From Vision to Market
A Whitepaper by Nancy J Stark, PhD
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It starts with a technology
Time and again, companies develop a new technology, and then go on a clinical trial Easter egg hunt to find a claim they can make for it.They know the technology works, but aren't sure how to design a trial to give them the most efficient regulatory pathway (significant risk or non-significant risk, 510k or premarket approval) and whose outcomes will maximize their chances for FDA approval and third-party reimbursement.
Let's say you have a technology and you are confident that it works. You are at the stage of designing the clinical trial, but are struggling with where to start. It starts with the claims: well really it starts with the intended use and indications for use you want to make for the technology.
The first decision is to decide on the intended use you will pursue. When considering intended use, think in terms of verbs acting on the body: stimulates nerves, measures impedance, or measures biomarker concentrations.
Perhaps you have a neurostimulation technology; you might intend to use it for transcutaneous electrical nerve stimulation (TENS), functional electrically stimulation (FES), muscle stimulation, neural stimulation arrays to act as cochlear or retinal prostheses, or deep brain stimulation. Perhaps you have a biomedical impedance technology and you want to measure lean body mass, daily calorie expenditure, or tomography imaging. Or perhaps you have identified a family of biomarkers characteristic of a medical condition. Do you intend to diagnose a symptomatic patient for the condition, screen large populations for the condition, or act as an adjunct diagnostic tool?
Indications for use
Indications for use are more specific than an intended use, here we are talking about a disease or condition to treat, cure, mitigate, prevent or diagnose. There may be many indications for a single intended use. Your deep brain stimulator might be indicated to mitigate epileptic seizures, prevent depression, and treat headache.
And then the claim, i.e. the study outcome
A claim is an assertion of truth. There is no regulatory definition for a claim. Claims result from the outcome of the clinical study. So in essence, the marketing department writes copy for the glossy brochure first, and the clinical department designs the study to match it.
Clinical Evaluation Report
Next you need a thorough clinical evaluation report. What's this, you ask? There is no such thing in the FDA regulations or guidances. The requirements comes from ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practice" (2010), which coordinate with Europe's Medical Device Directive and Active Implantable Medical Device Directive.
The process involves an evaluation of published clinical data (a literature review), sponsored clinical data, and the manufacturers risk management system (complaint history) to determine if sufficient clinical data already exist to support safety and performance for the indications or if new clinical data are needed. If a new study is needed, the report is necessary to justify the study's design.
Do You Need A Clinical Research Quality Management System?
CDG's Clinical Research Quality Management System is a comprehensive collection of statements, policies, procedures, templates, and supporting documents that contains everything you need to set up a clinical research function.
Each procedure is designed to tell you 'how to' do something and results in a work product such as a document or report. The procedures are organized chronologically, the way you would organize a project schedule, to walk you step-by-step through the process of running a clinical trial and a clinical department.The manual is divided in sections that follow the major activities of a clinical project. For more information click here.
The next big step is designing the protocol, i.e. the plan for the study. It's an interactive process and you and the product development team will change your minds many times along the way.
You'll need to choose a study design, such as single arm, superiority to a comparator, equivalence to a comparator, non-inferiority to a comparator, or registry.
Objectives, hypotheses, endpoints, outcomes
There are endless arguments over what is meant by study objectives, but in my view of the world it refers to why you are doing the study:  research,  feasibility to prove a concept, develop a hypothesis, refine a design, or obtain data for sample size calculations,  manufacturability,  pivotal—this is the study on which the success or failure of the 510k or PMA pivots,  new claim substantiation,  consumer preference,  market positioning,  marketing support,  reimbursement,  post-market approval.
Hypotheses are testable statements of safety, efficacy, or performance. The 'null' hypothesis is usually the statement we want to to be false (my product is worse than yours), and the 'alternate' hypothesis is the statement we want to be true (my product is better than yours). In most protocols we only write the alternate hypothesis and we let the statistician make the translation in the Statistical Analysis Plan (SAP). But for non-inferiority studies we want to prove the null hypothesis (my product is no worse than yours); a technique devised by FDA statisticians to help device manufacturers demonstrate substantial equivalence. A study may have a primary hypothesis and several secondary hypotheses.
An endpoint is a method for measuring device success or failure. The word used to signal the end of treatment, but end of treatment is not a meaningful concept for devices that mitigate or manage diseases or conditions. Remember the endpoint as a measurement method and you will be fine. A study must have a primary endpoint to measure the primary hypothesis, and will have secondary endpoints for other hypotheses.
The outcomes are the result—did the device work or not? You'll need to decide now what value will be required to declare success. Here are some possibilities:  time to a distinct event, such as range of motion or death,  number of events by a certain time, such as number of adverse events within the first month,  correlation of observations to a diagnosis from another test, or  correlation of observations to a distinct event, such as disease or death
In designing the study, you'll make choices about screening procedures, stratification, blinding (difficult to do), randomization, washout periods, baseline measurements, follow-up schedules, and exposure assignments. Exposure assignments refer to whether you'll do a single group (aka single arm), parallel group, crossover group, Latin square, matched pair, a factorial design, or some other variation of these basics.
Sample size—how many subjects
Here's the deal, every choice you've made so far has influenced the sample size of the study. That's why you'll go through these steps many times before reaching a firm design. Most of the time, top management worries that a study is too expensive and will take too long. The only solution is to adjust the design elements to reach a lower sample size.
You must think like a project manager to successfully implement a clinical trial. Begin by working backwards from the intended use, diseases or conditions, and claims the marketing department wants to make. Use these to develop the hypotheses, endpoints, and outcomes measures for the study. These critical parameters will dictate the size, duration, and resource requirements for the trial. From here we can build a Gantt chart and study budget.
Clinical Research Quality Management System
The clinical research quality management system has procedures for who does what by when, provides template forms and checklists, and assures efficiency and inter-departmental effectiveness through top management endorsement. ISO/FDIS 14155 (2010) falls just short of an outright requirement for a Clinical Research Quality Management System, but compliance with the coming standard will be difficult without one.
Clinical Trial Project Manager
The Clinical Trial Project Manager is the person who provides forward motion to the clinical trial; the job is often performed by a Clinical Research Associate. Much more than monitoring a trial and reporting back to management, serving as project manager means analyzing problems, offering solutions, and knowing the regulations well enough to offer meaningful work-arounds.
A project manager can also build you a Gantt Chart, a cost estimate, and a resource schedule, and provide ongoing reports on the cost and resource consumption of the trial.
The next big-ticket documentation item is the Investigator's Brochure. Often double or triple the length of the protocol, this document is meant to give investigators all the information they need in order to make informed decisions about device safety. The Investigator's Brochure contains the following sections:  device description including a description of the mechanism of action, instructions for use, storage, handling, preparation, or pre-use checks,  preclinical testing including design calculations, in vitro tests, mechanical and electrical tests, reliability tests, software validation, performance tests, ex vivo tests, biological safety tests,  existing clinical data,  risk management, and  regulatory references.
You'll use the Investigator's Brochure over and over again, for every clinical trial you do on the new technology. So write it with thoroughness and be sure to keep it under version control.
Other study documents
Case report forms and informed consent are prepared next. The case report form should follow exactly from the protocol, asking for no more and no less information than the protocol requires. The informed consent should follow from the risk analysis, but with a subject-centric approach.
You'll also need a signed Investigator Agreement, investigator's and key study staff's CVs (signed and dated), log of key study staff, IRB approval, IDE clearance for significant risk studies, financial agreements with the site, and a host of other documentation forms.
Pre-study visits are like job interviews; these are the visits the Clinical Research Associate (CRA) makes to the potential investigative site to assess physical capabilities and investigator credentials. Not every company lets a CRA do this; site selection is so important it is frequently done by management.
Initiation visits are the process in which the study is implemented at each site. The process can be complex, consisting of several steps. For example, here is the process for one device:  presentation of technology background,  presentation of biological safety and warnings,  on-hands device use in a mechanical dummy,  on-hands device use in an animal, and finally  on-hands device use under direct supervision of the coordinating investigator. In addition there was training to regulatory expectations, study staff training, and documentation in a log with original signatures. The technology associated with this company's process has been on the market for several years now.
Routine monitoring visits
Routine monitoring visits are the bread and butter of study implementation. This is the process where the sponsor's agent (employee, CRO, or independent contractor) travel to the study site to inspect the progress of the study. Disliked intensely by investigators when first introduced by FDA in 1976, it was FDA's way of telling manufacturers that they are responsible for how their investigational devices are used!
Perhaps the most important part of monitoring is source verification of the data collected. Data transcribed onto case report forms by the study staff are compared to entries made in the subject's original medical records. The opposite is true too, entries in the medical records are compared to data logs (such as concomitant medications) to ensure that all data have been captured.
Adverse event review is another critical part of routine monitoring visits. Have all adverse device effects been recorded and reported? Have other adverse events, as required by FDA or the IRB, been recorded and reported?
The study close-out visit will be a time for celebration, if the investigator has done a good job of record-keeping along the way. It is like your taxes. You can file in one day if you have kept good records all year.
Data management is a ongoing process that begins while the protocol and case report forms are being designed. If consulted early on, a good data manager can save you thousands of dollars in wasted effort by advising in question construction and layout. Data management consists of:  designing a database in Excel, Access, SAS, or other application to receive the data,  entering faux data and validating the database calculations, queries, and reports,  entering the actual data,  verifying the actual data, usually with a sampling plan, and  upon agreement, locking the database so no changes can be made.
Statistical analysis and final report
Now it is time to close the circle. In statistical analysis, a qualified biostatistician tests the hypothesis using the outcomes data from the related endpoint. The product is successful if it has reached the pre-determined value.
The final report should contain the following elements per FDA:  product identification,  study progress including number of devices shipped, subjects enrolled, subject exposure to device, disposition of devices, brief summary of results, summary of anticipated and unanticipated adverse effects, and description of deviations from the protocol,  risk analysis,  any changes in manufacturing practices or quality control; or per ISO/FDIS 14155 (2010):  cover page administrative information,  table of contents,  executive summary,  introduction,  description of device and methods,  protocol summary,  statistical results including analysis of outcomes data and adverse event data,  discussion and overall conclusions,  terms and definitions,  ethics confirmation,  investigators and administrative structure,  signature page, and  list of annexes.
If you liked this whitepaper, hire us as your CRO
Clinical Device Group has the capabilities to perform all of these tasks for you—we are a full-service CRO. Or, if you prefer, hire us to perform specific tasks or act as an advisor to your staff.
Nancy J Stark, PhD
President, Clinical Device Group Inc