ISO/FDIS 14155 (2010) and Clinical Evaluations

Clinical evaluations justify design of clinical investigations A Whitepaper by Nancy J Stark, PhD.

Today I want to discuss the role that clinical evaluations will play in justifying the implementation and design of device clinical trials once the 2010 ISO/DIS 14155 "Clinical investigations for medical devices in human subjects--good clinical practices" becomes a published standard. Over the past several months I've written extensively about clinical evaluation reports, but always within the context of obtaining or maintaining a CE Mark and quality system certification. What does the standard say? The ISO/DIS 14155 (2010) standard states: Clinical evaluations may be indication specific The intent of the standard is that a clinical evaluation report be prepared before any clinical trial begins. The results of the clinical evaluation report--performed with selected indications in mind--should lead naturally to the decision as to whether or not new clinical data are needed to confirm the safety and performance of the device, or that existing data are sufficient in and of themselves. Shades of the American system The idea of using existing data to support an argument of safety and performance (i.e., safety and efficacy) is not new to Americans. Although there is no literature review requirement for non-significant risk studies under the abbreviated IDE system, an extensive Report of Prior Investigations is required for every full IDE before FDA will grant approval to conduct a significant risk clinical trial. Part 812.20(b)(2) states: A sponsor shall submit "...a complete report of prior investigations of the device..." as part of the IDE application. GHTF SG5 is the guiding document The Global Harmonization Task Force (GHTF) Study Group 5 document "Clinical Evaluation" is the guiding light for preparing clinical evaluation reports. While you may choose to follow MEDDEV 2.7.1 Rev 3, the European (region specific) document couldn't be referenced in an international standard. The steps for preparing clinical evaluation reports to justify a clinical trial are the same as those for a clinical evaluation report for maintaining certification and CE Marking except that pre-clinical testing becomes an important part of the review. Briefly, the steps are: [1] Define the key questions. [2] Identify the databases to search (usually MedLine, Embase, MAUDE, and Cochrane). [3] Define scope of search and search strategies using a qualified information specialist. [4] Assess abstracts to identify articles for weighting. [5] Acquire full-texts of articles. [6] Read and weight the articles for relevance. [7] Weight the articles for statistical significance using a qualified biostatistician. [8] Review only those articles with the highest weightings; typically 6-8 articles per indication. [9] Review existing sponsored clinical investigations. [10] Review the risk management system. And additionally, [11] Review the pre-clinical and biocompatibility data. [12] Finalize the report, taking into account the four elements of: ----[b] existing clinical data from the literature, ----[c] data from existing clinical investigations sponsored by the manufacturer, ----[d] the risk management system, and ----[a] pre-clinical testing including bench, animal, and biocompatibility data. The clinical evaluation should lead you naturally to a decision as to whether a new clinical investigation is necessary and, if so, to its design. A shift in thinking The thinking is a little bit different than what I was trained to do. Perhaps erroneously, the default position was always to do a clinical investigation to demonstrate safety and efficacy in humans unless you could justify not doing one. But so many trials are being done today there is a critical shortage of subjects. The new (European) thinking is that a clinical investigation is only performed if existing literature data, existing clinical data, the risk management system, and pre-clinical data--taken together--cannot confirm the safety and performance of your device for a selected indication. Rephrase the indication As the manufacturer, you will have some choices in situations where new clinical trials are deemed necessary. If a study is too expensive for your corporate budget, you can probably rephrase the indication. For example, an indication for the prevention of epileptic seizures by early neurological intervention might require a different level of data than the abatement of epileptic seizures by neurological intervention triggered by the seizure itself. Or the relief of cancer pain might require a different level of data than the management of physical discomfort. Or a wrist support to heal carpal tunnel syndrome might require more data than a wrist support to stabilize the joint. Return on investment If the indication represents a large enough market size, the cost of the clinical trial may be justifiable. It's a simple enough exercise: estimate the cost of the clinical trial, estimate the profits from the new indication, and determine profit/loss over the next six months. Return on investment (ROI) = (estimated new profits - cost of trial)/(cost of trial); for example, the ROI for pediatric clinical trials ranged from -$8.9 million to +$507.9 million over six months. Many companies consider their estimated daily sales for a new indication and view every day the trial is delayed as a lost opportunity cost. Once the decision to implement the clinical trial is made by top management the pressure is on to get the trial underway and completed. CDG can help Clinical Device Group is poised to help you work through the process of evaluating existing data and justifying the design of a clinical trial. We have a vast network of professionals who are experts in biocompatibility, information technology, medical writing, clinical research, biostatistics, data management, market size estimation, cost estimation, scheduling and Gantt chart preparation, and regulatory submissions. Our experts are ready to: [1] Assess your pre-clinical and biocompatibility data, [2] Prepare a clinical evaluation report, [3] Suggest design variations for a clinical trial with larger or smaller sample sizes, depending the indication's wording, [4] Write or review your protocol, [5] Estimate the market size and profitability of the indication, [6] Estimate the cost of the clinical trial, [7] Calculate the return on investment, [8] Implement and monitor the trial, [9] Enter and manage the data, [10] Analyze the data to support or refute the indication, [11] Prepare the final trial report, [12] Prepare the regulatory submissions for product commercialization. Contact us Phone or email us at 773-489-5706 or cdginc@clinicaldevice.com.