Midterm results - Grades B to A+, mostly low A

ethical theories 14rising health care costs 723andme tests 13how are snps assayed 4GWAS 6critical eval of GWAS 0genome size and mutations 11genome seq. info. 6patenting 14Venter, dealing with discrepancies 3GINA 14disease prediction and insurance 2early detection and PSA 6

Significance of FDA approval

Need it to sell device, drug

If FDA approved device harms you, can you suefor medical damages? Riegel vs Medtronic says noWhy? Supreme court interprets law intended to

prevent States from adding to regulatory requirements as preventing tort suitsunder state law – see article by Jostin

So do you want FDA review to be rigorous?

If FDA approves a device (or drug) for 1 indication,can it be used for another indication?

Yes – “off label” use

Could you sue if damaged by an off-label use?

Dhruva et al reviewed Summary of Safety and Effectiveness Data reports from all FDA PMAs for cardiovascular devices 2000-7

Issues – Are study endpoints well defined?Are FDA guidelines met? Are the guidelines fair?

Drug evaluations often have control groups,double-blind designs, large # pts.

Device trials often have smaller # pts.,use historical controls – is this too lax?

Pretend you are on review committee for cryoablation catheter

Cardiac Cryoablation Catheter and Console System

2.0 INDICATIONS FOR USEcryoablation of the conducting tissues of the heart in the treatment of patients with atrioventricular nodal reentrant tachycardia (AVNRT).

Why is there data for AVT, AF as well as AVNRT if the indication is only AVNRT?

5.0 DEVICE DESCRIPTION …8.0 POTENTIAL ADVERSE EFFECTS OF THE DEVICE* cardiac arrest and/or death;*cardiac perforation*catheter entrapment in cardiac structures

requiring surgical intervention;* coronary artery spasm/dissection/thrombosis* gas embolism with possible tissue infarction;*heart block, partial or complete* hemorrhage;* hemothorax;*myocardial infarction

Is this a class I, II or III device?

9.0 SUMMARY OF PRECLINICAL STUDIES…

9.4 ANIMAL TESTING performed in over 275 dogs…

10.0 SUMMARY OF CLINICAL STUDIESThe study was designed as a nonrandomized,single-arm, multicenter study to assess the safety and effectiveness of the device used percutaneously in the treatment of AVNRT, AVRT and refractory AF in subjects acting as their own controls.

Could it have been randomized?

Endpoints for the study were:

*procedural safety - absence of serious complications *acute procedural success - non-inducibility of

sustained SVT at the end of the procedure.•chronic success - no recurrence of sustained SVT

at 3-6 mo. follow-up

objective performance criterion (OPC) as described in the FDA guidance, "Cardiac Ablation Catheters Arrhythmia Indications for Use; Guidance for Industry

Table 1. Endpoint Criteria from FDA Guidance

Endpoint Tgt Value 95 % Confid. BoundAcute Success > 95 % >85 %Chronic Success > 90 % >80 %Major Complications < 2.5 % < 7 %

Should these be used, as they are from Guidancedocument for RF ablation catheters?

Demographic Data of Enrolled Subjects (n=166)

Diagnosis n ageAVNRT 103 50± 15 AVRT 51 39± 13AF 12 73±11

AF, atrial fibrillation; AVRT, atrioventricular reentrant tachycardia;

Safety EvaluationSubjects with Adverse Events (n=166)

AVNRT AVRT AF All n 103 51 12 166# (%) withacute majorcomplication 3 (3) 4 (8) 0 (0) 7 (4.2)

Eight (8) acute major complications were reported in 7/166 patients (4.2%, upper bound 8.5%). The clinical study safety results exceeded the safety objective performance criteria of 2% with an upper bound of 7.5%

Is this enough to disqualify?

Effectiveness Evaluation

%, (lower bound CI %) Diagnosis N Acute Success Chronic SuccessAVNRT 103 91 (82) 93 (85)AVRT 49 69 (51) 88 (69)AF 12 67 (29) 75 (28)Overall 164 83 (76) 91 (85)

Guideline >95 (>85) >90 (>80)

Cryomapping effect was demonstrated in 64% (87/135) of subjects attempted. One AVNRT subject had a cryomnapping related adverse event (transient AV block lasting 25 seconds).

Your recommendation?Panel voted to approve, subject to submission of a post-approval study to evaluate the rate of AV block. The indication of cryomapping not be approved.

CDRH DECISION CDRH determined that the OPCs shouldnot be used to evaluate the safety and effectiveness of the device in the AVNRT subgroup. As a result, the devicesystem was evaluated on its merits… The sponsor demon-strated reasonable assurance of safety and effectiveness..The cryomapping feature should be enabled for use …The labeling should include a warning to indicate that the effectiveness of the cryomapping feature has not been established.

Next panel – Avastin (antibody to factor thatpromotes blood vessel growth in tumor)

Genentech, Inc submitted two efficacy supplements to the Biologics License Application (BLA) for Avastinto support label expansion for first-linetreatment of metastatic breast cancer in combination with docetaxel …and to support conversion from accelerated approval to regular approval for first-line treatment of metastatic breast cancer.

Avastin in combination with paclitaxel received accelerated approval in 2008 based on the results of a randomized, multicenter, open-labeled trial of avastin with paclitaxel or paclitaxel alone that enrolled patients with HER-2 neu negative breast cancer whoreceived no previous chemotherapy for metastatic disease. The addition of avastin resulted in a 52% increase in progression-free survival (HR 0.48, 95% CI0.39, 0.61; p< 0.0001) with an observed 5.5-month difference in median PFS, based on an independent radiographic review. There was no significant difference in overall survival.Sounds pretty good, but what is progression-free survival (PFS), why use it rather than survival or disease-free survival as a measure of success?

How did they measure PFS? Might it be subject to subjective judgments? Was the study double-blind?

Baseline or PFS-determining radiographic scans were missing in 10% of the patients and 34% of the patients were not followed until an IRRC-determined PFS event or the end of the study. In addition, there was a high rate of discordance (50%) between investigator andindependent review determined PFS events.

Raw data were mean PFS of 5.8 months in controls vs 11.3 months in avastin group. How this is “52% increase” in PFS I can’t say.

Some committee members raised the concern that, given the uncertainties in the PFS effect size due to missing data, patients could be offered false hope.

The initial committee voted 5-4 against approval,but were overridden in view of 5 month PFS increase.

Follow-up studies

Trial #1 (AVADO) 736 pts., taxol alone vs taxol + low (or high)dose avastin. Low (high) dose avastin added 0.8 (or 0.9)months to PFS. Is that a long time? Why did 5 monthsdrop to <1 month?

Safety data showed an increase in serious adverse eventsin the avastin groups. Actual survival was higher (but notstatistically significantly) in the non-avastin group.

Trial #2 (RIBBON) 1237 pts., drug A (or B) + avastin. Withdrug A (or B), avastin added 1.2 (or 2.9) months to PFS. Serious side-effects were ~ 2x higher in the avastin groups.

Avastin is approved for lung and colon CA

Do you vote to approve avastin for metastatic breast CA,or to reverse the FDA’s original approval?

Would physicians be able to use avastin for breastCA if FDA withdraws its approval?

Other reasons for controversy – cost

$50,000-100,000/year; earns Genentech $3.5B/yr

‘Roy Vagelos, a former chief executive of Merck who is considered an elder statesman of the industry, said in a recent speech that he was troubled by a drug, which he would not name but which was a clear reference to Avastin, that costs $50,000 a year and adds four months of life. “There is a shocking disparity between value and price,” he said, “and it’s not sustainable.”’http://www.nytimes.com/2008/07/06/health/06avastin.html

What ELSI issues are posed by regulation of expensive drugs with minimal but non-zero benefit, used to treat life-threatening illnesses?

What is your view?

Next week – ethical issues in research

Famous “unethical” studies in the past

Tuskeegee (syphillis), Willowbrook (hepatitis)Were they unethical when proposed?How have standards changed?Could what went wrong be prevented?Do genetic studies today pose similar risks?