Over the past several years, we have written numerous times about legal settlements involving pharmaceutical companies who were charged with the off-label promotion of drugs. The Food and Drug Administration (FDA) approves drugs for specific intended uses, which are then placed on the labeling of the drug for physicians. Doctors, however, can prescribe these FDA approved drugs for uses not approved by FDA, or off-label uses.
The catch-22 is that manufacturers of such drugs are prohibited from marketing their drugs to healthcare professionals or these off-label uses, even though many of them are commonly used, and in some cases such as oncology, the standard of care. Consequently, a recent scandal in France involving the drug Mediator has “paved the way for major changes in [France’s] regulatory system, including new measures aimed at strongly regulating access to drugs during their postmarketing ‘real life.’”
Mediator (benfluorex) — a fenfluramine derivative approved for treating diabetes but prescribed for indications (weight loss) not included in the “summary of product characteristics” (label), caused sometimes-fatal valvular heart disease. For regulatory agencies who approve such drugs, there is a delicate need to balance “rapid access to drugs for new indications against the limited information on their benefit–risk ratio for those uses.”
A recently passed French law aimed at strengthening the safety of medicines and health care products (Law number 2011-2012, December 29, 2011) and a related decree regarding “Temporary Recommendations for Use” (TRUs; Decree number 2012-743, May 9, 2012) fill part of the gap, providing France with a regulatory process for temporarily supervising the prescribing of drugs for indications for which they are not yet licensed, according to a recent article in the New England Journal of Medicine.
Marketing authorization for drugs is granted on the basis of their safety for specific indications, as ensured by a positive benefit–risk ratio in clinical studies. To be appropriate and safe, a drug’s use should adhere to its summary of product characteristics.
The authors recognized, however, that “some licensed medicines may be prescribed for indications outside their marketing authorization in order to treat health problems for which there are currently no other approved medications — for instance, in the case of rare diseases or specific subgroups of patients.” In addition, they noted that “Some off-label prescribing should be permitted to allow physicians to take good care of patients and offer them some therapeutic options, but such prescriptions must remain the exception to the rule and should be scrutinized and controlled by regulatory agencies using well-defined frameworks.”
“The intention of the French law and the TRU decree is to open a relatively long observation window in order to assess the benefits and risks of a marketed drug for an unlicensed indication and to collect scientific information to ensure its safe use,” the article explained. A TRU is granted for a maximum of 3 years, a window that should permit the manufacturer to expand its marketing authorization through the usual procedures.
In addition, “the law gives pharmaceutical firms the responsibility for controlling off-label prescribing: they must monitor prescriptions’ adherence to marketing authorizations and must not market their drugs for unlicensed indications. If unconventional prescribing is observed, pharmaceutical firms must immediately inform the National Agency of Medicine and Health Product Safety (Agence Nationale de Sécurité du Médicament et des Produits de Santé [ANSM]) and take all appropriate measures to inform health care professionals and prevent off-label use.”
“A TRU decision is issued a single time for any given drug and may result in a right to reimbursement for the drug for the designated indication. The ANSM will authorize a TRU if there are no other appropriate medications available. The ANSM may be alerted to the possible need for a TRU by the Ministry of Health, the institution in charge of Social Security Insurance, the High Health Authority, the National Cancer Institute, the reference centers for rare diseases, or patient advocacy groups. After the agency assesses the data provided by the manufacturer and from academic scientific studies, it can issue a TRU.”
A formal contract may be signed between the company marketing the drug and the ANSM. Such an agreement would define
- the patient follow-up,
- the efficacy and safety information to be collected,
- the real conditions of use, and
- the schedule for reporting data to the ANSM.
“The cost of this follow-up must be covered by the pharmaceutical firms, but the follow-up itself can be delegated to specialized organizations or reference centers. This monitoring does not cover other off-label use not included in the TRU. If there is found to be a risk to public health or a lack of follow-up of patients, the ANSM can modify, suspend, or withdraw the TRU.”
The authors noted that several factors must be considered and carefully balanced by an expert committee before a TRU can be issued.
- The quality of the scientific evidence
- The drug’s safety.
- The prognosis associated with a given disease
- Frequency of the disease’s occurrence.
If only anecdotal evidence or poor-quality studies exist, “further clinical trials will have to be conducted so that stronger scientific evidence may be gathered before a TRU can be obtained.” In addition, it will be safe to issue a TRU for a well-known drug with few side effects “than for a drug with serious side effects that has been on the market for only a short time.” The authors noted that risks associated with other drug interactions and potential harm in specific populations (e.g., pregnant women, elderly, etc) should also be considered.
The authors also noted that TRU’s should be issued for a more severe disease than a trivial one because patients and caregivers are more willing to accept greater uncertainty regarding the benefit-risk assessment for life-threatening disease with no alternatives (e.g., oncology and hematology, or infections diseases). Finally, the authors expressed concern that a TRU could “hasten the conduct of clinical research” for rare diseases; something they wish to avoid since randomized trials remain the gold standard for drug development and approval. However, they recognized the difficulty of performing such large trials for rare diseases.
The authors asserted that “The regulatory rules for off-label use warrant strengthening not only in France, but also in the European Union and other countries, to reduce the potential harm to patients.” They noted that the new French legislation also aims to
- Facilitate and promote the development of new indications,
- Refine benefit–risk assessments for real-life prescribing practices, and
- Avert the loss of therapeutic options for eligible patients.
“The advantage of TRUs is that they will encourage the development of possibly viable uses for marketed drugs and the monitoring of benefit–risk ratios for new indications. The potential downside is that once a new use has been temporarily authorized, it may be difficult to stop physicians from prescribing the drug for that indication even if new market authorization is not granted.”