The Institute of Medicine today awarded the 2010 Rhoda and Bernard Sarnat International Prize in Mental Health to two scientists – Charles P. O’Brien, MD, PhD, the Kenneth Appel Professor of Psychiatry and vice chair of psychiatry at the University of Pennsylvania School of Medicine; and Eric J. Nestler, MD, PhD, the Nash Family Professor of Neuroscience, chair of the department of neuroscience, and director of the Friedman Brain Institute at Mount Sinai School of Medicine – for their complementary achievements in addiction science. The Sarnat Prize, consisting of a medal and $20,000, recognizes the researchers’ leading roles in elucidating the biological mechanics of addiction, improving the quality of care offered by treatment programs, and ultimately reducing the stigma associated with the condition. The prize was presented to O’Brien and Nestler at IOM’s annual meeting in Washington, D.C.
Mark Geyer is Professor and Vice-Chair for Scientific Affairs in the Department of Psychiatry at the University of California San Diego. A pioneer in the translational study of sensorimotor gating deficits in schizophrenia and related animal models, Dr. Geyer is the Director of the Neuropsychopharmacology Unit of the VISN 22 VA’s Mental Illness Research, Clinical, and Education Center and Associate Chief of the Psychophysiology Unit of the VA Center of Excellence for Stress and Mental Health. He has been involved intensively in the NIMH-funded MATRICS, TURNS, and CNTRICS Programs.
The award is presented to a woman physician who has made exceptional contributions to medical science, especially in women’s health, through her basic clinical research, her publications, and leadership in her field.
Divisions of Pharmacotherapy and Psychopharmacology of the American Psychological Association sponsored a panel at their August 2011 annual meeting in Washington, DC to honor the pioneering work of Martin M. Katz in advancing understanding of the central role of behavior in its interaction with biology in the depressive state, thus, contributing importantly, to the integration of pharmacotherapy and psychotherapy in the treatment of the depressive disorders
ACNP Statement on Mental Health Parity
The American College of Neuropsychopharmacology (ACNP) supports access to comprehensive treatment for individuals suffering from mental illnesses parallel to the treatment of other medical illness. Without adequate treatment, debilitating and chronic functional impairment often results, along with a substantial increase in general healthcare costs. It is in the best interests of our society that that all affected individuals have sufficient health insurance coverage to allow access to adequate treatment.
Research Implications of FDA Tobacco Regulation Authority
Dear colleagues:
Now that the FDA regulation of tobacco is law – with remarkable bi-partisan support by the way, the real challenge to researchers, funders and tobacco control supporters begins. The regulatory framework contemplated will give the agency tools appropriate to regulate tobacco (a category of product with no medical use) in a manner that gives the agency broad authority over how the product is marketed and sold, claims made about the product and the content of the product, but does not give FDA the authority to impose an outright ban all cigarettes or all smokeless products. The approach could contribute to a reduction in prevalence of tobacco use by actions that are expected to contribute to prevention and cessation interventions, and possibly reduce the harmful consequences (including addiction risk) of products that remain on the market. To accomplish these goals there is a need for scientists to be heavily involved and to further develop a science base to guide regulatory approaches and evaluate the actual effects of the regulation (desired and unintended).
The bill gives the FDA authority in 6 broad categories: 1) Requires extensive disclosures by the tobacco industry to the FDA, including substantial scientific information (Section 904); 2) Includes specific restrictions on tobacco marketing, and gives FDA authority to further restrict tobacco marketing “to protect the public health” to the extent permitted by the First Amendment (Section 906 and 102); 3) Strengthens restrictions on sales to youth (Section 102); 4) Has new tools to provide more accurate, more relevant information to consumers – improved warning labels (Sections 201 – 204); replaces the current tar and nicotine testing system (Sections 915 and 206); and imposes scientific standards and a review process to govern any explicit or implicit health claims (Section 911); 5) Gives FDA authority over the content of tobacco products, including smokes constituents (Section 907); and 6) Lays out the continued authority of the states to pursue tobacco prevention and cessation (Section 916).
The regulatory tools FDA will have will lead to the creation of evidence-based policy. Support for the creation of that evidence base could comes from direct funding of needed research and testing capacity, as well as support via existing NIH and CDC mechanisms. The legislation also requires FDA to consult with other governmental agencies, professional scientific organizations (such as ours) and experts (such as many of you). This provides an opportunity for us to continue to contribute to tobacco control. Indeed, it provides an opportunity for an expanded role for the scientific community because it both provides the scientific community with access to additional information and requires that the most important decisions to be made by FDA be based on science.
One model of potential research and testing capacity that is supported by the World Health Organization may be of interest in your own thinking about the range of needs and strategies that may be worth consideration for FDA (see WHO TobReg “Guiding Principles for the Development of Tobacco Product Research and Testing Capacity and Proposed Protocols for the Initiation of Tobacco Product Testing” at http://www.who.int/tobacco/global_interaction/tobreg/goa_2003_principles/en/index.html).
I encourage you to take a look at the bill itself H.R. 1256, FAMILY SMOKING PREVENTION AND TOBACCO CONTROL ACT, at www.tobaccofreekids.org), and to see some of the summaries of its major provisions (www.tobaccofreekids.org). The bill requires FDA to create a new center with funding guaranteed through the assessment of annual user fees on the tobacco industry.
Some of FDA’s actions are mandated in the bill and will occur within specified time points. These include items such as banning candy-flavored and branded cigarettes (3 months), banning the marketing and branding of cigarettes as “light”, “mild” and “low tar” (12 months), new stronger warnings smokeless products covering 30% of the front and back package panels (12 months), graphic warnings on cigarettes covering 50% of the top front and top back of packs as have proven so effective in Canada and Australia (not more than 39 months), a ban on explicit and implicit health claims that have not been reviewed by the FDA (immediate) and development regulations or guidance on the scientific evidence required for assessment and ongoing review of all health related claims for tobacco products. Marketing restrictions will include limiting advertising and promotion to a black and white text-only format in stores that children can enter. (12 months)
However, most of FDA’s regulatory decision making will be based on the evolving science base and driven by public health considerations built into the legislation. These include the evaluation of product designs and ingredients, including the by products of combustion and naturally occurring components of tobacco products, that FDA determines should be regulated to “protect the public health”, a broad standard that includes control over anything that can, for example, affect harm and addictiveness. Section 907 gives FDA the the authority to set standards for compounds that can be prohibited or restricted or, if the science warrants increased. For example, nicotine could be reduced to negligible and non addicting levels, though not to zero. In addition, menthol levels could be reduced or eliminated. Ingredients such as ammonia compounds, burn accelerating chemicals and various flavorings could be limited or banned altogether (H.R. 1256, Section 907).
Claims for products with a potential to reduce harm whether as a modification to a conventional product or when used in place of conventional products are given a pathway to market but will be evaluated by FDA using a rigorous set of science-based standards(H.R. 1256, Section 911).
Both FDA’s authority of the content of tobacco products and claims for products instructs FDA to look at both the impact on tobacco users and on the population as a whole, taking into account the predicted impact on potential tobacco users, potential quitters and former tobacco users. This means FDA will be looking at the overall impact of a tobacco industry action or a new FDA mandate, not just a narrow look at whether a product is itself less harmful than a conventional product.
FDA is required to consider innovative treatments for tobacco dependence. The legislation encourages FDA to explore potential applications of current medications such as relief of withdrawal, relapse prevention, exposure reduction, and regulatory tools such as Fast Track approval processes as appropriate (H.R. 1256, Section 918).
Much of this will require greatly expanded and rapidly implemented research to provide direction and assess desired and unintended consequences. Research in a broad range of areas will be needed to guide many aspects of implementation of the regulation (e.g., behavioral testing on the effects of potential alterations in tobacco product design and contents including abuse liability testing), surveillance research to determine the effects of regulation implementation and the need for potential modification of the regulatory approach, and exploration of potential “innovative” medications development and applications.
You can learn more about the various aspects of implementation of the bill, at the following website(s). You might also contact NIDA and NCI for information concerning potentially applicable existing RFP’s and to recommend and assist in the development of new RFPs relevant to FDA regulation of tobacco products. There will likely be many opportunities and avenues to influence FDA’s regulatory approach and actions through advisory meetings, Institute of Medicine Reports, Rule Making and federal dockets for commenting, and more.
For researchers, this legislation marks the beginning of the real work and a call to action to develop and implement research to assist the FDA in achieving former Surgeon General C. Everett Koop’s vision of a 21st century which ends with tobacco associated disease the rarity that it was in the 19th century (Nicotine and Tobacco Research, 5:611-6-20, 2003).
____________________________________
Jack E. Henningfield, Ph.D.
Vice President, Research and Health Policy Pinney Associates
3 Bethesda Metro Center, Suite 1400
Bethesda, MD 20814-3472
Voice: 301-718-8440
Fax: 301-718-0034
Email: jhenning@pinneyassociates.com
Web site: www.pinneyassociates.com
and
Professor and Director
Innovators Awards Program
Dept. of Psychiatry and Behavioral Sciences
600 North Wolfe Street, Meyer 3-142
The Johns Hopkins University
School of Medicine
Baltimore, Maryland 21287 www.InnovatorsAwards.org
Gene alteration affects cannabis-induced psychosis in adolescent mice
PRESS RELEASE FROM
NEUROPSYCHOPHARMACOLOGY
This press release is copyrighted to the journal Neuropsychopharmacology. Its use is granted only for journalists and news media receiving it directly from the Nature Publishing Group.
PLEASE CITE NEUROPSYCHOPHARMACOLOGY AND THE NEUROPSYCHOPHARMACOLOGY WEBSITE AS THE SOURCE OF THE FOLLOWING ITEM. IF PUBLISHING ONLINE, PLEASE CARRY A HYPERLINK TO http://www.nature.com/npp
Gene alteration affects cannabis-induced psychosis in adolescent mice
While there is a well-recognized association between cannabis use and psychotic illness, the mechanism that confers individual risk is not yet fully understood. Adolescent male mice are particularly susceptible to the psychosis-like effects of cannabis, reports a study published online this week in Neuropsychopharmacology, indicating that age at exposure and genotype are important factors. The underlying mechanism appears to involve variation in the gene for catechol-O-methyltransferase (COMT), which breaks down dopamine in the brain.
Colm O’Tuathaigh and colleagues subjected mice lacking the COMT gene to chronic THC exposure – a component of cannabis already thought to be involved in psychosis – during
either adolescence or adulthood. Their adult behavioral phenotypes were then measured and assessed for psychosis-like symptoms. Adolescent THC exposure in mice lacking the COMT gene modified exploratory activity and spatial working memory, together with anxiety-related behaviors, particularly in male mice. Each of these behaviors is associated with brain areas known to play a role in psychosis.
These findings indicate a genetic factor that, together with developmental factors, contributes to the vulnerability of adolescent cannabis users to psychosis. The authors caution, however, that further studies are needed to clarify the overall risk for psychosis in human consumers of cannabis.
Author contacts:
Colm O’Tuathaigh (Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland) Tel: +35 31 402 2377; E-mail: cotuathaigh@rcsi.ie
ACNP Statement to IOM Committee on the Assessment of US Drug Safety System
The American College of Neuropsychopharmacology (ACNP) is devoted to promoting the interaction of a broad range of scientific disciplines of brain and behavior in order to advance the understanding of prevention and treatment of diseases of the nervous system including psychiatric, neurological, behavioral and addictive disorders.
These IOM proceedings are welcomed as of prime importance to improving the public health. This ACNP statement focuses on key issues in system development for objectively evaluating medication safety and effectiveness.
EVALUATING HARMS
The central issue is that harms may occur to patients while being treated with medications. These may (infrequently) be reported to the FDA as Adverse Event Reports via its voluntary system (MedWatch) or by industry.
However such reports are only of concomitance and do not establish causality. The usual difficult case is that the harm in question often occurs in the absence of treatment and may actually occur with increased frequency in the untreated patient. Therefore definitive causal attributions are unwarranted. Even the proportion of medicated patients supposedly affected is unknown because reporting is incomplete. Such reports have been negotiated between industry and the FDA as to their labeling inclusion as concerns and warnings. However, this practice was recently brought into question when public concern was incited by a controlled clinical trial yielding a clear causal inference of a rare, possibly lethal, effect of an FDA approved medication, Vioxx (rofecoxib).
A major point is that the inference that this drug caused rare but potentially lethal effects was based on a large clinical trial conducted for other purposes. Therefore, questions about FDA effectiveness in recognizing safety issues gained in substance.
Such concerns were further reinforced by the FDA review and eventual warning actions concerning anti-depressant treatment and “suicidality” in children. The issue of firm causality was, again, central.
I submitted to this IOM committee a personal critique of the data and analyses used by the FDA in justifying its Black Box warning and public statements. This review concludes: The central concern of the FDA and its advisory boards was whether antidepressants could be lethal, by causing suicide in children and adolescents. Since no suicide occurred in these clinical trials that studied approximately 4,400 children, the analyses relied upon “suicidality” as a surrogate.
The classification of adverse events by the Columbia group necessarily relied on shaky inferences, because the available evidence was not prospectively collected for this purpose; and thus does not fulfill requirements for evaluating “suicidality” e.g., direct interview as well as circumstantial evidence concerning necessary intent to die, self harm, lethality of attempt, required medical attention, definite plan, concealment etc. The threshold used for the crucial inference of intent to die seems to have been even the slightest suspicion.
Strategies used in data analysis: The data analysis relied on a composite marker of “suicidality” including “ideation”. This was an inappropriate, misleading surrogate for completed suicide that grossly overestimates potential risk for a rare event.
The failure of the FDA’s post-marketing surveillance system is evident. Accusations about the FDA’s structure, bungling or industry influence deflect attention from the central issue.
THE CENTRAL LACK OF RELEVANT DATA
The FDA cannot, objectively or timely, detect or evaluate rare or delayed toxicities because of the limited safety information it relies upon, spontaneous adverse event reports or short term, necessarily underpowered, clinical trials. Since most prescriptions are “off-label” even minimal clinical trial signals re possible harms rarely exist. Therefore recommendations that all approved medications require prompt large-scale post-marketing trials would serve quite incompletely besides being impractical.
Unfortunately, the FDA’s ability to rapidly communicate about realistic possible harms, worthy of public concern, is limited to the problematic information it can obtain from Adverse Event Reports. Further, the public often reacts to such warnings, despite FDA qualifications, as if they were firmly established. The FDA does not know whether such communications are helpful or have a net negative public health effect by frightening public and professionals from availing themselves of safe, useful treatments.
PHARMACOVIGILANCE/PHARMACOEPIDEMIOLOGY
Alternative methods for systematically collecting evaluable safety data must be developed. Proper post-marketing surveillance by linked computerized medical records is a leading possibility that deserves major public and political attention and appropriate action. Unfortunately, it has not received any public attention. Therefore we present a concrete example of a well functioning current system – PHARMO.
Also, we present a concrete example how a complex cross-linked database – such as PHARMO – would have helped clarify any causal relationship of SSRIs to suicidality.
PHARMO-Institute for Drug Outcome Studies.
PHARMO, a system developed in the Netherlands , is reviewable at: ( http://www.pharmo.nl/).
“The PHARMO Institute is an independent scientific research organization dedicated to study drug use and outcomes in daily practice. The PHARMO Institute has direct access to large and high quality pharmacoepidemiological databases, is staffed with academic trained specialists in epidemiology, pharmacotherapy, medicine and informatics, and works closely together with the international renowned department of Pharmaco-epidemiology and Pharmaco-therapy of the University of Utrecht (http://www.pharm.uu.nl/). This unique combination of expertise and access to patient-based data enables fast and professional handling of research questions meeting state-of-the-art research standards. The PHARMO databases constitute a well-defined population including one million residents in the Netherlands and enable us to follow-up drug use and hospitalizations in patients for an average of ten years. Access to medical charts and other clinical data is available within the prerequisites of the Dutch privacy regulations. Studies and results are representative for the whole Dutch population. For optimal transparency, we strive to publish the results of studies in order to fulfill our mission to learn and disclose more about the safety, effectiveness and costs of drugs for implementation in current pharmacotherapeutic practice. Clients are amongst others: universities, governmental agencies and pharmaceutical companies.”
THE COMPLEX PHARMO DATABASE
“The PHARMO Institute has direct access to the data source PHARMO Record Linkage System that was established at the Dutch Universities of Utrecht and Rotterdam in the early nineties. This PHARMO system links patients’ medical histories to the use and cost of prescription drugs (U-Expo database), diagnostic/therapeutic data from hospitals (LMR), clinical lab and pathological findings, GP records and drug histories in hospital. The PHARMO Institute has access to a variety of databases, each of them having their relevant and specific items to link them to the PHARMO database on patient level, following the history of drug use and other medical events of an anonymous patient. Currently, data are collected from a population of about two million residents in the Netherlands and are representative for the Netherlands .”
Since reinventing the infrastructure needed for appraising each treatment or indication is too costly and prohibitive for timely results, the only feasible procedure is a standing high quality cross-linked computerized general medical data base.
Epidemiological approaches attempt to contrast samples matched except for treatment exposure. However since receiving treatment is not a random event analyses are not straight forward. Analyses must pay particular attention to selection biases and confounding to avoid false positive relationships. Given a vast population based data base numerous possible comparison groups can be constructed via stratification, regression etc. to allow for these problems. This complex area should be at the forefront of methodological development, combined with specific clinical/biological understanding of disease processes.
EXAMPLE OF POTENTIAL UTILITY – MEDICATION INDUCED SUICIDALITY
Given national concern about suicide, a specific file would accumulate longitudinally, by anonymized individual, all reports that specify self-harms, suicide attempts or attempted suicides gathered from computerized, structured:
Diagnoses and demographics in medical records
Specification of illness severity and functional impairment
Clinical lab and pathological findings
Emergency room records
Diagnostic/therapeutic data from hospitals
Death certificates
Census records
These would be correlated and contrasted, using various analytical methods e.g. time series, case controls, cohort analyses, etc. with prescription records and toxicology tests to search for beyond base-rate and beyond chance differences attributable to various treatments. Textbooks of Pharmacoepidemiology address these issues.
Following the marketing of a medication, a focused comparative analysis cross-linked to the developing prescriptive data base may yield an early signal of problems. Detection of such signals would lead to even more refined, medically informed, analyses to further rule out possible confounds and selection biases. These analyses would estimate the actual risk/benefit ratio because the utilization denominators are known, which not the current case is. Therefore the magnitude of public health concern can be estimated much more firmly. Public communications and warnings would have a much firmer, more timely, and more informative basis. Such a database would allow evaluation of the net public health effects of FDA warnings.
PRACTICALITY FOR USA
It might be thought that such a system would not be feasible within the private practice network of the U.S. or by federal budgetary constraints. However, the billions already lost by industry, and the likelihood that a crescendo of such losses are forthcoming, places in perspective costs to industry and the public of providing a safety/effectiveness program adequate to current requirements. Further, there would be huge advantages for individuals’ medical care since they would have available to them a completely detailed medical record. This is far advanced beyond the current reality.
FOSTERING CHANGE
However, the need for such systems is simply not on the public radar screen. The political will for drastic change is often stirred by catastrophes revealing the gross inadequacies of current safety nets. The Elixir Sulfanilamide catastrophe of the 1930’s and the thalidomide tragedy of the 1960’s are almost entirely responsible for the current system of pharmaceutical regulation re safety and efficacy—not just in the USA but across the developed world. In addition to the drug safety issue the mounting crescendo of medical costs, as well as ensuring that individual treatments are immediately informed of all past evaluations and care, has brought Health Information Technology into the political arena. However, current efforts focus narrowly on technical problems such as facilitating inter-computer communication.
There is a fortunate confluence of interests here since cross-linked computerized medical records may provide the crucial advance needed for ameliorating these tremendous problems.
RECOMENDATIONS TO THE IOM
The mission of this IOM Committee includes “make recommendations in the areas of organization, legislation, regulation, and resources to improve risk assessment, surveillance and the safe use of drugs.”
Federally directed complex medical systems such as the VA, Armed Forces, and PHS provide entry points for legislatively mandating a cross-linked computerized surveillance system that speaks objectively to both safety and effectiveness. The Veterans Administration has already made substantial strides in Health Information Technology use. This should be carefully reviewed.
The ACNP believes that developing the public understanding and political will necessary to realize such medical documentation innovations via cross-linked computerized Health Information Technology, requires ongoing public discussions by the range of stakeholders. In particular, detailed analyses of PHARMO and similar systems are required.
Work groups should proffer plans and analyses. Conflicting views are inevitable. Public meetings organized by a variety of patient support groups, academics, professional, and political organizations, etc., should accelerate public debate.
The IOM can foster this democratic process by initiating such meetings in the near future. The ACNP is actively considering promptly sponsoring a Washington DC meeting for analysis of pharmacovigilance systems promoting medication safety.
ACNP, founded in 1961, is a professional organization of more than 700 leading scientists, including three Nobel Laureates. The mission of ACNP is to further research and education in neuropsychopharmacology and related fields in the following ways: promoting the interaction of a broad range of scientific disciplines of brain and behavior in order to advance the understanding of prevention and treatment of disease of the nervous system including psychiatric, neurological, behavioral and addictive disorders; encouraging scientists to enter research careers in fields related to these disorders and their treatment; and ensuring the dissemination of relevant scientific advances.
ACNP Statement to IOM Committee on the Assessment of US Drug Safety System
The American College of Neuropsychopharmacology (ACNP) is devoted to promoting the interaction of a broad range of scientific disciplines of brain and behavior in order to advance the understanding of prevention and treatment of diseases of the nervous system including psychiatric, neurological, behavioral and addictive disorders.
These IOM proceedings are welcomed as of prime importance to improving the public health. This ACNP statement focuses on key issues in system development for objectively evaluating medication safety and effectiveness.
EVALUATING HARMS
The central issue is that harms may occur to patients while being treated with medications. These may (infrequently) be reported to the FDA as Adverse Event Reports via its voluntary system (MedWatch) or by industry.
However such reports are only of concomitance and do not establish causality. The usual difficult case is that the harm in question often occurs in the absence of treatment and may actually occur with increased frequency in the untreated patient. Therefore definitive causal attributions are unwarranted. Even the proportion of medicated patients supposedly affected is unknown because reporting is incomplete. Such reports have been negotiated between industry and the FDA as to their labeling inclusion as concerns and warnings. However, this practice was recently brought into question when public concern was incited by a controlled clinical trial yielding a clear causal inference of a rare, possibly lethal, effect of an FDA approved medication, Vioxx (rofecoxib).
A major point is that the inference that this drug caused rare but potentially lethal effects was based on a large clinical trial conducted for other purposes. Therefore, questions about FDA effectiveness in recognizing safety issues gained in substance.
Such concerns were further reinforced by the FDA review and eventual warning actions concerning anti-depressant treatment and “suicidality” in children. The issue of firm causality was, again, central.
I submitted to this IOM committee a personal critique of the data and analyses used by the FDA in justifying its Black Box warning and public statements. This review concludes: The central concern of the FDA and its advisory boards was whether antidepressants could be lethal, by causing suicide in children and adolescents. Since no suicide occurred in these clinical trials that studied approximately 4,400 children, the analyses relied upon “suicidality” as a surrogate.
The classification of adverse events by the Columbia group necessarily relied on shaky inferences, because the available evidence was not prospectively collected for this purpose; and thus does not fulfill requirements for evaluating “suicidality” e.g., direct interview as well as circumstantial evidence concerning necessary intent to die, self harm, lethality of attempt, required medical attention, definite plan, concealment etc. The threshold used for the crucial inference of intent to die seems to have been even the slightest suspicion.
Strategies used in data analysis: The data analysis relied on a composite marker of “suicidality” including “ideation”. This was an inappropriate, misleading surrogate for completed suicide that grossly overestimates potential risk for a rare event.
The failure of the FDA’s post-marketing surveillance system is evident. Accusations about the FDA’s structure, bungling or industry influence deflect attention from the central issue.
THE CENTRAL LACK OF RELEVANT DATA
The FDA cannot, objectively or timely, detect or evaluate rare or delayed toxicities because of the limited safety information it relies upon, spontaneous adverse event reports or short term, necessarily underpowered, clinical trials. Since most prescriptions are “off-label” even minimal clinical trial signals re possible harms rarely exist. Therefore recommendations that all approved medications require prompt large-scale post-marketing trials would serve quite incompletely besides being impractical.
Unfortunately, the FDA’s ability to rapidly communicate about realistic possible harms, worthy of public concern, is limited to the problematic information it can obtain from Adverse Event Reports. Further, the public often reacts to such warnings, despite FDA qualifications, as if they were firmly established. The FDA does not know whether such communications are helpful or have a net negative public health effect by frightening public and professionals from availing themselves of safe, useful treatments.
PHARMACOVIGILANCE/PHARMACOEPIDEMIOLOGY
Alternative methods for systematically collecting evaluable safety data must be developed. Proper post-marketing surveillance by linked computerized medical records is a leading possibility that deserves major public and political attention and appropriate action. Unfortunately, it has not received any public attention. Therefore we present a concrete example of a well functioning current system – PHARMO.
Also, we present a concrete example how a complex cross-linked database – such as PHARMO – would have helped clarify any causal relationship of SSRIs to suicidality.
PHARMO-Institute for Drug Outcome Studies.
PHARMO, a system developed in the Netherlands , is reviewable at: ( http://www.pharmo.nl/).
“The PHARMO Institute is an independent scientific research organization dedicated to study drug use and outcomes in daily practice. The PHARMO Institute has direct access to large and high quality pharmacoepidemiological databases, is staffed with academic trained specialists in epidemiology, pharmacotherapy, medicine and informatics, and works closely together with the international renowned department of Pharmaco-epidemiology and Pharmaco-therapy of the University of Utrecht (http://www.pharm.uu.nl/). This unique combination of expertise and access to patient-based data enables fast and professional handling of research questions meeting state-of-the-art research standards. The PHARMO databases constitute a well-defined population including one million residents in the Netherlands and enable us to follow-up drug use and hospitalizations in patients for an average of ten years. Access to medical charts and other clinical data is available within the prerequisites of the Dutch privacy regulations. Studies and results are representative for the whole Dutch population. For optimal transparency, we strive to publish the results of studies in order to fulfill our mission to learn and disclose more about the safety, effectiveness and costs of drugs for implementation in current pharmacotherapeutic practice. Clients are amongst others: universities, governmental agencies and pharmaceutical companies.”
THE COMPLEX PHARMO DATABASE
“The PHARMO Institute has direct access to the data source PHARMO Record Linkage System that was established at the Dutch Universities of Utrecht and Rotterdam in the early nineties. This PHARMO system links patients’ medical histories to the use and cost of prescription drugs (U-Expo database), diagnostic/therapeutic data from hospitals (LMR), clinical lab and pathological findings, GP records and drug histories in hospital. The PHARMO Institute has access to a variety of databases, each of them having their relevant and specific items to link them to the PHARMO database on patient level, following the history of drug use and other medical events of an anonymous patient. Currently, data are collected from a population of about two million residents in the Netherlands and are representative for the Netherlands .”
Since reinventing the infrastructure needed for appraising each treatment or indication is too costly and prohibitive for timely results, the only feasible procedure is a standing high quality cross-linked computerized general medical data base.
Epidemiological approaches attempt to contrast samples matched except for treatment exposure. However since receiving treatment is not a random event analyses are not straight forward. Analyses must pay particular attention to selection biases and confounding to avoid false positive relationships. Given a vast population based data base numerous possible comparison groups can be constructed via stratification, regression etc. to allow for these problems. This complex area should be at the forefront of methodological development, combined with specific clinical/biological understanding of disease processes.
EXAMPLE OF POTENTIAL UTILITY – MEDICATION INDUCED SUICIDALITY
Given national concern about suicide, a specific file would accumulate longitudinally, by anonymized individual, all reports that specify self-harms, suicide attempts or attempted suicides gathered from computerized, structured:
Diagnoses and demographics in medical records
Specification of illness severity and functional impairment
Clinical lab and pathological findings
Emergency room records
Diagnostic/therapeutic data from hospitals
Death certificates
Census records
These would be correlated and contrasted, using various analytical methods e.g. time series, case controls, cohort analyses, etc. with prescription records and toxicology tests to search for beyond base-rate and beyond chance differences attributable to various treatments. Textbooks of Pharmacoepidemiology address these issues.
Following the marketing of a medication, a focused comparative analysis cross-linked to the developing prescriptive data base may yield an early signal of problems. Detection of such signals would lead to even more refined, medically informed, analyses to further rule out possible confounds and selection biases. These analyses would estimate the actual risk/benefit ratio because the utilization denominators are known, which not the current case is. Therefore the magnitude of public health concern can be estimated much more firmly. Public communications and warnings would have a much firmer, more timely, and more informative basis. Such a database would allow evaluation of the net public health effects of FDA warnings.
PRACTICALITY FOR USA
It might be thought that such a system would not be feasible within the private practice network of the U.S. or by federal budgetary constraints. However, the billions already lost by industry, and the likelihood that a crescendo of such losses are forthcoming, places in perspective costs to industry and the public of providing a safety/effectiveness program adequate to current requirements. Further, there would be huge advantages for individuals’ medical care since they would have available to them a completely detailed medical record. This is far advanced beyond the current reality.
FOSTERING CHANGE
However, the need for such systems is simply not on the public radar screen. The political will for drastic change is often stirred by catastrophes revealing the gross inadequacies of current safety nets. The Elixir Sulfanilamide catastrophe of the 1930’s and the thalidomide tragedy of the 1960’s are almost entirely responsible for the current system of pharmaceutical regulation re safety and efficacy—not just in the USA but across the developed world. In addition to the drug safety issue the mounting crescendo of medical costs, as well as ensuring that individual treatments are immediately informed of all past evaluations and care, has brought Health Information Technology into the political arena. However, current efforts focus narrowly on technical problems such as facilitating inter-computer communication.
There is a fortunate confluence of interests here since cross-linked computerized medical records may provide the crucial advance needed for ameliorating these tremendous problems.
RECOMENDATIONS TO THE IOM
The mission of this IOM Committee includes “make recommendations in the areas of organization, legislation, regulation, and resources to improve risk assessment, surveillance and the safe use of drugs.”
Federally directed complex medical systems such as the VA, Armed Forces, and PHS provide entry points for legislatively mandating a cross-linked computerized surveillance system that speaks objectively to both safety and effectiveness. The Veterans Administration has already made substantial strides in Health Information Technology use. This should be carefully reviewed.
The ACNP believes that developing the public understanding and political will necessary to realize such medical documentation innovations via cross-linked computerized Health Information Technology, requires ongoing public discussions by the range of stakeholders. In particular, detailed analyses of PHARMO and similar systems are required.
Work groups should proffer plans and analyses. Conflicting views are inevitable. Public meetings organized by a variety of patient support groups, academics, professional, and political organizations, etc., should accelerate public debate.
The IOM can foster this democratic process by initiating such meetings in the near future. The ACNP is actively considering promptly sponsoring a Washington DC meeting for analysis of pharmacovigilance systems promoting medication safety.
ACNP, founded in 1961, is a professional organization of more than 700 leading scientists, including three Nobel Laureates. The mission of ACNP is to further research and education in neuropsychopharmacology and related fields in the following ways: promoting the interaction of a broad range of scientific disciplines of brain and behavior in order to advance the understanding of prevention and treatment of disease of the nervous system including psychiatric, neurological, behavioral and addictive disorders; encouraging scientists to enter research careers in fields related to these disorders and their treatment; and ensuring the dissemination of relevant scientific advances.
