**Public Comment**

**Concept Paper: Risk Management Programs**

Dockets Management Branch (HFA-305)

Food & Drug Administration

5630 Fishers Lane rm 1061

Rockville, MD 20852

e-mail: <fdadockets@oc.fda.gov>

Internet:
[www.accessdata.fda.gov/scripts/oc/dockets/edockethome.cfm](http://www.accessdata.fda.gov/scripts/oc/dockets/edockethome.cfm)

**Executive Summary:** Below is the text of the slide that I presented
orally at the workshop. They were also submitted as a PowerPoint
presentation. In this summary I will focus on the main points. The stark
reality is that postmarketing surveillance (PMS) (or now, risk
management or RM) will never be a rigorous public health tool unless
long-standing barriers (slide 1) are removed. The pharmaceutical
industry considers PMS/RM a marginal cost with no return on investment.
However, that need not be the case. If the FDA would signal its
willingness to use the "substantial clinical experience" (21CFR202.1
(e)(4)(ii)(b), and (c) ) criteria for efficacy (for comparative safety
claims in labeling) it may stimulate the dedicated data sources required
to produce those data. Those same data sources would be used to
characterize and quantitate the safety profile of a drug product in the
clinical practice arena. Therefore, it would be a win-win!

As currently conceptualized, FDA's Risk Management strategy, as outlined
in these concept papers, possesses a fatal flaw (an Achilles' heel!).
That is the lack of quantitative data from clinical practice
environments. These data do not exist in the US. If you cannot measure
the impact of an intervention RM will never be the rigorous tool that
our public health requires it to be.

The only way to encourage the development of these dedicated data
sources is to create a business incentive for doing so. Just like IMS
surveys prescription use in the US, some third party enterprise may
develop dedicated sources for drug safety data. They would then be able
to sell these data to the industry for both relative safety claims and
drug safety profile characterizations and risk assessments.

If this is not done, the industry will need to develop limited data
sources for each new drug. Over time this would grow too complex and
then counterproductive.

I urge FDA to re-examine this issue and consider issuing guidance on the
evidence required to fulfill the " substantial clinical experience"
criteria. This is what was intended since the 1962 amendments. It is
time that the FDA applies these criteria and allows the growth of
businesses that will develop these data sources. Public health demands
it!

Before closing, I'd like to draw attention to my answer to FDA's
question #1. Given the huge potential for patient exposure mandatory
risk management must be required for all potential blockbusters and any
drug that intends to use DTC within the first three years of marketing.
This is the only way to prevent harm from serious rare reactions given
the huge exposure potential within months of market launch.

Lastly, in the usual case, even the most rigorous observational study
performed on medical record or administrative billing data are not
rigorous enough to be used to measure the impact of an intervention.

**Text of slides:**

1\] Major Barriers to Drug Safety Profile Characterization

> •FDA's Priorities
>
> --RCT and initial market approval
>
> •Tort Liability
>
> --"Duty to Warn" at Information level
>
> •Marketing Freedom
>
> --Now Incl. DTC
>
> •FDA's Marketing restrictions
>
> --Safety comparisons
>
> •Lack of dedicated data sources
>
> --Supply & Demand

2\] FDA's Post-Marketing Risk Management Strategy (RMS)

--Communicate initial risk data

--**Measure** actual risk

--Intervene when problems arise

•Communicate to practitioners

--**Re-measure** risk to determine the impact of the intervention

--Intervene again if required

--RMS is continual!

3\] FDA's Post-Marketing Risk Management Strategy Requires...

•Metrics and measurement are key to the FDA's Post-Marketing Risk
Management Strategy

•**Quantitative data** are required !

•Neither spontaneous (qualitative) or record linkage (semi-quantitative)
data can accurately measure change

4\] The quality and type of current Postmarket safety data is the
"Achilles Heel" of FDA's Risk Management Strategy

5\] PMS Data for Labeling Updates

•**What's Available**

--Qualitative data on serious, rare

--Quantitative experiment data from limited RCT's

•**What's Needed**

--Qualitative data on serious, rare

--Quantitative descriptive epidemiological data on the serious, common
and less serious, very common

--Risk factors: D-D-I, age, gender, etc

6\] Relative Safety Claims in Labeling:\
What Standard of Evidence ?

•"substantial evidence" standard

--Defined in 21CFR314.126b, or

•"substantial clinical experience" standard

--Defined in 21CFR202.1 (e)(4)(ii)(b), and (c)

7\] Ironically: FDA's current interpretation of the regulations have
been one of the barriers that has prevented the acquisition of the
quality data needed for risk management and for rational drug therapy !

8\] FACTS!

•RMS requires quantitative data.

•Labeling claims of relative safety require quantitative data

•[Informative]{.underline} safety data in labeling from clinical
practice requires quantitative data

•Public health, through more rational drug therapy, is served by more
accurate labels with clinical practice safety data

•Quantitative data are expensive

9\] The dilemma!

•Both FDA's Risk Management Strategy and their labeling and advertising
policy regarding safety claims require quantitative safety data

•It doesn\'t exist!

9\] Merge the goals and needs

•Public Health via Drug Safety

•Accurate Marketing

•Accurate Labeling

--Via

•Characterization of the safety profile of pharmaceuticals in clinical
practice environments

•Using quantitative data and applying "Substantial Clinical Evidence"
criteria

10\] FDA Question #1\
Consideration on what comprises and prompts a risk management program

•RMP consistent with FDAMA & PDUFA-3 guidance should be routinely
applied to the following drug product categories:

--all potential 'blockbusters' (given large potential population
exposure)

--all products that will use DTC within first three years

--all cosmetic, lifestyle products

--all drugs with residual concerns from RCTs

--all drugs where safety problems were previously identified within the
pharmaceutical class

11\] FDA Question #2\
The selection and development of risk management tools

•Define Goals:

--ID new

--Quantitate known

--Reduce predictable

--Maximize rational drug therapy

•Quantitative data -\> Information

12\] FDA Question #3\
The evaluation of risk\
management programs

•Quantitative Metrics

•Need dedicated drug safety databases

•**NOT** medical records or administrative DB (proxy, ICD9CM codes are
not specific for ADRS)

•Certainly NOT qualitative databases like spontaneous reporting schemes

13\] FDA Question #4\
**The recommended elements of a risk management program submission to
FDA**

•Developed early, modified constantly, performed rigorously

--Consistent with FDAMA & PDUFA-3

• New Drug Development Continuum & Rigor

--Continual ISS (aka PSUR)

--Annotated Label with Underlying Evidence Hyperlink

•Well documented (ISPE Guidelines - Updated?)

•Part 11 compliant data source!

--Can record linkage/administrative data qualify?