Off-Label Drug Regulations Must Change Says Lupus Advocate

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by Charles Moore |

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Sandra C. Raymond, President and CEO of the Lupus Foundation of America recently participated in a briefing for U.S. Senate staff discussing off-label uses of medications for treating lupus and the importance of physicians having vital information about the impact these off-label medications may have on lupus patients.

Lupus (Systemic Lupus Erythematosus or SLE) is a severe and disabling systemic and chronic autoimmune disorder of unknown etiology in which various cell types and immunological pathways become dysregulated, allowing the immune system to go awry and dysfunctionally produce antibodies to cells within the body that attack and destroy healthy tissue — causing pain, swelling and inflammation, and damages to joints, skin, blood, heart, brain, kidneys, lungs, bones, and nervous system.

Lupus primarily affects women of childbearing age (ie: between 20 to 40), and women of color, who are two to three times more likely to develop the disease than Caucasians. However, men, children, and teenagers and people of all races and ethnic groups can develop Lupus. Typically affecting many parts of the body, including the joints, kidneys, central nervous system, heart, hematological system and others, and can cause severe complications that make aggressive therapies obligatory. Other risk factors include exposure to sunlight, some prescription medications, infection with Epstein-Barr virus, and exposure to certain chemicals.

The Lupus Foundation of America estimates that based on its research at least 1.5 million Americans have lupus, but that the actual number may be as high as 2 million or more, since there have been no large-scale studies to determine the actual number of people in the U.S. living with the condition. More than 16,000 new cases of lupus are reported annually across the country, representing a huge unmet medical need, with only one new treatment having been approved by the FDA in the past 50 years.

Lupus symptoms vary from one person to another, and the Foundation advises that in many cases, the best treatment approach will be provided by a health care team that can tailor treatment to the individual’s specific condition using a wide variety of medicines ranging in strength from mild to extremely strong. Prescribed medications will usually change during a person’s lifetime with lupus. However, they caution that it can take months –sometimes years — before a health care team finds just the right combination of medicines to keep a patient’s lupus symptoms under control.

A wide variety of drugs are under consideration for treating Lupus. More information can be found at:

When a drug is used in a way that differs or deviates from what is described in the U.S. Food and Drug Administration (FDA) approved drug label, it’s said to be an off-label use. FDA regulations permit physicians to prescribe approved medications for other than their intended indications, but do not allow companies that manufacture the drugs to advertise or provide information on off-label modes of usage to physicians.

However, off-label prescription is quite common. A 2012 study by investigators at McGill University in Montreal and published in the journal Archives of Internal Medicine (now JAMA Internal Medicine) found that overall, 11 percent of medications were prescribed for an off-label indication and 79 percent of off-label use lacked strong scientific evidence. They also noted that the highest proportion of off-label prescribing involved central nervous system medications (26.3 percent) and anti-infective agents (17.1 percent). Moreover, 66 percent of anticonvulsants, 44 percent of antipsychotics and 33 percent of antidepressants were prescribed for off-label conditions.

The Open Source study, entitled “Drug, Patient, and Physician Characteristics Associated With Off-label Prescribing in Primary Care” (Arch Intern Med. 2012;172(10):781-788. doi:10.1001/archinternmed.2012.340″ was coauthored by Tewodros Eguale, MD, MSc; David L. Buckeridge, MD, PhD; Nancy E. Winslade, PharmD; Andrea Benedetti, PhD; James A. Hanley, PhD; Robyn Tamblyn, PhD; of various McGill University departments. The McGill scientists take a generally dim view of off-label prescribing, which they found is common, occurring with up to 21 percent of prescribed drugs. They acknowledge that the absence of regulatory approval for a treatment indication does not mean a drug is harmful in that circumstance, but note that off-label use is suspected to be an important determinant of preventable adverse drug events, and that in addition, little is known about the factors that contribute to off-label prescribing that may determine systematic differences in treatment outcome. The researchers advocate that electronic prescribing should document treatment indication to monitor off-label use.

The FDA is likewise lukewarm about off-label prescribing.FDA guidance on off-label drug use maintains:

“Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgement. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects. Use of a marketed product in this manner when the intent is the ‘practice of medicine’ does not require the submission of an Investigational New Drug Application (IND), Investigational Device Exemption (IDE) or review by an Institutional Review Board (IRB). However, the institution at which the product will be used may, under its own authority, require IRB review or other institutional oversight.”

RaymondSIn her presentation to the Senate staffers, Ms. Raymond observed: “If any topic is a shade of gray, the education of physicians about the use of off-label drugs is one. I would posit that lupus is the poster child for the position that we must educate and promote education directly to physicians to ensure the medications for individuals with lupus are appropriately prescribed and monitored.”

“The FDA’s current regulations prohibit the pharmaceutical industry from sharing information about a medically accepted alternative use of an FDA-approved medication,” she continued. “We need to ensure that physicians are knowledgeable and are able to access the knowledge about the potential uses of a medication and the significant side effects a medication can have on complicated patients with complicated diseases.”

Ms. Raymond also observed that “Many medications used to treat lupus symptoms represents the standard of care (SOCs) for people with lupus. We have strong, anecdotal evidence that when a person with lupus goes to the emergency room they may receive high doses of prednisone to knock down an organ threatening flare. Yet, when the rheumatologist sees that patient after the episode it is common to see they have been give far too high a dose and it may take many months to stabilize the patient.”

Ms. Raymond pointed to two SOCs used to treat one of the more serious aspects of lupus, lupus nephritis, are cellcept, an organ anti-rejection drug, and cyclophosphamide, a chemotherapy. These drugs have never been fully tested or approved for use in lupus by the FDA.”

In their study, the McGill University investigators conclude: “Our findings indicate that off-label prescribing is common in primary care and varies by drug class, the number of approved indications for the drug, the age of the drug, patients’ sex and physicians’ attitude toward evidence-based medicine. “Electronic health records can be used to document treatment indication at the time of prescribing and may pave the way for enhanced postmarketing evaluation of drugs if linked to treatment outcomes.”

TewodrosEgualeLooking ahead, the study’s lead author Dr. Tewodros Eguale, then a researcher at McGill’s Dept. of Epidemiology, Biostatistics & Occupational Health, and currently a Postdoctoral Fellow at Brigham Women’s Hospital and Harvard Medical School in Boston, Massachusetts, suggested that the next step would be to link these drug and treatment indications with patient outcomes – such as whether medical conditions have improved or whether there were adverse reactions, noting: “It will give us a very novel way of looking at the safety and effectiveness of drugs.

“We need to ensure that physicians are able to access the knowledge about potential uses of medications and the significant side effects these therapies can have on individuals with complicated diseases” says Ms. Raymond.

To address this, she suggests that FDA modify its existing regulatory framework and through a process of revising regulation and updating guidance, the agency should ensure:

• All communications about medicines should be truthful and non-misleading.
• A balance between patient benefit and potential risk to determine appropriate limitations on healthcare communications.
• Companies are allowed to provide adequate directions for use for both approved and medically accepted alternative uses.

The Lupus Foundation of America
U.S. Food and Drug Administration (FDA)
Archives of Internal Medicine /JAMA Internal Medicine
McGill University

Image Credits:
The Lupus Foundation of America