“Physican-Directed Applications”: A Clinician’s Case To Open Up Off-Label Promotion

In testimony during the House Energy & Commerce Committee’s “21^st Century Cures” initiative, a rheumatologist makes the case for broader access to off-label use information – but not for eliminating FDA review before dissemination.

It is the mission of physicians in all specialties to use the safest and most effective means to assist patients in health maintenance, disease prevention, effective disease management and accessing curative therapies.

Most of these endeavors are accomplished with the use of treatment modalities that are not only the standard of care but also FDA approved. However, in instances and circumstances where no definitive FDA-approved indication is available, the use of medically accepted alternative uses of approved medicines is often necessary.

Gregory Schimizzi is a rheumatologist at the Carolina Arthritis Associates in Wilmington, North Carolina. He is the past President of the coalition of State Rheumatology Organizations (CSRO). This article is an excerpt from his testimony given on behalf of the Alliance of Specialty Medicine during a July 22 Energy & Commerce/Health Subcommittee hearing.

Non-approved use of medical products has actually become the standard of care in the treatment of many orphan diseases and also frequently used when standard, accepted treatments fail in common diseases.

In my specialty of rheumatology, there are many diseases where little or no scientific or clinical information is present regarding the treatment of certain autoimmune diseases, including Sjögren’s syndrome, Behcet's disease, many forms of vasculitis, inflammatory muscle diseases, scleroderma, calcium pyrophosphate deposition disease and other conditions.

Given the small patient population, manufacturers may not consider pursuing new indications for a pharmaceutical agent economically feasible since the costs of such endeavors are daunting. Despite the lack of FDA approved indications, those patients still require treatment and, as their physicians, we endeavor to use whatever information is available to help with informed decision-making. For instance, many non-approved indications can be found in standard textbooks of medicine and surgery in all specialties and subspecialties for patients of all ages and are the generally accepted standard of medical care.

The use of medical products, devices and medications is always undertaken using the best available clinical evidence, judgment and consideration with the utmost care, thoughtfulness and regard for patient safety. These decisions take into consideration the patient's co-morbid conditions and concomitant medical therapies. In some patients with orphan diseases or illnesses that are poorly understood, non-approved therapies are the only treatments available. Management modalities for these are frequently publicized in scientific meetings, peer-reviewed literature and other compendia. Publicizing these treatments is an important method of communicating effective treatments in the medical community and a source of investigational stimulation to academicians and clinicians into new areas of research and development.

The goals of medicine and medical research in these areas must continue to be the improvement of health of our population, prevention of disease, and the safest and most effective treatment for individuals afflicted with any illness or condition. It is my belief and that of my colleagues that open discussions and distribution of truthful scientific information is a cornerstone to achieve those goals where sound research and data have been completed but it must be shared and distributed.

“Unnecessary Delays” In Access To Information

As a member of the Alliance of Specialty Medicine, the CSRO supports the Alliance’s recently developed position statement focused on Physician-Directed Applications (also known as “off-label use.

One key component of that position statement is that “[i]f specialty physicians use a product for an indication not in the approved or cleared labeling, they have the responsibility: (1) to be well informed about the product; (2) to base its use on a firm scientific rationale and sound medical evidence; and (3) to maintain awareness of the product’s use and effects.”

I agree wholeheartedly with this requirement and would like to highlight some potential problems with recent Food and Drug Administration requirements which may hamper my ability as a physician to be well informed about a product and to base its use on firm scientific rationale and sound medical evidence.

My understanding is that the FDA does not allow pharmaceutical companies to actively distribute any key information, even if it is related to the on-label indication, unless it is explicitly referenced in the package insert. Therefore, observational data, subpopulation information, comparative data derived from clinical trials other than randomized controlled trials, and pharmacoeconomic or comparative cost data cannot be proactively shared with clinicians unless such data is directly referenced in the package insert.

Further, for medically acceptable alternative uses, such as those which may be referenced in various compendia or practice guidelines as an appropriate treatment, that data can only be shared if a clinician directly and specifically requests such information. By limiting the sharing of information, physicians are hampered in their ability to access all available sound medical evidence and firm scientific rationale necessary to treat patients with difficult problems.

For example, one of our distinguished colleagues attempted to proactively request information to aid in the treatment of a patient with sclerits, which is an inflammatory disease of the eye that can occur in diseases such as rheumatoid arthritis. Left untreated this condition has potentially devastating consequences including complete loss of vision or even perforation of the eye itself.

Due to current regulations and limitations that require a physician to explicitly request information, effective treatment of this patient’s condition was delayed. This particular patient did not immediately respond to traditional therapy options, but our colleague remembered a presentation suggesting that rituximab may be a suitable physician-directed application. After several failed attempts to contact the speaker, he contacted the pharmaceutical company directly and requested any specific data that the manufacturer possessed relating to this specific potential use. He received the required information, and the product helped his patient.

However, the 2-3 weeks required to obtain all of the necessary information, patient consent, and then insurance authorization, caused unnecessary delays in treating his patient and impacted the outcome by delaying access to safe effective care.

FDA Process To Qualify Off-Label Data

It would be preferable to allow the pharmaceutical company with its wealth of information to share key data in order to inform and assist in decision–making.

That is not to say that I would recommend a change in all of the current requirements for the FDA to review such information to ensure that it is truthful and not misleading.

The CSRO urges the FDA to expand the current process of review of materials beyond what is included in the package insert to also cover other key data. The FDA review process should be in real-time and not potentially delayed for a year or more.

In addition, The CSRO urges the FDA, through a public process, to develop standards for qualifying real world data, so that clinicians can be better informed.

With additional comparative effectiveness research, the focus on quality outcomes, and other health care reforms, Congress and the FDA should be encouraging the exchange of scientific information, not hampering it. Blocking access to data on medically acceptable alternative uses seem to countermand these new requirements and complicate my ethical responsibility to provide patients with information on risks, benefits and alternatives to medical treatments as part of the informed consent process. As we move closer to newer, alternative payment models, where shared decision-making tools will likely be a key component, I am concerned about how this lack of information will impact my ability to truly educate my patients on their options and give them a fair opportunity to engage in the establishment of their care plan.

I hope that Congress will examine ways to allow for more proactive exchanges among clinicians with appropriate safeguards to assure that such information is truthful and not misleading.