How the F.D.A. Determines The "Safety" of Drugs -
Just How Safe Is "Safe"?

Women's Health Network

A REPORT RELEASED TO THE CONGRESS OF THE UNITED STATES

• There is no prescription drug or over-the-counter remedy that is without risk, even when taken according to directions.

• FDA approval of a drug does not mean that the drug-has been approved as safe for general use.

• Most prescription and over-the-counter drugs have not been tested for safety in the elderly infants, children, pregnant women and lactating mothers.

• Many health care providers, including doctors and nurses, have not been taught how to distinguish between an FDA approved use of a drug and a non-approved use.

• There are no laws or regulations which prohibit a doctor, or any other health care provider licensed to prescribe drugs, from prescribing or administering to you a drug which has not been approved by the FDA as safe for the treatment of your illness or condition-and which, in fact, may subject you to a risk that you may not be willing to take.

• You owe it to yourself (and if pregnant, you owe it to your baby) to learn as much as possible about the drugs you take.


THE INFORMATION ON THIS PAGE MAY BE DISTURBING, BUT IT IS INFORMATION YOU WILL NEED FOR MAKING INFORMED DECISIONS REGARDING YOUR HEALTH CARE.

Prepared by Doris Haire, Chair
Committee on Health Law and Regulation,
National Women's Health Network,
Washington, D.C.

Question Your Doctor and Pharmacist

It is alarming but true that many health professionals have not been taught how to distinguish an FDA-approved use of a drug from a non-approved use. Therefore, before you purchase or take a prescription drug you may wish to ask your doctor or pharmacist to let you read the drug's package insert (the information leaflet which comes in the carton from the manufacturer). II you are hospitalized and your doctor is not available, ask the hospital pharmacist to let you read the package insert. The package insert is written and supplied by the manufacturer and approved by the FDA. Although written for the physician, most consumers can understand the relevant sections (i.e., "Indications," "Contraindications," "Warnings," "Precautions," "Ad verse Reactions," etc.).

Don't hesitate to question your doctor about the risks vs. the benefits of the drug he or she may prescribe for you and about the alternatives, including non-treatment. Your doctor is legally obligated to obtain your informed consent to treatment. This requires your doctor to inform you of the drug's known adverse effects, the FDA approval status of the drug, the "areas of uncertainty" regarding the drug's delayed, long-term effects, and the non-pharmacologic alternatives to the drug.

Since your doctor may not be aware of the information in this pamphlet, you may wish to share with him or her the following information, presented in the form of answers to commonly asked questions about drug safety.

A simple but important question to ask is "Has this drug been approved by the FDA as safe and effective for the treatment of my condition?"

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How the FDA Determines the "Safety" of Drugs


Does FDA approval of a drug mean that the drug has been approved as safe for general use?

No. The FDA does not approve a prescription or over-the-counter drug as sale for universal (general) use.

The FDA approves specific doses of a drug for the treatment of specific conditions or illnesses. If the "Indications" section of the package insert does not specifically mention your condition, then the FDA has not approved the drug as safe and effective for that use.


What does "approved as safe by the FDA" really mean?

FDA does not guarantee the safety of FDA-approved drugs

FDA approval of a drug as safe does not automatically mean that the drug has been subjected to a properly controlled scientific evaluation and follow-up of individuals exposed to the direct and indirect effects of the drug. The Director of the FDA's Bureau of Drugs has confirmed in writing that the FDA does not guarantee the safety of any drug-not even those drugs which the FDA has officially approved as safe.

Dictionary and FDA differ on definition of safe

When the FDA does use the term "safe" the agency does not use the definition, "free from harm or injury," which is found in every U.S. dictionary. To the FDA the term "safe" is a relative term, based on data on the known risks and what the FDA considers to be the acceptable potential risks and benefits of the particular drug.


How can one tell if the FDA has approved a drug as safe for a particular use?

Only those uses of a drug which are mentioned in the "Indications" section of the package insert are FDA- approved uses of the drug

The fact that a use of a drug is mentioned in a section of the package insert other than the "Indications" section does NOT in itself, indicate FDA approval of that use. If, for example, the section of the package insert entitled "Usage in Pregnancy/Obstetrics" mentions the use of the drug during pregnancy, obstetrics (labor and delivery), or lactation but such uses are not specifically mentioned in the "Indications" section, then the FDA has NOT approved the drug as safe for use in pregnancy, labor, delivery, or lactation.

Absence of contraindication(s) no guarantee of safety.

The absence of a contraindication to a specific use or condition such as infancy, childhood, pregnancy, elderly, etc., in the package insert does not mean that the FDA has approved the drug as safe for that intended use.


How does the FDA determine whether a drug is safe?

FDA relies on manufacturer's honesty regarding drug's safety

The FDA now requires the drug sponsor (manufacturer) to carry out animal studies (rats, mice, etc.) and three phases of human testing. However, the manufacturer's data on safety are usually accepted in good faith by the FDA. The FDA does not check all data to make sure the data submitted are not inaccurate or fraudulent unless there is reason for the agency to believe otherwise.

Valid comparison not required.

The FDA does NOT require a drug manufacturer to use a research study design that permits a valid comparison between drug-exposed and non-exposed research subjects.

Data on safety withheld from public scrutiny

The FDA does not allow concerned consumer groups or responsible citizens to examine the design of the research study, or to check the accuracy of the manufacturer's data presented to the FDA. Without such examination it is almost impossible for concerned individuals or groups to effectively challenge the appropriateness of the study's design or the accuracy of the data before the drug is approved by the FDA.

FDA accepts unpublished data as evidence of drug safety

Although the scientific community questions the validity of research data which have not been subjected to review by specialists with equal or greater knowledge before publication in a recognized medical journal, the FDA accepts unpublished data from the manufacturer as evidence of a drug's safety.

Data may be biased due to economic pressures

Data accepted by the FDA as evidence of a drug's safety may be prepared by researchers who are in the employ of or under contract to the manufacturer of the drug, or by researchers who are members of university departments receiving grants or gifts from the drug's manufacturer.

Combinations of separate drugs not required to be tested for safety

Only single drugs are evaluated for approval. Common combinations of separate drugs are not usually subjected to any review for adverse reactions by the FDA. Combinations which are known to be ineffective or unsafe, however, may sometimes be noted in the package insert.

Many drugs bypass FDA's advisory committees

Many drugs approved as safe are allowed to bypass the deliberations of the outside experts who make up the FDA advisory committee responsible for the category of drugs under which the drugs in question fall. While the outside experts have been faulted for having a pro-specialty bias, their participation in FDA deliberations at least broadens the base for decision-making.

"Me too" drugs approved without adequate scientific evaluation

A drug may be approved as safe for a specific use merely because it is similar to a drug already on the market-even though the old drug was never subjected to a properly controlled scientific investigation or follow-up to determine its safety when used in general medicine, under non-research conditions.


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Who has access to FDA data on "safety"?

FDA declares research data on safety to be "trade secret'; therefore withheld from public scrutiny

The FDA does not allow concerned consumer groups or responsible citizens to examine the design of the research study, or to check the accuracy of the manufacturer's data presented to the FDA. Without such examination it is almost impossible for concerned individuals or groups to effectively challenge the appropriateness of the study's design or the accuracy of the data before the drug is approved by the FDA.

Despite repeated objections by various federal investigative panels the FDA continues to classify as "trade secrets" the raw (basic) data on safety which the manufacturer presents to the FDA when seeking the agency's approval of the drug. Such a classification makes the data unavailable to concerned groups which have reason to believe there may have been serious flaws in the design of the study on safety, including the possibility of deliberate exclusion of subjects who may have been adversely affected by the drug.

Proposed new drug bills would legalize FDA's withholding data on safety from the public

The FDA supports the proposed Drug Regulation Reform Act and similar bills which, if enacted, would classify the manufacturer's basic data on safety as a "trade secret" as a matter of law rather than FDA preference. If enacted, this bill would put the information permanently beyond public scrutiny.


Who determines the safety of drugs?

Makeup of FDA advisory committees suggests professional bias in decision-making

Members of FDA advisory committees, who analyze the relative benefits and risks of a drug, are usually chosen from the ranks of the specialty which administers the category of drugs on which they are asked to deliberate. Seldom do the committees include a balance of experts who must deal with the adverse effects of the drugs under deliberation. For example, the FDA's Anesthetic and Life Support Drug Advisory Committee is made up almost exclusively of anesthesiologists. Neurologists and internists, who deal with some of the very serious adverse effects of surgical and obstetric anesthesia, are not included as members of that advisory committee.

FDA reluctant to divulge names of FDA officers responsible for approving specific drugs

The FDA remains unclear as to whether this information may be requested and obtained under the Freedom of Information Act. Requesting information through one's U.S. Senator or Representative is more likely to get results. (If you need the full name and address of your Senator or Representative, your local library or newspaper will provide you with that information.)


Does the FDA make an effort to determine if there are delayed adverse effects of drugs?

Public used to determine delayed adverse effects of drugs

The FDA does not require, as part of the approval process, that the manufacturer of the drug carry out a systematic, long-term follow-up of individuals exposed to the drug. Nor does the FDA have any system of periodic review of drug effects once the drug is on the market.

Negative or adverse effects of drugs may only appear after widespread use. The lack of follow-up to evaluate the effects on the child of drugs ingested by or administered to the mother during pregnancy, childbirth, and breastfeeding is particularly irresponsible since no drug has been adequately tested for safety in regard to the exposed offspring.

System for collecting data on adverse effects inadequate

An investigation by the U.S. General Accounting Office (the federal "watchdog" agency) of the FDA's policies, procedures, and systems found a notable discrepancy between the data collected by the FDA's adverse reaction reporting system and that data which appeared in the published literature. In the case of one fetal effect, that effect appeared 20 times more often in the published literature than the incidence noted by the FDA. FDA explanations for the incomplete data include not putting research literature reports into the computer system and physician reluctance to report adverse drug reactions to the FDA.

FDA relies on manufacturer for information on adverse effects

In reviewing the safety of drugs already on the market, the FDA tends to rely on the manufacturer to keep the agency current in regard to the adverse effects of his products. Understandably, a manufacturer is not anxious to report adverse reactions to his product because of the possibility of loss of sales and of litigation resulting from drug induced injury.


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How does the FDA handle adverse reaction reports?

Physicians not required to report adverse drug reactions to FDA

The FDA has no legal authority to require physicians, nurses, or other health professionals to report adverse drug reactions to the FDA. Therefore, there is no way the FDA can determine the exact rate of adverse reactions to an FDA-approved drug when it is used in general medicine under non-research conditions.

Changing an adverse reaction "Report" to an "Inquiry" removes manufacturer's legal obligation to inform FDA

The FDA does require drug manufacturers to file with the FDA all adverse drug reaction reports received from physicians. However, the manufacturer can avoid filing such a report if the physician can be persuaded to change a "Report" to an "Inquiry," which the manufacturer is not required to file with the FDA.

FDA makes no real effort to facilitate public inquiry or reporting of adverse reactions

The FDA does not require the manufacturer to note in the drug's package insert the name and address of the FDA division responsible for evaluating the safety and effectiveness of the drug in order to facilitate reporting of an adverse drug reaction or a request for information by concerned consumers.

FDA seldom follows up on adverse reaction report by consumers

If a patient reports an adverse drug reaction to the FDA but the prescribing physician refuses to provide the FDA with the patient's medical records, the FDA will usually not follow up and investigate the consumer's report. To obtain a copy of your hospital medical records see What You Can Do.


What if a physician uses a drug for a non-approved use?

Physician is free to use drug in ways not approved as safe by FDA

The FDA cannot prohibit a physician from using a drug for a use not approved by the FDA. However, in the event of drug-induced injury, the use of a drug not approved for such use by the FDA may affect the court's decision should litigation arise.


Can one trust the information in the "package insert"?

Package insert is written by the manufacturer

In the majority of cases, the information in the package insert is written by the manufacturer. The text is then submitted to the FDA. If deemed appropriate, the text is approved by the FDA. The result is that the text of many package inserts (especially those drugs used in obstetrics) appears to be purposely ambiguous when discussing the drug's known adverse effects, the inherent risks, and the relevant "areas of uncertainty" regarding the delayed, long-term effects of the drug on human development and neurologic functioning.

Information in insert is rarely current

Whether due to FDA inertia or pressure from the pharmaceutical industry, once information is known regarding a drug's adverse effects it may be years before that information appears in the package insert (if it ever appears at all).

FDA officers have publicly acknowledged that there is significant under-reporting of adverse drug reactions by physicians because of fear of litigation following such reports. Yet the FDA continues to rely on reports from physicians and manufacturers as the primary sources of information for the package insert.

The FDA's other source of information is articles published in the medical journals, most of which appear a year or more after the research findings are known. Unfortunately most of the researchers who write the articles tend to share the bias (and fear of litigation) shown by the medical specialty which sponsors or is served by the journal. In addition, many researchers receive research grants and other remuneration from the very drug companies whose products they publish articles about.

Insert vague on date of last FDA review

The FDA has chosen not to identify the date printed on the package insert as being either the date of the last reprint of the insert or the date of the last FDA review of the research data on the drug. The reader of a package insert, therefore, has no way of knowing if the package insert reflects the current state of knowledge regarding the drug.

No system for retrieving drug information according to use

The FDA has no ready means of identifying those drugs which the agency has approved for a specific use (such as for high blood pressure, diabetes, pregnancy, obstetrics, etc.), according to the Office of Consumer Safety. The FDA has chosen to store drug information in its computer according to the drug's generic (chemical) name and by the manufacturer's trade name, but not according to indication (approved use). In other words, the FDA has chosen not to store in the computer that information which could identify whether a drug has or has not been approved by the FDA for a specific use.

FDA does not distinguish between exhaustive scientific investigation and cursory evaluation in the package insert

The FDA has provided no system to enable the reader of the package insert to distinguish between those uses of the drug which have been subjected to a controlled scientific investigation, evaluation, and FDA review before being approved as safe by the FDA and those uses of the drug approved as safe by the FDA after relatively superficial testing and review, or because the drug is similar to a drug already on the market.


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Can the consumer get the package insert?

FDA quiet regarding consumer access to drug information

There is no state or federal law which prohibits the pharmacist from giving the consumer the package insert which comes in the carton of prescription drugs.
However, the FDA has made no significant effort to inform the public that this information can legally be made available to consumers by pharmacists, or that the same information in the package insert can be found in the PHYSICIANS' DESK REFERENCE, found in most libraries.

The enactment of state laws requiring the licensed pharmacist to offer the consumer the opportunity to read or copy the package insert of the prescribed drug, prior to purchase, would help the consumer to make a
more informed decision as to whether to take or forego the drug.

Pharmacists are required to supply FDA-approved patient package inserts (PPIs) with all estrogen drugs

To date, the FDA has not taken punitive action against pharmacists who fail to comply with the law. In the event of drug-induced injury, the pharmacist's failure to protect the consumer from harm may affect a court's decision in favor of the consumer if a lawsuit should be brought.



How Safe Are the Drugs Administered to childbearing Women?

Majority of drugs given to pregnant and lactating women never approved by the FDA as safe for such use

Although dozens of different drugs are prescribed for or administered to women during pregnancy, labor, birth, and lactation, approximately 12 have actually been approved by the FDA as "safe" for such use. As mentioned on page 1, the fact that the package insert mentions use of the drug during pregnancy, labor, delivery, and lactation does not mean that the FDA has approved the drug as safe for such use. Unless a term such as "pregnancy" "labor", "delivery" or "lactation" is specifically mentioned in the "Indications" section of the drug's package insert the FDA has NOT approved the drug for that purpose.

No drug has been proven safe for the unborn child

The Committee on Drugs of the American Academy of Pediatrics has cautioned that there is no drug, whether an over-the-counter remedy or a prescription drug, that has been proven to be without risk for the unborn infant when that drug is taken by or administered to a childbearing woman.

No FDA requirement that obstetric drugs be proven safe for the unborn child

The criteria used by the FDA to determine the relative safety or risk of an obstetric-related drug (a drug administered to women during labor and delivery) have not included a requirement that the drug be proven safe for the unborn child exposed to the drug in utero (in the womb).

None of the methods currently accepted by the FDA to evaluate the effects of drugs on the offspring is sensitive enough to detect subtle neurologic damage, i.e., learning disability, minimal brain dysfunction, dyslexia, hyperkinesis, perceptual handicap, attentional deficit disorders, etc.

FDA's illogical code of ethics regarding drugs and childbearing women

The FDA has taken the position that it is unethical to test drugs in pregnant women by means of controlled clinical trials and follow-up. Yet the FDA approves the use of drugs as safe for use during pregnancy, labor, and birth without requiring an initial or subsequent long-term, controlled follow-up on a limited number of the exposed offspring in order to determine if there are delayed adverse effects of the drug.

Neither "old" nor new obstetric drugs (and devices) adequately tested for safety

Of those few drugs approved by the FDA as safe for use in pregnancy and obstetrics, there is no evidence that the FDA made its decision on the basis of appropriate, properly controlled, scientific investigation in humans. The safety of many "old" drugs used in obstetrics today was determined by studying the effects of the drug on men, postmenopausal women, and one or sometimes two species of animals and extrapolating those effects.

As previously mentioned, the FDA does not require, prior to giving approval of a drug for obstetric use, that a controlled investigation and long-term follow-up be carried out on infants exposed to the drug in utero (hereafter referred to as "the exposed off-spring"). Yet such a follow-up is essential in order to determine whether or not a drug may have latent, delayed, long-term, adverse effects on the subsequent physical, neurological, and mental development of the exposed offspring. The FDA does not even require that such an investigation and follow-up be carried out in primates (whose neurologic system is closest to that of human offspring) before the FDA approves the drug as safe for use as an obstetric drug.

FDA rehashes outdated, uncontrolled data

Although there was no control group of healthy, unmedicated mothers included in the Collaborative Perinatal Project (1959-1965) to serve as a baseline against which to measure deviation from normal human development in the offspring, the U.S. Department of Health and Human Services and the FDA continue to examine that data rather than utilizing more current scientific methodology

FDA has no way of accurately determining the Benefit/risk ratio of an obstetric drug for the offspring

The FDA has not required the manufacturers of obstetric drugs to investigate the effects of their drugs on the subsequent physical and neurologic development of the exposed offspring beyond the first minutes of life. Therefore, it is impossible for the FDA to accurately determine the risk/benefit ratio of a drug as it pertains to the exposed offspring. Nor can the FDA know whether a drug's effect observed in the newborn infant is significant unless such an investigation and follow-up is carried out.

A minimum of 10 years would be required for such a follow-up. A drug's more subtle effects on brain function may not become apparent until the child reaches at least the age of eight, when the brain is called upon to carry out more analytic tasks, such as those necessary for mathematical division, etc. (Our experience with DES has taught us that it may take 20 years before we know the effect of a drug (or medical procedure) on the physical development of the offspring.)

Outmoded method for assessing newborn still accepted by FDA

None of the current methods accepted by the FDA as evidence of safety have been proven effective in determining a drug's more dysmorphogenic properties--the ability of a drug to cause functional or structural abnormality~ The FDA has traditionally considered the offspring to be essentially unaffected by drugs administered to the mother if the infant scores 7 or above (on a scale of 10) on the Apgar Scale at one minute after birth. The Apgar Scale rates two points each for normal: (a.) heart rate, (b.) respiration, (c.) muscle tone, (d.) response and (e.) skin color. The rating is crude and subject to bias since frequently it is based on the opinion of those responsible for the infant's delivery.

The American Academy of Pediatrics' Committee on Drugs has cautioned that the Apgar Score will identify only the most gross signs of neurologic dysfunction or brain damage. A follow-up by the National Institutes of Health of over 50,000 children revealed that among the children subsequently found to have cerebral palsy, 43% had been diagnosed as normal when they were discharged from the hospitals' newborn nurseries.

FDA ignores its own guidelines for evaluating neurotoxicity in newborns

The FDA's own guidelines for the evaluation of drugs used in pregnant women and in children* note that drugs circulating in the bloodstream of the newborn infant can penetrate the infant's brain. Drugs trapped in the infant's brain at birth can adversely affect the rapidly developing nerve circuitry of the brain and central nervous system by altering the following brain processes:

a. Neuronal maturation: the rate at which the nerve cells in the brain mature

b. Cell differentiation: the process by which the brain cells develop individual characteristics and capacity to carry out specific functions

c. Cell migration: the process by which the brain cells are guided into their proper place within the brain and central nervous system

d. Dendritic arborization: the interconnecting of the branch-like nerve fibers as the circuitry of the brain is formed

e. Myelinization of nerve fibers: the forming of an insulating sheath of myelin (fat-like substance) around the nerve fibers. This insulation helps to assure that the nerve impulses-the messages to and from the brain-will travel their normal route at the normal rate of speed.

Any alteration in the development of the intricately complex nerve circuitry of the brain has the potential for permanently altering the way the brain processes and responds to information. Yet the FDA does not require the manufacturer to state in the package insert the fact that the delayed, long-term effects of the drug on the subsequent neurologic development of the exposed offspring are unknown.

The implication of these changes in brain circuitry were succinctly stated by Dr. Donald Tower when, as Director of the National institute of Neurological and Communicative Disorders and Stroke, he cautioned:

"It is the biochemical circuitry-the biochemical messengers and the relevant nerve cells in the brain-that form the basis for mankind's behavior."

* "General Considerations for the Clinical Evaluation of Drugs in Infants and Children," HEW (FDA) No.77-1977, U.S. Govt. Printing off., Wash., DC 20402

"Criteria for exclusion" permitted to bias research conclusions

The FDA appears to make no effort to evaluate how the "criteria for exclusion" (reasons for excluding an infant from the group to be tested) skew the findings of safety in regard to the infant. For example, many studies of FDA approved obstetric drugs excluded from testing any infant born to a healthy mother who received an epidural block during labor if that infant showed evidence of severe intrauterine trauma and/or an abnormal physical or neurologic condition at birth or during the postpartum period (the first days of life). These exclusions ignore the fact that the trauma and abnormal conditions observed in the infant could have been caused by the drugs administered to the mother during labor and birth.


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Who determines the "safety" of obstetric drugs in regard to the unborn infant?

Obstetricians, not pediatricians, decide the safety of drugs administered to childbearing women

It is well recognized that it is the fetus and newborn infant who are the most vulnerable to the adverse effects of obstetric-related drugs. Yet the FDA relies primarily upon its Fertility and Maternal Health Drugs Advisory Committee (FMHD), comprised essentially of obstetricians, for advice on the safety of new drugs and also of drugs currently marketed for use in childbearing women. No expert specifically concerned with the effects of obstetric drugs on the subsequent development of the exposed offspring nor any interdisciplinary consultants regularly attend the FMHD Advisory Committee meetings.

The obstetricians who make up the FDA's FMHD Advisory Committee are aware that if they recommend that the FDA remove its approval of a drug used in obstetrics, they will increase the possibility of malpractice litigation for themselves and their colleagues who have had "trouble" with the drug. Their own self interest works against their recommending that the FDA remove its approval of a drug for use in obstetrics unless there is blatant evidence of danger. Such self interest results in a considerable effort being made to avoid wording such as "inadvertent" or "accidental" in the package insert since such words suggest malpractice.

FDA refuses to establish a perinatal drug committee

The FDA has no advisory committee or department which has the expertise to evaluate the effect on the child of drugs used in pregnancy and/or obstetrics. The FDA has refused repeated appeals to establish a multidisciplinary perinatal drug advisory committee to consider the effects on the child of drugs administered to the mother during pregnancy childbirth, and lactation.


How reliable are the package inserts for obstetric drugs?

FDA permits manufacturers to imply that the major risk to the fetus is limited to the first three months of pregnancy

The FDA permits manufacturers to use statements such as, "This drug should not be taken during the first three months of pregnancy" (or words to that effect), which imply that the fetus is at risk for serious adverse drug effects only if the mother is given the drug during the first trimester of pregnancy.

While the formation of the fetal heart and other internal organs is relatively complete by the end of the first three months, the fetal brain and the nerve circuitry which make up the fetal central nervous system (CNS) are developing very rapidly around the time of birth. Therefore, the circuitry of the brain and the rest of the CNS of the fetus and newborn infant are vulnerable to drug-induced damage at that time.


Evasive wording permitted in package insert

Manufacturers are permitted to use wording in the package insert which implies that a serious adverse reaction to the drug will occur in the mother, the fetus, or the newborn infant only if the mother is "hypersensitive" to the drug. In one recent study, one out of every four infants whose mothers received only 50 mg. of meperidine during labor (considered by many to be a minimal dose) showed signs of neurologic depression at birth.

The FDA permits manufacturers to state in the package insert that a drug has "no significant effect on fetal development," or words to that effect, even though the manufacturer has made no effort to carry out, and the FDA has not required, a controlled scientific investigation and longterm follow-up of the exposed offspring to determine whether an observed effect in the newborn is or is not significant to the child's physical and neurologic development.

Another example of evasive wording the FDA permits manufacturers to use is the statement, "Safe use in pregnant women other than in labor has not been established" (or words to. that effect). Such a misleading statement implies that the drug has been proven safe for use during labor when, in fact, no such proof exists.

Manufacturers permitted to bury warnings on serious risks

Until 1983 the FDA permitted the manufacturers of bupivacaine, a drug frequently used in epidural block, etc. to note some of the drug's most serious adverse effects under the section of the package insert entitled 1'Allergic Reactions", far removed from the section entitled 1'Usage in Pregnancy" or "Use in Obstetrics" under which such adverse effects should he noted.

The 1983 package insert of bupivacaine contains the following cautions:

"Local anesthetics rapidly cross the placenta, and when used for epidural, caudal or pudendal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity. Adverse reactions in the parturient, fetus and neonate involve alteration of the central nervous system, peripheral vascular tone and cardiac function."

"Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia; paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control all of which may have slow, incomplete or no recovery; headache, backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid."

FDA officers responsible for approving and overseeing the drug and its package insert continued to permit the manufacturer to note these serious adverse effects under the inappropriate section headed "Allergic Reactions"-long after the situation had been brought to their attention.

Despite the growing concern that regional block anesthesia (epidural, spinal, etc.) may he contributing to the rising rate of cesarean section in the U.S., the FDA has made no effort to investigate whether regional block anesthesia increases the need for cesarean section performed because of dysfunctional labor and/or fetal distress.

Most dangerous effects of obstetric drugs frequently omitted from package insert

The loss of the gag reflex is one of the most dangerous effects of obstetric drugs. If the drugged mother retches vomitus or gastric fluid and her gag reflex fails to prevent the acidic, caustic substance from being inhaled into her lungs, pneumonia or a life-threatening condition called
"aspiration of vomitus" can result. This condition can also occur in the newborn infant whose neurologic system is depressed by its mother's obstetric drugs. Yet these effects are not mentioned in the package insert of those drugs which can cause these hazardous neurologic dysfunctions. (Administering an antacid to the mother during labor will reduce the acidity of her stomach. However, aspiration of the antacid can create problems in itself.) The true incidence of suffocation or chemical pneumonia resulting from aspiration of vomitus is unknown. Death certificates are not always specific, and physicians are reluctant to report such occurrences to the FDA.

Another very dangerous but unmentioned adverse effect occurs when the obstetric drug is inadvertently injected into the mother's bloodstream, into the wrong area of her spine, or into the fetus itself. The result can be a neurologic shutdown for the mother or her baby. Yet the manufacturer is not required to note this very real possibility and its potential effects in the package insert.

These dangers are intensified il the anesthetic agent or block is administered by a nurse-anesthetist when no physician is present to handle a sudden, drug-induced emergency.

Time of fetal exposure to obstetric drug not required in package insert

With rare exception, those drugs administered to the mother during labor and delivery, including pudendal block and local perineal infiltration, rapidly filter through the placental membranes and enter the fetal circulation and brain. The drugs and their metabolites, which for some drugs are equally hazardous, continue to circulate in the fetal blood, brain, and other organs during labor and for several hours or days alter birth.

Drug manufacturers are not required to note in the package insert the average lapse of time between administration of the drug to the mother and the time the drug enters the fetal circulation. Nor are they required to note the number of hours or days the drug and its metabolites can still be detected in the blood of the newborn infant. This information is important to pediatricians and others caring for and prescribing for the newborn infant.

Biochemical factors determine drug's effect

The effects on the unborn child of a drug administered to or taken by the pregnant or parturient (laboring) woman depend on many factors:

a. the skill and training of the health care provider,
b. the type and quantity 9f the drug,
c. when and how often the drug is administered,
d. the condition of the mother, the placenta, and the fetus when the drug is administered,
e. the interaction of the drug with other drugs, etc.

If all biochemical factors are favorable, the development of the exposed offspring may not be affected, or at least not to any discernible degree. Unfortunately, it is impossible to predetermine how an individual fetus will be affected by a drug or combination of drugs adininistered to the pregnant woman.


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Can one get a list of those drugs which have been approved by the FDA as safe for obstetric use?

FDA unable to single out those drugs the agency has approved for use in obstetrics

Until recently the FDA did not appear to show particular concern regarding the adverse effects on the fetus of the various drugs ingested by or administered to pregnant and parturient women. Efforts to obtain from the FDA a list of obstetric-related drugs which have been approved as safe for such use by the FDA have proven fruitless.


What about the FDA's risk categories for obstetric drugs?

Categories of obstetric-drug risk tend to give a false sense of safety

The FDA has established five categories to indicate a drug's potential for causing birth defects. However, even drugs in Category "A" (the category of least risk, in which well controlled studies in women have failed to demonstrate immediate risk to the fetus) have not been tested to determine whether or not there are delayed, long-term risks to the physical and neurologic development of the exposed offspring.


What about ultrasound and medical devices such as fetal monitors?

Same flaws seen in FDA regulation of medical devices

The general policy of the FDA's Center for Devices and Radiological Health is to notify manufacturers and physicians, but not the public, when the agency becomes aware of a "problem" with an FDA approved medical device.

The FDA approved the use of ultrasound (high frequency sound) for fetal imaging (sonogram) and fetal monitoring during labor without requiring manufacturers of the devices to advise the physician and the patient that the delayed, long-term effects of ultrasound on the subsequent development of the fetus, and especially on the ova of the female fetus, are unknown.

In February 1984 an FDA/NIH panel of experts issued a statement recommending against the routine use of ultrasound in obstetrics, stating that "there is not enough evidence that routine screening with ultrasound benefits either the mother or the fetus." The panel recommended that ultrasound be used only when there is a valid medical indication. That note of caution was expressed earlier by FDA officials during a Senate hearing on obstetric management in 1978. Unfortunately, the general public does not read federal proceedings, nor would they have heard FDA officer Marion Finkel in 1979 when she summarized the FDA's concern to health professionals:

"Increasing concern has arisen regarding the fetal safety of widely used diagnostic ultrasound in obstetrics. Animal studies have been reported to reveal delayed neuromuscular development, altered emotional behavior, EEG (brain wave) changes, anomalies, and decreased survival. Genetic alterations have also been demonstrated in vitro systems."

Several major research studies have failed to show that routine electronic fetal monitoring improves maternal and infant outcome except in very high-risk mothers. The fact that the FDA waited several years before bringing this and the above information to the attention of the public via a news release or the FDA Consumer magazine has led the public to assume falsely that diagnostic ultrasound used in fetal imagery and fetal monitoring is without risk.

For further information read the report of the FDA's
Center for Devices and Radiological Health entitled An
Overview of Ultrasound: Theory, Measurement, Medical
Applications, and Biological Effects. HHS Publication,
FDA 82-8190, U.S. Govt. Printing Office, Washington,
DC 20402.


Does the FDA's magazine for consumers deal truthfully with the risks of approved drugs and devices?

FDA magazine for consumers withholds information on risks

The FDA Consumer magazine, prepared and published by the FDA, frequently withholds from the public information on the serious side effects, risks, and pertinent areas of uncertainty regarding the drugs and devices discussed in articles which appear in that publication.



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What You Can Do:

Get the Package Insert

For information regarding a specific drug, ask your physician or pharmacist for a copy of the package insert, or consult the PHYSICIANS' DESK REFERENCE (PDR) at your pharmacy or local library The information in the PDR is usually the same as that in the package insert. However, keep in mind that the information, while approved by the FDA, is actually written by the manufacturer. (Some drugs are not listed in the PDR, or if listed, the text of the package insert is not included. The FDA does not require manufacturers to list their drug products in the PDR.)

II your pharmacist refuses to give you the package insert or to allow you to read it or the relevant pages in the PDR, find another pharmacist who will allow you to read the information. Feel free to return the unopened drug for a refund if, after reading the package insert information (from another source), you decide against taking the drug.

A generic package insert is not a substitute for the manufacturer's package insert since it may not contain the information you need to make an informed decision as to whether or not to take the drug.

If your public library does not have the latest PDR, which is published annually, ask the librarian to order it.

Check for Drug Interactions

Check with your pharmacist as to the interaction of the drug with food, beverages, or other drugs you are taking.

Keep a Record

Save prescription labels. Keep a record of all drugs taken brand name, generic name, amount prescribed, and
number of times taken. In the case of pregnancy, keep a record of all drugs taken during pregnancy (beginning with the date of the last menstrual period), labor, birth, and breastfeeding. Remember, the overwhelming majority of drugs have never been evaluated for use in obstetrics.

Drugs and the Elderly

II you have a member of your family in a nursing home or institution, ask to read the package inserts of the drugs he or she is being given. Over-medication or improper medication can produce "chemical senility."

If the drugs are supplied by an independent pharmacist, withholding payment to the pharmacist until the desired information is provided frequently brings quick results.

Additional Reading

Check with your local library for consumer-oriented books which discuss drug actions and interactions (i.e., "The People's Pharmacy" "Pills, Politics and Profits", "Pills That Don't Work", etc.

Information Source

For information unavailable elsewhere, or to report an adverse drug reaction or a suspected drug-related birth defect, write to:
Assoc. Commissioner, Office of Consumer Affairs
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857

Getting Your Hospital Medical Records

In the event of hospitalization, obtain and preserve a complete copy of your hospital medical records. If hospitalized for childbirth, also obtain and preserve a complete copy of your infant's hospital medical records, including nursing notes, lab reports, brand name of fetal monitor (long-term effects of ultrasound are unknown), any x-rays, fetal monitor strip charts, etc.

The following states have laws or regulations providing the patient with access to his/her hospital medical records from the hospital's Medical Records Administrator:
Alaska Ill. Md. Mo. Okla. S. Dak.
Calif. Ind. Mass. Nev. Oregon Tenn.
Cob. Ky. Mich. N.J. Penn. Virg.
Conn. La. Minn. Ohio R.I. Wisc.
Fla. Maine Miss.

A model statute providing for patient's access to their hospital medical records is available from the National Women's Health Network for $1.00.

Legislation

Ask your state senator and representative to sponsor a bill which will require pharmacists to provide consumers with a copy of the package insert for their prescription drugs and a bill which will protect health professionals, particularly nurses, from punitive action by the hospital if they report an adverse drug reaction to the FDA.


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BIBLIOGRAPHY:

Final Report: Joint Commission on Prescription Drug Use, January 1980, Department of Health, Education and Welfare (DHEW).

Final Report: Review Panel on New Drug Regulation, DHEW, May 1977.

General Accounting Office Report, Evaluating Benefits and Risks of Obstetric Practices, HRD-79-85A, September 1979.
"The Brain," Scientific American 241: 44-246, September 1979.

"Medical Records: Getting Yours," Health Research Group, Wash., DC, 1980.

"Pregnant Patient's Bill of Rights," American Foundation for Maternal and Child Health, New York.

Author's Acknowledgment

Many FDA officers, staff members, and advisors contributed to the information in this report. The author is especially grateful for the encouragement and counsel of Sumner J. Yaffe, M.D., former Chairman of the Committee on Drugs of the American Academy of Pediatrics and presently Director Center for Research for Mothers and Children, National Institute of Child Health and Human
Development. -Doris Haire

To Order Copies:

Copies of this publication are available at $1.50 each (includes postage and handling) from either of the following organizations.

National Women's Health Network
224 Seventh St., S.E., Washington, DC 20003
or
American Foundation for Maternal and Child Health
P0. Box 6464, New York, NY 10022


"Every American who reads the Haire report on the FDA will be better informed and therefore safer for having read it."

U.S. Representative Albert Gore, Jr.
Chairman, Investigations and Oversight Subcommittee, House Science and Technology Committee; Member, Energy and Commerce Committee

"This is an extremely careful piece of work that will be of value to all who read it. The report makes obvious the need for legislation which will require the FDA to open up its drug approval process to public scrutiny"

Professor Norman Dorsen
New York University School of Law
F6rmer Chairman, Review Panel on New Drug Regulation,
HEW Faculty Food and Drug Law Institute

"The Haire report serves the public interest in bringing attention to the fact that FDA approval of a drug does not mean that pregnant women taking the drug will not suffer harm or injury Pregnant women run inherent risks in taking any prescription or over-the-counter drug, even those approved by the FDA."

U.S. Representative Douglas Walgren
Chairman, Science, Research and Technology Subcommittee, Science and Technology Committee
Member Energy and Commerce Committee

"We need a balanced view of drugs. While rightly enthusiastic about the benefits of medicine, our society is too sanguine about its safety Consumers need to know that no drug is risk-free.
"The freedom to control one's own body as well as its rhind is an essential civil liberty But like other freedoms, it is best enjoyed when choices are informed, when the market-place of information is open to diverse sources, and when these sources engage in lively debate. Doris Haire's pamphlet contributes to these ends."

William W. Vodra, Esq.
Former legal counsel to the U.S. Food and Drug Administration

"Few expectant parents realize that among the hundreds of drugs administered to pregnant women little more than a dozen have been approved by the FDA as safe for use in obstetrics. Nor do they realize that even am6ng those drugs approved as safe none have been adequately tested. Expectant parents owe it to their unborn children and to themselves to read this pamphlet so as to be able to make informed, intelligent decisions about the drugs they take."

U.S. Representative Jonathan Bingham



The National Women's Health Network

You can keep up to date on the latest health and medical information for women by becoming a member of the National Women's Health Network. You'll receive bimonthly newsletters and emergency alerts requiring immediate action. Through the Network, you can link up with groups and individuals m: your region who are working on the issues of patients' rights, drug safety, and women's health advocacy. For more information write:

NWHN, 224 Seventh St., S.E., Washington, D.C. 20003.

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