many consumers may believe that the food and drug administration ( fda ) approval of a new therapeutic implies that its benefits have been proven to exceed its harms . indeed , the fda s  for consumers  website encourages precisely that interpretation , stating [ i]f fda grants an approval , it means the agency has determined that the benefits of the product outweigh the risks for the intended use.1 arguably , much of the backlash directed at the fda after the withdrawal of over 12 high - profile brand - name drugs ( eg , rofecoxib , troglitazone)25 originated because consumers interpreted these withdrawals as proof that a presumptive judgment about benefits exceeding harms was inaccurate and premature.6 however , it is well documented that fda approval does not indicate proof that benefits exceed harms.7 a marginally effective but  safe  drug may still have harms that exceed its benefits and , conversely , an unequivocally effective but  unsafe  drug may have benefits that exceed its harms . magnifying confusion about these two distinct ideas , the fda considers available information about benefit  risk balance at the same time that it assesses safety and efficacy for approval decisions , although risk / benefit information is applied implicitly and unsystematically rather than explicitly , systematically , and quantitatively.8,9 consequently , the fda does not require  proof  that benefits exceed harms , whereas it does require proof of safety and effectiveness . while it can be argued that the fda should make proof that benefits exceed harms a prerequisite for approval , this criterion may be infeasible because detecting unknown , infrequent events sometimes requires huge sample sizes that are impractical for pre - marketing studies . however , an alternative approach to make benefit / harm assessment more explicit could be to create a new label that would be conferred only after sufficient evidence has accumulated to prove that benefits exceed harms . the fda could supplement its standard label denoting safety and efficacy with a secondary label denoting benefits exceeding harms . unlike the  safe and effective  label , this secondary  benefits exceed harms  label would not necessarily be linked to marketing restrictions or other commercial prohibitions but , rather , would be only information for consumers and clinicians , and could be harmonized with other approaches , such as the  drug box ,  to make drug information more transparent to consumers.10 because this secondary label would evaluate a concept with immediate relevance for decision making rather than the more abstract and context - dependent idea of  safety,8 it could lead to more informed shared decision making for consumers and physicians . there are many systematic frameworks for quantitatively estimating whether benefits exceed harms69 ( benefit  risk assessment [ bra ] ) . while the purpose of this paper is not to systematically review bra frameworks or to advocate using one framework over another , i will choose one particular bra approach , incremental net health benefit ( inhb ) , for illustration.7 this approach quantitatively compares benefits and harms on the same scale , and explicitly considers the idea that regulators or consumers may be risk averse ( ie , weigh a harm more than they would weigh a benefit of equal magnitude ) . ( briefly , the inhb of therapy 2 versus therapy 1 can be expressed as inhb = ( e2  e1 )  ( r2  r1 ) , where effectiveness [ e ] and risk [ r ] are measured in the same units . favorable  benefit  risk balance occurs when ( e2  e1 ) > ( r2  r1 ) + x or ( e2  e1 ) > ( r2  r1 ) * x , where  x  is an additive or multiplicative factor that can reflect the risk aversion of regulators and can increase the mandated margin by which benefits exceed risks.)7 suppose the fda grants pre - marketing approval for a weight - loss drug based on pre - marketing studies that show clinically significant improvements in 20% of patients . further , assume that the 20% improvement is a reasonable approximation of the true biological effect . the pre - marketing studies did not suggest any serious adverse events , and the drug s biological mechanism did not raise any concerns about particular harms . however , assume that the drug confers a true biological harm , life - threatening bleeding , in 0.2% of patients . this adverse event was too rare to be detected in the two pre - marketing studies , each of which enrolled 800 patients . regulators could use inhb to address this question by asking how many people would need to have the demonstrated incremental improvement in weight loss to offset one person having a serious adverse event from the drug . while one of the challenges of applying bra to a new therapeutic is that the adverse event profile of a new therapeutic may be unknown , it is possible to test a plausible range of assumptions regarding the morbidity and mortality profile of hypothetical unknown adverse events , and to assess the sample size and/or follow - up necessary to have adequate statistical power to detect them . for example , applying inhb with substantial risk aversion might suggest that 100 persons would need to have clinically significant weight loss to offset one person having serious harm . consequently , to evaluate the suitability of a  benefits exceed harms  label , regulators would need to determine whether sufficient data have accumulated to rule out an adverse event occurring at a corresponding frequency ( eg , in this case , at least 1/100 of the frequency of the anticipated benefit , or two events per 1000 patients ) . using a standard power criterion of 80% and assuming a baseline frequency of one event per 1000 patients , this threshold therefore , this weight - loss drug could go on the market with fda approval after the standard pre - marketing studies are concluded but would not receive a benefits exceed harms  label until data have accumulated on at least 12,340 patients and until these data are investigated for unanticipated harm signals ( table 1 ) . it is important to note that while the  safe and effective  label would generally precede the  benefits exceed harms  label , this is not necessarily the case . indeed , for a new therapeutic that confers a very large incremental benefit , the number of observations needed to demonstrate that benefits exceed harms would be small , and the  benefits exceed harms  label could be granted before the  safe and effective  label is granted ( in this context , it could fill the role of the current  experimental use  designation ) . suppose the fda grants pre - marketing approval for a weight - loss drug based on pre - marketing studies that show clinically significant improvements in 20% of patients . further , assume that the 20% improvement is a reasonable approximation of the true biological effect . the pre - marketing studies did not suggest any serious adverse events , and the drug s biological mechanism did not raise any concerns about particular harms . however , assume that the drug confers a true biological harm , life - threatening bleeding , in 0.2% of patients . this adverse event was too rare to be detected in the two pre - marketing studies , each of which enrolled 800 patients . regulators could use inhb to address this question by asking how many people would need to have the demonstrated incremental improvement in weight loss to offset one person having a serious adverse event from the drug . while one of the challenges of applying bra to a new therapeutic is that the adverse event profile of a new therapeutic may be unknown , it is possible to test a plausible range of assumptions regarding the morbidity and mortality profile of hypothetical unknown adverse events , and to assess the sample size and/or follow - up necessary to have adequate statistical power to detect them . for example , applying inhb with substantial risk aversion might suggest that 100 persons would need to have clinically significant weight loss to offset one person having serious harm . benefits exceed harms  label , regulators would need to determine whether sufficient data have accumulated to rule out an adverse event occurring at a corresponding frequency ( eg , in this case , at least 1/100 of the frequency of the anticipated benefit , or two events per 1000 patients ) . using a standard power criterion of 80% and assuming a baseline frequency of one event per 1000 patients , this threshold therefore , this weight - loss drug could go on the market with fda approval after the standard pre - marketing studies are concluded but would not receive a benefits exceed harms  label until data have accumulated on at least 12,340 patients and until these data are investigated for unanticipated harm signals ( table 1 ) . it is important to note that while the  safe and effective  label would generally precede the  benefits exceed harms  label , this is not necessarily the case . indeed , for a new therapeutic that confers a very large incremental benefit , the number of observations needed to demonstrate that benefits exceed harms would be small , and the  benefits exceed harms  label could be granted before the  safe and effective  label is granted ( in this context , it could fill the role of the current  experimental use  designation ) . bra approaches in general , and the inhb method in particular , require embedded assumptions about what level of risk aversion is most suitable for a regulatory authority , and about what level of statistical certitude should be required.7 for example , it may be argued that the standard criterion for null hypothesis testing in clinical studies ( requiring p values < 5% ) is too strict for disproving the analogous null hypothesis for bra ( ie , that benefits do not exceed harms ) , and therefore alternative criteria should be preferred . it might be suggested that societal or regulatory preferences regarding bra may differ greatly from individual patient preferences and risk tolerances and , therefore , it is neither possible nor desirable for regulatory authorities to attempt to make a particular bra decision on behalf of society.11 however , it is important to appreciate that analogous arguments may be made for most other regulatory activities . individuals may have greatly differing definitions and evidence standards for  safety  and  effectiveness ,  for example , yet the fda implicitly chooses a particular societal standard when it approves therapeutics . indeed , one way to mitigate this concern is to make explicit in a  benefits exceeding harms  label that individual preferences , risks , and benefits vary ; therefore , patients should make an individualized and shared decision with their clinician ( figure 1 ) . for example , risk - tolerant patients may choose to try a new effective drug even before its benefits have been proven to exceed its harms , because they may be satisfied with a reasonable likelihood , rather than proof , that benefits exceed harms , particularly if they have a high symptom burden . it may be appreciated that evaluations of incremental benefits and harms will not be static , even without new evidence generation , because comparators may change over time as new alternatives become available and old alternatives are removed from the market . however , secondary labels can be revisited at suitable time intervals ( eg , 5 years ) that are used in other situations in which evidence reviews need to be updated , such as systematic reviews used for updating clinical guidelines . some may argue that backlash about withdrawn drugs has occurred because of unknown effects , and such effects would not have been included in a quantitative benefit / harm analysis . however , this argument does not consider the idea that a quantitative benefit / harm analysis should only be performed after accumulation of evidence with sufficient statistical power to detect harms that would outweigh observed benefits . backlash about unknown effects has generally occurred when drugs were approved before evidence accumulated with sufficient statistical power to detect those rare harmful events . finally , it may be questioned whether adding a second  benefits exceed harms  label would be preferable to classifying a newly marketed drug as experimental  until sufficient post - marketing data have accumulated to prove that benefits exceed harms . indeed , expanding the use of the  experimental  designation to all situations in which benefits have not yet been proven to exceed harms may accomplish the same goal . however , expanding the experimental designation in this manner would likely result in many new drugs coming to market labeled  experimental . such a sudden and sharp change in the use of a term currently associated with terminal illness could lead to substantial confusion . in contrast , adding a  benefits exceed harms  label could avoid this confusion and , indeed , may clarify the distinction between the separate criteria of  safe and effective  and  benefits exceed harms . developing a second label for  benefits exceed harms  may lead to more informed decision making about  off - label  uses for therapeutics . for example , a therapeutic approved for condition a may receive a label for condition a , but still be used off - label for condition b. while this off - label use may continue to be permitted , consumers and clinicians would potentially be more aware that benefits have not been demonstrated to exceed harms for these off - label uses . indeed , this growing awareness may lead manufacturers to seek  benefits exceed harms  labels for uses that had primarily been off - label and may encourage more circumspect utilization of new therapeutics beyond their approved indication . it is possible that a  benefits exceeding harms  label would incentivize longer - term adverse - event monitoring and reporting by manufacturers of new therapeutics , as this longer - term follow - up would often be necessary to generate the additional evidence to establish that benefits exceed harms . indeed , if the fda adopted a  benefits exceeding harms  label , this may facilitate a more systematic assessment of post - marketing data to look for harm signals . label for a particular therapeutic need not preclude payers reimbursement for that therapeutic . even when benefits have not been demonstrated to exceed harms overall , benefits might be likely to exceed harms for a particular patient in a particular situation . however , payers may wish to require evidence of a shared decision between consumer and clinician that considers known benefits and harms ( analogous to informed consent ) before reimbursing therapeutics that do not have the  benefits exceeds harms  label . finally , it can be appreciated that circumstances in which additional evidence would be necessary to establish that benefits exceed harms are also circumstances where a formal analysis of expected value of information would support additional gathering of evidence , unless both benefits and risks are very small . in these circumstances , conversely , situations where benefits have been shown to exceed harms are situations in which the value of information will not support additional research because there is already a clear inference for decision making.11 if it is infeasible for the fda to require proof that benefits exceed harms prior to marketing approval , it is worth asking whether the fda should supplement its standard label denoting  safe and effective  with a secondary label denoting  benefits have been demonstrated to exceed harms .  because this secondary label would evaluate a concept with more relevance for decision making than the abstract and context - dependent idea of  safety ,
many consumers and clinicians incorrectly believe that the food and drug administration ( fda ) approval of a new therapeutic implies that its benefits have been proven to exceed its harms . 
 while the fda could require proof that benefits exceed harms prior to approval , it has been argued that this approach would be infeasible because of prohibitively large sample sizes . 
 one possible alternative would be for the fda to supplement its standard  label  denoting  safe and effective  with a secondary  label  denoting benefits have been demonstrated to exceed harms , which would be granted only after sufficient post - marketing data had accumulated to prove that its benefits exceeded its harms . 
 this secondary label would not necessarily be linked to marketing restrictions or other commercial prohibitions but , rather , would be only information for consumers and clinicians . 
 strengths , weaknesses , and feasibility challenges of this approach are discussed .