Pharma’s Cutting Edge

ASBMR was eventful this year, with PMP osteoporosis trial news from several companies, most notably fracture data from Amgen’s denosumab and comparative BMD data from Merck’s odanacatib.

Of course, it’s easy enough for you to learn about these presentations from other news sources, so I won’t spend much time on them.  Here’s the gist:  Denosumab, the most advanced RANKL inhibitor,  administered as twice yearly injections  worked as well as Fosamax once a week tablet to prevent vertebral and nonvertebral fractures.  Odanacatib, the most advanced Cathepsin K inhibitor, looks like it has similar efficacy–measured as ability to increase BMD at spine and hip–as Fosamax and appears to be free from the AEs that have stopped other Cathepsin K inhibitors from advancing to Phase 3. 

On the trying-to-find-a-silver-lining side of the news, Wyeth failed to demonstrate that its most advanced SERM, bazedoxifene, can prevent nonvertebral fragility fractures in the overall treatment population of its Phase 3 study of 7,500 women, but a subgroup of high-risk women suggested a dose-related benefit compared with raloxifene.  Bazedoxifene, which has been in clinical trials for approximately forever, is likely to be the second or third marketed SERM, entering the US marketplace some 10 years after raloxifene (disclosure:  I participated in the development and registrations of raloxifene).  The other SERM vying for US marketing approval is Pfizer’s lasofoxifene (in contrast to bazedoxifene, this drug has only been in clinical development for a REALLY LONG TIME), which was given the green light last week by an FDA Advisory Committee.

Okay, so that’s the news and it’s interesting that practitioners will likely have a bunch more drugs to choose from to treat and eventually to prevent PMP osteoporosis, including, perhaps, drugs with two new mechanisms of actions.  Analysts like the market outlook for denosumab in particular, as it is given very infrequently by subcutaneous injection.  We’ll see.  I’m not quite as convinced of its multi-billion dollar potential. 

None of these new drugs has demonstrated improved efficacy compared with any bisphosphanate, including Fosamax, which is now generic in its immediate-release formulation.  All of the new drugs are variations of the antiresportive theme.  That is, they all work by suppressing bone resporption by osteoclasts.  The only purely anabolic (bone-building) drug marketed for PMP osteoporosis is still PTH, which was first approved in the US in 2002 as Forteo (Lilly; disclosure:  I also contributed to the registration of Forteo).

Now…here’s the interesting bit regarding all of the above trials (at least to me) that you’re not reading as much about in the lay press.  All of the pivotal trials for new drugs to treat PMP osteoporosis include a placebo group of women that are given only calcium and vitamin D, and sometimes are only offered these nutrients if their dietary intake is self-reported to be inadequate.  The active-treatment groups are also offered the same supplements.  But here’s the thing.  There are well-established drugs available in every developed country to treat this debilitating disease.  These clinical trials are several years long, and women are expected to remain in the study taking their assigned therapies until they lose enough bone or suffer a fragility fracture, at which time they are offered the option of taking a proven effective drug. 

Is this study design ethical?  There is a concept when evaluating the appropriateness of random allocation studies called clinical equipoise.  It refers to the need for clinician-researchers to be doubtful as to which treatment assignment is superior.  Equipoise must be established when the consequences of subjects being assigned to receive a potentially inferior treatment could be severe or irreversible. 

When consequences of ineffective therapy are less severe and effective therapies exist, the following type of analysis (from Emmanuel and Miller) should be done to ascertain the appropriateness of a treatment group choice.  It considers whether a compelling methodologic need for a placebo group exists:

When effective treatments exist, there must be compelling methodologic reasons to conduct a placebo-controlled trial….A placebo-controlled trial has a sound scientific rationale if the following criteria are met: there is a high placebo-response rate; the condition is typically characterized by a waxing-and-waning course, frequent spontaneous remissions, or both; and existing therapies are only partly effective or have very serious side effects; or the low frequency of the condition means that an equivalence trial would have to be so large that it would reasonably prevent adequate enrollment and completion of the study.

Applying these criteria to the PMP osteoporosis studies, it is clear that there is no compelling methodologic reason to conduct placebo-controlled studies in this disease.  None of the above methodologic criteria that could justify use of a placebo control apply to PMP osteoporosis.

Effective therapies have been available to treat PMP osteoporosis for many years.  Clinical equipoise is clearly absent when considering the use of an investigational drug vs. nutritional supplementation over a prolonged period of time in women with established osteoporosis.  It is clear in such trials that calcium and vitamin supplementation is a far inferior therapeutic option, exposing placebo-treated women to needless bone loss and its attendant loss of stature, back pain, and decrement of quality-of-life and/or fracture and its accompanying morbidities and mortality risk.  Finally, it is clear that there is no compelling methodologic reason to warrant placebo-controlled trials in this disease.

Sponsors insist on running placebo-controlled trials in PMP osteoporosis because such trials are still mandated by regulators, particularly the FDA.  However, sponsors must not allow FDA to dictate research ethics.  They have a responsibility to their customers to correct FDA when it is wrong, and to defy FDA when it fails to recognize that it is wrong.  Why haven’t IRBs stopped such trials from being run?  In some regions of the world they have (eg, parts of Germany).  For the most part, though, IRBs have shirked their ethical responsibilities.  It’s just that simple.  IRBs are beholden to study sponsors.  As long as sponsors keep designing such trials, they’ll keep getting IRB approvals to run them.

The issue of placebo-controlled trials in PMP osteoporosis has been debated publicly very rarely and not recently.  The US Office of Human Research Protections has been silent on the issue.  FDA hasn’t updated its clinical guidance for PMP osteoporosis drug development since 1994, and it remains a draft document!  Let’s use these new research findings as an impetus to finally stop the practice of assigning women with osteoporosis to 3+ years of treatment with nothing more than modest amounts of nutritional supplements.  These women have volunteered to help further the treatment of this awful disease, and they deserve more consideration.

Radiograph (right image at top) courtesy of Bio-Imaging Technologies, Inc.

September 18th, 2008 | Tags: bisphosphanate, cathepsin K, osteoporosis, RANKL, SERM | Category: Clinical Research, FDA, Public Perceptions, Technology | Subscribe to comments | Leave a comment | Trackback URL