Author Archive

Clinical and Regulatory Aspects of Trials with Negative Symptoms of Schizophrenia Discussed at ISCTM Meeting

Monday, November 9th, 2009

October 14, 2009 09:47 AM Central Time

SAN DIEGO–(BUSINESS WIRE)–A half-day workshop on issues in the design of clinical trials to evaluate treatments for negative symptoms of schizophrenia, chaired by Stephen Marder, MD, UCLA Department of Psychiatry and David Daniel, M.D., United BioSource Corporation was held 5 October 2009, as part of the International Society for CNS Clinical Trials and Methodology (ISCTM) Autumn Conference in San Diego, CA.

Negative symptoms, characterized by reduced motivation, reduced emotional experience, social withdrawal and slowing of psychomotor functions, remain a key unmet treatment need for persons with schizophrenia. Questions addressed at this workshop centered on the optimal designs of clinical studies that might be developed to achieve regulatory approval for monotherapy and adjunctive therapy indications for the treatment of negative symptoms. Discussion centered on whether a functional co-primary is necessary to gain approval from regulatory authorities and how to differentiate negative symptoms from other conditions with similar phenotypes like depression, extrapyramidal symptoms, paranoia, cognitive dysfunction, side effects of medication, etc. A representative from the FDA, Dr. Robert Levin, indicated that a co-primary functional endpoint would not be necessary to gain approval for this indication in the US. Nevertheless, measures of potentially confounding symptoms would have to be included in such trials to demonstrate that the effect identified in these trials is specific to the treatment of negative symptoms. Additional discussion focused on the need for negative symptoms to be stable and persistent in clinical trials aimed at demonstrating efficacy of a therapeutic agent. Dr. Marder concluded “Representatives from academia, industry, and government agreed that negative symptoms represent an attractive target for drug development.”

The ISCTM (www.isctm.org) was founded in 2004 to gather representatives from academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges; to examine the development of novel treatments for major psychiatric and neuropsychiatric disorders; and to support advances in methods of evaluating such treatments that are scientifically sound, ethical, and feasible. To achieve this mission, ISCTM conducts two scientific meetings per year. The 6th Annual Scientific Meeting, (including a National Mental Health Research-to-Policy Forum) will be held 22-24 February 2010, at The Fairmont, Washington D.C.

Contacts

ISCTM
Carlotta McKee, 615-383-7688
Executive Director
isctm@isctm.org

Advancing Adaptive Design and Personalized Medicine in CNS Trials: Clinical, Regulatory and Statistical Viewpoints

Monday, November 9th, 2009

July 23, 2009 10:07 AM Central Time

SAN DIEGO–(BUSINESS WIRE)–Ever-increasing costs of developing medicines over the past decade necessitate drug development methods that allow for faster, more efficient decision making based on informed utilization of emerging, cumulative data to mitigate this worrisome trend. One approach to this challenge is the application of adaptive trial designs to the drug development process. Pharmaceutical companies, and regulatory agencies around the world, are increasingly interested in the appropriate utilization of adaptive design methods. Though these methods are being used more extensively in certain therapeutic areas, such as oncology and cardiovascular diseases, the application in disorders of the central nervous system is less apparent.

Realizing the need to examine and discuss the application of adaptive design for more efficient conduct of CNS trials, the International Society for CNS Clinical Trials and Methodology (ISCTM) will gather key stakeholders from Academia, Industry and Regulatory agencies, 5-6 October 2009, in San Diego. Co-Chairs Donald Berry, Ph.D., Andrew C. Leon, Ph.D., with a team of experts (Conference Presenter Profiles) will present sessions ranging from an introduction to concepts of adaptation to how trials with pre-specified design modification might expedite the regulatory approval process for specific indications. Target areas for adaptation to be considered include modification of inclusion/exclusion criteria, sample size, number of treatment cells, and treatment duration. There will be a focus on methods to control the rate of false positive results and other safeguards, such as blinding of investigators and comparison of results pre and post modifications. Updates on guidance from regulators in the US, Europe and Japan will also be presented. Interactive CNS case study practical application sessions will highlight logistics and pragmatics of the application of adaptive design. (Detailed Agenda)

“This important conference, sponsored by the ISCTM, brings together some of the foremost experts on adaptive design methodologies, and, along with clinicians and scientists from academia, industry and government, will help to advance the application of these innovative strategies to CNS drug development.” -Andrew C. Leon, PhD, Professor of Biostatistics in Psychiatry and Professor of Public Health/Weill Cornell Medical College.

Second day of conference will address the opportunities and challenges of advancing personalized medicine for disorders of the central nervous system. The sequencing of the human genome has informed more tailored approaches to certain diseases. However, there are significant hurdles which must be overcome to realize its full potential. This session will show how clinical trials can be adapted to help realize the value of personalized medicine for CNS conditions. Selection of viable indications, study questions, study populations, endpoints and optimal designs will be covered. Approaches to statistical and regulatory challenges will be addressed by international experts in the field. Examples of work that is already being developed according to this new paradigm will be presented.

In addition the October meeting of ISCTM will host workshops on specific methodological challenges in the areas of negative symptoms of schizophrenia, suicidal thinking and behavior, placebo response and conducting large clinical trials with specific participatory workshops led by leading trialists in each of these areas.

Detailed Agenda

The International Society for CNS Clinical Trials and Methodology (ISCTM) is a multi-disciplinary, independent organization devoted to addressing strategic clinical, regulatory, and methodological challenges that arise in the development and clinical use of CNS therapeutic agents through partnership with industry, academia, governmental and non-governmental agencies and the public.

Contacts

ISCTM
Carlotta McKee, 615-383-7688
Executive Director
isctm.org

Advances in Conceptualizing Disease Progression in Alzheimer’s Disease

Monday, November 9th, 2009

August 21, 2008 03:11 PM Central Time

TORONTO–(BUSINESS WIRE)–A hallmark of this year’s ICAD meeting was the wealth of new clinical trials information in Alzheimers Disease (AD). Years of basic and preclinical research have paved the road for development of new medications and biologics. Results from many new clinical trials were provided, ranging from promising Phase I and II trials to some disappointing Phase II and III results.

Hundreds of new agents for the treatment of dementias are now in or approaching clinical trials. It is essential that new CNS-drug development generally, and clinical trials specifically, keep pace with the explosive growth in translational opportunities in AD and other CNS disorders. Emergence of novel treatments aimed at disease-progression requires improvements in methodology, particularly in definitions of clinical outcomes, so that health-authorities, patients, physicians, and payers are satisfied.

George Grossberg states: At the recently concluded ICAD in Chicago, we witnessed negative results from several large Phase 3 trials of compounds which were touted as potentially having disease-modifying effects for treating AD. Could problems such as those exemplified by these studies have been avoided with better clinical trial designs? The ISCTM meeting Advances in the Conceptualization of Disease Progression in Alzheimers DiseaseAn Interdisciplinary Conference, will prove an immensely valuable follow up to ICAD for scientists, clinical trialists, pharmaceutical industry and regulatory authorities worldwide who are trying to make our research endeavors more efficient and effective. Ravi Anand and George Grossberg will co-chair the fall ISCTM meeting to pursue this important discussion.

The International Society for CNS Clinical Trials and Methodology (ISCTM) will gather world-reknowned experts to discuss challenges identified at ICAD and by others, on October 67, 2008, in Toronto. Topics to be addressed include: “Disease Progression in AD,” “Optimal Trial-Designs For Disease Modification In AD,” “Clinical and Biological Endpoints in Disease Progression/Modification,” and “Statistical Issues In Disease-Modifying Therapies In AD Trials.” (Detailed Agenda and Presenters)

The International Society for CNS Clinical Trials and Methodology (ISCTM) is a multi-disciplinary, independent organization devoted to addressing strategic clinical, regulatory, and methodological challenges that arise in the development and clinical use of CNS therapeutic agents through partnership with industry, academia, governmental and non-governmental agencies and the public.

Contacts

ISCTM
Carlotta D. McKee, 615-383-7688
Executive Director
https://isctm.org

Clarification on Regulatory Decisions on Antipsychotic Trials Brought During ISCTM Annual Meeting

Monday, November 9th, 2009

March 11, 2009 06:05 AM Central Time

WASHINGTON–(BUSINESS WIRE)–A half-day symposium on emerging regulatory practice around approvals for antipsychotic compounds was held March 4, 2009, at the Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Arlington, VA. The meeting was chaired by Ravi Anand, M.D., Anand Consulting, and Larry Alphs, M.D., Ph.D., Ortho-McNeill Janssen. Speakers included Jeffrey Lieberman, M.D., Columbia University, Amir Kalali, M.D. Quintiles, Andrew C. Leon, Ph.D. Cornell University, Thomas Laughren, M.D., FDA, Karl Broich, M.D., BfArM.

Recent public comments around regulatory submissions for antipsychotic compounds have raised questions regarding development of CNS drugs and the role of active comparators in trials submitted for regulatory approval. During this session the background and implications of including or repurposing active controls in clinical trials was presented. Dr. Laughren indicated that current FDA policy on the role of relative efficacy in risk benefit decisions for psychiatric drugs is that active controls are not required in registration trials, but are recommended because active controls provide a context in which to test assay sensitivity. Further, negative trials (but not necessarily “failed trials”) count against a drug during review by US Regulators. He indicated that the choice of the active control is left to the sponsor and that claims for superior efficacy can be considered, but would have to be based on hypothesis testing in a superiority design. Laughren further indicated that observed inferior efficacy, whether or not resulting from hypothesis testing, may be noted in labeling if it is considered sufficiently robust and clinically relevant. He acknowledged that drug-drug comparisons are usually unplanned and post-hoc, and indicated that inferiority observed in active controlled trials not specifically designed to test this hypothesis would not likely be the sole basis for failure to approve a new antipsychotic agent.

Dr. Broich indicated that to gain approval of a new antipsychotic product by EMEA, clinical development of new drugs must provide adequate assessment of benefit-risk for the treatment of schizophrenia. To do this efficacy and safety must be established using randomized, controlled, double-blind clinical trials with the novel compounds. These trials must include at least two positive short-term studies (6-8 weeks) with both placebo and active controls (for assay sensitivity, distinction of negative and failed studies); and demonstrate statistical significance and clinical relevance (responder rates, e.g. 30 % improvement on PANSS). Demonstration of short-term improvement must be supported by one positive maintenance of effect study (usually 6 months duration with randomized withdrawal as the preferred study design). He indicated that effectiveness studies like CATIE, CUtLASS, EuroSC or SOHO may provide complimentary information for clinical treatment guidance. However, internal validity of these studies and interpretation of the results might be difficult due to many potentially confounding factors. Therefore, such studies are not required for approval by EMEA. Broich further indicated that improvements of negative symptoms or cognitive symptoms are considered as possible treatment claims by EMEA. However, for such studies clinical relevance of improvement must be confirmed by improvement in functional outcome measures studied as co-primary endpoints.

ISCTM was founded in 2004 to gather representatives of academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges, to examine the design and development of novel treatments for major psychiatric and neuropsychiatric disorders, and to support development of methods of evaluating them that are scientifically sound, ethical, and feasible.

Contacts

ISCTM
Carlotta D. McKee, 615-383-7688
Executive Director
https://isctm.org

ISCTM Meeting Discusses Clinical and Regulatory Aspects of Using Adaptive Designs in Clinical Trials for Central Nervous System Drug Approvals (Press Release)

Thursday, October 15th, 2009

October 15, 2009 10:07 AM Central Time

SAN DIEGO–(BUSINESS WIRE)–A one day session on the use of adaptive designs for more efficient conduct of clinical trials for CNS indications chaired by Andrew C. Leon, PhD, Cornell University, and Donald Berry, PhD, M. D. Anderson, Department of Biostatistics, was held 5 October 2009, at the International Society for CNS Clinical Trials and Methodology (ISCTM) Autumn Meeting in San Diego, CA.

This session included an introduction to concepts of adaptation and how trials with pre-specified design modification might expedite the regulatory approval process for specific indications by V Dragalin, PhD, Wyeth Research Department of Biostatistics. Target areas for adaptation that were considered include modification of inclusion/exclusion criteria, dosing, sample size, number of cells, and treatment duration. HM Hung and SJ Wang, both from the US FDA and A Koch, from Germany’s BfArM, provided regulatory insights into the use of adaptive designs by reviewing the FDA’s Draft Guidance for Adaptive Designs and the Reflection Paper on adaptive designs recently developed by the European Medicines Agency (EMEA). Y Ando from Japan’s PMDA discussed issues from applications that have been reviewed by the PMDA. The session concluded with CNS case studies that highlighted logistic and pragmatic challenges to the application of adaptive design. Dr. Leon stated, “This session provides sponsors an overview of the costs and benefits of adaptive designs so that they can be more effectively incorporated into the designs of clinical trials for CNS indications.”

The ISCTM (www.isctm.org) was founded in 2004 to gather representatives of academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges; to examine the development of novel treatments for major psychiatric and neuropsychiatric disorders; and to support advances in methods of evaluating such treatments that are scientifically sound, ethical, and feasible. To achieve this mission, ISCTM conducts two scientific meetings per year. The 6th Annual Scientific Meeting, (including the National Mental Health Research-to-Policy Forum) will be held 22-24 February 2010, at The Fairmont, Washington D.C.

Contacts

ISCTM
Carlotta McKee, 615-383-7688
Executive Director
isctm@isctm.org

2009 5th Annual Scientific Meeting – Development of Treatments for Bipolar Depression – Session Summary

Monday, August 31st, 2009

Treatment of Bipolar Depression

A Plenary Symposium of the International Society for CNS Drug Trials Methodology (ISCTM),
Arlington, VA, 3 March 2009

Chairmen: Ross J. Baldessarini, M.D., Harvard Medical School, Boston; Eduard Vieta, M.D., Ph.D., University of Barcelona, Spain
Speakers: Drs. Baldessarini and Vieta, plus Joseph Calabrese, M.D., Chase-Western Reserve University, Cleveland; Mauricio Tohen, M.D., Dr.P.H., M.B.A., University of Texas Health Science Center at San Antonio
Primary Discussant: Charles Bowden, M.D., University of Texas Health Science Center at San Antonio

Summary

The premise of this symposium was that depression in bipolar disorder (BPD) patients is different from unipolar forms of major depressive disorder in many ways, notably including treatment responses [1]. Indeed, BP-depression remains a leading clinical and public-health challenge for psychiatry [2]. The disorder is often misdiagnosed as unipolar depression, particularly early and if only the patient is interviewed, without corroborating information from family or friends. Many BPD patients do not recognize increased mood, energy, libido, and activity as pathological, whereas most urgently seek relief from BP-depression. Average international latency to an appropriate diagnosis and the start of maintenance treatment with a mood-stabilizer is 5–10 years from illness-onset, and longer among women with type II bipolar disorder (BPD) than men with type I BPD [3]. Recurrent BP-depression commonly follows initial episodes of depression or mixed states of dysphoric agitation [4]. Even with acute episodes considered to represent pure depression, more than two-thirds of BP-depressive patients have at least subtle manic features [5]. Such mixed-states predict poor responses to standard treatments, risk of manic-switching, and perhaps rapid-cycling or recurring mood-shifts [5,6]. BP-depression and its subsyndromal or dysthymic forms remain the leading unresolved form of long-term morbidity among both types I and II BPD patients, both in mid-course of the illness and even from onset, including during treatment with commonly clinically employed mood-stabilizing or mood-elevating agents [7,8]. In BPD patients, depression and dysthymia account for approximately three-quarters of the typical 40%–45% of weeks/year in morbid states. Such unresolved depression is associated with long-term dysfunction and disability, substance abuse (particularly alcohol), and mortality due to a very high risk of suicide, accidents or other violence in youth, and moderately increased risk of dying from inter-current medical illnesses in later life [9–12]. 

Perhaps not surprisingly, antidepressants continue to be, by far, the leading drugs given to BPD patients in the US, both initially and long-term, in part owing to patient-demands and clinician optimism [13]. International practices vary greatly in use of antidepressants for BPD patients [14–16]. Ironically, there is no explicit regulatory approval for these practices, unless, implausibly, one construes all forms of major depression to be similar and responsive to similar treatments. Antidepressants perform unevenly in acute BP-depression, often fail initially or within several months, and their long-term prophylactic benefits appear to be both limited and very little-studied [17–18]. In addition, virtually all mood-elevating drugs carry dose-dependent risks of “switching” into excited, agitated, hypomanic, manic, mixed (much more broadly defined than by narrow DSM-IV criteria), or psychotic states [16,20]. This risk may be less than in the era before modern antidepressants, and appears to vary with specific drugs and doses, with highest risks associated with less-often used tricyclic-type antidepressants (TCAs), in adults diagnosed with BPD. Some modern antidepressants that potentiate both serotonin and norepinephrine, notably including venlafaxine, especially at high doses, also appear to have relatively high risks of inducing mood switching [21]. The value of co-treatment with a proved or putative mood-stabilizing agent and an antidepressant, as a means of potentiating benefits and diminishing risk of emotional destabilization also remains unclear [22]. 

Risk of switching or destabilizing mood may be lower with modern, selective serotonin reuptake-inhibitor antidepressants (SRIs) and bupropion. Whether mood-elevating agents can induce mania or excitement in otherwise non-bipolar, depressed patients as an adverse pharmacological effect also remains uncertain. Nevertheless, the presence of established BPD encourages extra caution with any mood-elevating agent, particularly in juveniles with apparent “depression ” [23]. Risk of switching into mania from depression may be greater in depressed juveniles than in adults, if only because BPD was not recognized early in depressed adolescents or children (Martin et al. 2004). This high risk seems paradoxical since antidepressants of all types have shown inferior efficacy in juvenile versus adult unipolar depression (Tsapakis et al. 2008). Curiously, risk of mood-switching with an SRI may exceed that with a TCA in juvenile depressed patients below age 14 years, suggesting important, but undefined, developmental changes [24]. Developmental changes may also be reflected in the generally poor antisuicidal effects of antidepressants in the young, with evidence that they may increase risk of self-damaging behaviors as well as suicidal thoughts in persons below age 25, but lower risk in older adults over age 60 [25,26]. 

Given the growing list of partially effective treatments for BP-depression, and its common resistance to full recovery, it is not surprising that most such patients end up with complex combinations of treatments. Such polytherapies are relatively expensive, and can exert complex risks of drug interactions and adverse effects. Indeed a worse history of BP-depression has been associated with complex treatment regimens among BPD patients, but the cause-effect relationships involved are not clear [27]. 

For depressive phases of BPDs, owing to poor short-term benefits of antidepressants, their limited long-term prophylactic value, nontrivial mood-destabilizing risk, and uncertain or variable antisuicidal efficacy, there is growing interest in considering alternative treatments [28]. Some experts recommend lithium or anticonvulsants including divalproex, carbamazepine (and its unapproved analog oxcarbazepine), or lamotrigine for both short- and long-term treatment of recurrent BP-depression, and perhaps other forms of recurrent major depression [29–37]. In addition, antimanic-antipsychotic agents, including aripiprazole, olanzapine, or quetiapine, are used increasingly to treat BP-depression, often in relatively low doses as adjuncts to other agents [38–47]. Older neuroleptics are suspected of inducing or worsening BP-depression, although evidence for this possibility remains limited and largely anecdotal [48,49]. 

Randomized, controlled trials (RCT) designed to test mood-stabilizers and antimanic-antipsychotics in the treatment of acute or recurrent BP-depression challenge trial-designs. BP-depression is a far more complex and rapidly-changing disorder than ordinary unipolar depression, and much more prone to recurrences, including when a presumably protective treatment is withdrawn rapidly, with or without obvious preceding clinical benefit [50,51]. In addition, high levels of substance-use or anxiety disorders, disability, and very high risk of suicide or accidents and later mortality from medical conditions among BPD patients add to their complexity, and should be considered in the design and conduct of trials. These characteristics call for innovative trial designs that not only score the degree and timing of improvement or recovery from an acute BP-depressive episode, but also consider risks of spontaneous or drug-associated switching into excited, mixed, manic, or psychotic states, as well as long-term protection against recurrences of all forms of BPD, including new episodes of depression, self-injurious behaviors, and consideration of complex patients who are commonly encountered clinically. 

Initiatives aimed at improving the validity of clinical trials for the treatment of BP-depression, in addition to this symposium, are emerging [52]. A recent ECNP report emphasizes challenges related to diagnostic, methodological, ethical, and regulatory issues of treatment trials for BP-depression. That report emphasizes the requirement of a longitudinal perspective and verification of prior episodes, including mania-related phases, and particularly of sometimes overlooked or misdiagnosed hypomanic or mixed states, as well as depression dysphoria. The statement also encourages trials that not only are randomized and double-blind, but also include both placebo and an active-comparator drug as controls (so-called “three-arm” trials). They also need adequate power and sensitivity to yield clear outcomes, with reasonable efforts to yield estimates of benefit/risk relationships. However, a major challenge is the choice of active comparator, since few drugs have adequate evidence of short-term efficacy or specific regulatory approval for treatment of BP-depression, even fewer for long-term prophylaxis, and almost none for type II BPD, which mainly involves recurrent depression as the primary clinical problem. Trials with placebo and active controls are well-suited for testing the efficacy of many new treatments, and specifically can limit exposure of larger numbers of BPD patients to experimental therapies in “non-inferiority” trials (new versus established treatment) that lack a placebo control. The ethics of including placebo-controls can be improved with adequate information in subject-consent procedures, as well as considering the severity and impact of BPD in particular candidate patient-subjects [53]. In addition, fixed-dose designs have been more successful in some trials than with flexible dosing (e.g. with olanzapine+fluoxetine and quetiapine, in contrast to aripiprazole). Finally, no pharmaceutical company has sought an indication for BP-depression (in either type I or II) for any drug classified as an “antidepressant,” despite widespread empirical use of these agents to treat or protect patients with BP-depression with little evidence of short- or long-term efficacy or safety [54,55]. Although, it is widely assumed that indications for “major depression” (MDD) support use of antidepressants in all types of depressive episodes, this assumption requires explicit and adequate testing for efficacy and safety in BPD-depression [56]. These and other complexities to be considered in the design of trials primarily directed at the depressive phase of BPD are summarized below (Table). 

Speakers at this ISCTM symposium considered various aspects of trials design that are not unique to BD-depression. Some standard international diagnostic schemes, such as DSM-IV, are not sensitive in distinguishing subgroups of BPD patients, other than the I/II dichotomy, very narrowly defined “rapid cycling,” and a narrow view of juvenile BPD that may be overly modeled on typical adult criteria [57]. In addition, standard rating scales may not be ideally suited for studies of BP-depressed patients, especially those with simultaneous minor mania-like features, and so-called “atypical” (for UP depression) symptoms, such as anergy, hypersomnia, or hyperphagia, which are common in BP-depression. However, among standard rating schemes for depression, the Montgomery-Åsberg scale (MADRS) may be less likely to show placebo responses than the older Hamilton scale (HDRS; [58]. The need for more sensitive measurement methods, especially those that detect subtle mixed states, hypomania, and changes in these and other symptoms are being developed [59]. 

Among other aspects of trial design, factors that limit responses in placebo-arms of trials can be important. These include selection of relatively severely ill but clinically homogeneous patient-subjects, initially hospitalized patients, enlisting the cooperation of subjects, close follow-up and assessments with sensitive rating scales, and limited use of adjunctive or “rescue” medicines, such as sedatives, and attention to apparently “nonspecific” but potentially influential effects, such as milieu influences, the impact of frequent supportive personal interactions, and the like. Generally, circumstances that favor larger contrasts from intake to end-point include relatively severe illness at baseline, relatively homogenous samples of patient-subjects without extensive anxiety or substance-use disorder co-morbidities, simplified regimens (even though use of more than one drug may seem necessary and is common in clinical practice), including fixed-doses of active trial agents, and inclusion of an active control drug as well as a placebo to assure adequate sensitivity of trial conditions to change and treatment effects. Longer trials are likely to limit placebo effects, but risk encountering relapses if continued beyond 2–3 months [43]. Nevertheless, relatively long trials are likely to be required to allow clinically relevant endpoints such as remission, rather than mere separation of drug from placebo on a symptom rating scale. Long-term trials currently often involve initial “enrichment” (short-term response in acute depression) as a precondition for continuing into a long-term phase, often, seemingly, to emphasize the virtues of a novel test agent, particularly versus placebo, but often at the expense of a standard comparator, especially if subjects initially have not been proved to tolerate and respond to it. Such trials may include treatment-discontinuation at some point when it is considered safe to do so, but with great uncertainty about the impact of drug-discontinuation itself, especially if abrupt or rapid, if patients are barely recovering, and without empirical information about optimal duration of dose-reduction protocols for most agents [50,60]. Such designs can lead to ethical questions if the ongoing treatment of initially severely ill, suicidal, or barely recovered patients is interrupted, and if the agents employed have uncertain effects and an unknown requirement for safe discontinuation rates and times [61]. 

Avoiding heterogeneous and complicated BPD patients may require more subjects to counteract variance, although narrow sampling is likely to constrain generalization to more typical, clinically encountered, BPD patients, who usually are often unstable and changeable over time, and commonly co-morbid with substance use or anxiety disorders. Very long-term trials, designed specifically to test for prophylaxis, and especially against recurrences of major BP-depression or continuation of BPD dysthymia or minor depressions, are conspicuous by their absence from the international experimental therapeutics literature. Most reported studies involve initial enrichment based on short-term responses of a specific type of acute BPD illness, followed by discontinuation of an apparently effective medicine, and relatively brief follow-up that rarely exceeds a few months [62]. Endpoints of such trials typically are time-to-a-recurrence of an illness similar to the index condition, or to clinically required therapeutic intervention. However, in BPD, illness other than major depression often intervenes, adding complexity to determining end-points based only on time-to-recurrence, rather than seeking reductions of episode-counts, sustained decreases in morbidity ratings, or improved functional status, over very long observation times. To some extent, polarities of subsequent illness episodes can be predicted from onset-polarity [4,8,63], the polarity of the most recent episode [64], or the predominant polarity of previous episodes [65]. Some limitations of currently standard trial-designs may be overcome by application of novel designs, or allowing for multiple randomizations to more than one treatment option per trial [66–68].

References

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2009 5th Annual Scientific Meeting – Improving Methodology of RCTs in Post-traumatic Stress Disorder – Session Summary

Monday, August 31st, 2009

Improving Methodology of Randomized Clinical Trials in Post-traumatic Stress Disorder

A Plenary Symposium of the International Society for CNS Drug Trials Methodology (ISCTM),
Arlington, VA, 4 March 2009

Chairmen: Andrew C. Leon, Ph.D., Weill Cornell Medical College, New York; Lori L. Davis, M.D., Veterans Administration Medical Center, Alabama
Speakers: Drs. Leon and Davis, plus Thomas Neylan, M.D., University of California; Timothy O’Leary, Veterans Affairs, Washington, D.C.

Summary

The basis of this session originated in the Institute of Medicine (IOM) review of randomized controlled trials (RCT) for interventions for posttraumatic stress disorder (PTSD) which concluded that 1) the evidence was inadequate regarding the effectiveness of most pharmacologic and psychosocial interventions for PTSD, 2) most studies that were reviewed had methodological limitations, some of which compromised the credibility of the results and 3) well-designed studies are needed to define efficacious treatments for PTSD.

Timothy O’Leary, MD, PhD, the Director of VA Clinical Science Research and Development (VA CSR&D) gave a short introduction entitled “National Priorities for Clinical Trial Research in PTSD.”  The 2008/2009 research funding initiatives include the VA Cooperative Clinical Trial Award (CCTA) Program to support smaller scale clinical trials, resourcing with Coordinating Center expertise, the VA Central DMC to monitor smaller scale clinical trials, the DOD (USAMRMC) 150M budget for PTSD and TBI research, including PTSD/TBI Clinical Trials Coordinating Center, PTSD Research Consortium, intramural and extramural programs, a joint collaboration with the NIMH, VA CSR&D funding opportunity entitled “Clinical Pharmacotherapy for PTSD: Single and Collaborative Studies“ (R34), and additional solicitations planned by the VA in coordination with other federal funding agencies.  The challenges for the field were discussed and include the concern that preclinical investigations in PTSD are not leading to new therapeutic modalities or development of PTSD-specific molecular entities, the use of pharmacologic interventions optimized for other conditions may not be optimal for PTSD, and comorbid conditions need to be addressed more effectively.

Lori Davis, M.D., Professor of Psychiatry at the University of Alabama School of Medicine and Chief of Research Service at the Tuscaloosa VA, presented a comprehensive review of PTSD and the issues related to pharmacological treatments and randomized controlled trials in PTSD.  The lifetime prevalence of PTSD is 7% of the US population (3-5% men, 10% women), 19% of Vietnam veterans, 13% Iraqi war veterans, and  32% of the treatment seeking Iraqi war veterans.  PTSD is chronic and may persist for decades or a lifetime.  PTSD is commonly comorbid with other Axis I (>50%) disorders. Despite its high prevalence and chronicity, there are only two FDA-approved medications: sertraline and paroxetine.

Dr. Davis reviewed the nosology of PTSD, pointing out that in addition to exposure to a life-threatening event involving intense fear, helplessness, or horror (criterion A), the current DSM-IV criteria involved three clusters of symptoms: re-experiencing symptoms (criterion B), avoidance and emotional numbing symptoms (criterion C), and hyperarousal symptoms (criterion D).  The symptoms must be present for at least one month duration (acute < 3 mo; chronic > 3 mo) and cause significant social dysfunction, occupational dysfunction, or significant personal distress. DSM-IV uses a conventional 3-Factor Model, whereas more recent research suggests that consideration of the King 4-Factor Model that separates avoidance symptoms from numbing symptoms.  Symptoms of dissociation, shame and guilt continue to be insufficiently accounted for in the diagnostic criteria.

Dr. Davis discussed the etiologic Bio-Psycho-Social Model of PTSD, that include biological disturbances (monoamines, amino acid neurotransmitters, neurohormones, neuroanatomical pathways), psychological disturbances (in sense of self and integrity, trust vs. suspiciousness, guilt and shame, and difficulties with relationships) and behavioral disturbances (avoidance, checking for safety, and social and occupational difficulties).

The pharmacologic treatment for PTSD has included antidepressants (SSRI, TCA, mirtazapine, nefazodone, venlafaxine, MAOIs), alpha-adrenergic blockers, atypical neuroleptics, anticonvulsants, and benzodiazepines. The Institute of Medicine  Treatment of PTSD: An Assessment of the Evidence concluded that the evidence for all classes of drugs was inadequate to determine efficacy for PTSD.  However, one of the PTSD expert panelists Thomas Mellman, MD did not concur and wrote the dissenting comment that the evidence is suggestive but not sufficient to conclude efficacy of SSRIs in general population with PTSD and the evidence is suggestive that SSRIs are not effective in populations consisting of predominantly male veterans with chronic PTSD.  In addition, Dr. Mellman wrote that the evidence is suggestive but not sufficient to conclude the efficacy of second generation antipsychotic medications as adjunctive treatment for PTSD.  Dr. Davis discussed the methodologic issues raised by the IOM Review of RCTs in PTSD that include challenges to internal validity, standardization of treatment and outcome measures, attrition, multiplicity, credible control group, investigator independence, need to study special veteran populations , applicability to VA and veteran populations, inconsistent definitions of recovery and remission, and lack of studies to define early intervention, length of treatment, and length of follow-up.

Dr. Davis reviewed the limited literature regarding analysis of individual PTSD item response to SSRI and also venlafaxine.  In these pooled analyses, anger is consistently an early response item (week 1) with other items being delayed  and nightmares or dreams typically not responding by week 12. (Sertraline: week 6 psychological distress at cues/triggers, anhedonia, detachment, numbness, hypervigilance; week 10 avoidance of activities, foreshortened future. Venlafaxine: week 2 physiological reactivity, week 4 intrusive recollections, psych distress at exposure to cues, week 6-12 avoidance of thoughts/feelings or conversations, diminished interest, detachment or estrangement, restricted range of affect, sense of foreshortened future, difficulty concentrating, hypervigilance, exaggerated startle response).  These data suggest that there may be some symptoms of PTSD that are more biologically driven (anger and impulsivity) and others that may be behaviorally driven (avoidance) and respond differently to different treatments based on mechanism of action.

Dr. Davis concluded with a list of dilemmas faced when designing an RCT for the treatment of PTSD, which include study population issues such as civilian vs. veterans, gender balance, number of lifetime traumatic events, type of traumatic index event, chronicity of exposure to trauma, subtypes of PTSD, chronicity of PTSD illness, comorbidities, prior treatment resistant or refractory, and genetic polymorphisms or markers. The alternatives for intervention include novel antidepressants,  modulators of norepinephrine, atypical neuroleptics, CRF antagonists, modulators of GABA and glutamate, combination psychopharmacology, combination of medications with psychotherapy.  Design issues include monotherapy  vs. placebo, combination strategies, and augmentation designs.  The targeted outcomes include the full PTS score, PTSD symptom clusters (subdimensions), response and remission, and quality of life and reintegration.   Also consideration of frequency of assessments, length of trial, adherence to protocol and treatment, and retention is important in the planning for RCTs in PTSD.

Dr. Davis concluded with the points that PTSD is common, chronic, and complex. To date, we are limited by the small number of RCTs, small sample sizes, and modest effect sizes. Innovative treatments are needed and sound study designs are essential.

Andrew C. Leon, Ph.D. of Weill Cornell Medical College, New York, NY described “Strategies to Examine Moderators of Treatment for PTSD”.  The talk covered four general areas:  1) Roles of moderators in RCTs 2) A contrast between two designs for RCTs with moderators 3) A consideration of  hypotheses that each design addresses  3) A comparison of the required sample size for each design

A moderator of treatment is a baseline characteristic of subject that is associated (positively or negatively) with response.  (see Kraemer et al., Mediators and Moderators of Treatment Effects in RCTs.  Arch Gen Psych, 2002 )  For example if there is no active-placebo separation for males, but active is superior to placebo for females,   gender would be a moderator of treatment.

Dr. Leon described an ongoing study “Vocational Rehabilitation For PTSD Interventions” (PI: LL Davis) where two interventions are being compared: Individual Placement and Support vs. Standard Vocational Rehabilitation Program.   There are four hypothesized moderators of treatment.  The between intervention effect size is hypothesized to be smaller for subjects with any of the following:   1) inadequate transportation  2) inadequate housing  3) little to no financial reserve/means 4) family care burden

Two approaches to examining moderators in RCTs were discussed:

1) Design RCT to examine moderator by treatment interaction with hypothesis testing
2) Exploratory hypotheses in RCT protocol that examine pre-specified, hypothesized moderators of treatment.

Kraemer and colleagues (2002) urge that exploratory analyses of a moderator focus on magnitude of effect and not on p-values.  The magnitude of effect can be quantified with Cohen’s d, Number needed to treat (NNT), number needed to harm (NNH), AUC (as defined in Kraemer & Kupfer, Biological Psych , 2006). Exploratory results are tentative, they are not for treatment decision making.    If exploratory analyses support moderating effect, 2 subsequent designs might be considered:   1) 2 x 2 factorial RCT   2) Main effect design

The 2 x 2 factorial RCT would randomize subjects to either Active or Control and the randomization would be stratified by the moderator.  For example, in examining a genotype as a moderator,  one might test to see if there is a differential treatment effect for SNP+ & SNP- .  H0: ActiveSNP+- ControlSNP+ = ActiveSNP– ControlSNP-  .  The significance test involves a Treatment by SNP interaction.

The sample size required to detect clinically meaningful differences with an interaction is fourfold that of main effect.  This has been shown for ANOVA (Fleiss, 1986. Design & Analysis of Clinical Experiments) and for both 2 level mixed-effects models (Leon & Heo, CSDA, 2008 and 2 level mixed-effects models (Heo & Leon, J Biopharm Stat, 2009).   Therefore the cost of 1 RCT testing an Interaction will be at lest the cost of 2 or 3 RCTs for main effects.

The Main Effects strategy was then considered.  Initially include exploratory hypotheses in an RCT protocol.  If the results suggest moderator is associated with enhanced response (as identified in Exploratory), and use in design of subsequent RCT.  In contrast, if moderator is associated with decreased response, use to select (or develop) a novel intervention and test in subsequent RCT.   Finally, attempt to replicate RCT results in subsequent trial.  For example, one might examine whether there is treatment effect for SNP- .  H0: ActiveSNP- = ControlSNP-. The significance test involves the main effect of treatment.  The generalizability of such a design is limited to SNP- .  Importantly, because the sample size is 25% that of an 2×2 design testing an interaction, there is an opportunity to replicate.

In a similar fashion, one could test a novel intervention for those expected to have decreased response.   This would be done by limiting recruitment to those with characteristics of decreased response (as identified in exploratory).   Randomize subjects either to a Novel Active or the Control.   For example it would examine the question, “Is there treatment effect for SNP+ ? and test  H0: ActiveSNP+ = ControlSNP+ .   The significance test would involve the  Main effect of Treatment.  Once again the generalizability is limited, in this case  to SNP+.  The Main effect N is 25% that of interaction and this provides an opportunity to replicate.

Dr. Leon summarized by stating that moderators are baseline characteristics of subjects.   Initially exploratory analyses of RCTs can examine moderators.   The exploratory results can guide design of subsequent RCT, particularly the inclusion and exclusion criteria.   Most importantly, the sample size required to detect an effect size for an interaction is fourfold that for main effect of the same magnitude.   Consider recruiting only S’s with target characteristic (e.g., genotype), but this limits generalizability.   Develop and evaluate novel treatments for those with characteristic associated with decreased or adverse response.   A limitation of the approach that was described is that the examples involved the simplest case, in which the cell sizes are equivalent and the dependent variable is continuous.  If the design differs from that the same general principles apply, but the details will vary somewhat.

Alina Suris, Ph.D., ABPP, an Associate Professor of Psychiatry from the University of Texas Southwestern Medical Center, Dallas, TX presentation entitled “Psychotherapy Methodological Issues: Choice of Comparison Group” reviewed the literature on psychotherapy comparison groups. Gold (1954) developed placebo controlled studies in the US to establish that the benefits observed with medications were due to their chemical properties rather than to patients’ expectations, hopes, or other psychological processes. Rosenthal and Frank (1956) suggested that placebo designs be applied to psychotherapy research as well, to rule out factors that are incidental to the active “ingredients” specified by the treatment protocol. Unlike placebo vs. active medication trials, psychotherapy trials cannot use placebo controlled designs in which all factors except the therapy’s active ingredient are held constant—challenge to control all non-specific factors.  She compared Psychotherapy vs. Medication RCTs and pointed out that in psychotherapy trials patient and providers are not blinded to treatment (“solution”= blinded raters), the impact of patient provider interactions on outcome (provider skill/ impacts drop out) is a factor, the provider & patient adherence to the treatment protocol is important, the psychotherapy is a manualized treatment, and the timing of outcome/symptom measures are usually at baseline and endpoint.

Dr. Suris discussed the traditional psychotherapy designs that include: randomized wait list (currently being challenged as a credible control), nonspecific comparison, dismantling, additive, parametric designs, and direct comparisons of two treatments.  She highlighted that the randomized Wait List Control design have been held by proponents to use as a way to assess an untreated comparison group at the same intervals as the treatment group.  Wait list controls for many threats to internal validity (maturation, testing, instrumentation, regression, selection, etc.), but it can be viewed by the participant detrimental.  While it controls for the passage of time, the disadvantages of wait list control include the concern that it does not control for increased attention, expectation of  therapeutic intervention, psychological consequences of legitimized sick role (Klerman, 1986).

Dr. Suris reviewed the common ingredients of psychotherapy and non-specific treatment comparison, which include contact with therapist, attention to a problem, suggestions for change, and the generation of faith, hope, and expectancy for improvement. Treatment effect is impacted by type of design and how well conditions are equated (e.g., more active comparison group and greater control for non-specific factors = smaller effect size).  It is not appropriate to compare effect sizes from a study that used wait list with study that used non-specific design.

Dr. Suris concluded that medication and psychotherapy RCT for PTSD vary on multiple factors (comparison group choice, blinding, manualization, fidelity, interactions of provider & patients,  adherence to protocol, timing of symptom and outcome measurement), psychotherapy RCT have no true placebo control comparison, comparison groups differ depending on questions being addressed, and effect sizes vary depending on comparison group and how well groups equated.

Thomas C. Neylan, M.D. for the University of California San Francisco presented the final segment entitled “Methodological Challenges for Secondary Prevention Trials in PTSD.”  He outlined the challenges related to designing clinical trials aimed for the secondary prevention of PTSD in acutely traumatized victims. The first part of his talk focused on prospective studies that have helped to target those who are at the highest risk for developing PTSD who may be the target group for novel interventions. He subsequently reviewed the current status of secondary prevention trials and challenges with recruitment, enrollment, and retention. Dr. Neylan concluded his presentation on several novel approaches for conducting such trials and the potential for clinician researchers (e.g. anesthesiologists, emergency medicine physicians) outside of the mental health field to help accelerate the development of this field.

According to Dr. Neylan, the goal of secondary prevention is to prevent the development of PTSD and other consequences of traumatic stress exposure.  This may involve a prophylactic intervention in high risk individuals (e.g. “Battlemind” training),  a blanket approach to everyone exposed to a traumatic event (“Re-Set” training-DoD), or an intervention to a targeted subgroup at high risk for PTSD.  There are problems with nontargeted intervention that include a question of when to intervene?, i.e. immediate (0-48 hours) versus acute (0-4 weeks).  Interventions such as debriefing and psychological first aid may be intrusive and not feasible.  We may need to focus on education and reducing stigma for seeking care after symptoms present. Identifying high risk subgroups requires prospective studies of high risk individuals and most longitudinal studies involve subjects recruited post exposure.  These designs have practical and economic advantages but may suffers from selection bias and retrospective biases.  Military populations and first responders (police and firefighters) are good samples to start with despite problems with generalizability.  We know that risk factors for PTSD include severity of trauma (ie, threat, duration, injury, loss), prior traumatization, gender, ethnicity, prior mood and/or anxiety disorders, family history of mood or anxiety disorders, education level, and peritraumatic dissociation, distress, and panic, increased heart rate variability, low cortisol, and reduced hippocampal volume.

Dr. Neylan gave a brief review of Secondary Prevention Trials which include cognitive behavioral therapy for Acute PTSD, propranolol medication, and SSRIs.  Studies involving  self help booklet were not helpful and debriefing is not well supported.  The problems encountered by Secondary Treatment Trials include Recruitment (Must be embedded in emergency room setting, the research is often must subordinate to immediate critical care interventions, and the study may have iatrogenic effects), retention, and generalizability.  Novel Approaches are needed and Dr. Neylan suggests that we take a long view of who will implement successful interventions and the likelihood of taking place in mental health treatment settings dependent on technical complexity of intervention. He concluded that if mental health personnel are involved, ideally it would be in settings with integrated care and studies should likely will involve emergency care staff or settings outside of traditional health care.   Novel Approaches with Treatment Provided by Mental Health for PTSD are currently focusing on telephone psychotherapy (e.g. CBT), web interaction, cyber CBT.  The novel interventions led by non mental health personnel likely to involve pharmacologic agents, psychoeducation, or effective referral strategies, may focus on non-stigmatized primary outcomes (e.g. sleep, pain, speed of physical recovery), and may involve anesthesiologists (e.g. beta blocker studies), Critical Care and Burn Specialists (e.g. steroid use), Trauma Surgeons (hypnotics, anti-adrenergic agents, etc.), and Primary Care providers (antidepressants, or any of the above). Dr. Neylan concluded that access to effective treatment for the secondary prevention of PTSD will vary as a function of the need for technical expertise in mental health (e.g., the less dependent on mental health, the greater likelihood for wider distribution). Specialists outside of mental health may be ideally suited to lead pharmacologic treatment trials for preventing PTSD.

ISCTM 2009 NATIONAL MENTAL HEALTH RESEARCH-TO-POLICY FORUM

Tuesday, June 16th, 2009

Interface of Mental Health Research and Policy in the Era of National Health Reform

Presentations  |   Abstract   |  Speaker Bios  | Program Committee   |   Contact

Both mental health researchers and mental health policy makers are being challenged by the lack of an effective interface between these fields.  Mental health researchers produce analyses that policy makers can’t use effectively.  Policy makers ask questions that have not been fully researched. The ability of mental health research to provide policy makers with data they can use is further challenged by compartmentalization between clinical interventions research and health care services research. The upcoming national health reform debate will accelerate demands for answers to important mental health policy questions.

The National Mental Health Research-to-Policy Forum will attempt to provide a compass for researchers and policy experts interested in the changing mental health science-policy-services landscape. The program will feature leading researchers, policy experts and decision makers who are engaged in advancing the capabilities of research for improving mental health.

2010 National Mental Health Research-to-Policy Forum page

FDA Gives Clarification on Regulatory Decisions on Antipsychotic Trials

Monday, June 8th, 2009

Recent public comments around regulatory submissions for antipsychotic compounds have raised questions regarding development of CNS drugs and the role of active comparators in trials submitted for regulatory approval. A half-day symposium on emerging regulatory practice around approvals for antipsychotic compounds was held March 4, 2009, at the Annual Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Arlington, VA.  The meeting was chaired by Ravi Anand, M.D., Anand Consulting, and Larry Alphs, M.D., Ph.D., Ortho-McNeill Janssen.  Speakers included Jeffrey Lieberman, M.D., Columbia University, Amir Kalali, M.D. Quintiles, Andrew C. Leon, Ph.D. Cornell University, Thomas Laughren, M.D., FDA, Karl Broich, M.D., BfArM.

During this session the background and implications of including or repurposing active controls in clinical trials was presented.  Dr. Laughren indicated that current FDA policy on the role of relative efficacy in risk benefit decisions for psychiatric drugs is that active controls are not required in registration trials, but are recommended because active controls provide a context in which to test assay sensitivity.  Further, negative trials (but not necessarily “failed trials”) count against a drug during review by US Regulators.  He indicated that the choice of the active control is left to the sponsor and that claims for superior efficacy can be considered, but would have to be based on hypothesis testing in a superiority design.  Laughren further indicated that observed inferior efficacy, whether or not resulting from hypothesis testing, may be noted in labeling if it is considered sufficiently robust and clinically relevant.  He acknowledged that drug-drug comparisons are usually unplanned and post-hoc, and indicated that inferiority observed in active controlled trials not specifically designed to test this hypothesis would not likely be the sole basis for failure to approve a new antipsychotic agent.

Dr. Broich indicated that to gain approval of a new antipsychotic product by EMEA, clinical development of new drugs must provide adequate assessment of benefit-risk for the treatment of schizophrenia.  To do this efficacy and safety must be established using randomized, controlled, double-blind clinical trials with the novel compounds.  These trials must include at least two positive short-term studies (6-8 weeks) with both placebo and active controls (for assay sensitivity, distinction of negative and failed studies); and demonstrate statistical significance and clinical relevance (responder rates, e.g. 30 % improvement on PANSS). Demonstration of short-term improvement must be supported by one positive maintenance of effect study (usually 6 months duration with randomized withdrawal as the preferred study design). He indicated that effectiveness studies like CATIE, CUtLASS, EuroSC or SOHO may provide complimentary information for clinical treatment guidance.  However, internal validity of these studies and interpretation of the results might be difficult due to many potentially confounding factors. Therefore, such studies are not required for approval by EMEA.  Broich further indicated that improvements of negative symptoms or cognitive symptoms are considered as possible treatment claims by EMEA.  However, for such studies clinical relevance of improvement must be confirmed by improvement in functional outcome measures studied as co-primary endpoints.

Presentations as well as streaming video of this session and others from the 5th Annual meeting will be available on the website shortly.  Please check back.  Previous meeting presentations and video are available to ISCTM members and may be accessed through the Library tab.

ISCTM was founded in 2004 to gather representatives of academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges, to examine the design and development of novel treatments for major psychiatric and neuropsychiatric disorders, and to support development of methods of evaluating them that are scientifically sound, ethical, and feasible.

Developing Country List

Thursday, June 21st, 2007

This is the list of countries* that currently qualify for ISCTM Developing World membership status:

Afghanistan
Albania
Algeria
Angola
Argentina
Armenia
Azerbaijan
Bangladesh
Belarus
Belize
Benin
Bhutan
Bolivia
Bosnia and Herzegovina
Botswana
Brazil
Burkina Faso
Burundi
Cabo Verde
Cambodia
Cameroon
Central African Republic
Chad
Colombia
Comoros
Congo, Dem. Rep.
Congo, Rep.
Costa Rica
Côte d’Ivoire
Cuba
Djibouti
Dominica
Dominican Republic
Ecuador
El Salvador
Egypt, Arab Rep.
Equatorial Guinea
Eritrea
Eswatini
Ethiopia
Fiji
Gabon
Gambia, The
Georgia
Ghana
Grenada
Guinea
Guinea-Bissau
Haiti
Honduras
India
Indonesia
Iran, Islamic Rep.
Iraq
Jamaica
Jordan
Kazakhstan
Kenya
Kiribati
Korea, Dem. People’s Rep.
Kosovo
Kyrgyz Republic
Lao PDR
Lebanon
Lesotho
Liberia
Libya
Madagascar
Malawi
Malaysia
Maldives
Mali
Marshall Islands
Mauritania
Mauritius
Mexico
Micronesia, Fed. Sts.
Moldova
Mongolia
Montenegro
Morocco
Mozambique
Myanmar
Namibia
Nepal
Nicaragua
Niger
Nigeria
North Macedonia
Pakistan
Papua New Guinea
Paraguay
Peru
Philippines
Rwanda
Samoa
São Tomé and Príncipe
Senegal
Serbia
Sierra Leone
Solomon Islands
Somalia
South Africa
South Sudan
Sri Lanka
St. Lucia
St. Vincent and the Grenadines
Sudan
Suriname
Syrian Arab Republic
Tajikistan
Tanzania
Thailand
Timor-Leste
Tonga
Togo
Tunisia
Türkiye
Turkmenistan
Tuvalu
Uganda
Ukraine
Uzbekistan
Vanuatu
Vietnam
West Bank and Gaza
Yemen, Rep.
Zambia
Zimbabwe
 
* As derived from The World Bank Country and Lending Groups listing.