Sunday, September 18, 2011

CLINICAL RESEARCH IN MEDICAL DEVICES –Innovative Designs to overcome constrains

The Clinical Trials of medical device's are complex in comparison to drug. So, one has to design the study to overcome the constrains in medical device clinical trials, especially pertaining to comparability and establishment of universal outcomes. There is no perfect control in a medical devices study. Moreover, as there is no “Absolute safety and efficacy” available from experimentation in healthy human subjects, the outcomes of studies remain majorly study specific. Applicability of the trial outcomes to real world is grossly limited.
One of the major problems in Medical Device clinical trials as discussed is lack of a perfect control. Even if some control is selected, the control may have different indications. For example, Stent implant angioplasty and coronary artery bypass graft are the common comparable entities. Both of these treatments and thereby the device “Stent” is studied against a control of CABG. If seen in further details, the coronary artery bypass graft is indicated for some different subset of coronary artery stenosis than angioplasty by stent. Hence even after several trials including ambitious large trials such as Freedom and Subgroup trials such as MAIN-COMPARE, the dispute of which one would be a better treatment was still on. Not this alone, but several other conditions where medical device needs to be compared with a control, which is usually not a perfect control, the outcome is usually disputed. Higher the data available, higher is the confusion. What could be a suggested solution?
Among these, SYNTAX was a trial, which was able to establish some results and lay down definitive guidelines to an extent though. What differs in SYNTAX from other studies was design of the trial. The trial was designed based upon minute details of the therapeutic variations. For comparability, they established a score and made it a compound trial.  In only a few other cases, such as LEADERS trial, due to an innovative study design, the outcomes of the trials are closely matching to the real-world observations, unlike many other studies such as from SPIRIT group, Endeavor group, where the outcomes fail to match the day to day clinical outcomes.  This makes the point that innovative study designs can overcome some major constrains in Medical Device Clinical trials and can yield reliable and more accurate clinical data which can be used as a standard reference in day to day clinical practice.
What can be different designs of studies? There can be several design options. The first is variation of the hypothesis. In many Medical Device Clinical Trials, the study hypothesis is developed in a way that specific outcomes are tested. For example, in many studies, the hypothesis is designed to register an “Event Free Survival” or “proportion of population free from events in a defined period”. Though these both study questions sound good, practically, the comparison of a medical device on these outcomes is too vague to prove anything in favor of any of the arms. Instead, if the same evaluation is defined in a converse, such as “frequency of adverse events reported in a particular period” or “time taken to relive or produce desired or undesired effect” would be more specific and in a smaller group of population, a better study outcomes can be obtained.
The second important postulate of an innovative study design is inclusion of subsets. In many conditions it is seen that the study design exclude many subsets of the populations, which make the results differ from “real world” scenario. Instead, the predetermined subsets inclusion can give a study a wider acceptance and better power. In fact, based upon this one postulate, the study can be an union matrix study, a multi-arm study, overlapping matrix study etc. These designs are uncommon to use but an intelligent statistician will take efforts to make these ambitious designs. These types of designs may have several expressions such as compartmental design (Tight Subset matrix), blocks design (Loose Subsets Matrix) , clusters design(Loose subsets with stratified or multiple overlapping) ; and the study cohort can be stratified to establish relative betterment.

When a device has no perfect control, but if it is considered to be remedial in a particular condition, way of designing the study is multiple controls. This design of study enables the researcher to establish practical comparison of the device with several aspects of treatment such as untreated subjects, Subjects treated with one or more other modes, Subjects treated with device alone, subjects treated with device and subjects treated with combination of therapies. This type of study can be best suited to derive outcomes for new types of devices. The other type of designs can be compound design of multi-arm and single arm trials. This design is best suitable when there is an established treatment for some particular condition. The device which is either new or newly indicated for this condition is to be compared with established treatment. In This scenario, there can be great variance of indication of the device and the established treatment within the same condition. This complexity can be addressed by a compound design of the study, making the arms comparable more correctly. 

 Use of Standard or Specifically developed scores can be one of the important tools in design for Medical Device Clinical Trials. The Standard Scores Such as Comorbidity Index, Medina Score for Cardiology bifurcation lesion or Study specific scores such as SYNTAX Scores can be highly useful in designing a study and meet specific comparability needs.

Dr. Ashish Indani
Clinical Operations Head
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1 comment:

  1. Hello Everyone!!

    To begin with, I am a biomedical engineer but have explored my vocational career in a different, rather challenging domain - health technology assessment and implementation research! Why so? I would not hesitate to say that so called "technical domain"- the most common fate with Biomedical Engineer- did not attract my mind much. Because to me, it was always more or less similar to what the electronics engineer does!

    It would not be overstatement if I would say that Biomedical engineering is considered very superficially in most of undergraduation and graduation programmes. To be specific, I would say from my personal experience that hardly any college would be there which actually focuses on medical device policy related aspects. I would like to bring to discussion this new paradigm with 6 rarely explored aspects on Biomedical Engineering.

    Medical device clinical trials: Unlike Pharmaceutical technologies, there are no dedicated established centers- MEDICAL DEVICE CROs in ample amount which could satisfactorily facilitate a medical device product evaluation and commercialization nor clinical evaluation guidelines in medical devices sector i.e. ISO-14155, ICH-GCP in adaptation oriented towards medical devices are taught in institutions so as to enable the students take such projects and come up with an excellent guideline document for producing local, national or global impact.

    Medical device related health economics: The education could be imparted with Intended Learning Objective (ILO) of providing insight to economic evaluation of clinical effectiveness or diagnostic accuracy of medical devices with respective cost dimensions. This may comprise projects like preparation of costs database, estimation of budget for reimbursement schemes on medical device failure and so on.

    Medical Technology Surveillance: There is little guidance available in field of post-marketing surveillance of medical devices especially in India. Unlike PvPI and hemovigilance, no such programme is available for medical devices. A model or strategy for the same could be invoked for purpose of brainstorming in students.

    Regulatory Affairs and Standardization: Understanding how to put boundaries to innovations while their diffusion is something highly expected to be taught. It is fact that MATLAB,LABVIEW related digital image processing projects are promoted always but no project is seen which might have explored ethical issues related pros and cons associated with image processing i.e. violation of PNDT act, misdiagnosis of any abnormality or disorder. Moreover, there is less education provided on CE marking, Medical device standards, Medical device testing.

    Intellectual Property Rights: No course I came across so far incorporates this aspect from project perspective i.e. project on assessing IPR issues faced by device manufacturers, comparison of device patentization framework of different countries, petty patents.

    Bridging translational gap: It is hard fact that even after outstanding project model, there is no support in terms of how to accelerate it for professional growth with commercialisation purposes. Most of projects are just for sake of completion and not with realization and/or continuation of further journey. Such lacking in system is also proposes threat of plagiarised projects (ready-made models/circuits in markets) or “frog-in-well” approach during project.

    I believe if this type of thinking could be done "apriori", then biomedical engineering’s value could be realised like never before. And also I believe that these aspects, when ingrained in curriculums, it would be “pride” rather than “speechlessness” or “cluelessness” when somebody would ask the reason for choosing this branch.

    I would be happy to see as many as comments and suggestions for this post.

    Let's start our journey for evidence-based-medical device research and development !!