Sham Controls in Medical Device Trials: Perspective

PERS PE C T IV E Sham Controls in Medical Device Trials
Sham Controls in Medical Device Trials

Rita F. Redberg, M.D.
W hen a drug is found, after

being approved by the Food
and Drug Administration (FDA),
tients are subjected to a sham
procedure or implant. However,
it has long been established that
invasive procedure to be useful
because of its placebo effect. In-
deed, had there been no trial in-
to have unacceptably dangerous benefits do not have to accrue to cluding sham surgery, many
side effects or insufficient thera- all patients in a clinical trial. Americans with Parkinson’s dis-
peutic benefits to outweigh its In light of mounting evidence ease might be receiving cranioto-
risks, patients can discontinue its that medical procedures can pro- mies for only a placebo benefit.
use. But what if the approved duce a strong placebo effect that Another important lesson on
therapy that is later discovered can be mistaken for actual effec- the value of sham controls came
to be ineffective or unsafe is an tiveness, I believe it is time for from vertebroplasty, a procedure
invasive procedure or an implant- more frequent use of interven- in which bone cement is injected
ed medical device? Patients who tional trials in which patients are into a fractured vertebra for treat-
have already undergone the pro- unaware of their randomized as- ment of a compression fracture.
cedure were put at unwarranted signment. Vertebroplasty became popular
risk, and those with an ineffec- For example, on the basis of in the early 2000s, on the basis
tive or dangerous implanted de- unblinded trials, a catheter-based of observational studies and a
vice must decide whether to leave radiofrequency ablation of the nonrandomized trial. Fueled by
it in their body or incur the risk renal arteries, known as renal-

position statements from various
associated with another proce- artery denervation, was thought U.S. radiologic and neurologic
dure in order to remove it. In to lower blood pressure. The re- surgical societies arguing the
this sense, medical procedures cent SYMPLICITY trial, however, benefits of these procedures, the
and devices pose potentially found renal-artery denervation had number of vertebroplasties per-
greater harm to patients than no beneficial effect on blood pres- formed in Medicare patients near-
drugs do. sure beyond that achieved with a ly doubled between 2001 and
Approval standards for high- sham procedure.2 Although the 2005, increasing from 45.0 to
risk medical devices, however, are reasons for this lack of benefit 86.8 per 100,000 enrollees.3 In
generally less rigorous than those will be debated for some time, 2009, however, RCTs that includ-
for pharmaceuticals. Only 1% of this important result would not ed a group assigned to receive a
all medical devices reach the have been discovered without use nontherapeutic procedure found
market through the premarket- of a nontherapeutic intervention. that pain relief in the sham-pro-
approval route — the only path- Debate over the ethics of per- cedure group was no different
way that requires the submission forming a sham procedure or from that in the group that re-
of clinical data. Research has surgery dates back more than 15 ceived the actual procedure.4 These
shown that premarket approvals years to double-blind trials of examples establish not just ethi-
are often based on data from one fetal-tissue transplantation for cal precedent but also the impor-
small trial that used surrogate Parkinson’s disease, discussed by tance of comparing device-based
end points and included only Freeman et al. (1999). The sham interventions and surgeries with
short-term follow-up.1 Blinded, procedure involved making twist- an equivalent sham control.
randomized, controlled trials drill holes in the patient’s fore- It’s important to understand
(RCTs), in which the proposed head and was considered neces- the power of the placebo effect.
therapy is compared with a place- sary and ethical for determining Researchers at the Institute of
bo or a “sham” (nontherapeutic) whether there was an effect of Medical Psychology in Munich re-
intervention, are common for treatment beyond the placebo ef- cently quantified that power for
drugs but rare for medical de- fect (there was not). The institu- various types of placebo treat-
vices. The lack of such trials for tional review board believed that ments in studies of migraine pro-
devices is due, in part, to the the risks of sham surgery had to phylaxis. They found that 58% of
understandable reluctance to con- be weighed against the greater patients had a positive response
duct a trial in which some pa- risks of mistakenly believing an to sham surgery and 38% had a
892 n engl j med 371;10 nejm.org september 4, 2014
The New England Journal of Medicine

Downloaded from nejm.org on March 25, 2019. For personal use only. No other uses without permission.
Copyright © 2014 Massachusetts Medical Society. All rights reserved.
PE R S PE C T IV E Sham Controls in Medical Device Trials
positive response to sham acu- ward if two groups of patients risks were weighed and managed.
puncture, while only 22% had a were randomly assigned to a car- There were risks associated with
positive response to oral pharma- diac catheterization procedure, as the sham control, which includ-
cologic placebos.5 This research was done for renal-artery dener- ed a femoral-artery puncture and
shows not only an astonishingly vation, such a study has yet to be renal angiography. However, the
high response rate for sham pro- performed, and the important finding that the procedure lacks
cedures, but also a significantly question of PCI’s actual clinical any apparent benefit will spare
higher response rate for placebo benefit therefore remains unan- many patients from undergoing
physical interventions than for swered. a risky procedure that apparently
placebo drugs. These results high- Subjecting patients to sham has only placebo value. There are
light the importance of devising procedures is not without risk, clear benefits of preventing inef-
a control that will sufficiently and it gives rise to ethical con- fective procedures and devices
distinguish the specific effect at- cerns about “unnecessary” inva- from gaining widespread use,
tributable to the placebo. sive procedures that will have no which means that true therapeu-
Not all device trials necessar- actual therapeutic effect. I believe, tic benefit should be established
ily require nontherapeutic con- however, that the examples above before FDA approval.
trols. For example, after a thera- show that sham interventions are The SYMPLICITY trial thus
peutic benefit beyond the placebo ethical when the benefits of in- adds to mounting evidence that
effect was established, subsequent formation from a sham-control medical procedures can have a
iterations of a device would not trial exceed the risks of using an substantial placebo effect. This
need to be compared with a intervention not shown to be knowledge may require Congress
sham control. In addition, trials more therapeutic than a sham. to articulate a clear standard for
with only objective end points, Moreover, the risk associated with establishing true therapeutic ben-
such as mortality, do not need a performing unnecessary proce- efit for FDA approval, to ensure
nontherapeutic control. Interven- dures should be weighed against that all devices we provide to our
tional studies that would most the risk of mistaking a placebo patients are safe and effective.
appropriately be conducted as effect for therapeutic benefit and Disclosure forms provided by the author
blinded RCTs include early studies therefore subjecting thousands are available with the full text of this article
of a new technology and studies or millions of patients to a pro- at NEJM.org.
whose primary outcome measure cedure that actually does them
is susceptible to a placebo effect, no good. In a controlled trial, From the University of California, San Fran-
cisco, Medical Center, San Francisco.
such as pain. patients are informed of and
For example, percutaneous cor- consent to the risks; when an in-
1. Dhruva SS, Bero LA, Redberg RF. Strength
onary intervention (PCI), a widely effective procedure is accepted of study evidence examined by the FDA in
used procedure for treating sta- into practice, however, patients premarket approval of cardiovascular devices.
ble coronary artery disease, has who subsequently undergo it most JAMA 2009;302:2679-85.
2. Bhatt DL, Kandzari DE, O’Neill WW, et al.
never been investigated in a blind- certainly have not knowingly con- A controlled trial of renal denervation for re-
ed trial. Some nonblinded RCTs sented to an ineffectual proce- sistant hypertension. N Engl J Med 2014;370:
have shown that PCI has a bene- dure. Without careful use of non- 1393-401.
3. Gray DT, Hollingworth W, Onwudiwe N,
ficial effect on anginal symp- therapeutic controls, we may be Deyo RA, Jarvik JG. Thoracic and lumbar ver-
toms, but there appears to be no subjecting millions of Americans tebroplasties performed in US Medicare en-
difference between PCI and med- to harm from risky, invasive pro- rollees, 2001-2005. JAMA 2007;298:1760-2.
4. Buchbinder R, Osborne RH, Ebeling PR,
ical therapy in rates of the objec- cedures without benefit. Ethical et al. A randomized trial of vertebroplasty
tive end points of nonfatal myo- concerns regarding a placebo for painful osteoporotic vertebral fractures.
cardial infarction and death due group should, of course, be ac- N Engl J Med 2009;361:557-68.
5. Meissner K, Fässler M, Rücker G, et al.
to cardiac causes. It is possible, knowledged and addressed by in- Differential effectiveness of placebo treat-
therefore, that the perceived symp- stitutional review boards and ments: a systematic review of migraine pro-
tomatic benefit is actually a pla- through informed consent, as they phylaxis. JAMA Intern Med 2013;173:1941-
51.
cebo effect and not attributable are in drug trials and have been
to PCI. Although a blinded trial in the examples above. DOI: 10.1056/NEJMp1406388
would be relatively straightfor- In the SYMPLICITY trial, the Copyright © 2014 Massachusetts Medical Society.
n engl j med 371;10 nejm.org september 4, 2014 893

The New England Journal of Medicine
Downloaded from nejm.org on March 25, 2019. For personal use only. No other uses without permission.
Copyright © 2014 Massachusetts Medical Society. All rights reserved.

Sham Controls in Medical Device Trials: Perspective

Uploaded by

Copyright:

Available Formats

Sham Controls in Medical Device Trials: Perspective

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Sham Controls in Medical Device Trials: Perspective

Uploaded by

Copyright:

Available Formats

PERS PE C T IV E Sham Controls in Medical Device Trials

Sham Controls in Medical Device Trials

W hen a drug is found, after

892 n engl j med 371;10 nejm.org september 4, 2014

The New England Journal of Medicine

n engl j med 371;10 nejm.org september 4, 2014 893

You might also like