u.s. guidance for the development of drugs for osteoporosis: rationale, durability and evolution...
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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 GuidelinesPrinciples 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 AgentsPreclinical 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
Preclinical Studies in Osteoporosis--Study Design
Preclinical Endpoints for Testing of Anti-Osteoporotic AgentsPreclinical 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
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