Bad Medicine: The Prescription Drug Industry in the Third World 9780804766678

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THE PRESCRIPTION DRUG INDUSTRY IN THE THIRD WORLD

Milton Silverman Mia Lydecker Philip R. Lee

STANFORD UNIVERSITY PRESS STANFORD, CALIFORNIA

1992

Stanford University Press Stanford, California © 1992 by the Board of Trustees of the Leland Stanford junior University Printed in the United States of America CIP data appear at the end of the book

CONTENTS

Preface

IX

A Note About the Authors

xv

1. THE PATIENTS: HEALTH FOR ALL BY- WHEN? Disaster in the 1g8os, 3 An Excess of Illness, 6

2. DRuG LABELING: How SAFE? How DEADLY? g The Latest Round, 10 Drugs Against Fever and Pain, 13 Antiarthritis Drugs, 16 Antidiarrhea Agents, 20 Antibacterials, 26 Appetite Stimulants, 31 Cardiovascular Agents, 32 Cerebral Vasodilators, 33 Major Tranquilizers, 36 Minor Tranquilizers, 37 Antidepressants, 38 Anabolic Steroid, 39 Female Sex Hormones, 40 "Sex Tonics," 40 Trouble in Africa-Again, 41 An Evident Change, 42 3. THE COMPANIES: HEROES OR VILLAINS? 43 Anatomy of the Drug Industry, 43 End of the Glory Days, 45 Essential Drugs Lists, 4 7 Patent Infringement, so Storm over Mr. Medawar, 54 An Alternative Voice from the Industry, 57 4. THE GREAT GENERics CoNTROVERSY 63 The Antigenerics Rumors, 66 Generics Overseas, 70 The Generic Drugs Scandal, 72 The Dingell Committee Drug Hearings, 73 Shortcut to Drug Approval, 76 A Search for the Culprit, 78 Generics in the Philippines, 83 5. THE DIPYRONE AFFAIR 86 The Curious Case of Paracetamol, 88 The Entrance of Dipyrone, go The Matter of Merital, 97 The Thailand Debacle, 100

vi/CONTENTS

6. THE CASE OF THE DEADLY PREGNANCY TEST 107 The Campaign Against High-Dosage Products, 110 The Public Hearings, 115 The Party Lines, 120 Finally, the Verdict, 123 7. BANGLADESH AND THE NOBLE EXPERIMENT 125 The Experiment Is Launched, 129 The Experiment Explodes, 131 The Experiment Pays Off, 136 8. THE DRUG SWINDLERS 145 Deceit in Indonesia, 146 Incident in India, 151 Fraud Brasileiro Style, 154

Drug

9. So SHINES A GooD DEED 160 A Better Drug Chain, 162 The Essential Generics War, 165 The Tropicare Project, 170 The Damn Fly and Its Worms, 172 10. AMMUNITION FOR THE CoNsUMERS 176 The Task Force Reports, 177 The "Drugging" Books, 179 The Marketing Codes, 18o The Consumerist Campaigns, 183 The HAl Proposals, 186 11. CoNSUMER PowER: THE HANSSONICIBA-GEIGY CoNNECTION 190 The Appearance of SMON, 192 Start of the Damage Suits, 194 The Tanabe and Takeda Apologies, 196 Hansson and the Press, 198 Threat of a Boycott, 199 The Ciba-Geigy Meetings, 200 The Butazone Confrontation, 204 Problems with Mr. Knop, 205 Failed Mission, But-, 208 12. THE EssENTIAL RoLE OF GovERNMENT 209 Regulation in the United States, 209 The Dreadful Drug Lag, 2 11 Regulation by Persuasion, 2 13 The Nairobi Nonconfrontation, 218 Export of Unapproved Drugs, 221 13. HARD CHOICES 228 Problems Related to the Crisis, 230 The Silverman, Lydecker, and Lee Studies, 232 The Work of Many, 234

CONTENTS/ vii

The Problems at Hand, 235 The Matter of Quality Assurance, 236 Essential Drugs Lists: Some Progress, 237 The Matter of Bribery, 238 Domestic Drug Industries: Some Hard Choices, 240 External Vigilance, Unending Consultation, 242 Appendix: Tables of Product Indications, Contraindications, and Warnings References Index

341

319

24 7

PREFACE

The

pharmaceutical industry has long and vehemently insisted that it had the willingness, the dedication, and the ability to police itself-not necessarily to do a perfect job of policing, but to do an adequate one-to see that the majority of the public would not be unnecessarily harmed or ripped off. This was wishful thinking. Virtually no industry or professional group has ever adequately policed itself-not the Knights of the Round Table, not the medical or the legal profession, not the clergy, neither academicians nor scientists, and certainly not the media. Where the more flagrant abuses have been exposed and corrected, major credit must probably be divided among the media that broadly publicized the situation, consumerists who applied pressure, governmental workers who took often unpopular therapeutic actions, and members of the industry itself who had the courage to face up to their social responsibilities. Specifically, a limited number of drug companies, for a variety of reasons, have taken such responsibilities quite seriously. The record will show that a few companies-notably Syntex, Merck Sharp & Dohme, Upjohn, and SmithKline in the United States and, in recent years, Ciba-Geigy in Switzerland-have only rarely been found guilty of making unsubstantiated claims or of glossing over the hazards of their products. The most memorable explanation came from a Syntex official who once confided to us, "We have found that we can tell the truth and still make a decent profit." As the following pages will reveal, in their promotion of drug products in developing countries, the worst offenders were originally the big multinational companies based in the United States, Europe, and, more recently, Japan. By the end of the 1g8os, however, the situation had changed remarkably. More and more, it was the multinationals which had discovered that they could tell the truth and still make money. Instead, it was the local or domestic firms-many with enor-

X/PREFACE

mous political power-that were lying to, defrauding, and endangering the lives of their fellow citizens. For many in the Third World, this was a distressing discovery. The enemy was not some faceless anonymity sitting in a board room in far-off New York or Zurich or London or Frankfurt. It was their neighbor who lived down the street. Most of this report is devoted to areas of drug use and the pharmaceutical business which have long held our attention: the patients in the Third World and the illnesses that afflict them, the so-called prescription drugs promoted to control those illnesses, the various categories of drug companies, the constantly renewed battle against usually inexpensive generic products (spiced this time by disclosures of fraud and bribery in the U.S. Food and Drug Administration), the actions of consumerist groups, and the key role of government. In addition, we describe a remarkable attempt in Bangladesh, one of the poorest of all the developing countries, to develop a high-quality local drug industry. We examine what has until now been a largely unexplored area, the rise in the production and use of fraudulent drugs and the role of the drug swindlers. And, as case histories, we report on three extremely important drug products or groupsthe dipyrones (for control of pain and fever), high-dosage estrogenprogesterone hormone products (for use in pregnancy tests), and clioquinol or Enterovioform (for treatment of diarrhea)-all of which were or still are centers of worldwide, heated controversy. Much of Chapter 8, "The Drug Swindlers," was taken from Silverman, Lydecker, and Lee, "The Drug Swindlers," Int.]. Health Serv. 20:561-72 (1ggo). Much of Chapter 11, "Consumer Power: The Hansson/Ciba-Geigy Connection," was taken from Silverman, M., "The Hansson/Ciba-Geigy Connection," in Hansson, 0., Inside CibaGeigy (Penang, Malaysia: International Organization of Consumers Unions, 1g8g), pp. 194-227. In the more than three years that were invested in this study, a small army of people played vital roles. These individuals-old friends and new-came from consumer organizations, drug companies, governmental regulatory agencies, universities and medical schools, clinics and hospitals both in big cities and in the boondocks, and research institutes. Many were former colleagues from press and radio and television, which gave us particular pleasure. Some were former stu-

PREFACE/xi

dents. They gave us help, support, and cooperation at interviews, medical meetings, and press conferences. They did this, we hope, not out of friendship or affection but because they, too, wanted the truth to be reported. We gratefully call the roll, as it were, country by country. Australia: Peter Mansfield. Bangladesh: Zafrullah Chowdhury and S. H. Kabir. Brazil: Bruno Carlos de Almeida, Jose Augusto Cabral de Barros, Augustinho Betarello, Elizaldo Luiz Carlini, Maria des Gra.

..c

~

1i

.5

.5

u

.9

.9

c -~

u'"

u"'

u'"

/

/

/

/

"'""c

""" c

'5

OJ

c

'5

>. i:

c

1::

" -o" :.a -.; u c

c -o ;.:;;

" u'"

.... OJ >

OJ

1i '8 t:

:2 ""' .5

::9

.5

.5

0

c .9

c

"§

"' u"' u'5"'

Venezuela

Apranax-SmithKline & French (U.S.) Synaprosyn-SmithKline & French (U.S.)

/ /

Peru

Naprosyn-Griinenthal (West Germany) Sinartrin-Sanitas (Peru)

/

/

/

/ /

Brazil

Nap ros yn-Sy ntex

u.s.

Most of the products listed here are contraindicated in pregnancy, in patients sensitive to aspirin and NSAIDs, and in those with a history of GI disorders. (a) Footnote reference to warnings.

NOTE:

APPENDIX/261

Table 8

INDICATIONS

Tiaprofenic Acid

.,

(single entities only)

.-

""'0

c

::

-

c

!::

:;:

-;::

-

..:

~ =' u

:.;;1

c: ='

.5

""'0.. "' ='.t:

0

-~"

~

..,."

~

-~

u

"c: "tl

I:" "' 80

.,.,

·;;:

:g

"

c:

='

.5"' c:

~-~

u"'

='

.g =' u"'

./

./

./

./

./

./

·;;:

rJl

zu

'0

~

=' .t:-

·i ~

c: :Jl

·=='0 "'e:0.. U"tl "'" ./ ./ ./ ./ ./

Colombia Lomotii-Searle (U.S.)

./

2

Ecuador Lomotii-Searle (U.S.)

./

Venezuela Lomotii-Searle (U.S.) Brazil Lomotil-Searle (U.S.) •Sedatives, tranquilizers, alcohol, MAO inhibitors.

./

./

./

./

./

2

./

./

./

./

2

./

272 f APPENDIX

Table 12

WARNINGS

INDICATIONS

Loperamide (single entities only)

:~

-, ....

'6"

·au0 ....

.5

u

0

:.:l

~

c

.., >

~

~

'5

..,>.. c

~.., ·;:: t:

]"'

..c

1:

.!:."

"2

>.. u

.9 !:

"'c fl ""..,.... .5~

iil

~

c

0..

.5

~

~

~

I

I

I

I

0..

>
-.

i:2

~ ·;::

~

"'

~

1:

.2!>

>-.

-a

u

8 1:

"bllc c"' "...0.. ~.E

~

:l

c

.E

.E

u"

~ >
c c c- .5 o>"- 1i ., ='·> ·=" :s c

·-"' ~]

./

./

./

(a)

(a)

(a)

(a)

./

./

./

./

./

./

(a)

./

~a

(a)

./ ./

./ ./

~

·= .g 0 oz "' ; ~ z zu u u ,f ~

(a)

./

.l:i

~

./ ./

./ ./

./

./

./

APPENDIX/ 305

Table 32 Diazepam

WARNINGS

s"'0

(selected countries; single entities only)

.9

bb " bb

"

""'

·a..c: 8: ~

u

.5 :ll

z" 0

I

rJ

u

[ u u 0

~

·;;:

"

a

·a"' "'0 "E0 "0 ..c:., -5" "' ~ -~ ~ & "' 0 ..c: ~ ~~ !:: "' -~ ~ ~ !: " " ] :..=oo ~ 1': "'.5 .5..c:"' Q.. -~..c:.,~ .5"'" .5 ..c:"' 1': 1': .5"'Ei ·-" c:-. ~ "'" 1': 1': ..!; .... 0 ~~ .g "::l £ :ll .a" :e -~0 ~>- :ll "0 "'0 ""' 0 0 oZ " " § ~"0 u"' u"' """ u:.;;a z z" z" z zu 1':

~

~

~ ....

"'

u

0

~

0::

1': 1': b.O

:ll

N

United States

Diazepam-Warner-Chilcott (U.S.) Valium-Roche (Switzerland)

j j

j

j j

j j

j j j j j j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

India

Calmod-IDPL (India) Calmpose-Ranbaxy (India) Elcion CR-Ranbaxy (India) Paci-Quil-Stadmed (India) Paxum-East India (India) Soma tin- Khandelwal (India) Valium-Roche (Switzerland)

j j

j j

j j

j j

j j

j j

j

j j j

j j j j j

j

j

j

j

Mexico

Alboral-Silanes (Mexico) Arzepam-Solfran (Mexico) Britazepam-Briter (Mexico) Nerozen-Welfer (Mexico) Ortopsique-Psicofarma (Mexico) Pacitran-Grossman (Mexico) Valium-Roche (Switzerland)

j j j j j

j j

j

j

j j j j j

j j j j

j

j

j j j j

j j

j

j j j

j j

j

Central America

Alboral-Silanes (Mexico) Diazepam-McKesson (U.S.) Diazepan-Feltrex (Dominican Republic) Paranten-Bonin (Guatemala) Paxium-Vijosa (El Salvador) Valium-Roche (Switzerland)

j

j

j

j j

j j

j j j

j j j

j

j

j

j

j

j

j

j j

j j j j j

306/ APPENDIX

Table 32 continued

WARNINGS

s"'0 u :l

"'c -~

::su " "" u

·~

s,

bD v

bD

c

0

:;

....

"~ 0 '"C~ 0~!3 ......0 "E -5 .; ~ "' "' IS. "'c ..c"' ·~ ..c"' .:: ~

"' ~ ..cu

.5 ~

.5 ~

.5 ~

::s

::s

::s

0

0

0

z Colombia Diazepam-Ecar (Colombia) Valium- Roche (Switzerland)

N

z

z

c.

2 .0

"'0 z

"'c c ..,"' ..,...btl" -.:: '"C l

j

.~

..,c

i

s"'

.5

:;" 0 z

j j

j

/

/

Ecuador

Consilium-Rocnarf-Francor (Ecuador) Dipaz-ECU (Ecuador) Paxate-Mead-Johnson (U.S.)

j

/

/

j

/ /

/

j

/

Venezuela

Diazepam-McKesson (U.S.) Diazum-Klinos (Venezuela) Elinar-Beta (Venezuela) Pacitran-U.S. Vitamin (U.S.) Rendin-Interfarma (Venezuela) Talema-Palenzona (Venezuela) Taximel-Physia (Venezuela) Valium-Roche (Switzerland)

/

/

j

j

j j

/

/ j

/

/

/

Peru

Pacitran-Peikard (Peru) Reposepan-Unidos (Peru) Vazen-Farmindustria (Venezuela)

/

/

/

/

j

/ / /

/

Brazil

Dienpax-Sanofi (France) Dualid-Labofarma (West Germany) Kiatrium-Gross (Brazil) Valium-Roche Switzerland

j

j

j

/

j

j

/ j

j

/ /

APPENDIX/307 WARNINGS

Table 33 Lorazepam (selected countries; single entities only)

"a0 u

"'0 ·g"

"" uuc.." " 0 ;. bo "' "'~ " "0 "0"...0 "0"... ;. ..c::u -5 !:: >. :s.. "' ..c::""' ·~ .5 .5" .5 c.

·;::"'

bo

"

N

1;1

1;1

1;1

2

.t:J

~

>. u

0

-§!3

~ ~

..c::"' -~ f: ;. c.. ~~

.!2" " """... ::2-.:::" ;;; ]" c.. " >.

bD

.5

.5

0 0 ·g" ·g"

z

oz " z" z" z" zu ""' 0

u"'

u"'

j

j

j

j

j

j j

j j j

j j

j j

0

0

0

~

...- ""'

"·~ ,.-o

:.=bD

c " ·~

.t:J

0 >. ·~

..!< ~

"

~"

"a>.

"--"" 1;1 " u:.;; z"

..c::"

·;;; ~

.::!

~ ~"0

.5 0

United States

Ativan-Wyeth (U.S.)

j

j

j

India

Ativan-Wyeth (U.S.) Larpose-Cipla (India) Trapex-Sun Pharm (India)

j j j

j j j

Mexico

Ativan-Wyeth Ayerst (U.S.) Sinestron-Medix (Spain)

j j

j

j j

j

j

j

j

j j

Central America

Ativan-Wyeth (U.S.) Enerpax-Raven (Costa Rica) Lorazepam-McKesson (U.S.) Sinestron-Medix (Spain)

j j j j

j

j j j

j j

j

j

j j

Colombia

Ativan-Wyeth (U.S.)

j

j

j

j

j

j

Ecuador

j

Ativan-Wyeth (U.S.) Venezuela

Ativan-Wyeth (U.S.) Lorazepam-Klinos (Venezuela)

j j

j j

j

j j

j j

Brazil

Lorax-Fontoura-Wyeth (U.S.)

j

j

j

j

j

j

308/ APPENDIX WARNINGS

Table 34 Bromazepam (single entities only)

~

0 .... .... 6

~

..."' "0

N

'i

"' "' 0::: u .-

"@

"' ...

::l 0 "0

;:l

;:l

0

u

z

iS

0 ~:3

.;

u

0:::

"'

0:::

""

~ !: c.. .-

IS.

....

.s

u u 0

..c: ·~

:g 0

0 ..c: 0

..!:I

"' :€

"E

2l

c

"' "'c ;:g!: "'c ·;:;c5 ..c:"' !: ..c: N

bO

"C

Malaysia/ Singapore Buspar-Bristol (U.S.) j

j

0

> ....

"'

..c:u

"' "' ~

~

"'c"

"C

u

::0 u

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

United Kingdom Buspar-Bristol-M yers (U.S.)

:g

c

.a

c..

u

:.;2

.5

.5

j

j

rJc

~ "':l

..c: ·~ c

j

0

~

"'

~ ,:.

z

::0

Mexico Buspar-Meadjoh nson (U.S.)

....

>-

0 0 0 :l"' 1i::0" .9 :; ·g ·=::0 ·g 0 0 z z u"' u"' u"' u"'

1i

United States Buspar-Meadjoh nson (U.S.)

~ :::;

1i 1i"' 'ti

"

~

9 ;§ ..c:

c

c

"'c

..c:

1i

1i

:l"'

j

j

"' "'>- "u"'>- u>-"' >:::;"' :::;"' ::E"' :::;"'

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

j

Peru

j

Buspar-MeadJoh nson (U.S.)

Brazil Buspar-Bristol (U.S.)

j

j

j

APPENDIX/ 311

Table 36

Imipramine (single entities only)

WARNINGS

No use with MAO inhibitor

Caution in cardiovascular disease

/

/

(a)

(a)

/ / / /

/ / / /

(a)

(a)

(a) (a) (a)

(a) (a) (a)

(a) (a)

(a)

(a)

/

(a) (a) (a)

(a) (a) (a)

/

/

(a) (a)

(a) (a)

(a) (a)

(a) (a)

(a)

(a) (a)

United States

Tofranil-Geigy (Switzerland) United Kingdom

Tofranil-Geigy (Switzerland) India

Antidep-Torrent (India) Depsol-Intas (India) Depsonil-SG Pharmaceuticals (India) Impramine-Sun Pharma (India) Indonesia

Tofranil-Geigy (Switzerland) Thailand

Antidep-Torrent (India) Tofranil-Ciba-Geigy (Switzerland) Topramine-Condrugs (Thailand) Malaysia/ Singapore

Imprin-Protea (U.K.) Tofranil-Geigy (Switzerland)

/

Philippines

Tofranil-Geigy (Switzerland) Africa

Melipramine-Medimpex (Hungary) Surmontil-May & Baker (France) Tofranil-Geigy (Switzerland) West Africa

Tofranil-Geigy (Switzerland) Middle East

Imiprex-Dumex (Denmark) Pryleugan-Germed (West Germany) Surmontil-May & Baker (France) Tofranil-Geigy (Switzerland) Caribbean

Melipramine-Egis/Medimpex (Hungary) Surmontil-May & Baker (France) Tofranil-Geigy (Switzerland)

(a) (a)

(a)

312/ APPENDIX

Table 36 continued

WARNINGS

No use with MAO inhibitor

Mexico Talpramin-Psicofarma (Mexico) Tofranil-Geigy (Switzerland)

Caution in cardiovascular disease

j

Central America

Imipramina-Profacasa (Guatemala)

j

Venezuela Surmontil-Rhone-Poulenc (France) Tofranil-Geigy (Switzerland)

j

Brazil

Tofranil-Geigy (Switzerland) (a) Footnote reference to warnings.

j

j

j

APPENDIX/313

Table 37 Stanozolol (single entitus only)

WARNINGS

Growth stunting in children

Masculinization of girls, women

No use to enhance athletic ability

j

j

j

United States

Winstrol-Winthrop (U.S.) United Kingdom

j

Stromba-Sterling Research Labs (U.S.) India

Menaboi-CFL Pharma (India) Stromba-Win-Medicare (U.S.)

j j

j j

j j

(a)

(a)

(a)

(a)

(a)

(a)

Africa Winstrol-Winthrop (U.S.) Middle East

Winstrol-Winthrop (U.S.) (a) Footnote reference to .warnings.

314/ APPENDIX

Table 38

INDICA-

(single entities only)

WARNINGS

TIONS

Allyl Estranol ~

·e00

..Q

...0

"' ... :l ~ ~8

'"

~

..Q

..!S -

1i '6 ~lj

1i 1i"' '6

~

~

-~

~.... t: ..!:!iS. 8" -5 "0 8 :a 0 :;j "" '" ""~ :€..8 ~ "u :.;;!.s .s~" .s"" ·a. "0 "0 " .s .s "~ ~" ~ .s"" ~ 8 ·~] ,.- .g .Sl .S! 0 .Sl l" "'~ "'~ E" 1i:l0 1;] 8 :0"" :; :; g :; :l 1-< ~ &:: z z'E z :s u"' u"' u" u" u"' ~

....

~

.Sl

u

~

"'

~

~

~

~..8

"'... ~

...u