Phase IV Studies: What Clinicians Need to Know!

Phase IV trials, also known as postmarketing safety and efficacy studies and postmarketing surveillance (PMS) studies, occur after a drug or medical device has received regulatory approval and is available in the market. These trials are designed to collect additional information regarding the product's safety, efficacy, and prolonged effects in a larger and more diverse patient population. The foremost goal of phase IV trials is to detect any rare or long-term adverse effects that may not have been identified during the prior phases of clinical development. During phase IV trials, pharmaceutical companies, academic institutions, or other research organizations conduct studies to evaluate various aspects of the product, including its real-world effectiveness, optimal use, and any potential safety concerns. The regulatory agencies play a role in overseeing these trials to ensure that they are conducted ethically and in compliance with good clinical practice (GCP) guidelines.

Comparative pharmacokinetics, efficacy, and safety of bevacizumab biosimilar to reference bevacizumab in patients with metastatic colorectal cancer.

OBJECTIVE: To establish clinical biosimilarity of BevaciRel™ bevacizumab biosimilar (study bevacizumab) with the reference innovator bevacizumab in terms of pharmacokinetics, efficacy, and safety in metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A total of 119 patients with mCRC were enrolled across 20 centers and randomized to receive study and reference bevacizumab in this Phase III clinical study. Of these, 116 patients were administered bevacizumab 5 mg/kg intravenously every 2 weeks with folinic acid, fluorouracil, and irinotecan regimen. The primary endpoint of the study was objective response rate (ORR) at week 25, and the secondary endpoints assessed were progression-free survival (PFS), overall survival (OS), and assessment of pharmacokinetics and safety along with immunogenicity in both treatment arms. RESULTS: The ORR was 60.53% in study bevacizumab and 66.67% in reference arm. The proportions of subjects showing CR and PR were comparable in both the arms. The median PFS at 1 year was 3.83 months in test arm and 4.6 months in reference arm. The mean OS was 10.91 months in test arm and 14.68 months in reference arm. The difference in ORR, median PFS, and OS was not statistically significant (P > 0.05). The median Tmaxwas 6.00 h in both the arms. The median t½ was 330.63 h and 226.14 h, respectively, for test and reference bevacizumab. The adverse event profile of both products was in line with the known profile of bevacizumab. CONCLUSION: The study biosimilar bevacizumab was found to be noninferior and clinically biosimilar to the reference bevacizumab, thereby meeting an unmet medical alternative need in mCRC.

A comparative phase III clinical study to evaluate efficacy and safety of TrastuRel™ (biosimilar trastuzumab) and innovator trastuzumab in patients with metastatic human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer.

INTRODUCTION: The present study for biosimilar trastuzumab was a multicentric, randomized, two-arm parallel-group, comparative phase III study in patients with metastatic breast cancer. MATERIALS AND METHODS: Stage I of the study was conducted among 42 participants with equal distribution in the study and reference arm. After a loading dose of 8 mg/kg trastuzumab was administered intravenously on day 1 of the first cycle; serum samples were obtained at 0, 1.5 (end of IP infusion), 3, 6, 8, 24, 96, 168, and 336 h after the first infusion for the first cycle only. Cmax and AUC0-336 were calculated for a single dose. Stage II enrolled a total of 106 patients across 20 centers who were randomized to receive biosimilar trastuzumab (study trastuzumab) or the reference trastuzumab with paclitaxel. The primary endpoint of the objective response rate (ORR) was analyzed after last the dosed participant had completed 25-week evaluation. The secondary outcome measures included time to tumor progression, progression-free survival and overall survival at week 48, and safety evaluation. RESULTS: For reference and study trastuzumab products, mean Cmax of 229.02 and 210.68 µg/mL and AUC0-336 of 24298.29 and 25809.33 (µg × h/mL), respectively, were obtained. The efficacy results demonstrated that study trastuzumab and reference trastuzumab had comparable ORR (48.44% vs. 44.44%). The proportions of participants showing complete response and partial response in each arm were found to be comparable. There were 56 (68.29%) participants in the study arm and 13 (59.09%) participants in the reference arm who had at least one adverse event during the study. Immunogenicity assessment also revealed no participants with positive antibody titer in any of the study arms. CONCLUSION: The pharmacokinetics, overall response rate at 25 weeks, and safety of the biosimilar trastuzumab was comparable to the reference trastuzumab.

Gangrenous cholecystitis in an asymptomatic patient found during an elective laparoscopic cholecystectomy: a case report.

INTRODUCTION: Gangrenous cholecystitis is a severe complication of acute cholecystitis. We present an unusual case of gangrenous cholecystitis which was totally asymptomatic, with normal pre-operative parameters, and was discovered incidentally during a laparoscopic cholecystectomy. We have not found any similar cases in the published literature. CASE PRESENTATION: A 79-year-old British Caucasian man presented initially with acute cholecystitis which responded to conservative management. After six weeks he was asymptomatic and had normal blood parameters. An elective laparoscopic cholecystectomy was performed and our patient was found to have a totally gangrenous gall bladder. CONCLUSION: It is important to keep a high index of suspicion for the diagnosis of gangrenous cholecystitis in order to avoid potentially serious complications.

An unusually long appendix in a child: a case report.

INTRODUCTION: Appendicitis is the most common surgical emergency, but its diagnosis in children can be a challenge to the treating surgeon. CASE PRESENTATION: A 10 years-old girl was admitted to the paediatrics surgical ward with a right sided abdominal pain. The initial clinical presentation was vague. She underwent an appendicectomy which revealed a very long appendix. CONCLUSION: About half of the adult patients with appendicitis present with the known classical signs and symptoms, but the clinical scenario might be completely different in children. This case is educational as it highlights the importance of the atypical presentations of an unusually long appendix in children.