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A Skeptic’s View of Pharmaceutical Progress

Reynold Spector

Volume 34.4, July / August 2010

To obtain a balanced view of pharmaceutical progress (or lack thereof), we need to step back, define a few terms and concepts, and make explicit certain assumptions.

In the late 1980s and early 1990s, one pharmaceutical company was named the world’s “most admired” company by Fortune magazine seven years in a row. During those years, the pharmaceutical industry was widely recognized for its integrity and productivity. What more noble activity is there than curing or preventing disease? Much of the progress in the pharmaceutical industry was based on foundational biological science performed by academicians and government scientists.

However, for the last ten years, there has been intense criticism of the research pharmaceutical industry over questionable practices (see table 1) (Angell 2004, 2008; Relman 2008; Steinbrook 2009). Although the industry argues that many of these practices are actually positive (e.g., direct-to-consumer advertising “educates” the public), the consensus of those outside the pharmaceutical industry is that these practices are, on balance, harmful. In fact, although there are many well-documented flagrant examples in newspapers, magazines, and books, it is extremely difficult to obtain quantitative data on the frequency of these practices. However, in general, I agree with these criticisms (see table 1). The industry has also been criticized for the lack of research and development productivity considering the amount of money spent.

But to obtain a balanced view of pharmaceutical progress (or lack thereof), we need to step back, define a few terms and concepts, and make explicit certain assumptions. Only then can we evaluate the “good” done by new pharmaceutical products over the last thirty years versus the abuses in table 1. I will refer to drugs by their chemical names and use generic (off patent) examples as much as possible, since generics are generally much cheaper and in many cases as good as or better than brand name drugs in their class.

Obviously, pharmaceutical agents, including vaccines, should prolong life or significantly decrease clinical disease and its attendant pain and suffering with minimal or no side effects. In other words, the risk/benefit ratio should favor the patient and the costs should be reasonable.

Generally, in thinking about prevention and treatment, we divide prevention of disease into two categories: primary and secondary. Primary prevention is treatment in high-risk persons to prevent disease; secondary prevention is treatment to prevent further disease. Examples of primary prevention are vaccines to prevent disease or the use of a now generic statin (e.g., simva­statin) to prevent heart attacks and strokes in high-risk persons. With simvastatin, secondary prevention would prevent deaths and further heart attacks and/or strokes in patients with previous episodes (see below). Treatment is the use of drugs to ameliorate disease—sometimes with a curative intent.

To prove the value of preventatives (including vaccines) and treatments, the European Medicines Agency and the U.S. FDA have rigorous “gold standard” criteria discussed in the Method­ological and Statistical section of a recent article in the Skeptical Inquirer and other publications (Spector 2009; Spector and Vesell 2006a). Generally, this involves doing two large (i.e., thousands of patients) randomized blinded trials of the drug versus a placebo (or comparator agent) that both show statistically significant results (Spector and Vesell 2006a). These studies are carried out after dose-finding studies in which the correct dose is determined. Ideally, the endpoint of such trials should be the number of deaths or events (e.g., heart attacks), but sometimes surrogate markers are accepted (e.g., lowering blood pressure or cholesterol) (Spector and Vesell 2006a).

Implicit in these standards is the definition of an ideal drug or vaccine (see table 2) (Spector 2002). Note that ideal drugs and vaccines must also stand the “test of time.” Table 3 shows examples of ideal (or near ideal) drugs discovered, developed, and marketed in the last thirty years. There is now nearly universal agreement (because of the large number of controlled trials) that moderate doses of statins not only lower blood cholesterol but substantially decrease death (secondary prevention) by about 30 percent and heart attacks and strokes by 30 to 50 percent (Scandinavian Simvastatin Survival Study [4S] 1994). To show the quantitative importance of these results, based on data from the 4S trial in patients with stable heart disease or angina, 12 percent died on placebo and only 8 percent died on simvastatin in five years. This 4 percentage point differential (assuming there are ten million U.S. patients with stable coronary heart disease [CHD], a conservative estimate, who took simvastatin) amounts to four hundred thousand fewer deaths due to the drug in five years. Aspirin, beta-blockers, and angiotensin converting enzyme (ACE) inhibitors or sartans (see below) each save about 5 to 15 percent of lives in such patients. When statins are appropriately combined with these drugs, there is probably about a 50 percent improvement in survival, or six hundred thousand lives (per ten million) saved in CHD patients over five years (Baker et al. 2009). In primary prevention, statins decrease heart attacks, strokes, and procedures by 20 to 50 percent depending on the population (Baigent et al. 2005; Brugts et al. 2009). The side effects and cost of moderate doses of statins (now generic) are generally not issues. Notwithstanding these impressive results, there is obviously more work to be done.

The now generic ACE inhibitors and the newer sartans effectively lower blood pressure with minimal side effects and decrease strokes, heart failure, and kidney damage (see table 3) (Spector and Vesell 2006b).

Proton pump inhibitors (PPI), which block stomach acid secretion, have had a huge impact on common stomach and esophageal disorders—disorders, in large part, due to stomach acid—including dyspepsia, ulcer, gastritis, and esophagitis due to acid reflux. Moreover, stomach operations for the complications of stomach and duodenal ulceration (perforation, obstruction, bleeding, and intractable pain) since the marketing of histamine blockers and especially PPI have decreased dramatically. Millions of Americans with these problems have been cured or have had their symptoms controlled with a safe daily pill or two—and no surgery (Spector and Vesell 2006c). Helicobacter pylori, a bacterium that often plays a contributory role in stomach ulceration, is also eliminable with antibiotics (Spector and Vesell 2006c). (This latter work led to a Nobel Prize.)

Certain newer antibacterial agents, including penems and ceftriaxone, save lives with minimal side effects. The penems have a very broad spectrum and kill bacteria (i.e., they are bacteriocidal). Similarly, ceftriaxone is generally bacteriocidal and needs to be given parenterally (i.e., by injection) only once daily—thus allowing for outpatient therapy of serious bacterial infections.

The vaccines listed in table 3, marketed over the last thirty years, are remarkably effective and safe. These vaccines are over 95 percent effective in preventing clinically significant disease (Offit 2008). One exception is the varicella vaccine, after which mild cases can still occur.

Finally, table 3 contains three examples of cancer chemo-preventatives. Hepatitis B, which in the past has infected hundreds of millions of people, can be eliminated by vaccination, with an attendant decline in liver cancer—a consequence of chronic hepatitis B infection (Offit 2008). Similarly, the current papilloma virus vaccines prevent infection with virus types 16 and 18, reducing cervical cancer in women by about 70 percent. And 5-alpha-reductase inhibitors can decrease cancer of the prostate by about 20 percent. These three examples are one of the few bright spots in the war on cancer (see below).

Examples of moderately useful drugs are shown in table 4. Before the mid-1990s, there were no useful, nonhormonal drugs for the treatment and prevention of osteoporosis and fractures—a huge clinical problem. Now, bisphosphonates can prevent approximately 50 percent of vertebral fractures and 25 percent of hip fractures—a good but obviously imperfect result. Moreover, they can be taken orally once weekly, once monthly, or intravenously once yearly (Spector and Vesell 2006b).

The new calcium channel blockers are effective agents in the treatment of high blood pressure but cause edema (swelling) in 5 to 15 percent of users. They do, however, prevent strokes, renal damage, and heart failure more than placebo.

The H-2 histamine blockers inhibit histamine-stimulated acid production by the stomach but are not as effective as the PPI discussed in table 2. However, for the treatment of milder acid-induced stomach disorders (heartburn, dyspepsia, esophageal reflux), they are useful, safe, and very inexpensive.

The tumor necrosis factor alpha (TNF a) blockers are the first of the biotechnology drugs useful in crippling rheumatoid arthritis (RA) and psoriasis. However, they have substantial and serious side effects, placing some patients at risk of severe infectious diseases. Their ability to slow or stop the relentless progression of RA puts the risk/benefit ratio in most patients’ favor, but these patented drugs are also expensive.

Finally, the SSRIs (see table 4) have a complex developmental history in the treatment of depression and generalized anxiety, but what is now clear is that the SSRIs are barely better than placebo in patients with mild depression (Mayer 2008). In severe depression, however, they are unequivocally useful with acceptable side effects. Severe depression is a devastating disease that ruins lives and can lead to suicide and other dire consequences. The SSRIs are helpful in these patients but by no means generally curative (Mayer 2008).

The three vaccines listed in table 4 (which were developed in the last twenty years) prevent shingles, childhood pneumococcal infections, and influenza, respectively, in 25 to 75 percent of vaccinated subjects. Specifically, the shingles vaccine prevents 75 percent of severe cases of shingles and 50 percent of total cases. Severe cases of shingles can affect the eye, causing terrible pain and damage to the cornea with loss of vision; more commonly, shingles can cause a severe chronic pain syndrome in the affected area that, on occasion, can drive people to suicide. The problem with the influenza vaccine is that it is formulated and manufactured before the flu season and thus sometimes the current formulation is ineffective against the current strain (compare the unexpected outbreak of “swine” flu in 2009).

Shown in table 5 are examples of FDA-approved drugs that are barely better than placebo on the average (P<.05 in two studies, although there were also negative studies) (Spector and Vesell 2002; 2006a). For example, loratadine is about 12 percent better than placebo (on the average) in relieving symptoms of allergic rhinitis; montelukast is even worse (about 6 percent), according to the company’s own label. To me, it seems outrageous to pay around $3 for a tablet of montelukast for a 6 percent chance of effect, when safe generic drugs yield a 20 to 60 percent response and are cheaper. In my view, the wide use of montelukast for allergic rhinitis is an example of the power of noncomparative direct-to-consumer advertising (see table 1). Similarly, 4 mg of tolteradine daily (for overactive bladder) gives (net of placebo) a less than 10 percent decrease in trips to the bathroom (micturations) and a less than 20 percent decrease in “accidents” (incontinence). Tol­teradine also has side effects (e.g., dry mouth, urinary retention) and contraindications to its use. Finally, tacrine is liver-toxic, and it has never been established that tacrine has clinical utility.

I would place many of the newer cancer drugs, especially the biotechnology agents, in table 5. In fact, in a recent thoughtful analysis of cancer therapy, Gina Kolata (2009) of The New York Times pointed out the minimal progress (with a few notable exceptions, like the treatment of chronic myelogenous leukemia with Gleevac) in the “war against cancer.” She points out that we are only 5 percent better off today than we were in 1950, notwithstanding billions of dollars spent on cancer research and treatments. Alas, there has been little progress against the major cancers (e.g., lung, stomach, pancreas, brain, breast, renal, etc.) when surgeons cannot totally remove it. (For more, see Kolata’s piece and my article “The War on Cancer: A Progress Report for Skeptics,” SI, January/February 2010.) This is in stark contrast to the tremendous progress against heart disease and stroke.

Discussion

As a society, where should we go from here with the problems outlined in table 1? Notwithstanding the hundreds of articles and books (see, for example, Angell’s work in 2004 and 2008), as noted above, it is difficult to assess quantitatively the magnitude of the questionable practices in table 1. In fact, though we have all seen fancy mainstream drug advertising that contains no quantitative data (e.g., how much improvement there is on the average) or important comparative data (e.g., in allergic rhinitis ads), there are some advertisements that are accurate and informative. But clearly misleading direct-to-consumer ads should be stopped.

There is also no doubt that some companies have flagrantly covered up negative data. In some cases, after being “caught” the companies paid hundreds of millions of dollars in fines or, in one recent case, settled with harmed patients for $5 billion (Singer 2009).

Almost everyone outside the industry feels an excessive amount of money is spent on misleading advertising—especially for drugs like those in table 5 that would not “sell themselves.” Also, the use of ghost writers and excessive payments to thought leaders, florid conflicts of interest, and payments to practicing physicians to encourage specific drug use clearly occur (see table 1). These practices should be outlawed (Stein­brook 2009).

Finally, scientifically worthless seeding studies (i.e., studies that do not test a hypothesis but are meant to familiarize physicians with the drug with the intent of increasing sales) may be on the wane, as is publishing only positive data and encouraging biased talks and literature. The press, academicians, journals, and public have wisely cracked down and lampooned such practices endlessly.

However, I submit that incredible good has been done by the drugs and vaccines in tables 3 and 4 (and many others not mentioned because of space limitations, like erythropoetin for certain types of anemia). As I discussed above, generic statins, ACE inhibitors, beta-blockers, and aspirin used in patients with coronary heart disease (CHD) save hundreds of thousands of lives yearly worldwide. Moreover, these drugs, when used optimally in patients with stable CHD, are as effective as invasive surgical procedures (e.g., coronary artery stenting) in most patients (Boden et al. 2007). Great progress against fatal heart disease (64 percent decline since 1950) and fatal stroke (74 percent decline since 1950) has been made in the face of increasing obesity and diabetes mellitus—two problems that exacerbate CHD and stroke (Kolata 2009). The drugs in table 3 and old drugs like beta-blockers and aspirin have made these tremendous advances possible.

The vaccines in table 3 basically eliminate the diseases (primary prevention) at which they are aimed. The harm done by hepatitis B alone—in the hundreds of millions—is now in principle eliminable with universal vaccination (Offit 2008). Hepatitis B is often a dreadful clinical problem and, as noted above, can lead to liver cancer (Offit 2008).

However, the failed war on cancer (Kolata 2009) and the lack of progress against Alzheimer’s and Parkinson’s diseases and many other chronic disabling diseases, unlike the tremendous progress made against heart disease and stroke, are very discouraging.

I would note that the drugs and vaccines in table 4, al­though not ideal, are also very useful; the risk/benefit ratio is clearly in the patient’s favor.

We should encourage the discovery and development of drugs and vaccines like those in table 3—especially against unsolved medical problems like cancer and Alzheimer’s and Parkinson’s diseases. Equally important, we should bridle or stop the abuses in table 1 and demand honest advertising of the drugs in table 5 (i.e., quantitative differences from placebo and comparative efficacy results). The abuses in table 1 could be eliminated by the combined and concerted efforts of the FDA, Securities and Exchange Commission, universities, journals, and medical societies. The FDA should also allow easier access to unpublished negative studies, as has been done with antidepressants (SSRI), allowing their “true efficacy” to be calculated (Mayer 2008).

Finally, the old saw that efficacy data must be clinically im­por­tant and not just statistically significant (Spector and Vesell 2006a; Spector 2009) must never be forgotten. Unbiased and objective experts, beholden to the public good, should discourage the pharmaceutical industry from marketing drugs that are statistically better than placebo but have no clinically meaningful efficacy. The FDA does not do this; they approve drugs but do not generally make comparative judgments.

In summary, over the past thirty years the pharmaceutical industry has made tremendous progress leading to greatly improved health and longer life spans with a substantial and correct focus on primary and secondary prevention, not just treatment, notwithstanding its failures (e.g., against cancer, Alzheimer’s and Parkinson’s diseases). In my view the future is bright with the steady march of new scientific progress. The problems in table 1 need work, but the solutions are obvious and should be relatively easily corrected. l

Acknowledgments

I wish to thank Michiko Spector for her help in the preparation of this manuscript.

References

Angell, M. 2004. The Truth about the Drug Companies: How They Deceive Us and What to Do About It. New York: Random House.

———. 2008. Industry-sponsored clinical research: A broken system. Journal of the American Medical Association 300: 1069–1071.

Baigent, C., et al. 2005. Cholesterol Treatment Trailists’ (CTT) collaboration. The Lancet 366: 1267–1278.

Baker, W.L., et al. 2009. Systematic review: Comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II–receptor blockers for ischemic heart disease. Annals of Internal Medicine 151: 861–871.

Brugts, J.J., et al. 2009. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: Meta-analysis of randomized controlled trials. British Medical Journal 338(301): b2376, June 30.

Boden, W.E., et al. 2007. Optimal medical therapy with or without PCI for stable coronary disease. New England Journal of Medicine 356: 1503–1516.

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Scandinavian Simvastatin Survival Study Group. 1994. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease (4S). The Lancet 344: 1383–1389.

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———. 2009. Science and pseudoscience in adult nutrition and practice. Skeptical Inquirer 33(3) (May/June): 35–41.

———. 2010. The war on cancer: A progress report for skeptics. Skeptical Inquirer 34(1) (January/February): 25–31.

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Reynold Spector

Reynold Spector, MD has served as a professor of medicine (and pharmacology and/or biochemistry) at Iowa, Stanford, and Harvard-MIT. He is currently clinical professor of medicine at the Robert Wood Johnson Medical School (New Jersey) and is the author of almost 200 peer-reviewed scientific papers and one textbook. His award-winning work has concerned itself principally with vitamin function, transport, and homeostasis in the central nervous system, the effect of food on the function of the kidneys, and the treatment of the poisoned patient. Dr. Spector also served as executive vice president in charge of drug development at Merck from 1987 to 1999, where he oversaw the introduction of fifteen new drugs and vaccines.