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

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OsteoporosisA 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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OsteoporosisA 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 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 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 requirementsrelationship 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 txd castrated males

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Preclinical Studies in Osteoporosis --Study
Design

• 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

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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

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Preclinical Studies in Osteoporosis --Measurement

• 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

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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