Discussion and Consideration of Proposed Radiographic Outcome Measures
for Investigational Agents for the Treatment of Rheumatoid Arthritis

# Briefing Document for Arthritis Advisory Committee

**Afternoon of July 12^th^, 2000**

**Purpose:** To begin a discussion with the committee about a) claims
for *prevention* of structural damage and b) the usefulness of measuring
other structural outcomes not listed in agency guidance documents,
including *reduction* or *healing* of erosions.

**Background:** The document entitled "Guidance for Industry: Clinical
Development Programs for Drugs, Devices, and Biological Products for the
Treatment of Rheumatoid Arthritis (RA), February 1999" addresses
potential claims for the treatment of RA. Among these is *prevention of
structural damage.* Examples are provided in the guidance document of
outcome measures that could support a prevention of structural damage
claim. They include:

1.  "Slowing X-ray progression\--using either the Larsen, the modified
    Sharp, or other validated radiographic index".

2.  "Prevention of new X-ray erosions\--maintaining an erosion free
    state or preventing new erosions."

The document adds that "because slowing of radiographic progression does
not in itself define a patient benefit, it is expected that the claim of
prevention of structural damage would be submitted for an agent that has
been shown (previously or concomitantly) to be effective for one of the
other claims (e.g. prevention of disability). It also states that
"...the ultimate goals of slowing joint destruction are to improve
symptoms and to preserve functional ability. Therefore, slowing
radiographic progressions of disease is considered a surrogate marker
for overall patient benefit in RA. "

Finally, in the context of accelerated approval, the document states
"One example of a significant effect on radiographic progression might
be the demonstration, in a randomized controlled trial, of maintenance
of an erosion-free state in a large majority of treated patients when
control patients develop multiple erosions...The use of the *accelerated
approval* pathway would necessitate timely completion of phase 4 studies
using acceptable clinical endpoints evaluating signs and symptoms or
prevention of disability."

Since the guidance issued, a number of products have been studied in
clinical trials in which radiographic outcomes, as well as clinical
outcomes, were assessed. Two of these products are labeled for improving
structural outcomes. In addition to showing a beneficial effect on signs
and symptoms, leflunomide (Arava) is indicated "to retard structural
damage as evidenced by X-ray erosions and joint space narrowing" and
etanercept (Enbrel) for "delaying structural damage in patients with
moderately to severely active rheumatoid arthritis" Note that neither of
these products is specifically indicated for *prevention of structural
damage*.

Sponsors have now sought advice from the agency about the type of data
required to allow claims of *prevention of structural damage*. In
addition, sponsors are interested in pursuing other claims not included
in the guidance document, including *reduction* or *complete healing* of
\[existing\] erosions. The agency seeks this committee\'s input as to
how to advise sponsors, given uncertainties about how best to define
*prevention of structural damage* and the absence of established
methodologies to study erosion healing.

### Arthritis Advisory Committee

Food and Drug Administration

Center for Drug Evaluation and Research

**July 12, 2000**

Holiday Inn Gaithersburg, 2 Montgomery Village Avenue, Gaithersburg, MD

**Questions to the Committee:**

1\) The agency's guidance document for sponsors developing therapeutic
agents to treat rheumatoid arthritis lists a claim for *prevention of
structural damage*. Sponsors pursuing this claim must conduct a study of
at least one year in duration. Two agents recently approved by the
agency showed effects on radiographic progression in patients treated
for one year. These products are indicated for *retarding* or *delaying*
structural damage and not for *preventing* structural damage*,* however,
since many patients were observed to have worsened structural damage on
treatment. In this context a *prevention* claim seemed inappropriate.

a)  **Is *prevention of structural damage* a viable claim in RA given
    that, even following treatment with very active agents, some
    patients are likely to have some evidence some disease
    progression?**

**[If yes:]{.underline}**

b)  **Please comment on criteria that could be used to label a product
    for *prevention* of structural damage. Are data from trials of one
    year duration adequate for this claim, or should data on longer-term
    effects be collected before such a claim is considered? Are there
    criteria available to select patient populations who are likely,
    without treatment, to develop erosions? If so, which ones? Should
    there be a minimum proportion of patients who do not show
    progression before such a claim is given?**

```{=html}
<!-- -->
```
2)  There is considerable interest by sponsors to pursue claims not
    listed in the agency guidance document. These include reduction or
    elimination (healing) of erosions. The agency seeks input from the
    committee about whether and/or how such claims should be pursued.

```{=html}
<!-- -->
```
a)  **Is a *reduction in number of* *existing erosions* a viable claim
    in RA?**

**If yes:**

b)  **Please discuss ways in which these outcomes could be measured
    (e.g., which imaging modalities, duration of study to determine
    durability of effect, etc). Is there a minimum \# of erosions
    (compared to baseline) that should be healed in order to consider a
    product reasonably likely to confer clinical benefit?**