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How the FDA Manages Drug Safety With Black Box Warnings, Use Restrictions, and Drug Removal, With Attention to Gastrointestinal Medications

This article provides an overview of FDA's regulatory processes for drug development and approval, and the estimated costs associated with the development of a drug, and also examines the issues and challenges facing the FDA in the near future.A literature search was performed using MEDLINE to summarize the current FDA drug approval processes and future directions. MEDLINE was further utilized to search for all cost analysis studies performed to evaluate the pharmaceutical industry RD productivity and drug development cost estimates.While the drug approval process remains at high risk and spans over multiple years, the FDA drug review and approval process has improved, with the median approval time for new molecular drugs been reduced from 19 months to 10 months. The overall cost to development of a drug remains quite high and has been estimated to range from $868M to $1,241M USD. Several new laws have been enacted, including the FDA Safety and Innovation Act (FDASIA) of 2013, which is designed to improve the drug approval process and enhance access to new medicines.The FDA's improved processes for drug approval and post-market surveillance have achieved the goal of providing patients with timely access to effective drugs while minimizing the risk of drug-related harm. The FDA drug approval process is not without controversy, as a number of well-known gastroenterology drugs have been withdrawn from the US market over the past few years. With the approval of the new FDASIA law, the FDA will continue to improve their processes and, working together with the ACG through the FDA-Related Matters Committee, continue to develop safe and effective drugs for our patients.

What Gastroenterologists Should Know About the Gray Market, Herbal Remedies, and Compounded Pharmaceuticals and Their Regulation by the Food and Drug Administration

Neuroendocrine tumors are well-differentiated low grade malignant neoplasms. Their pathogenesis is thought to be secondary to the unrestricted proliferation of neuroendocrine cells. They most commonly arise in the bronchopulmonary or gastrointestinal tract but can originate from almost any organ. While the liver is a common site of metastases, primary hepatic neuroendocrine tumors are an exceedingly rare pathology, of which fewer than 100 cases have been described in world literature. Thus, there exists a paucity of data regarding the clinical presentation, diagnosis and management of this disease. We present a case of a 35-year-old patient who presented to our facility for evaluation of a cough and cervical lymphadenopathy. Two biopsies of the lymph nodes were negative, however on workup for an occult malignancy a hypodense heterogeneous hypervascular lesion measuring 3.7 cm × 2.7 cm in segment IVb of the liver was noted on computer tomography (CT) scan. The levels of laboratory studies such as liver enzymes, alkaline phospatase, chromogranin A, 24-hour 5 hydroxyindoleacetic acid (5-HIAA) and tumor markers including alpha fetoprotein were not elevated. An MRI confirmed the mass, and the patient underwent CT guided biopsy of the hepatic lesion. Staining from the biopsy resulted in cells reactive for synaptophysin, chromogranin, anti-Cytokeratin (CAM 5.2), MOC31, CD 56 and mucin glycoprotein (MUC) confirming a nonsecretory neuroendocrine tumor. Patient underwent octreotide scan, PET scan, CT chest, MRI head along with EUS, EGD and colonoscopy to evaluate for a primary source, however, none was found. The well localized presentation without extensive hepatic invasion made the patient a candidate for surgical resection which was successfully performed. The patient remains disease free over 36 months after initial presentation. Primary hepatic neuroendocrine tumors are an exceedingly rare entity whose variable presentation necessitates provider familiarity with this condition. Once identified, excluding other primary locations with thorough investigation and treatment with surgical resection has been shown to provide the most patient benefit.

The current study is based on the hypothesis that aging predisposes gastric mucosa to carcinogenesis through altered expression and/or mutations of genes involved in cell growth. To test this hypothesis, we investigated the age-associated changes in mutation of adenomatous polyposis coli ( APC), deleted in colorectal cancer ( DCC), p53, and K- ras genes in the gastric mucosa of 19 healthy subjects of varying ages (25–91 yr). Specifically, we studied the loss of heterozygosity (LOH) of these genes in cardia, body, and antrum of the stomach. We observed that 3 of 19 subjects (16%) over 60 yr of age show LOH of at least one of the tumor suppressor genes. Among the subjects over 60 yr of age, the incidence of LOH is 38% (3/8). Two of three subjects had mutations in more than one tumor suppressor gene. In all three affected subjects, mutation in APC, DCC, or p53 was located mainly in the body of the stomach, suggesting increased susceptibility of this region to neoplastic changes. However, no LOH of K- ras was observed in these subjects. Our observation that subjects over 60 yr of age show mutation in one or more of the tumor suppressor genes suggests an age-related increase in predisposition of the stomach to neoplasia.

A 56-year-old man presented to the emergency department with a 1-week history of dark-colored urine and acholic stools followed by 3 days of intermittent right upper quadrant abdominal pain and overt jaundice. He had been healthy and did not smoke or drink alcohol. His family history was unremarkable. He recently lost 15 lb and experienced early satiety and intermittent night sweats.

Introduction: Screening cirrhotic patients with EGD for esophageal varices (EV) to identify those at risk for catastrophic gastrointestinal hemorrhage is the current standard of care. Esophageal capsule endoscopy (ESO) is increasingly recognized as an alternative non-invasive screening tool to detect EV. This trial was designed to determine if ESO could assess the presence and grade of EV with accuracy comparable to EGD. ESO and EGD were also compared in terms of procedural complications and their ability to detect gastric varices (GV) and stigmata of potential bleeding. Methods: 34 patients with ESLD were prospectively enrolled in an IRB-approved protocol in this study. Each underwent ESO followed by EGD on the same day. EGD and ESO were performed by separate trained Gastroenterologists who were blinded to the results of the other. Each ESO study was also evaluated by another ESO-experienced Gastroenterologist. Findings were reviewed and analyzed. Findings: Using EGD as the gold standard, detecting EV by ESO had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100%, 66.7%, 93.3%, and 100% respectively. EV grade was classified as absent, small, medium, or large. Complete agreement of EV grade occurred in 25/34 (73.5%) cases. Strength of association using the Kendall tau-b score was 0.7991. Only 1/18 patients with small EV by ESO had medium EV on EGD. Conversely, 2/12 patients with medium or large EV by ESO had small EV on EGD. Evaluation of stigmata of potential bleeding with ESO compared to EGD had a sensitivity, specificity, PPV, and NVP of 92.6%, 85.7%, 96.1% and 75% respectively. Utility of ESO in the detection of GV was limited where sensitivity was only 33.3%. Four minor adverse events occurred with EGD that included hypotension, hypoxia and possible aspiration. No complications occurred with ESO. There was no significant difference in the side effect profiles of ESO and EGD. Conclusions: Based on minimal invasiveness, lack of need for sedation, less discomfort, and fewer side effects, ESO may be a more desirable procedure for cirrhotic patients that need EV screening. This study shows good correlation between ESO and EGD in detecting EV and assessing grade for treatment purposes as noted on published studies. ESO lacks sensitivity for assessment of gastric varices. Larger studies with additional patients are needed for further evaluation.

Granulomatous prostatitis and colitis following intravesical BCG for TCC of bladder: endoscopic and EUS features