Start-ups and SBIR and STTR Grants Clinical Studies for Medical Device Development Carla M Lema Tome, MBA, PhD Medical Device Clinical Development Source: FDA Regulatory Affairs: Third Edition. 2014...

Start-ups and SBIR and STTR Grants
Clinical Studies for Medical Device Development
Carla M Lema Tome, MBA, PhD
Medical Device Clinical Development
Source: FDA Regulatory Affairs: Third Edition. 2014
Wake Forest School of Medicine
Once the regulatory pathway has been determined and development is underway,
clinical data may be necessary.
In this figure, you can see the different pathways
for medical device clinical research. Unlike the pharmaceutical model, there
are three levels of regulation of medical device clinical research. Some research
is exempted from the investigational device exemption (IDE) regulation; some
esearch is subject to just some sections of the IDE regulation; and other types of research are subject to all sections of the IDE regulation.
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Medical Device Clinical Development
Because of the diversity of medical devices, the types and extent of testing also varies across the product categories.
Many Class I and II medical devices do not undergo clinical studies prior to their market release.
The exception to this is in vitro diagnostic devices, many of which undergo clinical studies in support of FDA clearance.
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Stages of Medical Device Clinical Studies
Exploratory Stage – first-in-human and feasibility/pilot studies, iterative learning and product development.
Pivotal Stage – definitive study to support the safety and effectiveness evaluation of the medical device for its intended use.
Postmarket Stage – includes studies intended to better understand the long-term effectiveness and safety of the device, including rare adverse events.
Not all products will go through all stages.
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Exempted Studies
Most exempted studies involve either previously cleared or approved devices or investigational in vitro diagnostic devices.
If a sponsor wishes to conduct a study that, for example, compares the performance of their own previously cleared device with the performance of their competitor’s previously cleared device, that study would be exempt from the IDE regulations, so long as both devices are used for their cleared indications.
No prior FDA review or approval of the study is necessary.
The clinical trial should use an informed consent form and be reviewed and approved by the appropriate institutional review board.
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Non-significant Risk Studies
Many studies that do not involve highly invasive devices, risky procedures, and/or frail patients can be conducted under the nonsignificant risk (NSR) provisions of the IDE regulation.
These provisions provide an intermediate level of control for the study without requiring the study sponsor to prepare and file an IDE.
When a sponsor determines that a study is NSR, no FDA involvement is required, although many sponsors will consult with the FDA to confirm that the study is indeed NSR and that its design is consistent with the FDA expectations.
Each IRB that reviews an NSR study must document three conclusions.
Concur with the sponsor’s NSR determination.
Approve study protocol.
Approve consent form.
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Significant Risk Studies
Significant risk studies require an approved IDE to treat patients in the United States.
Typical significant risk studies involve implantable devices or devices that introduce significant quantities of energy into the body.
Studies with devices that sustain or support life are nearly always considered significant risk.
These types of studies are typically performed in two rounds
Pilot
Small study XXXXXXXXXXpatients)
Determine initial performance and safety
Pivotal
Larger study XXXXXXXXXXpatients)
Determine efficacy and adverse events
Wake Forest School of Medicine
Wake Forest School of Medicine

Start-ups and SBIR and STTR Grants
Clinical Phases for Pharmaceutical Development
Carla M Lema Tome, MBA, PhD
Bringing a Drug to Market
Preclinical (animal) studies
Exploratory IND/ Phase 0 Studies
Investigational New Drug Application (IND)
Phase 1 studies
Phase 2 studies
Phase 3 studies
New Drug Application (NDA)
Phase 4 (Post-market Surveillance)
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Drug Development Process
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Bringing a Drug to Market
The estimated average pre-tax industry cost per new prescription drug approval (inclusive of failures and capital costs) is: $2.87 billion
Tufts Center for the Study of Drug Development, March 2016
The time to market is estimated between 11 and 14 years.
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Pre - Preclinical Studies
Target Identification – isolate target of interest
Target Validation – compare target with counterparts based on association with specific disease
Lead Identification – new compound(s)
Lead Optimization – compare analogs of initial “lead compound”
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Preclinical Studies
The actual laboratory tests:
Computer Simulations
In vitro studies
Experimental animal studies
Formulation studies (Pharmaceutics)
Toxicology (safety)
Pharmacological (effectiveness)
From drug discovery through preclinical studies takes ~6.5 years
Note: FDA is not involved, but data will be reviewed

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Phase 0 Studies
New designation for exploratory first-in-human trials
Need Exploratory Investigational New Drug (ex-IND)
“Human micro-dosing” trials
Goal:
To determine pharmacodynamics (what drug does)
To determine pharmacokinetics (what body does)
Provides no data on safety or efficacy
Subjects: ~10-15 healthy subjects
This Phase focuses on ranking drug candidates
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Investigational New Drug (IND)
Formal process by which a “sponsor” requests FDA approval for testing of drug in humans (and allows drug transport across state lines)
Usually follows CDER “Pre-IND Consultation Program” where FDA provides guidance
Sponsor shows drug is safe and effective
Provides outline of Phase 1 study
If approval, sponsor can begin clinical trials
Similar to IDE for medical devices.
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Phase I Studies
Goal:
To determine the drug’s frequent side effects
How the drug is abso
ed, distributed, metabolized, excreted, and toxicity results (ADMET)
Subjects: ~20-80 healthy subjects
Multiple doses – single ascending dose (SAD) and multiple ascending dose (MAD) studies
Between 64 and 67% of new compounds pass Phase 1
This Phase focuses on safety
Duration: 1 yea
Cost: $100,000 - $1,000,000
Objective: to determine safety and dosage
Hay et al XXXXXXXXXXNature Biotechnology 32(1), 40-51
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Phase 2 Studies
Goal: Obtain preliminary data on whether the drug works in people who have a specific disease/condition
Predicted results are called “endpoints”
Subjects: XXXXXXXXXXdepending on disease or condition)
Phase 2 estimates: $40M over 2-4 years
Between 32 and 39% of Phase 2 clinical trials are successful
This Phase focuses on efficacy (with a continued interest in safety)
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Phase 3 Studies
FDA and sponsors determine how the large-scale Phase 3 studies should be run (agree on endpoints)
Goal: To confirm Phase 2 results in a larger patient pool, and usually
Gather more info on safety and effectiveness
Test different dosages
Test drug in different populations
Compare to placebo or existing therapy
Subjects: XXXXXXXXXXsubjects with specific disease or indication (often multiple site trials)
Between 60-68% of Phase 3 Clinical Trials are successful
Phase 3 estimates: $50-300M over 2-3 years
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NDA
This is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured
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Phase 4 Post-Marketing Studies
The main objective of the phase 4 trial is to check the drug's performance in real life scenarios, to study the long-term risks and benefits of using the drug and to discover any rare side effects.
In a phase 4 trial, any rare or long-term effects of the drug can be observed in a much larger population of patients and over a much longer period of time. If safety surveillance does indeed reveal concerns about the drug, it may be withdrawn from the market and no longer made available on prescription.
Wake Forest School of Medicine
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