature of exposure varies widely Short half-life in body

Typically durable; available for study after use Consumed by use

Focus on biocompatibility of materials Focus on systemic and local toxicity

Relatively limited populations of exposure Large populations of exposure

Not metabolized… Most undergo ‘first pass’ mechanism

FDA 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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 Risk classification system: Singapore

Risk class Risk level Medical device examples

A Low risk Surgical retractors/tongue
depressors
B Low-moderate risk Hypodermic needles/suction
equipment
C Moderate-high Lung ventilator/bone fixation
risk plate
D High risk Heart valves/implantable
defibrillator
 Risk based AI-MD classification

Although this is for local Singapore market, a similar strategy is applied by FDA as well as
other regulatory agencies
 Salient features of accepted ‘Quality Standards’

ISO 13485 21 CFR 820

Globally accepted standard and Imposed by FDA for US market
facilitates comply with general
regulatory requirements
It was derived from ISO 9001 and It is FDA-regulated good manufacturing
moreso to make it more specific to practices (GMP) for medical devices
medical devices
ISO 13485 is a voluntary standard Mandatory quality system regulation
(guidance document) and not a (QSR) for medical device distribution in
compulsory structure/law for QMS USA, but some flexibility is allowed
Fulfilment is called conformance Fulfilment is called compliance
Onus of Conformance to this standard Compliance is imposed by FDA on
lies with the company medical device manufacturers
FDA provided some input for its No influence by ISO on its development
development
 Quality System Regulation Key Elements

Complaint
Handling Complaint Files

Design Transfer
Corrective and
Design Review Preventive Actions
Facility & Equipment
Design Controls
Controls

Quality System
Record Management Training

Material Controls Production and

Process Controls Computer System
Records, Documents Validation
Procurement /Handling, Storage,
and Change Controls
Distribution & Installation
Process
Validation

Key sub-systems/controls of QSR with Management at the helm/overall responsibility

to ensure that all processes are followed
 Design Verification and Validation process
Aka…waterfall diagram…

Verification: To ensure output is same as intended outcome, determined during input process
Validation: Conforms to user needs and thus address the intended unmet clinical needs of patient
 21 Code of Federal Regulation (CFR)
Part Specifics
800 GENERAL
801 LABELLING
806 CORRCTION AND REMOVAL REPORTS
807 REGISTRATION OF DEVICES AND
ESTABLISHMENTS
Regulations 809 IVD
810 RECALL OF MEDICAL DEVICES
21 CFR; Parts 800-1050
- 800-861: Device 812 INVESTIGATIONAL DEVICE EXEMPTION
requirements 814 PRE MARKET APPROVAL
- 862-1050: Device 820 QSR
specific requirements
821 MEDICAL DEVICE TRACKING
822 POST MARKET SURVEILLANCE
830 UNIQUE DEVICE IDENTIFICATION
860 MEDICAL DEVICE CLASSIFICATION
861 PERFORMANCE STANDARDS
 Risk Management

• Risk management is the identification, assessment, prioritization and mitigation of risks

• Coordinated and economical application of resources to minimize, monitor, and control the probability and/or
impact of unfortunate events
• How they may be controlled (don’t confuse with removal of the risk)
• Assess risk/benefit ratio of risks that could not be reduced to an acceptable level
• Concept of residual risk and risk acceptability : Minimal risk that is acceptable to patients as part and parcel of
using a particular high risk medical device
 Harm/hazard matrix

Severity/Probability Not likely Remote Occasional Frequent

low Low Low Moderate High

moderate Low Moderate Moderate High
major Low Moderate High V. high
Severe (fatal) Moderate High V. high V. high

High and V high: not acceptable ;

Moderate risk: risk analysis and mitigation plan
Low risk: acceptable and approved
 Proactive vs. Reactive strategies

Proactive surviellance Reactive surveillance

Expert uses groups/focus groups Customer complaints
Customer surveys User feedback
Post-market clinical trials Devoted phone# and email ID to
Medical Affairs immediate redressal
Device tracking/implant registries List of FAQ’s
Central database of FAQ’s Regulatory agencies
Active ongoing communication with
stakeholders

• PMS could be ‘proactive’ – endeavours meant to anticipate and curtail events before they occur; there are
many types such as user surveys, manufacturer-sponsored studies, feedback forms etc. In ‘proactive’ PMS
activities, information is actively sought to gain insight and data into the real-world performance of the device.

• PMS could be ‘reactive’ – responding after an event; of which there are many types ranging from complaints to
those involving serious injury or in an extreme case where a serious injury or death has occurred. May involve
feedback forms on adverse events and ‘hotline’ phone to connect to the company and medical affairs
 Feedback for next iteration in the
medical device development process

Destruction,
Disposal,
C
Manufacture,
use of parts
Concept
C

Product
C
realization
End of
C
product life

Placing
C
on
Feedback market
C
on product
References
RAPS.org
NUS-RAPS MDRA program

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 Lets learn together on the following Medical
device controversies

• Group 11: Newport ventilators by Medtronic

• Group 13: The Dalkon shield recall
• Group 14: Bayer’s sterilisation device recall
• Group 15: Boston Scientific’s heart valve recall

10-12 minutes per group followed by QnA/discussion

Objective: To encourage individual and peer-to-peer learning which is typically followed in an industrial setting
where small groups working together come up a potential suggestion/brainstorm
 Suggestions for expected deliverables/
domains that may be covered

In your presentation you can discuss on issues like;

1. The background of this scandal
2. How and why it happened
3. What effect the scandal/controversy had on medical device regulations?
Can such occurrences be prevented in the future?
4. What role did the regulatory authority play in the controversy? Were there
any shortcomings on their part?
5. How was ethics compromised in your opinion?
6. Any other relevant/interesting findings from your research on the topic…