Pharmaceutical Risk Management for Physicians

While Risk Management seeks to minimize liability, Risk Avoidance attempts to avoid liability.

  • PRM Guideline 1
    • If you do not prescribe or administer a drug to a patient, your patient cannot have an adverse drug reaction (ADR) to it.
    • Limit prescribing drugs to situations where the need for pharmacotherapeutic intervention is clearly indicated.
  • PRM Guideline 2 – Before prescribing a new drug, take an adequate drug history to determine:
    • (1) if your patient is currently taking any other medications prescribed by yourself or another physician,
    • (2) if your patient is currently taking any Over-the-Counter (OTC, nonprescription) medications such as NSAIDs (e.g., ibuprofen or naprosyn), H-2 Receptor Blockers (e.g., cimetidine, ranitidine or famotidine), or analgesics or “Health Foods”.
  • PRM Guideline 3 – Always begin with the lowest possible dose and titrate upwards cautiously.
  • PRM Guideline 4 – Before prescribing any medication, always provide your patient with an adequate Informed Consent instruction (see section on Informed Consent for a discussion of the components of an adequate warning) and make a note in the patient’s chart that you have discussed the benefits and risks of the proposed therapy with your patient. You may also find it helpful to ask your patients to maintain a daily diary or journal in which they can record their response to therapy using the following simple scale: -2, -1, 0=No Change, +1, +2. The patient should also be asked to record any symptoms of drug intolerance such as: nausea, rash, diarrhea, etc. In your Informed Consent warning, be certain to instruct your patient about which potentially serious ADRs your patient should call you to report. For example, antibiotics, NSAIDs and anticonvulsants can cause severe, life-threatening rashes like Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) which require immediate discontinuation of medication, medical intervention and, possibly, hospitalization.
  • PRM Guideline 5 – Exercise extreme caution when prescribing new drugs which have been approved within the past 1-2 years. These drugs have only been tested in small populations (e.g., 2,500-5,000 patients) of selected patients and complete safety data on serious but rare ADRs (e.g., incidence<1 in 10,000) have not as yet been compiled. According to a study conducted by the US General Accounting Office (GAO) on the Postapproval Risks of 198 drugs approved by the Food and Drug Administration (FDA) between 1976-1985, 102 (or 51.5%) had serious postapproval risks, as evidenced by labeling changes or withdrawal from the market. The GAO study, FDA Postapproval Risks 1976-85 (GAO/PEMD-90-15) is available by calling (202)-275-6241 or by writing to: P.O. Box 6015, Gaithersburg, MD 20877. Remember that after this study was published, Omniflox (temofloxin) was withdrawn from the market June 9, 1992, just 5 months after its introduction to the market. Felbamate (Felbatrol), a new anti-seizure medication was withdrawn from the market in August 1994 due to the appearance of an unacceptable incidence of aplastic anemia. Other notable drug withdrawals during the 1980s include Zomax and Oraflex.

Characterizing Adverse Drug Reactions (ADRs)

Types of Reactions

  1. Acute Drug Overdose – The consumption of Prescription Drugs, OTC Drugs, Illicit Drugs, Combinations of drugs, frequently including alcohol in doses large enough to produce an undesirable toxic reaction. The severity of such a reaction could be as mild as sedation, or so severe that it is life threatening.
  2. Drug Side Effect – A therapeutically undesirable but unavoidable pharmacologic action of a drug (e.g., sedation associated with antihistamines, or dry mouth with anticholinergic drugs like tricyclic antidepressants).
  3. Secondary Drug Effect – Additional drug effects unrelated to the drug’s primary (therapeutic) pharmacologic action (e.g., corticosteroids and the development of Cushingoid Symptoms).
  4. Drug Interaction (pharmacokinetic and pharmacodynamic) – Action of one drug on the effectiveness or toxicity of another concomitantly administered drug (e.g., Ca++ & Mg++ antacids chelate tetracycline antibiotics and prevent their complete absorption leading to a failure to cure the infection for which the tetracycline was prescribed, and amoxicillin decreases the effectiveness of estrogen-containing oral contraceptives leading to unwanted pregnancies. For a comprehensive discussion of drug interactions including a helpful tabulation of common mechanisms and interactions see: Benjamin, DM and Buckman, RW, Minimizing the Risk of Adverse Drug Interactions, The Female Patient, 1996;21:47 (April 1996).
  5. Teratogenicity – First trimester administration of known teratogens like Accutane (isotretinoin), anti-seizure medications like the hydantoins, and carbamazepine, coumarin anticoagulants, antimetabolites and ethanol can lead to drug-induced congenital malformations.
  6. Mutagenicity – Certain drugs like colchcine and antimetabolites can cause chromosome mutations.
  7. Carcinogenicity – A few drugs in clinical use are known to be carcinogenic. Lindane (gamma-hexachlorobenzene) and Dapsone (4,4′-diaminodiphenylsulfone, DDS) are two such examples. Some of you may remember the DES (diethylstilbesterol) tragedy of the 1970s when pregnant women received this estrogen-like compound which caused the daughters (and sometimes granddaughters) of these women to develop vaginal carcinoma and fertility problems.
  8. Maternal-Child – Many drugs taken by women are secreted into breast milk and can be transmitted to children who are being nursed by their mothers.
  9. Idiosyncratic Reactions – This term is one of the most frequently misused expressions in medicine and pharmacology. In fact, idiosynchratic reactions refer to situations in which an individual lacks a certain enzyme like glucose-6-phosphate dehydrogenase (G-6-PDH Deficiency) causing the patient to exhibit a peculiar and unanticipated reaction to certain medications (primiquine) or foods (fava beans). However, the expression has come to mean any unusual susceptibility or sensitivity to a drug characterized by a quantitatively excessive or qualitatively different response which may resemble an allegic reaction, but which is not immunologically mediated. Idiosynchratic reactions are not predictable or foreseeable (unless they have occurred previously); however, they should not be confused with infrequent but predictable ADRs like SJS or TEN.

Applying Warnings To Prescribing Medication

Elements of a Warning Example
1. Identify the Hazard Specify the ADR (e.g., Nausea, Rash, Fainting, Sedation)
2. Indicate The Degree of Risk A Combination of Severity and Frequency
3. Indicate The Consequences of Exposure “You may develop a dry mouth”, “You may feel sleepy”, or “You could develop a rash”.
4. Describe Conditions Under Which Product is Likely to be Hazardous Hepatic or Renal Insufficiency, People Over 60, Those With…..
5. List Precautions and Means of Avoiding Take as Directed, Take With Food, Avoid Drinking Alcohol
6. Describe Actions to be Taken Should Hazard Occur Discontinue Medication Immediately if…
Call Physician Immediately if…
7. Explanation is Understandable by Patient No Jargon or Medical Terms
8. Conforms to Common Standards, Regulations, and Practices What’s the Law? What’s the “Standard of Care?” (e.g., the way other MDs with similar training do it)

The Learned Intermediary Doctrine For Physicians, Dentists and Other Prescribers

When you or I (or any consumer) go to the hardware store to buy a power saw, the manufacturer of that tool has a duty to warn us (the consumer and “end user”) directly about the hazards associated with the proper use of that product. The manufacturer must also provide precautionary information about how to prevent (foreseeable) accidents from happening. Some simple precautions include: wear safety glasses, plug into 3-hole grounded electrical outlet, etc.

However, with prescription drugs, it is the physician who interprets the scientific/medical information supplied by the manufacturer in the labeling (e.g., the package insert, or in the Physicians’ Desk Reference, PDR) on behalf of the patient. Based on this information, the physician weighs the potential benefits of drug therapy against the possible risks of toxic reactions and injury, and selects the appropriate medication for the patient. In making a decision about therapy for the patient, the physician acts as a “Learned Intermediary” between the pharmaceutical manufacturer and the patient. Because specialized learning is required to select the proper medication, in general, the pharmaceutical manufacturer has a duty to warn only the physician directly, rather than the patient. Exceptions to this rule exist for drugs like oral contraceptives, IUDs, conjugated estrogens and some other drugs like Accutane (for cystic acne) where the patient is generally healthy and has significant input into the selection of treatment. With these types of drugs, the Food and Drug Administration (FDA) requires the manufacturer to warn the patients directly as well as the prescribers. Once provided with the safety and efficacy data in the labeling, the physician or prescriber then assumes the duty of warning the patient about the potential hazards of therapy during the Informed Consent process with the patient.

The “flow” of information from the manufacturer to the patient may be viewed schemnatically as follows:

Warns Physician Warns
Pharmaceutical Manufacturer———> Learned—————-> Patient
Intermediary Informed Consent

Informed Consent

The doctrine of Informed Consent derives, in part, from two principles:

  1. A person’s inherent right to control what happens to his/her body as annunciated in Justice Cardozo’s landmark opinion:
    • “[E]very human being of adult yearsand sound mind has a right to determine what shall be done with his own body…” [see: Schloendorff v. Society of NY Hospital, 211 NY 125, 129-130, N.E. 92-93 (1914)].
  2. The physician’s fiduciary duty to the patient. The physician has the duty to warn the patient…and the patient has the right to know what a “reasonable man” would want to know. The patient has no duty to inquire about the risks involved in medical treatment [see: Keomaka v. Zakaib, 811 P.2d. 478 (Haw. Ct. App. 1991)].

Basic Elements of Informed Consent

Informed Consent consists of two components: Information and Consent.

The physician informs the patient of the material risks (physician’s judgment) of a proposed treatment or procedure, and the patient, having been informed, either gives consent or withholds consent (informed refusal).

Prescribers often ask “How much information do I have to give the patient in order to meet my duty?” or, “How can I tell my patients about all the possible ADRs?” “I can’t read them the whole PDR, and even if I could, they wouldn’t understand most of it.” One approach is to develop Drug Information sheets for your patients on the drugs you prescribe most often, or purchase drug information leaflets from an organization like the United States Pharmacopeial Convention (USP). You may reach the USP at: 12601 Twinbrook Pkwy., Rockville, MD 20852, or by calling 1-800-638-6725.

What does the law say about warnings? In one case, the court said, a duty of a manufacturer to warn exists “If particular injury is reasonably foreseeable, however rare…” [see: Advance Chemical Co. v. Harter, 478 So.2d 444 (Fla.App.1 Dist. 1985)]. Therefore, if the ADR is in the labeling (i.e., package insert), then the physician should provide that information to the patient. In a second Florida case, the court opined that “Implicit in the duty of a distributor of a potentially dangerous commodity to warn of the dangers in its use is the duty to warn with a degree of intensity that would cause a reasonable man to exercise for his own safety precaution commensurate with the potential danger, and it is the failure to exercise such a degree of precaution after proper warning that constitutes contributory negligence on the part of the user.” (see: Tampa Drug Co v. Wait, Fla., 103 So.2d.603, 1958). Although these two cases involved the duty of a manufacturer or distributor of a potentially dangerous product, rather than a physician’s informed consent warning to a patient, it is clear that the law requires that all warnings contain enough information to permit a reasonable person to receive enough information to make an informed choice regarding the benefits vs. risks of medical treatment.

What information should the physician give the patient?

  1. The nature of the proposed treatment or procedure.
  2. A description of any reasonably foreseeable material risks or discomforts. (Webster’s Dictionary defines material as “Having real importance or great consequences”, but what does “reasonably foreseeable” mean?…Published in the medical literature, widely known, capable of being deduced, present in the labeling (i.e., package insert or PDR)? My suggestion is that if the adverse effect is in the labeling or could require medical treatment or hospitalization, you ought to warn the patient about it.
  3. A description of the anticipated benefits.
  4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous (e.g., diet or exercise as alternatives to medication for mild obesity, hypertension, or oral anti-diabetic agents).
  5. Any foreseeable risks should the patient be or become pregnant.
  6. Special instructions regarding food, drink, or lifestyles (e.g., No Chianti with MAOIs, warnings about Postural Hypotension with alpha blockers and tricyclic antidepressants, etc.).

If your patient sues you due to an ADR he/she developed from a drug you prescribed, what factors will be important during litigation?

  1. Was the treating physician familiar with the product’s labeling (i.e., the package insert or PDR)?
  2. Did the treating physician read the package insert recently? When?
  3. Did the treating physician rely, in part, on the manufacturer’s labeling for prescribing information?
  4. Did the treating physician consider the manufacturer’s warning (in the labeling) to have been adequate to sufficiently educate the physician so he/she could give the patient an adequate warning (informed consent)?
  5. In addition to the manufacturer’s labeling, what else did the physician rely on for prescribing information about the drug in question?
  6. Did the prescribing physician receive a visit from the manufacturer’s “Detailperson”?
  7. Did the Detailperson fail to discuss the drug’s toxicities in relation to its benefits in “Fair Balance”?
  8. Did the patient hear or see a “Direct-to-Consumer” advertisement that stimulated the patient to come to the physician and request a specific drug? Some examples of prescription drugs that are marketed directly to consumers are: Minoxoidil for baldness, Nicotine transdermal patches, Seldane, Hismanyl, Imitrex, and many others.
  9. Did you prescribe a marketed drug for a non FDA-approved indication? This is not illegal, but the “Off-Label” use of a prescription drug for a non FDA-approved indication legally differs from the prescribing of a prescription drug for an FDA-approved use.

The answers to these questions will help determine whether or not the medical negligence (malpractice) claim against you will be dismissed before trial, or if you will haave to remain a party to the suit till it is either settled or tried.

How To Learn The Most From A Detailperson

Detailpersons are salespeople, not pharmacologists. They want to influence and persuade you to prescribe their company’s drug. Accordingly, they may tend to exagerate the benefits of their products and minimize the drug’s toxicities. In order to ensure that you are not misled or “Overpromoted” by the detailperson and understand the significance of the labeling and any research studies the detailperson shows you, ask the following four questions:

  1. Why is this drug different from all other drugs used to treat this condition? (Sounds like Passover, huh?)
  2. What major adverse drug reactions does this drug share with other drugs of this class?
  3. What unusual (atypical) adverse drug reactions does this drug possess?
  4. How long has this drug been on the market? If the answer is less than two years, the warnings in the labeling are probably based on no more than 2,500-5,000 patients who participated in pre-market clinical studies upon which the New Drug Application (NDA) was based. This population of patients is too small to detect many adverse reactions that occur at a frequency of 1 in 10,000 or less. Although this sounds like a low frequency of occurrence, chloramphenacol-induced bone marrow depression is an example of just such an adverse reaction which was not detected during pre-market testing, but was discovered after approval, from post-marketing reports. (see: Competitive Problems In The Drug Industry Chloramphenacol (Chloromycetin) – Summary and Analysis, based on the 1968-69 Congressional Hearings, and prepared by the Congressional Research Service, Library of Congress, April 9, 1979.

Pharmaceutical Risk Management For Hospitals

Hospitals face special problems regarding drug-related litigation which differ significantly from those of physician prescribers. In many instances, hospitals find themselves being sued under legal theories called “vicarious liability”. Webster’s defines vicarious as:

  1. serving instead of someone or something else,
  2. suffered by one person as a substitute for another or to the benefit or advantage of another, or
  3. experienced or realized through imaginative or sympathetic participation of another.

In medical negligence, a physician allegedly deviates from the acceptable standard of care and directly commits a “tort” (tort is French for wrong) against the patient. In the case of hospital liability, the hospital doesn’t directly injure the patient (or claimant), but instead employs the individual who prescribes, dispenses or administers the medication which causes injury to the patient. When the physician, pharmacist, or nurse involved in the care of the injured patient is an employee of the hospital or Health Maintenance Organization (HMO), then the employer can also be sued under the legal doctrine of “Respondeat superior” (Let the master answer). Just as the Captain of a ship is indirectly responsible for the actions of the crew, the hospital may also be held legally accountable for the actions of its employees. Another legal theory of hospital liability is called “Negligent Credentialing”. This claim is based on an allegation that the hospital hired an individual to perform certain professional services in the hospital, but the individual was not truly qualified to perform those services at the standard of care generally recognized in the community.

One area of the hospital especially vulnerable to malpractice suits is the Emergency Department (ED). A recent study reviewed all malpractice claims against a large teaching hospital’s pediatric ED between 1984 and 1990. Before 1987, on weekdays, attending-level MDs were on duty in the ED only 16 hours per day. From 1984-87, there were 12 claims against the ED, and an attending physician had examined the child in only two of thoses cases. A total of $807,500 was paid out on those 12 claims. In 1987, the hospital increased attending-level coverage in the ED to 24 hours per day. From 1987-90, visits to the pediatric ED decreased 12.5% but malpractice claims fell by almost 42%. In all, there were seven claims against the hospital. In each case, the child was seen by an attending physician, and the total amount of money paid on those claims totaled $450,000. The authors attributed the decrease in claims and money spent to settle claims to having more experienced MDs in the ED. Although some may argue that the costs associated with employing only attending-level physicians in the ED may be expensive, the increased cost is associated with a decrease in the risk of medical liability and the actual amount of money paid per claim. Additional benefits include an increase in teaching excellence and the quality of care as well as happier patients. Once again, an ounce of prevention is better than a pound of cure. (see: Press, S., et al. Full-time Attending Physician coverage in a Pediatric Emergency Department: Effect on Risk Management. Arch. Pediatr. Adolesc. Med. 1994 (June);148:578-81). A second similar study has indicated that in an Intensive Care Unit (ICU), care directed by a dedicated critical care specialist is associated with a shorter length of stay, fewer total days of mechanical ventilation, fewer complications and more efficient use of resources than care directed by a non-intensivist general surgeon. The authors point out how important studies of this sort are in determining “the most effective and cost-efficient approach to management of the intensive care patient.” (see: Hanson, WC., et al. Does An Intensivist in the ICU Alter Outcomes? Anesthesiology Vol. 83, No. 3A, September 1995, Abstract A213).

PRM Hospital Guideline 1 – Employing specialists may cost the hospital more in salaries, but decreases the risk of liability and monies that may have to be paid on negligence claims.

Another area of potential liability for hospitals involves vicarious liability claims arising out of Drug Product Liability claims against the manufacturers of prescription drugs. This is especially true for newly-approved drugs which have been on the market for less than two years. See PRM Guideline 5 under Pharmaceutical Risk Management for Physicians. Since newly-approved drugs have only been tested in limited numbers of patients (~2,500-5,000), the full story on serious but rare (<1 in 10,000) ADRs has yet to be determined. For this reason, the first two years post-marketing is the time when many Drug Product Liability suits are filed. If one of your employed physicians prescribed the drug, your pharmacist dispensed it, and your nurse administered it, your hospital and its employees may find themselves named vicariously as co-defendants for negligence in the Drug Product Liability suit against the drug’s manufacturer. Examples of two such suits involve the IV gamma globulin product, Gammagard, which was voluntarily recalled by the manufacturer, Baxter Healthcare Corporation, Hyland Division, in February 1994 because the product was contaminated with Hepatitis C virus. Despite the fact that neither the hospital itself nor the hospital pharmacy that dispensed the product, the nurse who administered it and the physician who prescribed it did not contribute to the contamination of the product and could not have known about it until notified by the manufacturer, the hospital and its employees could still be named as co-defendants in the law suit. A second drug which is causing similar legal problems for hospitals and physicians alike is Imitrex (sumatriptan), the new drug for the treatment of migraine headaches. Although this drug was tested in almost 10,000 patients before approval by the Food and Drug Administration (FDA), since the marketing of the parenteral form of this drug in March 1993 (there is now an oral form available, too), an alarming number of patients have suffered cardiac events which have been associated with the death of 14 patients during just the first year of marketing. Hospitals and Emergency Room physicians have also been named (vicariously) as defendants in a number of ongoing Drug Product Liability cases against Glaxo Wellcome, the drugs manufacturer.

How can hospitals minimize their risk of liability in drug-related suits?

  • PRM Hospital Guideline 2 – Adopt a strict set of criteria for adding new drugs to the hospital’s formulary. The selection of a newly-approved drug for addition to the hospital’s formulary should be based on a “novel” and previously unavailable therapeutic effect of a drug. Avoid “Me-Too” drugs which offer no benefit over existing therapies already in the hospital’s formulary.
  • PRM Hospital Guideline 3 – Before adding a new drug to the hospital’s formulary, carefully review all existing toxicity and safety data about the drug. Do not rely soley on information provided by the drug’s manufacturer. Consult the FDA, the USP, other hospital risk managers, independent clinical pharmacologists and hospital clinical pharmacists familiar with the product. Pay special attention to the number of patients upon which the safety data is based, and the predictability of ADRs similar to other drugs in its class, or predicted by structure-activity-relationships (SAR). See nine factors to consider if your patient sues you listed below Informed Consent under Pharmaceutical Risk Management for Physicians, as well as How To Learn The Most From A Detailperson in the same section.
  • PRM Hospital Guideline 4 – Recognize the “First Year Effect” of drugs (see: Benjamin, DM. The Pharmacoepidemiology of Adverse Drug Reactions: The “First Year Effect” or Expansion of the Denominator, 1994 Proceedings of the Annual Meeting of the Drug Information Association, Washington, DC, June 7, 1994). Drugs like Omniflox and Felbatrol were withdrawn fromthe market due to unacceptable toxicity during the first year of marketing. Older drugs with similar post-approval risks included: Oraflex, Suprofen, Zomax, and many more!