# Presentation: 726286

## The Size, Scope and Implications of Placebo and Active Controlled Trials

**Steven R. Cummings, MD, FACP**
**SF Coordinating Center**
- Research support, consultation or honoraria from Pfizer, Novartis, Organon, Merck, Lilly, Roche, ILEX, GE-Lunar

## Acknowledgements

**Charles McCulloch, PhD**
**	****(Chief of Biostatistics, UCSF)**
**Dennis Black, PhD**

## Acknowledgements

**Charles McCulloch, PhD**
**	****(Chief of Biostatistics, UCSF)**
**Dennis Black, PhD**
**Input about assumptions from**
**Eric Colman, PhD**
**Several physician-investigators in osteoporosis**

## Acknowledgements

**Charles McCulloch, PhD**
**	****(Chief of Biostatistics, UCSF)**
**Dennis Black, PhD**
**Input about assumptions from**
**Eric Colman, PhD**
**Several physician-investigators in osteoporosis**
**No input from any sponsor**

## Outline

**Placebo-controls**
**Risk of assignment to placebo if you have osteoporosis **
**Non-inferiority trials**
**Sample sizes for trials with BMD and vertebral fracture outcomes**
**Principle for setting non-inferiority margins **
**Proposals for duration of trials**
**A principle for registration and labeling drugs**
**An ethical and feasible design for studying long-term effects of drugs**

## Revised Declaration of Helsinki

**“****...**** a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:**
**“****Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or...**

## Revised Declaration of Helsinki

**“****Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm****.” **

## Current standard of care for participants receiving placebos

_**All osteoporosis trials**_
**give all participants supplemental calcium and vitamin D **
**Alert and allow approved treatments for participants who lose BMD excessively or suffer fractures**

## Feasibility of placebo-controlled trials

**Some US IRBs will not approve enrollment of women with vertebral fractures into placebo-controlled trials**
**Current trials involving women with osteoporosis are recruiting 90 to 95% of participants outside the U.S. **

## Reductions in annual risk of x-ray vertebral deformities

**Women with vertebral fracture**
**	****	****	****	****	****	****	****Risk****	****	**
**Risedronate US****	****	****      1.5%****	**
**Raloxifene****	****	****	****      2.2%****	**
**Alendronate ****(FIT1)****	****	****       ****2.3%**
**Risedronate Eur****	****	****      4.1%**
**Parathyroid hormone****	****      5.1%****	**

## Reductions in annual risk of new vertebral deformities

***Women with******	*****	****	****	**
**Vertebral fracture****	**** ****1.5-5%**
**Hip T≤ -2.5****	****	****     0.5 - 1.5%**

## Reductions in annual risk of hip fractures

***Women with****** ***
**osteoporosis****	****1-4/1000**

## How often do fractures cause death in trials?

**Fracture Intervention Trial**
**6459 women**
**907 women suffered 1149 fractures**
**122 deaths**
**No (0) deaths due to fractures**

## 						  Annual mortality (%)
Study		 	 	Treatment		Placebo
Alendronate (FIT 1)   		0.8 		0.7	
Alendronate (FIT 2)		0.4		0.4
Risedronate (VERT US) 	  	0.6		0.7
Risedronate (VERT EUR) 	0.9		1.4
Raloxifene				0.4		0.4	

_**Study**_**	****	**** ****	**** ****	**_**Treatment**__**	**_**	**_**Placebo**_
**Alendronate ****(FIT 1)****   ****	****	****0.8 ****	****	****0.7****	**
**Alendronate ****(FIT 2)****	****	****0.4****	****	****0.4**
**Risedronate ****(VERT US) ****	****  ****	****0.6****	****	****0.7**
**Risedronate ****(VERT EUR)**** ****	****0.9****	****	****1.4**
**Raloxifene****	****	****	****	****0.4****	****	****0.4****	**

**Do proven treatments for osteoporosis reduce mortality?**

## Meta-analysis of mortality

**Pooled data from trials finding reduced risk of fracture**
**Treatment vs. placebo:**
**	****	**_**Relative risk**_**	****	****	****	****	**** ****	****0.9****	****	****Overall mortality ****	****  (0.7 to 1.1)**

## FIT Trial

**SF-12 at baseline and end**
**6 scales of functional status: **
**- Physical****	****	****- Mental health**
**- Social****	****	****	****- Health perception**
**- Role****	****	****	****- Body pain**

## Change in functional status in women with vertebral fracture

- No significant
- differences

## Quality of Life: The MORE TrialWomen with vertebral fractures

**Nottingham Health Profile**
**954 raloxifene, 447 placebo**
**“****Osteoporosis-targeted”**
**OPAQ**
**590 raloxifene, 279 placebo**
**EFFO**
**212 raloxifene, 94 placebo**
**Scales for back pain, body image, independence, mobility...**

## Quality of Life: The MORE TrialWomen with vertebral fractures

**Nottingham Health Profile**
**954 raloxifene, 447 placebo**
**“****Osteoporosis-targeted”**
**OPAQ**
**590 raloxifene, 279 placebo**
**EFFO**
**212 raloxifene, 94 placebo**
**Scales for back pain, body image, independence, mobility...**

## Limited Activity Days after common fractures

**Placebo group****	**
- 				Days			Mean		Range
- All types	109.7		2-668
- Spine	148.8		7-556
- Hip		140.0		10-405
- Wrist	  78.0		2-295

## Effect of alendronate on LADs due to fracture

_**Women with vertebral fx: over 3 years**_
- 		_**Aln**_**	**_**Pbo**_**	**_**Diff.**_**	**_95% CI_
**All****	****10.2****	****19.0****	****8.8****	**3.7-13.9
_**Women with hip T-score ≤ -2.5**__**:**__** 4 years**_
**All****	****11.6****	****20.0****	****8.4****	****2.6-14.3 ****	**

## 	Risk group 		Days of limited activity / year 
	Vertebral fracture*	2.9	due to fracture
					3.8 	due to back pain

					Days in bed / year
					1 	due to back pain

	* Includes women with recent, multiple and clinically diagnosed fractures

**	****Vertebral fracture*****	****2.9****	****due to ****fracture**
**	****	****	****	****	****3.8 ****	****due to ****back pain**
**	****	****	****	****	**
**	****	****	****	****	**_**Days in bed / year**_
**	****	****	****	****	****1 ****	****due to ****back pain**
**	***** Includes women with recent, multiple and clinically diagnosed fractures**

**Average days of limited activity per year****in placebo vs. alendronate**

## 	Risk group 		Days of limited activity / year 
	Hip BMD T ≤ -2.5		2.1 	due to fracture
					NS 	due to back pain	

**	****Hip BMD T ≤ -2.5****	****	****2.1 ****	****due to ****fracture**
**	****	****	****	****	****NS ****	****due to back pain****	**

**Average days of limited activity per year****in placebo vs. alendronate**

## Recent spine fracture

## Recent vertebral fractures mean a 4 to 5-fold higher risk of another fracture

**	****	****Risk of spine fx  next year**
_**Study**_** ****	****	**_**Recent***_**	**_**‘Old’**_
**VERT (Lindsay)****	****	****20%****	****?**
**FIT I****	****	****16%****	****3%**
**MORE****	****	**** 7%****	****2%**
*** In the past 1 or 2 years**

## Conclusions

**Average risk of being in the placebo instead of treatment group depends on severity of osteoporosis**
**	****	****	****	****    ****Risk of     Limited ****	****	****	****	****	****    **_**fracture**_**	****   **_**activity**_
**	****T-score <-2.5****	****      ~1%****	****   2 days**
**	****Spine fracture****	****      ~2%****	****   ~ 7 days**
**	****Recent fx****	****     ~10%****	****   Several weeks**

## SummaryRisks of being in a placebo group

**In past trials of effective drugs assignment to placebo instead of active treatment, on average,**
**did not significantly increase mortality**
**has not measurably reduced ‘quality of life’**
**Risk of disability depends on the severity of osteoporosis**

## The central issue

**Are the risks so great that IRBs and investigators should prevent women with T-score < -2.5 or one vertebral deformity from making informed choices to participate in a trial?**

## Even if ethical, placebo-controlled trials in the US are becoming less feasible

**Current trials involving women with osteoporosis are recruiting 90 to 95% of participants outside the U.S. **

## Alternative designs

## Ways to minimize risk to participants in placebo-controlled trials

**Exclude high risk women**
**multiple vertebral fractures**
**recent vertebral fractures**
**Or, perhaps women with vertebral fractures**

## Ways to minimize risk to participants in placebo-controlled trials

**Exclude high risk women**
**multiple vertebral fractures**
**recent vertebral fractures**
**Or, perhaps women with vertebral fractures**
**Large (5-10,000) sample sizes for fracture outcome trials**

## Non-inferiority trialsnew drugs vs. active comparators

**Outcomes: BMD and vertebral deformity **
**Treatments: Bisphosphonates and SERMS**

## Process

**Developed assumptions from discussions with physician-investigators in osteoporosis before calculating sample size**
**Statistical models provided by Chuck McCulloch, PhD  ****	****	****Chief of Biostatistics, UCSF**

## Assumptions in all models

**One-sided confidence intervals (alpha = 0.025)**
**Power = 0.8 (also tested 0.9)**
**BMD trials last 2 years**
**Fracture trials last 3 years (also tested 1 year)**
**Did *****not***** increase sample sizes to compensate for drop-outs**

## A key specification:“Non-inferiority margin”

**How much “inferiority” will you allow and still approve the new drug?**

## A key specification:“Non-inferiority margin”

**How much “inferiority” will you allow and still approve the new drug?**
**Margin = difference between mean value for the ‘active’ approved comparator and the end of the one-sided confidence interval.**

## Approved (A) vs. new bisphosphonate (B)

**C.I.**
**How wide is**
**allowable?**

**%**
**change**

**Year**

## Approved (A) vs. new bisphosphonate (B)

**“****Non-inferior” if <2.5% chance **
**that the effect of B is 1% lower **
**than the effect of A**

**1.0%**

**%**
**change**

**Year**

## Approved (A) vs. new bisphosphonate (B)

**1.0%**

**Assume A and B have about**
**the same mean effect on BMD**

**%**
**change**

**Year**

## Approved (A) vs. new bisphosphonate (B)

**1.0%**

**Assume A and B have about**
**the same mean effect on BMD**
**B is “non-inferior” to A**

**%**
**change**

**Year**

## Approved (A) vs. new bisphosphonate (B)

**1.0%**

**The difference between**
**A and B exceeds the**
**non-inferiority margin.**
**“****Inferior”**

**%**
**change**

**Year**

## “Non-inferiority margin”

**How much “inferiority” will you allow and still approve the new drug?**
**Difference between mean value for the ‘active’ approved comparator and the end of the confidence interval.**

## New vs. approved bisphosphonate:Effect on BMD

**Assumptions**
**Approved bisphosphonate effects:**
**Spine = 4.5%; hip = 3.0% at 2 years**
**New drug has the same effect**

## New vs. approved bisphosphonate:Effect on BMD

**Assumptions**
**‘****Non-inferiority margin’ = 1.0% lower**
**Tested a range of 0.5 to 2%**
**S.D. of 2 year change in BMD* **
**Spine = 5%; total hip = 4%**
*** *****From the Fracture Intervention Trial treatment groups ***

## Sample size for non-inferiority:spine BMD

**128**

**200**

**506**

**2002**

**Power**

**Non-inferiority margin**

**Size**

## Sample size for non-inferiority:total hip BMD

**200**

**350**

**788**

**3152**

**Power**

**Non-inferiority margin**

**Size**

## Sample size for non-inferiority:spine BMD

**172**

**250**

**676**

**2687**

**Power**

**Non-inferiority margin**

**Size**

## Assumptions about vertebral deformities

**“****Vertebral deformity” = change in measurement or semiquantitative grade on lateral spine films**
**Defined as 20% decrease in any vertebral height**

## New vs. approved bisphosphonate:Effect on new vertebral deformities

**Assumptions**
**High risk group: women with vertebral fractures**
**Placebo rate = 5% per year**
**15% cumulative incidence at 3 years**
**Approved drug (alendronate) decreases fracture risk 47%**

## New vs. approved bisphosphonate:Effect on new vertebral deformities

**Assumptions**
**High risk group: women with vertebral fractures**
**Placebo rate = 5% per year**
**15% cumulative incidence at 3 years**
**Approved drug (alendronate) decreases fracture risk 47%**
**8% cumulative incidence at 3 years**

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47%**** **

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47%**** **
**	****	****      ****9%****	****	****      40%**
**	****	****     ****10%****	****	****      33%  **
**	****	****     ****11%****	****	****      27%**
**	****	****     ****12%****	****	****      20%  **

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47%**** **
**	****	****      ****9%****	****	****      40%  **
**	****	****     ****10%****	****	****      33%  (~2/3)**
**	****	****     ****11%****	****	****      27%  (~1/2)**
**	****	****     ****12%****	****	****      20%  **

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47%**** **
**	****	****      ****9%****	****	****      40%**
**	****	****     ****10%****	****	****      33%  (~2/3)**
**	****	****     ****11%****	****	****      27%  (~1/2)**
**	****	****     ****12%****	****	****      20%  **

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47%**** **
**	****	****      ****9%****	****	****      40%**
**	****	****     ****10%****	****	****      33%  (~2/3)**
**	****	****     ****11%****	****	****      27%  (~1/2)**
**	****	****     ****12%****	****	****      20%  **

## New vs. approved bisphosphonate:vertebral deformities

**Assumptions***
**Approved bisphosphonate:**
**47% reduction in risk of vertebral deformity**
**Equivalent to 8% incidence by 3 years**

## New vs. approved bisphosphonate:vertebral deformities

**Assumptions***
**Approved bisphosphonate:**
**47% reduction in risk of vertebral deformity**
**Equivalent to 8% incidence by 3 years**
**New drug has the same effect**

## New vs. approved bisphosphonate:vertebral deformities

**Assumptions***
**Approved bisphosphonate:**
**47% reduction in risk of vertebral deformity**
**Equivalent to 8% incidence by 3 years**
**New drug has the same effect**
**‘****Non-inferiority margin’ = 2% **

## New vs. approved bisphosphonate:vertebral deformities

**Assumptions***
**Approved bisphosphonate:**
**47% reduction in risk of vertebral deformity**
**Equivalent to 8% incidence by 3 years**
**New drug has the same effect**
**‘****Non-inferiority margin’ = 2% **
**10% incidence (~33% reduction in risk)**
**Tested 11% (~40%) and 9% (~27%)**

## Sample size for non-inferiority:vertebral deformity

**23,100**

**5,777**

**2,567**

**Power**

**Non-inferiority margin**

**Size**

## Sample size for non-inferiority:vertebral deformity

**Power**

**30,934**

**7,733**

**3,437**

**Non-inferiority margin**

**Size**

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47% **
**	****	****      ****9%****	****	****      40%**
**	****	****     ****10%****	****	****      33%**
**	****	****     ****11%****	****	****      27%**
**	****	****     ****12%****	****	****      20%**

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47% **
**	****	****      ****9%****	****	****      40% ****comparator?**
**	****	****     ****10%****	****	****      33%**
**	****	****     ****11%****	****	****      27% (2/3)**
**	****	****     ****12%****	****	****      20% (1/2)  **

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47% **
**	****	****      ****9%****	****	****      40% ****comparator**
**	****	****     ****10%****	****	****      33%**
**	****	****     ****11%****	****	****      27% (2/3)**
**	****	****     ****12%****	****	****      20% (1/2)  **

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47% **
**	****	****      ****9%****	****	****      40% ****comparator**
**	****	****     ****10%****	****	****      33%**
**	****	****     ****11%****	****	****      27% (2/3)**
**	****	****     ****12%****	****	****      20% (1/2)  **

## Sample size for non-inferiority:vertebral deformity

**23,100**

**6,428**

**Power**

**Non-inferiority margin**

## Issue: Aiming low

**If a fixed margin is allowed, then choosing the weakest comparator will produce smaller sample sizes**
**This may lead to approval of drugs that are less and less and less distinguishable from placebo.**

## PrincipleNon-inferiority trials for a class

**Base margins on minimal estimated effectiveness**
**30-33% reduction in 3 year risk of vertebral deformity?**

## SERMs

## SERM Issues

**Effects on multiple organs and conditions**
**Only one (raloxifene) in the class has been tested for fracture effects**
**Approval based on non-inferiority for fracture effects seems premature**

## New vs. approved SERM:Effect on BMD

**Assumptions**
**Approved SERM (raloxifene) effects:**
**Spine = 2.0%**
**New drug has the same effect**
**‘****Non-inferiority margin’ = 0.5% lower**
**Also tested 1.0%**
**S.D. of 2 year change = 3.5%* **
*** *****From the MORE Trial  60 mg treatment groups ***

## Sample size for non-inferiority:spine BMD for SERM

**192**

**771**

**Power**

**Non-inferiority margin**

**Size**

## New vs. approved SERM:Effect on new vertebral deformities

**Assumptions**
**Placebo rate = 5% per year**
**15% cumulative incidence at 3 years**
**Approved drug (raloxifene) decreases fracture risk 35-40%**
**~9% incidence at 3 years**

## 3 year rates and estimated effectiveness vs. placebo

**	****  ****	****	****	****	****Estimated ****	**** ****	****	**_**3 year rate**_** ****	**_**effectiveness**_
**	****	****      ****8%****	****	****      47% **
**	****	****      ****9%****	****	****      40% ****comparator**
**	****	****     ****10%****	****	****      33%**
**	****	****     ****11%****	****	****      27% (2/3)**
**	****	****     ****12%****	****	****      20% (1/2)  **

## Sample size for non-inferiority:vertebral deformity

**23,100**

**6,428**

**Power**

**Non-inferiority margin**

## What non-inferiority margin?

## Choosing non-inferiority margins:A suggested principle

**Use standard non-inferiority margins for drugs with**
**Other health benefits**
**Safer**
**More convenient; better adherence**
**Less expensive**

## Choosing non-inferiority margins:A suggested principle

**Use standard non-inferiority margins for drugs with**
**Other health benefits**
**Safer**
**More convenient; better adherence**
**Less expensive**
**New drugs with no advantagess should prove superiority or demonstrate very narrow margins**

## Duration of trials1 year

## 1 year study

**60% reduction in risk of vertebral fracture at 1 year.**
**Non-inferiority margin for new drug: 20% (test range from 10 to 30%)**

## 1 year study

**Assumptions **
**5% per year placebo risk**
**60% reduction in risk of vertebral deformity**
**2% fracture rate with approved drug **
**Non-inferiority margin**
**2/3 effect (~40% risk reduction)**** **
**1/2 effect (~30% risk reduction)**

## Sample size for non-inferiority:vertebral deformity at 1 year

**13,708**

**6,154**

**Power**

**Non-inferiority margin**

**1% (50%)**

**2% (40%)**

**3% (30%)**

**4,478**

## 12-18 month study

**What if the risk were higher?**
**Placebo: 10% new vertebral deformity**
**Treatment: 60% reduction in risk**
**Comparator: tested at estimated 40% and 30% risk reduction (margins = 2/3 or 1/2 effectiveness)**

## Sample size for non-inferiority:vertebral deformity at 12-18 months

**12,056**

**3,014**

**Power**

**Margin (estimated effectiveness)**

**1,340**

**1% (50%)**

**2% (40%)**

**3% (30%)**

## Duration of trials

**Stronger effect on vertebral fractures in the first than 2nd or 3rd years. **
**There is concern about the long-term effects of potent anti-resorptive drugs**
**Placebo-controlled fracture trials have lasted 3 to 4 years**

## BMD continues to improveRisedronate reduces risk in first year

**Years**

- Spine
- BMD** **
**(%)**

**61-65%**

**Years**

- % ** **
-  risk

**Risedronate**

**Risedronate**

## BMD continues to improveRisk reduction seems to wane

**Years**

- Spine
- BMD** **
**(%)**

**61-65%**

**25-30%?**

**Years**

- % ** **
-  risk

**Risedronate**

**Risedronate**

- ?

## Alendronate has a similar pattern

**Alendronate**

**Year(s)**

***10 mg***

***5 mg***

**Risedronate**

**61-65%**

**25-30%?**

**Years**

- ?

**From the FIT trial and from the VERT trials**

** ****65% **
**(50,76) **

** ****40% **
**(6,62) **

- % ** **
-  risk

- % ** **
-  risk

## A statistical artifact?

**Depletion of ‘susceptibles’ in the placebo group?**

## A statistical artifact?

**Depletion of ‘susceptibles’ in the placebo group?**
**Models with extreme assumptions cannot account for the observed declines in effect.**
**Requires a substantial decline in the placebo rate; not observed in the VERT or FIT trials**

## A biological effect?

**Possibilities**
**Dramatic first year effect on resorption is followed by sustained, more modest (~30-40%) reduction in risk due to BMD**
**Inhibition of resorption initially strengthens then weakens bone**

## Duration of trialsA suggestion

**Consider: approve drugs for use equal to the duration of trials (1 to 4 years)**
**Extend approved duration of use based on results of longer (> 5 year) trials**

## Duration of trialsA suggestion

**Consider: approve drugs for use equal to the duration of trials (1 to 4 years)**
**Extend approved duration of use based on results of longer (> 5 year) trials**
**Challenge: Not feasible to continue placebo-controlled trials beyond 3 years**

## An alternative design to assess long-term effect on fracture risk

**Placebo-controlled for 3 years**
**Continue treatment group longer (10 years?)**

## Sustained effectiveness

## An alternative design to assess long-term effect on fracture risk

**Compare fracture rate in treatment group after 7-10 years with the rate in the placebo group during first 3 years.**
**Adjust for age and differences between groups**

## Sustained effectiveness

**Comparison**
**Adjusted for age**
**and differences **
**in characteristics**

## Loss of effectiveness

**Comparison**
**Adjusted for age**
**and differences **
**in characteristics**

## Long-term comparisons are feasible

**Trials with **
**>1,000 per group at baseline and**
**≥ ****50% retention of treated subjects by 10 years**
**will have ≥ 80% power to confirm that a 30% lower risk in the last 3 years vs. placebo rates remains statistically significantly lower.**

## An alternative design to assess long-term effect on fracture risk

**Consider re-randomizing after 3-4 years**
**Example: the FLEX trial of alendronate rerandomized the treatment group to placebo vs. alendronate for additional 5 years**

## Summary

**Participating in controlled trials of treatments for women with osteoporosis entail**
**No measurable risk of death or loss of ‘quality of life’**
**Risk of several days of limited activity for those assigned to placebo**
**Risk depends on severity of osteoporosis**

## Summary

**Alternative designs**
**Noninferiority studies for fracture require very large sample sizes**
**Non-inferiority for BMD requires modest to small sample sizes.**

## Suggested principles

**Placebo controlled trials for new classes of agents with women with T≤ -2.5 (or one ‘indeterminate age’ vertebral fracture)**
**Approve new drugs for duration of the trial.  Extend approved duration based on long-term treatment  vs. initial placebo rate.**
**Moderate non-inferiority margins if new drugs have advantages.**
**Set margins that preserve a minimal effectivess of treatment over placebo.**