It is imperative to allow immediate and accurate publication that alerts every health care professional as soon as manufacturers acknowledge problems with their medical products. The United States needs national legislation or FDA regulation to improve communication. An existing web site can be improved or a new web site created.

Problem

According to Tom Pelton of the Baltimore Sun, “More than 1,000 of the 80,000 medical instruments used in the United State are recalled every year. But because the recalls are run by manufacturers with little government oversight, they are often ineffectual, leading to deaths and injuries.”¹

When manufacturers become aware of possibly serious or fatal effects from products approved by the FDA, they typically send out “Dear Health Professional” or “Dear Doctor” letters.² Other methods are also used, each of which have problems. 

Statements by Health Care Professionals about Recall Notification

According to Tom Pelton the following statements were made by health care professionals about recall notification:¹

• “ ‘It’s obviously a problem,’ said Dr. David Kirschke, an investigator with the federal Centers for Disease Control and Prevention. ‘I would hope that word gets out to hospitals in some more efficient and effective way in the future.’ ”
   
• “Dr. David Rorison, senior vice president for medical affairs at the University of Maryland Medical System, explained the difficulties in relying on manufacturers to sound the alarm about their own products. ‘The current system puts companies in the situation where they kind of want you to know about the problem, but they don’t want you to know they are responsible for it,’ Rorison said. ‘They want to alert you but not alarm you and not implicate themselves.’ ”
   
• “ ‘It doesn’t make any sense. We get better recall notices for our cars than our medical devices,’ said Dr. Steven Schonfeld, director of pulmonary medicine at Sinai Hospital in Baltimore.‘ There has to be a much more rigorous process that we could use for device recalls.’ ”
   
• “ ‘We’ve had many, many cases of recall notices being sent to the wrong place. It’s a common problem,’ said Maryanne Spicer, director of corporate compliance at Massachusetts General Hospital in Boston. ‘The recall system should really be improved.’ ”
   
• “Sometimes communication breakdowns are the fault of unwieldy hospital bureaucracies, federal regulators say, with important recall notices becoming lost in billing departments or on loading docks. But manufacturers also cause problems by sending registered letters to old addresses based on outdated billing or delivery databases, according to hospital administrators.” 
   
• “ ‘The recall information has to get to the right person in the hospital, and that doesn’t always happen,’ said Mark Bruley. Mr. Bruley is an investigator and biomedical engineer for ECRI a nonprofit Pennsylvania group that monitors reports and warns hospitals about the safety of medical devices.” 

Dr. Mark McClellan, the commissioner of the FDA, stressed the need for better communication in a paper, Outbreak of Infection Associated with Bronchoscopes, he co-authored with Dr. D. W. Feigal and Dr. N. Gardner in a January 2003 issue of the New England Journal of Medicine.

Example of a Problem Medical Device

From 1997, when it was approved, until November 2001, when it was recalled, Olympus America, Inc. manufactured a bronchoscope. It was a tiny instrument with a camera on one end used to probe the lungs. Olympus America, Inc. described this defective instrument as having a loose valve that trapped bacteria called pseudomonas that could spread potentially life-threatening lung infections to patients.¹ 

Since 1997, FDA records show 17 reports from hospitals describing the Olympus bronchoscope as being involved in the spread of pseudomonas among patients.¹ “These reports, which do not give the names of the hospitals, list at least 36 infections and three deaths, although the causes are not always clear.”¹ We do not know the dates and details of these events; but we do know the time and place of the following events:

• “On Nov. 30, [2001] the company sent 4,700 recall notices to hospitals across the country, because the instruments had a defect that sometimes harbored pseudomonas and allowed the dangerous bacteria to spread among patients. But officials at Johns Hopkins and several other hospitals said in March that their notices were sent to the wrong addresses, and 60 percent of the bronchoscopes nationwide continued to be used by doctors more than three months after the warning.”¹ 
   
• On December 31, 2001, the pulmonologists at Johns Hopkins raised concerns about unexpected rates of infections caused by pseudomonas in several very sick and immune compromised patients.⁷ 
   
• At the end of January 2002, someone at Johns Hopkins Medical suggested testing the bronchoscopes by flushing fluid through them in the reverse direction from the industry standard. This retrograde flushing revealed the contamination which Johns Hopkins doctors believe is related to the loose port on the bronchoscope that is the subject of the nationwide recall.⁷
   
• By early February 2002, Hopkins confirmed bacterial contamination in three of seven Olympus America Inc. bronchoscopes that had been recalled three months earlier.⁷ Coincidentally, in early February, Hopkins became aware of the national recall notice.⁷
    
• On March 4, 2002, the recall finally received national publicity only when physicians at Hopkins made an announcement of the danger in using these fatally flawed instruments.¹ 
   
•  On March 20, 2002, MedWatch posted a notice of the Olympus bronchoscope recall.
   
• On March 27, 2002, the FDA Enforcement Report listed the Olympus America, Inc. bronchoscope as the 17th item in a list of 45 items. There are no page numbers to determine which item is on which page. The bronchoscope recall is split between two pages, which makes it difficult to print and post the recall.⁶

“For its part, Olympus officials have expressed frustration with hospitals. Some apparently received the notices but didn’t respond, the company told the FDA.” 1 “In the Olympus recall, many hospitals – including Mercy Medical Center in Baltimore, the University of Michigan Health Centers and the University of Chicago Hospital – said they had no evidence they even received the Nov. 30 notice. Others, such as the University of Maryland Medical System, said they received the notices, but the letters bounced around in-house mail systems without reaching the doctors who use the instruments.”¹

Reportedly, Olympus America, Inc. did not telephone or personally notify doctors at Johns Hopkins, which is the home of the Johns Hopkins University Cystic Fibrosis Research Development Center.⁷ If they had known, Johns Hopkins could have easily notified every other cystic fibrosis research center. Instead, death and injury continued to patients that these doctors had sworn to protect. The Cystic Fibrosis Research Development Center and the National Institutes of Health financially support Johns Hopkins and other similar research centers. In addition to death and injury, the charitable donations and federal tax money at these institutions were wasted by the continued use of these dangerous instruments.

Publishing a problem can make a difference. The percentages of Olympus America, Inc. bronchoscopes returned before and after a March 4, 2002, news conference at Johns Hopkins are: before - 40% and after - 90%. This can be compared with the percentage of consumer goods over $1,000.00 successfully recalled which is 90% and the percentage of automobiles successfully recalled which is 72%.¹

Percentage of Products Returned for Replacement or Modification after
Recall Notification by Manufacturer

What the manufacturer, various doctors and hospitals, and the FDA reported is known, but nobody will ever know the answers to the following questions about the use of the bronchoscope after the recall letters were sent:

• How many letters that were sent to loading docks or billing departments were unopened?
   
• How many babies, children, and adults with cystic fibrosis, AIDS, lung transplants, or cancer died unnecessarily? 
   
• How many existing medical conditions were exacerbated causing severe health problems or death?
   
• How much of our financial resources were wasted treating people made ill by the bronchoscopes?
   
• How much were research projects complicated by unnecessary exacerbation of existing health problems?
   
• How much were the results of the clinical research trials of other products unwittingly skewed by the unaccountable exacerbation of existing health problems? 

Bronchoscopes are often used on very sick patients, usually patients with cystic fibrosis, AIDS, lung transplants, or cancer.⁷ These patients frequently die and never easily recover from bronchial or lung infections.

Example of a Problem Drug

Propulsid (Cisapride) is an effective gastrointestinal drug for a serious, life-threatening condition. It would probably still be on the market in the United States, if it had received carefully controlled use with excellent physician information, patient education, and patient monitoring. Unfortunately, none of this happened, and Propulsid was removed from the market. Physician education was slow, incomplete, and contradicted itself. Patients are left struggling for effective help. 

The following are some of the events that occurred before Janssen Pharmaceutica [Johnson & Johnson, (J&J)] removed Propulsid from the market in the United States on July 14, 2000:

• On July 29, 1993, the FDA approved Propulsid.^8,9 ”FDA medical officer Andre Dubois noted that 48 of 1,993, or 2.4%, of the patients who took Propulsid in U.S. studies experienced: ‘heart rate and rhythm disorders.’ In addition, eight children age 6 or younger who were given Propulsid had died.”⁸ No cardiac specialists were consulted although the QT interval was prolonged.^8,9 The QT interval is defined as the time between the Q wave of the ECG (when the heart’s muscles contract) and the T wave (when the muscles relax again.) “If the QT interval—typically about 4/10 of a second—is extended even slightly, it can trigger a disruption or cessation of the heartbeat. Called an arrhythmia, it can result in sudden death.”⁸ “In approving Propulsid, the FDA agreed to labeling that advised doctors of ‘rare cases’ of increased heartbeats. The labeling said Propulsid’s role in the events ‘was not clear.’ “⁸
   
• In the August 1993 issue of The American Journal of Cardiology, Dr. Raymond J. Lipicky, Head of the FDA’s Cardio-Renal Drugs Division, stated that if a drug that prolonged the QT interval had a benefit that was “less than lifesaving...any risk of death would likely be considered unacceptable.”
   
• “On Jan. 25, 1995, a senior FDA medical officer, Dr. Stephen B. Fredd, told Janssen executives that recent adverse-reaction reports show their drug was prolonging the QT interval, perhaps resulting in deaths.”⁸
   
• In February 1995, “the FDA and the company agreed to the first of five safety-labeling changes that would help keep the drug on the market over the next five years.⁹
   
• On October 14, 1995, a “Dear Doctor” letter advised against prescribing Propulsid to patients who were taking various antibiotics and patients with various renal or cardiac problems,²
   
• On July 25, 1996, The New England Journal of Medicine published a paper entitled “Cisapride and Fatal Arrhythmia.”⁴
   
• On August 15, 1996, the FDA informed Janssen that Propulsid was ‘not approvable’ for children, but this was not announced publicly. ^8,9
   
• In August 1997, the FDA requested additional labeling changes.^8,9
   
• On June 26, 1998, J&J sent a “Dear Doctor” letter about Propulsid defining the following adverse effects:³

Sudden death 

Cardiac arrest 

Dramatic impact on the heart rhythm with a distortion of the cardiac wave form causing fibrillation and QT prolongation

Twisting of the EKG complexes (sometimes with loss of consciousness) technically known as torsades de points (sometimes with syncope) 

• The June 26, 1998, “Dear Doctor” letter stated “Safety and effectiveness in pediatric patients have not been established. Although causality has not been established, serious adverse events, including death, have been reported in infants and children treated with cisapride. Several pediatric deaths were due to cardiovascular events (third degree heart block and ventricular tachycardia.)³
   
• In October 1998, the North American Society for Pediatric Gastroenterology and Nutrition, which admits on its web site generous support from Janssen, held a conference on Propulsid use. The society printed doctor’s literature advising that Propulsid was safe and effective for children with colic. ^8,9
   
• In 1999, nine-month-old Gage Stevens died suddenly. He had been entered in a clinical trial for children with colic. His parents signed Pittsburgh Children’s Hospital consent forms that falsely stated that the FDA has approved Propulsid for use in children.^8,12 His autopsy report, done by Dr. Cyril Wetch, showed that his esophagus “failed to show signs of significant inflammation or other hallmarks of gastroesophageal reflux.”¹² The baby, Gage Stevens, was entered as a subject into a clinical trial that took his life, even though he did not have the condition that was the subject of the trial.¹² His parents were told the drug had been approved for children, when the opposite was true. They were not told that sudden death was a possibility, when it was true.¹² Tom Grant and Nonny de la Pena detail the impact on the families of children, including Gage Stevens, who were killed or injured by prescription drugs. Their paper, “I didn’t hurt my child,” was published on the American Family Rights Association web site on February 6, 2003.
   
• In 1999, the Cardiovascular and Renal Drugs Advisory Committee of the FDA reported the effect of the June 1998 regulatory actions, a “Dear Doctor” letter and additional safety labeling changes, on the contraindicated prescribing of Propulsid. The committee made the following statements:¹⁰

“At one state Medicaid site surveyed for the study, in the year prior to new warnings about the drug, the use of cisapride was contraindicated in 60 percent of those for whom the drug was prescribed. In the year after, the proportion of contraindicated patients prescribed this drug had decreased [only  2 percent] to ... 58 percent.” 

“The FDA’s 1998 regulatory action regarding cisapride use had no material effect on contraindicated cisapride use.” 

“More effective ways to communicate new information about drug safety are needed.”

• On July 14, 2000, Johnson & Johnson removed Propulsid from the market in the United States after five safety-labeling changes.⁸
   
• No FDA Enforcement Report ever listed Propulsid.

Summary of Events Surrounding Propulsid

Rep. Bart Stupak reported “The FDA has tens of reports that only 1% of side effects that actually occur is reported to the FDA.” during the Safety of the Acne Medication Accutane Panel before the House Energy and Commerce Subcommittee. 

The July 29, 2000, Pharmaceutical Journal reported that the following problems occurred:¹¹

• 50 cases of sudden, unexplained death occurred among people using Propulsid. If the 1% estimate is correct, that means 5,000 people died with sudden, unexplained death in 2,542 days, an average of two people died with sudden, unexplained death each day.
   
• 125 reports of fatal ventricular arrhythmias happened to people using Propulsid in the seven years Propulsid was marketed.11 If the 1% estimate is correct, that means 12,500 people died of ventricular arrhythmia in 2,542 days; an average of five people died from fatal ventricular arrhythmia every day. 
   
• 261 reports of non-fatal but serious ventricular arrhythmias that were seemingly associated with Propulsid occurred.11 If the 1% estimate is correct, this means approximately 26,100 people were affected by ventricular arrhythmia in 2,542 days; an average of more than 10 lives were severely and adversely changed every day.

“William Weldon, worldwide chairman of J&J, reported after five attempts to warn doctors, the majority of side effects took place among people who have been identified as at risk. Some doctors were even prescribing Propulsid to infants and children resulting in 14 deaths.”¹³ If the 1% estimate is correct, that means that 1,400 infants and children died.

On March 6, 2002, the House of Representatives Committee on Energy and Commerce, Subcommittee on Health, heard a panel on the Reauthorization of the Prescription Drug User Fee Act. It was reported there that the Adverse Event Reporting System received reports on 288 people in the United States alone that had deaths associated with Propulsid. If the 1% estimate is correct, this means approximately 28,800 people in the United States alone had deaths associated with Propulsid 

In addition to death and injury, many of our nation’s resources were wasted. Economically, we are told that these are some of the things that happened:

• Sales of Propulsid in the United States alone passed $2,500,000,000 ($2.5 billion).¹³
   
• It was estimated that the J&J lost $700,000,000 ($700 million) in projected revenue from Propulsid in the year 2000 after it was taken off the market in the United States on July 14, 2000. That is more than $100,000,000 ($100 millions) per month..¹³ 
  
• “Risperdal, Procrit, Levaquin and Propulsid accounted for over 65% of J&J’s profit.”14
   
• In Mississippi, a jury awarded 155 plaintiffs damages of $100,000,000 ($100 million) in a Propulsid lawsuit against Johnson & Johnson.¹⁵ One plaintiff was ten days old at the time the drug was given.

The medical community knows what the manufacturer, the FDA, a panel in the United States House of Representatives, two medical journals, the Wall Street Journal and William Weldon said about Propulsid. Nobody will ever know the answer to any of the following questions about the use of Propulsid after the “Dear Doctor” letter written in 1998 warned of serious cardiac problems and the danger to babies and children:

• How many babies, children, teenagers, and adults unnecessarily experienced sudden, unexplained death?
   
• How many people were resuscitated from unnecessary cardiac arrests with permanently damaged brains?
   
• How many people had their lives adversely affected by unnecessary ventricular arrhythmias?
   
• How many existing medical conditions were unnecessarily exacerbated causing severe health problems or death even after Propulsid was discontinued?
   
• How long did problems caused by Propulsid continue to be exacerbated by continued use of the drug even after emergency room visits, because the treating physicians had not read the letters and did not associate the problems with the drug?
   
• How much money was spent on medical care that should not have been necessary?
   
• How often were the scarce resources of EMT and emergency room personnel and equipment stretched thinner because of medical care that should not have been necessary?
   
• How much were research projects complicated by the unnecessary exacerbation of existing medical conditions?
   
• How much were the results of the research trials of other products unwittingly skewed by the unnecessary exacerbation of existing medical conditions?
   
• How often did the drugs used to treat the problems caused by Propulsid render other drugs less effective because of drug interactions?
   
• How often did representatives of Johnson & Johnson make personal telephone calls to doctors to explain the possibly fatal dangers of Propulsid?
   
• How often did representatives of Johnson & Johnson make visits to doctor’s offices to explain the possibly fatal dangers associated with Propulsid? 
   
• How often did journals go unread?
   
• How often was packaging ignored?
   
• How often did letters go unopened?

Proposal

The following legislative changes should be made immediately:

Reports

• Information from manufacturers reporting dangerous drugs, devices or foods must be released by the FDA they day it is received from the manufacturers. Medical professionals need access to current information. Patients deserve it.
   
• Daily publication of the FDA Enforcement Report instead of weekly publication with a “class undetermined” classification to allow immediate publication of data received from manufacturer.
   
• Definition of the purpose of the FDA MedWatch report as differentiated from the purpose of the FDA Enforcement Report. What is the target group of each report? Why are there two reports with some information included on only one of them?

Physician Education 

• Mandatory, immediate, prominent display on all literature of “NOT APPROVABLE FOR CHILDREN,” “MAY CAUSE SUDDEN DEATH,” and other significant prescribing information.
   
• Release of the statistical data from the clinical trial of the product. It is not possible to evaluate the statistical importance of the deaths of eight children, if you do not know how many children were in the original group, how many children were withdrawn, and the reasons for the withdrawals.

Patient Education

• Mandatory, immediate, prominent display on all literature of “NOT APROVABLE FOR CHILDREN,” “MAY CAUSE SUDDEN DEATH,” and other significant patient information.
   
• Information on container of any drug prescribed for a child that the drug is “APPROVED FOR CHILDREN,“ “FAILED TEST TO BE APPROVED FOR CHILDREN,” or “UNTESTED FOR CHILDREN.”
    
• A warning to patient or patient’s caregiver of known life-threatening side effects by both physician and pharmacist even if the events happen to less than 1% of patients. Most pharmacies only list side effects if they happen to at least 1% of the population studied.
   
• Requirement for signed consent, if either “SUDDEN DEATH,” or “PERMANENT HARM” is a possible side effect or if the drug has been deemed “NOT APPROVABLE FOR CHILDREN.”

In the field of information science there is a saying “too much information is no information.” The example usually given is an unsorted telephone book. Medical information has become a set of unsorted documents with notices of fatal complications mixed up with billing notices and advertising copy.

The need is obvious ^{1,6,7,8,10,12,16,17} Lives could be saved; hospitalizations and injuries could be avoided. This is to respectfully request that you consider these cost effective and humane proposals that capitalize on cutting-edge technology to speed communication of critical medical information in a heartbeat.

Bibliography

*Caroline Horton  313 Baycrest Drive League, Texas  Chorton@ev1.net 281 334 9688

1. Tom Pelton, Baltimore Sun, May 27, 2002,” Ineffectual recalls of medical devices have proved deadly”

2. IMPORTANT DRUG WARNING, “Dear Doctor”, Janssen Pharmaceutica Inc, June 1995-revised Sept. 1995. Review letter Oct. 1995. www.fda.gov/MedWatch/safety/2000/propul.htm

3. U.S. Food and Drug Administration, Janssen Pharmaceutica Research Foundation, June 26, 1998 www.fda.gov/medwatch/safety/1998/propul.htm.htm

4. Cisapride and Fatal Arrhythmia, New England Journal of Medicine, July 24, 1996 – Volume 335, Number 4., pages 2,3 www.geocities.com/HotSprings/Villa/2193/oct.htm

5. Cisapride, Clinical Toxicology Review, Massachusetts Poison Control System, Feb. 1996 Vol. 18, No.5 www.maripoisoncenter.com/ctr/9602cisapride.html

6. FDA Enforcement Report for March 27, 2002. www.fda.gov/bbs/topics/enforce/2002/ENF00736.html

7. Johns Hopkins Medical Institutions, Defective Bronchoscopes Identified as Probable Cause of Infections Are Part of Manufacturer’s National Recall, March 4, 2002, www.hopkinsmedine.org/press/2002/MARCH/020304.htm 

8. Willman, David “Drug After Drug, Warnings Ignored” Los Angeles Times, http://www.pulitzer.org/year/2001/investigative-reporting/works/willman2.html

9. Vivisection Information Network - Newsletter 9 http://vivisection-asbsurd.org.uk/vin09.html

10. United States Of America Department Of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research Cardiovascular and Renal Drugs Advisory Committee 92 Meeting www.fda.gov/ohms/dockets/ac/01/transcripts/3749

11. Cisapride withdrawn because of cardiac side effects, The Pharmaceutical Journal Vol. 265 No 7107 p 152 July 29, 2000 Clinical www.pharmj.com/Editorial/20000729/clinical/cisapride;html

12. Sharan, Vera H, Children in Clinical Research: A Conflict of Moral Values, American Journal of Bioethics 3(1): In Focus.

13. Winslow, Ron and Leuck, Sarah “Johnson and Johnson Ceases Marketing Heartburn Drug Amid Health Concerns.” Wall Street Journal, March 24, 2000. Interactive Edition

14. Winslow, Ron, “Johnson & Johnson Defends Prospects as Shares Drive 11%.” Wall Street Journal, March 27, 2000. Interactive Edition 

15. In First of Many Cases, Drug Maker Loses $100 Million, Margaret Cronin Fisk, The National Law Journal, 10-05-2001 www.law.com

16. Clinical Decisionmaking: Inappropriate prescribing continues despite FDA regulatory action. Lessons from Cisapride, CMAJ* May 1, 200l; 164 (10) www.cma.ca/cmaj/vol.164/issue=9/1269.asp

17. FDA Regulatory Actions Fail to Protect Patients from Known Serious Adverse Drug Reactions, Colorado HealthSite, December 20, 2000