Human Feasibility Clinical Trials:

Transcription

1 Human Feasibility Clinical Trials: How to Begin and How to Succeed Michael P. Otlewski Clinical Program Scientist, MED Institute Incorporated 1

2 MED Institute Located in West Lafayette, Indiana Over 30 years of experience with medical device engineering, global regulatory submissions, and clinical trial design and management Founded in 1983 Engineering Services R&D Simulation Testing Regulatory Consulting Clinical Study Management ISO Accredited Laboratory ISO and ISO Certified (BSI) We serve on several medical device standard committees 2

3 Overview Objectives: Present background information related to clinical trials Expand understanding of the US regulatory framework for clinical trials Elevate clinical trial process considerations and pass on some lessons learned 3

4 Why Clinical Trials? One cannot determine in an uncontrolled setting whether intervention has made a difference in outcome Help determine incidence of side effects and complications Contribute invaluable information about benefits and safety of existing therapies Theory not always best path There are limits to the information gained in non-clinical testing 4

5 Clinical Trials Background Human clinical data may be needed to continue product development, support regulatory submissions, publications, or simply to advance knowledge of diseases and associated treatments. MED can help you decide when clinical data may be necessary. 5

6 Device Trials Are Unique Device trials tend to be smaller than drug trials Many are difficult to blind, randomize and control Many depend on physician technique Device modifications may occur during the trial Endpoints highly diverse Typically, pivotal trial follows feasibility stage 6

7 US Regulatory Framework for Clinical Trials There are many types of trials; you need to run the right one. Non-significant risk study IDE study (aka, Significant Risk Study) (Early) Feasibility study Pivotal Study (confirmatory data) Post-market study o Registry o Additional study groups o 5 year long-term follow-up o 522 study o Randomized, controlled trial Double-blinded trial Placebo-controlled trial Historical/literature control MED can help you determine what trial type is applicable. 7

8 Clinical Trials Background Progression of clinical trials throughout development Safety Tolerability in healthy subjects Feasibility and dose-ranging Do signals warrant further development? Pivotal Study (confirmatory data to support safety & effectiveness) Post-Market Within each group, there are many different design possibilities. MED can help you determine what trial type you want to run. 8

9 Early Feasibility Trial Generally less than 10 subjects Device may be early in development before the device design has been finalized Approval of an early feasibility trial IDE will be based on non-clinical data Some non-clinical testing may be deferred Testing plan must be approved by FDA, as these devices are usually so novel there is not an accepted non-clinical testing scheme 9

10 Feasibility Trials Primarily to examine safety prior to moving into larger (pivotal) studies, but can provide efficacy information that helps decision-making about the continued development of the device Provide support and study design elements for future pivotal study Potentially leads to improvements in device design Not intended to be the primary support for marketing application Endpoints and sample size generally not statistically driven Often required by FDA prior to pivotal study to assess safety and potential for effectiveness 10

11 Basic Submission Elements Background of medical issue, study goals and importance Detailed description of device Previous studies (pre-clinical and clinical) Risk analysis Patient monitoring and follow-up plan Inclusion/Exclusion criteria Informed Consent Form Sample size and sites 11

12 FDA s Feasibility IDE Review Focused on safety Critical issues: 1. Reasonable study concept? 2. Adequate pre-clinical validation of device? 3. Appropriate enrollment criteria? 4. Patients adequately informed? 5. Sample size appropriate? 12

13 US Regulatory Framework for Clinical Trials Clinical trial sponsor responsibilities (21 CFR parts 312 and 812): IDE/IND application and approval IRB application and approval Selection of qualified investigators Accountability of the investigational products Signed agreements from each investigator Properly inform all investigators about the study protocol and any prior investigations Ensure proper monitoring of the investigation, including: o Secure compliance with the investigational plan, study-specific IRB or FDA requirements, and all applicable regulations o Investigate any UADEs or SUSARs and, if unreasonable risk to patients is determined, notify all investigative sites, FDA, IRB, and terminate the study Host FDA inspections of investigational products, study records, or records identifying study subjects Maintain records of: o All correspondence with other sponsors, a monitor, an investigator, an IRB, FDA, including required reports o Records of product shipment and disposition o Signed investigator agreements including financial conflict disclosure o Records concerning adverse product effects or reactions Submit reports to FDA and all reviewing IRBs, regarding: o UADEs or SUSARs o Withdrawal of FDA or any IRB approval o Current investigator list o Periodic progress reports o Any recall of study product for any reason o Final study report o Report of any product use without subject informed consent o Any change in significant risk designation 13

14 US Regulatory Framework for Clinical Trials Additional sponsor responsibilities: Control investigational product logistics Design the clinical study and write the complete clinical investigation plan and associated documents Find suitable study sites and negotiate contracts with each Find suitable vendors (e.g., core labs) and negotiate contracts with each Obtain clinical trial insurance Create study database and case report forms Create study plans, that FDA can later audit against (e.g., Site Training Plan, Monitoring Plan) Register the study on Host investigator meeting(s) Provide guidance for use of study product at study cases Review study data for completeness, accuracy, and potentially-reportable adverse events Convene a Data Safety Monitoring Board and summarize study data to present Convene a Clinical Events Committee and summarize study data to present Reimburse study sites according to contractual milestones Identify and resolve incidents of noncompliance by the study sites Identify and implement methods to increase study enrollment Close out the study with each site and IRB (Statistical) Analysis of study results Post study results on 14

15 Startup Activities Sponsor Site Create study protocol and obtain regulatory approval for conducting the trial Contact site, obtain CDA, send protocol and feasibility questionnaire to site Signs CDA, review protocol and complete feasibility assessment Schedule and conduct site evaluation visit, send site selection notifications via or letter Receive essential regulatory documents for IRB submission, CTA and trial budget for review, preparation and submission Receive IRB approval from site, receive signed CTA, schedule and conduct SIV Start recruitment of study subjects 15

16 Assessing Protocol Feasibility Adequate patient population? Competing protocol/studies? Resources required to execute protocol activities available? Additional space, training or equipment required? Adequate availability of time; PI and CRC? Possibility of strengthened collaborations with sponsor for future studies? Collaborations with other departments (lab, pharmacy, radiology) for the protocol? Proposed findings if any? 16

17 Clinical Trial Awareness 85% of clinical trials fail to retain enough patients 80% of clinical trials fail to finish on time 50% of sites enroll 1 or no patients in their studies 40% of total US clinical trial budget goes toward recruitment 30% of patients drop out of a clinical trial Source: Nuttal, Aidan, Considerations for improving patient recruitment into clinical trials, RDP Clinical Outsourcing, 23 March

18 Clinical Trial Awareness 50% of sites enroll 1 or no patients in their studies Source: Nuttal, Aidan, Considerations for improving patient recruitment into clinical trials, RDP Clinical Outsourcing, 23 March

19 Non-performing Sites Average $50k start-up cost Result in budget overrun Many never enroll a single patient or very low enrollment Selection of sites often carried out in a non-scientific, nonsystematic way Causes delay, impacting trial schedule and timeline Source: Addressing Ever-rising Cost in Conducting Clinical Trials, Covance Inc

20 Barriers to Enrollment Patients unaware of open clinical trials Unrealistic, inconvenient protocol requirements Unrealistically restrictive inclusion/exclusion criteria Physicians or hospitals concerned about patient liability Site staffing and slow trial activation Lack of standard processes for patient screening Overly optimistic accrual goals and limited feasibility assessment Inadequate recruitment planning during trial development process 20

21 Barriers to Enrollment Unrealistic, inconvenient protocol requirements 21

22 Wound Care Impractical Follow-up Control group when could have used literature-based control (resulted in unnecessary, extra enrollment) Treatment/follow-up exam schedule was rigorous and impractical Patients with chronic wounds often do not comply with instructions Failed study enrolled 2 patients in 2 years 22

23 Barriers to Trial Success Run the wrong trial Run the right trial, but collect the wrong data Run the right trial, but collect too much unnecessary data Run the right trial and collect the right data, but enrollment takes forever, data are late, or data are riddled with errors 23

24 Barriers to Trial Success Run the wrong trial 24

25 Barriers to Trial Success Run the wrong trial (e.g., wrong patient cohort) Negative results may represent unreasonable performance goals rather than failure of the study product Negative results may represent targeting of inappropriate patients rather than failure of the study product 25

26 Barriers to Trial Success Run the wrong trial (e.g., wrong patient cohort) Negative results may represent unreasonable performance goals rather than failure of the study product Negative results may represent targeting of inappropriate patients rather than failure of the study product Consequences: Need to revise protocol / start over Significant delays Additional expenses Possibly abandoned product 26

27 Venous Stent Wrong Patient Cohort Stent designed to precise anatomical criteria (e.g., diameters, angulation) Another clinical group took it to principal investigator, an aggressive physician who was overly anxious to use it ALL three of the first three patients had anatomy grossly outside of the engineering design parameters Rather than wait for appropriate patients, physician performed implants Not surprisingly, the stent thrombosed Clinical group message to senior executives was failed design Two-year delay 27

28 Barriers to Trial Success Run the wrong trial Run the right trial, but collect the wrong data Run the right trial, but collect too much unnecessary data Run the right trial and collect the right data, but enrollment takes forever, data are late, or data are riddled with errors 28

29 Barriers to Trial Success Run the right trial, but collect the wrong data 29

30 Barriers to Trial Success Run the right trial, but collect the wrong data Data may not accurately reflect the desired study endpoints Potentially-confounding data may be unaccounted for Data may not address regulators concerns 30

31 Barriers to Trial Success Run the right trial, but collect the wrong data Data may not accurately reflect the desired study endpoints Potentially-confounding data may be unaccounted for Data may not address regulators concerns Consequences: Need to revise protocol / start over Addition of more patients Significant delays Additional expenses 31

32 Nipple Reconstruction Wrong Study Endpoint Bioabsorbable device to reconstruct the nipple following mastectomy Device performance relied on continuing projection / incomplete absorption Study endpoint reflected that fact (maintenance of 50% of original projection length after 6 months) Study primary endpoint failed, however A secondary endpoint was patient satisfaction which scored through the roof! 32

33 Barriers to Trial Success Run the wrong trial Run the right trial, but collect the wrong data Run the right trial, but collect too much unnecessary data Run the right trial and collect the right data, but enrollment takes forever, data are late, or data are riddled with errors 33

34 Barriers to Trial Success Run the right trial, but collect the wrong data Run the right trial, but collect too much unnecessary data 34

35 Barriers to Trial Success Run the right trial, collect too much unnecessary data Poor design of data forms Poorly-trained study site staff 35

36 Barriers to Trial Success Run the right trial, collect too much unnecessary data Poor design of data forms Poorly-trained study site staff Consequences: Trial takes longer than necessary More data queries = even more work More missing data increases the chances of a failed trial More non-compliances to report to regulators Human nature: if running multiple trials, Research Coordinators select simpler trials to work on, and enroll patients 36

37 Aortic Graft Unnecessary Data Previous studies required X-rays of similar devices Chest vs. abdomen made X-rays much less useful Advancements in CT scans made X-rays largely redundant Many, many non-compliances from sites neglecting to order this exam No longer standard of care Sites were so used to ordering a chest X-ray rather than a device X-ray Took this information to FDA to convince them to drop the requirement 37

38 Barriers to Trial Success Run the wrong trial Run the right trial, but collect the wrong data Run the right trial, but collect too much unnecessary data Run the right trial and collect the right data, but enrollment takes forever, data are late, or data are riddled with errors 38

39 Barriers to Trial Success Study drags on and on and on and on and Slow enrollment rate (e.g., sites with few eligible patients) Study site staff not engaged Poor study design (e.g., entry criteria too strict) Follow-up data is not well collected Patients are non-compliant with protocol (i.e. they do not return)rcs have trouble collecting all the data requested, or resist 39

40 Barriers to Trial Success Study drags on and on and on and on and Slow enrollment rate (e.g., sites with few eligible patients) Study site staff not engaged Poor study design (e.g., entry criteria too strict) Follow-up data is not well collected Possible reasons: Study design does not follow standard of care Requested data is not usually collected and may seem unnecessary Patients resist coming back more often than standard of care typically requires Patients are non-compliant with protocol (i.e. they do not return)rcs have trouble collecting all the data requested, or resist 40

41 MED s Lessons Learned MED has helped with clinical trials for 25+ years and a 90% success rate. MED has significant experience designing and managing clinical trials that comply with regulatory requirements and laws, but also meeting clinical study objectives efficiently, potentially saving on development time and money. Phase I Human Safety Phase I/II Expanded Safety Phase III Efficacy & Safety Tens Hundreds Thousands 41

42 MED s Lessons Learned Knowledge Running the trial RIGHT Focuses on execution Checklist mentality Garbage in = garbage out 42

43 MED s Lessons Learned Knowledge Wisdom Running the trial RIGHT Focuses on execution Checklist mentality Garbage in = garbage out Running the RIGHT TRIAL Focuses on strategy, communication, relationships, collaboration and active management Passively managing a trial gives rise to tribulations. 43

44 Wisdom is important for early stage trials These studies are often run to provide important initial answers: Does the concept work in humans? Does the concept appear as safe as expected? Are the proper patients being targeted for this product (i.e., are the patient selection criteria correct)? Are the correct follow-up tests being used to evaluate the study treatment? Is the patient follow-up schedule correct? Can these physicians become future proctors for training if needed? Are there any initial unanticipated adverse events? Does the regulatory agency agree with your study design? Does the regulatory agency agree with the endpoints you plan to measure to demonstrate safety and effectiveness? Wrong can = restart from the beginning 44

45 Core Values Matter Work with someone whose principal core value is to help patients, not their profits Patients and their families place their trust in all people and entities involved in every aspect of the clinical trial Your name (your company s name) is on the device; that s your reputation and it should matter to those who support you 45

46 Core Values Matter Work with someone whose principal core value is to help patients, not their profits Quality and integrity of the people involved with the clinical trials as well as the products and therapies are of the utmost importance Quality of the study being run is more important to us than the number of studies we can run simultaneously 46

47 Communication & Relationships Build relationships With regulators With physician/investigators With research coordinators How? Wisely understand human nature Make their lives easier, help solve their problems and they will want to work with you 47

48 Relationships with Regulators Early and often (In US, use Pre-Submission Program) Don t ask regulators what to do, or what data to collect Provide proposals, ask if reasonable, ask for suggestions (are we missing something?) Provide non-clinical testing plan before doing the testing Clinical plan (e.g., feasibility and pivotal, pivotal-only, none needed) Do the regulators believe the clinical trial design will provide data suitable to assess the device and support approval? Remain engaged with them by phone, and/or in person 48

49 Relationships with Investigators Value their experience/opinions Involve them in trial design Involve them in data analysis Keep in contact and always be available during the trial Consider a weekly newsletter/status update to the sites Bring them together at investigator meetings Consider pre-enrollment screening assistance to reduce noncompliances Phone, , and on-site visits to support them REALLY listen to their site specific issues and help resolve them Ask questions, remove roadblocks 49

50 Relationships with Research Coordinators They are critical to trials functioning effectively Value their experience/opinions Ask for their input into Case Report Form design /on-site visits to support and ask questions; don t flog them for enrollment Make their lives easier and help solve their problems and they will want to work with you Provide source document templates Provide training Provide demonstration devices to show patients Provide draft consent forms Send helpful monitors who can assist with sorting data 50

51 Once Upon a Time a Success Story 51

52 Why It Worked Good relationships with regulators at FDA High level of trust from them Known problem being neglected/denied by other manufacturer Product built off of a well-established technology platform Accepted extremely limited bench data Did not require an animal study Risk / benefit picture different than for original primary repair We had a history with FDA of successfully running high enrollment, multi-year post market registries 52

53 MED Institute We provide thoughtful guidance and quality clinical trial services to clients who require expertise in the efficient development of novel medical products and therapies. 53