FDLI’s Introduction to Medical Device Law and
Regulation: Understanding How FDA Regulates the
Medical Device Industry
October 28-29, 2002
The Westin Grand Hotel
Washington, D.C.
Premarket Approval Applications (PMAs),
Product Development Protocols (PDPs), and
Humanitarian Device Exemptions
presented by
Suzan Onel, Partner
Kirkpatrick & Lockhart, LLP
1800 Massachusetts Ave., N.W.
Washington, D.C. 20036
Phone: 202-778-9134
Fax: 202-778-9100
sonel@kl.com
DC-537219 v1 0950000-102
PREMARKET APPROVAL APPLICATIONS (PMAs),
PRODUCT DEVELOPMENT PROTOCOLS (PDPs),
AND HUMANITARIAN DEVICE EXEMPTIONS
Suzan Onel, Esq.
I.
PMA REVIEW (FDCA § 515 (21 U.S.C. § 360(e)); 21 C.F.R. Part 814)
A.
B.
C.
Overview.
1.
Standard: Reasonable Assurance Of Safety and Effectiveness.
2.
Filing Date Is Date FDA Receives Complete PMA.
3.
Clock Is 180-Day Review Time.
4.
Substantial Changes Will Restart The Clock.
5.
Review By FDA Personnel And Possibly Referred To FDA Advisory
Committee.
6.
FDA Notifies Applicant Of Approval By Letter.
7.
Notice Announcing The Decision And Availability Of Summary Of
Safety And Effectiveness Data Used To Be Published In Federal Register,
Now On Internet.
Early Collaboration Meetings.
1.
Determination Meeting – Type Of Scientific Evidence That Will Be
Required. FDCA § 513(a)(3)(D).
2.
Agreement Meeting – Pre-IDE Meeting To Agree On Investigational Plan.
FDCA § 520(g)(7).
3.
Binding On The Agency Unless Contrary To Public Health.
4.
“Early Collaboration Meetings Under the FDA Modernization Act
(FDAMA), Guidance for Industry and CDRH Staff” (Feb. 19, 1998)
[Exhibit 1]
PMA Application Should Contain (21 C.F.R. § 814.20):
See “PMA Manual” at http://www.fda.gov/cdrh/manual/pmamanul.pdf and PMA
Elements Used [Exhibit 2]
1.
Name And Address Of Applicant.
2
D.
2.
Comprehensive Summary.
3.
Complete Description Of The Device Including Photographs And
Drawings.
4.
Full Reports Of Investigations On Safety And Effectiveness.
5.
Components.
6.
Methods And Controls Used For Manufacturing Or Processing.
7.
Reference To Any Performance Standard Under 21 U.S.C. § 514.
8.
Bibliography Of All Publications.
9.
Summary Of Unpublished Information.
10.
Statement That Nonclinical Studies Meet FDA Requirements (21 C.F.R.
§ 58).
11.
Summary Of Clinical And Nonclinical Investigation.
12.
Investigator Financial Disclosure Or Certification
13.
Sample (When Reasonable).
14.
Labeling, Literature And Installation Instructions.
15.
An Environmental Assessment.
16.
If Only One Investigator Has Participated, A Justification That A Single
Investigator Was Sufficient To Demonstrate Safety And Effectiveness Of
Device.
Filing The PMA Application.
1.
Send To:
Document Mail Center
Food and Drug Administration
HFZ-401
9200 Corporate Blvd.
Rockville, MD 20850
(301) 594-3027
2.
FDA Will Acknowledge Receipt And Provide Unique Application
Number.
3.
Only Authorized Person Submitting Application Can Obtain Information.
3
4.
E.
FDA, By Regulation, May Take 45 Days To Review Application To
Determine If Complete. If Filed, FDA Begins Substantive Review.
FDA Refusal To File PMA.
1.
FDA May By Letter Cite Deficiencies In PMA And Refuse To Accept For
Filing.
2.
Sponsor May Contest Deficiencies.
3.
Sponsor May, Within 10 Working Days, Request Informal Conference
With Office Of Device Evaluation (ODE).
4.
ODE Will Hold An Informal Conference Within 10 Working Days Of Its
Receipt Of Sponsor's Request.
5.
ODE Will Advise Sponsor Within 5 Working Days After Conference If
PMA To Be Filed.
6.
Sponsor May Request Reconsideration By Director Of CDRH.
7.
Guidance Document -- “Center For Devices And Radiological Health’s
Premarket Approval Application (PMA) Refuse To File Policy” (6/30/93).
F.
Scope Of Review Limited To Conditions Of Use Submitted In Proposed Labeling
(FDCA § 515(d)(1)(A)).
G.
Review By Advisory Committee (FDCA § 515(c)(2)).
H.
1.
FDA May Refer PMA To Advisory Committee On Its Own Initiative Or
Upon The Request Of Applicant.
2.
Meeting On PMA Is Public Except for Discussion of Confidential
Information.
3.
Panel Must Provide Report And Recommendation On PMA To FDA.
Planning For And Meeting With Panel.
1
Obtain From Executive Secretary Copies Of All Material Submitted To
Panel -- Pursuant To 21 C.F.R. 14.75.
2
Obtain Information Regarding Panel Consultants.
3
Attend Public Meeting Or Obtain Transcript From Prior Panel Meetings.
4
FDAMA Reforms (FDCA § 513(b)(6)(A)).
a.
Same Access To Data And Information As FDA;
4
I.
J.
K.
b.
Same Opportunity To Submit Additional Information As FDA;
c.
Same Opportunity To Participate As FDA;
d.
FDA Must Notify Applicant In Writing After Making Decision,
Detailed Reasons For Variation From Panel Recommendations.
e.
“Guidance on Amended Procedures for Advisory Panel Meetings”
(Jan. 26, 1999).
Day-100 Meeting (FDCA § 515(d)(3)).
1.
Meeting To Discuss Status Of Review.
2.
Must Be Requested Either When The PMA Is Filed Or No Later Than 70
Days After Filing. See “Guidance on PMA Interative Procedures for Day100 Meetings and Subsequent Deficiencies – for Use by CDRH and
Industry” (Feb. 19, 1998).
Approval/Denial Of PMA.
1.
Approval Order (21 C.F.R. § 814.44(d)).
2.
Approvable Letter (21 C.F.R. § 814.44(e)).
3.
Not Approvable Letter (21 C.F.R. § 814.44(f)).
4.
Denial Order (21 C.F.R. § 814.45) With A Finding Of:
a.
Lack Of Reasonable Assurance Of Safety Or Effectiveness.
b.
Lack Of GMP In Manufacturing.
c.
Labeling False And/Or Misleading.
d.
Failure To Conform To Performance Standard.
e.
Sponsor May Appeal Denial Order To Special Panel.
f.
Special Panel Decision May Be Appealed To Court.
Modular PMAs.
1.
Review Of The PMA In Pieces Or “Modules.”
2.
Allows For Closure Of One Or More Modules Before PMA Is Submitted
(e.g., manufacturing information).
3.
“PMA Shell” – Outline of Sections.
5
4.
L.
“Guidance for Industry: Guidances for the Medical Device Industry on
PMA Shell Development and Modular Review” (Nov. 6, 1998) [Exhibit
3].
Use And Availability Of PMA Data.
1.
FDAMA Repealed "Four-Of-A-Kind" Rule For Release of PMA Data By
Which Certain Clinical And Preclinical Test Data Compiled To Prove
Safety And Effectiveness Would Become Available For Use By The
Agency One Year After The Application For The Fourth Device "Of A
Kind" Is Approved. This Rule Is Replaced With A Similar Provision By
Which The Data Is Available Six Years After The Approval Of The
Application That Is The Source Of The Data.
Note: method of manufacture and composition of material remains
confidential.
Note: FDA has never declared that four devices "of a kind” have been
approved.
2.
M.
PMA Guidances -- FDA Has Published Guidances On Various Devices
And Testing Protocols For Devices.
Dispute Resolution Process.
See Guidance: “Resolving Scientific Disputes concerning the Regulation of
Medical Devices, A Guide to Use of The Medical Devices Dispute Resolution
Panel,” (7/2/01) [Exhibit 4].
II.
MAKING CHANGES TO PMA APPROVED DEVICES – PMA SUPPLEMENTS
A.
Device Changes Affecting Safety Or Effectiveness Require Approval Of A PMA
Supplement (21 C.F.R. § 814.39).
1.
Examples Of Changes That Require A Supplement If Affecting Safety Or
Effectiveness:
a.
New Indications For Use;
b.
Labeling Changes;
c.
Change in Manufacturing, Processing, Or Packaging Facility;
d.
Changes In Sterilization Procedures;
e.
Changes In Packaging;
f.
Changes In Specifications, Circuits, Components, Ingredients,
Principle Of Operation, Or Physical Layout; or
6
g.
B.
C.
D.
III.
Extension Of Expiration Date Based On Data From An
Unapproved Stability Protocol.
2.
PMA Holder’s Obligation To Determine If A Supplement Is Required.
Draft Guidance: “Guidance for Industry: Modifications To Devices
Subject to Premarket Approval – The PMA Supplement Decision Making
Process” (Aug. 6, 1998) [Exhibit 5].
3.
135-Day Review Period.
“Special PMA Supplement – Changes Being Effected” – Used For Changes That
Enhance Safety. 21 C.F.R. § 814.39(d)
1.
Do Not Have To Wait For FDA Approval, But Must Wait For
Acknowledgment.
2.
May Be Used For The Following Changes:
a.
Strengthening Of Warnings, Contraindications, Or Precautions;
b.
Adding Or Strengthening An Instruction Intended To Enhance The
Safe Use Of The Device;
c.
Deletion Of Misleading, False, Or Unsupported Indications;
d.
Quality Control Changes That Provide Additional Assurance Of
Purity, Identity, Strength, Or Reliability.
“30-Day Notice” – Used For Changes In Manufacturing That Affect Safety And
Effectiveness. FDCA § 515(d)(6); 21 C.F.R. § 814.39(f).
1.
Notify FDA Of A Modification To The Manufacturing Procedures Made
In Accordance With QSRs.
2.
May Implement Change 30 Days After FDA Receives The Notice Unless
FDA Notifies The Manufacturer That The Notice Is Inadequate.
3.
If A PMA Supplement Is Required – Time Under Review As A 30-Day
Notice Is Subtracted From The 135 Day Review Period.
Changes That Do Not Affect Safety Or Effectiveness Can Be Documented In File
Or, If Required By FDA, Reported In Annual (or Periodic) Reports.
PRODUCT DEVELOPMENT PROTOCOLS (PDP)
A.
Alternative To Submission Of PMA.
7
IV.
B.
FDA And Applicant Reach Pre-Application Agreement As To Data Requirements
For Approval Of Device. Completion Of Protocol Results In Approval Of
Device.
C.
FDA Has Not Issued Regulations.
D.
FDA Draft Guidance, “Contents Of A Product Development Protocol” (5/14/98)
(Full Text Available At [http://www.fda.gov/cdrh/pdp/pdpguide.pdf].
E.
Usually Works Best for Devices Already Well Understood By FDA.
HUMANITARIAN DEVICE EXEMPTION (HDE) (FDCA § 520(m); 21 C.F.R. Part
814, Subpart H)
A.
Allows Marketing Of A Humanitarian Use Device (HUD) Without Reasonable
Assurance Of Effectiveness.
B.
Limited To Devices Intended To Benefit Patients In The Treatment Or Diagnosis
Of Diseases Or Conditions That Affect Or Are Manifested In Fewer Than 4,000
Individuals In The U.S. Per Year.
C.
Amount Charged For The Device Cannot Exceed The Costs Of the Research,
Development, Fabrication, And Distribution.
D.
After Approval, Must Periodically Provide Detailed Information On Cost, Safety,
And Continued Justification For HUD Status.
E.
Must Be Used Only Under The Review Of An Institutional Review Board
(“IRB”).
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