Latest FDA caution for the use of off-label drugs in intrathecal drug delivery systems deemed “inconsistent with current practice”


While the US Food and Drug Administration (FDA) has called for caution regarding the use of off-label medications administered intrathecally, pain management experts have come together and, in a letter to the editor of Neuromodulation, call for an addendum to the communication due to its “inconsistency with current practice”.

“Use caution with implanted pumps for intrathecal administration of medicines for pain management,” reported the recent FDA safety communication. With the action aiming to improve safety, it was intended for patients who have an implanted pump, as well as caregivers and healthcare providers. Several physician leaders feel this caution needs more clarification, including Timothy Deer (The Spine and Nerve Center of the Virginias, Charleston, USA) and Philip Kim (Center for Interventional Pain Spine, Bryn Mawr, USA), among an array of pain treatment experts. “We are concerned that this FDA alert may have the unintentional action of inappropriately limiting our ability to offer treatments within the standard of care for our chronic intractable pain patients,” write principal authors Deer and Kim.

While Deer and colleagues say they agree with the FDA’s goal of improving safety and reducing risks, they put forward that general use of off-label medications has been an ongoing practice standard for many years and suggest that the safety communication “will have a detrimental impact on many patients and on the practice of medicine in the USA and potentially abroad”.

According to manufacturer registry data highlighted in the letter, over 80% of patients treated for chronic pain of a noncancerous origin receive drugs that currently remain unapproved in the USA for chronic intrathecal use. For patients treated for cancer pain syndromes, this figure rises to greater than 90%. Although Deer and colleagues write that reasons for these current practice standards are “multidimensional”, they say many include those patients who failed on-label medications due to side-effects or a poor response to treatment with a lack of efficacy at reasonable dosing. Further, a “lack of commercially available concentrations and national drug availability” has also contributed to current practices carried out today.

Timothy Deer

Acknowledging the issues raised within the FDA communication, the authors conclude that many of these were “inaccurately linked to only non-FDA approved medications”. Specifically, pump failure with rotor malfunction and corrosion related to off-label use was referenced in the FDA safety communication. However, Deer and colleagues point to an array of evidence revoking this association. For instance, a registry specific to targeted drug delivery that enrolled 60 centres and included data from 7,459 patients from 2003–2016 (2,330 on-label programmable pumps; 5,189 off-label) found no statistically significant difference in risk of failure between the on-label and off-label pumps implanted for the treatment of pain (p=0.31). The authors posit that such findings supporting the use of off-label medications have been maintained in post-market studies, where the majority of patients continued on intrathecal therapy received off-label medications.

Additionally, dosing errors—which can occur when there is inadequate vigilance regarding drug ordering, dosage entry and device programming—have also been linked to only non-FDA approved drugs. Although Deer and colleagues propose that device malfunction can be directly related to intrathecal catheter granuloma from morphine, even if used in the labelled fashion, they argue that publications highlighted by the polyanalgesic consensus conference (PACC)—formed of an international multidisciplinary body of pain treatment experts—aim to address the need for protocols to alleviate these dosing errors.

The PACC was formed in 2000, as the panel of experts set out to review evidence pertaining to the efficacy and safety of intrathecal therapy in view to providing guidelines and recommendations for use. In the letter, Deer and colleagues write that both continued innovations and PACC reassessments shed light on the importance of a strong patient-physicians-industry-regulatory partnership.

Thus, the authors argue that the FDA alert needs to be clarified in order to achieve protecting patients and for FDA oversight to improve care. “In this era of opioid misuse, overdose, and death, it is even more important that the option of intrathecal drug delivery remains viable and continued communication be ongoing with the physicians who treat these intractable pain patients, the manufacturers of the devices, and the FDA.”

Thus, the authors concluded their letter to the editor with an array of recommendations. First, they maintain that off-label medications have been used safely for over 20 years, with no substantive data suggesting that off-label targeted drug delivery is unsafe as long as the PACC guidelines are followed. Regardless, they write: “When medically appropriate, physicians should consider the use of on-label drugs in the treatment of chronic pain with intrathecal drug delivery devices. This is true in both the noncancer and cancer-pain populations.”

They further suggest that where off-label agents or adjuvants are used to alleviate any side effects or loss of efficacy in patients receiving intrathecal drug delivery, this should be approached based on “proper animal data, human studies of safety, or an established track record of safety and efficacy in the medical literature”. Moreover, the authors recommend that ongoing patient evaluation with careful monitoring of side effects should occur. If any adverse events are to occur, Deer and colleagues emphasise, “patient care should be immediately reassessed, and treatment modification should be carried out”, while they call for any reporting of such events to be “transparent, timely […], fully categorised and made available to physicians to assist in risk to benefit discussions and decision-making”.

Reiterating the practicality of physicians, manufacturers, and the FDA all working together to assess additional labelling for drugs that are commonly used, the authors also highlight that the presence or large device registries should allow for safety analyses, further assisting in improved guidance. Importantly, Deer and colleagues recommend that the FDA considers funding a prospective intrathecal drug delivery registry to track the safety and dosing with various intrathecal medications.

Ultimately, they write: “Our recommendation is to create a collaboration of physicians, medical societies, manufacturers, pharmacies, and the FDA to focus on this important issue.” Subsequently, they stress the need for the FDA to provide an addendum to their recent safety communication, as it remains “inconsistent with current practice”.

“The [FDA’s statement] places physicians at potential increased liability despite practicing within the standard of care”, claim Deer et al, as they conclude by calling for collaborative discussions with the FDA to develop additional guidance for patients receiving intrathecal drug delivery systems in the USA.


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