• Toxic Rx: Prescription for Error?
  • Table I: Testing Drugs in Humans
  • Table II: Medication Errors
• Selected Bibliography
• Brief History of United States Drug Law
• Toxic Notes
• Toxic Tip

Table I

Testing Drugs in Humans
	Number of Patients	Length	Purpose	% of Drugs Successfully Tested
Phase 1	20-100	Several Months	Mainly Safety	70 %
Phase 2	Up to several Hundred	Several Months 2 years	Some short-term safety mainly effectiveness	33%
Phase 3	Several hundred to Several Thousand	1-4 years	Safety, dosage Effectiveness	25-30%

After this lengthy process is completed the company submits proof to the FDA via their clinical trials that the drug is effective and safe for the prescribed use. The FDA's Center for Drug Evaluation Research reviews the studies, weighs the risks versus benefits and approves or disapproves as required. Newly marketed drugs are carefully followed for adverse reactions, doctors prescribe, and patients use the new medications.

It all sounds like a very neat, clean process: consumers are happy, the FDA is happy, and the pharmaceutical companies are happy; and most of the time this is indeed the case. However, buried in the process is the chilling realization that no prescription drug is absolutely safe and all along the way from lab to consumer there is considerable room for error which can and often does leave in its wake preventable tragedies. Thalidomide is one dramatic example from the 1960s of a drug not being thoroughly scrutinized. Drug manufacturers failed to test the teratogenic capabilities of this potent medication and thousands of babies were born with missing or deformed limbs.

The FDA drug approval process is ostensibly constructed to minimize the possibility of drug errors making their way to consumers. However, political pressure is adding yet another dimension to the already complicated process. To combat the charges by consumers, drug manufacturers and other special interest groups that the approval process was taking too long, Congress passed The Prescription Drug User Fee Act in 1992 requiring manufacturers to pay a fee to expedite approval time. This has worked so well the number of new drugs approved for use doubled from 26 in 1992 to an amazing 53 in 1996. Overall in 1996 the average approval time for new drugs was 20.5 months; in 1997 the average approval time was 10.8 months. One of the drugs was approved by FDA in an incredible 42 days! Many are concerned that this fast track approach accelerates the possibility for error and a drug's hidden menace may not be evident until the post-marketing surveillance stage when the adverse reaction reports will also skyrocket. While the drug approval process has been speeded up for some priority drugs, the reporting of the total number of adverse effects of drugs approved since fast tracking has not been very expeditious. In1990 the FDA reported 37,000 adverse prescription drug events filed. By 1995 the number jumped to 130, 950 events reported and there has been no public announcement for 1996 or 1997. MTI was informed by FDA that we could obtain this information only by filing a Freedom of Information request.

In the initial marketing stage adverse reports are carefully monitored by the pharmaceutical producer and the FDA.If a drug has an excess number of adverse reports it will be pulled by the manufacturer. This system has proved to be very effective for most drugs; however, a small number of drugs have been found to have latent effects which were only evident after an extended period of time. As an example, drugs that have estrogenic or hormonal properties and have received wide distribution, are followed closely for many years after the initial surveillance to ensure they do not present an excess risk to consumers.

Distribution is yet another area where error can infiltrate the drug to consumer process. In years past drug manufacturers marketed almost exclusively to health care professionals. Now a large share of marketing dollars is spent marketing directly to consumers. The ever escalating number of prescriptions filled is proof this type of marketing is succeeding. However, physicians less informed, coupled with greater pressure from patients who want to take charge of their own health has created a whole new world of prescribing errors. In fact, according to one recent report in JAMA 30% of prescribing errors were related to the knowledge and application of knowledge regarding drug therapy by physicians.

U.S. Prescription Drug Sales 1983..............................$17 Billion 1992..............................$50 Billion 1996..............................$84.5 Billion

Some other types of medication errors from a sample of 679 hospital adverse patient events include the following:

Table II

Medication Errors
	Resulting Error Type	No. Of Errors	% of Errors	95% Confidence Interval
	Overdose	291	41.8	38.1-45.5
	Underdose	115	16.5	13.7-19.3
	Allergy	90	12.9	10.4-15.4
	Dosage Form	81	11.6	9.2-14
	Wrong Drug	35	5	3.4-8.4
	Duplicate Therapy	35	5	3.4-8.4
	Wrong Route	23	3.3	2.0-4.6
	Wrong Patient	3	0.4	***
	Miscellaneous	23	3.3	2.0-4.6
	Total	696	***	***

With over 2.5 billion prescriptions filled in 1997 in the United States it is evident there are many opportunities for errors to occur from the R&D stage, through the approval process to the consumer. And after all is said and done and the manufacturer has created the perfect drug that is perfectly prescribed by the physician there is still the X factor of patient compliance, another newsletter indeed!

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1. "FDA Reform?" Science Jan 9; 279(5348):157-158, 1998.
2. Glaser, Martha "Annual RX Survey" Drug Topics Apr 8; 140(7):97-104, 1996.
3. "Inside FDA: The Center for Drug Evaluation and Research" FDA Consumer Jul/Aug; 1996.
4. Leape, L.L. et al "Systems Analysis of Adverse Drug Events. ADE Prevention Group" JAMA Jul 5; 274(1):35- 43, 1995.
5. Lesar, Timothy S. Et al "Factors Related to Errors In Medication Prescribing" JAMA Jan 22/29; 277(4):312- 317, 1997.
6. "The Drug Approval Process" CQ Researcher Jun 6; 7(21):489, 1997.
7. Vanchieri, C. "Preparing for the Thalidomide Comeback" Ann Intern Med Nov 15; 127(10): 951-952, 1997.

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The Freedom of Information Act (FOIA) allows anyone to request copies of records not normally prepared for public distribution, such as drug adverse reaction reports. All FOIA requests must be in writing and should include the following information:

1. Requestor's name, address & phone #.
2. Description of the records sought.
3. Statement that you are willing to pay fees.

Mail to: Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville MD20857

To date the Spontaneous Reporting System database which collects the adverse drug reactions filed contains over 1 million reports.

  TIME SAVING TIP: LET MTI ORDER YOUR FOI REQUESTS AND ORGANIZE THEM TO YOUR SPECIFICATIONS.

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The Serveso 15-year update has been published. The findings, surprising many, including IARC, concluded there were no statistically significant reports of cancer for individuals exposed to Dioxin in 1976. See Epidemiology 8 (1997): 646-652.

The American Association for the Advancement of Science (AAAS) is drafting a proposal for making experts available to the court for nonpartisan advice. "Gatekeeper"-Judges are seeking help to separate junk science from "sound" science. Supreme Court Justice Stephen Breyer told the AAAS in February that "the law itself increasingly needs access to sound science."

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1. Briggs, Gerald G., Freeman, Yaffe DRUGS IN PREGNANCY and LACTATION: REFERENCE GUIDE TO FETAL & NEONATAL RISK 5th ed. Baltimore: Williams & Wilkins, 1998.
2. Carruthers-Czyzewski, Gillis, Claire, Letwin NONPRESCRIPTION DRUG REFERENCE FOR HEALTH PROFESSIONALS Premier ed. Ottawa, Ontario, Canada: Canadian Pharmaceutical Association, 1996.
3. World Health Organization ADVERSE EFFECTS OF HERBAL DRUGS 1 Berlin, NY: SpringerVerlag, 1992

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