Fen-phen Pre-Trial Presentation: Sally X vs American Home Products.

Javier RamirezMarco Morales

Human Molecular Biology and GeneticsMarch 7, 2016

Introduction (Why we are here?)

Fen-phen was a very popular drug prescribed for weight loss. In 1997, 24 cases of valvular heart disease in women who used

Fen-phen were reported. Cases of Primary Pulmonary Hypertension cases were also reported. The pathology of the valvular disease reported was similar to

carcinoid-induced valvular disease, a serotonin-related syndrome. The “Fen” part promotes the rapid release of serotonin and inhibits

its reuptake. In 1997, The FDA requested voluntary withdrawal of these drugs

from the market.

What is Fen-phen?Fen-phen

Fenfluramine and phentermine.-Fenfluramines are Cogeners of amphetamines.-They affect the metabolism of serotonin in the brain.-By changing the serotonin levels in the brain, the fen’s make their users feel full after eating small portions of food.-Fen was approved by the FDA in 1973 as a appetite suppressant.-Fen was marketed under the name Pondimin by American Home Products.-Phentermine (phen) was combined with Fen to minimize its side effects and it’s still on the market. It is not part of the trial.

Fen-phen by the numbers

18 million U.S. prescriptions (Dr. Heidi Connolly – New England Journal of Medicine).

An estimated 3 million persons in the U.S. used the drug (CDC report 1061 Vol. 46, No.45, Nov 14, 1997).

An estimated 60 million used the drug worldwide (Lance and Tortorich, Popular Diet Drugs Pulled From the Market, 9 Loy.).

The total number of cases of unusual valvular morphology reported to the FDA, that prompted the agency to pull out Fen-phen of the market:

24!

Data used by the FDA in Fen-phenTABLE 1.Selected characteristics of five echocardiographic prevalence surveys of persons exposed to fenfluramine or dexfenfluramine*,b y reporting area, 1997

.

*A lone or in com bina tion w ith phe nte rm ine . tO = d exfe n flu ram ine, F = fen f lu ra m ine , and P = phenterm ine . §Convenience sample. 11R andom sam p le.

**C o m p lete study sam p le (n..19); conven ience sam p le (n= 2 ). ttA to ta l o f 15 pe rsons received dex fe nflu ram ine a lo ne; 2 1 ,dex fenflu ram ine and ph en term ine ;

and 45 , dexfenflu ram ine (w ith o r w ithout phen te rm in e ) an d fenflu ram i ne (w ith o r w ithout phen te rm ine ) seque n tia lly .

S ource: D ivision o f P harm a cov ig ilance an d E p idem io lo gy,C ente r fo r D rug E va luation and R esearch , FD A .

M edian

M e dia n dose of

M e dian duration

S am ple % Median initia l drug(s)t of exposu re R eporting area size Females age (yrs) weight (lbs) (m g/d ) (mos)

F lorida 115§ 87% 48 190 F, 20 .0 12 P, 30.0 D , 16 .0 Minnesota

F enf lu ram ine 47, 85% 51 234

F, 60 .0 30 P, 30.0

Dexfenfluramine 2ot 80% 46 239

D , 30.0 9 P, 30.0 Wisconsin 50§ 94% 4 8 2

39

F, 60.0 14 P, 37.5 0,30.0 Ind iana 31§ 77% 47 2

34

F, 20.0 6 P, 37.5 D , 15.0 Pennsylvania 21** 100% 48 2

13

F, 60.0 24 P, 15.0 Total 284 87% 48 2

19

F, 40.0 14 P. 30.0

o , 3o.ott

Findings of FDA study

0 1---1 95% Confidence Interva ls

-----O------

Vol. 46 / No. 45 MMWR 1063

C ard iac Va /vu /apathy - C on tinued F IG U R E 1. P e rc e n ta g e o f p e r so n s w h o h a d re c e iv e d fe n flu ra m in e o r d e x fe n flu ra m in e * w h o h a d v a lv u lo p a th y - f iv e e c h o c a rd io g ra p h ic p re v a le n c e surveys,19 9 7

R eporting Area Florida Minnesota

Fenfluramine

Dexfenfluramin

Wisconsin

Indiana

Pennsylvania

To ta l

0 1 0 2 0 30 40 50 60 7 0 80 90 100

Percentage

FDA Report Findings and Conclusions.

A 32% prevalence of valvular lesions in patients using Fen-phen.

Preliminary reports from large-population studies estimate ≤5%.

The conclusions of the FDA study were based, mainly, in statistical data.

The FDA report does not address: The mechanism of how Fen produces heart valve injury. Who is at risk of developing valve disease? The public health impact.

FDA References on Fen-phen report.

References 1. Connolly HM,Crary JL, McGoon MO, et al. Valvular heart disease associated

with fenfluramine phentermine. N Engl J Med 1997;337:581-8. 2. Lumpkin MM. FDA health advisory. FDA Bulletin 1997;27:2. 3. Klein AL,Burstow DJ, Tajik AJ, et al. Age-related prevalence of valvular

regurgitation in normal subjects: a comprehensive color flow examination of 118 volunteers. J Am Soc Echocardiogr 1990;3:53.

4. Reid CL, Gardin JM, Yunis C, Kurosaki T, Flack JM. Prevalence and clinical correlates of aortic and mitral regurgitation in a young adult population:The CARDIA Study [Abstract]. Circulation 1994;90:1519.

5. Anonymous. National Prescription Audit. Plymouth Meeting, Pennsylvania: IMS America, 1997.

6. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendation of the American Heart Association. JAMA 1997;277:1794-801.

Dr. Anonymous

Recent Studies on Valvular Heart Desease (VHD).

Dr. Andrew Burger at Beth Israel Medical Center in Boston He looked at the echo’s of 226 patients who took Fen-phen Only 4% were positive to VHD using the FDA guidelines. Dr. Burger observed that a high portion of healthy people had

abnormal echo’s without clinical disease, whether or not they took fen-phen.

The only real conclusion that can be reached on Fen-phen and valvular heart disease to date is that studies have produced “contradictory data on the extent of heart valve disease caused by Fen-phen”.

American College of Cardiology website, Oct 1, 1999, www.acc.org/media/highlights/oct99/phenfen.html.

Journal of the American College of Cardiology, 1999 editorial on Fen-

phen. Dr. Nelson Schiller, M.D. of UC-San Francisco stated:

“this was the biggest drug recall the FDA has ever dealt with and has probably cost billions of dollars if

you consider the cost of withdrawal, echocardiograms, and litigation. But instead of turning to the experts

from the start….. the FDA put out a call for cases from weight loss centers that lacked expertise in

cardiology.”ACC MedianINfo, American College of Cardiology Website, Dec. 1, 1999.

www.acc.org/media/highlights/dec99/heart.html.

Fen-phen use as an Off-label drug.

Use of drugs in manners other that those described by FDA.

After FDA approves a prescription drug for one ailment, doctors & researchers often find other ways to use it.

Physicians are allowed to prescribe Off-label drug. Off-label use is a common and legal practice.

(See Cheyenne v. Heckler, 718 F. 2d 1174, 1191). Off-label prescription allows the use of new treatments. Without the necessity to apply for a new drug to the FDA.

Obesity as a serious health problem.

33% of the U.S. population is obese (NHANES III, 1988-1991). Therefore, obesity is an epidemic in this country. Every year 300,000 people in the U.S. die from obesity (out of

a population of 200 million). 184 people per year will die from PPH (Primary Pulmonary

Hypertension) out of a population of 8 million adults who used Fen-phen.

Death rate of Obesity: 1,500/million adults each year. Assumed, death rate of Fen-related diseases: 23/million. More people die from aspirin every year than from Fen-phen

(Dr. Krentzman, M.D.)

References

http://nrs.harvard.edu/urn-3:HUL.InstRepos:8965626. “Fen-Phen Litigation Against American Home Products Corporation”. Harvard University’s DASH Repository.

Khan, Mehmood A. M.D.; Herzog, Charles A. M.D. “Valvular Insuffiency assessed by Transthoracic Echocardiography in Obese Patients Treated with Appetite-Suppressant Drugs”. NEJM Volume 339, Number 11. September 10, 1998.

Kolata, Gina. “How Fen-phen, A Diet “Miracle”, Rose and Fell”. New York Times. September, 23, 1997.