May 292011
 

The story of Rezulin's approval and the failure to withdraw it promptly from the market is a shameful chapter in the history of the FDA.

A Japanese company developed a drug belonging to an entirely new category of drugs for use in diabetics. The drug was later  named Rezulin and was licensed by Warner-Lambert.  Early tests showed that the drug had a tendency to cause liver damage. When Warner-Lambert applied to the FDA for approval, John Gueriguian reviewed the research and asked Warner-Lambert to wait for more data. The drug company complained to Gueriguian's superiors and he was removed from the oversight committee. In January 1997, the FDA approved the drug without waiting for more data.

Soon, the drug was rapidly gaining notoriety as the cause of liver failure often ending in death. In England, the government removed Rezulin from the market in December of 1997. In the USA, NIH ended a Rezulin trial because of liver damage in patients in the study. The group, Public Citizen, and others call for the removal of Rezulin from the market.

The FDA convened advisory committee meetings. The labeling of Rezulin was changed to reflect the fact that it could cause liver damage. Doctors were asked to check liver function frequently. The number of people dying from Rezulin kept increasing. By March of 1999, 430 patients had developed liver failure. New data showed that Rezulin patients were 1200 times more likely to have liver failure compared to patients not taking Rezulin.

The FDA kept dragging its feet. More frequent liver tests were recommended for patients on Rezulin. Warner-Lambert was doing monthly liver tests on a group of patients taking Rezulin. One patient died of liver failure in spite of the monthly liver tests.

Finally on March 21, 2000, the FDA removed Rezulin from the US market. By then Warner-Lambert had made over two billion dollars in sales from Rezulin. About half a million patients in the USA alone took Rezulin. About one in 500 would develop liver damage. Some of them will die and others may live although with substantial liver damage.

All of this was done for a drug that made no difference in the longevity of diabetic patients. Researchers were never able to show that the drug helped to reduce or prevent long term organ damage from diabetes. The drug was never shown to be superior to the standard diabetic drugs like sulfonylureas, metformin and insulin.

 

 Posted by at 12:02 pm
May 222011
 

Bronchial Asthma is a disease that lasts for years, and unfortunately in many people, a lifetime. Spontaneous remissions and relapses are common during an asthmatic's lifetime. Sometimes a person knows why his asthma is better or worse but most of the time there are no obvious reasons.

Magic cures are common in all such chronic diseases where there are spontaneous remissions and relapses. Asthma patients all over the world are looking for a cure because the scientific community has not found one. The fish treatment of the city of Hyderabad, India is one such magic cure. A family claims to have a secret recipe that they share with asthmatics free of charge. It has to be given on an auspicious day which only occurs once a year. There are several thousand people who line up to swallow the fish.

My uncle had severe asthma and went to Hyderabad to be cured. After his fish treatment he felt a lot better and spread the word to family and friends. His son also had severe asthma and decided to give it a try but without success. My cousin does not talk about it to everyone but the miracle of the fish cure lives on. Those who get better spread the word and the ones who do not get better stay quiet. The failures are always explained away -- maybe they did not follow the strict 45-day diet or maybe they did not repeat the cure for three years as recommended. Slowly my uncle’s asthma returned but by this time he had convinced several people to go to Hyderabad.

The point is that those who suffer from incurable diseases like asthma are often too willing to be convinced that the treatment waiting around the corner will be the answer. For-profit companies take advantage of their willingness and push their drug and surgical treatments regardless of their effectiveness. We need to make sure these treatments work before allowing patients to be guinea pigs or to spend their health dollars unwisely.

Cure for Asthma

Click on the link above to hear patient testimonials about the effects of miracle fish. You can also google about cures for asthma and you will find all sorts of testimonials from people whose asthma was cured from different miracle cures.

 Posted by at 11:33 am
May 212011
 

If you spend $10,000 for a single injection you would expect the medicine to be very effective for the condition for which it is being used. However this is not the case with Factor VIIa (FaVIIa) which is sold under the brand name NovoSeven RT. This drug is approved by the FDA only for use in hemophilia and related inherited bleeding disorders and a few other very rare conditions. But through clever marketing and manipulated research this drug is being used to stop bleeding in patients who do not have any bleeding disorders.

Originally the drug was approved under a fast track system for use in patients with bleeding disorders. Once approved by the FDA,  doctors are free to prescribe it for other conditions which is called off-label use. This is perfectly legal. The company producing FaVIIa sponsored studies on the use of this drug in various conditions such as prostate surgery, cardio-vascular surgeries, and bleeding from multiple trauma.

An independent analysis of these studies (1) revealed that FaVIIa does not improve mortality in any of the off-label conditions for which it is being used. The individual studies, sponsored by the company, emphasize that using FaVIIa reduces the number of blood units transfused. The fact that FaVIIa does not help the patient and may be detrimental was omitted from the reports. This drug increases blood coagulation leading to thrombotic episodes. So the overall effect of the drug is negative.

Doctors are inundated with conferences, medical articles, drug reps, and other promotional tools that push the use of FaVIIa for treatment of almost any bleeding patient. Several self-serving clinical trials appear to say that the drug is very useful. No wonder doctors feel they must use this very expensive drug to give their patients every chance even though independent studies shows it does not work.

Reference

1. Veronica Yank, M.D., C. Vaughan Touhy, B.S., Aaron C. Logan, M.D. et al: Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications; Ann Inter Med, 2011;154:529-540.

 

 Posted by at 5:24 pm
May 202011
 

This is story of how a company called Asthmatx introduced a new surgery. The promoters call this surgery Bronchial Thermoplasty. However “plasty” is a misnomer for this surgery since there is no repair, molding or reshaping involved. A more accurate term is Bronchial Thermal Cautery (BTC) since the bronchial walls are cauterized using a heat probe. The heat probe called Alair® has been approved by the FDA. The probe is introduced in the lungs using bronchoscopy. Then the Alair® Thermoplasty System uses radio frequency waves to heat the probe. The end result is that the interior of the bronchial walls is cauterized by heat. There is heat damage to bronchial lining, muscles and cartilage. Then the healing occurs. There is some evidence that the muscle wall thickness is reduced, based upon studies in dogs. There are no studies in asthmatic patients as bronchial biopsies were not done.

It is not often that an entirely new surgery appears in the medical field. This is especially true if the surgery is for a medical condition like asthma, and there is no similar surgery for any other disease or any other part of the human body.

Theory of Surgery: Asthma is a chronic disease without a clear cut explanation of its cause in most patients. There is narrowing of airway passages, bronchi, causing the patient to gasp for breath. The narrowing is caused by inflammation inside bronchi and constriction of muscles in the bronchial wall. The muscles of bronchial wall are called Airway Smooth Muscle (ASM). There is increase in size of ASM in asthmatics as compared to non-asthmatics. No one knows for sure if the increase in ASM is the result or the cause of asthma. It is theorized that reduction of ASM may benefit asthmatics.

Procedure: A heat cautery probe in inserted in bronchi using a bronchoscope. Then the probe is heated using radio frequency energy. Then the probe is moved to a different bronchus and the procedure is repeated. The whole lung is treated in three different sessions.

Animal Experiments: Investigators carried out heat cautery on bronchial walls of dogs. After cautery the dogs were subject to a test, called Methacholine Challenge Test (MCT). A similar test, also called Methacholine Challenge Test in humans, tests for a person’s tendency to have bronchial asthma. The company implied that since MCT in dogs showed improvement and therefore the surgery might be beneficial to asthmatic patients. The FDA asked for more studies in dogs and then approved studies in human beings.

Human Experiments: The company with the FDA approval, first tested the surgery in patients of lung cancer who were scheduled to have their diseased lungs removed. The surgery was tolerated by these non-asthmatic patients.

Clinical Trials: Three clinical trials were conducted on asthmatic patients. The first trial was called AIR trial and conducted on mild and moderate asthmatics. The trial compared surgery with regular medical care. The second trial was called RISA trial and was conducted on severe asthmatics. It compared surgery with medical treatment. The third trial called AIR-2 was conducted in moderate asthmatics. It compared surgery with sham surgery. Sham surgery was carried out by performing bronchoscopy but not cauterizing the bronchial walls.

AIR trial: The study involved about 115 moderately severe asthmatics who were divided into two groups. One group received surgery and the other regular medical care. The severe asthmatics were excluded from this study. When the study was first registered at the web site, the primary end point was “symptom free days.” Later on it was changed to “Asthma Quality of Life Questionnaire (AQLQ) score.” After the study was completed the primary end point was again changed to “mild exacerbations of asthma.”

The investigators claimed that the rate of mild exacerbation was reduced by surgery. There was no change in severe exacerbations, symptom free days or FEV1. There were more hospitalizations in the surgery group.

Five Year Follow-up: The surgery patients were followed for five years. The medical patients were followed for three years. There was no difference in control of asthma in the two groups, except that the surgery patients required more hospital admissions than patients on medical treatment.

RISA trial: This is the only clinical study of this surgery on severe asthmatic patients. Fifteen patients were subjected to surgery and seventeen patients on medical treatment served as controls. Almost 25% of the patients developed complications from surgery, severe enough to need hospitalization. The study was designed to evaluate the safety of surgery in severe asthmatics. The investigators concluded that the study showed that surgery was safe in severe asthmatics. This conclusion drawn by the company investigators does not make any sense. When 25% of the patients develop severe asthma, lung collapse, etc, severe enough to need hospitalization, than that surgery is not safe. The company realized this and excluded all severe asthmatics from their next study, the AIR-2 trial.

AIR-2 trial: This study was mandated by the FDA for approval of this surgery. The company set the selection criteria in such a way that the most severe of the severe asthmatics were excluded. The FDA overlooked such obvious flaw in the study design.

The study divided patients in two groups, surgery group and sham group. The surgery group patients had bronchoscopy and cauterization of bronchial walls. The sham group had bronchoscopies without cautery.

The study lasted one year. The surgery group had more severe asthma episodes than the sham group. However if you removed the episodes in the first two months the sham group had more asthma episodes. The company seized upon this very selected data and made it the most prominent finding in their article. They claimed that surgery reduced the number of severe asthma episodes.

One single patient in the sham group developed severe asthma after bronchoscopy. He/she needed nine hospital admissions in the study period. If we exclude this one outlier from the study the sham group had a better outcome than the surgery group.

Overall there was no clinical benefit of surgery over sham treatment. All of the parameters of asthma were equal in surgery and sham group. The company claimed that the surgery patients had statistically significant improvement in AQLQ score. However the difference between the surgery and the sham group was very small and of no clinical significance.

The FDA convened an advisory panel. The minutes of the panel meeting, presentation and discussion revealed that the panel members did not ask any important questions about measurements of asthma, like FEV1, symptom score, rescue inhaler use etc. There were more questions about why the results were different in USA compared to overseas, then about asthma control.

First there was presentation by the FDA staff. Then the company staff presented the data. Then there was one hour for public to make comments. The whole hour was packed by Alair® supporters. Doctors and patients gave glaring testimony as how their asthma had improved dramatically after treatment with Alair®. No one from the sham group came to tell how they had improved just as much as the surgery group.

The advisory panel recommended approval of surgical device for this new surgery for asthma. The FDA approved the Alair® device.

A new surgery, that was unknown to doctors a few years ago, was born.

 

 

 

 

 Posted by at 8:35 pm
May 202011
 

Drug companies sponsor clinical research so that they can influence the results to their advantage.  There is no incentive to be truthful and there is no penalty for dishonesty. Should a drug have serious side effects resulting in lawsuits then the discovery process might reveal some manipulation of the research results. But this happens far too rarely and even if dishonesty is revealed there are no effective penalties.  Usually problems take years to come to light and by that time the drug company has already made millions or billions in profits. There is no way to force the drug company to disgorge the profits.

Authorship of a clinical study: Most clinical studies are published in medical journals as “articles” with a principal author and often several co-authors. The articles are judged on the prestige of the medical journal where they are published and the prestige of the principal author. The authors tend to be on teaching faculties of various medical schools. However, frequently the articles are written by drug company employees and some professor of medicine simply signs off on it. In one case it was found that the drug company completed the clinical trial and then went looking for some academic doctor to sign in as the principal author (1).  So the authors may have no knowledge of the study until after it is over.

Multi-center Studies: Many clinical studies are carried out in medical centers spread across the world. The principal investigator does not have the time or the resources to monitor the study or to analyze the data from other centers. The drug company employees are happy to do that. All of the data is collected by the drug company employees and analyzed by company consultants. This data is treated as confidential information. The investigators may be prohibited by contract to divulge this data to anyone. The principal investigator may not even get the data from the different centers (2). The results of the trial, as written by the company employees, are presented to the investigators for their signatures.

Small Companies: There is trend toward small companies carrying out clinical trials. Each small company is engaged in the development of only one drug. The employees of the company are given stocks and stock options in that company. If the drug is not shown to be effective these stocks and stock options are worthless. These same employees are then given the job of running the clinical trials for that drug. They are gathering the data and doing the statistical analysis. If they err on the side beneficial to their company, they stand to gain financially. There is no downside to this for them. If “mistakes” are uncovered it could be years later and by that time they would have sold their stocks. There is no civil or criminal liability for such mistakes.

Patient Selection: There are criteria for inclusion and exclusion of patients for clinical trials. The company sets these criteria and usually excludes those patients that may be harmed by the drug. The investigators may take this a step further and restrict inclusion to relatively healthy individuals. Patients who get the drug after it is approved generally have a very different profile than the study patients.

After the drug is approved by the FDA there is no mention of the fact that some particular types of patients were excluded from the study.

Adverse Effects: Drug companies use various methods to minimize the reporting and statistical impact of adverse effects. Some investigators simply ignore a side effect and do not record it at all. Others use various cut-off dates to remove the adverse effects from the analysis. For example they might say that the data collection was stopped at a certain date, excluding adverse effects that happened after that date (3). At other times the company may remove the adverse effect if it happened immediately following a treatment, noting that it occurred during the normal recovery period. Only the data in the post-treatment period is analyzed (4).

If there are more deaths in the treatment group than the placebo group the difference is not analyzed statistically. Usually a statement is made saying the total number was too small or that the deaths were unrelated (5).

Statistical Analysis: This is where drug companies influence the outcomes of the trials most easily. Usually the patients in a study are evaluated in several different ways. Patients are often asked to keep a diary of their symptoms which provides a “symptom score.” Doctors examining the patients keep detailed notes. There is data from blood tests, x-rays, and other clinical tests. All this data is collected and analyzed by the drug company employees. Wherever the drug seems to produce a statistically significant benefit that particular finding becomes the center point of the clinical trial report. Areas where the patients on the study drug did worse than the patients on a placebo are not reported.

When the effects between the study drug and the placebo are small the data is analyzed in various ways to find some place where there is a statistically significant improvement for the study drug. For example, they may focus on the total number of patients who got better on the study drug, or on the degree of improvement from the drug, or on the percentage of patients who had a particular degree of improvement from the drug. The data that shows benefit, no matter how insignificant, becomes the selling point. The data that shows the placebo was equal to or better than the study drug gets ignored.

Publication of results of clinical study: If the clinical study shows beneficial results then it is published and publicized extensively. One study may be published in several journals in slightly different versions, giving the impression that there were multiple studies. If the study shows no benefit it may not get published, be delayed or be published in some obscure journal.

 

References

1. Merck designed and conducted study on its drug Vioxx. Then it went looking for authors in academic field. The study was published as ADVANTAGE study in Annals of Internal Medicine. 2003; 139(7):539-546. The lead author did not know of the study till after its completion.

Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. JAMA. 2008;299(15):1800-1812.

2. The Pharmaceutical Research and Manufacturers of America, the trade association of the industry,  justified withholding data in this way: “As owners of the study database, sponsors have discretion to determine who will have access to the database.”

Steinbrook R. Gag clauses in clinical-trial agreements. N Engl J Med. 2005; 352(21):2160-2162.

3. Merck was testing Vioxx for prevention and/or treatment of Alzheimer’s disease. The company monitored the patients for one year after the discontinuation of drugs for possible improvement but did not report the excess heart attacks in the patients who had taken Vioxx.  There were four times as many heart attacks on patients on Vioxx as compared to patients on placebo. The company did not notify the FDA, the volunteers or the institutes who carried out similar studies in subsequent years.

Reines SA, Block GA, Morris JC, et al. Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology. 2004; 62(1):66-71. See the analysis of this study by Psaty et.al. in JAMA. 2008;299(15):1813-1817.

4. A medical device company, Asthmarx®, conducted studies on asthma patients. The patients were subject to a surgery called Bronchial Thermal Cautery (promoters call it Bronchial Thermoplasty). A large number of patients developed severe asthma immediately after surgery. The total number of asthma episodes was more in treatment group as compared to the placebo group, in the one year study period. However the company reported that asthma attacks decreased after the surgery. They excluded all asthma attacks in the post-operative period, calling it “treatment phase” and counted only the ones in “post treatment phase.”

Castro M, Rubin AS, Laviolette M, for the AIR2 Trial Study Group, et al: Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma: A Multicenter, Randomized, Double-blind, Sham controlled Clinical Trial. Am J Respir Crit Care Med 2010, 181:116-124.

5. In two studies on Alzheimer’s patients there were 57 deaths in 1069 patients on Vioxx and 29 deaths in 1074 patients on placebo (p=<0.001). However no statistical analysis was given in the articles. The articles concluded that “Vioxx is generally well tolerated by elderly patients.”

Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation. JAMA. 2008;299(15):1813-1817.

 

 

 

 

 Posted by at 7:52 pm