# Presentation: 121293

## Uric acid and Gout

- James Witter MD, PhD
- Arthritis Advisory Meeting
- June 2, 2004

## Goals of Meeting

- Address an important, and often ignored, public health issue
- Gather input regarding issues to consider for clinical trials intended to support the development and approval for drugs that treat gout and/or uric acid
- Acute situations
- Chronic situations

## Gout: The Problem

- Important unmet medical need
- acute and chronic pain
- joint and renal damage
- Increasing incidence and severity
- estimates of 8.4 per 1,000 in U.S.
- female: male = 1:6
- increase not related to diuretics
- Earlier age
- especially males
- Increases may be related to obesity
- insulin resistance syndrome

## Gout: Approved Treatments

- Limited options
- NSAIDs
- prostaglandins
- colchicine
- microtubules
- oral, IV
- allopurinol
- xanthine oxidase inhibitor
- probenecid
- renal tubule inhibitor

## Claims and Labels

- Although **label claims** have legal and regulatory uses, their central purpose is to inform health care providers and patients about the _**documented **_benefits and risks associated with a product
- Claims describe clinical benefit
**Promotion allowed on approved claims**
- Accurate product labels allow for effective risk management

## Labeling Options?

- For chronic use:
- For treatment of hyperuricemia associated with:
- Gouty flares
- Gouty arthritis
- Tophi
- Renal calculi
- For acute or prophylactic use:
- For the short-term treatment of uric acid-induced gout

## Approved INDICATIONS:

**Indocin****®**** (indomethacin)**
- effective in active stages of acute gouty arthritis
**Benemid****®**** (probenecid)**
- for treatment of the hyperuricemia associated with gout and gouty arthritis
**Zyloprim****®**** (allopurinol)**
- the management of patients with signs and symptoms of primary and secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy)
- not innocuous drug...not for asymptomatic hyperuricemia
**Colchicine**
- for the treatment of gout...relieving pain of acute attacks
- as interval therapy to prevent acute attacks of gout

## The Urate Pool ?

- urine

- Joint

- diet

- Tophus

- 10 mg/dl

- 6 mg/dl

- Jump in!

- serum level

## Inclusion Issues

- Baseline serum uric acid **(SUA)**
- prevalence of gout is 30% at 10 mg/dl but only 0.6% at 7 mg/dl
- poor correlation of SUA to gouty flares
- Prior flares at ***target**** *joint
- number and/or severity
- diagnosis by
- crystals
- physician
- self-report
- Tophi
- not nodules (RA) or nodes (OA)
- size
- Renal status
- chronic insufficiency

## Exclusion Issues

- Other crystal-induced diseases
- Other inflammatory diseases or infection
- Renal status
- diuretics
- Co-morbid diseases
- obesity
- Special populations
- transplant
- genetic defects

## Efficacy Issues

- Endpoint and Duration
- Is SUA a valid **surrogate**?
- Number of gouty attacks
- early events excluded?
- Change in tophi
- size
- number
- Disability/quality-of-life domains
- Duration
- 6-12 months (SUA)
- 1-2 years (tophi)

## “Surrogate” ApprovalSubpart H21 CFR 314.510

- FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a _***surrogate endpoint***_* that* is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit _**or**_ on the basis of an effect on a clinical endpoint other than ***survival or irreversible mortality***.

## Surrogate Endpoint: Definition

- A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a _*clinically meaningful endpoint that measures directly how a  patient feels, functions, or survives*_
- Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint

## Subpart HApproval Caveats 314.510

- Requirement that applicant study the drug further to verify and describe its clinical  benefit where there is uncertainty of:
- the surrogate to clinical benefit
- observed benefit to ultimate clinical outcome
- Post-marketing studies usually underway
- must be adequate and well controlled
- must be carried out with due diligence

## Subpart HWithdrawal Caveats 314.530

- FDA may withdraw approval, following a hearing if:
- Postmarketing clinical study fails to verify clinical benefit
- Applicant fails to perform the required postmarketing study with due diligence
- The promotional materials are false or misleading
- Other evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use

## Current State: Surrogates

- Blood pressure
- Lipid lowering agents
- Blood sugar/HBA1c
- Bone mineral density
- HIV load

## Primary Endpoints

- SUA
- are these valid surrogate endpoints?
- change in serum concentration
- change to a selected endpoint (5 or 6 mg/dl)
- long-term precision of the serum estimate
- multiple values, at multiple times
- Target and non-targeted joints
- evaluated together or separately
- Tophus
- imaging modality (MRI) vs. manual methods
- percent vs. complete resolution

## Design/Statistical Issues

**Initial titration to minimize flares**
**Placebo control**
- superiority to placebo
**Active/standard-of-care control**
- non-inferiority
- how “different” can the test be from control?
- depends on new drug under development
- Dose ranges to achieve target SUA goals
- Means or responder approach
- minimal important difference

## Co-Meds and Diet Issues

- Prophylactic
- ASA (low vs. high dose)
- colchicine
- NSAIDs/COX-2 agents
- Etoh use
- patient diary
- Diet
- restrictions

## How safe is safe?

**Life-long use**
- daily
- intermittent
**Co-medications**
- for gout prophylaxis or treatment
- myopathy with colchicine
**Special populations**
- chronic renal insufficiency
**Are ICH guidelines adequate?**
- 300-600 ( 6 months)
- 100 (1 year)
- 1500 (total)

## Slide 21