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

GENELIFE CLINICAL RESEARCH

33,34,37 Ground Floor, Cinewonder Mall, Ghodbandar Road, Thane West-400607. INDIA
Telephone:             +91-(0)22-65242666                   +91-(0)983316130       Fax: +91 22 25841316
Email:  info@genelifecr.com Website: http://www.genelifecr.com/, Blog:http://genelifecr.blogspot.com/

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CLINICAL RESEARCH IN MEDICAL DEVICES

Medical Devices are any therapeutic or diagnostic agents or their accessories, which work on non-biochemical mode in the body.  The primary scientific consideration in medical devices clinical trials is determination of ‘Which devices require clinical trial?” or “Does my device need clinical trial?” to undergo clinical studies.

WHICH MEDICAL DEVICES REQUIRE CLINICAL EVALUATION?

In Medical device life-cycle, preclinical bench-top analysis for mechanical and design tests; are the major determination criteria for acceptance of that device. It can be considered as Phase 0 studies for medical devices. Unlike the drugs, feasibility of medical devices practically is done in a combination of engineering tests and Animal studies. The pre Clinical studies become more important in medical device compared to drug because the evaluation of Medical devices (Both performance and safely) depends upon its adverse event occurrence (In contrast to drugs where Pharmaco-dynamics and tolerance are major safety endpoints and bioavailability and Improved life quality are performance outcomes).

From clinical research perspective, medical devices can be classified into four main categories-Therapeutic (Whether active or inactive), Non-therapeutic-non-diagnostic (Accessory), Diagnostic and Contraceptive medical devices.

The clinical trials for diagnostic devices are wider and diagnostic test outcome oriented. The clinical trials are required only to introduce new techniques. Same is the case with contraceptive devices. Contraceptive devices studies are mainly failure oriented single arm trials and accessories do not require clinical trial for regulatory or clinical evaluation.

The therapeutic medical devices, which mainly require clinical evaluation, have mainly two types, Implantable and external. The implantable devices includes Pacemaker, stents, arterio-venous fistulae, dental implants, orthopedic implants etc. and the non-implantable group include Cardio-Pulmonary Resuscitation (CPR) Devices , Heart and Lung Machine, Dialysis unit, Defibrillator (External) etc.  Clinical trials in these Medical Devices are major concentrated on its performance and safety analysis. Most devices in this group need repeated confirmation of utility by clinical trials.  Highly dynamic devices like stents hence require recurrent validation. Similar but relatively less severe is the case with a pace makers etc.

PHASES IN MEDICAL DEVICE CLINICAL TRIALS

Unlike drug Clinical studies medical device clinical trials can be divided into three phases:

1. Pilot Clinical Trial

2. Pivotal Clinical Trials

3.   Post Marketing servilence

Study types	Primary Intention	Desired outcomes	Points to be evaluated
First in human Studies	1.       Feasibility of the device in Human subjects	1.Non-inferior performance over control arm	1.       Logical Reasoning for determination of given endpoints (Cross check animal data)
	2.       "No Additional Risk" profile of the device	2.       No Additional risk over control arm
	3.       Performance of the device in target condition
	4.       The studies are  performed in Simple population for performance demonstration; have lowest risk		2.       Other parameters if missed by study reporting (Source Animal data)
Pivotal Studies	1.       Safety and efficacy of the device in human subjects	"Safe for human wider human use"	1.       Performance of the device in given end points (efficacy / safety)
	2.       Performance of the device in target condition		2.       Methodology of study
Post marketing surveillance	Evaluation of Device in more defined / Difficult subgroups	1.       Performance and safety in More difficult conditions	1.       Effect of parallel medication etc
		2.       Marketing tool	2.       Study methodology
			3.       Preserved safety interest

CONSTRAINTS IN MEDICAL DEVICE CLINICAL TRIALS

Like drug, it is necessary to evaluate the safety and efficacy of medical device before for marketing approval.  Apart from that medical devices will require performance evaluation, which makes the medical device studies more tricky compared to drug studies.

Another biggest constrain in most of the medical devices is lack of a perfect control. In most cases, earlier treatment by surgery, drug or previous generation device may also not prove a good control as indications in higher versions may differ from of the previous. Classical examples are randomization of stents against Bypass surgery, renal transplant against repetitive dialysis, Drug eluting liposuction versus pseudo-trimmer devices are all non-decisive. In most of these cases, even the design of the study was a challenging job. Even in previous versions of devices, there is similar propensity. DES versus metal stent, ERCP device versus laparoscopic cholecystectomy apparatus failed to achieve even primary endpoints due to lack of specificity in comparisons.  Wise design of the study is important to mitigate such failure risks.

Apart from this, human safety is still a major clinical and ethical concern especially with implantable device related clinical procedures, as most of them are almost irreversible. Taking for example, a coronary stent, once implanted, even if it causes complications such as stent thrombosis, has no way to reverse the implant. Clinical studies for most of the therapeutic medical devices, unlike drugs, again are not possible in healthy subjects. Hence, there cannot be an “absolute safety” outcome for any medical device.

Another constraint is scope of error, which is very less in case of medical device clinical trial.  Clinical data from all phases of medical devices is used as a very critical selection criterion by medical practitioners. Yet, making out-standing scientific value for the study and its outcome is difficult due to “lack of innovation” in many cases. Except a few clinical trials like REALTY, SYNTAX, LEADERS for DES, and a few more for Nephrological, neurological and urological devices, there are too few innovative designs. Achieving “Superiority” is also difficult task in medical device trial. Pertaining to all these major points, there is a lot of opportunity for young scientists to invest their mind in making several developments.

Indian Clinical research industry is progressively developing and adding newer segments to its overall expansion. In last few years, Medical Devices have made a significant share in the overall statistics. Considering the regulatory scenario, most of these trials take place simply on a notification. A few CROs like Genelife in Mumbai, have taken initiatives in making medical device based clinical trials more innovative and standard. Even if in current time there are no many pilot/pivotal studies and FIM studies taking place, we see closest future having wider prospects and scopes for Medical devices clinical research in India.

Kind Regards,

Dhirendra V. Singh
Managing Director

GENELIFE CLINICAL RESEARCH

33,34,37 Ground Floor, Cinewonder Mall, Ghodbandar Road, Thane West-400607. INDIA
Telephone: +91-(0)22-65242666 begin_of_the_skype_highlighting            +91-(0)22-65242666      end_of_the_skype_highlighting Mob: +91-(0)9819055580 begin_of_the_skype_highlighting            +91-(0)9819055580      end_of_the_skype_highlighting Fax: +91 22 25841316
Email:  info@genelifecr.com Website: http://www.genelifecr.com/, Blog:http://genelifecr.blogspot.com/

Genelife Clinical Research: Onging Respiratory Clinical Trials on Asthma

Genelife Clinical Research has started its first study for DCGI submission. After playing significant role in conducting pre-clinical studies and global US FDA studies, Genelife Clinical Research has given a progressive start for its first trial for DCGI submission for “Asthma”. As known, Asthma is a common chronic disorder of the airways that involves a complex interaction of airflow obstruction, bronchial hyper responsiveness and an underlying inflammation. This interaction can be highly variable among patients and with patients over time. The study is a prospective “A Multi-Centric, Double Blind, Randomized, Comparative Clinical Trail to Evaluate the Efficacy and Safety of ZU/SER10 in the treatment of Asthma”. In this study the test Drug will evaluated against "Montelukast" one of the best Drug of Asthma. In this study we have to generate data for 200 completed subjects across four sites in two months of recruitment period. 

The identification of site was based upon historic performance metrics, type of Institute and its geographic location, paramedical staff, Investigator’s qualifications and their availability for the entire duration of the study, and most importantly their recruitment rate. And to get all the details we performed a feasibility assessment by telephone to determine each PI’s availability, interest, and ability to meet study requirements and procedures.These identified sites comprise of both private institutions as well as government institutions to recruit patients from all economical sets. 

Considering the patient recruitment as bottleneck, we at Genelife stressed a lot on selection of right site. Recruitment rate has become more important criterion considering the short recruitment duration. We performed the site selection process with outmost care. 

During the site selection processes we have carefully observed the facilities available at site, their patient recruitment rate and their training & amp; knowledge about ICH - GCP guidelines, performance of site in previous trials for a similar indication, audit findings, patient recruitment, lost- to-follow-up rates and finally, results of site selection visits. Site staffing, ability to communicate internally and externally, experience in the area of clinical trials, and logistical handling of case report forms and other data collection instruments. For this particular study we have selected four sites and those are at Mumbai, Lucknow, Hyderabad and Varanasi.

For this Asthma study we have generated additional Logs, to reduce the percentage of errors and discrepancies considering the number of data to be generated at site by the investigator. 

Genelife Clinical Research has improved its facilities for conducting this Study in order to provide high Quality Standard.

Thanks & Regards,

GENELIFE CLINICAL RESEARCH

E mail :  info@genelifecr.com

Blog    : www.genelife.blogspot.com  

1 st Anniversary of Genelife Clinical Research

We take the opportunity to update our esteemed and valued client, that we have completed one year in serving the research needs of the Drug Development Process.

We have celebrated our anniversary on 26^th of February 2011. The inception and working journey of past one year has been a motivating experience for us which will remain a cornerstone on which we shall build our future.

On this auspicious occasion, I would like to thank everybody who directly or indirectly helped us in reaching this milestone.

At this time, it would be myopic to attribute our greatest thanks to one particular individual who trusted our capabilities which helped us in converting our dream into reality. On the other hand joined forces of several people helped Genelife to make it so far.

The journey was difficult and challenging but we came off with flying colors. One year back we started a new organization on a shoe-string budget which now have grown into a business far exceeding anyone's expectations. We are all very proud of this accomplishment and grateful to our customers and employees who helped us in achieving these feet. 

Genelife Clinical Research was founded in February 2010 by a small group of entrepreneurs headquartered in Thane, initially started as a Clinical Research Organization then quickly diversified into all aspects of drug development process. With the proliferation of consumer’s needs we started our Pre-Clinical organization with the name of Acuro Research Centre in Pune. With this success, Genelife has become one of those CROs who have the capability of conducting both clinical as well as pre-clinical studies in house.

In this past one year, we successfully conducted 14 Preclinical studies. Another 13 are currently in pipeline. We are also participating in two global US FDA studies. At present we are conducting one study for DCGI submission in Asthma and we are looking forward to start a Cancer study in Europe for US FDA submission. Also Genelife has taken initiative and conducted Disease Surveillance Survey (DSR), in order to identify fresh sites and potential investigators for upcoming studies in (medical conditions). It is an ongoing process and presently Genelife has a database of around 800 new investigators and sites. 

This all become possible because of your support and trust. From inception, the Genelife CR capitalized on the company's policy “to become the partner of choice for sponsors”. We have translated our knowledge into a full portfolio of drug development which empowers clients to close the gap between their requirement and regulatory needs.

Looking back at this moment I feel proud to be a part of the winning team here at Genelife and also visualize a great collaboration and partnership with you for the foreseeable future.  

ALL THE BEST FOR FUTURE

Kind Regards,

Dhirendra V. SinghManaging Director

GENELIFE CLINICAL RESEARCH

Significance of Disease Surveillance Report (DSR) in Patient recruitment

Disease surveillance is the systematic and regular collection of information on the occurrence, distribution, and trends for prevalence of disease. It is an essential obligation for early detection of emerging (new) or re-emerging (resurgent) infectious diseases. However, in context of Clinical Research Disease Surveillance is predominantly used to identify site & Investigator according to prevalence of disease for higher and cost effective patient recruitment.

“Generally considered to be biomedical or health-related research studies in human beings that follow a pre-defined protocol”. ClinicalTrials.gov 

Patient recruitment is one of the most imperative task that is need to be performed for conducting a significant clinical research. In clinical research subject recruitment is often stand by as a huge challenge as more than 80% of global trials fail to enroll on time, with 52% delayed by 1-6 months1; this kind of delay can affect company’s commercial standpoint by an unforeseen deficit.

Although in comparison to the western frontier the patient enrollment rate in India is about 3-4 times higher; but as most of the CRO’s are operating at places where clinical studies are already being conducted recruitment is going to be a key hitch because the patient population is shrinking.

Keeping recruitment problem in mind we at Genelife have modified Disease surveillance for Clinical Research purpose. 

Genelife used DSR as a tool for deriving a solution for enhancing the investigator/site selection and patient recruitment process. The primary focus of the survey was to screen unsullied and experienced site/investigator on the basis of patient pool and to understand the disease trend in India. Secondly it was also focused to build empathy with the site/investigator and to spread awareness about the importance of Clinical research and GCP at unexplored or new sites. DSR also used to make out referral sites moreover to make the generation of the feasibility report faster. 

Genelife has conducted a questionnaire survey amongst the investigator to access the patient pool and the disease trends across all regions of India. The Questionnaire was focus on to assess Experience of the investigator in conducting Clinical research, Prevalence of the disease and Number of patient he/she can recruit (with respect to therapeutic area). It also tried to assess the experience and interest of the Doctor/ Investigator/Site in conducting a Clinical Research. 

The DSR was conducted in two phases. In 1st phase therapeutic areas were chosen according to the number of Clinical Trials going on in India & future assumptions along with general physician’s database. The therapeutic areas included in this phase were Cardiology, Dermatology, Gastroenterology, Oncology, Orthopedics and Diabetes. In 2nd Phase Genelife identified the therapeutic area for which we were contacted more, which includes Allergy /Asthma, Endocrinology, Infectious Disease, Metabolic Disorders, Nephrology, Obstetrics/Gynecology, Surgery (Cardiac surgery for medical device), Urology etc. Genelife Clinical Research has isolated India into four demographic region east, west, north and south. A questionnaire was distributed amongst the Investigators/Doctors. 

Genelife has reached almost 800 Investigators/Doctors of different therapeutic area across India evaluating their experience in conducting Clinical Research and accessing the patient pool. Genelife with the help of Disease surveillance survey attempted to access fresh site by providing training to the Doctor who were interested in clinical research but were not trained nor having knowledge of conducting a Clinical Research.

Reference:

1. http://www.pharmabiz.com/article/detnews.asp?articleid=22867&sectionid=50 (December 29, 2010).

Kind Regards,

Iftekhar Kazmi 

Assistant Manager Business Development/Program Manager

GENELIFE CLINICAL RESEARCH

Telephone: +91-(0)22-65242666/555

Email: info@genelifecr.com Website: http://www.genelifecr.com/,

Difference Between Indian GCP & ICH-GCP

1. In Informed Consent Process, As per ICH - GCP any one designated by the investigator to conduct and to sign the consent form. (Section 4.8.8) but in Indian GCP Investigator should sign the form. (Section 2.4.3.1).

2. In IEC section, Indian GCP recommended the maximum no. of IEC member (12-15) but ICH-GCP Maximum number is not detailed. In IEC section, Indian GCP recommended that Member Secretary belongs to the same Institution but ICH- GCP Not recommended.

3. As per Indian GCP Monitor is also responsible for ensuring that CRFs are legible. where ICH-GCP state that Monitor has to verify that the documents provided by the investigator are legible.

4. As per Indian GCP, Study related documents/materials should be safe guarded by the sponsor for 3 years. (Section 3.1.5) but in ICH-GCP the records are linked to marketing approval.

5. Investigator qualifications: The Indian GCP investigator should be qualified as per the requirement of the Medical Council of India (MCI).

6. Investigator and sponsor’s Sops: The Indian guideline mandates that the sponsor and the investigator should sign a copy of the Standard Operating Procedures (SOPs). Besides, the investigator and his staff have to be aware and comply with SOPs; ICH-GCP expects the investigator to comply with the protocol.

7. Investigators responsibility for data analysis: As per ICH-GCP, when the trial is completed, the investigator has to provide the Independent Ethics Committee (IEC) with a summary of the outcome of trial. In contrast, Indian GCP demands that the investigator should sign and forward the data like Case Report Forms (CRF), results and interpretations, analyses and reports of the study from his/her centre to the sponsor and the ethics committee.

8. Powers of IEC: According to Indian GCP (2.4.2.6), the IEC has power to order discontinuation of a trial if the IEC finds that the goals of the trial have already been achieved mid-way or unequivocal results obtained. As per ICH-GCP, this is the responsibility of independent data-monitoring committee (IDMC).

9. EC Quorum: ICH GCP min of 5 members and Indian GCP min of 7 members.

10. EC Members: Indian GCP gender representation at least 1 women

Progression with Pre- Clinical Studies

With the vision to be a preferred partner by the sponsor in providing complete management to the drug development services; we are working with the unique hallmark of Quality and Innovation. Genelife Clinical Research understands that Pre-Clinical Study is the foremost step to initiate the drug development process.

After playing a significant role in two Clinical studies for US FDA; Genelife has given a fine start with the preclinical Study. We are conducting Ten Pre- Clinical Studies; viz. Acute and Sub Acute studies for the a Inhalation Study, Four intravenous injectable, Five oral formulations. Apart from these Toxicity studies we are also conducting Non-Clinical studies like Capillary Electrophoresis and Stability Study. The Capillary Electrophoresis study we have conducted by Capillary Zone Electrophoresis (CZE). In Capillary Zone Electrophoresis analytes moves in the EOF but separate into bands because of difference in their electrophoretic mobilities. Further to this Capillary Electrophoresis study of a protein molecule. we are looking forward to do conduct another Capillary Electrophoresis of an Alkaloid. Conducting Capillary Electrophoresis study is unique experience as very few CRO's has the capability to conduct Capillary Eletrophorasis study. Now we at Genelife has developed facility for conducting these Studies and will play a vital role in setting up the highest Quality Standard and Expertise.

After these few Pre-Clinical Studies, we have erudite that for perfection one needs experience in the field. We are looking forward for more such preclinical studies and the Clinical Trials of these drugs in near future.

Rahul Bhalla

Clinical Research Associate

Genelife CR on a roll with successful Site Selections

Genelife has given a fine start with its projects. Currently we are selecting five sites for Ulcerative Colitis study and twenty sites for Psoriasis study. The site selection is the initial and very crucial part of successful clinical research conduction. During the site selection visit, the site is identified and observed with the infrastructure and number of patients visited at the site along with the technical discussions of the study with the principal investigator.
The very first stage is to select the city for the study. According to the prevalence of the disease and the type of the study for Ulcerative Colitis, we selected Western Maharashtra, Eastern Uttar Pradesh, Punjab, etc. and for Psoriasis study, we have selected cities in Western Maharashtra, Central Madhya Pradesh, Eastern Uttar Pradesh, and some parts of Andhra Pradesh and in the Northern part of India. The experience gained during the site selection was priceless. The doctors’ approach towards our project was appreciable. We conducted the site selection visits in Western Maharashtra, Central Madhya Pradesh, Eastern Uttar Pradesh and Andhra Pradesh. We faced many problems during the process. While selecting the site, we looked for facilities available at the site, patient recruitment rate, and compliance of ICH-GCP guidelines. We also considered important suggestions from investigators related to protocol of the study, exclusion and inclusion criteria for recruiting the patients for the study. After the few site selections, we learned that along with the experience one becomes perfect in the field. We are looking forward for the site selection in Western India in next week and we would like to take all this experience for our future projects.

Ujwala Nikambe
CRA
Genelife Clinical Research