Prasad Kulkarni

How Drugs are Developed and Approved by the FDA: Current Process and Future Directions

OBJECTIVES:This article provides an overview of FDAs 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.METHODS: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 R&D productivity and drug development cost estimates.RESULTS: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

Biosimilars: The Need, The Challenge, The Future: The FDA Perspective

868M to

Safety of conscious sedation in patients with sleep apnea in a veteran population.

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.CONCLUSIONS:The FDAs 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 The FDA drug approval process is not without controversy, as a number of well-known gastroenterology drugs have been withdrawn from the US market over the past few years.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.

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

OBJECTIVES:This article summarizes the brief history of the biosimilars industry, the FDAs regulations and guidance for biosimilars development, and the issues and challenges facing developers and regulators in bringing biosimilars to market.METHODS:Current literature, regulations, and FDA guidance documents were summarized and interpreted to define biosimilars and to present their financial and clinical implications.RESULTS:Some biologic agents that will lose patent protection during the next few years may be replaced with lower cost follow-on biologics. However, unlike generic drugs, biosimilars may be structurally and functionally different from the reference product they are designed to resemble. The FDA has yet to approve any agent via the abbreviated licensure pathway for biosimilars that was passed as part of the Affordable Care Act. The FDA has issued new guidance describing processes by which manufacturers may demonstrate either biosimilarity or interchangeability with an FDA-approved biologic agent, which is required for abbreviated licensure. Biosimilars approved in Europe consist of relatively small molecules; complex large-molecule biosimilars could be subjected to a rigorous and prolonged FDA approval process, which would defeat attempts to develop lower-cost versions of biologic drugs.CONCLUSIONS:Biosimilar development is a consequence of the financial success of biologic therapies and their eventual patent expiration. The pharmaceutical industry must now develop complex biosimilars that resemble FDA-approved biologic agents and invent analytical tools and end points to demonstrate similarity to regulatory authorities. Already in development is a new wave of “biobetter” or “biosuperior” drugs that mimic but also improve upon a biologic drugs chemistry, formulation, or delivery.

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

Objectives: Due to the presumed higher risk of cardiopulmonary complications in patients with obstructive sleep apnea (OSA), many endoscopy centers consider OSA a contraindication to using conscious sedation. We evaluated the safety of conscious sedation during endoscopy for patients with OSA in a veteran population, and compared this to patients without OSA. Methods: Polysomnography studies were reviewed from 2004 to 2009 to identify 200 patients with OSA who had undergone endoscopy. Controls included the last 200 consecutive endoscopies in this institution for patients without OSA. Sixty-three upper endoscopies, 136 colonoscopies, and one enteroscopy were included in the OSA group. Sixty-five upper endoscopies, 133 colonoscopies, one sigmoidoscopy, and one endoscopic ultrasound comprised the control group. Data obtained included demographics, medications prescribed, and any complication noted in the procedure report. Results: No complications occurred in the control group. In the OSA group, a patient experienced oxygen desaturation during an upper endoscopy and required oxygen supplementation. The procedure was completed and did not require an extended stay in the endoscopy suite. Conclusion: This study demonstrated that endoscopy can be safely done in OSA patients using conscious sedation, and the complication rate is not significantly different than patients without OSA.

Safety of Gastrointestinal Endoscopy With Conscious Sedation in Patients With and Without Obstructive Sleep Apnea.

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

Metastatic leiomyosarcoma to the pancreas presenting as a massive upper gastrointestinal hemorrhage.

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

A rare case of a primary hepatic neuroendocrine tumor

Background and Study Aims: Patients with obstructive sleep apnea (OSA) undergoing endoscopy with sedation are considered by practitioners to be at a higher risk for cardiopulmonary complications. The aim of the present study was to evaluate the safety of conscious sedation in patients with OSA undergoing gastrointestinal endoscopy. Patients and Methods: This is an IRB-approved prospective cohort study performed at the James A. Haley VA. A total of 248 patients with confirmed moderate or severe OSA by polysomnography and 252 patients without OSA were enrolled. Cardiopulmonary variables such as heart rate, blood pressure, and level of blood oxygen saturation were recorded at 3-minute intervals throughout the endoscopic procedure. Results: In total, 302 colonoscopies, 119 esophagogastroduodenoscopies, 6 flexible sigmoidoscopies, and 60 esophagogastroduodenoscopy/colonoscopies were performed. None of the patients in the study required endotracheal intubation, pharmacologic reversal, or experienced an adverse outcome as a result of changes in blood pressure, heart rate, or blood oxygen saturation. There were no significant differences in the rate of tachycardia (P=0.749), bradycardia (P=0.438), hypotension (systolic/diastolic, P=0.460; mean arterial pressure, P=0.571), or hypoxia (P=0.787) between groups. The average length of time spent in each procedure and the average dose of sedation administered also did not differ significantly between the groups. Conclusions: Despite the presumed increased risk of cardiopulmonary complications, patients with OSA who undergo endoscopy with conscious sedation have clinically insignificant variations in cardiopulmonary parameters that do not differ from those without OSA. Costly preventative measures in patients with OSA are not warranted.

Endoscopic Removal of a Solitary Metastatic Renal Cell Carcinoma Lesion to the Stomach

Leiomyosarcomas are rare, comprising only 0.1 % of all primary pancreatic malignancies [1]. They originate from smooth muscle and are most commonly found within the stomach and small intestine as well as in the large intestine, uterus, and retroperitoneum [2]. Leiomyosarcomas have a predilection for hematogenous spread with the liver and lungs being the most common sites of metastasis. Diagnosis requires immunohistochemical confirmation with positivity most commonly seen for smooth muscle actin (SMA), caldesmon, vimentin, and desmin. In a recent review, only 25 cases of solitary metastatic leiomyosarcomas were found in the literature [3]. In general, pancreatic metastatic lesions are rare, with the most commonly reported primary malignancies being of lung, renal, and gastric origin [4–6]. In a series of 4,955 adult autopsy cases, Adsay et al. found only 81 (1.6 %) cases of metastatic tumors to the pancreas [7]. At the time of diagnoses, most cases of metastatic pancreatic tumors are associated with multiorgan involvement [8, 9]. In this clinical context, literature regarding the treatment of such lesions is limited with respect to survival or quality of life but is generally regarded as poor. Here, we report a case of metastatic leiomyosarcoma to the pancreatic tail and lung. To our knowledge, it is the only known case of pancreatic metastasis presenting with life-threatening massive upper gastrointestinal hemorrhage resulting from a gastric variceal rupture.

New Pancreatic Adenocarcinoma in a Crohn’s Patient Treated with Tumor Necrosis Factor (TNF) Inhibitors for 6 Months

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.