2010 6th Annual Scientific Meeting – New Approaches to Assessing the Safety of Marketed Drugs – FDA, Industry, and Academia Perspective – Session Summary

International Society for CNS Clinical Trials and Methodology Annual Meeting
Washington, DC
22-24 February 2010

New Approaches to Assessing the Safety of Marketed Drugs – FDA, Industry, and Academia Perspective

Chairs: Stephen Marder, MD; Mauricio Tohen, MD
Speakers: Philip Wang MD, DrPH; Bennett Levitan MD, PhD; Judith Racoosin, MD, MPH

Approaches to Safety Assessment: A Pharmacoepidemiological Perspective

Philip Wang MD, DrPH

The first presentation was by Philip Wang who reviewed recent developments in the availability of datasources and methods enabling pharmacoepidemiologists to play an expanded role in post marketing surveilance of medicines. Examples of studies were presented to illustrate how pharmacoepidemiology can help ensure that the use of psychotropic medications is safe, effective, and cost-beneficial.

Psychopharmacoepidemiology arose (as did pharmacoepidemiology) largely following the thalidomide experience and the subsequent changes at the FDA (Kefauver-Harris Act). Pharmacoepidemiological tools include general population surveys, use of data from practice-based networks, government administrative data, and health plan data. New study designs include effectiveness trials and simulations. The scope of pharmacoepidemiology is expanding to include descriptive work, in order to provide a more real-world perspective, as well as analytic approaches to evaluate modifiable determinants of use/outcomes and interventions. An example (Wang, J Clin Psychopharm 2005) was shown in the area of depression treatment, illustrating suboptimal antidepressant use trends not changing over time. An additional example was a review of conventional antipsychotic use in the elderly (Wang NEJM 2005) which identified a risk of short-term mortality that appeared greater than that observed with atypicals. Wang also referred to an evaluation of the impact of co-pay introduction in British Columbia from 2002 to 2003 on elderly antidepressant use, showing a decline in new starts of antidepressants. An additional evaluation assessed a change allowing the first-line use of clozapine and found declines in mortality suggested to be due to a reduction in suicide. Wang also referred to an evaluation of the cost-effectiveness of the use of a genomic responsiveness test for clozapine at an incremental cost of $950 resulting in a QALY value 0.02, incremental C/E ratio $48K/QALY (favorable convention less than $50K/QALY) (Perlis J Clin Psychopharm 2005). In contrast, the use of an SSRI genomic responsiveness test at $500 translated into an incremental QALY of 0.0054, and unfavorable $94K/QALY (Perlis Neuropsychopharm 2009).

Approaches to Safety Assessment: An Industry Perspective

Bennett Levitan, MD, PhD

Pharmaceutical companies are increasingly pressed to demonstrate not simply efficacy and safety of their products, but a superior benefit-risk profile compared to alternative treatments. The increased pressure for these benefit-risk assessments is made all the more difficult by the lack of any standardized or approved approach to performing them. The variety of safety endpoints, with varying timescales and degree of impact on patients, makes quantitative approaches difficult. As a result, efficacy and safety results from clinical studies are often reported separately, and benefit-risk is often only characterized qualitatively. This presentation focused on approaches to prepare for, characterize and communicate benefit-risk assessments quantitatively. Topics included considerations for endpoint definition, number needed to treat/harm, net clinical benefit, maximum acceptable risk and the use of patient preference approaches to weighting the different health states patients may experience in a clinical trial.

Levitan highlighted an increasing pressure on sponsors to demonstrate a favorable benefit-risk for new treatments relative to existing treatments, but noted a tendency to delay benefit-risk assessment until late in development. Selected unweighted methods include Number Needed to Treat/Harm (# patients treated to provide 1 additional favorable or adverse event) – benefit-risk as ratio between NNT and NNH. Introducing confidence intervals complicates understanding and brings out limitations – example provided where safety outcome is not statistically significant (CI overlap with 0). Benefits of NNT/NNH is that it is relatively easy to calculate and interpret, but overstates small risk differences and does not lend itself easily to comparing more than 2 endpoints. Excess Number of Events provides the additional number of patients with an event between treatments – doesn’t have problem of ratio with 0 as with NNT/NNH. Value of visualization of excess events by category but problem is bundling diverse events that may not be equally important. Weighting strategies include Utility Weighting, Preference Weighting, Multicriteria Decision Analysis (MCDA), and Quality-Adjusted Life Years (QALYs). Favors Preference Weighting, which are determined by asking subjects (~n=200) to choose between treatments in a web-based survey and building model with preferences converted to weights that reflect relative importance. Example provided of choosing HRT with steeper slopes on satisfaction score from none to severe quantifies impact. MI risk relative to benefit with HRT demonstrated that good and best benefit are favorable relative to risk. Second example in AD demonstrates delay in progression highly valued relative to risk. Approach can inform regulatory interactions. Display of risks with weighting may help to manage diverse adverse event reports (including events that may be difficult to separate from disease process). Idea suggested to include a box similar to food labeling with NNT/NNH or Excess Number of Events. Calculation of Net Clinical Benefit integrates benefit and risk as difference in excess number of events in one treatment versus a second. Issue of weighting ethics was discussed by Margaret Somerville.

Approaches to Marketed Medical Product Safety Assessment: An FDA Perspective

Judith Racoosin, MD, MPH

The last several years have witnessed a remarkable growth in interest in medical product safety, and especially in post-approval medical product safety. At the US Food and Drug Administration (FDA), many new initiatives have developed in the Center for Drug Evaluation and Research. In addition to evaluating spontaneous adverse event reports and examining specific drug/adverse event association in large, population-based databases, FDA is also interested in using external databases to identify drug safety signals earlier than current methods do. The New Molecular Entity (NME) Pilot Project was completed in March, 2008, and ongoing implementation has begun; it involves a systematic, collaborative, and comprehensive review of available safety data. The FDA Amendments Act of 2007 includes several initiatives aimed at increasing transparency of the FDA in the area of post-marketing safety. All these initiatives were discussed in some detail.

FDA receives reports through “passive” Adverse Event Reporting System (AERS) with in excess of 4 million reports. Sources include patients, healthcare professionals (and sponsors – not on slide). Helpful to have challenge/dechallenge/rechallenge data and co morbidities impact interpretation. Good reports characterized as having event description, details of all treatments, patient details (including medical condition, co-morbidities, family history, other risk factors), diagnostic documentation, and information on dechallenge/rechallenge. Recognizes external events can complicate reporting by inflating perception of effect. Cases often confounded by other possible etiologies than treatment and complete diagnostic information is frequently lacking. AERS limitations include duplicate reporting, “extensive” underreporting, variable report quality, reporting biases, and core problem around uncertainty of actual numerator for events in population versus actual denominator of number exposed (and matching them accurately). AERS strengths include inclusion of all US products, simple reporting system, ability to detect events not seen in clinical trials, good for events with rare background rates (e.g., agran), and case series evaluation for identification of trends, drug indication, population, and other safety concerns. Also can look at large subpopulations (e.g., elderly), use in indications beyond what is labeled, chronic use, and medically complicated patients. ASTOR project is a new FDA initiative on AE reporting.

SENTINEL approach may provide a more “active” system with access to large safety databases. This may permit real-time surveillance, improved access to subpopulations of interest, and better monitoring of common adverse events (that may not be suspected to be related to a treatment). Sentinel initiative was launched in May 2008 with on-going effort to define the “how and what”.

There has been a public-private partnership between FNIH, FDA, and PhRMA called OMOP (Observational Medical Outcomes Partnership) to evaluate value, feasibility, and utility of observational data to evaluate risk/benefit. Select events known to be of concern (e.g., aplastic anemia, acute liver injury, MI, renal failure) with a defined list of commonly prescribed drug classes (ACEi, antidepressants) will be investigated. Also, a “Mini Sentinel” contract has been awareded to Harvard Pilgrim Healthcare to develop a coordinating center for a distributed system.

New Molecular Entity Postmarketing Safety Evaluation Pilot Program is a collaboration between Office of Surveillance and Epidemiology and Office of Drug Evaluation I. It utilizes SAE reports, periodic safety reports, medical literature, data from clinical trials, and data on related compounds (in same pharmacologic class).

The Title IX of 2007 FDA Amendments Act covers enhanced authorities regarding postmarketing safety of drugs. It includes provisions on enforcement, postmarketing studies, benefit-risk assessment, DTC advertising, assurance of pharmaceutical safety, database for authorized generic drugs, and adverse drug reaction reports and postmarket safety.

McMahon provided the following websites as reference:

1.http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm
2.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm185252.htm
3.http://www.fda.gov/Safety/FDAsSentinelInitiative/default.htm