the more you know , or anyone knows , the better decisions can be made. vermont physician quoted in sorrell v. ims health inc .
the history of the fda 's regulation of drug approval and promotion demonstrates the necessary and delicate balancing act that rests at the core of the agency 's mandate under the federal food , drug , and cosmetic act (  fdca or the 
act ) : to promote the public health by enhancing patient access to products that are safe and effective for their intended uses .
fda 's statutory and regulatory framework governing drug labeling and advertising was originally developed more than 50 years ago at a time when methods of drug promotion by manufacturers , and the level of medical information available to healthcare professionals were very different than they are today .
the agency generally considers any use of a drug , including dosage , patient population , and route of administration that does not conform to the fda - approved label to be an  off - label use .
the fda 's regulatory framework generally prohibits a manufacturer from promoting an off - label use .
fda and courts have long recognized that healthcare professionals may prescribe a drug for such an off - label use and speak openly about it , and fda acknowledges that off - label uses may in some cases constitute the recognized standard of care .
off - label uses are especially critical for the treatment of oncology , heart disease , aids , kidney disease , osteoporosis , and psychiatric illnesses .
one fda regulation even expressly permits  scientific exchange about unapproved uses of investigational drug products .
nevertheless , because the precise contours of scientific exchange are unclear , fda 's regulatory framework significantly restricts manufacturers from sharing information about their products that deviates , in any way , from the fda - approved label .
the consequences for manufacturers who engage in off - label promotion can be severe : the government can seek criminal penalties under the fdca ( and may exclude manufacturers from participation in medicare and medicaid in the event of a criminal conviction ) , and acts of off - label promotion may also serve as the basis for qui tam lawsuits under the false claims act (  fca ) .
the current regulatory framework appears outdated and does not fit with the modern communications and promotional landscape in which manufacturers seek to communicate with a host of players , including healthcare professionals , payors , formulary committees , and consumers , among others , by a range of traditional and contemporary media .
not all manufacturer communications are intended to propose an immediate commercial transaction for a drug ; indeed , many modern communications by manufacturers are more educational than promotional and are intended to provide healthcare professionals with the most accurate , up - to - date medical information to inform their medical decision - making .
fda 's current regulatory framework overly limits access to information about new uses of previously approved drugs by significantly restricting manufacturers communications about their products . the current regulatory and enforcement approach
come at the expense of fostering innovation and enhancing access to up - to - date information about therapeutic agents , and it also conflicts with manufacturers first amendment rights under the constitution .
accordingly , we propose a new regulatory framework ( the  new model ) which attempts to restore the balance between information access and patient safety , while also aligning fda 's regulatory approach with the fdca and the constitution .
the new model we propose would create three categories of manufacturer communications(1 ) scientific exchange and other exempt communications , ( 2 ) non - core communications , and ( 3 ) core communications  that would be regulated consistent with the first amendment and according to the strength of the government 's interest in regulating the specific communications included within each category .
the new model should address the fda 's concerns related to off - label speech while protecting manufacturers freedom to engage in truthful and non - misleading communications about their products .
part ii of this article describes the commercial speech doctrine and first amendment case law relevant to assessing fda 's regulatory framework .
part iv discusses the need for a new regulatory framework and describes what the objectives and underpinnings of any new model should be .
finally , part v describes the new model in detail by defining each category of communications , providing representative examples , and justifying the level of proposed authority provided to fda for each category .
one of the most familiar , fundamental constitutional rights is the first amendment right to freedom of speech .
supreme court jurisprudence analyzing laws and regulations that restrict freedom of speech has established that different categories of speech are afforded with different levels of protection . today , pharmaceutical manufacturer speech is generally considered 
however , fda 's regulatory framework , as described in part iii , infra , was originally developed at a time when the first amendment rights of pharmaceutical manufacturers were less concrete .
commercial speech as a form of protected speech . in virginia state board of pharmacy v. virginia citizens consumer council , inc . in 1976 , the supreme court held that commercial speech  speech that may do  no more than propose a commercial transactionstill enjoys constitutional protection .
as discussed in this part , subsequent cases have expounded upon the definition of commercial speech and the level of scrutiny that applies to commercial speech , both generally and in the context of several cases that have examined fda 's regulatory framework .
and united states v. caronia  has even indicated that content- and speaker - based restrictions on drug manufacturer speech are subject to  heightened scrutiny under the first amendment . additionally , recent caselaw addressing 
fair notice requirements under the due process clause of the fifth amendment is highly relevant to this first amendment analysis . in the years following virginia state board of pharmacy , the supreme court established both a framework for analyzing restrictions on commercial speech and for distinguishing between commercial and non - commercial speech , but fda , relying on a court of appeals decision suggesting that this commercial speech analysis was not directly applicable in highly regulated industries , attempted to sidestep first amendment concerns regarding its regulatory framework .
commercial speech in its purest form is  expression related solely to the economic interests of the speaker and  speech which does no more than propose a commercial transaction. in bolger v. youngs drug products corp .
, the court set forth three factors that , when taken together , strongly supported the classification of the materials at issue in the case as commercial speech : ( 1 ) the speech is meant to be an advertisement , ( 2 ) the speech references a particular product , and ( 3 ) there is an economic motivation for disseminating the material . to a certain extent
, this three - factor test calls into question the regulation of certain drug manufacturer speech as commercial speech , given that some manufacturer communications are intended for educational or scientific purposes , rather than as advertisements proposing a commercial transaction .
the supreme court has emphasized that commercial speech still deserves constitutional protection , albeit a 
 with respect to non - commercial speech , the court has  sustained content - based restrictions only in the most extraordinary circumstances. for commercial speech , on the other hand , the court has noted that content - based restrictions  may be permissible due to  the greater potential for deception or confusion in the context of certain advertising messages. in central hudson gas & electric corp .
v. public service commission , the court established a four - part test for assessing the constitutionality of a restriction on commercial speech : ( 1 ) whether the speech at issue concerns lawful activity and is not misleading ; ( 2 ) whether the asserted government interest is substantial ; ( 3 ) if so , whether the regulation directly advances the governmental interest asserted ; and ( 4 ) whether it is not more extensive than is necessary to serve that interest . because drug manufacturer speech is generally considered commercial speech , courts have typically applied the central hudson test , a form of 
despite the broad holding in central hudson applicable to all forms of commercial speech , the d.c .
circuit 's 1988 decision in sec v. wall street publishing institute , inc . rejected the application of central hudson test in the context of securities regulation .
the court concluded that the central hudson test was not applicable , explaining :  in areas of extensive federal regulation  like securities dealing  we do not believe the constitution requires the judiciary to weigh the relative merits of particular regulatory objectives that impinge upon communications occurring within the umbrella of an overall regulatory scheme. fda viewed the rationale of wall street publishing as equally applicable to the agency 's regulatory framework for drugs and medical devices . when issuing a 1997 guidance document addressing industry supported continuing medical education activities (  cme guidance ) , fda relied on wall street publishing for the proposition that in heavily regulated industries , the government has great authority to restrict speech that would otherwise be protected under the first amendment .
the agency concluded :  in view of the fact that the regulation of drugs and devices is an area of extensive federal regulation , the agency may regulate the communications at industry - supported scientific and educational activities without violating the first amendment. fda has not expressly cited wall street publishing in recent years to justify its restrictions on off - label speech likely because the relevance of wall street publishing to fda 's regulatory framework was rejected in subsequent litigation .
nonetheless , the agency 's actions are generally still consistent with the position expressed in 1997 supporting the applicability of wall street publishing to fda 's regulatory framework .
caselaw subsequent to wall street publishing  notably litigation brought by the washington legal foundation (  wlf ) against fda  has highlighted growing judicial skepticism regarding the constitutionality of fda 's regulatory framework as applied to manufacturer speech . in the 1990s and early 2000s , several courts addressing first amendment challenges to fda 's regulatory framework found that various restrictions on speech by fda failed the central hudson test . in a first amendment challenge brought by the wlf to three fda guidance documents that touched on off - label speech by addressing the dissemination of journal articles and reference texts and industry - supported continuing medical education ( and the statutory provisions that subsequently superseded the guidance documents relating to journal articles and reference texts ) , the district court rejected fda 's argument based on wall street publishing that restrictions on speech should receive only limited first amendment scrutiny . applying central hudson , the court concluded that off - label speech is not inherently misleading merely by virtue of addressing an unapproved use , nor is off - label speech directed toward unlawful activities because off - label prescribing is perfectly legal .
the court held that the restrictions on off - label speech , although they advanced a  substantial government interest , were 
more extensive than necessary to serve this interest , thereby failing the central hudson test and violating the first amendment .
circuit treated the case as moot because fda stipulated that the relevant statutory provisions in fdama did not provide any independent authority for enforcement but merely operated as a 
safe harbor. hence , the wlf 's victory against fda was completely vacated , and the fda managed to avoid what would have been a significant blow to the agency 's ability to prohibit off - label promotion . nonetheless , the wlf line of cases is still instructive for how a court would assess the fda 's regulatory framework today .
other cases have also emphasized the government 's difficult burden in satisfying the fourth prong of the central hudson test : that a restriction on speech be no more extensive than necessary to serve the government 's interest . in thompson v. western states medical center , the supreme court 's only decision addressing a first amendment challenge to fda regulation  albeit in the context of pharmacy compounding , rather than the context of traditionally manufactured drugs , the court emphasized  [ i]f the government could achieve its interests in a manner that does not restrict speech , or that restricts less speech , the government must do so. this principle makes clear that any restriction on drug manufacturer speech will fail the fourth prong of the central hudson test , unless there are no less restrictive alternatives that could achieve the same objectives .
one such less restrictive alternative to an outright prohibition on particular speech is to permit the speech , provided it is accompanied by an appropriate disclaimer . in other words , a disclaimer can mitigate or cure the potentially misleading nature of a claim .
put another way by one legal commentator : western states leaves outright prohibitions designed to dampen demand ( or to serve other collateral purposes ) vulnerable to constitutional invalidation , while more limited restrictions or disclosure requirements designed to guard against potentially misleading promotional messages would seem to survive .
united states v. caronia  have applied heightened first amendment scrutiny to restrictions on drug manufacturer speech . additionally , the supreme court 's recent decision in fcc v. fox television stations , inc .
(  fox ii ) under the due process clause of the fifth amendment indicates that 
fair notice considerations are highly relevant in the context of first amendment challenges . a decade after the wlf litigation , the supreme court weighed in on the government 's ability to restrict speech related to the marketing of prescription drugs .
the state law being challenged in sorrell severely restricted the ability of pharmacies to disclose , and the ability of pharmaceutical manufacturers to use , prescriber - identifying information for marketing purposes .
heightened scrutiny to the state law because it impermissibly created both speaker - based and content - based restrictions on speech .
 disfavor[ed ] specific speakers , namely pharmaceutical manufacturers , and facially  content - based because it 
disfavor[ed ] marketing. the court 's heightened scrutiny analysis assessed whether the law  directly advance[d ] a substantial government interest and was  drawn to achieve that interest. without definitively classifying the speech as 
commercial , the court concluded that the law could not withstand heightened scrutiny because it did not advance the asserted state interests  in a permissible way. for example , the state 's asserted interest in preventing detailers ( i.e. , sales representatives ) from  influenc[ing ] treatment decisions was  contrary to basic first amendment principles , since a  fear that speech might persuade provides no lawful basis for quieting it. the court further cautioned that speech restrictions  seek[ing ] to keep people in the dark for what the government perceives to be their own good are especially suspect , and emphasized the importance of the  free flow of commercial speech in the  fields of medicine and public health. the following year , the second circuit in caronia applied the sorrell  heightened scrutiny analysis to a first amendment challenge by alfred caronia , a pharmaceutical sales representative who had been criminally prosecuted under the fdca based on his alleged off - label promotion of a drug .
caronia argued that the first amendment does not permit the government to restrict a pharmaceutical manufacturer 's truthful and non - misleading speech involving off - label promotion when other actors do not face the same restrictions .
the court rejected the government 's argument that caronia was not actually prosecuted for his speech and that the first amendment therefore did not apply .
however , the court relied on numerous statements in the trial transcript to demonstrate that  the government 's theory of prosecution identified caronia 's speech alone as the proscribed conduct. the government clearly did not treat his speech as mere  evidence of intent. the court evaluated caronia 's conviction under the 
heightened scrutiny standard set forth in sorrell : content - based and speaker - based speech restrictions are  subject to heightened scrutiny and   presumptively invalid. just as in sorrell , the caronia court determined that the fdca , as applied by the government , would fail both heightened scrutiny and intermediate scrutiny under the central hudson test .
in addition , the court recognized that criminal restrictions on speech must be  scrutinized with particular care. notably , the court did not hold fdca 's misbranding provisions unconstitutional . applying the  constitutional avoidance canon , the court interpreted the fdca to not prohibit manufacturer  speech promoting the lawful , off - label use of an fda - approved drug , because under a contrary interpretation
although both sorrell and caronia seem to extend greater protection to off - label manufacturer speech , the exact scope of their holdings is not completely clear .
first , sorrell concluded that  heightened scrutiny should apply in cases of speaker- and content - based restrictions on speech , but the court did not define the  heightened scrutiny standard .
as both cases held that the challenged restrictions failed both intermediate and heightened scrutiny , courts are left with little guidance on how to resolve a case if a restriction fails heightened scrutiny but passes intermediate scrutiny .
second , while caronia clearly holds that the fdca does not authorize the government to prosecute 
manufacturer promotion alone , it may be unclear how caronia applies to cases of off - label promotion that involve additional activities beyond pure speech . going forward , the government may focus its enforcement efforts on false and misleading aspects of off - label speech .
the same year caronia was decided , the supreme court handed down another highly relevant speech case , in which it applied not the first amendment but the fifth . in fox ii , the federal communication commission (  fcc ) brought an enforcement action against two television networks for broadcasting  obscene , indecent , or profane language in violation of federal law . without addressing the first amendment question , the supreme court held that the fcc violated the due process clause of the fifth amendment for failing to give the broadcasters 
actionably indecent. thus , the fcc 's standards as applied in fox ii were unconstitutionally vague .
the court recognized that adherence to fair notice requirements is especially critical when speech regulations are involved so as  to ensure that ambiguity does not chill protected speech. this holding is highly relevant to fda 's regulation of off - label speech by drug manufacturers because fda 's regulatory framework is marked by a significant lack of clarity . in brief , the cases described in this part establish ( or at least , with respect to the second circuit 's caronia decision , strongly support ) four fundamental principles . 

the first amendment does not allow the government to prosecute truthful and non - misleading off - label speech by drug manufacturers under the fdca.restrictions on drug manufacturer speech that are content - based and speaker - based are presumptively unconstitutional.broad , categorical bans on speech are unconstitutional unless no less restrictive alternatives would achieve the same objectives.restrictions on speech must be sufficiently clear to provide fair notice to regulated parties of what is required of them .
the first amendment does not allow the government to prosecute truthful and non - misleading off - label speech by drug manufacturers under the fdca .
restrictions on drug manufacturer speech that are content - based and speaker - based are presumptively unconstitutional .
broad , categorical bans on speech are unconstitutional unless no less restrictive alternatives would achieve the same objectives
. restrictions on speech must be sufficiently clear to provide fair notice to regulated parties of what is required of them .
the fdca gives fda the authority to regulate the labeling and advertising of drugs . a complex system of provisions in the fdca and fda regulations  derived from fda 's authority over labeling and advertising and the regulatory definition of  intended usecreate an implicit , yet well - known prohibition of off - label promotion .
other fda regulations further limit and sometimes effectively prohibit even on - label communications by manufacturers by requiring such communications to generally be supported by  substantial evidence. notably , the fdca and fda 's implementing regulations do not in any way restrict communications about a drug among physicians , scientists , and other healthcare professionals not affiliated with the pharmaceutical company .
we contend that fda 's regulatory approach to off - label promotion , and lack of clarity regarding what manufacturer communications addressing off - label uses may be permitted , results in a chilling effect : to avoid the risk of a criminal prosecution or qui tam lawsuit under the fdca , many drug manufacturers choose to refrain from even truthful and non - misleading communications if they could be construed by the government as off - label promotion .
this part first describes fda 's current regulatory framework , including the agency 's authority over labeling , the intended use regulation , and the substantial evidence requirement .
it concludes by discussing recent agency efforts  in the form of one - off guidance documents on various specific issues  that have attempted , but largely failed , to provide drug manufacturers with some leeway to make certain communications that the agency would otherwise consider off - label or lacking in substantial evidence .
the fdca affords fda broad authority to regulate labeling , with only narrow authority over prescription drug advertising and no specific authority over over - the - counter drug advertising .
label as  a display of written , printed , or graphic matter upon the immediate container of any article.  labeling is defined as  all labels and other written , printed , or graphic matter ( 1 ) upon any article or any of its containers or wrappers or ( 2 ) accompanying such article at any time while a device is held for sale after shipment or delivery for shipment in interstate commerce. the fdca does not define 
advertising , although fda regulations suggest that the term refers to forms of manufacturer speech that are  published or 
broadcast in third - party media . in a landmark decision in kordel v. united states in 1948 , the supreme court held that the term  accompanying such article does not restrict the definition of labeling to materials that physically accompany the article .
one article or thing is accompanied by another when it supplements or explains it , in the manner that a committee report of the congress accompanies a bill .
it is the textual relationship that is significant. under this analysis , the court concluded that materials shipped separately from a product can constitute 
labeling when they  perform the function of labeling even if they are not physically shipped with the product .
the court , however , did not hold that any material or document related to the drug constitutes labeling .
it emphasized that the materials at issue were part of an  integrated distribution program and  interdependent , serving as an 
the court specifically noted that the literature at issue  explained the [ ] uses of the drugs and that 
[ n]owhere else was the purchaser advised how to use them. one issue that was not made entirely clear by the court 's decision was whether materials , even if shipped separately from the product , could constitute labeling if they do not come together with the product at some point after shipment in interstate commerce . in the decades since kordel
, fda has taken the position that physical proximity to a product does not matter when determining whether materials are labeling and takes an expansive view of the materials that qualify as labeling .
today , fda generally recognizes two types of labeling : ( 1 ) fda - required labeling and ( 2 ) promotional labeling .
fda - required labeling , ( i.e. , labeling on or within the package from which the drug is to be dispensed ) is subject to fda 's review as part of the fda 's drug approval process .
fda interprets the category of promotional labeling to include a wide - range of written communications , including , among other things , statements made in television ads , brochures , booklets , detailing pieces , internet web sites , print ads , exhibits , and sound recordings or radio ads . to satisfy fda 's mandate to promote the public health , those items that fall within the purview of the agency 's 
labeling authority are subject to stringent safety and efficacy requirements . as discussed in the following sections
labeling from discussing unapproved uses of a drug , and the agency applies the same substantiation standard required to obtain drug approval  the  substantial evidence standard  when assessing labeling claims related to safety and effectiveness .
the  intended uses of a drug matter when determining whether a drug is an 
intended use regulation provides the agency with authority to reach beyond the actual fda - approved labeling of a product to  oral and written statements and  circumstances surrounding the distribution of the article. the fdca prohibits the introduction into interstate commerce of a new drug without fda approval .
if an approved drug is intended for an unapproved use , the drug is considered an unapproved new drug with respect to the unapproved use in violation of the fdca .
admittedly , the  unapproved new drug approach for restricting off - label promotion has limitations because the definition of 
new drug ( 1 ) refers only to uses recommended in labeling and ( 2 ) excludes uses that are generally recognized as safe and effective .
consequently , an  unapproved new drug charge likely could not be sustained for off - label promotion carried out only orally or for an off - label use that is strongly supported by the scientific literature and by established standards for clinical care . as an additional method for restricting off - label promotion under the fdca ,
 misbranded if its labeling fails to include  adequate directions for use. fda regulations define  adequate directions for use as those that allow a layperson to  use a drug safely and for the purposes for which it is intended. prescription drugs are technically exempt from the statutory requirement to be labeled with  adequate directions for use if they comply with specific regulatory requirements applicable to prescription drugs , including requirements that labeling ( 1 )  bears adequate information for 
use of the drug such that a licensed practitioner may  use the drug safely and for the purposes for which it is intended , including all purposes for which it is advertised or represented ; and ( 2 ) must be the same as the fda - approved labeling with respect to the use of the drug and must be consistent with the fda - approved labeling with respect to any other information . because prescription drug labeling must match the fda - approved labeling , a prescription drug promoted for an off - label use can not satisfy the regulatory requirements to be exempt from the statutory requirement to be labeled with adequate directions for use
. put more simply , a prescription drug promoted for an off - label use can not be labeled , consistent with the fdca and fda regulations , with adequate directions for use .
fda implemented the intended use regulation in an effort to address the agency 's concern that manufacturers would circumvent the fdca 's labeling requirements by providing unapproved information to consumers in communications falling outside the traditional labeling definition .
fda defines  intended uses as referring to  the objective intent of the persons legally responsible for the labeling of drugs.
fda explains : the intent is determined by such persons expressions or may be shown by the circumstances surrounding the distribution of the article .
this objective intent may , for example , be shown by labeling claims , advertising matter , or oral or written statements by such persons or their representatives .
it may be shown by the circumstances that the article is , with the knowledge of such persons or their representatives , offered and used for a purpose for which it is neither labeled nor advertised .
the intended uses of an article may change after it has been introduced into interstate commerce by its manufacturer . if , for example , a packer , distributor , or seller intends an article for different uses than those intended by the person from whom he received the drug , such packer , distributor , or seller is required to supply adequate labeling in accordance with the new intended uses .
but if a manufacturer knows , or has knowledge of facts that would give him notice , that a drug introduced into interstate commerce by him is to be used for conditions , purposes , or uses other than the ones for which he offers it , he is required to provide adequate labeling for such a drug which accords with such other uses to which the article is to be put .
fda often relies on the intended use regulation to argue that manufacturer communications regarding off - label uses serve as evidence of a new  intended use for an approved drug . if the labeling fails to bear adequate directions for this unapproved intended use ,
if the manufacturer includes directions for this unapproved use , then the drug is an unapproved new drug . while fda has historically determined the intended uses of a product based on a manufacturer 's representations , the intended use regulation allows fda to consider other factors to establish intended use , including the manufacturer 's knowledge that the product is being used for an unapproved purpose . in more recent years
, the agency and the department of justice (  doj ) ( in criminal prosecutions ) have suggested that the following , among other things , may create a new intended use : ( 1 ) the known effect of a product on a user , ( 2 ) visits by sales representatives and the information conveyed during such visits , and ( 3 ) the subjective intent of the manufacturer . in sum , fda 's intended use regulation allows the agency to proscribe virtually all speech about a drug that goes beyond the fda - approved labeling under the theory that the drug lacks adequate directions for use , and therefore , the drug is misbranded or is an unapproved new drug .
the 1962 amendments to the fdca required a drug company to demonstrate the effectiveness of a new drug , rather than just safety , prior to approval .
the fdca defines substantial evidence as : evidence consisting of adequate and well - controlled investigations , including clinical investigations , by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved , on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed , recommended , or suggested in the labeling or proposed labeling thereof . relying on the plurality of terms  investigations , including clinical investigations , fda has interpreted 
substantial evidence as generally requiring  at least two adequate and well - controlled studies , each convincing on its own , to establish effectiveness. fda regulations set forth detailed criteria necessary to satisfy the  adequate and well - controlled studies requirement and further provide that the agency can refuse to approve a new drug application if  [ t]here is a lack of substantial evidence consisting of adequate and well - controlled investigations  that the drug product will have the effect it purports or is represented to have under the conditions of use prescribed , recommended , or suggested in its proposed labeling. the requirement of two adequate and well - controlled studies to establish effectiveness has come to be known as the  gold standard for fda approval . while the substantial evidence standard was developed in the context of drug approval , fda regulations apply this rigorous approval standard to any claim made in a wide - range of communications made about a previously approved product , setting a high bar for manufacturers  both in time and money  to share truthful and non - misleading , up - to - date information about their products . substantial evidence is required to support claims  recommended or suggested in drug labeling .
additionally , fda regulations indicate that an advertisement will be considered false or misleading if , for among other reasons , the advertisement represents or suggests the drug is more effective or safer than has been demonstrated by substantial evidence . as a limited exception to the generally applicable substantial evidence requirement
, the fdca authorizes manufacturers to provide to  a formulary committee , or other similar entity healthcare economic information (  hcei ) that  directly relates to an approved indication , so long as the information is based on  competent and reliable scientific evidence. hcei is defined as  any analysis that identifies , measures , or compares the economic consequences , including the costs of the represented health outcomes , of the use of a drug to the use of another drug , to another healthcare intervention , or to no intervention. nonetheless , despite the existence of this statutory hcei exception , at least one senior fda official in the center for drug evaluation and research takes the position that  clinical outcomes assumptions used as the basis for hcei claims must still be based on substantial evidence .
this interpretation greatly limits the ability of drug manufacturers to make hcei claims without substantial evidence to support them because drug manufacturers frequently do not have clinical outcomes data from head - to - head , adequate , well - controlled trials comparing the treatments that form the basis for the hcei claim .
generally , fda only directly applies the substantial evidence standard to  on - label statements , choosing instead to regulate off - label claims by the 
intended use analysis discussed in part iii.b , supra . however , under the agency 's asserted broad authority over promotional labeling  which includes nearly all materials that mention a product 's name  fda has effectively created a regulatory structure in which any written statements related to efficacy that a manufacturer creates about a particular product fall within fda 's regulatory authority and therefore need to be substantiated by two adequate and well - controlled clinical trials . as further discussed in part iv , infra , this strict substantiation requirement restricts manufacturers from disseminating a significant amount of truthful and non - misleading information . despite the statutory and regulatory framework described above that could be interpreted as categorically prohibiting off - label promotion ,
fda has acknowledged in one regulation that certain types of manufacturer communications fall outside the agency 's reach and are not prohibited . in a regulation addressing the promotion of investigational new drugs , fda states :
a sponsor or investigator , or any person acting on behalf of a sponsor or investigator , shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug .
this provision is not intended to restrict the full exchange of scientific information concerning the [ investigational ] drug , including dissemination of scientific findings in scientific or lay media .
the regulation does not elaborate upon the scope or definition of scientific exchange , and the agency has never clearly defined the scope of materials or manufacturer communications that fall under the umbrella of scientific exchange .
furthermore , the regulation is difficult to interpret because of its use of the term 
fda has also never specified whether the regulation applies to drugs that are not subject to an investigational new drug application .
fda 's lack of specificity to date regarding the scope of permissible scientific exchange and numerous other aspects of its regulatory framework ( e.g. , the evidence needed to support an hcei claim ) leaves manufacturers with little guidance regarding their ability to communicate truthful and non - misleading scientific information to healthcare professionals , payors , and other key stakeholders . although the regulatory schemes of many administrative agencies include vague or undefined terms , the fda 's regulatory framework is especially difficult to interpret and apply because of how interrelated the various unclear terms and provisions are to one another . in our experience as practitioners , this lack of regulatory clarity has forced manufacturers to develop their promotional compliance policies and processes by attempting to  read the tea leaves through fda enforcement letters and non - binding statements from the agency and other government officials as well as publicly available documents from government settlements with drug manufacturers .
for example , a government prosecutor stated at a public conference that relevant factors in determining whether to prosecute a manufacturer for off - label promotion include : ( 1 ) the size of the total market for the approved uses of the drug and ( 2 ) whether the manufacturer promotes the drug to doctors who do not treat patients suffering from the diseases or conditions covered by the approved uses of the drug .
the consequence of the  read the tea leaves approach is that the tea leaves may be read incorrectly , which can result in either unintended adverse judgments and penalties or unnecessary inaction .
fda has recently begun to recognize to some degree the lack of clarity and flexibility in its promotional policies and has taken strides in recent years to rectify some of these concerns via one - off guidance documents addressing certain safe harbors that , although fda had acknowledged their existence for some time , had not previously been well - defined .
these guidance documents include : a final guidance in 2009 and a revised draft guidance in 2014 addressing manufacturer dissemination of scientific publications , including medical journal articles , reference texts , and clinical practice guidelines , addressing off - label uses . under the revised draft reprints guidance ,
drug manufacturers are limited to providing articles based on adequate and well - controlled studies , even though device manufacturers  but not drug manufacturers  are permitted to distribute articles based on other scientific evidence , such as meta - analyses , pharmacokinetic and pharmacodynamics studies , or significant non - clinical research .
additionally , the revised draft reprints guidance permits the dissemination of clinical practice guidelines (  cpgs ) but only if they meet certain rigorous criteria , including that the cpg  be based on a systematic review of the evidence ( which fda does not define ) and that the cpg must satisfy standards for  trustworthiness established by the institute of medicine ( even though one recent review of 169 oncology - related cpgs found that none of the cpgs satisfied the iom standards).a draft guidance in 2011 addressing how manufacturers may respond to unsolicited requests for off - label information . under this unsolicited requests draft guidance , a request is considered 
unsolicited only if initiated by persons or entities  completely independent of the drug manufacturer and not  prompted in any way by a manufacturer or its representatives. the document also distinguishes between  public and  non - public ( i.e. , one - on - one ) unsolicited requests .
fda asserts that a manufacturer is not permitted to provide any substantive off - label information in response to a public request ; instead , the manufacturer is only permitted to invite the requestor to follow up with the manufacturer 's medical or scientific affairs department to make a  non - public request .
this limitation on a manufacturer 's ability to communicate truthful and non - misleading information simply because the communication occurs in a public forum raises both constitutional and policy concerns.a draft guidance in 2014 addressing the circumstances when a manufacturer may disseminate scientific publications discussing risk information that is inconsistent with the fda - approved labeling for the drug . under this risk information draft guidance
, drug manufacturers are permitted to communicate new risk information about a drug based on , among other things , a pharmacoepidemiologic study or a rigorous meta - analysis , that may rebut or mitigate risk information in the approved labeling .
this guidance appears to establish an exception to the agency 's substantial evidence rule , but fda does not explicitly acknowledge that its non - binding guidance is somehow intended to overrule a binding regulation . a final guidance in 2009 and a revised draft guidance in 2014 addressing manufacturer dissemination of scientific publications , including medical journal articles , reference texts , and clinical practice guidelines , addressing off - label uses . under the revised draft reprints guidance ,
drug manufacturers are limited to providing articles based on adequate and well - controlled studies , even though device manufacturers  but not drug manufacturers  are permitted to distribute articles based on other scientific evidence , such as meta - analyses , pharmacokinetic and pharmacodynamics studies , or significant non - clinical research .
additionally , the revised draft reprints guidance permits the dissemination of clinical practice guidelines (  cpgs ) but only if they meet certain rigorous criteria , including that the cpg  be based on a systematic review of the evidence ( which fda does not define ) and that the cpg must satisfy standards for  trustworthiness established by the institute of medicine ( even though one recent review of 169 oncology - related cpgs found that none of the cpgs satisfied the iom standards ) . a draft guidance in 2011 addressing how manufacturers may respond to unsolicited requests for off - label information .
unsolicited only if initiated by persons or entities  completely independent of the drug manufacturer and not  prompted in any way by a manufacturer or its representatives. the document also distinguishes between  public and  non - public ( i.e. , one - on - one ) unsolicited requests .
fda asserts that a manufacturer is not permitted to provide any substantive off - label information in response to a public request ; instead , the manufacturer is only permitted to invite the requestor to follow up with the manufacturer 's medical or scientific affairs department to make a  non - public request .
this limitation on a manufacturer 's ability to communicate truthful and non - misleading information simply because the communication occurs in a public forum raises both constitutional and policy concerns . a draft guidance in 2014 addressing the circumstances when a manufacturer may disseminate scientific publications discussing risk information that is inconsistent with the fda - approved labeling for the drug . under this risk information draft guidance
, drug manufacturers are permitted to communicate new risk information about a drug based on , among other things , a pharmacoepidemiologic study or a rigorous meta - analysis , that may rebut or mitigate risk information in the approved labeling .
this guidance appears to establish an exception to the agency 's substantial evidence rule , but fda does not explicitly acknowledge that its non - binding guidance is somehow intended to overrule a binding regulation . importantly ,
none of the guidance documents provide any discussion of how fda 's regulatory framework and policies comport with the first amendment .
they also do not address a number of other significant areas of ambiguity , such as communications with payors and formulary committees or the scope of permissible scientific exchange more broadly .
the recent guidances also do not alter existing statutory and regulatory requirements and , at least according to their express terms , do not  bind fda or the public. rather , if a manufacturer follows the recommendations provided by these guidance documents ,  fda does not intend to object to the manufacturer 's actions and  does not intend to use the manufacturer 's actions as evidence of a new , unapproved intended use for a product .
such language indicates that fda believes these practices do not technically comply with the fdca and fda regulations but may be permissible under the agency 's exercise of enforcement discretion .
nonetheless , fda 's apparent  narrow carve - outs from otherwise applicable promotional restrictions are unlikely to save fda 's current regulatory framework from a first amendment challenge . additionally , because the guidance documents claim to not even be binding on fda , they are also non - binding on the doj  the entity responsible for actually prosecuting violations of the fdca .
fda has released the recent guidance documents at least partially in response to recent citizen petitions . in july 2011 ,
seven members of the medical information working group (  miwg ) , a consortium of certain pharmaceutical and medical device manufacturers , filed a citizen petition requesting an explanation of the contours of certain promotional safe harbors . in march 2012 , in response to questions posed by fda on the meaning of scientific exchange , the miwg commented that fda had no authority to regulate scientific exchange , and that fda should more carefully define labeling and advertising to be mindful of statutory and constitutional limitations .
then , in september 2013 , the miwg filed another citizen petition reiterating the manufacturers request that the agency provide clarity with respect to the promotional safe harbors , and also asked the agency to reconsider its regulatory regime in light of new first amendment case law , particularly with respect to the definitions of 
labeling ,  advertising , and  intended use. in june 2014 , the agency granted the miwg 's citizen petition and committed to a  comprehensive review of its regulations and guidance documents in an effort to harmonize the goal of protecting the public health with first amendment interests.
today , drug manufacturers communicate with healthcare professionals by many avenues : traditional office - based and hospital - based detailing , journal advertising , internet promotion , and medical conferences and meetings , among others .
manufacturers also increasingly rely on medical science liaisons (  msls ) , specialized employees with advanced degrees and scientific training , to disseminate medical information to healthcare professionals , payors , and formulary committees ( to the extent permitted by fda ) and to engage healthcare professionals regarding mutual clinical interests and the dynamics and unmet needs in the medical community .
many of these communication methods were not contemplated when the fdca was enacted and when the fda 's restrictive regulatory framework was originally established .
fda 's restrictions on even truthful and non - misleading manufacturer speech fail to recognize the full potential of these modern communication methods to meet the urgent need in the medical community for accurate , up - to - date information about drugs to guide patient care . in the area of scientific exchange and the communication of off - label information by manufacturers , fda 's constrained rules
the fda 's effort to constrain the communication of off - label information runs counter to the clinician 's need for access to the latest clinical research and insights .
fda 's current regulatory framework also conflicts with the first amendment by imposing significant speaker - based and content - based limitations on manufacturers ability to communicate important medical information .
we believe a new regulatory framework  a new model  is necessary to address the limitations of the current framework and to permit more truthful and non - misleading communications by manufacturers .
the new model seeks to achieve the following five objectives : 
 protect the public health , consistent with fda 's mission , by ensuring healthcare professionals , payors , and other healthcare decision - makers have access to accurate , up - to - date information about drugs while at the same time ensuring that promotional communications accurately describe information submitted to fda as the basis for approval;comport with the first amendment protections afforded to drug manufacturers as emphasized by sorrell , caronia , and related cases;establish understandable and translatable rules so that manufacturers are on fair notice of what is required of them and healthcare professionals , payors , and other recipients of such information understand the context of what is being communicated;maintain the fda approval process as the  gold standard around the world while permitting truthful and non - misleading statements that may not meet the rigorous fda approval standard ; andpromote the development of new uses and maintain appropriate incentives to entry .
protect the public health , consistent with fda 's mission , by ensuring healthcare professionals , payors , and other healthcare decision - makers have access to accurate , up - to - date information about drugs while at the same time ensuring that promotional communications accurately describe information submitted to fda as the basis for approval ; comport with the first amendment protections afforded to drug manufacturers as emphasized by sorrell , caronia , and related cases ; establish understandable and translatable rules so that manufacturers are on fair notice of what is required of them and healthcare professionals , payors , and other recipients of such information understand the context of what is being communicated ; maintain the fda approval process as the  gold standard around the world while permitting truthful and non - misleading statements that may not meet the rigorous fda approval standard ; and promote the development of new uses and maintain appropriate incentives to entry . by significantly limiting the dissemination of useful knowledge by manufacturers about their drugs , fda 's restrictions on truthful and non - misleading speech actually conflict with fda 's public health mission .
fda itself openly recognizes the  the important public health and policy justification supporting dissemination of truthful and non - misleading scientific literature addressing off - label uses and even acknowledges that off - label uses  may be important and may even constitute a medically recognized standard of care. off - label use is not only highly prevalent but often critical for patient care .
5075 per cent of all oncology drug use is estimated to be off - label , and off - label use is also highly prevalent for the treatment of heart disease , aids , kidney disease , osteoporosis , and psychiatric illnesses .
one study published in 2006 estimated 21 per cent of all drug use is off - label .
additionally ,  medically accepted off - label uses are reimbursed by federal healthcare programs .
off - label treatment is often the only option for pediatric patients or patients with orphan diseases where no fda - approved drug is available .
off - label treatment also plays a key role in clinical innovation , given the time , delay , and expense in seeking fda approval for a new indication or change in the label , and such innovative flexibility is especially important when no approved treatment regimen is available to or effective for a patient .
therefore ,  open dissemination of scientific and medical information on off - label use is critical to furthering the public health .
further examples of the beneficial impact of off - label information include the clinical management of patients suffering from infection with hiv , hepatitis b virus , or hepatitis c virus .
very soon after single drugs were approved by the fda to treat patients with hiv infection , investigators , clinicians , patient advocates , and others quickly collaborated to identify and use more effective off - label , multidrug combinations .
reports of rapidly advancing clinical research demonstrated that three - agent combinations were highly effective regimens and , thus , they were quickly adopted into clinical practice and became the standard of care prior to fda approval of the combination uses .
the hiv / aids experience , underscores the importance of information exchange in accelerating the sharing of clinical insights and enhancing quality of care and related outcomes .
additionally , the fact that off - label drug use can be efficiently detected using automated information technology systems means that potentially beneficial off - label uses gleaned from prescribing data can be effectively prioritized for more in - depth , scientifically rigorous clinical research .
certainly , not all off - label uses of approved drugs ultimately prove beneficial for patients and the public health , so special care must be taken to ensure that communications regarding off - label uses are based on the most current , accurate , and complete scientific information and clinical experience available and accurately disclose the limitations of existing data . in discussing risks associated with off - label uses ,
fda officials routinely cite several examples of drugs that were widely used off - label but later found to be unsafe or ineffective . yet
, these examples do not counsel in favor of an outright ban on off - label prescribing , or even an outright ban on manufacturer communications regarding off - label uses .
as other statements by fda on the value of off - label uses and the hiv / aids example discussed above demonstrate , the benefits of off - label uses frequently outweigh the risks , and off - label uses can further the public health .
although the best evidence for drug efficacy and safety is typically one or more adequate , well - controlled studies , such evidence may not be practical to obtain in many cases .
moreover , other types of evidence , such as meta - analyses , observational studies , and real - world evidence , are valuable to healthcare professionals , payors , and other stakeholders not only for assessing effectiveness but also for assessing cost and utilization of drugs . to limit the likelihood that off - label uses are adopted by the medical community that ultimately are found to be unsafe or ineffective ,
healthcare professionals should be informed of the most accurate , up - to - date data regarding off - label uses and made aware of the relevant limitations of the data ( e.g. , is the off - label use supported by a rigorous meta - analysis of adequate , well - controlled studies , or is the off - label use supported only by anecdotal evidence consisting of a few case reports ? ) .
access to more information regarding off - label uses  provided that such information is truthful and non - misleading , and reflects the current state of the science  actually furthers the public health by ensuring that healthcare professionals determine whether to prescribe a drug off - label based on the best evidence currently available . in general , manufacturers are in the best position to disseminate information about their own products .
they are the  most efficient aggregators of information about their products and may be able to provide the timeliest data .
critics of off - label communications by manufacturers have argued that even though manufacturers maintain that off - label communications are 
truthful , these communications may not  provide the whole truth and may present information  in a manner that is inherently fraudulent or misleading. but even assuming that information dissemination by firms is driven by profit considerations , as critics have argued , a manufacturer 's economic interest does not counsel in favor of absolute suppression of the manufacturer 's speech .
rather , it just means that policies should ensure the accuracy of the information communicated .
accordingly , in implementing our proposed new model , fda should ensure that information is communicated by manufacturers along with all relevant assumptions and limitations to promote an understanding of the objectivity of the information .
fda 's framework essentially limits manufacturers to communicating only information that is contained in the fda - approved labeling .
this fda - approved labeling represents a frozen  snapshot in time that reflects the state of information at the time of approval , but it may not be updated to reflect new clinical studies and new findings in peer - reviewed publications about the drug . because healthcare professionals lack the benefit of the learning about an off - label use from the label , they have to look elsewhere for accurate , up - to - date information about the safe and appropriate use of a drug .
these other sources of information may include  academic detailers ( also known as  counter detailers ) , pharmacy benefits managers , and payors whose primary focus is reducing healthcare costs .
academic detailers may communicate with healthcare professionals , formulary committees , and payors regarding comparative effectiveness research (  cer ) for a drug , which may be based on meta - analyses , observational studies , clinical trial registries , and other real - world evidence that do not , standing alone , satisfy fda 's  substantial evidence standard .
the practice of academic detailing is not subject to fda regulations and is otherwise generally unregulated , even though in many cases it is funded by government entities .
the asymmetry in the communication of information by academic detailers versus manufacturers does not serve the public health because it may result in healthcare professionals and patients receiving incomplete or inaccurate information about a drug  potentially jeopardizing the safe and accurate use of the product .
while academic detailers and other entities may freely disseminate cer findings regarding a drug , and may be financially motivated to do so , manufacturers may be unable to respond to such findings out of fear of incurring a misbranding or off - label promotion charge .
the new model attempts to address these concerns by enabling manufacturers to communicate critical medical information relating to the safety and effectiveness of off - label uses with healthcare professionals .
enhanced communications will promote the public health by ensuring medical decision - making is based on the most current and accurate information available . at the same time , the new model would preserve fda 's exacting communication standards in traditional promotional contexts , such as a detailing visit by a sales representative to a healthcare professional 's office .
fda 's current regulatory framework raises significant first amendment concerns and does not comport with current supreme court precedent . as discussed in part ii ,
commercial speech in its truest , simplest form  does no more than propose a commercial transaction and relates  solely to the economic interests of the speaker and its audience. many materials that constitute 
labeling under the fdca , such as package inserts , product brochures , and detailing pieces , clearly fall within this commercial speech framework because they are provided to a healthcare professional to propose a commercial transaction or provided with the drug itself as part of an immediate commercial transaction .
the government 's interest in restricting drug manufacturer speech is strongest for these types of 
however , not all manufacturer communications and not all materials that might qualify as  labeling under the fda 's expansive interpretation directly propose an immediate commercial transaction .
although all manufacturer communications may be at least in some part commercially - motivated , some communications do far more than propose a commercial transaction . for example
, the distribution of a medical reprint about a drug by a manufacturer to a healthcare professional is intended primarily to educate , rather than propose an immediate sale of the drug . in the revised draft reprints guidance
, fda recognizes the value of  truthful and non - misleading scientific or medical publications on unapproved new uses and implicitly acknowledges the educational , rather than promotional , nature of this activity by recommending that a reprint be distributed separately from information that is  promotional in nature. accordingly , the distribution of the medical reprint by the manufacturer should be considered a mix of both commercial and  non - commercial speech .
the government 's interest in regulating the non - commercial aspects of drug manufacturer speech ( i.e. , dissemination of truthful and non - misleading medical information ) is certainly weaker than the government 's interest in regulating purely commercial speech .
fda 's current regulatory framework conflicts with the first amendment under the rationale of sorrell and caronia by imposing significant speaker - based and content - based restrictions on manufacturers ability to communicate important medical information .
the supreme court in sorrell emphasized that government regulations disfavoring a specific type of speech ( i.e. , marketing ) as expressed by specific parties ( i.e. , pharmaceutical manufacturers ) are subject to heightened scrutiny and presumptively unconstitutional .
the fda 's restrictions are speaker - based because they only apply to the manufacturer of the drug ; healthcare professionals , academics , and other speakers are free to discuss off - label uses of a drug . indeed , the volume of information about drugs disseminated on the internet and via social media for healthcare professionals and consumer audiences is staggering , yet the fda restricts the ability of drug manufacturers to partake in these valuable discussions .
the fda 's restrictions are also content - based because they prohibit off - label speech , and other speech with respect to drugs and biologics that is not supported by substantial evidence .
relying on sorrell , the caronia court confirmed that the first amendment protects truthful and non - misleading speech  regardless of whether that speech is off - label or relates to a commercial purpose .
the first amendment analysis in caronia also suggests that truthful , non - misleading speech , in and of itself , can not be regulated in the absence of an accompanying unlawful act because the court construed the fdca  as not criminalizing the simple promotion of a drug 's off - label use because such a construction would raise first amendment concerns. admittedly , not all legal commentators agree with the analyses of sorrell and caronia , some academics have suggested that the caronia court erred in applying heightened scrutiny and that the government could have made a stronger case that its regulatory framework satisfies the central hudson test .
some commentators have even objected to the premise that off - label communications can be truthful ; they argue that off - label communications may be considered  inherently misleading. the basis for this position appears to be an assumption that the  truth is unknowable until all of the manufacturer 's research has been evaluated , and until the off - label statement has been proven by substantial evidence ; in other words , some commentators appear to believe that the truth of any statement related to an off - label use is  unknown because it may not be supported by the same level of evidence as claims that have already been approved by fda . despite these contentions ,
the argument that off - label communications are inherently misleading was rejected more than 15 years ago in the wlf cases .
the district court in wlf explained : in asserting that any and all scientific claims about the safety , effectiveness , contraindications , side effects , and the like regarding prescription drugs are presumptively untruthful or misleading until the fda has had the opportunity to evaluate them , fda exaggerates its overall place in the universe .  
moreover , an oft - cited analysis of evidentiary support for off - label uses found that more than a quarter of the off - label uses studied  were supported by strong scientific evidence. the  truth of an off - label communication lies not in whether the off - label use has been approved by fda or in whether the off - label use is supported by substantial evidence , but in whether the communication accurately reflects all the available evidence . applying the logic of caronia and sorrell
, any first amendment - compliant regulatory framework should not restrict manufacturers from their right to engage in truthful and non - misleading dialog about the safety or efficacy of a drug , unless the framework is narrowly drawn to support a substantial government interest .
this level of heightened scrutiny sets a very high bar for the government . because as stated by the supreme court , if the government can achieve its interest without restricting speech , then it must do so .
resort. courts are more likely to uphold a regulatory scheme that allows for alternative means of communication .
accordingly , fda may establish reasonable restrictions for well - defined , limited categories of speech , so long as meaningful , alternative avenues of communication are open .
however , fda 's current regulatory framework does not impose reasonable restrictions on certain well - defined types of communication ; rather , despite a handful of fda guidance documents that very narrowly authorize certain categories of manufacturer communications ( e.g. , distribution of reprints ) in very limited circumstances under fda 's exercise of enforcement discretion , fda broadly prohibits nearly all communications by manufacturers regarding off - label uses .
such a broad , content- and speaker - based prohibition on speech is presumptively unconstitutional . in light of these first amendment considerations ,
the regulation of manufacturer speech under the new model does not focus on suppressing information but instead ensures that manufacturers may provide patients and prescribers with truthful and non - misleading , up - to - date information about therapeutic options .
although certain fda guidance documents attempt to clarify fda 's regulatory requirements for certain limited categories of communications , none of these materials provide any clear explanation regarding how fda 's regulatory framework comports to the first amendment , even though such an explanation is crucial to ensuring , consistent with the supreme court 's fox ii decision , that fda 's regulatory framework is not enforced in an arbitrary or discriminatory manner that chills protected speech .
for example , as discussed above , the recent risk information draft guidance purports to permit drug manufacturers to communicate new risk information about a drug that may not satisfy the agency 's substantial evidence regulation . because fda does not even acknowledge that its non - binding guidance is intended to overrule a binding regulation , much less explain how this sort of rulemaking is legally permissible
, drug manufacturers can not be certain that fda will not allege a violation of the substantial evidence regulation even if they comply with all the terms of the risk information draft guidance .
essentially , unless fda has specifically authorized a particular type of communication ( e.g. , dissemination of reprints ) and issued specific , precise guidance , manufacturers can not be sure whether or not the agency considers the communication to be impermissible off - label promotion .
such vagueness may not comport with the due process clause requirement that laws  must give fair notice of conduct that is forbidden or required , as recently reiterated by the supreme court in fox ii .
given fda 's expansive view of what constitutes labeling and what evidence may support a new intended use for a drug , almost any utterance by an employee or agent of the manufacturer in any context could run afoul of fda 's promotional rules . while fda guidance documents have described several extra regulatory 
safe harbors for certain manufacturer communications on the basis of enforcement discretion , for the most part drug company speakers and their agents must tread at their own peril when not speaking within the four corners of the fda - approved label .
this vagueness in fda 's regulatory framework , especially with respect to what communications qualify as permissible  scientific exchange , results in a chilling effect among manufacturers .
accordingly , the new model aims to be understandable by all stakeholders in a way that is actionable and translatable to the benefit of the public health .
fda will only approve a drug on the basis of substantial evidence of effectiveness  generally two adequate and well - controlled clinical studies . because the standard of replication of adequate and well - controlled clinical studies is the most rigorous way to develop persuasive evidence that a product is likely to be effective
, this drug approval standard should be maintained in the interest of the public health . while the substantial evidence standard makes sense in the context of fda review and approval decisions
, requiring this same level of evidence to substantiate any claim or communication about a drug , as fda regulations currently mandate but which is not required by the fdca , fails to recognize that other valid sources of data and information can be used to support product claims .
healthcare professionals , formulary committees , and payors frequently rely upon evidence other than adequate and well - controlled studies to make informed decisions about the proper uses of a product .
for example , claims based on economic modeling , government or third - party treatment guidelines , and patient case studies may offer valuable safety and efficacy information that would benefit patients , yet such claims would not amount to substantial evidence under fda 's current regime . additionally , observational research has become increasingly reliable and robust , due to remarkable technological advances in data analysis , recording , and storage .
therefore , the new model should protect the integrity of the fda approval process by maintaining the substantial evidence standard in the context of the approval of new drug applications and supplemental new drug applications , but it should also permit truthful and non - misleading claims about a drug based on  competent and reliable scientific evidencethe substantiation standard employed by the federal trade commission (  ftc)that may not rise to the level of substantial evidence .
competent and reliable scientific evidence has been defined as tests , analyses , research , studies , or other evidence based upon the expertise of professionals in the relevant area , that has been conducted and evaluated in an objective manner by persons qualified to do so , using procedures generally accepted in the profession to yield accurate and reliable results .
this standard would permit flexibility by potentially enabling myriad sources of relevant evidence , taking into account considerations of the relevant scientific community , to constitute adequate substantiation for drug claims . criticism that a more permissive framework for the communication of product information would discourage the development of new uses for approved products
the underlying assumption of this criticism is that a more permissive framework would encourage sponsors to seek narrow uses to bring a product to market and then disseminate data on unapproved uses instead of seeking fda approval for those uses .
there are several market - driven and legal reasons that make this outcome less likely .
first , in the post - healthcare reform era of evidenced - based medicine where the need to demonstrate value and cost - effectiveness to payors and healthcare professionals is as great as it has ever been , an off - label use of a product with limited safety and efficacy data is unlikely to gain significant market acceptance .
moreover , sponsors would likely be hesitant to rely on less than substantial evidence to fuel growth in commercially important uses given the product liability risks that such a marketing strategy would entail .
similar liability concerns would likely dissuade healthcare professionals from rapid adoption of unproven uses of drugs . notwithstanding these protective , market - driven forces
, there are relatively modest legislative incentives that could be enacted to fully address the theoretical problem of manufacturers not seeking fda approval for new uses .
as evidenced by the success of the pediatric exclusivity program , similar incentives could be legislated to support the development and fda approval of new uses if this theoretical problem materialized .
the fda approval process not only safeguards the public health by setting a high bar to minimize the possibility that approved uses will turn out to be unsafe or ineffective , but it can also promote higher quality information about drugs , as well as innovation , so long as a careful balance is maintained in terms of the standards for information exchange .
the fda approval process assesses , among other things , the limitations and potential biases in the clinical data for a drug . in that way
nonetheless , reliance on the suppression of speech as a means of creating the incentive for drug manufacturers to pursue fda approval for off - label uses is problematic .
accordingly , the new model seeks to balance information exchange with the need to maintain high regulatory approval standards while ensuring that incentives still exist for the development and approval of new uses for previously - approved drugs .
this part proposes a new model for the regulation of drug promotion intended to achieve the objectives described in part iv .
legal commentators have previously suggested various modifications to fda 's regulatory framework and enforcement strategy that would address similar policy and constitutional objectives .
safe harbors to permit certain off - label communications , requiring drug manufacturers to bear the burden of establishing the truthfulness of off - label communications in any enforcement proceeding , permitting drug manufacturers to communicate off - label information  whether solicited or unsolicited  under certain circumstances depending on the strength of the information and the sophistication of the audience while imposing additional training , monitoring , reporting , and auditing requirements on manufacturers , and requiring manufacturers to submit a supplemental new drug application for any particular off - label use that exceeds a specified percentage of the total prescriptions for the drug or a specified dollar amount of total sales of the drug . as an attempt at a more comprehensive proposal , our new model would create a three - tiered regulatory framework corresponding to three different categories of manufacturer communications : ( 1 ) scientific exchange and other exempt communications , ( 2 ) non - core communications , and ( 3 ) core communications .
the new model is premised on the idea that fda may , consistent with the first amendment , set reasonable limits on well - defined categories of speech , provided that meaningful , alternative avenues of communication remain open .
the level of regulation provided fda for each category under the new model is associated with the strength of the government 's interest in regulating the specific communications included within each category and the immediacy of the commercial transaction being proposed . as discussed further below
, scientific exchange and other exempt communications would include those communications either intended to advance the scientific enterprise or that otherwise do not qualify as labeling or advertising and that do not propose an immediate commercial transaction of the drug .
the new model would clarify that fda has no authority to regulate scientific exchange and other exempt communications .
non - core communications would include those communications that present truthful and non - misleading scientific information and that , due to the context of the communications and the entities involved , only tangentially relate to an immediate commercial transaction .
fda would have the authority to regulate such communications under a  false and misleading standard , but fda would not be able to consider non - core communications as evidence of a new intended use by the manufacturer .
lastly , core communications would include those communications , such as product package inserts , that directly propose an immediate commercial transaction and that are considered labeling .
fda would retain its full authority to require that all core communications be consistent with fda - approved labeling and be supported by substantial evidence .
this new model could largely be implemented through fda 's regulatory process ( e.g. , rulemakings to clarify the definition of  scientific exchange and the applicability of the intended use regulation and substantial evidence requirements ) , although certain legislative changes would likely be required . under the new model , communications and materials that qualify as scientific exchange and other exempt communications would be outside the scope of fda 's jurisdiction .
although existing fda regulations state that fda does not intend to restrict full access to the  full exchange of scientific information , fda has never spoken on the full scope and applicability of this valuable 
exchange to drug manufacturer communications , including , for instance , communications about a drug that is not the subject of an investigational new drug application .
fda 's limited statements on the subject include one regulatory preamble from over 25 years ago in which the agency noted : fda 's understanding of commercial promotion does not place limits on the free exchange of scientific information ( e.g. , publishing results of scientific studies , letters to the editor in defense of public challenges , investigator conferences ) .
however , responses by sponsors or investigators to unsolicited media inquiries or statements made in the exchange of scientific information should ( 1 ) make clear that the drug is investigational ; ( 2 ) make no claims that the drug has been proven to be safe or effective ; and ( 3 ) be truthful and non - misleading when measured against available information on the drug  and fairly represent available information .  to allow manufacturers to engage in this important form of communication , without incurring the risk of enforcement actions or criminal prosecutions , the fda must clarify the term  scientific exchange and build upon its limited prior statements . the new model , therefore , more clearly defines scientific exchange and sets forth the category of materials that qualify as such .
the new model would also define a related category of  other exempt communications that fall outside the scope of fda regulation because they do not qualify as labeling or advertising under the fdca , even if they do not technically qualify as scientific exchange . under the new model , scientific exchange includes communications that advance the scientific enterprise and do not primarily promote the sale of any particular drug for any particular use .
the four essential requirements for scientific exchange are as follows : 
 scientific exchange involves interactions that advance the systematic pursuit of knowledge among only sophisticated , highly educated , and experienced entities , such as biopharmaceutical companies , scientific researchers , healthcare professionals , formulary committees , and payors.the information disseminated is factual , scientific , and data-driven.the information disseminated is placed in the appropriate context ( e.g. , trial design limitations and potential biases are disclosed ) , so that the audience may evaluate the proper weight to afford such data.the information does not include conclusions or promotional claims about the safety or effectiveness of a drug for a particular use .
scientific exchange involves interactions that advance the systematic pursuit of knowledge among only sophisticated , highly educated , and experienced entities , such as biopharmaceutical companies , scientific researchers , healthcare professionals , formulary committees , and payors .
the information disseminated is placed in the appropriate context ( e.g. , trial design limitations and potential biases are disclosed ) , so that the audience may evaluate the proper weight to afford such data .
the information does not include conclusions or promotional claims about the safety or effectiveness of a drug for a particular use .
examples of scientific exchange include , among others : 
 presentations , speeches , abstracts , and other information disseminated during meetings or conferences sponsored by healthcare professionals , medical associations , or scientific research organizations;dissemination of scientifically rigorous , peer - reviewed publications in scientific and medical journals , regardless of whether or not such publications address adequate , well - controlled studies , provided that limitations of the data relied on in such publications are appropriately disclosed , and provided that the publications comply with internationally - recognized guidelines on authorship and the disclosure of conflicts of interest;dissemination of peer - reviewed scientific or medical reference textbooks;dissemination of scientifically rigorous cpgs developed by governmental bodies , medical organizations , non - profit organizations , or other third parties;direct communications among scientific and medical researchers regarding research studies and a manufacturer 's product pipeline ; andrebuttals of erroneous or incomplete scientific information about a drug , which may include responses to cer findings presented by academic detailers .
presentations , speeches , abstracts , and other information disseminated during meetings or conferences sponsored by healthcare professionals , medical associations , or scientific research organizations ; dissemination of scientifically rigorous , peer - reviewed publications in scientific and medical journals , regardless of whether or not such publications address adequate , well - controlled studies , provided that limitations of the data relied on in such publications are appropriately disclosed , and provided that the publications comply with internationally - recognized guidelines on authorship and the disclosure of conflicts of interest ; dissemination of peer - reviewed scientific or medical reference textbooks ; dissemination of scientifically rigorous cpgs developed by governmental bodies , medical organizations , non - profit organizations , or other third parties ; direct communications among scientific and medical researchers regarding research studies and a manufacturer 's product pipeline ; and rebuttals of erroneous or incomplete scientific information about a drug , which may include responses to cer findings presented by academic detailers . besides scientific exchange , there are other exempt communications that fall outside the scope of fda regulation because fda has no statutory authority to regulate them .
as discussed in parts iii.ab , supra , fda 's authority does not extend to all forms of 
promotion. rather , fda only has the authority to regulate  labeling and  advertising ( although oral statements may fall within the scope of the intended use regulation and are indirectly subject to fda regulation )
. other exempt communications are those communications , other than scientific exchange , that do not qualify as labeling or advertising . examples of other exempt communications include , among others : 
 communications specifically directed toward investors , rather than the general public , such as annual reports or other securities filings , that may reference the results of clinical research , a regulatory event ( e.g. , submission or approval of a new drug application ) , or other product - specific information material to a drug manufacturer 's shareholders ; andindustry - supported , independent , and accredited cme programs intended to educate physicians but that may not directly advance the scientific enterprise and therefore may not qualify as scientific exchange .
communications specifically directed toward investors , rather than the general public , such as annual reports or other securities filings , that may reference the results of clinical research , a regulatory event ( e.g. , submission or approval of a new drug application ) , or other product - specific information material to a drug manufacturer 's shareholders ; and industry - supported , independent , and accredited cme programs intended to educate physicians but that may not directly advance the scientific enterprise and therefore may not qualify as scientific exchange .
in contrast to product labeling , detailing materials , and oral communications by sales representatives , scientific exchange and other exempt communications cover manufacturers communications that do not directly prescribe , recommend , or suggest a use related to any commercial transaction .
hence , scientific exchange and other exempt communications are not purely commercial speech under the first amendment because scientific exchange and other exempt communications do not directly 
the government 's interest in regulating the non - commercial aspects of scientific exchange ( i.e. , the scientific expression itself ) is far less significant than the government 's interest in regulating commercial speech .
information that is exchanged in the interest of scientific discovery is at the heart of the protection provided by the first amendment . yet
, fda 's current regulatory framework does not provide sufficient clarity to manufacturers that the types of scientific exchange listed above will not be considered unlawful by the agency .
consequently , a chilling effect results , meaning that manufacturers may refrain from engaging in scientific exchange that would otherwise be beneficial to the public health by providing accurate , up - to - date medical information to support research and to guide patient care .
therefore , the new model would make clear that fda has no authority to regulate such scientific exchange , so that manufacturers would be assured that engaging in scientific exchange would not run afoul of the fdca and fda regulations .
with respect to other exempt communications , fda currently has no authority to regulate them because they do not qualify as labeling or advertising .
the new model would therefore maintain the status quo with respect to this category of communications . under fda 's current regulatory framework ,
a wide range of truthful and non - misleading manufacturer communications of important scientific information about a drug are prohibited or significantly restricted merely because the communications deviate from the fda - approved labeling of the drug or are not supported by substantial evidence .
fda 's current framework essentially only includes two categories of communications : ( 1 )  promotional communications over
which fda asserts its full regulatory authority and ( 2 ) scientific exchange over which fda has no regulatory authority .
as previously noted , not all manufacturer communications are designed to propose the immediate sale and distribution of a drug in interstate commerce .
rather , many manufacturer communications have a mix of both commercial and non - commercial aspects .
the primary intent of these communications may be to educate healthcare professionals , payors , and formulary committees to inform treatment decisions ( in the case of healthcare professionals ) or coverage and reimbursement decisions ( in the case of payors and formulary committees ) .
such non - core communications are only indirectly related to a commercial transaction , so the justification for regulating non - core communications in the same manner as traditional promotional communications and advertising is unconvincing .
promotional. on the other hand , not all communications that do not propose the immediate sale of a drug are scientific exchange .
the non - core communications category of the new model would remove the chilling effect associated with certain types of communications , such as manufacturer - sponsored speaker presentations by expert healthcare professionals to other healthcare professionals , that fda might today view as evidence of a new intended use of a drug . at the same time , the non - core communications category would alleviate the need for industry to argue that any non - promotional communication necessarily qualifies as scientific exchange . in other words ,
some communications like speaker presentations that manufacturers previously might have argued fell under the umbrella of scientific exchange and were therefore exempt from fda regulation would instead be subject to direct fda regulation as non - core communications . under the new model
, fda would not have the authority to consider non - core communications as evidence of a new intended use nor would fda have the authority to require that non - core communications be supported by substantial evidence .
fda would have the authority to regulate non - core communications that are false or misleading . in determining whether a non - core communication is false or misleading ,
fda would rely on a more flexible substantiation standard than the current substantial evidence requirement .
non - core communications include those written materials and oral statements that do not qualify as core communications , discussed infra , but that may still be considered to indirectly propose the sale and distribution of a drug .
manufacturer - sponsored speaker programs recruit leading healthcare professionals to speak to other healthcare professionals in local communities about a particular drug .
this physician - to - physician communication is useful to help educate and inform the medical community about the benefits , risks , and appropriate uses of a drug .
admittedly , speaker presentations have been the subject of some government scrutiny and public controversy in recent years , as some pharmaceutical companies have allegedly used them to market their drugs improperly or to provide unlawful kickbacks to physician speakers . nevertheless , properly - executed speaker presentations do have educational value because they tend to be highly data - driven and focus on detailed scientific information , such as the results of clinical trials of a drug .
their function is to raise awareness of a drug in the medical community and educate healthcare professionals who may otherwise lack enough information to know whether or not to prescribe the drug .
moreover , pharmaceutical industry codes provide that legitimate speaker programs may not be intended as inducements or rewards for prescribing a particular drug .
nevertheless , manufacturer - sponsored speaker presentations , unlike industry - supported cme programs delivered by healthcare professionals , include conclusions and promotional claims about the safety and effectiveness of a drug for particular uses , so they are properly considered non - core communications , rather than scientific exchange.discussions by 
msls with healthcare professionals that do not make conclusions or promotional claims of safety or effectiveness . unlike sales representatives , msls are employed by drug companies to serve as scientific resources to the medical community and develop and maintain relationships with key opinion leaders .
msls responsibilities include conveying complex medical and technical information to healthcare professionals , keeping abreast of relevant scientific developments , representing the manufacturer at scientific symposia and meetings , supporting clinical trials by identifying sites , educating investigators , and attending investigator meetings , and responding to unsolicited requests .
because msls are communicating to an educated audience of healthcare professionals who have the expertise to evaluate the merits of the information presented , the new model would permit an msl to reactively and proactively communicate truthful , non - misleading information to healthcare professionals , even if such information relates to an off - label use or is not supported by substantial evidence , provided that the msl does not make conclusions related to safety and effectiveness and provided that the msl discloses the relevant limitations of the data.dissemination of hcei and pipeline information to payors , formulary committees , and similar entities .
payors and formulary committees evaluate hcei , even where a drug is not yet approved for a particular indication , in making coverage and reimbursement decisions .
although the fdca currently allows manufacturers to provide to  a formulary committee , or other similar entity hcei that  directly relates to an approved indication if the information is based on  competent and reliable scientific evidence , this provision does not permit the communication of hcei about off - label uses nor does it permit communication of hcei to healthcare professionals .
manufacturers should be permitted to communicate hcei about unapproved , investigational products to payors , formulary committees , and compendia publishers to facilitate this decision - making and ensure that patients will have access to reimbursement for a drug upon its approval .
such communications do not propose an immediate commercial transaction because payors , formulary committees , and related entities do not directly purchase or prescribe a drug.manufacturer-sponsored scientific symposia that are primarily intended to educate physicians but that do not satisfy the criteria of fda 's cme guidance . fda 's existing cme guidance outlines numerous criteria for differentiating between industry - supported cme programs that are independent of a manufacturer 's influence and which are not subject to fda regulation , and those that are influenced by the manufacturer and which fda insists should be subject to the full gamut of fda regulation . because of fda 's longstanding position , manufacturers have generally refrained from sponsoring and hosting their own scientific symposia and educational programs to discuss the latest clinical research regarding a drug or other clinical developments out of fear that such programs will be viewed as creating a new , off - label intended use .
such manufacturer - sponsored symposia would not be discouraged in this manner under the new model . despite their lack of 
independence , they can still serve a valuable educational function , provided of course that the information communicated by the manufacturer is truthful and non - misleading and includes appropriate disclosures .
manufacturer - sponsored speaker programs recruit leading healthcare professionals to speak to other healthcare professionals in local communities about a particular drug .
this physician - to - physician communication is useful to help educate and inform the medical community about the benefits , risks , and appropriate uses of a drug .
admittedly , speaker presentations have been the subject of some government scrutiny and public controversy in recent years , as some pharmaceutical companies have allegedly used them to market their drugs improperly or to provide unlawful kickbacks to physician speakers .
nevertheless , properly - executed speaker presentations do have educational value because they tend to be highly data - driven and focus on detailed scientific information , such as the results of clinical trials of a drug .
their function is to raise awareness of a drug in the medical community and educate healthcare professionals who may otherwise lack enough information to know whether or not to prescribe the drug .
moreover , pharmaceutical industry codes provide that legitimate speaker programs may not be intended as inducements or rewards for prescribing a particular drug . nevertheless , manufacturer - sponsored speaker presentations , unlike industry - supported cme programs delivered by healthcare professionals , include conclusions and promotional claims about the safety and effectiveness of a drug for particular uses , so they are properly considered non - core communications , rather than scientific exchange .
discussions by  msls with healthcare professionals that do not make conclusions or promotional claims of safety or effectiveness . unlike sales representatives , msls are employed by drug companies to serve as scientific resources to the medical community and develop and maintain relationships with key opinion leaders .
msls responsibilities include conveying complex medical and technical information to healthcare professionals , keeping abreast of relevant scientific developments , representing the manufacturer at scientific symposia and meetings , supporting clinical trials by identifying sites , educating investigators , and attending investigator meetings , and responding to unsolicited requests .
because msls are communicating to an educated audience of healthcare professionals who have the expertise to evaluate the merits of the information presented , the new model would permit an msl to reactively and proactively communicate truthful , non - misleading information to healthcare professionals , even if such information relates to an off - label use or is not supported by substantial evidence , provided that the msl does not make conclusions related to safety and effectiveness and provided that the msl discloses the relevant limitations of the data .
dissemination of hcei and pipeline information to payors , formulary committees , and similar entities .
payors and formulary committees evaluate hcei , even where a drug is not yet approved for a particular indication , in making coverage and reimbursement decisions .
although the fdca currently allows manufacturers to provide to  a formulary committee , or other similar entity hcei that  directly relates to an approved indication
if the information is based on  competent and reliable scientific evidence , this provision does not permit the communication of hcei about off - label uses nor does it permit communication of hcei to healthcare professionals .
manufacturers should be permitted to communicate hcei about unapproved , investigational products to payors , formulary committees , and compendia publishers to facilitate this decision - making and ensure that patients will have access to reimbursement for a drug upon its approval .
such communications do not propose an immediate commercial transaction because payors , formulary committees , and related entities do not directly purchase or prescribe a drug .
manufacturer - sponsored scientific symposia that are primarily intended to educate physicians but that do not satisfy the criteria of fda 's cme guidance .
fda 's existing cme guidance outlines numerous criteria for differentiating between industry - supported cme programs that are independent of a manufacturer 's influence and which are not subject to fda regulation , and those that are influenced by the manufacturer and which fda insists should be subject to the full gamut of fda regulation . because of fda 's longstanding position , manufacturers have generally refrained from sponsoring and hosting their own scientific symposia and educational programs to discuss the latest clinical research regarding a drug or other clinical developments out of fear that such programs will be viewed as creating a new , off - label intended use .
such manufacturer - sponsored symposia would not be discouraged in this manner under the new model . despite their lack of 
independence , they can still serve a valuable educational function , provided of course that the information communicated by the manufacturer is truthful and non - misleading and includes appropriate disclosures . for all non - core communications ,
fda 's authority would be limited to the prohibition of false and misleading speech because such communications do not propose a direct , immediate commercial transaction , so the government 's interest in regulating these communications is relatively weak .
fda would not have the authority under the new model to rely on non - core communications as evidence that a manufacturer intended a new , unapproved use for a drug nor would fda be able to require substantial evidence to substantiate all promotional claims of safety or effectiveness in non - core communications .
consistent with the first amendment principles espoused in sorrell and caronia , fda would not be able to construe a manufacturer 's truthful and non - misleading speech about the lawful use of a drug ( i.e. , off - label prescribing ) as unlawful activity ( i.e. , introducing an unapproved or misbranded drug into interstate commerce ) . also consistent with the first amendment , fda would retain the authority to prohibit all false and misleading non - core communications because false and misleading speech warrants no constitutional protection .
however , the new model would not deem communications to be false and misleading simply because they are not supported by two adequate and well - controlled studies . rather
, the new model would consider non - core communications to be false and misleading if they are not supported by competent and reliable scientific evidence .
this standard would permit flexibility by allowing a wide range of relevant evidence to be considered in determining whether a statement is adequately substantiated , taking into account the level of substantiation that experts in the field believe is reasonable .
it would not strictly require two adequate , well - controlled studies to support all efficacy and safety claims . applying this substantiation standard to non - core communications would still limit the ability of manufacturers to disseminate false and misleading product information while also providing healthcare professionals , payors , and other audiences the benefit of access to up - to - date information about a drug .
furthermore , the likelihood that information conveyed via non - core communications would  mislead the audience is low given that non - core communications are primarily intended for learned , sophisticated audiences like healthcare professionals , payors , and formulary committees . recognizing the ability of these audiences to evaluate critically the merit of scientific and medical information , the supreme court has rejected the paternalistic notion that healthcare professionals might make 
bad decisions ( e.g. , prescribe unnecessary medications ) when presented with truthful , factual information about drugs . by limiting fda 's regulatory authority over non - core communications and adopting a more flexible substantiation standard for claims made in non - core communications ,
the new model would increase access to product information while ensuring that such information is based on data that can be replicated and validated by others in the relevant scientific community .
core communications would include those communications , such as product package inserts , that directly propose a commercial transaction and that are properly considered 
labeling under the fdca ( i.e. , materials that are part of an integrated distribution program and serve as essential supplements to the drug label , even if not shipped directly with the drug ) .
the government 's interest in restricting drug manufacturer speech is at its strongest when restricting such promotional communications that are directed toward the sale and distribution of a drug .
fda would retain its existing authority to require that all core communications be consistent with the fda - approved labeling for the drug and be supported by substantial evidence .
the new model 's restrictions on core communications should nonetheless comport with the first amendment because of the alternative , less restrictive avenues of communication also provided by the new model with regard to scientific exchange and non - core communications .
core communications include only those written materials that are specifically designed to promote an immediate commercial transaction involving the drug .
examples of core communications include : the fda - approved label and package insert for the drug , sales aids presented to healthcare professionals , product - specific websites intended for healthcare professionals and patients , direct - to - consumer advertisements , andother written materials developed by the manufacturer that describe the drug and are part of an immediate commercial transaction involving the drug , such as promotional brochures provided to healthcare professionals . the fda - approved label and package insert for the drug , sales aids presented to healthcare professionals , product - specific websites intended for healthcare professionals and patients , direct - to - consumer advertisements , and other written materials developed by the manufacturer that describe the drug and are part of an immediate commercial transaction involving the drug , such as promotional brochures provided to healthcare professionals .
they describe the uses of the drug in the context of an immediate commercial transaction : the purchase ( or more accurately , the prescribing ) of a drug offered for sale in interstate commerce .
core communications do not encompass every statement that could possibly , at some point in the future , have some bearing on a healthcare professional 's decision to prescribe a drug .
rather , core communications are limited to those communications primarily intended to propose an immediate commercial transaction .
in other words , fda could consider core communications as evidence that a drug is intended for an unapproved new use and could determine that core communications are false and misleading because they are not supported by substantial evidence .
the logic of fda 's existing regulations describing intended uses and substantial evidence would remain in effect , but their reach would be limited only to core communications and not non - core communications or scientific exchange .
hence , all core communications would need to be consistent with the fda - approved labeling for the drug , and claims of safety and effectiveness would generally need to be substantiated by two adequate , well - controlled studies . additionally , oral statements about core communications , such as a sales representative 's description of the package insert or a sales representative 's presentation of a sales aid to a healthcare professional , could be used as evidence of intended use . even though the new model would limit the dissemination of off - label information in core communications ,
first , it is necessary to advance the government 's interest in protecting the fda approval process and ensuring that manufacturers can not advertise and promote a drug in a commercial context for an unapproved use .
second , the restriction only applies to core communications , leaving manufacturers free to share truthful and non - misleading information about off - label uses in non - core communications and scientific exchange and other exempt communications . by leaving open alternative channels of communication
fda 's current regulatory framework for drug promotion , by significantly restricting the ability of drug manufacturers to communicate important , accurate , up - to - date scientific information about their products that is truthful and non - misleading , runs afoul of the first amendment and actually runs counter to the agency 's public health mission .
industry stakeholders have long been urging fda to announce clearer , more flexible rules that respect manufacturers first amendment rights . yet , fda 's limited actions to date 
the release of several non - binding guidance documents on particular topic areas  fail to provide the pharmaceutical industry with the clarity it is seeking and also fail to elucidate how the agency 's regulatory framework comports with the first amendment .
the new model described in this article represents an initial proposal for a modern , sustainable regulatory framework that comprehensively addresses drug promotion while protecting the public health , protecting manufacturers first amendment rights , establishing clear and understandable rules , and maintaining the integrity of the fda approval process .
we believe that healthcare professionals and patients , in addition to drug manufacturers , would benefit from the implementation of the new model .
we hope that the new model can be used as a framework to guide discussions between industry , fda , and congress regarding the future of the regulation of drug promotion .
 the us food and drug administration 's (  fda or the  
 agency ) current regulatory framework for drug promotion , by significantly restricting the ability of drug manufacturers to communicate important , accurate , up - to - date scientific information about their products that is truthful and non - misleading , runs afoul of the first amendment and actually runs counter to the agency 's public health mission . 
 our article proposes a new model that represents an initial proposal for a modern , sustainable regulatory framework that comprehensively addresses drug promotion while protecting the public health , protecting manufacturers first amendment rights , establishing clear and understandable rules , and maintaining the integrity of the fda approval process . 
 the new model would create three categories of manufacturer communications(1 ) scientific exchange and other exempt communications , ( 2 ) non - core communications , and ( 3 ) core communications  that would be regulated consistent with the first amendment and according to the strength of the government 's interest in regulating the specific communications included within each category . 
 the new model should address the fda 's concerns related to off - label speech while protecting drug manufacturers freedom to engage in truthful and non - misleading communications about their products . 
INTRODUCTION
FIRST AMENDMENT PROTECTION OF DRUG MANUFACTURER SPEECH
FDA'S CURRENT REGULATORY FRAMEWORK
THE NEED FOR A NEW REGULATORY MODEL AND ITS OBJECTIVES
THE NEW MODEL
CONCLUSION