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Transcript of U.S. Guidance for the Development of Drugs for Osteoporosis: Rationale, Durability and Evolution...
![Page 1: U.S. Guidance for the Development of Drugs for Osteoporosis: Rationale, Durability and Evolution Henry Bone, M.D. Michigan Bone & Mineral Clinic Detroit,](https://reader035.fdocuments.in/reader035/viewer/2022062321/56649d9c5503460f94a855a2/html5/thumbnails/1.jpg)
U.S. Guidance for the Development of Drugs for Osteoporosis: Rationale, Durability and Evolution
Henry Bone, M.D.
Michigan Bone & Mineral Clinic
Detroit, Michigan
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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”
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Osteoporosis:A spectrum of disorders
Accelerated osteoporoses
• Immobilization– neurological, other
• Transplantation– renal, liver, heart, lung
• Recent fracture
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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.
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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”
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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
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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
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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
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Rationale for 3 year observation
• BMD– Reequilibration? (SQ sCT)
• Fx– Accrual of adverse effect? (EHDP)
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“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
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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
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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
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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– ???
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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
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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
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Interaction of FDA and CPMP guidances
• Alendronate and raloxifene registered per US guidance
• Subsequent development programs were carried out to meet stricter CPMP requirements
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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
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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
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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
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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
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Specific points
• Preclinical testing requirements—relationship to phase III / registration
• Clinical trial endpoints– Registration– Outcomes
• Analysis / inference– Statistics– Multiple specific indications
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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
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Purpose of models
– Models validated for adverse effects• Elucidate mechanisms • Demonstrate efficacy• Detect adverse effects
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Preclinical Studies for Osteoporosis-- Bone Quality
• Mass
• Architecture
• Strength
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Preclinical Studies in Osteoporosis--Animal Systems
• Two Species– Ovariectomized rat
• Larger, remodeling species– usually primates– justify
• also refers to GCS tx’d & castrated males
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• 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
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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
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• 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
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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