Escolar Documentos
Profissional Documentos
Cultura Documentos
Robert J. Russell
President - RJR Consulting
March 15-16 2011
Course Agenda
Global Regulatory
Compliance
Business Consulting
Solutions
Strategy Development
Project Management
Selection
Marketing Authorizations /
License Renewals
NDAs / Variations /
Amendment Filings
Manufacturing
Authorizations
International Regulatory
5
Government / Agency
Affairs
New Business
Development
Global Business
Expansion
Industry Training
Process Development &
Improvement
Distribution and
Global Reach
RJR Consulting, Inc. is headquartered in New Albany, Ohio
and has affiliate offices strategically located around the
world. These offices provide the in-country expertise needed
to deliver successful projects to our clients
North America
New Albany,
Ohio, US
Vancouver,
Canada
Latin America
Sao Paulo, Brazil
Mexico City,
Mexico
Buenos Aires,
Argentina
European Union
Brussels,
Belgium
Hamburg,
Germany
Asia Pacific
Japan
China
Korea
Taiwan
Chile & UK
Alcohol
Tobacco
Drugs
Consumer Products
(shampoo, toothpaste, soap, etc.)
Medical Devices
Drugs of abuse
Biologics
Health Insurance
Veterinary products
Cosmetics
Pesticides
Radiation-emitting
Products
Combination Products
(any combination of drug,
device or biologic)
Restaurants
Water
the Commissioner
Centers
All centers report into the
Office of the Commissioner
Office of Regulatory Affairs is
an additional Center in
charge of field operations
divisions
10
CBER
CDER
CFSAN
Center for Food Safety
& Applied Nutrition
CDRH
Center for Radiological
Devices & Health
NCTR
CVM
Center for Veterinary
Medicine
11
Source: www.fda.gov
combination products
applications
handled by CBER, CDER, CDRH
12
13
Markets/countries
outside of EU
14
Device
15
Combination
Product
Ph I - Toxicity
Ph II - Efficacy
Ph III Statistical Efficacy & Adverse
Events
16
Regulatory Requirements
Many different factors are involved in obtaining regulatory
Questions to ask
Is it a combination product?
What is the primary mode of action?
Is it a device, drug or biologic?
Is it exempt from classification?
If not exempt, is it already classified by the FDA?
Is there another device that is similar that has already
been approved?
market?
and effective?
Combination Products
18
regulatory submission
Process & requirements outlined in 21 CFR Part 3 no official
form
Submission must be limited to 15 pages
Sponsor submits formal request to FDA to determine:
1. Primary mode of action
Is it primarily a device, drug or biologic?
IVR with microbicide is a drug (device used as delivery
method)
Stent is a device (drug is added for infection prevention)
Vaccine filled syringe is a biologic (with a delivery
device)
2. Lead Agency Center to be assigned for pre-market review
Determination of jurisdiction usually takes 45-60 days
Request can also be made informally by contacting Office of
Combination Products
19
Intercenter Agreements
Agreements entered into in 1991 by CDER, CBER and CDRH
Provided guidance to determine how lead agency works with
determination
Sets guidelines for how centers work together during
review
20
Product Type
Drug
Device
Biologic
Lead Agency
Center
CDER
CDRH
CBER
IDE
510(k)
PMA
IND
BLA
510K
PMA
NDA
Approval
Processes
21
IND
NDA
Safety Concerns
Combination
22
Pre-IDE Process
Contact FDA prior to submission of request for IDE
FDA will provide one time pre-IDE feedback to sponsor at no cost
Increases sponsor understanding of regulations and process
Helps to minimize delay during actual submission process
Typical 30-60 day response time
FDA may have guidance meetings with sponsor about Pre-IDE
submission
Can be conference calls or face-to-face
Meetings are usually formal but informal conversations can be
had prior to official meeting to ask questions
Formal meetings are Determination meetings or Agreement
meetings
Determination meeting request to discuss scientific
information needed in submission
Agreement meeting reach official agreement on parameters
of clinical protocol and investigational plan
approved
23
Implants
24
25
initiated
Significant risk device requires FDA approval along with
IRB
Informed consent for patients
Investigational use only labeling
On-going monitoring of clinical study
Records and reports supporting the study
Classification Types
All devices will be classified as one of the following types:
Class I
Low risk, subject to general controls*
Examples: gloves, scalpels, enema kits
Class II
Medium risk, subject to general and special controls*
Examples: pregnancy tests, infusion pumps, powered
wheelchairs
Class III
High risk, subject to general and special controls
Devices that support/sustain human life or pose excess
risk
Examples: pacemakers, artificial hearts, implants
Exempt (Class I or Class II)
Very low risk, subject to general controls
Some devices may be exempt from GMP as well
Examples: Non-sterile surgical tools
*description in next slide
26
General Controls
Basic rules that allow FDA the authority to regulate
devices
Required to be followed for all device classes
Allows FDA to regulate many things including
device registration, product listing, labeling,
quality measures (including misrepresentation) &
reporting
Special Controls
Additional controls applied to Class II and Class III
27
Classification Statistics
Class
I
Class
II
Class
III
Exem
pt
95%
3%
0%
NonExem
pt
5%
97%
100%
Class III
Class I
Class II
28
Determining Classification
Device class is determined by many different factors:
Previous similar devices
Intended use of the device
Indications for use (specifics of intended use)
Risk to the public
You can use a number of methods to determine class of
specific products
CFR Search
Search regulations on FDA website
Determine the medical specialty (panel) of the device
Each panel has list of products classified (16 panels)
Located in 21 CFR 862-892
Identify the classification regulation
Search the product code classification database
29
Device Exemption
A device is considered exempt if:
Category is included on the Class I & Class II Exempt
Devices list
List covers 21 CFR 862 892
Grandfathered in from original amendment (May 28,
1976)
as sterile
30
Reclassification Process
Classification is occasionally adjusted through a
reclassification process
safety
devices
31
Regulatory Submission
With the device class and non-exempt status known, the type
submitted to FDA:
effectiveness
May require new 510(k) depending on what was changed
Change to materials, sterilization or manufacturing
process will likely require new submission
Burden is on Manufacturer
33
distributed
manufactured device
28, 1976
Substantial Equivalence
35
Traditional
Abbreviated
Used when guidance documents exist, special controls
are in place and standards are already in place
Must prove conformity to the recognized standard
Includes summary reports on use of guidance docs to
expedite review
Special
Done for device modification that does not affect
intended use or technological standards
Contains a Declaration of Conformity to specific design
controls
Submission does not include data
36
37
37
such as:
Would have bridged gap between medium and high risk devices
similar to EMA
Ex: No predicate exists but risk is in line with Class II device
38
precedent
in US
Good science practices and scientific writing are key
for approval
39
Traditional PMA
All volumes submitted to FDA at once
For devices that have had clinical testing or have been approved
elsewhere
Modular PMA
PMA broken into modules and each module submitted upon
completion
Meant for products in early stages of clinical study
streamlined
device
Work at own pace and keep FDA informed and involved
Recommended for devices where the technology is well established
40
PMA Amendment
Submission during application process before FDA approval is
obtained
When additional data requested or modification to application is
needed
Restarts the submission process at beginning
PMA Supplement
For product changes after approval has been obtained
Usually needed when changes impact safety, effectiveness or
labeling
Different timeframes for review (30-180 days) based on impact of
change
U.S.
Similar to orphan drug designation, except for devices
HDEs are exempt from effectiveness requirements
Must justify risk to FDA and demonstrate lack of predicate
41
PMA Requirements
traditional PMA:
Name, address and table of contents
Description of the device form and function
Practices and procedures what device is used for
Foreign and domestic market history of the device, if any
Details about manufacturing process in making the device
Summary of clinical and non-clinical studies
Conclusion of studies, include safety and effectiveness of
device
Reference to any performance standards followed
Labeling and advertising literature (Ex: pamphlets)
Results of non-clinical lab studies
Results of clinical studies on human patients
Financial certification and disclosure statement
Bibliography of reports about safety/effectiveness of
device
42
43
labs
Performed to monitor compliance with BIMO program
2. Directed Inspections (For-Cause)
Inspection requested due to problem or issue
Problem observed during 510k or PMA submission
process
Complaints from doctors/patients can also lead to
inspection
Inspector will assign a classification to the overall
inspection based on compliance:
NAI No Action Indicated
VAI Voluntary Action Indicated
OAI Official Action Indicated
Warning letter may be issued based on severity of findings
44
Sponsor Responsibilities
comes to BIMO:
Selecting a qualified investigator
Ensuring proper monitoring of the investigation
Verify investigator follows investigation plan
and IND protocols
Ensuring FDA and investigators stay informed of
new risks or adverse effects of drug/device
Obtaining proper information from the
investigator prior to inspection
Review and evaluate safety and effectiveness
data
Discontinue investigations that pose significant
risk
Maintain accurate records regarding financial
interest and receipt/shipment of the drug
45
patients/subjects
plan
46
47
48
Monitoring Plan
Safety Plan
Communication Plan
Risk Assessment
Monitoring Plan
Outlines the monitoring guidelines and tasks not outlined
the database
Safety Plan
Outlines SAE process and reconciliation
Additionally can outline medical monitor review and
49
database
analysis methods
Communication Plan
Outlines all the communication paths with internal
can adversely
Version controlled
Signed by sponsor and CRO
Reviewed and updated, as needed
Become part of the Central Clinical Project Files
51
52
Austria
Belgium
Denmark
Finland
France
Germany
United Kingdom
Greece
Ireland
Italy
Luxembourg
The Netherlands
Portugal
Spain
EU Applicants
Croatia
Turkey
53
Sweden
Cyprus
Czech Republic
Estonia
Hungary
Lithuania
Latvia
Malta
Poland
Slovakia
Slovenia
Bulgaria
Romania
EU Regulatory Bodies
54
Responsible for proposing and upholding laws for EU related to drugs & devices
EU Regulatory Structure
EC (Commission)
Project Manager
(Scientific/Medical
Advisors)
CHMP
Rapporteur/
Co-rapporteur
55
EMA (EMEA)
MRFG
(Medical
Devices)
NCAs
Notified Bodies
Inspectors
Ethics Committee
EU Requirements for
Medical Devices &
Combination Products
56
57
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
CE Marking Device
12.
Is it a Drug? Device?
Combo?
If its a device.
58
alleviation of disease
control of conception
A Medical Device does not achieve its principal intended
59
Rules for full classification of Class I, IIa, IIb and III are well defined
60
EU Classification Matrix
Device
Class
I (sterile
and/or
measuring)
II a
II b
III
Risk
Potential
Low
Low
Medium
Elevated
High
Product
Examples
Non-sterile
dressings,
bandages,
hospital
gowns, light
sources
Spirometers,
urine
drainage
bags, digital
thermometer
s
IV catheters,
tubing's for
anesthesia/v
entilation
Intraocular
lenses,
breast
implants,
endoprosthe
ses,
ventilators
Heart
valves,
reabsorbabl
e implants
Involveme
nt of
Notified
Body
Selfcertification
Declaration
of
Conformity
Selfcertification
Declaration
of Conformity
+ Notified
Body for
measuring
function/
sterility
Mandatory
Mandatory
Mandatory
61
62
63
64
65
66
67
storage
electrical/thermal risks
Manufacturer Information
The class attributed to the product will determine the route that
manufacture
69
Article 11
procedure
70
71
72
Part B: Full report containing detailed data and test reports on the
design, manufacture and testing of the device
Class IIa: Brief overview to confirm all sections are present but no
detailed review
Class III: Full review (like IIb) but looks to substantiate the evidence
presented with primary clinical research in support of the clinical
evidence section
73
2.
74
3.
4.
5.
6.
7.
8.
9.
10.
Risk Analysis
11.
Clinical Data
75
1.
2.
Index
3.
4.
5.
All variants
Indications / contraindications
76
including:
Parts list
Drawings, assembly drawings
Sub-assembly drawings
Drawings of components
Specifications of materials used incl. data sheets
List of standards applied
Manufacturing specifications
Sterilization specifications (if required)
Packaging specifications
QA specifications (QC specs., in-process controls etc.)
Labeling
Accompanying documents
Packaging insert/Instructions for Use
Service Manual
16.Clinical Data
77
(AIMDD)
Herbal Medicines Directives (HMD)
Example: an antibiotic coated catheter is a
78
combination products:
1. For administration of medicines
Ex: Empty single-use syringe, reusable spoons or
droppers
Regulated by medicinal device (MD) regulations
2. Combined with a medicinal product to form a single, integral
product designed to be used only in the combination
Ex: Non-reusable products such as Pre-filled syringes
Subject to assessment by drug regulatory authorities
(DRA)
Must meet requirements of the MDD (satisfied by use of CE
mark)
3. Incorporated with a substance which, if used separately, may
be considered a medicinal product
Ex: Heparin-coated catheter
Notified Body will assess the product while drug info is
sent to DRA to verify safety, efficacy, and usefulness of
drug
79
80
Classification of Combination
Products
Certain groups of combination products fit easily into
action is achieved
Usually comes down to whether the principal intended
action are:
action are:
82
Neither the device nor the medicine alone would achieve desired
effect
Regulatory Regime
84
This may necessitate some duplication-- the device section and the
medicine section each need to stand alone
85
EC Certificate / Declaration of
Conformity
EC will issue a certificate demonstrating that all conditions of the
purposes
86
information:
87
Overview of Article 58
Refers to Article 58 within EC Regulation 726/2004
Allows for CHMP to give opinions on medicinal products
(WHO)
WHO cooperation allows for outreach to countries in need
Goal is to provide medicines to countries where regulatory
capacity is lacking
Products may no longer be marketed in EU due to demand or
88
Scope of Article 58
Medicines used to prevent/treat diseases of major public
health interest
89
HIV/AIDS
Malaria
Tuberculosis
Leishmaniasis
Onchocerciasis
Dengue Fever
Leprosy
exchange
Meetings complement other formal procedures on
scientific advice
Applicant information kept confidential
Services are provided free of charge
90
Pre-Article 58 Advice
If a combination product is classified as a medicinal
to
complete PreInitial
Notificatio Submissio
n
n Meeting
March 2011
June 2011
Sept/Oct
2011(dependin
g on additional
meeting
requested)
91
Additional Considerations
92
93
Differences Between
FDA & EU/EMA
94
device class
95
Class II devices
96
97
98
99
100
101
Review of Implantable
Medical Devices
containing Microbicides
102
regulatory review
Requires an IDE for the Device and an IND for the Drug
Requires a Technical File and performance against
polymeric ring
103
The cervical cap is a reusable, deep cup that fits tightly over the cervix
104
The cervical cap is held in place by suction and has a strap to help with
removal
Only one cervical cap FemCap has Food and Drug Administration
(FDA) approval in the U.S.
Both the spermicide must be approved along with the device separately
Medicated Condoms
Sec. 884.5310 Condom with spermicidal lubricant
A condom with spermicidal lubricant is a sheath which
Medicated Films
Polymeric drug delivery systems shaped as thin sheets
homogenous surface
106
agreement)
followed
107
Manufact
urer
Dimensions
(Diameter)
Composition
Indication
Active
Ingredie
nt
Cataly
st
Femring
Warner
Chilcott
Outer: 56 mm
Cross-section:
7.6 mm
Core: 2 mm
Cured silicone
elastomer composed
of dimethyl
polysiloxane sinanol,
silica, propyl
orthosilicate,
stannous octoate,
barium sulfate &
estradiol acetate
Vulvar and
vaginal
atrophy
symptoms
related to
menopause
Estradiol
acetate
Tin
Nuvarin
g
Organon
Outer: 54 mm
Cross-section: 4
mm
Ethylene
vinylacetate
copolymers &
magnesium stearate
Hormonal
Contraceptive
Etonoges
trel
& ethinyl
estradiol
N/A
Estring
Pfizer
Outer: 55 mm
Cross-section: 9
mm
Core: 2 mm
Silicone elastomers
Q7-4735 A&B, SFD
119 silicone fluid &
barium sulfate
Symptoms
related to
postmenopausal
atrophy of
vagina and
lower UT
Estradiol
Platinu
m
108
Minimal Regulatory
Requirements for
Testing & Standards
109
equivalence
life of study)
commercialization
reports
111
clinically studied?
manufacturing lines
112
10993-5)
10)
Genotoxicity (ISO-10993-3)
Bacterial reverse mutation study
_____ lymphoma assay
Subacute / subchronic toxicity
XX day intravaginal toxicity study in _____
113
Novel Microbicides
Definition:
New API, no Pre-clinical data, previous published
Requirements:
Pre-clinical studies (full toxicity and
biocompatibility assessment)
Ph. I ,II, III Clinical Trials
Full IND review
CT Efficacy Data
Pharmacovigilance profile
Risk / Reward evaluation
115
Microbicide Combinations
Possible Combinations:
1. One known and one novel
2.
116
Requirements:
Reaction by-products
use of compound)
117
finished device?
changes???
Si
EVA
PVOH
Best approach:
Assemble vendor data on candidate materials
Conduct analytical and vitro screening of materials
Conduct confirmatory testing on a composite sample
118
119
Therapeutic indications
Contraindications
Overdose
List of excipients
Incompatibilities
Shelf Life
Regulatory Challenges in
Developing IVRs
121
used
122
Date
microbicide development due to its proven in-vitro and invivo efficacy and safety profiles
.also its physical and chemical properties
124
125
Nanotechnology
The use of nanotechnology in the field of medicine could
antibotics
If an infection starts the harmful bacteria in the wound causes
the nanocapsules to break open, releasing the antibotics
This allows much quicker treatment of an infection and
reduces the number of times a dressing has to be changed
126
Nanotechnology in Medicine
127
NanoBio --- Nanoemulsions for nasal delivery to fight viruses (such as the
flu and colds) or through the skin to fight bacteria
128
Nanoviricides
Works the same way that the virus normally attaches to receptors
on a cell surface
Once attached, the flexible nanoviricide glob wraps around the virus
and traps it
Virus loses its coat proteins that it needs to bind to a cell and is
thus neutralized and effectively destroyed
129
This binding site does not change significantly when a virus mutates
nanodevices
1. Top-down approach
The top-down approach involves molding or
etching materials into smaller components
This approach has traditionally been used in
making parts for computers and electronics
2. Bottom-up approach
The bottom-up approach involves assembling
130
Nanodevices
Nanodevices are small enough to enter into cells
Cell
Nanodevices
Nanodevices
Water
molecule
131
White
blood cell
Regulating Nanodevices
133
contraceptive
Chemical interaction
Biological and physiological interaction
Study Plan & testing regimen must be developed to
134
The three components of Atripla have been in use for some time,
their characteristics and effects are well known
135
contraceptive drug
136
contraceptive drug
137
2.
3.
4.
5.
6.
7.
8.
9.
Regulatory Challenges
for Imaging Devices
138
emitting Products
1040.10 --- Laser products
1040.11 --- Specific purpose laser products
1040.20 --- Sunlamp products and ultraviolet
discharge lamps
139
major components
1020.31 --- Radiographic equipment
1020.32 --- Fluoroscopic equipment
1020.33 --- Computed tomography (CT) equipment
1020.40 --- Cabinet x-ray systems
140
142
The law is drafted so FDA also regulates those electronic products that
would emit radiation if the source of radiation was not properly shielded
Agency has jurisdiction if radiation is accessible or humans are
exposed
Jurisdiction also exists if the electronic product produces or
generates radiation, even if such radiation is inside some sort of
shielding
to user
143
not surgically)
144
Recommended Mitigation
Ineffective treatment
Performance specifications
Performance specifications
Electrical injury
Electromagnetic interference
Cross-contamination
Improper use
Labeling
145
510(k) exempt
Establishment registration
146
Proper labeling
determination
application
147
and Documentation (21 CFR 820.40 [6]) detailing how the system
was built and tested are essential, and should be completed as the
clinical prototypes are being built
Following construction, extensive testing is necessary
Internal testing should be performed to ensure device safety
Qualified consultants should conduct independent mechanical and
Any new device intended for use in patient care must also be
submitted
148
149
150
Potential Development
Process Concerns
151
proceeding
Assign specific team members for accountability on
each issue resolution
described)
problematic species
data
prior to initiation
153
licensing phase
154
155
Associated Costs
cost risk
Number of Products
Number of Arms
Single product, 2-arm study is X
3 Product, 6-arm study is a multiple of X
The more people, the more management burden, the more risk,
the more set backs, the more it costs and the longer it takes
of products in trial
develop
156
157
Emerging Global
Requirements
for Devices with Microbicides
158
Global Challenges
Regulatory pathways for combinations products need clarification
process
literacy rates
countries of interest
159
compounds
160
WHO Considerations
WHO has partnered with many organizations regarding HIV/AIDS
prevention
need by:
organizations
161
Considerations in Africa
However, African HCAs and FDA both like to have patients from
developed countries included in the research
162
America
own RA
times
163
Malaysia
RA
alterations
164
Conclusions &
Wrap-up
165
taken
Pre-IND meetings with FDA very valuable
Scientific Advice meeting / discussion with EMA (CHMP)
registration pathway
Device alone= likely Class II, IIa, IIb depending on region;
Web References
http://www.emea.europa.eu
World Health Organization http://www.who.int
168
Material Copyright
169
Questions?
170