EasyDiagnosis Second Opinions

There are three types of mendacity in the world, lies, damn lies and statistics.

- Mark Twain

The Food and Drug Administration (FDA) maintains a large, but incomplete repository of randomized controlled trials (RCT) as part of its new drug application process. Before  conducting new drug application trials, pharmaceutical companies must register them with the FDA. This registration includes pre-specifying various outcome measures and analytic methods. Pre-specification is supposed to ensure the integrity of a trial, but there is a catch-22 here. What if the investigators already have an idea-or prior knowledge of some trial results? This is a form of research bias know as HARKing or “hypothesizing after the results are known”, an open invitation for audacious cheating.

Key findings in a recently published combined (meta)-analysis (see (Psychother Psychosom. 2010;79:267) compared all trials for new drugs approved by the FDA from 2001 to 2002 with publication status of these trials 5 years later. The authors found:

New drug application studies with favorable outcomes were almost five times more likely to be published as those with unfavorable ones. 26.5% of pre-specified primary outcome measures were omitted from journal articles of new drug trials. Of the 43 primary measures not supporting efficacy, 20 (47%) were not included in the published results.

The analysis of these articles, in other words, showed significant ”publication bias,” HARKing, in other words, a nice way of describing research inflating the apparent effectiveness of new drugs.  Is cherry picking the results of drug trials simply a form of lying? Or did I use a dirty word?

“A misdirected zeal in matters of religion befogs the truth most grievously.”

Charles Mackay

Same old story, might as well call any cell in the body an embryonic stem cell, for what the old laws are hoping to accomplish. We’re back in the midst of theological dysfunction now with a Federal District Judge, Roce C. Lambert ruling that President Obama’s 2009 executive order that expanded embryonic stem cell research  violated a ban on federal money being used to destroy embryos.Of course, private industry can still invest in this area, but massive Federal money for supporting this vital research which may ultimately pave the way to success from everything for organ replacement to a cure for Alzheimer’s, is for the moment at least, dead in the water.  The decision of Judge Lambert, originally appointed by Reagan, means that the health institutes had to resume using harsh Bush administration rules for future grants.

Dr. George Q. Daley, director of the stem cell transplantation program at Children’s Hospital, Boston , referring to culture fluid given to cells, said, “This ruling means an immediate disruption of dozens of labs doing this work since the Obama administration made its order.”

Stay tuned.

Are you surprised to learn that more than 80 percent of the drugs approved for sale in 2008 involved trials in foreign countries, and 78 percent of all people who participated in clinical trials were enrolled at foreign sites? This, according to a recent investigation the inspector general of the Department of Health and Human Services. Medical authorities, especially ethicists, have long worried that many of these trials are in countries that federal auditors rarely visit and where research controls are questionable.According to the New York Times, at least a dozen major drug and device makers are under investigation by federal prosecutors in a broadening bribery inquiry into whether the companies made illegal payments to doctors and health officials in foreign countries.

Last month, a federal drug official reported repeated instances in a foreign clinical trial of Avandia, a controversial diabetes medicine, in which patients appeared to suffer serious heart problems that were not counted in the study’s crucial tally of adverse events. This “landmark” study is a main reason that Avandia remains on the market in the United States. So far Government officials have not accused GlaxoSmithKline, the trial’s sponsor, of fraud.

CBS Evening News (6/28, story 10, 0:30, Smith) reported FDA experts meet in two weeks to decide whether or not to pull Avandia (GlaxoSmithKline) off the market, while Brian Williams of NBC News also reported yesterday (June 28,3010) , however, that the drug’s maker, GlaxoSmithKline, “said today the drug is effective and safe.” The drug (Rosiglitazone) is still used for millions of patients with type II diabetes, although several other drugs are available for treatment of the condition.The drug was linked to 304 deaths in the third quarter of last year.

Yet, three years ago in May 2007, and followed by many other reports, Avandia was linked to a 43 percent greater risk of heart attack and death in a study published by the New England Journal. See this link.The FDA is still in a bind despite a recommendation last February that the drug be taken off the market. (Supposedly) when a drug maker refuses to pull a potentially fatal medication off the market, the FDA, believe it or not, does not necessarily have the authority to force a recall. “In the interests of free commerce” (see link above), though The FDA has authority to force a black box warning be placed on the drug, the Agency does not have explicit power to force a company to remove the drug from the market. According to the above link “As long as the risks and benefits of a drug are fully disclosed to a patient and the patient voluntarily consents to its use, the FDA has no power to interfere in that patient’s treatment.”Stay tuned.

According to the AMA Morning Rounds, World Health Organization (WHO) official still insist that the swine flu, H1N1 continues to be a “pandemic,” even though the period of most intense activity appears to have passed. The June 3 announcement came two days after a virtual meeting of international flu experts who advise Director-General Margaret Chan “on setting the global body’s pandemic alert level.”

This was surprising to many observers, because they “had expected the 15-member committee of experts, whose members are anonymous, to declare that the pandemic was in its ‘post-peak’ phase, or even in its ‘post-pandemic’ phase, which would mean that the pandemic was over.” But, Dr. Chan quickly pointed out that while “‘the period of most intense pandemic appears likely to have passed for many parts of the world,’ activity is continuing in some areas (Cuba, Central America) and many people remain vulnerable.”See my blog of Jan.26  and comments by Dr. Wolfgang Wodarg, chairman of the Parliamentary Assembly of the Council of Europe (PACE) Health Committee, cited previously, whom I quoted, “The WHO’s “false pandemic” flu campaign is “one of the greatest medicine scandals of the century.” Dr. Wodarg introduced the parliamentary motion to hold an emergency debate and inquiry into the “influence” exerted by the pharmaceutical industry on the World Health Organization’s (WHO) global H1N1 flu campaign.  “The definition of an alarming pandemic must not be under the influence of drug-sellers,” he added.

Orlistat (Xenical), used as a weight loss drug, is notorious for its gastrointestinal side effects- described as “treatment effects”, which can include steatorrhea  (oily, loose stools), since it inhibits the digestion of fat. The drug, which appeared to be safe for long-term use-don’t all drugs?-is available without prescription in the United States, the European Union, and Australia. Over-the-counter approval was controversial in the United States with consumer advocacy group, Public Citizen repeatedly opposing it on safety and efficacy grounds.

The AMA in its “Morning Rounds” reports the FDA is now requiring a liver-injury warning label, after receiving reports of liver damage by patients on this wildly popular diet drug.  (ABC World News 5/26, story 8, 0:20, Diane Sawyer.) The drug has been taken by nearly 40 million people.

The FDA has decided to put the new warning on Xenical (orlistat), developed by Roche’s Genentech, and its over-the-counter version,”Alli,” which is manufactured by GlaxoSmithKline (GSK).  To date, the agency has identified 32 cases of severe liver damage hepatocellular necrosis or acute hepatic failure, 2 of them outside the US.

Now, the revised label for orlistat (Xenical) will include new safety information about rare cases of severe liver injury. The agency stated, however, that “it has not yet established a causal relationship between orlistat use and severe liver injury.” For instance, some of the patients in question were taking other drugs while using the diet medications, others may have had conditions that exacerbated their liver disease.

Still, HealthDay (5/26, Gardner) reported, the agency is “‘telling consumers and healthcare providers to be vigilant should patients develop symptoms suggestive of liver impairment,” said FDA spokeswoman Elaine Gansz Bobo. She added, “We are not advising routine monitoring of liver enzymes as that will not help predict who may develop hepatic impairment on the drug.” People taking Orlistat — the active ingredient in both drugs — were warned to be on the lookout for itching, yellow eyes or skin, dark urine and loss of appetite, all of which are symptoms of liver problems.

If history is any guide, many more cases of serious liver problems will emerge in future.  The true extent of most drug reactions, serious, and not-so-serious-take years to come to the attention of the authorities and the public before proper warnings are issued or the offending drug is taken off the market.

Proton pump inhibitors (PPIs) are among the most popular drugs used to treat acid reflux and ulcers. They are sold under brand names like Nexium (the famous “purple pill”), Prilosec and Prevacid, and generate “$13.5 billion in sales. In 2009, approximately 119 million PPI prescriptions were written in the US, making the medicines part of the third-largest selling class of drugs. The six available PPI medicines are roughly equal in effectiveness and safety but differ markedly in cost. Two—omeprazole (Prilosec, Prilosec OTC) and lansoprazole (Prevacid,)—are available as both a prescription and a nonprescription drug. Taking effectiveness, safety, cost, and other factors into account, if you need a PPI,  consider following Consumer Reports Best Buy Drugs:

■ Prilosec OTC
■ Generic omeprazole OTC

Both of these drugs are available without a prescription. You could save about $200 a month or more by choosing one of these drugs over a more expensive medication listed above. See this informative report.

Unfortunately, like all drugs, PPI’s have problems. The Wall Street Journal reviews several recent reports from the medical literature about complications, and CNN  reported on its website that medical experts claim the risks of taking PPIs may outweigh the benefits for people with less serious conditions. PPI’s can have rare but serious side effects, including an increased risk of GI bacterial infection and bone fracture, according to several new studies in the Archives of Internal Medicine.  Over prescribing these drugs for simple heartburn or dyspepsia has become almost reflexive.

The Boston Globe (5/10, Cooney) “WhiteCoat Notes” blog reported that patients on PPI’s had a 47 percent increased risk of spine fractures, a 26 percent increased risk of forearm or wrist fractures, and a 25 percent increased risk of other fractures.”

Doctors at the Beth Israel Deaconess Medical Center in Boston, analyzed data on more than 100,000 patients discharged from the hospital over a five-year period, HealthDay (5/10, Goodwin). They found that taking a proton pump inhibitor each day increased the chances of a serious diarrheal disease, C. difficile infection by 74 percent,” and “patients who took proton pump inhibitors longer than that had more than double the chance.”

Five years ago, I wrote that “the oldest and still the most widely used first line drugs for heartburn and dyspeptic symptoms are the antacids, such as Tums, Maalox, Mylanta, Rolaids, etc. These have the advantage of rapid relief in most patients, and low price. …With GERD and ulcer, the H2-receptor antagonists, Zantac (ranitidine), Pepcid (famotidine), and Tagamet (cimetidine), etc. are in most cases as effective as the PPI’s.

“Proton pump inhibitors are often over prescribed in long-term care, disregarding published guidelines for their use..”  It is interesting to note that PPI’s are not approved for treatment of simple dyspepsia or uncomplicated heartburn.

 

NBC Nightly News (4/29, story 3, 2:00, Williams) reported that “the FDA has approved” Provenge (sipuleucel-T), “a vaccine for prostate cancer. It doesn’t prevent the disease, so vaccine is a bit of a misnomer, ..it could be a game-changer.”  The the media hype goes on: “It could help as many as 100,000 men with advanced prostate cancer,” the CBS Evening News (4/29, story 7, 2:00, Katie Couric) reported.  It offers “a new way to attack the disease which could be deployed against other kinds of cancer,” ABC World News (4/29, story 7, 1:55, Diane Sawyer) reported. But this is typical media hype, unsupported pure speculation.

 

The AP  reports that “three years ago…the FDA delayed a decision on the treatment, “despite an expert panel’s recommendation for approval.” According to the Los Angeles Times  “agency officials were concerned that, even though the vaccine extended lifespan in men with metastatic cancer who did not respond to hormone-deprivation therapy…it did not slow tumor growth.” The FDA also said that too few men given Provenge had been studied and asked Dendreon to perform a larger trial in more than 500 men.

 

Those results were presented last year, see TheWashington Post. During the trial, which involved “512 patients with advanced prostate cancer, Provenge increased overall survival by about four months, boosting median survival from 21.7 months to 25.8 months.”

 

The New York Times (4/30, A13, Pollack) reports that “a full treatment (with Provenge) will cost $93,000. Dendreon officials defended that price, saying it was in line with those of other cancer drugs in terms of cost per extra month of life provided by the drug.”

 

Bloomberg News said that the treatment “will initially be available at about 50 sites used for clinical trials, and more widely distributed after four plants are cleared for use by mid-2011, Seattle-based Dendreon said in a statement.”

 

But why did the FDA approve the drug without further testing?  It’s increasingly clear that  public pressure for life-extending new drugs for cancer is irresistible.  Would you like to take a chance on 4 miserable months for $23,000 a month, on the basis of this single study? Tough question. Is it time to load up on Dendreon stock?

The new Health Care Reform Act recently signed into law by President Obama has been attacked  by opposition to the legislation, now more virulently than before the bill was passed by the Senate. Yet here are some of the benefits we can expect from this, the first Federal health legislation passed in over forty years. See this site for some valuable information, including but not limited to the following:

“It makes insurance more affordable by providing the largest middle class tax cut for health care in history, reducing premium costs for tens of millions of families and small business owners who are priced out of coverage today.  This helps 32 million Americans afford health care who do not get it today – and makes coverage more affordable for many more.  Under the plan, 95% of Americans will be insured.

“It sets up a new competitive health insurance market giving millions of Americans the same choices of insurance that members of Congress will have.

“It brings greater accountability to health care by laying out commonsense rules of the road to keep premiums down and prevent insurance industry abuses and denial of care.

“It will end discrimination against Americans with pre-existing conditions. …
The Children’s Health Insurance Reauthorization Act on February 4, 2009, provides quality health care to 11 million kids – 4 million who were previously uninsured.

“The President’s American Recovery and Reinvestment Act protects health coverage for 7 million Americans who lose their jobs through a 65 percent COBRA subsidy to make coverage affordable.

“The Recovery Act also invests $19 billion in computerized medical records that will help to reduce costs and improve quality while ensuring patients’ privacy.

The Recovery Act also provides: $1 billion for prevention and wellness to improve America’s health and help to reduce health care costs;$1.1 billion for research to give doctors tools to make the best treatment decisions for their patients by providing objective information on the relative benefits of treatments; and$500 million for health workforce to help train the next generation of doctors and nurses.”

Another summary in The New York Times Science Section, Mar. 30, is a “must read.”

SO, WHAT’S NOT TO LIKE? The continued opposition to this landmark legislation boggles the mind. Yet I am convinced that once the vast majority of Americans begin to experience the changes and improvements in their access to health care and innovations in providing that care health care the outrageous opposition to this bill will melt away.

According to Dr. Richard J. Ablin, Research Professor of Immunobiology at the University of Arizona College of Medicine in a New York Times Op-Ed article March 10, “Prostate screening is inaccurate and a waste of money.”   Each year 30 million American men undergo testing for  prostate-specific antigen (P.S.A.), a prostate enzyme believed, when elevated, to be a reliable marker for the presence of prostate cancer.  While 16% of men have a lifetime chance of receiving a diagnosis of prostate cancer, they have only 3% chance of dying from the disease. Curious, isn’t it.  The fact is, that infections, over-the-counter drugs like ibuprofen and simple prostatic enlargement occurring in the majority of older men, can all falsely elevate PSA. Moreover, the test detects only a small percentage of cases, and cannot distinguish between the cancers that kill and the vast majority which grow so slowly that 97% of men will die of something else.

As Dr. Ablin points out, the FDA in approving the procedure relied “heavily” on a study showing that testing could detect 3.8% of prostate cancers.  Not a very large figure.  The result over the past several years has been the subjection of hundreds of thousands of men to radical prostate cancer surgery or radiation, resulting in a tragically high percentage of permanent impotence,  incontinence of urine, or both.

Last year the New England Journal of Medicine published the two largest studies of the screening procedure, one in Europe which showed that 48 men would have to be treated to save one life “That’s 47 men who, in all likelihood, can no longer function sexually or stay out of the bathroom for long.”  The American study showed that over a period of 7 to 10 years, screening did not reduce the death rate in men 55 and over.

Dr. Ablin asks why PSA screening is still used, and answers his own question.”Because drug companies continue peddling the tests and advocacy groups push “prostate cancer awareness” by encouraging men to get screened. Increasing numbers of early screening proponents, like Thomas Stamey, a well-know Stanford urologist came out against routine testing, and the American Cancer Society urged more caution in using the test. Certain subsets of patients, e.g. those with a family history of prostate cancer, those patients after treatment with rising levels should be tested, of course.  But this is quite different from subjecting a normal population to widespread screening, something I have discussed in a previous blog, and re-published in my newsletter, Second Opinions, an interview with Dr. Otis Brawley by Maryann Napoli in 2004!

By the way, the good Dr.  Albin who wrote the Op-Ed article from which this blog borrowed freely, invented the PSA test 40 years ago.

Stay tuned.