Replies to post #6691 on US Stem Cell Inc (USRM)

[Dragon Lady]

"AMONG OTHER RELEVANT FACTORS" - sorta missed that little ole "tid bit" of KEY language? Sorta. Further, that is a citation of ONLY 3.1. There's about another 500 pages of "review process/standards" missing there?

For example- something as simple as "the magnitude of the so called "benefit" is a determining criteria. In other words, a "small" benefit may be deemed not worth it by FDA: FDA-
"The magnitude of the benefit(s) – we often assess benefit along a scale or according to specific endpoints or criteria (types of benefits), or by evaluating whether a pre-identified health threshold was achieved. The change in subjects’ condition or clinical management as measured on that scale, or as determined by
an improvement or worsening of the endpoint, is what allows us to determine the magnitude of the benefit in subjects. Variation in the magnitude of the benefit across a population may also be considered. "

A "refection" can come down to something as simple as the FDA saying, "the benefit is small to almost nothing at all, therefor there is no purpose to approve this "new" drug/procedure/device"- seen it happen many, many times.

Other examples:
:In addition to section 513(a), the criteria for establishing safety and effectiveness of a device are set forth
in 21 CFR 860.7. Subsection (b)(1) notes, “In determining the safety and effectiveness of a device … the
Commissioner and the classification panels will consider the following, among other relevant factors …The
probable benefit to health from the use of the device weighed against any probable injury or illness from
such use.” (21 CFR 860.7(b)).
To make this determination, “the agency relies upon only valid scientific evidence.” (21 CFR 860.7(c)(1)).
Valid scientific evidence is defined as “evidence from well-controlled investigations, partially controlled
studies, studies and objective trials without matched controls, well-documented case histories conducted by
qualified experts, and reports of significant human experience with a marketed device, from which it can
fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and
effectiveness of a device under its conditions of use.” (21 CFR 860.7(c)(2)).
A reasonable assurance of safety occurs when “it can be determined, based upon valid scientific evidence,
that the probable benefits … outweigh any probable risks,” and can be demonstrated by establishing “the
absence of unreasonable risk of illness or injury associated with the use of the device for its intended uses
and conditions of use.” (21 CFR 860.7(d)(1)).
Similarly, a reasonable assurance of effectiveness occurs when “it can be determined, based upon valid
scientific evidence … the use of the device for its intended uses … will provide clinically significant
results.” (21 CFR 860.7(e)(1)). The evidence of which is demonstrated principally through “well-controlled
investigations” (see 21 CFR 860.7(e)(2)), as defined in 21 CFR 860.7(f).
2
Section 513(a)(3)(A) of the FD&C Act."

And that's just a small, smattering of how complex that section is and how many pages and sub-references and other "statutes" and other areas of FDA regulation are involved.

[Dragon Lady]

For example- kinda left out 4.3: (further, these sections being cited, are "recommendations" and are "non-binding") they're part of a much, much bigger set of rules/regulations the FDA relies on, IMO and as far as I'm aware of. 3.1, 4.3, etc are just one, of many "recommendation" of process/procedure.

Also, If I'm not mistaken, it's the "CFR" (Code of Federal Regulations) sections that are the actual "law" as codified, passed by congress, etc. The area you cited is equivalent to FDA internal "guidelines" as far as I am aware and reference back to the relevant "CFR" actual law/regulations which are book-thick as far as I am aware. My opinion. Example:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?FR=860.7

That's the actual "law" portion- and it's long, complicated and goes into sub, sub, sub categories, etc

4.3 Additional Factors in the Assessment of the Probable Benefits and
Risks of Devices
Uncertainty – there is never 100% certainty when determining reasonable assurance of
safety and effectiveness of a device. However, the degree of certainty of the benefits and
risks of a device is a factor we consider when making benefit-risk determinations.
Factors such as poor design or poor conduct of clinical trials, or inadequate analysis of
data, can render the outcomes of the study unreliable. Additionally, for certain device
types, it is sometimes difficult to distinguish between a real effect and a placebo effect in
the absence of a trial design that is capable of blinding investigators and subjects.
Furthermore, the repeatability of the study results, the validation of the analytical
approach, and the results of other similar studies and whether the study is the first of its
kind or a standalone investigation can all influence the level of certainty. In addition, the
generalizability of the trial results to the intended treatment and user population is
important. For example, if the device requires in-depth user training or specialization, the
results of the clinical study may not be generalizable to a wider physician population.
Likewise, if the device is intended to diagnose a disease in a subpopulation, it may not be
useful in the general population. In general, it is important to consider the degree to
which a clinical trial population is representative of the intended marketing or target
population.
Characterization of the disease – the treated or diagnosed condition, its clinical
manifestation, how it affects the patients who have it, how and whether a diagnosed
condition is treated, and the condition’s natural history and progression (i.e., does it get
progressively better or worse for the patient and at what expected rate) are all important
factors that FDA considers when characterizing disease and determining benefits and
risks.
Patient tolerance for risk and perspective on benefit – if the risks are identifiable and
definable, risk tolerance will vary among patients, and this will affect individual patient
decisions as to whether the risks are acceptable15
in exchange for a probable benefit.
When making a benefit-risk determination at the time of approval or de novo
classification, FDA recognizes that patient tolerance for risk and a patient-centric
assessment of risk may reveal reasonable patients who are willing to tolerate a very high
level of risk to achieve a probable benefit, especially if that benefit results in an
improvement in quality of life. How data concerning patient risk tolerance and other
patient-centered metrics are developed will vary depending on a number of factors,
including the nature of the disease or condition and the availability of existing treatments,
as well as the risks and benefits they present. FDA encourages any sponsor that is

15
21 CFR 860.7(d)(1) states that “The valid scientific evidence used to determine the safety of a device
shall adequately demonstrate the absence of unreasonable risk of illness or injury associated with the use of
the device for its intended uses and conditions of use.”