scholarly journals Off-label innovation: characterization through a case study of rhBMP-2 for spinal fusion

2016 ◽  
Vol 25 (3) ◽  
pp. 406-414 ◽  
Author(s):  
Zane Schnurman ◽  
Michael L. Smith ◽  
Douglas Kondziolka
Keyword(s):  
Interbody Fusion ◽  
Bone Morphogenetic Protein 2 ◽  
Lumbar Interbody Fusion ◽  
Off Label Use ◽  
Off Label ◽  
Publication Patterns ◽  
Publication Data ◽  
Number Of Patients ◽  
Label Use

OBJECTIVE Off-label therapies are widely used in clinical practice by spinal surgeons. Some patients and practitioners have advocated for increased regulation of their use, and payers have increasingly questioned reimbursment for off-label therapies. In this study, the authors applied a model that quantifies publication data to analyze the developmental process from initial on-label use to off-label innovation, using as an example recombinant human bone morphogenetic protein 2 (rhBMP-2) because of its wide off-label use. METHODS As a case study of off-label innovation, the developmental patterns of rhBMP-2 from FDA-approved use for anterior lumbar interbody fusion to several of its off-label uses, including posterolateral lumbar fusion, anterior cervical discectomy and fusion, and posterior lumbar interbody fusion/transforaminal lumbar interbody fusion, were evaluated using the “progressive scholarly acceptance” (PSA) model. In this model, PSA is used as an end point indicating acceptance of a therapy or procedure by the relevant scientific community and is reached when the total number of peer-reviewed studies devoted to refinement or improvement of a therapy surpasses the total number assessing initial efficacy. Report characteristics, including the number of patients studied and study design, were assessed in addition to the time to and pattern of community acceptance, and results compared with previous developmental study findings. Disclosures and reported conflicts of interest for all articles were reviewed, and these data were also used in the analysis. RESULTS Publication data indicated that the acceptance of rhBMP-2 off-label therapies occurred more rapidly and with less evidence than previously studied on-label therapies. Additionally, the community appeared to respond more robustly (by rapidly changing publication patterns) to reports of adverse events than to new questions of efficacy. CONCLUSIONS The development of off-label therapies, including the influence of investigative methods, regulation, and changing perspectives, can be characterized on the basis of publication patterns. The approach and findings in this report could inform future off-label development of therapies and procedures as well as attempts to regulate off-label use.

Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion

2010 ◽  
Vol 12 (1) ◽  
pp. 40-46 ◽  
Author(s):  
Nan-Fu Chen ◽  
Zachary A. Smith ◽  
Eric Stiner ◽  
Sean Armin ◽  
Hormoz Sheikh ◽  
...  
Keyword(s):  
Lumbar Spine ◽  
Interbody Fusion ◽  
Transforaminal Lumbar Interbody Fusion ◽  
Bone Morphogenetic Protein 2 ◽  
Lumbar Interbody Fusion ◽  
Off Label Use ◽  
Off Label ◽  
Ectopic Bone ◽  
Human Bone Morphogenetic Protein ◽  
Label Use

Object Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been approved for use in the lumbar spine in conjunction with the lumbar tapered cage. However, off-label use of this osteoinductive agent is observed with anterior fusion applications as well as with both posterior lumbar interbody fusion and transforaminal lumbar interbody fusion (TLIF). Complications using rhBMP-2 in the cervical spine have been reported. Although radiographic evidence of ectopic bone in the lumbar spine has been described following rhBMP-2 use, this finding was not previously believed to be of clinical relevance. Methods This study was a retrospective review of 4 patients who underwent minimally invasive spinal TLIF (MIS-TLIF) in which bone fusion was augmented with rhBMP-2 applied to an absorbable collagen sponge. Case presentations, operative findings, imaging data, and follow-up findings were reviewed. Results Four cases with delayed symptomatic neural compression following the off-label use of rhBMP-2 with MIS-TLIF were identified. Conclusions Although previously believed to be only a radiographic finding, the development of ectopic bone following rhBMP-2 use in lumbar fusion can be clinically significant. This paper describes 4 cases of delayed neural compression following MIS-TLIF. The reader should be aware of this potential complication following the off-label use of rhBMP-2 in the lumbar spine.

Pre-Transplant Rituximab Is Associated with Reduced Rate of Acute GvHD After RIC-Allosct In Lymphoma Patients: Results From A Retrospective Monocenter Analysis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1319-1319
Author(s):  
Roberto Crocchiolo ◽  
Jean El Cheikh ◽  
Luca Castagna ◽  
Alix Helvig ◽  
Sabine Furst ◽  
...  
Keyword(s):  
Cumulative Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Off Label Use ◽  
Off Label ◽  
Number Of Patients ◽  
Grade 3 ◽  
Reduced Rate ◽  
Label Use

Abstract Abstract 1319 Introduction: both B and T cells are implicated in the pathophysiology of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (AlloSCT). Anti-thymocyte globulin (ATG) administered during conditioning has been shown to reduce both acute and chronic GvHD, while rituximab has been claimed to reduce incidence of GvHD: previous studies indicated a reduced incidence of acute and/or chronic GvHD, but sometimes with controversial results. Here we present results from a retrospective, monocenter analysis on a selected population of lymphoma patients undergoing reduced-intensity (RIC) AlloSCT, with or without ATG in the conditioning regimen. Methods: adult patients receiving RIC-AlloSCT from a HLA-identical sibling donor for relapsed CD20+ lymphoproliferative disease at our Institution were included in the analysis. Data on patients and donors, conditioning regimen, use of rituximab and cumulative dose during the six and three months before AlloSCT were collected. Rituximab was administered in association or not with chemotherapy, according to each patient's treatment strategy. Analysis was conducted separately on patients receiving ATG (ATG cohort) or not (non-ATG cohort). Correlation analysis between ATG, rituximab cumulative dose before AlloSCT and grade 2–4, grade 3–4 acute GvHD (aGvHD), or limited/extensive chronic GvHD (cGvHD) was performed. Results: a total of 57 patients transplanted between Avril 1999 and November 2009 were included in the study, 18 and 39 in the non-ATG and ATG group respectively. Of these 57 patients, 32 were treated with rituximab for a median (range) cumulative dose within 6 months before AlloSCT of 1500 (375-3375) mg/mq, ending at a median (range) of 43 (5-177) days prior to transplant. Details are shown in table 1. Median follow-up was 749 days (146-4051). No significant differences existed between patients receiving rituximab vs. those without rituximab, with the exception of a different number of patients with CLL or FCL. Among the 18 non-ATG patients, we observed a slightly reduced rate of severe (grade 3 or 4) aGvHD in those patients who received >= 375 mg/mq rituximab within three months before AlloSCT (n=13) compared to those receiving < 375 mg/mq or no rituximab (n=5): 2/13 vs. 2/5 (p=ns). In the ATG cohort, rituximab use at a dose >= 375 mg/mq (n=10) within three months was associated with a reduced rate of severe aGvHD compared with < 375 mg/mq or no rituximab (n=29): 0/10 vs. 7/29 (p=0.08). Reduction of grade 2–4 aGvHD rate was also observed: 1/10 vs. 14/29 (p=0.03). No effect on cGvHD appeared in the two cohorts. Discussion: present data suggest a role of rituximab administered before AlloSCT in reducing the incidence of aGvHD. This effect was more pronounced when concomitant administration of ATG was performed during conditioning regimen, indicating a possibly sinergistic effect of both T- and B-cell depletion in preventing GvHD. Although retrospective and small-sized, the present analysis, conducted on a quite homogeneous population of patients, confirms previous findings and enhances further investigations on larger number of patients. Disclosures: Off Label Use: Zevalin is off-label use in conditioning regimen in France.

Off-label drug use in women with breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1016-1016
Author(s):  
W. Dean-Colomb ◽  
S. Fang ◽  
W. Smith ◽  
L. Michaud ◽  
G. N. Hortabagyi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast ◽  
Scientific Data ◽  
Supporting Evidence ◽  
Breast Cancer Patients ◽  
Off Label Use ◽  
Off Label ◽  
Chemotherapy Drugs ◽  
Number Of Patients ◽  
Label Use

1016 Background: Despite reports of widespread use of off-label agents in cancer treatment, little is known about the off-label use of agents in the treatment of breast cancer patients. Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) - Medicare linked database to identify 2082 persons older than 65 years who were diagnosed with distant stage breast cancer between 1991 and 2002 and who were treated with chemotherapy between diagnosis and death. Off versus on-label classification was based upon FDA-approved indication in the treatment of breast cancer. We calculated the percentage of patients receiving off-label chemotherapy and used multivariate logistic regression models to estimate predictors of off-label chemotherapy use. We also evaluated the appropriateness of off-label chemotherapy drugs using DRUGDEX classifications. Results: Overall, 34.9% of patients were treated with off-label chemotherapy drugs. Of the thirty-six agents that were used to treat these patients, only 8 (22%) were FDA-approved for use in the treatment of breast cancer. Off-label use was least common in patients age 80 years and older (OR 1.93, 95% 1.35–2.76 for 80+ vs. 66–70 years) and varied by diagnosis year and geographic region. The most commonly used off-label agents were vinorelbine and gemcitabine, with 16.0% and 8.4% of patients receiving these agents, respectively. While 71% of the drugs used off-label lacked supporting evidence for their use in the treatment of breast cancer, these drugs were used in a small number of patients. Only 6.7% of patients were treated with drugs considered inappropriate for use in the treatment of breast cancer. Conclusions: Off-label chemotherapy use is widespread among patients with metastatic breast cancer. However, the majority of patients who received off-label chemotherapy received drugs with scientific data supporting such use. No significant financial relationships to disclose.

Commercial Speech and Off-Label Drug Uses: What Role for Wide Acceptance, General Recognition and Research Incentives?

2011 ◽  
Vol 37 (2-3) ◽  
pp. 258-277 ◽  
Author(s):  
Margaret Gilhooley
Keyword(s):  
Controlled Study ◽  
Off Label Use ◽  
Off Label ◽  
Commercial Speech ◽  
Abuse Case ◽  
Drug Companies ◽  
Number Of Patients ◽  
Constitutional Protections ◽  
Research Incentives ◽  
Label Use

This article provides an overview of how the constitutional protections for commercial speech affect the Food and Drug Administration's (FDA) regulation of drugs, and the emerging issues about the scope of these protections. A federal district court has already found that commercial speech allows manufacturers to distribute reprints of medical articles about a new off-label use of a drug as long as it contains disclosures to prevent deception and to inform readers about the lack of FDA review. This paper summarizes the current agency guidance that accepts the manufacturer's distribution of reprints with disclosures.Allergan, the maker of Botox, recently maintained in a lawsuit that the First Amendment permits drug companies to provide “truthful information” to doctors about “widely accepted” off-label uses of a drug. While the case was settled as part of a fraud and abuse case on other grounds, extending constitutional protections generally to “widely accepted” uses is not warranted, especially if it covers the use of a drug for a new purpose that needs more proof of efficacy, and that can involve substantial risks.A health law academic pointed out in an article examining a fraud and abuse case that off-label use of drugs is common, and that practitioners may lack adequate dosage information about the off-label uses. Drug companies may obtain approval of a drug for a narrow use, such as for a specific type of pain, but practitioners use the drug for similar uses based on their experience. The writer maintained that a controlled study may not be necessary to establish efficacy for an expanded use of a drug for pain. Even if this is the case, as discussed below in this paper, added safety risks may exist if the expansion covers a longer period of time and use by a wider number of patients. The protections for commercial speech should not be extended to allow manufacturers to distribute information about practitioner use with a disclosure about the lack of FDA approval. Distributions of information about unapproved uses should not be acceptable unless experts consider the expanded use to be generally recognized as safe and effective based on adequate studies.The last part of this paper considers the need to develop better research incentives to encourage more testing and post-market risk surveillance by drug makers on off-label uses of their drugs. Violations of the Federal Food Drug and Cosmetic Act (FFDCA) can be considered violations of the False Claims Act, which opens the way to fraud and abuse suits. The scale of penalties involved in these suits may lead to more examination of the scope of FDA regulation and commercial speech protections. Thus this symposium's consideration of these issues is timely and important.

scholarly journals Prescription Pattern and Off-Label Use of Antipsychotics in a Middle Eastern Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Kholoud Bastaki ◽  
Mohammed El Anbari ◽  
Suhaila Ghuloum ◽  
Puthen Veettil Jithesh
Keyword(s):  
Precision Medicine ◽  
Middle Eastern ◽  
Healthcare Providers ◽  
Outcome Data ◽  
Off Label Use ◽  
Cross Sectional ◽  
Prescription Pattern ◽  
Off Label ◽  
Number Of Patients ◽  
Label Use

Background: Understanding the prescription pattern of medications in a population can help reveal the potential usage scenarios, including off-label prescriptions, and the need for precision medicine implementation. Therefore, the aim of this study was to assess the prescription pattern and off-label use of antipsychotics in the Qatari population.Methods: We performed a cross-sectional study of Qatari patients who received antipsychotic prescriptions from the major healthcare providers in the country during the 2-year period between June 2018 and May 2020. The number of patients, prescriptions dispensed, and clinical indications were collected and statistical analysis using chi-square test was conducted.Results: Among the 9,349 Qatari patients prescribed with antipsychotics during the study period, the majority were female (57%; p &lt; 0.001) and were in the age categories 20–39 and 30–39 years (both 22%; p &lt; 0.001). Among the 35,938 antipsychotic prescriptions dispensed, second-generation antipsychotics were the most highly prescribed (59%), specifically, quetiapine (16%) and olanzapine (12%), but the first-generation antipsychotic prochlorperazine (13%) was also highly prescribed. Most of the indications of antipsychotics (69%) were for off-label use such as for controlling chronic diseases, sleeping disorders, benign paroxysmal positional vertigo and irritable bowel syndrome.Conclusion: Non-mental health and off-label prescriptions of several antipsychotics were observed. Integration of this data with pharmacogenomic and clinical outcome data will help in determining the course of action for implementing personalized and precision medicine in the country and beyond.

scholarly journals Open-Source Technology for Real-Time Continuous Glucose Monitoring in the Neonatal Intensive Care Unit: Case Study in a Neonate With Transient Congenital Hyperinsulinism

10.2196/21770 ◽  
2020 ◽  
Vol 22 (12) ◽  
pp. e21770
Author(s):  
Katarina Braune ◽  
Mandy Wäldchen ◽  
Klemens Raile ◽  
Sigrid Hahn ◽  
Tebbe Ubben ◽  
...  
Keyword(s):  
Open Source ◽  
Real Time ◽  
Continuous Glucose Monitoring ◽  
Newborn Infants ◽  
Glucose Monitoring ◽  
Congenital Hyperinsulinism ◽  
Off Label Use ◽  
Off Label ◽  
Label Use

Background Use of real-time continuous glucose monitoring (rtCGM) systems has been shown to be a low-pain, safe, and effective method of preventing hypoglycemia and hyperglycemia in people with diabetes of various age groups. Evidence on rtCGM use in infants and in patients with conditions other than diabetes remains limited. Objective This case study describes the off-label use of rtCGM and the use of an open-source app for glucose monitoring in a newborn with prolonged hypoglycemia secondary to transient congenital hyperinsulinism during the perinatal period. Methods The Dexcom G6 rtCGM system (Dexcom, Inc) was introduced at 39 hours of age. Capillary blood glucose checks were performed regularly. In order to benefit from customizable alert settings and detect hypoglycemic episodes, the open-source rtCGM app xDrip+ was introduced at 9 days of age. Results Time in range (45-180 mg/dL) for interstitial glucose remained consistently above 90%, whereas time in hypoglycemia (<45 mg/dL) decreased. Mean glucose was maintained above 70 mg/dL at 72 hours of life and thereafter. Daily sensor glucose profiles showed cyclic fluctuations that were less pronounced over time. Conclusions While off-label use of medication is both common practice and a necessity in newborn infants, there are few examples of off-label uses of medical devices, rtCGM being a notable exception. Real-time information allowed us to better understand glycemic patterns and to improve the quality of glycemic control accordingly. Severe hypoglycemia was prevented, and measurement of serum levels of insulin and further lab diagnostics were performed much faster, while the patient’s individual burden caused by invasive procedures was reduced. Greater customizability of threshold and alert settings would be beneficial for user groups with glycemic instability other than people with diabetes, and for hospitalized newborn infants in particular. Further research in the field of personal and off-label rtCGM use, efficacy studies evaluating the accuracy of low glucose readings, and studies on the differences between algorithms in translating raw sensor data, as well as customization of commercially available rtCGM systems, is needed.

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