# Presentation: 099254

## U.S. Guidance for the Development of Drugs for Osteoporosis: Rationale, Durability and Evolution

- Henry Bone, M.D.
- Michigan Bone & Mineral Clinic
- Detroit, Michigan

## Osteoporosis:A spectrum of disorders

- Chronic Osteoporoses
- _Postmenopausal osteoporosis_
- enormous numbers at risk
- wide spectrum of severity
- Chronic glucocorticosteroid exposure
- risk additive with underlying disease
- “Male Osteoporosis”

## Osteoporosis:A spectrum of disorders

- Accelerated osteoporoses
- Immobilization
- neurological, other
- Transplantation
- renal, liver, heart, lung
- Recent fracture

## Development Guidelines / Pathways

- US / FDA
- WHO working group
- EU / CPMP
- There are many similarities
- Main differences involve the role of BMD vs direct assessment of the effect on fracture rate for initial registration.

## Experience Leading to US Guidelines II Revision 1993-94

- Laws of physics not revoked, but
- Drugs that apparently increased mass but did not decrease fracture rates
- Preclinical abnormalities: F, EHDP
- Failed trial: sCT
- Issues: mass _vs_ strength,
-  	meaning of “quality”

## Principles of Current US Guidelines

- _Robust_ preclincal testing can identify drugs with harmful effects on bone
- The above statement is not “proven”
- Drugs which do not harm “quality” may be approved based on BMD _provided_ there is confirmatory trend in ongoing fracture studies, which must be completed
- Drugs with possible adverse effects on quality must be proven to reduce fx rate

## Preclinical Evaluation: General Considerations 

- Model systems have several purposes:
- model the disease and response to tx
- detect specific adverse effects
- model specific pharmacokinetic and/or pharmacodynamic phenomena
- Preclinical testing is generally reliable,
- but results need clinical confirmation

## Preclinical Evaluation of Anti-Osteoporotic Agents

_**Complementary to toxicology**_
- Studies of bone quality: architecture, mass and strength
- More limited requirements for E
- Primary objective: demonstrate that long-term treatment will not lead to deleterious effects

## Rationale for 3 year observation

- BMD
- Reequilibration? (SQ sCT)
- Fx
- Accrual of adverse effect? (EHDP)

## “Trust, but verify”

- Confirm qualitative effects in humans by evaluating fracture rate
- Vertebral, non-vertebral
- Supports specific claims
- Must this be repeated for each indication?
- What statistical tests should be applied for confirmation of effect at additional sites

## Osteoporosis Guidelines:	 WHO, FDA and CPMP

- Similar preclinical testing 	recommendations
- Similar phase II requirements
- Biochemical markers for mechanistic evaluation, dose findings
- One year BMD for phase IIb

## Osteoporosis Guidelines:	 WHO, FDA and CPMP 

- Main differences:
- WHO would register a drug based on BMD without fracture trial, if it has a satisfactory preclinical profile
- FDA requires favorable trend in fracture trial when allowing initial registration based on BMD, for drugs with good preclinical data
- CPMP requires definitive anti-fracture efficacy for initial registration

## Possible endpoints for registration trials

- Preclinical:  no bone quality problems at 5X dose
- BMD only
- BMD primary, with supportive fx data
- Fx only

- Preclinical: concerns about quality at high dose
- Fx endpoint primary
- Quit
- ???

## Context of the Guidance--1994

- Fewer therapeutic options, none with rigorously established antifracture efficacy
- Experience with drugs that induced quality problems
- Limited experience with well-validated therapeutic options

## Changes in the Scientific Context

- More therapeutic experience with
- Aminobisphosphonates
- SERM (one registered, several failed)
- Estrogen (WHI)
- PTH (pending)
- Technological advances
- More experience relating outcomes to preclinical and clinical measurements
- Better quantified risk estimates for trials

## Interaction of FDA and CPMP guidances

- Alendronate and raloxifene registered per US guidance
- Subsequent development programs were carried out to meet stricter CPMP requirements

## Changes in the Clinical Context

- Several drugs now available, 30-50% RRR
- Fracture rate reduction: widely accepted 	clinical outcome measure, but
- _Prevailing “standard” of care: no Rx_ for 	most 	osteoporotic women
- Less than 10%, even after hip fracture
- Some use of Ca and vitamin D, still a minority

## Emerging Issues in Osteoporosis Guidance

- Develop improved therapies
- Novel mechanisms, especially anabolic
- Alternative regimens (compliance)
- Combinations with complementary mechanisms
- Limit risk to participants
- Keep development time and costs within range that does not preclude drug development

## What about “placebo” controlled trials with fracture endpoints?

- “_Placebo” is a misnomer_
- Trials always include background Ca and vitamin D, compare active vs. PBO tablet
- Before effective therapies, high risk subjects included
- Current view: such trials are now considered acceptable in patients with relatively low  fracture risk, but not in high risk patients (e.g. with multiple or recent fractures)
- Implications for trial design

## In the present context, can we reevaluate endpoints?

- What do we need to know?  And when?
- What do regulators need to know to register a drug (safe and effective)?
- What do physicians need to know to make good clinical decisions?
- FDA regulates both registration and subsequent claims
- If less is required at registration, more may be needed later

## Specific points

- Preclinical testing requirements—relationship to phase III / registration
- Clinical trial endpoints
- _Registration_
- Outcomes
- Analysis / inference
- Statistics
- Multiple specific indications

## Biochemical markers of bone remodeling

- Emerging role of biochemical markers of bone remodeling: short response time, predictive of clinical effect
- No direct structural relationship between markers and strength
- Markers are indicative of bone remodeling activity, drug effect
- Indicate changes in remodeling space
- Relation to efficacy for antiresorptives only

## Purpose of models

- Models validated for adverse effects
- Elucidate mechanisms
- Demonstrate efficacy
- Detect adverse effects

## Preclinical Studies for Osteoporosis	-- Bone Quality

- Mass
- Architecture
- Strength

## Preclinical Studies in Osteoporosis	--Animal Systems

- Two Species
- Ovariectomized  rat
- Larger, remodeling species
- usually primates
- justify
- also refers to GCS tx’d & castrated males

## Reflects clinical indication
prevention vs. treatment
early vs. late post-ovx

Treatment schedule
continuous vs. intermittent

Dosage - 1x to 5x

Duration
comparable to 4 yrs of human exposure

- prevention vs. treatment
- early vs. late post-ovx
- Treatment schedule
- continuous vs. intermittent
- Dosage - 1x to 5x
- Duration
- comparable to 4 yrs of human exposure

- Preclinical Studies in Osteoporosis	--Study Design

## Preclinical Endpoints for Testing of Anti-Osteoporotic Agents

- Bone mass/density:
- ash weight, radiologic methods
- Histology, histomorphometry
- Biochemical markers of turnover
- Biomechanical testing:
- bending, torsion on long bones
- compression of vertebrae

## Biochemical markers of resorption & formation

Light microscopy, polarized light, tetracycline-labelled histomorphometry

Long Bones & Vertebrae
Histomorphometric analysis
Bone density / mass (ASU)
Biochemical testing of strength

Relate to clinical efficacy measurements

- Light microscopy, polarized light, tetracycline-labelled histomorphometry
- Long Bones & Vertebrae
- Histomorphometric analysis
- Bone density / mass (ASU)
- Biochemical testing of strength
- Relate to clinical efficacy measurements

- Preclinical Studies in Osteoporosis	--Measurement

## Experience with Preclinical Identification of Harmful Drug Effects on Bone Quality

- EHDP  mineralization defect
- F  histologic abnormalities
-         decreased strength
- _No_ examples of bone-toxic drugs identified by preclinical studies