2. The Creation of a New Drug 21
3. How Much Does the Pharmaceutical Industry Really Spend on R & D? 37
4. Just How Innovative Is This Industry? 52
5. "Me-Too" Drugs - The Main Business of the Pharmaceutical Industry 74
6. How Good Are New Drugs? 94
7. The Hard Sell... Lures, Bribes, and Kickbacks 115
8. Marketing Masquerading as Education 135
9. Marketing Masquerading as Research 156
10. Patent Games - Stretching Out Monopolies 173
11. Buying Influence - How the Industry Makes Sure It Gets Its Way 193
12. Is the Party Over? 217
13. How to Save the Pharmaceutical Industry - And Get Our Money's Worth 237
Det er mærkeligt, at vi tilpasser vore regler til USAs, når man ved, at USA er
det land, der bruger mest på sundhedsvæsenet - med en meget ringe service.
Mange af pengene (200 milliarder USD/år) går til medicin. De fleste amerikanere
har - i det mindste siden Clintons første valgkamp - i meningsundersøgelse
efter meningsundersøgelse givet udtryk for ønsket om et bedre sygesikringssystem.
Marcia Angell er læge og fhv. chefredaktør for det ansete amerikanske lægetidsskrift New England Journal of Medicine. Hun ved, hvad hun taler om. Hun har fulgt med på området gennem et antal år. Og hun har oplevet de samme ting på flere niveauer end de fleste. Der er derfor tale om en god, velskreven, velinformeret og aldeles nødvendig bog for enhver med blot den ringeste interesse for medicin og/eller samfundsøkonomi.
Det meste af forskningen foregår i offentligt regi, betalt af offentlige kasser. Derfor er det ganske urimeligt, at de farmaceutiske firmaer skal tildeles et langtids monopol på salget. (Og det er dybt ironisk, at firmaer, der har et regeringskontrolleret monopol og lever af at sælge til det offentlige og bygger det meste af sin udvikling på offentligt finansieret forskning kalder sig private - og privatiserer gevinsten). I det mindste burde man indføre priskontrol. Firmaernes største udgiftspost er ikke forskning og udvikling, men administration og reklame. Virksomhederne overdriver omkostningerne ved forskning og udvikling. Man kalder meget af reklamen overfor læger for uddannelse.("kurser" i/skjult betaling for at bruge netop denne virksomheds produkt, o.s.v.). Og man uddeler "medicin-prøver" til lægerne for 11 milliarder USD/år - bare i USA. Som i cigarettens barndom klemmer man reklame ind, hvor den kan smutte ubemærket ind - og hvor mange mennesker mødes. Det er afslørende at se den amerikanske farmaceutiske industris organisations (PhRMA's) opgørelse over medlemmernes reklameindsats. Der anvendes kun 2 % af den samlede sum til annoncering i lægernes fagblade. De læsende læger er det åbenbart ikke umagen værd at ofre annoncer på. De kan jo vurdere overdrivelserne. Det giver bedre pote, at give lægerne gratis prøver og direkte gaver ! Det vurderes jo ikke i samme saglige ånd, som indholdet i et lægetidsskrift. I det mindste i USA har man nu firmaer, der følger hver enkelt læges ordinationer og sælger registret til medicinfirmaerne, så repræsentanterne kan være velforberedte, når de møder lægen. De sælger også medicin til underpris til lægerne, som så kan forlange fuld pris fra Sygekassen (p. 130). Siden 1997 (Clinton) må man i USA reklamere uhæmmet for medicin i TV, indtil da skulle alle bivirkninger være med i reklamen !
Jeg har altid opfattet patientforeninger som primært overlæge-selvforherligelses-foreninger (De, alle kender, er Kræftforeningen og Gigtforeningen). Men de er også et reklameværktøj for den farmaceutiske industri (p. 151).
De fleste af de nye patenter er ikke til egentlig ny medicin, men til variationer af allerede godkendte produkter, evt. til et (lidt) andet formål, det Angell kalder "me-too" mediciner. Det ville være rimeligt at forlange, at offentligt finansieret forskning- og udvikling ikke giver anledning til en dyr patentafgift, der også skal betales af det offentlige. Selve fremstillingen af medicinen er oftest billig, det ses bedst på, at når patentet løber ud og vejen derfor åbnes for andre mærker (såkaldt generiske produkter), så falder prisen ofte til 1/5. Firmaerne forsøger med alle midler, også ulovlige, at hindre det.
Firmaerne arbejder ihærdigt på at få os til at bruge mere og mere af de samme mediciner. Det ses mest udpræget for blodtryksnedsættende mediciner, hvor man dels har nedsat den grænseværdi, hvor man begynder at behandle, dels har nedsat den "ønske"-værdi, som man tilstræber at opnå. Og de har jo ingen interesse i at oplyse om det, når en ikke-medicinsk behandling faktisk er bedst.
I USA må "sygekassen" ikke en gang forhandle sig til en lavere pris. (Hvordan er det egentlig her. Oplysninger og ideer til undersøgelse heraf modtages med begejstring).
Det kniber med nye mediciner. Firmaernes liste over produkter på vej er næsten tomme. Og endnu værre for industrien, de patenter, der giver de helt store penge er ved at løbe ud.
I USA har virksomhederne for stor indflydelse på godkendelsesprecessen, ikke mindst over den måde forskningen tilrettelægges på. Det vil også være rimeligt - og nødvendigt - at al Phase II og III forskning registreres og standardiseres, så der ikke fuskes med at stille det undersøgte præparat i et bedre lys end rimeligt er, og så alle resultater, også de, der er negative offentliggøres. Som det kører nu er endda egentlig bestikkelse mulig. Det nødvendige i, at nye præparater afprøves overfor eksisterende præparater, ikke bare vises at være bedre end kalktabletter (placebo) illustreres af ALLHAT-undersøgelsen, der sammenlignede 4 typer af blodtryksnedsættende medicin, Calcium-kanal-blokerere (type: Norvasc), en alfa-adrenergisk blokerer [type Doxazosin), en angiotensin converterende enzym inhibitor [type: Atacand, enalapril] og et gammeldags vanddrivende middel [type: tiazid ell. furosemid, CTR artikel]. Det vanddrivende middel var lige så godt som de øvrige til at nedsætte blodtrykket ! - men bedre til at forebygge hjertesygdomme og hjerteslag (stroke). (p. 96)
Det medfører en stor risiko for ansvarsforflygtigelse, at meget af Phase II og III afprøvningen nu overlades til særlige private virksomheder - som selvfølgelig kan gå konkurs, hvis det viser sig, at de har lavet dårligt arbejde. Og det giver medicinproducenten endnu større muligheder for at styre afprøvningen til et resultat, der kan fremstilles som positivt.
Patenterne kaldes, når man forhandler handelsaftaler, intellektuelle ejendomsrettigheder (intellectual property rights). Det skal man ikke tro på. Det er sjældent, at det er et intellekt, der får andel heri. Pengene plejer at gå til en multinational virksomhed.
Et patent til et kendt middel til en "ny" sygdomsvariant kan bruges til at firmaet skaffer sig en ekstra patentperiode til netop det formål, endda uden, at det er godtgjort, at den pågældende medicin er særlig god på netop det felt. Og det vil firmaerne hellere end at udføre de forlangte Phase IV kontroller for bivirkninger.
Tom Lehrer sang for omkring 50 år siden om det gode medicinske speciale "diseases of the rich", de riges sygdomme. Det er ikke bare mange læger, der har specialiseret sig i det. Hele den farmaceutiske industri er også meget mere interesseret i præparater mod forhøjet blodtryk, fedme, menstruationsgener, sure opstød/halsbrand, manglende potens, o.s.v. end mod AIDS og tropesygdomme, som reelt er "de fattiges sygdomme", lige som tuberkulose. Firmaerne er heller ikke særligt interesserede i præparater, der helbreder. Det er meget mere profitabelt at kunne blive ved med at "lindre" eller endnu bedre "forebygge". I lang tid mente man at kunne forebygge hjertesygdom hos (post)klimakterielle kvinder ved at give en erstatning for de naturlige kønshormoner, organismen på det tidspunkt i kvindens liv holder op med at lave selv. Det viste sig, da National Institutes of Health fik kigget på sagen, at den forebyggende behandling var skadelig ! Man "forebygger" stadig diabetes med metformin, selvom diæt og motion virker bedre.
Det er vel ikke overraskende, at depressioner er meget påvirkelige af kalktabletter (placebo), men det virker dog overvældende, at placebo virker i gennemsnit 80 % så godt, som de 6 mest solgte antidepressive mediciner.
Som biokemiker, altså uddannet netop til den branche, forstår jeg ikke, at noget anstændigt menneske kan arbejde i den branche. Det må i den situation være svært at se sig selv i øjenene hver morgen.
Firmaerne tillader sig endda at bare holde op med at fremstille et præparat, hvis de ikke synes, det giver tilstrækkelig stor profit. Et særligt problem i den sammenhæng er vacciner. Det er ikke bare vaccinationscentralen i Malmö, der til tider mangler rejsevacciner.
Man kan sammenfatte Marcia Angells bog i et centralt spørgsmål: "Hvis medinerne virkelig er så gode, hvorfor er det så nødvendigt at gøre så stor en indsats for at sælge dem ? p. 133
"the industry...spends less than half as much on research and development (R&D) as on marketing and administration...The argument that it needs to charge ever-higher prices to cover its research costs is simply not true. I also show how drug companies put most of their efforts into turning out higher-priced versions of existing medicines (called "me-too" drugs) and persuading us to take more and more of them." p. ix
One that it did dispute was the contention that the industry spends much more on marketing than on R&D. However, the industry's rebuttal depended on ignoring the billions of dollars drug companies spend on "educating" doctors - expenditures that come out of their marketing budgets and are probably their most effective means of promotion." p. x
"This situation underscores the utter foolishness of Congress in creating a drug benefit that explicitly forbids Medicare from using its purchasing power to negotiate prices with drug companies.....The most serious problem drug companies face is their dwindling pipelines. They are now turning out very few innovative medicines, and that situation is growing steadily worse." p. xiii
"In 2004, Pfizer, the largest drug company, had a profit margin of nearly 22 percent of sales (which were $53 billion). The same year, it spent 32 percent of sales on marketing and administration and only 15 percent on R&D." p. xv. "According to Securities and Exchange Commission (SEC) and shareholder reports for 2001, the biggest drug companies spent on average about 35 percent of their revenues on "marketing and administration" (called by slightly different names in different companies)." p. 119 "So defined, PhRMA reported that the sum total of its members' promotional spending in 2001 came to "only" $19.1 billion - $2.7 billion for DTC ads, $5.5 billion for visits to doctors, $10.5 billion for the retail value of free samples, and about $380 million for medical journal advertising." p. 121.
"Americans now spend a staggering $200 billion a year on prescription drugs." p. xx
"As hard as it is to believe, only a handful of truly important drugs have been brought to market in recent years, and they were mostly based on taxpayer-funded research at academic institutions, small biotechnology companies, or the National Institutes of Health (NIH)." p. xxiii-xxiv
"In other words, it's not private enterprise that draws them here but the very opposite - our publicly sponsored research enterprise." p. xxv
"I saw companies begin to exercise a level of control over the way research is done that was unheard of when I first came to the journal, and the aim was clearly to load the dice to make sure their drugs looked good. As an example, companies would require researchers to compare a new drug with a placebo (sugar pill) instead of with an older drug....Sometimes companies don't allow researchers to publish their results at all if they are unfavorable to the companies' drugs." p. xxvi
"From 1960 to 1980, prescription drug sales were fairly static as a percent of U.S. gross domestic product, but from 1980 to 2000, they tripled." p. 3
"In most cases, I use data from the year 2001" p. 4
"IMS Health, estimated total worldwide sales for prescription drugs to be about $400 billion in 2002." p. 5
"The election of Ronald Reagan in 1980 was perhaps the most fundamental element in the rapid rise of big pharma...Before..You could choose to do well or you could choose to do good, but most people who had any choice in the matter thought it difficult to do both. That belief was particularly strong among scientists and other intellectuals. They could choose to live a comfortable but not luxurious life in academia hoping to do exciting cutting-edge research, or they could "sell out" to industry." p. 6
"Bayh-Dole Act, a enabled universities and small businesses to patent discoveries emanating from research sponsored by the National Institutes of Health (NIH)....Until then, taxpayer-financed discoveries were in the public domain, available to any company that wanted to use them." p. 7
"These laws mean that drug companies no longer have to rely on their own research for new drugs, and few of the large ones do. Increasingly, they rely on academia, small biotech start-up companies, and the NIH for that." p. 8
"As the entrepreneurial spirit grew during the 1990s...[o]ne of the results has been growing pro-industry bias in medical research - exactly where such bias doesn't belong." p. 8
"After exclusive marketing rights expire, copies (called generic drugs) enter the market, and the price usually falls to as little as 20 percent of what it was. There are two forms of monopoly rights - patents granted by the U.S. Patent and Trademark Office (USPTO) and exclusivity granted by the Food and Drug Administration (FDA). While related, they operate somewhat independently, almost as backups for each other. Hatch-Waxman [Act], lengthened the patent life for brand-name drugs. Since then, industry lawyers have manipulated some of its provisions to extend patents far longer than the lawmakers intended." p. 9
"The result is that the effective patent life of brand-name drugs increased from about eight years in 1980 to about fourteen years in 2000....By 1990, the industry had assumed its present contours as a business with unprecedented control over its own fortunes. For example, if it didn't like something about the FDA, the federal agency that is supposed to regulate the industry, it could change it through direct pressure or through its friends in Congress." p. 10
profit se p. 11
"The biggest single item in the budget is... something usually called "marketing and administration" - a name that varies slightly from company to company. In 1990, a staggering 36 percent of sales revenues went into this category, and that proportion remained about the same for over a decade." p. 12
"[S]ome of the top-selling drugs - with combined sales of around $35 billion a year - are scheduled to go off patent within a few years of one another. This drop over the cliff began in 2001, with the expiration of Eli Lilly's patent on its blockbuster antidepressant Prozac. In the same year, AstraZeneca lost its patent on Prilosec." p. 15
"Of the seventy-eight drugs approved by the FDA in 2002, only seventeen contained new active ingredients, and only seven of these were classified by the FDA as improvements over older drugs." p. 16-7
"The industry is also being hit with a tidal wave of government investigations and civil and criminal lawsuits. The litany of charges includes illegally overcharging Medicaid and Medicare, paying kickbacks to doctors, engaging in anticompetitive practices, colluding with generic companies to keep generic drugs off the market, illegally promoting drugs for unapproved uses, engaging in misleading direct-to-consumer advertising, and, of course, covering up evidence." p. 18-9
"The Medicare prescription drug benefit enacted in 2003, and scheduled to go into effect in 2006, promises a windfall for big pharma since it prohibits the government from negotiating prices." p. 19 - 20.
"So learning about the disease or condition is usually the beginning of the "research" part of R & D, and it can take a ong time - sometimes decades. There is no question that this is the most creative, and the least certain, part of the R & D process. Contrary to industry propaganda, it is almost always carried out at universities or government research labs, either in this country or abroad." p. 22
"Phase I entails giving the drug to a small number of usually normal volunteers to establish safe dosage levels and study its metabolism and side effects. (The exceptions are cancer and AIDS drugs, which are tested on people with the disease even in Phase I.) If the drug looks promising, it moves into Phase II, which involves as many as a few hundred patients with the relevant disease or medical condition. The drug is given at various doses, and the effects are usually compared with those in a similar group of patients not given the drug. Finally, if all goes well, Phase III clinical trials are undertaken. These evaluate the safety and effectiveness of the drug in much larger numbers of patients (hundreds to tens of thousands), and they nearly always involve a comparison group of patients." p. 27-8.
"Because there are so many more trials nowadays, and because drug companies are so eager to get them done quickly, they have shifted much of their business to new, for-profit companies set up exclusively to organize and carry out trials for the industry. These are called contract research organizations (CROs)." p. 29
"Only some of the trials are to test new drugs to get FDA approval. Many are of drugs already on the market - called "postmarketing" or "Phase IV" studies. Often these are to find new uses for old drugs to expand their markets." p. 29 "[M]any - perhaps most - are really, in the view of many critics just excuses to pay doctors to put patients on a company's already-approved drug." p.30 "To get human subjects, drug companies or contract research organizations routinely offer doctors large bounties (averaging about $7000 per patient in 2001) and sometimes bonuses for rapid enrollment." p. 30-1.
The FDA - Regulation and Reaction, p. 31 - 36
"[O]nce they are on the market, doctors may prescribe them for any use and at any dose they deem appropriate." p. 32
"[A] growing fraction of clinical trials are Phase IV studies." p. 39 (derfor nok mest reklame)
"[A] very rough estimate. If you look at the year 2000, when the industry claims to have spent $26 billion on R & D and ninety-eight drugs entered the market, the average pretax cost for each drug was, under those assumptions, no greater than $265 million, and the after-tax cost about $175 million."p. 40 "Even using PhRMA's own figures for total R & D costs for the decade of the 1990s, it can be calculated that the cost per drug came to around $100 million after taxes. That is a lot, but it's a far cry from the much-vaunted $802 million." p. 41 "The $802 million is what the authors call the "capitalized" cost - that is, it includes the estimated revenue that might have been generated if the money spent on R & D had instead been invested in the equity market." p. 44 "And there is a third problem with the estimate. It is in pretax dollars. But R & D expenses are fully tax deductible." p. 45
"[O]ver the five years 1998 through 2002 - 415 new drugs were approved - an average of 83 per year. Of those, 133 (32 percent) were new molecular entities. The others were variations of old drugs. And of those 133, only 58 were priority review drugs." p. 54
"In both 2001 and 2002, only 7 innovative drugs (that is, new molecular entities with priority review) were approved each year, as compared with 9 in 2000, 19 in 1999, and 16 in 1998." p. 55
"Most of the drugs mentioned here, even though innovative, were last-ditch treatments - rarely cures....But the real scandal is the fact that the few innovative drugs that do come to market nearly always stem from publicly supported research." p. 56
"[I]ncreasingly, that is exactly what big pharma depends on - licensed drugs, which the drug companies then market and often patent for additional uses....In other cases, the drugs are acquired [fra universiteter og anden offentlig finansieret forskning] just before they are ready to enter large-scale clinical trials." p. 57
[Taxol, f.eks.] "All of the research on the drug was conducted at, or supported by, the National Cancer Instiute over nearly thirty years, at a cost to taxpayers of $183 million." p. 58 "In 1992, after Taxol was approved by the FDA for treatment of cancer of the ovary, entirely on the basis of NIH-supported research, Bristol-Myers Squibb was given five years of exclusive marketing rights." p. 59
"Epogen, an innovative drug to treat anemia in patients with kidney failure. [Det er et] hormone produced by the kidneys that stimulates the production of red blood cells. This hormone, called erythropoietin, was discovered in 1976 by Eugene Goldwasser at the University of Chicago.... Amgen, now a giant in the industry, makes over $2 billion a year selling Epogen to the Medicare...Goldwasser never received a penny of royalties for his seminal discovery." p. 60
" Before Amgen began reaping its huge profits from Epogen, it needed to come up vith a way to stay afloat. So it licensed to J & J its rights to sell Epogen in the United States for conditions other than kidney failure (mainly cancer) and for all uses in Europe. J & J paid Amgen a lump sum of several million dollars plus the promise of future royalties. Ortho, a division of J & J, markets the drug as Procrit. Procrit's worldwide sales are estimated at nearly $3 billion annually, of which a small percentage goes to Amgen...... I learned from sources at Amgen that J &: J made essentially no contribution to the original development of erythropoietin." p. 61.
"A recent study published in the journal Health Affairs reported that, in 1998, only about 15 percent of the scientific articles cited in patent applications for clinical medicine came from industry research, while 54 percent came from academic centers." p. 64
"The NIH had selected the five top-selling dngs in 1995 (Zantac, Zovirax, Capoten, Vasotec, and Prozac) and found that sixteen of the seventeen key scientific papers leading to their discovery and development came from outside the industry....A 1997 report by the National Bureau of Economic Research found that of the twenty-one most effective drugs approved between 1965 and 1992, public research was responsible for fifteen." p. 65
"But as soon as the government transferred that intellectual property to the company, they lost all control over the pricing.", p. 67
"NIH may require that work it supports in medical schools, teaching hospitals, and small biotechnology companies not be patented but remain in the public domain. The same is true of its intramural research. Thus, the right to patent or license NIHfunded work is not automatically assured. Second, Bayh-Dole requires that work licensed to drug companies be made "available to the public on reasonable terms."....Third, work patented and licensed under the terms of Bayh-Dole must be reported to the NIH, so that the institute can track of which drugs originate in that way. If profits are very large, there is a requirement that some part of the royalties be returned to the government." p. 69
"As we saw in the last chapter, in the five years 1998 through 2002, 415 new drugs were approved by the Food and Drug Administration (FDA), of which only 14 percent were truly innovative. A further 9 percent were old drugs that had been changed in some way that made them, in the FDA's view, significant improvements. And the remaining 77 percent? Incredibly, they were all me-too drugs - classified by the agency as being no better than drugs already on the market to treat the same condition..... They [virksomhederne] do not have to show that they are more effective than (or even as effective as) what is already being used for the same condition." p. 75.
"Shortly before the patent on Prilosec was set to expire, the company got FDA approval for the newly patented Nexium. Then it launched a massive advertising campaign to persuade Prilosec users and their doctors that Nexium was somehow better. p. 77...But what you may not appreciate is the role of clinical trials. To get FDA approval for Nexium, AstraZeneca had to test it in several clinical trials. ...But note what AstraZeneca did. Instead of comparing likely equivalent doses (which would have been no more than 20 and possibly as little as 10 milligrams of Nexium, versus the standard 20-milIigram dose of Prilosec), the company used higher doses of Nexium. It compared 20 milligrams and 40 milligrams of Nexium with 20 milligrams of Prilosec. With the dice loaded in that way, Nexium looked like an improvement - but still only marginally so and in just two of the four trials." p. 79
"The original statin drug, Merck's Mevacor, came on the narket in 1987. It was a truly innovative drug, based on search in many university and government laboratories throughout the world. The potential market was huge, since the theory that high cholesterol contributes to heart disease was gaining ground and the "normal" level of cholesterol was being revised downward." p. 80.
"For instance, a statin might be tested for how well it prevented future heart attacks in patients who had already had one and then promoted as the only statin approved for that use, even though the other statins, if tested in the same kinds of patients, would likely have shown the same effects." p. 81
"Mevacor [et statin] is now sold as generic lovastatin and is therefore cheaper than the others. But the me-too business relies heavily on marketing, and as a tribute to the fact that nearly anything can be marketed and people persuaded to pay more for it, both Lipitor and Zocor, which are more expensive than lovastatin, were among the top ten drugs in the world in 2002 - but not lovastatin. Like Prilosec, Mevacor is no longer mentioned." p. 82 "Prozac lost its patent protection in August 2001 and is now sold as generic fluoxetine at about 80 percent less than it used to cost. Nevertheless, the much more expensive Paxil and Zoloft are in the top ten drugs - but not fluoxetine. Like Prilosec and Mevacor, the original Prozac is forgotten. But that doesn't mean Eli Lilly just gave up. It tried to stay in the SSRl business by patenting a weekly dosage form of Prozac. And in a move even more audacious than the switches from Prilosec to Nexium or from Claritin to Clarinex, it renamed Prozac Sarafem, colored it pink and lavender, and got FDA approval to market it for "premenstrual dysphoric disorder," its term for severe premenstrual symptoms. Same drug, same dose, but priced three and a half times higher than generic Prozac at my local pharmacy." p. 83
"Second, the market has to consist of paying customers. It doesn't help the hottom line to turn out drugs for nonpaying customers. That is why the pharmaceutical indastry is supremely uninterested in finding drugs to treat tropical diseases, like malaria or sleeping sickness or schistosomiasis (an extremely common Third World disease caused by parasitic worms).....Even some diseases that strike people in rich countries as well as poor ones, like tuberculosis, are not of great interest to big pharma, since they occur mainly in pockets of poverty." p. 84-5
"But this panel decided to recognize something it called prehypertension. This, they said, is a blood pressure between 120 over 80 and 140 over 90. Overnight, people with blood pressures in this range found they had a medical condition....Similarly, the cutoff for high cholesterol has been lowered over the years. Once it was reserved for blood cholesterol levels over 280 milligrams per deciliter. Then it was lowered to 240, and now most doctors try to knock cholesterol down to below 200." p. 85
"Similarly, most young women experience at least some premenstrual tension from time to time. Lilly's launch of Sarafem made premenstrual symptoms a disease - now called "premenstrual dysphoric disorder (PMDD)."" p. 86
"If companies find drugs unprofitable, they just stop making them.... In 2001, there were serious shortages of many important drugs, including certain anesthetics, antivenins for poisonous snakebites, steroids for premature infants, antidotes for certain drug overdoses, an anticlotting drug for hemophilia [???, OJ,] an injectable drug used in cardiac resuscitation, an antibiotic for gonorrhea, a drug to induce labor in childbirth, and vaccines against flu and pneumonia in adults." p. 91
"Perhaps the worst shortages are of childhood vaccines. In 2000, the supply of the combined vaccine against diphtheria, tetanus, and whooping cough was so short that the U.S. Centers for Disease Control (CDC) recommended that infants receive only the first three of the five recommended doses. Booster shots were eliminated. The agency also suggested deferral of the second dose of the measles, munps, and German measles vaccine and of the chickenpox vaccine. While those shortages have eased somewhat, so that the CDC recommended resumption of the usual schedule in late 2002, the situation remains precarious because fewer drug companies are bothering to make vaccines. There are now just four such companies, compared with about four times that many twenty years ago." p. 92
"The results, reported in 2002 in The Journal of the American Medical Association, were startling. To nearly evtryone's surprise, the old-time diuretic turned out to be just as good for lowering blood pressure, and actually better better for preventing some of the devastating complications of high blood pressure mainly heart disease and strokes." p. 96
"But in addition, drug companies now have considerable control over the way the research is carried out and reported. That is new. Until the 1980s....They certainly did not attempt to tell the researchers how to run their clinical trials. Now, however, companies are involved in every detail of the research from design of the study through analysis of the data to the decision whether to publish the results. That involvement has nade bias not only possible but extremely likely. Researchers don't control clinical trials anymore; sponsors do." p. 100
"Sponsoring companies keep the data, and in multicenter trials, they may not even let the researchers themselves see all of it. They also analyze and interpret the results, and decide what, if anything, should be published." p. 102 - 103
"[David] Willman [in the Los Angeles Times] found that senior NIH scientists (who are among the highest paid employees in the government) routinely supplement their income by accepting large consulting fees and stock options from drug companies that have dealings with the institutes. At one time, most of these kinds of connections would have been prohibited, but in 1995, the then director of the institutes, Harold Varmus, with a stroke of the pen, lifted the restrictions." p. 104
"Moreover, the NIH did not even require most senior scientists to file public disclosures of their outside income." p. 105
"One of the most common ways to bias trials is to present only part of the data - the part that makes the product look good - and ignore the rest. That happened in a clinical trial of the arthritis drug Celebrex. A study sponsored by the drug company that makes it, Pharmacia (since acquired by Pfizer), ostensibly showed that Celebrex caused fewer side effects than two older arthritis drugs. These results were published, along with a favorable editorial, in The journal of the American Medical Association. Not until after publication did the editors learn that the results were based on only the first six months of a yearlong trial. When the entire trial was analyzed, there was no advantage to Celebrex." p. 108 - 9
"When a drug company applies to the FDA for approval of a new drug, it is required to submit results from every one of the clinical trials it has sponsored. But it is not required to publish them." p. 111 - 2.
"[A] recent study ... obtained FDA reviews of every placebo-controlled clinical trial submitted for initial approval of the six most widely used antidepressant drugs approved between 1987 and 1999....Their findings were sobering. On average, placebos were 80 percent as effective as the drugs." p. 112 - 3.
"But now a large NIH clinical trial indicates that, instead of preventing heart disease, combination hormone replacement actually increases it." p. 113
"IN 2001, DRUG COMPANIES GAVE DOCtors nearly $11 billion worth of "free samples." These were almost always the newest, most expensive me-too drugs.....The same year, drug companies sent some 88,000 sales representatives around to doctors' offices to hand out the free samples, plus lots of personal gifts, and talk up company products." p. 115
"In fact, to watch the 2004 Super Bowl was to wonder whether football causes erectile dysfunction." p. 116
"A new type of stealth ad consists of celebrities apparently spontaneously talking about health ailments on news or entertainment shows in the course of an ordinary interview." p. 117
"[D]rug companies are even more secretive about their marketing expenditures than they are about their research and development costs." p. 118
"Until 1997, drug companies didn't advertise much on television, because the Food and Drug Administration (FDA), which has jurisdiction over all prescription drug advertising, required them to include full information about side effects in their ads." p. 123 [Min fremhævelse, OJ].
""Christma! trees. Free tickets to a Washington Redskins game, with a champagne reception thrown in. A family vacation in Hawaii. And wads of cash. Such gifts would trigger a big red 'bribery' alert in the mind of just about any public official or government contractor. But not, it seems, in the minds of many doctors. They , have been raking in jaw-dropping gifts from pharmaceutical firms battling to give their products an edge in an increasingly competive market." p. 128
"Prescription-tracking companies buy information from big pharmacy chains about doctors' prescribing habits and sell it to drug companies. Using these physician profiles, drug reps know exactly what a doctor prescribes before each visit, so they can tailor their sales pitch and make every minute count." p. 129 - 130
"It is crucial for big pharma to maintain the fiction that these expenditures are for education, not promotion, because by doing so it can evade legal constraints on its marketing activities...... First, it is illegal for drug companies to market drugs for unapproved uses....Doctors, however, are not constrained by this law. They are permitted to prescribe drugs for whatever uses they want.....in most states doctors a required to receive continuing medical education (CME) throughout their professional lives to maintain their licenses. ...."Medical education is a powerful tool that can deliver your message to key audiences, and get those audiences to take action that benefits your product."" p. 138 - 9
"Another form of marketing disguised as education is the sponsorship of patient advocacy groups." p. 151
"It is much harder to excuse the medical profession and its institutions and organizations. Medical education worthy of the name requires an impartial analysis of all the available evidence, led by experts who have no vested interest in the drugs they are discussing." p. 154
"Alternatively, you could simply market the drug for unapproved ("off-label") uses - despite the fact that doing so is illegal. You do that by carrying out "research" that falls way below the standard required for FDA approval, then "educating" doctors about any favorable results." p. 157
"There are two legitimate reasons for Phase IV studies. The first is to see whether a drug is effective for an additional use....The second legitimate reason for Phase IV trials is to look for side effects or other properties of the drug that were missed in the earlier clinical trials. Even large, well-designed Phase III trials may not reveal side effects if they are very rare or no one thought to look for them." p. 161 - 162 [min fremhævelse, OJ].
"As a condition of accelerated approval, and sometimes even with regular approval, the FDA requires companies to conduct Phase IV confirmatory studies just to make sure the new drug is safe. In fact, about two-thirds of all new molecular entities approved in 2000 were supposed to undergo Phase IV studies." p. 162-3.
"The most common Phase IV trials are so-called surveillance studies. Here sponsors pay doctors to put patients on drugs and answer a few simple questions about how they fared. There is no randomization and no comparison group, so it is usually impossible to draw any reliable conclusions." p. 163
"One of the more convoluted examples of research that at least in part serves marketing purposes is the story of Eli Lilly's drug Xigris. In 2001, Xigris was approved to treat severe sepsis, blood-borne infections that are a common cause of death in intensive care units (ICUs). Its approval was not a sure thing. In the key clinical trial submitted to the FDA, 25 percent of patients taking Xigris died, compared with 31 percent of those on standard treatment. That is not a big difference, although it was statistically significant....But because of the high cost, many hospitals decided that the drug was not worth it. They could get more bang for the buck, they thought, by putting that money to other uses....The idea [of Lilly] was not to do more research on the drug's effectiveness but instead to do research on whether ICU patients were generally being deprived of treatments because of cost." p.167
"Lilly also managed to get a new federal diagnostic code for severe sepsis, so that the incidence could be tracked....Centers for Medicare & Medicaid Services [agreed] to reimburse half the charge for Xigris, up to $3400 a treatment. That kind of deal is unheard of. The standard way Medicare reimburses hospitals is according to the diagnosis - so much for aheart attack, so much for a stroke, so much for pneumonia, and so forth....The Xigris story shows how throwing money at academics can shift the focus from where it should be in this case - the exorbitant price of a drug of uncertain effectiveness - to the ethics of rationing" p. 168
"The FDA asked Lilly to conduct Phase IV commitment studies to elucidate further the risks and benefits. One would hope the company is as keen on doing those studies as on demonstrating rationing in ICUs, but somehow I doubt it." p.169
"This conclusion was underscored by a large trial sponsored by the National Institutes of Health of ways to prevent adult-onset diabetes in people at high risk for the disease. One group in the trial received placebo, and 29 percent of patients in that group developed diabetes over a three-year period. The second group received a drug called metformin (the generic form o Bristol-Myers Squibb's blockbuster Glucophage), and they did somewhat better - 22 percent developed diabetes. But the third group did much better than either of the other two. They were placed on a moderate diet and exercise program, and only 14 percent got diabetes. In other words, diet and exercise were better than the drug." p. 170
"For all the talk about free enterprise, the pharmaceutical industry's lifeblood is government-conferred monopolies - in the form of patents granted by the U.S. Patent and Trademark Office (USPTO) and exclusive marketing rights granted by the Food and Drug Administration (FDA)." p. 173
"There are several types of patents, but the one that applies to prescription drugs has a term of twenty years from the date the application is filed with the USPTO." p. 175
Kap. 10, Patent Games Stretching Out Monopolies handler om de mange kneb, der bruges for at forlænge den periode, hvor firmaet har monopol.
"Accordingly, the law greatly simplified the FDA approval process for generic companies. No longer did they have to test their drugs in clinical trials. All they had to do was show the FDA that their drugs contained the same active ingredients as the brand-name drugs they copied (called the "pioneer" drugf and acted in the same way in the body - that is, they were "bioequivalent." That made sense. After all, brand-name drugs have already been tested in clinical trials. Why do it again? That part of Hatch-Waxman has worked well." p. 179
"While it was meant to stimulate generic competition, it has often had exactly the opposite effect. Since then, brand-name drug companies routinely file not just one patent on their blockbusters but a series of them spread throughout the life of the first one." p. 180
"In accord with 1994 international trade agreements, Congress increased the basic patent term from seventeen years after issuance to twenty years after filing - which is usually longer." p. 182
"And the company had one more trick up its sleeve. When the string was finally running out, it petitioned the FDA to convert Prilosec from a prescription drug to an over-the-counter OTC) product. That was a very shrewd maneuver. According to Hatch-Waxman, switching from prescription to OTC status can buy another three years of exclusivity if it is accompanied by some minimal testing, mainly to show that consumers can understand the instructions for using the drug." p. 185
"Claritin was patented by Schering-Plough in 1981 but not approved by the FDA until 1993 - after much scientific controversy about whether it is any better than a placebo at the low doses necessary to prevent drowsiness." p. 186
". In sum, the FTC found evidence that Hatch-Waxman is regularly exploited to prevent generic competition, and it has taken antitrust action against several brand-name and generic drug companies that colluded to keep generic drugs off the market. It also criticized the use of bogus "citizen petitions" to slow the approval of generic drugs. Finally, it suggested changes to Hatch-Waxman that would curb the abuse - including limiting drug companies to one thirty-month stay per drug and prohibiting agreements between brand-name and generic companies to delay the entrance of generic drugs to market." p. 191
"But look at what Congress did. They passed a bill that explicitly prohibits Medicare from using its enormous purchasing power to bargain for low prices." p. 194
"The pharmaceutical industry has by far the largest lobby in Washington - and that's saying something. In 2002 it employed 675 lobbyists (more than one for each member of Congress) many drawn from 138 Washington lobbying firms - at a cost of over $91 million." p. 198
"Even without the political contributions (which I will describe next), this revolving door between government and lobbyists guarantees that the industry will have attentive and sympathetic ears in Washington." p. 199
"Defense Secretary Donald Rumsfeld was CEO, president, and chairman of G. D. Searle, a major drug firm that merged with Pharmacia, which in turn was bought by Pfizer." p.202
"In 1987, under industry pressure, Congress passed a law that prohibits anyone but the manufacturer from importing prescription drugs from another country - even if the drugs were made in the United States." p. 203
"...as many as half of all prescriptions are written for off-label uses." p. 204
"Both the Clinton and Bush administrations carried water for the pharmaceutical industry when Third World countries complained that big pharma was pricing HIV/AIDS drugs out of reach. When the World Trade Organization was formed in 1995, members were required to honor twenty-year patents on drugs. At the time, many countries did not even consider drugs patentable." p. 206
"A few drug companies, also embarrassed, announced they would lower prices in parts of Africa, but the reality appears to have fallen far short of the promises." p. 206
"Later, the Bush administration stood alone among 143 World Trade Organization countries in opposing the relaxation of patent protection in the Third World. The United States would agree only to permit poor countries to manufacture their own generic drugs for a limited number of diseases, not to import them. Since the poorest countries that most need drugs are least able to set up manufacturing plants, that was an empty concession. But more developed countries like India and Brazil, the likely producers of generics, would not risk economic retaliation by defying the United States....As if to underscore that impression, the administration, as of early 2004, has refused to allow any of the promised $15 billion in federal funds allotted for HIV/AIDS treatment in the Third World to be spent on generic drugs...In late 2003, South Africa's Competition Commission ruled that GlaxoSmithKline (the major manufacturer of AIDS drugs) and another company had violated the country's Competition Act by charging excessively high prices and refusing to license their patents to generic manufacturers in return for reasonable royalties. Following that ruling, Glaxo agreed to permit four generic companies in South Africa to make three of its AIDS drugs and sell them in all forty-seven sub-Saharan African countries. AIDS treatment now sells for as little as $300 a year in Africa, compared with more than $10,000 in the United States." p. 207-8
"Indeed, over the decade since the Prescription Drug User Fee Act was enacted, a record thirteen prescription drugs have had to be withdrawn from the market - after they caused hundreds of deaths." p. 209
"USA Today examined FDA hearing records in 2000 and found that "at 92 percent of the meetings at least one member had a financial conflict of interest," and "at 55 percent of metings, half or more of the FDA advisers had conflicts of interest." p. 210
"Perhaps the most arrogant allotment was $1 million "to change the Canadian health care system" [Det drejer sig om bevillinger fra PhRMA i henhold til et hemmeligt dokument refereret af New York Times i 2003] p. 215
"The United States is the only developed nation that does not regulate drug prices. All the others - Australia, Canada, France, Germany, Italy, Japan, the Netherlands, Spain, Switzerland, Sweden, Britain, and so on - do." p. 219
"The Prescription Access Litigation Project, for example, is an alliance of seventy consumer groups that has filed suits against more than twenty drug companies. Plaintiffs' attorneys skilled in class actions in the wake of their successes in asbestos and tobacco cases are today setting their sights on drug companies." p. 231
"But instead of passing these savings along to health plans and consumers, as they are contractually bound to do, the PBMs pocket them....In April 2004, Medco paid $29.3 million to settle state and federal complaints that it violated consumer protection and mail fraud laws by switching patients to drugs that added costs for patients and their health plans....Some of the fines and settlements in cases against big pharma have been enormous. Between 2000 and 2003, according to Michael Loucks, chief of the Health Care Fraud Unit in the U.S. Attorney's Office for the District of Massachusetts, eight companies paid out a total of $2.2 billion in fines and settlements" p. 232.
"In general, companies are only too willing to settle cases rather than risk being convicted of a felony and perhaps barred from Medicare and Medicaid." p. 233
"The very worst problem facing big pharma is its dwindling pipeline. Coupled with the cluster of patent expirations since 2001 on many of its biggest blockbusters, and new pressures to modulate prices, this problem may create a major disaster for the industry. And remember, this situation is not just a matter of bad luck. It is the result of a deliberate strategy to leave the risky research to others and concentrate on turning out me-too p drugs....Over the four years beginning in 2000, there were just 32 innovative drugs out of a total of 314 approved drugs. Even in this small collection, only seven came from the top ten U.S. drug companies." p. 234
Problems:
"1. Drug companies produce too many me-too drugs and too few innovative ones. (See Chapters 4 and 5.)
2. The Food and Drug Administration (FDA) is too much in the thrall of the industry it regulates. (Chapter 11)
3. Drug companies have too much control over clinical research on their own products. (Chapters 6 and 9)
4. Patents and other exclusive marketing rights are undesirably long and too elastic. (Chapter 10)
5. Drug companies have too much influence over medical education about their own products. (Chapter 8)
6. Important information about research and development, marketing, and pricing is kept secret. (Chapters 1, 3, and 7)
Prices are too high and too variable. (Chapters 1 and 12)" p. 239
"Courts have progressively weakened the requirement that new discoveries or inventions be useful, novel, and non-obvious....Food and Drug Administration regulations should require that new drugs be compared not just with placebos but with old drugs for the same conditions. Approval should depend on vhether the new drug adds something useful in terms of greater effectiveness, greater safety, fewer side effects, or substantially greater convenience." p. 240
"If there is really doubt about whether a standard treatment is effective, the FDA should require that clinical trials of new treatments have three comparison groups - new drug, old drug, and placebo." p. 241
"First, the Prescription Drug User Fee Act should be repealed - or allowed to expire in 2007. This act, you will remember, authorizes drug companies to pay "user fees" to the FDA for every drug reviewed. That practice puts the FDA on the industry's payroll, drug by drug. The more drugs the agency reviews, the more money it gets from industry.....Moreover, the very notion that private companies "use" a public regulatory agency is wrong, since the FDA is there to serve the public, not drug companies." p. 243
"Third, the FDA's advisory committees should not include experts with financial ties to industry." p. 244
"To ensure that clinical trials serve a genuine medical need and to see that they are properly designed, conducted, and reported, I propose that an Institute for Prescription Drug Trials he established within the National Institutes of Health (NIH) to administer clinical trials of prescription drugs....The institute would then contract with independent researchers in academic medical centers to conduct drug trials. The researchers would design the trials, analyze the data, write the papers, and decide about publication." p. 245
"This is not a perfect process, and there may be better alternatives, but the point is that an independent, public agency should administer all clinical trials to ensure that they are properly conducted - both scientifically and ethically. This is too important a matter to leave to private contract research organizations, whose only clients are the drug companies....To receive funding, academic institutions should not have equity interest in the pharmaceutical industry, and researchers should have no financial ties to companies whose drugs they evaluate. Similarly, expert advisers to the Institute for Prescription Drug Trials should have no conflicts of interest....The period of exclusivity for brand-name drugs is too long and too easily stretched.....Paradoxically, the first reform I would suggest to curb monopoly marketing rights allows drug companies more time to complete their clinical trials. I propose that even if patents are granted before clinical testing starts, the clock on the patents should not begin ticking until the drugs come to market. In other words, a company could patent a new drug before launching clinical trials to protect it from competition." p. 246-7
"There is no reason for a thirty-month stay on generic companies entering the market just because brand-name companies sue them. Even if a brand-name company genuinely believes hat a relevant patent would be violated, it could sue the generic company without an automatic extension of exclusive marketing rights." p. 249
"We need to end the fiction that big pharma provides medical education.....Good education about prescription drugs, like all education, needs to be as objective and critical as possible." p. 250.
"First, medical schools should teach students about drugs, not leave such education to industry-sponsored programs and teaching materials.....Second, teaching hospitals should regard drug company representatives just as they do other salespeople...Just as there should be no private clinical research industry, there should be no private medical education industry hired by the drug companies." p. 251
"Because of these special favors and the importance of its products to public health, as well as the fact that government is a major purchaser of its products, the pharmaceutical industry should be regarded much as a public utility. Its books should be open." p. 253
"At the time it was withdrawn, an estimated two million people took Vioxx, and it had yearly sales of $2.5 billion dollars." p. 265
"In late 1998 and early 1999, Celebrex and then Vioxx were approved by the FDA. They were given rapid "priority" reviews - which you will recall means they were seen as likely to be improvements over drugs already sold to treat arthritis pain. Was that warranted? Neither drug was ever shown to be any better for pain relief than over-the-counter remedies like aspirin or ibuprofen (Advil) or naproxen (Aleve). But theory predicted that COX-2 inhibitors would he easier on the stomach, and that was the reason for the enthusiasm. As it turned out, though, only Vioxx was shown to reduce the rate of gastrointestinal problems like bleeding ulcers, and then mainly in people already prone to these problems (a small fraction of users).....In this book, I discussed the conflicts of interest that permeate the FDA, including the fact that many members of FDA advisory committees are paid consultants for drug companies. Although they are supposed to excuse themselves from decisions when they have a financial connection with the company that makes the drug in question, that rule is regularly waived. With that in mind, I checked the minutes of the 1999 advisory :ommittee meeting that led to the approval of Vioxx. Sure enough, four of the six members, including the chairman. needed waivers because they had a "potential for a conflict of interest."' p. 268-9
"As is often the case, these ten conflicted members were not disqualified. And as it turned out, they voted nine to one in favor of Vioxx and Bextra. Without their votes, the panel would have recommended that these two COX-2 inhibitors be removed from the market." p. 270 (2005).
"In 2000, a company-sponsored trial...called the Vioxx Gastrointestinal Outcomes Research, or VIGOR, trial .... it was intended to show that Vioxx was easier on the stomach than naproxen. In terms of pain relief, the drugs proved to be the same, but those taking Vioxx had only half the risk of serious gastrointestinal problems. Unfortunately, the study also showed at least a fourfold increase in the risk of heart attacks." p. 270-1
"What Merck should have done after it got the results of the VIGOR trial is immediately launch a large enough dinical trial to investigate the cardiovascular risks rapidly....Note that the costs of even a very large clinical trial would almost certainly lave been less than what the company spent on ads." p. 271
"Less explicable is the dereliction of the FDA. If Merck didn't want to launch a study of the cardiovascular effects of Vioxx (and it had nothing to gain by doing so), why didn't the FDA insist on it?" p. 272-3
Orla Jordal, 2007
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