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5.2 Package Labels

5.3 Package Insert

The package insert used for a breast implant is typically a combination package insert / surgical technique manual. The sponsor may choose to provide this information in separate pieces of labeling. Otherwise, the information should include, but is not limited to, the following:

??device name;

??brief device description with material information;

??indications for use;

??list of any pertinent contraindications, warnings, precautions, and adverse events;

??sterile notation;

??a description of any pre-implant training necessary for the surgical team;

??a description of how to prepare the patient (e.g., prophylactic antibiotics), operating room (e.g., what supplies should be on hand), and implant for device implantation;

??instructions for implantation, including surgical approach and device specific information (depends on type of breast implant);

??intraoperative test procedures to ensure implant integrity and proper placement;

??instructions for follow-up, including whether patient antibiotic prophylaxis is recommended during the post-implant period and during any subsequent dental or other surgical procedures; and

??how to evaluate, and how often to evaluate, implant integrity and placement.

The directions should instruct caregivers to specifically question patients prior to surgery for any history of allergic reaction to any of the device materials or filling agents. Troubleshooting procedures should be completely described. The directions for use should incorporate the clinical experience with the implant and should be consistent with those provided in other sponsor-provided labeling.

5.4 Patient Labeling

Patient labeling should include the information needed to give prospective patients realistic expectations of the benefits and risks of device implantation. Such information should be written and formatted so as to be easily read and understood by most patients and should be provided to patients prior to scheduling implantation so that each patient has sufficient time to review the information and discuss it with her physician(s). Technical terms should be kept to a minimum and should be defined if they should be used. Patient information labeling should not exceed the seventh grade reading comprehension level. The patient labeling should include, at minimum, the following information:

??indications for use;

??relevant contraindications, warnings, and precautions;

??potential complications, including the possible methods of resolution;

??anticipated benefits and risks (to give patients realistic expectations of device performance);

??alternative treatments, including no treatment and the benefits and risks of each;

??advisement to talk with her doctor about the alternative treatments and which might be right for her;

??what to expect after surgery, including length of recovery;

??symptoms to tell her doctor about immediately;

??whom to contact if questions arise;

??activities that could damage or rupture the implant;

??why the implant is not a "lifetime" implant;

??possible need for device modification, removal, and/or replacement; and

??clinically supported information, if available, on the lifetime of the implant, including the possible need for modification, removal, and/or replacement.

Appendix I - Breast Implant Clinical Data Presentation

This appendix summarizes the types of data and data presentation suggested by FDA for reporting of safety and effectiveness clinical data for breast implants, in general. This summarizes the minimal types of data presentation for a PMA submission and are not to be interpreted as being all inclusive. Sponsors are encouraged to provide their own data presentations as well as those described herein. While this covers all types of implants, some data presentations, such as silent rupture information, are applicable to silicone gel-filled or possibly alternative-filled implants and not to saline-filled implants. The majority of the data requested below should be reported for the separate patient cohorts of primary augmentation, primary reconstruction, and revision (i.e., the patient status/indication at study entry) as well as the total population. See the Clinical Data General Information section 4.1 above regarding specific patient cohort classification. Furthermore, the data should be provided on both a per patient and per device basis for most of the items below. Lastly, it is essential for the sponsor to provide all available data, including those data beyond the 2-year time point. The specifics are discussed within each item.

I. Patient Accounting

A.

A full patient accounting table should be provided on both a per patient and per device basis for each separate patient cohort and the total population. See example Table 1 below. The deaths and explantations should be reported cumulatively (i.e., continue adding across the time points instead of just reporting the number specific to one time point). This information should include the following information, at minimum:

1. theoretically due - number of patients/devices who would have been examined according to implant date and follow-up schedules;

2. deaths;

3. explantation without replacement;

4. explantation and replacement with different manufacturer's implant;

5. explantation and replacement with same manufacturer's implant;

6. expected - number of patients/devices theoretically due minus deaths and explantation without replacement and explantation and replacement with different manufacturer's implant;

7. actual number evaluated number of complete patient/device follow-up examinations performed at each follow-up time point;

8. lost-to-follow-up - number expected minus actual number evaluated

9. % follow-up - actual number evaluated divided by expected

Example Table 1 showing patient accounting

Periop 1 year 2 years, etc.

Theoretically Due 100 85 50

Deaths 0 1 1

Explantation w/o Replacement 0 2 2

Explantation & Replacement w/ Different Manufacturer's

mplant 0 1 3

Explantation & Replacement w/ Same Manufacturer's

Implant 0 4 6

Expected 100 81 48

Actual Number Evaluated 100 68 39

Lost-to-Follow-Up 0 13 9 % Follow-up 100/100 (100%) 68/81 (84%) 39/48 (81%)

B. Provide the causes for patients lost to follow-up, as well as any measures to be taken to minimize such future events.

C. Provide the causes for patient and physician-initiated discontinuations.

D. Provide the cause of any deaths, as well as the reports from post mortem examinations. It is our expectation that a minimum of 80% follow-up at the 2-year time point be provided at the time of PMA filing.

II. Safety

A. Report the non-cumulative point prevalence of complications (events) at each scheduled follow-up visit on both a per patient and a per device basis for each separate patient cohort and the total population. Provide this for both individual types of complications as well as for total (overall) complications.

1. If the same complication occurs in the same breast/patient more than once since the last visit, it is reported more than once.

2. Complications reported at interim (i.e., unscheduled) visits should be reported at the previous scheduled time point if this event is reported at the interim visit and not at the next visit (i.e., if an episode of infection is reported at a 14 month-interim visit but has resolved by 24 months - the next scheduled visit - it is reported at the 12-month visit). If the same event in the same patient/breast occurs at both an interim visit and at the next scheduled follow-up visit, with no resolution of the event between those two time periods, it is counted once.

3. Provide the patient/device accounting for each scheduled visit.

4. Provide both the numerator and denominator used at each visit. The denominator is the number of patients/devices completing the specified visit.

B. Report the cumulative incidence of complications at each scheduled visit on both a per patient and per device basis for each separate patient cohort and the total population. Provide this for both individual types of complications as well as for total (overall) complications.

1. If the same complication is reported in the same patient/breast more than once, it is counted once in the numerator if that same complication never resolved during the entire follow-up period. If a complication occurs in a breast/patient, resolves, and then recurs at a subsequent time point in the same breast/patient, it is counted twice in the numerator.

2. If 1 different or new complication occurs in the same patient/breast cumulatively, it is counted more than once in the numerator and once in the denominator for per patient and per device reporting for the total (overall) data presentation. Note that each capsular contracture grade is considered a new or different complication.

3. Provide the numerator and denominator used and describe how these values were obtained. The denominator is the number of patients/devices at that visit.

C. Report the non-cumulative frequency distribution of the number of different or new events (complications) on both a per patient and per device basis at each visit for each separate patient cohort and the total population. Provide this information for the following three categories: any event, serious/severe events (this includes capsular contracture grades III or IV), and events necessitating or resulting in additional surgical procedures and/or operations. See example Table 2 below.

1. If the same event occurs in the same patient/breast more than once, it is counted more than once in the numerator.

2. Events at interim (unscheduled) visits should be reported at the previously scheduled time point if this event is reported at the interim visit and not at the next visit (i.e., if an episode of infection is reported at a 14 month-interim visit but has resolved by 24 months - the next scheduled visit - it is reported at the 12-month visit). If the same event in the same patient/breast occurs at both an interim visit and at the next scheduled follow-up visit, with no resolution of the event between those two time periods, it is counted once.

3. Provide the patient/device accounting for each scheduled visit.

4. Provide both the numerator and denominator used at each visit. The denominator is the number of patients/devices completing the specified visit. Example Table 2 showing the number of any event per patient at each follow-up visit

4

# Different or New Events

Periop Visit 1 Year Visit 2 Year Visit 0 50/100 patients (50%)

1

1 20/100 patients (20%)

2 50/90 patients (%) 30/85 patients (%)

2 10/100 patients (10%)

3, etc. 20/100 patients (20%)

Total 100/100 patients (100%)

3

1

There were 50 patients out of 100 (50%) who came for their periop visit who had no events.

2

The denominator (number of patients) at a given visit should be the same throughout the column. The denominators from visit to visit may not be the same.

3

The percent of patients should total 100% at the bottom of each column.

4

This example shows any event. Tables showing serious/severe events and events necessitating surgery should also be presented.

D. Report the cumulative frequency distribution of the number of different or new events (complications) on both a per patient and per device basis for each separate patient cohort and the total population. Provide this information for any event, serious/severe events, and events necessitating/resulting in additional surgical procedures/surgeries as in II.C. above. Provide this information for both 0, 1, 2, 3,

4, etc. events as shown in the example Table 3 below and for 0, ?1, ?2, ?3, etc. events as shown in example Table 4 below.

1. The denominator is the number of patients/devices at that visit.

2. If the same complication is reported in the same patient/breast more than once, it is counted once in the numerator if that same complication never resolved during the entire follow-up period. If an event occurs in a patient/breast, resolves, and then recurs in the same patient/breast at a subsequent time point, it is counted twice in the numerator.

3. Although Tables 3 and 4 are for the cumulative 2-year time point and for patients, provide separate tables for each follow-up visit and by implant as well. Example Table 3 showing the exact number of events per patient over the 2-year study period

4

# Different or New Events Number of Patients Percent

0 10/100 10%

1 20/100 20%

2 50/100

1

50%

3, etc. 20/100

2 20%

Total 100/100

3

100%

3

1

There were 50 of 100 patients (50%) who had 2 different types of any event in the cumulative 2-year follow-up period.

2

The denominator should be same number for every entry in this column.

3

The percent of patients should total 100%.

4

This example shows any event. Tables showing serious/severe events and events necessitating surgery should also be presented. Example Table 4 showing the total number of events per patient for any complication over the 2-year study period.

3

# Different Types of Events Number of Patients Percent

0 1/100 1%

??1 99/100

1 99%

??2 90/100

2

90%

??3, etc. 80/100 80%

1

There were 99 of 100 patients who had at least one of any event in the cumulative 2-year follow-up period.

2

The denominator should be same number in this column.

3

This example shows any event. Tables showing serious/severe events and events necessitating surgery should also be presented.

E. Report the total number of events on both a per patient and per device basis for the total population at each follow-up visit.

1. Provide the total number of events categorized as mild, moderate, severe, etc. (if available).

2. If the same event occurred more than once in the same patient/breast, count it more than once.

F. Report the mean and median time/duration of development of each different or new event from time of implantation to time of first occurrence of event on both a per patient and per device basis for the total population.

1. The denominator is the number of patients with ?1 occurrence of each different or new event at any time (cumulatively).

2. Include the following complications as separate events: capsular contracture grades II, III, and IV separately; explantation (removal) for any reason with replacement; explantation (removal) without replacement.

G. Perform Kaplan-Meier analyses (i.e., the complication-free survival rate over time) on both a per patient and per device basis for each separate patient cohort and the total population on the following complication endpoints:

1. Rupture/deflation;

2. Capsular contracture grades II, III, and IV separately;

3. Capsular contracture grades II and higher;

4. Capsular contracture grades III and higher;

5. Explantation (removal) for any reason regardless of replacement;

6. Explantation (removal) for any reason with replacement;

7. Explantation (removal) for any reason without replacement;

8. Infection;

9. Any surgery/procedure/reoperation (i.e., even drainage of hematoma or abscess) to the breast or surrounding area. For example, excision of masses/lymph nodes in the ipsilateral axilla or arm of an implanted breast can be considered the surrounding area;

10. Any surgery/procedure/reoperation due to complication; and

11. Occurrence of any (?1) complication.

General notes for reporting of complications:

1. Include a new (after implantation) diagnosis of breast cancer as a complication in the above analyses.

2. Explantation (removal) for any reason (cosmetic included), with or without revision, should be included as a complication and reported in the above analyses.

3. Revision (explantation with replacement) for any reason (cosmetic included) should be included as a complication and reported in the above analyses.

4. Note that each capsular contracture grade is considered a new or different complication.

III. Effectiveness

A. Size

1. Report the frequency distribution of bra cup size at baseline, end of study, and change from baseline. Report results on both a per patient and per device basis for each separate patient cohort and the total population.

2. Report mean, median, mode (??SD) values of chest/bust circumference/measurement at baseline, end of study, and change. Report results on both a per patient and per device basis for each separate patient cohort and the total population.

3. For the augmentation cohort, report a matched two-way table of the number of patients in each cell demonstrating a change in cup size from before to after (e.g., the before-values on the y-axis and after on the x-axis with each cell representing the number of patients with a change from each before to after).

B. Quality of Life

1. Report the mean (??SD) change in each QOL validated measure (pre-op to each visit). Report results on a per patient basis for each separate patient cohort and the total population.

2. The denominator is the number of patients at each visit.

3. Report results stratified by device placement (i.e., submuscular versus subglandular).

4. For reconstruction patients, report results for immediate versus delayed reconstruction separately.

IV. Covariate Analyses Perform the following covariable analyses for safety endpoints (i.e., by logistic or Cox regression analysis) and effectiveness endpoints on a per patient basis for the total population. At a minimum, this should include the endpoints described above in II.G. (Kaplan-Meier complications):

1. Placement (i.e., subglandular or retromuscular);

2. Smooth vs. textured implant;

3. Valve type (e.g., leaf, diaphragm, etc.); and

4. Shape (round vs. anatomical).

V. Connective Tissue Disease (CTD) Reporting

A. CTD Diagnosis - For each of the points below, provide the data on a per patient basis for each separate patient cohort and the total population. The denominator is the number of patients at that visit. Note that for purposes of data reporting in the PMA, fibromyalgia and chronic fatigue are considered CTD symptoms.

1. Report the non-cumulative point prevalence of CTD diagnoses on a per patient basis at each time point for each separate CTD diagnosis and for at least one CTD diagnosis.

2. Perform Kaplan-Meier analyses (i.e., the CTD diagnosis-free survival rate over time) on a per patient basis for each CTD diagnosis separately and for at least one CTD diagnosis.

3. Report the cumulative incidence of CTD diagnoses on a per patient basis at each time for each CTD diagnosis separately and for at least one CTD diagnosis.

B. CTD Symptom Categories - For each of the points below, provide the data on a per patient basis for each separate patient cohort and the total population. The denominator is the number of patients at that visit. A symptom category is defined as an anatomical or body function area (i.e., Skin, Muscle, Joint, Neurological, Gastrointestinal, and General). For example, the category of Skin includes alopecia, facial rash, pruritis, echymoses, etc. The category of Muscle includes myalgias, muscle weakness, and elevated CPK. The category of Joint includes arthralgia, arthritis, and morning stiffness. The category of Neurological includes cognitive dysfunction, memory problems, and multiple sclerosis-like symptoms. The General category includes fatigue, generalized pain, and fever.

1. Report the non-cumulative point prevalence of patients with at least one symptom in each symptom category at each time point for each symptom category separately and for at least one positive symptom category. (A positive symptom category is defined as one or more symptoms reported in that category.)

2. Perform Kaplan-Meier analyses (i.e., the CTD symptom category-free survival rate over time) on a per patient basis for each symptom category separately and for at least one symptom category.

3. Report the cumulative incidence of patients reporting at least one symptom per symptom category at each time point for each symptom category separately and for at least one positive symptom category.

C. CTD Symptoms - For each of the points below, report the results on a per patient basis for each separate patient cohort and the total population. The denominator is the number of patients at that visit.

1. Report the non-cumulative point prevalence of CTD symptoms on a per patient basis at each time point for each CTD separately and for at least one positive CTD symptom.

2. Report the cumulative incidence of CTD symptoms on a per patient basis at time for each CTD symptom separately and for at least one CTD symptom.

VI. Silent Rupture Reporting

With regards to silent rupture reporting, analyses should be provided for each of the following 3 events:

1. MRI diagnosis of rupture regardless of confirmation with explantation;

2. Rupture noted at explantation regardless of MRI diagnosis; and

3. Rupture noted at explantation for explanted patients or MRI diagnosis of rupture for non-explanted patients.

For each of the 3 events above, provide the following data analyses:

1. Report the non-cumulative point prevalence at each time point on both a per patient basis and a per device basis for each separate patient cohort and the total population. The denominator is the number of patients/devices at each time point.

2. Provide Kaplan-Meier analyses over time on both a per patient and a per device basis for each separate patient cohort and the total population.

3. Report the cumulative incidence (i.e., number of new patients/devices at each time with the event) at each time point on both a per patient and per device basis for each separate patient cohort and the total population.

VII. Mammography Data Presentation

For patients who undergo screening mammography during the study, analyses should be provided for each of the following 3 events:

1. Mammographic suspicion for tumor regardless of biopsy results;

2. Mammographic suspicion for tumor with a biopsy positive for malignant tumor; and

3. Mammographic suspicion for tumor with a biopsy negative for malignant tumor. Compare the data obtained in the first event with that reported in the literature for aged matched cohorts. For each of the 3 events above, provide the following data analyses:

1. Report the non-cumulative point prevalence at each time point on both a per patient and per device basis for each separate patient cohort and the total population. The denominator is number of patients/devices at each time point.

2. Report the cumulative incidence (i.e., number of new patients/devices at each time with the event) at each time point on both a per patient and per device basis for each separate patient cohort and the total population.