Treatment Trials and Drug Development: Overview
The largest program at SMRI is for the identification of medications that will improve the treatment of schizophrenia and bipolar disorder. Although some medications have been available since the 1960s, they have proven to be only partially effective. Many individuals affected with these diseases continue to have symptoms even when taking available medications, while others find it difficult to take medications because of side effects.
There are two parts of this SMRI program:
I. Regular Treatment Trials
The purpose of this program is to support the testing of medications to assess their efficacy for treating schizophrenia and bipolar disorder. SMRI is especially interested in supporting the testing of medications that are unlikely to be tested by pharmaceutical companies because they are not commercially profitable. At any given time, SMRI is supporting 40-50 treatment trials, the majority of which are on generic and/or off-label medications. To view a list of SMRI-funded trials, click on List of Awarded Treatment Trials. To view a description of a trial, click on the "select" button to the left of the grant identification number. The list can be sorted numerically/alphabetically by clicking on a column head.
Regular treatment trials can be funded for up to $300,000 per year. Applications must be submitted by October 1 of each year; applicants will be notified of the decision by the end of November.
2010 Drugs of Specific Interest to SMRI
SMRI is soliciting applications again this year for treatment trials of drugs
which may be useful for improving the symptoms of individuals with schizophrenia
or bipolar disorder. The deadline for applications is October 1st and the
procedure is outlined above. As noted, SMRI is most interested in supporting research on
drugs for which pharmaceutical companies are unlikely to be interested because
of the drugs lack o f commercial
potential. Such drugs include those which have lost patent protection,
off-label drugs etc. A listing of all drug trials supported by SMRI, both past
and present, is available on our website by clicking on List of Awarded
Treatment Trials.
Assistance for Applicants: For the first time this
year, SMRI is offering assistance for treatment trial applicants. Many
applicants have good ideas regarding a drug to be studied but are unfamiliar
with some of the complexities of carrying out such trials. Any applicants who
wish to do so can indicate on their applications that, if approved for funding,
they will ask SMRI consultants to help develop the details for any of the
following:
· Optimal trial design
· Inclusion and
exclusion criteria for patient selection
· Development of clinical
report form (CRF)
· Data management, including the possibility of
using SMRI for central data entry
· Evaluation of dropout
data
· Statistical analysis
The two consultants SMRI is using
in this regard are Drs. John Davis (University of Illinois at Chicago and SMRI Associate Director for
Treatment Trials) and Mark Weiser
(Chaim Sheba Medical Center, Tel Aviv), both experienced treatment trial
experts. If an applicant wishes to use these consultants for any of the above
list, they should not include a cost for this in their budget and SMRI will add
the estimated cost.
In addition this year we are offering applicants an
opportunity to use a new treatment trial design, the Sequential Parallel
Comparison Design (SPCD). This was originally
reported by Dr. Maurizio Fava and David Schoenfeld at Massachusetts General
Hospital (Fava et al., Psychotheraphy and Psychosomatics 72: 115-27,
2003). SPCD can reduce placebo response, and thereby
increases the power of a trial. MGH has licensed its rights related to SPCD to
RCT Logic, LLC (RCT), which is managed by Matt Bowman and his colleagues. An
explanation of SPCD, a bibliography, and contact information for RCT are
included in the attached memorandum (see attached). Applicants who wish to consider using SPCD may
contact Matt Bowman for further information. Those who elect to use SPCD and
obtain a sublicense from RCT should indicate this in their application, but
should not include a cost for this in their budget. SMRI will add the estimated
cost.
We are interested in supporting any good ideas,
including the following which have emerged from our previous
studies.
● Raloxifene for schizophrenia in women
Raloxifene
is an estrogen receptor modulator sold as Evista by Eli Lilly to prevent
post-menopausal osteoporosis. It is said to have effects similar to estrogen’s
but to not affect breast or uterine tissue and therefore to not carry the same
cancer risk. A small trial of 26 patients in Australia partially funded by SMRI
reported improvement in PANSS on 120 mg/d (Kulkarni et al.,
Psychoeuroendocrinology 2010, epub ahead of print). A small SMRI-funded trial of
33 patients in Spain using 60 mg/d reported improvements in both PANSS negative
and positive (Usall et al., submitted).
● Pramipexole for schizophrenia
Pramipexole
is a D2/D3 dopamine agonist used in Parkinson’s disease. It has been extensively
tested for BP disorder (see Aiken, J Clin Psychiatry 2007;68:1230–1236), and
SMRI is currently funding a study of 50 BP patients, data analysis underway. For
schizophrenia, pramipexole showed promise in a preliminary study of 15 patients
(Kasper et al., Eur Neuropsychopharmacol 1997;7:65–70), and the use of dopamine
agonists has been reviewed (Benkert et al., Eur Neuropsychopharmacol
1995;5(suppl):43–53). In 2000, SMRI funded a trial of pramipexole in 24 schiz
patients by Kelleher et al at McLean that reported dose-related positive results
(Kelleher et al., Schiz. Res. Suppl. 60:289, 2003, abstract).
●
Minocycline for schizophrenia
Minocycline is a second-generation
tetracycline thought to have neuroprotective properties associated with its
effects on iNOS, capsase 1 and 3, MAPK, cytochrome C, and others. In addition to
individual case reports, SMRI funded two trials. Levkovitz et al in Israel
randomized 54 patients and reported improvement in negative and cognitive
symptoms, (Levkovitz et al., J.Clin. Psychiatry 71: 138-49, 2010). Chaudhry et
al in Manchester randomized 51 patients and reported no effect after one year
but improvement in negative symptoms with longer use (submitted).
● Anti-inflammatory
agents
There is increasing evidence that there is an inflammatory
component to the schizophrenia disease process. Laan et al. recently published
the results of their SMRI-funded trial using aspirin (J. Clin. Psychiatry 71:
520-527, 2010). This needs confirmation, perhaps by using a
2X2 design. Other
anti-inflammatory agents have also shown promise, including celecoxib in
early-stage schizophrenia (Muller et al., Schiz. Res. 2010, epub ahead of
publication), but possible cardiac effects have limited
studies of this drug. SMRI funded two statin
trials last year so is unlikely to fund an additional trial at this time, but
other anti-inflammatory drugs would be of interest.
In summary, we
welcome applications for any promising drug. All applications will be reviewed
by at least three experienced reviewers. Applications are considered from a
cost-benefit point of view, so cost and possible benefits are considered
simultaneously.
II. Special Treatment Trials and Drug Development
SMRI also supports special treatment trials and occasional drug development. Special treatment trials are usually multi-center trials that require more than $300,000 per year to carry out. Such trials are usually reserved for medications for which preliminary SMRI-supported trials have been promising.
SMRI has, in the past, also supported the development of promising medications at selected corporate biotechnology companies. At this time, such funds are fully committed, and new applications are not being accepted.
SMRI Data and Safety Monitoring Board Policy Statement
Starting in 2009, the Stanley Medical Research Institute will require that all newly funded studies involving more than minimal risk be overseen by a Data and Safety Monitoring Board (DSMB). DSMBs are currently required for most studies funded by the National Institutes of Health ) (http://www.nimh.nih.gov/research-funding/grants/nimh-policy-on-data-and-safety-monitoring-in-extramural-investigator-initiated-clinical-trials.shtml) and the United States Food and Drug Administration. DSMBs are also being increasingly required for articles on clinical trials submitted to medical journals.
At this time, there is some variation in terms of how DSMBs are constituted and what their duties are. We would suggest that DSMBs overseeing SMRI-funded trials meet the following requirements:
- The DSMB should have a minimum of 3 members, at least one of whom is outside of the Institution performing the trial. It is strongly recommended that at least one member of the DSMB have proficiency in biostatistics or clinical trial design. It is also strongly recommended that at least one member of the DSMB be able to communicate in verbal and written English.
- The DSMB should meet at least once every 6 months. Meetings by teleconference are acceptable.
- The DSMB should prepare a written report at least once a year and at the end of the study. These reports should be submitted to SMRI along with the annual report.
- The DSMB should have access to all of the relevant data of the study, including the number and nature of serious adverse events in each treatment arm.
- Feel free to contact SMRI with any questions concerning the DSMB or with suggestions for DSMB members.
The most comprehensive reference can be found at:
Additional references:
- Wittes J et al. Monitoring the randomized trials of the Women’s Health Initiative: the experience of the Data and Safety Monitoring Board. Clin Trials 2007;4:205–206.
- Witts J. Forming your phase III trial’s data and safety monitoring board: a perspective on safety. J Investig Med 2004;52:453–458.
- Lang T et al. Data safety and monitoring boards for African clinical trials. Trans R Soc Trop Med Hyg 2008;102:1189–1194.
- NIMH Collaborative HIV/STD Prevention Trial. Role of data safety and monitoring board in an international trial. AIDS 2007;21(suppl 2): S99–102.
- Czaja SJ et al. Data and safety monitoring in social behavioral intervention trials: the REACH II experience. Clin Trials 2006;3:107–118.
- Hedenmalm K et al. The conscientious judgement of a DSMB—statistical stopping rules re-examined. Eur J Clin Pharmacol 2008;64:69–72.
updated July 2010