This pathway promotes evolutionary enhancements by providing a quicker pathway to market for newer versions of legally marketed lower-risk devices. Similarly, manufacturers may submit certain changes to devices approved under the premarket approval PMA process as PMA supplements that leverage previous device testing and experience where appropriate.
The Center has also created certain resource-intensive review processes to reduce Agency decision times while still allowing for adequate assessment of an application. These programs include "real-time review", wherein CDRH will issue a decision on a PMA supplement generally within five business days of meeting with the sponsor, and "interactive review", which facilitates the efficient and timely review and exchange of regulatory and scientific information between CDRH and the sponsor.
CDRH recognizes that transformative innovative devices typically present new scientific and regulatory challenges. The Innovation Initiative supports the development of innovative products by addressing some of the barriers that can impede a product's timely progress to market.
The Innovation Initiative proposes actions CDRH could take to help accelerate the development and regulatory evaluation of innovative devices safely and based on sound science.
These actions are:. Recognizing the important benefits truly innovative medical devices have on the public health of Americans, CDRH proposes to establish a priority review program - the Innovation Pathway - for eligible innovative products. CDRH has long recognized the importance of facilitating innovation and expediting the review of important new technologies.
Expedited review times are typically longer than standard review times and have not reliably met the targets FDA agreed to as part of Medical Device User Fee Act MDUFA negotiations, primarily due to the unique regulatory and scientific challenges presented by devices that are granted expedited review status. Nevertheless, compared to what would have occurred under the standard review program, expedited review has shortened the time to market for a number of important innovative technologies including drug-eluting coronary stents, implantable pacemakers, vision and hearing systems, and continuous glucose monitors.
The Innovation Pathway Figure 3 is intended to provide earlier investment of Center time and resources in devices that are truly pioneering technologies and that have the potential to revolutionize patient care or health care delivery. We anticipate that the devices reviewed under this pathway may raise scientific and regulatory questions that are novel, challenging and resource-intensive.
While it is critically important to take steps to facilitate the development of transformative innovative devices, we also recognize the importance of meeting our commitments under MDUFA. Therefore, the number of devices that we would be able to accommodate under the Innovation Pathway would depend on available resources. We would closely monitor our resources so that our performance and commitments for the review of other devices are not adversely affected, thus avoiding unintended consequences for devices reviewed under other pathways.
Figure 3. The Innovation Pathway recognizes the unique nature of transformative innovative product development. By front-loading critical aspects, such as identifying appropriate clinical endpoints and key scientific questions, and seeking advice from external experts, we can provide a more timely and efficient regulatory review process.
CDRH proposes that, to be eligible for consideration for the Innovation Pathway, the Center would have to determine that the device is radically different from any legally marketed medical device in the United States in its underlying technology or manner of use, and is designed to meet at least one of the following criteria:. Although the Innovation Pathway is a proposal for which CDRH seeks public comment, the Center has accepted a pilot submission into the program: a revolutionary brain-controlled upper-extremity prosthetic designed to restore near-natural arm, hand and finger function to patients suffering from spinal cord injury, stroke or upper-extremity amputation.
The arm system, funded by the Defense Advanced Research Projects Agency DARPA , will use a microchip implanted on the surface of the brain to record neuronal activity and decode the signals to actuate motor neurons that control the prosthesis. CDRH proposes that additional candidate devices for the Innovation Pathway may be identified in one of two ways: 1 at the request of the sponsor; or 2 at the suggestion of a CDRH employee or manager with the permission of the sponsor. No submissions would be considered for the Innovation Pathway without the explicit consent of the sponsor.
The Center Science Council, which is described in greater detail below, would meet regularly to evaluate applications to the Innovation Pathway and would communicate a decision to the sponsor within 30 days of the application submission date.
Decisions would be based on the revolutionary nature of the device, how well the submission meets the criteria listed above, and available and anticipated Center resources. Because of the innovative and transformative nature of the devices eligible for this pathway, it is expected that devices reviewed under this pathway generally will be PMA, PMA supplement, and de novo submissions. The Innovation Pathway would have the following key features designed to meet the unique requirements of transformative medical device development and regulatory review:.
The proposed Innovation Pathway is designed to facilitate the scientific and regulatory evaluation of transformative innovative products and invest Center time and resources in these products earlier in the review process.
Enrollment in the Innovation Pathway would not change the scientific or regulatory standards that CDRH would use to evaluate device submissions and determine their appropriateness for marketing.
Instead, the Innovation Pathway would recognize the challenges of developing transformative innovative devices and increases the commitment of Center resources to their development and evaluation. The de novo classification process was created 5 to provide a mechanism for the classification of certain lower-risk devices for which there is no predicate.
The de novo classification process is intended to apply to lower-risk devices that are classified into class III through the k process. In the following section a brief overview of this methodology and related issues is given. In his paper [ 4 ], Whitehead lists the key ingredients required to conduct a trial sequentially see Figure 1. The first two ingredients are common to both fixed sample size and sequential studies, but are worth emphasizing for completeness.
The second two are solutions to the particular problems of error rates and analysis in the sequential setting. Any combination of choices for the four ingredients is permissible, but, largely for historical reasons, particular combinations preferred by authors in the field have been extensively developed, incorporated into software see below and used in practice.
Each of the four ingredients will now be considered briefly in turn. As with a fixed sample size study the first stage in designing a phase III sequential clinical trial is to establish a primary measure of efficacy. The authority of any clinical trial will be greatly enhanced if a single primary response is specified in the protocol and is subsequently found to show significant benefit of the experimental treatment. The choice should depend upon such criteria as clinical relevance, ease of obtaining accurate measurements and familiarity to clinicians.
Appropriate choice for the associated parameter measuring treatment difference can then be made. This should depend upon such criteria as interpretability, for example whether a measurement based on a difference or a ratio is more familiar, and precision of the resulting analysis. A wide variety of continuous and discrete data types can be dealt with. Suppose that in a clinical trial the appropriate response is identified as survival time following treatment for cancer, then a suitable parameter of interest might be the log-hazard ratio.
If the primary response is a continuous measure such as the reduction in blood pressure after 1 month of antihypertensive medication then the difference in true unknown means is of interest. Finally, if we are considering a dichotomous variable, such as the occurrence or not of deep vein thrombosis following hip replacement, the log-odds ratio may be the parameter of interest.
A sequential test monitors a statistic summarizing the current difference between the experimental treatment and control at a series of times during the trial. If the absolute value of this statistic exceeds some specified critical value, the trial is stopped and the null hypothesis of no difference between treatments is rejected. The timing of the interim looks can be measured directly in terms of number of patients, or more flexibly in terms of information.
It should be noted that the test statistic measuring treatment difference may increase or decrease between looks, while the statistic measuring information will always increase. Early work in this area prescribed designs whereby traditional test statistics such as the t -statistic or the chi-squared statistic, were monitored after each patient's response was obtained. Examples can be found in the book by Armitage [ 5 ]. Since then, statisticians have developed more flexible ways of conducting sequential trials when considering the number and the timing of interim inspections.
Whitehead [ 8 ] monitors a statistic measuring treatment difference known in technical terms as the efficient score and times the interim looks in terms of a second statistic approximately proportional to study sample size known as observed Fisher's information. As highlighted above, a sequential test compares the test statistic measuring treatment difference with appropriate critical values.
These critical values form a stopping rule or boundary for the trial. At any stage in the trial, if the boundary is crossed, the study is stopped and an appropriate conclusion drawn. If the statistic stays within the test boundary then there is not enough evidence to come to a conclusion at present and a further interim look should be taken. It is possible to look after every patient or to have just one or two interim analyses.
The advantage of looking after every patient is that a trial can be stopped as soon as an additional patient response results in the boundary being crossed. In contrast, performing just one or two looks reduces the potential for stopping, and hence delays it. However, the logistics of performing interim analyses after groups of subjects are far easier to manage. In practice, planning for between 4 and 8 interim analyses appears sensible.
Once it had been established that there was a problem with inflating the type I error when using traditional tests and the usual fixed sample size critical values, designs had to be suggested which adjusted for this. It is the details of the derivation of the stopping rule that introduces much of the variety of sequential methodology.
A collection of designs based on straight line boundaries, which builds on work that has steadily accumulated since the s is discussed by Whitehead [ 8 ], the best known and most widely implemented of these being the triangular test. The important issues to focus upon are the desirable reasons for stopping or continuing a study.
Reasons for stopping may include:. A moderate advantage of the experimental treatment is likely and it is desired to estimate the magnitude carefully. These will determine the type of stopping rule that is appropriate for the study under consideration. Stopping rules are now available for testing superiority, noninferiority, equivalence and even safety aspects of clinical trials. As an example, consider a clinical trial conducted by the Medical Research Council Renal Cancer Collaborators between and [ 12 ].
Consequently its benefits over MPA needed to be substantial to justify its wider use. A stopping rule was required to satisfy the following requirements:. This suggested use of an asymmetric stopping rule. The design chosen was the triangular test [ 8 ], similar in appearance to the stopping rule in Figure 2. Interim analyses were planned every 6 months from the start of the trial. The precise form of the stopping rule is defined, as is the sample size in a fixed sample size trial, by consideration of significance level, power and desired treatment advantage, with reference to the primary endpoint.
The primary endpoint in the MRC study was survival time and the treatment difference was measured by the log-hazard ratio. Once a sequential trial has stopped, an analysis will be performed. The interim analyses determine only whether stopping should take place, they do not provide a complete interpretation of the data.
An appropriate final analysis must take account of the fact that a sequential design was used. But they can still test you on it. Use the Gantt Chart you made, or another calendar to plan out deadlines for your project.
I divided my major project into subprograms e. Testing will be a chore at times. Get other people to test it, because you never know what parts they might get stuck on. My partner and I asked to use a different language because the one we learnt was not cut out for the kind of game we were looking for. We had so much more fun coding, the program looked a lot better, and we learnt one new programming language out of the whole experience.
Software was easily one of my favourite subjects, and it is so worth the effort. To post a question, log into your account or register an account! And remember, Artificial Intelligence will probably control us all in a few years so consider this course your defense against our future overlords : D.
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