Stages of a funnel for Pharmaceutical

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module two promotion of pharmaceutical products the development and marketing of drugs for the prevention or treatment of diseases can present opportunities for contributions by scientists medical professionals or other people in the healthcare industry in the vast majority of instances they do so with the best of intentions and the purest of motives however they may also be challenged by temptations to circumvent the controls that have been put in place by the regulatory agencies that we discussed in the previous module breaking or stretching the rules can sometimes be rationalized based on humanitarian goals such as the possibility of allowing broader and cheaper access to medicines for disadvantaged patients at the other end of the spectrum however is the all-too-human desire for personal gain either in wealth or status that can sometimes be fulfilled by pursuing methods that compromise accepted legal or ethical standards regardless of the motivation these abuses can result in threats to public health and welfare in this module we'll examine some of the categories of violations that may be committed and how the law deals with them promotion of pharmaceutical products for most people the drug development process is a black box that only enters into their sphere of consciousness at the stage known as marketing it is at this point that drug companies promote the use of their drugs to consumers and to the physicians who prescribe it and the patients who use it in the late 1950s the pharmaceutical industry was confronted with an attack led by the late senator Estes Kefauver chairman of the Senate's antitrust and monopoly subcommittee he accused the industry of the following abuses one patient sustained predatory prices and excessive margins to costs and prices were extravagantly increased by large expenditures in marketing and three most of the industry's new products were no more effective than established drugs already on the market as a result of this campaign public perception of the industry was transformed as the image of life-saving researchers and white coats was now contested by one of greedy reps and cars the US Food and Drug Administration responded by developing legislation and non-binding guidances that were intended to regulate the pharmaceutical industry's promotional activities this activity is now managed by the office of prescription drug promotion also known as the OPD P the OU PDP and the bad ad program the OU PDP is composed of two divisions the division of professional promotion and the division of direct-to-consumer promotion the mission of the office is to protect the public health by ensuring that prescription drug information is truthful balanced and accurately communicated this is accomplished through a comprehensive surveillance enforcement and education program and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers Oh PDP reviewers ensure that information and prescription drug advertising and promotional labeling is not false or misleading this office worked for the pharmaceutical industry and within the FDA by providing advice education and guidance it may preview and provide comments on materials that are voluntarily submitted to them by sponsors but this is not always required after promotional materials have been published the OU PDP will monitor them and enforce the relevant regulations this monitoring may be done at its own discretion or in response to complaints by consumers in addition the fda has established a bad ad program administered by the OU PDP to help raise awareness among healthcare providers about misleading prescription drug promotion and provide them with an easy way to report this activity to the agency why drug makers may break the rules a drug maker has only a relatively narrow time frame during which it may recoup the expenses that it has put into developing its product and to generate profits the primary limitation is the period of patent exclusivity during which a drug may only be sold under the approved brand name and only by the original manufacturer and patent holder after this period is over competitors may obtain approval to manufacture and sell generic versions of the drug while the original manufacturer may also obtain approval to market a generic version of the drug competition assures that this is almost always going to be at a significantly reduced price with a much smaller profit margin patent protection is awarded for approximately twenty years however this period typically encompasses many of the pre approval clinical testing years including developments the length of this testing will vary depending on the number and duration of required trials which will in turn depend on the types of indications and populations for which the drug is intended to be used in addition the company must generally devote several years to optimizing the commercial manufacturing process and packaging thus the period of effective patent protection after the drug is approved for marketing is actually closer to between seven and twelve years this reduced window of opportunity for commercial profit provides one of the rationalizations that may tempt pharmaceutical companies to circumvent the regulations that impact the marketing of their products types of promotion there are two ways in which drugs are promoted advertising and promotional labeling the FDA is authorized to oversee both of these methods by virtue of the Federal Food Drug and Cosmetic Act and other legislation traditionally drug companies have advertised for prescription drugs only to doctors and pharmacists typically through ads and professional journals they may also publicize their products through oral communications between sales representatives and medical practitioners and through presentations at professional congresses although direct to consumer or DTC advertising has never been prohibited by federal law companies did not generally promote drugs directly to the general public until the mid 1980s we'll talk more about dtc advertising and its impacts later on in the course the other major marketing tool promotional labeling may take the form of sales aides brochures mailings and a wide variety of items that are imprinted with the name of the drug the next time you go to your doctor's office look for the lipitor clock or a nexium coffee mug as common examples of these promotional devices regulation of drug promotion the guidelines governing promotional activities for prescription drugs are contained in the Federal Food Drug and Cosmetic Act with detailed rules to find in title 21 of the Code of Federal Regulations parts 201 and 202 drug labeling and prescription drug advertising these require that promotional materials one are not false or misleading with regard to effectiveness side effects or contraindications if the information were to be relied upon it should not pose a significant public health risk to reflect a fair balance between effectiveness and side effects and contraindications three are consistent with the approved product labeling or a package insert for only include claims that are substantiated by adequate and well controlled clinical studies claims of superiority over other treatments must be supported by data from head-to-head trials 5 do not promote uses not contained in the product labeling also known as off-label use and 6 do not omit or minimize risks associated with the proper use of the drug this includes overstating safety claims and dismissing warnings that appear on the label there are also constraints on the types of proprietary names that may be used prohibiting the use of a variety name that could lead to confusion with the proprietary name of a different drug or ingredient or also prohibiting a fanciful proprietary name for the drug or any ingredient in such manner as to imply that the drug or ingredient has some unique effectiveness or composition when in fact the drug or ingredient is a common substance the limitations of which are readily recognized when the drug is listed by its established name thus in heed for an analgesic that has aspirin as its active ingredients must not call itself zero pain or claim that it contains a super pain relieving compound while most offenses relate to advertising drugs that are already on the market vo PDP also considers most pre-approval promotion of a new drug to be a violation unless there is no mention of safety efficacy or how to use the product how the law is enforced the OU PDP is empowered to enforce these regulations and impose penalties that are commensurate with the seriousness of the abuse tools that may be used in the enforcement include the following first notices of violations and advisory action letters these serve to document formal notifications from the FDA that a violation has been identified there are three main types of notices one an untitled letter this is an initial communication that the FDA is aware of a violation of federal law and that may allow the offender to come into compliance without further FDA action to an FDA form 483 which lists deficiencies found during an inspection of a pharmaceutical manufacturing facility and 3 a warning letter which notifies the offender that the action may be taken if violation is not promptly and adequately corrected these are issued to encourage voluntary compliance and to establish that the offender has received prior notice of the violation a warning letter may be issued if corrective action has not been taken to address the issues identified in an untitled letter or form 483 a second tool to enforcement is a consent decree or injunction if the violations that are brought to the attention of the firm by way of a warning letter are not adequately resolved the FDA and the Department of Justice may file a formal complaint against the offending organization the defendant in these cases will frequently agree to settle the matter through an FDA consent decree which turns into an injunction failure to comply with a consent decree may be considered grounds for contempt and a third tool is criminal charges violation of the Food Drugs and Cosmetics Act are civil offenses however repeated intentional and fraudulent violations can also be subject to criminal prosecution examples of prohibited types of promotion off-label use the term label in this context does not refer only to the physical label that's found on the vial bottle or box in which the drug is stored but more generally to a specifically formatted summary of the information about the drug that contains indications in usage dosage and administration a summary of the safety and efficacy data black box warnings that emphasize certain risks contraindications the most clinically significant known adverse drug reactions and how to treat and report them drug interactions use in specific populations and counseling information that should be shared with the patient most of this material may be found in the drugs package insert which is a leaflet that's provided to practitioners and patients along with both prescription and over-the-counter medications information about the drug that is provided in the package insert the container label or any other literature that's provided by the manufacturer must be consistent with and limited to what has been authorized by the FDA any deviation from this restriction is referred to as off-label in addition to the food Drugs and Cosmetics Act the government also enforces the prohibition against off-label promotion by bringing cases under the anti-kickback statute and the False Claims Act the prohibition against off-label promotion is intended to protect patients against the use of drugs in ways that have not been shown to be safe and effective however it is legal for doctors to prescribe the off-label use of approved drugs for indications that have not been approved by the FDA drug companies may learn of new uses for their product from anecdotal evidence that may be provided by doctors or patients who use it off-label they are however prohibited from sharing this information unless they have conducted controlled clinical investigations and have submitted the resulting data to the FDA for review to secure approval for an expanded label the costs in time and money of these activities may render this effort prohibitively expensive to make what may be only a minor change to this label thus it can be attractive for drug companies to increase sales by promoting the drug for an unapproved use without doing the required investigations even if a manufacturer does not engage directly in off-label promotion personal conversations social media and similar informal methods of communication by sales representatives may lead to the dissemination of subjective data whose reliability has not been verified regardless of the intentions of the party who's sharing the information this would be a violation of the rules thus regulatory agencies have been faced with the need to amend their criteria for enforcement or even revise the laws to better suit the reality for today's world as another example a common and often problematic practice has been for sales personnel to distribute to physicians medical literature that suggests that a drug may be useful in certain unapproved scenarios in response the FDA issued a in 2009 that detailed clearly defined circumstances under which manufacturers may distribute reprints of medical journal articles that describe off-label use of prescription drugs in response to unsolicited requests for information the agency has also found novel ways to clarify its interpretations of the regulations to make enforcement more straightforward in one example the FDA has recently directed that claims of safety or efficacy that are not approved in the label will be considered a violation of the prohibition against misbranding if they are not supported by scientifically appropriate and statistically sound evidence in another illustration the FDA requires that a drug maker provide directions for the use of a drug for an intended indication since these directions would not have been approved in the case of off-label use the FDA may choose to pursue an enforcement action for lack of adequate directions rather than for the absence of scientifically substantiated claims there continue to be however many examples of regulatory actions that are based on unsubstantiated claims let's take a look at a few of these one of the most common examples of unacceptable promotion is making claims about the attributes of a drug that are exaggerated or patently untrue a practice commonly referred to as false advertising some examples of advertising claims that were based on non-existent or discredited clinical data are that the use of marijuana derivatives to treat or cure cancer orally administered pills or capsules to replace sunscreen vitamin E supplements to provide alleged cardiovascular benefits and label claims that an allergy supplement was clinically proven to boost memory omission or minimization of risks risks that are known to be associated with the use of a drug are required to be listed in the label and package insert but drug manufacturers sometimes attempt to downplay the frequency or severity of those side effects when describing their products the following is a list of some of the drugs whose sponsors received FDA warning letters in 2009 or 2010 for misleading advertising including inadequate presentation of risks the first example is cymbalta from Eli Lilly in a print ad showing a patient suffering from fibromyalgia associated pain information on risks including an increased likelihood of suicidal thoughts appeared on an adjacent page between unrelated advertisements the second was Caleta from Abbott Laboratories in a DVD testimonial for this age drug by former basketball star Irvin Magic Johnson there was no mention of life-threatening risks like pancreatitis new onset diabetes and spontaneous skin hemorrhages next is Trek cement from GlaxoSmithKline in internet ads for this migraine medication risks only appeared in quickly scrolling text below the banner these included heart attack stroke and gastrointestinal bleeding and finally depakote ER from abbott laboratories pharmacy flashcards promoting this drug for bipolar disorder did not prominently discuss known side effects such as potentially fatal liver damage pancreatitis and brain and spinal cord birth defects in this module we have reviewed several types and examples of illegal promotion of drugs and the penalties wielded by regulatory agencies to enforce the laws we also consider some of the rationales used to attempt to justify these offences in the next module we will examine some other classes of marketing violations along with a few high-profile case studies