Adulteration and Misbranding Fa24.pdf

Adulteration, Misbranding and Related Requirements Today’s lecture is entitled Adulteration and Misbranding and Related Requirements. Adulteration and misbranding are the most common violations of the Food Drug and Cosmetic Act. The next two slides indicate some classic prohibitions in the Food Dr...

Adulteration, Misbranding and Related Requirements Today’s lecture is entitled Adulteration and Misbranding and Related Requirements. Adulteration and misbranding are the most common violations of the Food Drug and Cosmetic Act. The next two slides indicate some classic prohibitions in the Food Drug and Cosmetic Act. Most of them are intuitive. The first – introduction into interstate commerce of any food, drug, device, or cosmetic that is adulterated or misbranded. Similarly, their adulteration or misbranding while they are in interstate commerce. Or the receipt in interstate commerce of any adulterated or misbranded food, drug, device or cosmetic. And the delivery of a drug, device, cosmetic or food that is adulterated or misbranded for payment, or any other form of compensation for it. Or introduction into interstate commerce of any new drug without an FDA approval. As you know, the FDA requires drugs to have an NDA as part of the approval process, and if a drug doesn’t have an abbreviated NDA or an NDA, the manufacturer can’t introduce that product into commerce. On a housekeeping note, there is a prohibition on refusing to permit the FDA to gain access to or copy any required records, or failure to establish or maintain any records that are required as part of the Food Drug and Cosmetic Act. Some other prohibitions include refusing to permit entry to an FDA representative or refusing to permit a related FDA inspection. Also, the manufacture of any food, drug, device, or cosmetic that is adulterated or misbranded. Or causing the drug to be a counterfeit drug or selling a drug that’s a counterfeit drug. Or even holding for sale or dispensing of a counterfeit drug. Any alteration or any other way that you might tamper with the label which causes the product to be adulterated or misbranded. And then finally, the introduction into interstate commerce of any unsafe dietary supplements. We had referenced this earlier, stating that the FDA does not have direct control over the approval process for dietary supplements, but if a dietary supplement has been deemed unsafe, then the FDA, based on the Food Drug and Cosmetic Act can take a dietary supplement off the market. This slide lists the typical penalties that would be associated with violations of Section 301 of the Food Drug and Cosmetic Act. Initial offenses are punishable by imprisonment of not more than one year and/or a fine of not more than $1,000. Second offenses or any violation with the intent to defraud or mislead could lead to imprisonment for up to 3 years and/or fined up to $10,000. Keep in mind that the penalties listed on this slide are for violations of Section 301 of the Food Drug and Cosmetic Act and there are much more onerous penalties for violations of other aspects of the Food Drug and Cosmetic Act. For example, for violations of the PDMA, the penalties are much more severe. Before we get into any specific examples of adulteration or misbranding, there are some general principles you should also be aware of as they relate to adulteration and misbranding. And the first is that it is a strict liability offense, meaning that it doesn’t make any difference whether you had intent or knowledge. For example, if a pharmacist receives inventory from a manufacturer or wholesaler that’s adulterated, and the pharmacist has no idea that that product is adulterated, that pharmacist could be charged with an adulteration or misbranding offense. Fortunately, however, there is a good faith exception carved into this set of prohibitions. If a pharmacist unknowingly or unwittingly receives an adulterated drug, but upon discovering it, the pharmacist provides the FDA with all the pertinent details about where they purchased it from, etc., then the pharmacist would be off the hook as far as having committed an offense. Pharmacists should also be aware that whenever they repackage something--and many pharmacists repackage both prescription drugs, & over the counter drugs from a larger to a smaller container--you need to make sure that you have the identical information that’s on the manufacturer’s label carried over to the label on the smaller package. This slide lists various enforcement tools that the FDA can employ. Let’s say, for example, a manufacturer was shipping adulterated products and the FDA wanted to take action against them. They have a variety of things that they can do. The first of which would be to go to court and seek an injunction for the court to tell the violator that they needed to cease and desist whatever perceived illegal activity that they were engaged in. The FDA could also literally seize the product off the shelves whether it’s the pharmacy, the manufacturer, the wholesaler, and that is also called a libel action. They could also engage in criminal proceedings which could lead to fines and/or imprisonment. The FDA can also simply send a warning letter to the violator in the hopes that they’ll cease the practice that they are engaged in. It is totally discretionary on the part of the FDA which enforcement mechanism they want to employ. However, the most important thing to understand is that the FDA does not have the authority to automatically order a manufacturer to remove a drug product from the market. The reality, however, is that it would be rare for a manufacturer to ignore a request from the FDA to remove a drug product from the market. Keep in mind however, that the FDA can order a manufacturer to remove a device from the market. This slide underscores the importance of what we’ve been saying about these violations being strict liability offenses. They are not dependent upon intent or knowledge or awareness, and they are also criminal offenses. There are two very important strict liability cases – the Dotterweich Case and the Park Case that collectively are known as the Park Doctrine. In each of these cases, high level officials were charged or convicted of adulteration and misbranding. In the Dotterweich Case, the president of a repackaging and relabeling firm was convicted of adulteration and misbranding even though he had no knowledge of the offenses that were committed within his company. The court ruled that he was in a far better position to seek out and make sure those violations weren’t occurring as opposed to relying on the powerless public to find out later on, perhaps when someone got injured. The Park Case involved the president of Acme Markets who was charged with holding food products under unsanitary conditions. He similarly protested he had no idea what was happening, and he had delegated responsibility for maintaining sanitary conditions to other people. It was noted, however, that these were repeat violations and the court indicated that it was incumbent upon him to have instituted preventive measures. Another example of this strict liability concept was when officials at Purdue Pharma in 2007 were charged individually in a case that alleged Oxycontin was promoted by downplaying its abuse potential. Ultimately, the corporate officers had to pay millions of dollars out of their own pockets in addition to what the company paid for the misbranding offense that was committed by the company. But the allegations did not stop there. Purdue Pharma is among a group of opioid manufacturers that are currently being sued in thousands of lawsuits for helping to fuel the opioid crisis that are essentially based on 2 legal theories, namely that Purdue continued to market their opioid drugs when they knew they weren’t safe and effective, or by downplaying the incidence of addiction for people taking opioids. Next, you need to be familiar with the various classes of product recalls and operationally what happens when there is a product recall.  The first is a Class I recall which is the most serious. A Class I recall is when there is a reasonable probability that the product is going to cause serious adverse health consequences or death.  Class II recalls would involve a product that may cause temporary or medically reversible adverse health effects, but the probability of serious adverse consequences is remote.  Class III recalls involve products that are not likely to cause adverse health consequences and it could involve just simply a typographical error or something wrong with the product label. Operationally, the way a product recall works, is that the pharmacy will receive a notice by first class mail. On the envelope, the words: Urgent: Drug Recall” are very clearly portrayed (in red to make sure that your attention is drawn to it). Assuming you have received one of these drug recall notices and subsequently dispense a drug product that was part of that recall, it would probably be hard to assert a Good Faith defense, because if you were charged with a violation of the Food Drug Cosmetic Act and you received adequate notice and you just didn’t open up your mail for a couple of days, then you would probably be liable should the FDA would want to pursue an action against you. Also, keep in mind, should you dispense a product that was the subject of a recall which you should have removed from the shelves, you also have the prospect of civil liability in the event that one of your patients gets injured. And for that matter, if the state board gets knowledge of it, they could also take an administrative action against you. This next slide addresses adulteration. And even though it seems like the wording on the slide might be a bit busy, there are a couple of very important concepts that we need to get across about adulteration. Most of your thoughts on adulteration are likely valid in the sense that when one conjures up the word of adulteration, they think of something that’s contaminated or there’s something wrong with it, and that’s a good place to start in terms of how you think about adulteration. But looking through the laundry list of bullet points related to adulteration, we can see initially, and in keeping with that yucky kind of connotation of adulteration, anything that consist of any filthy, putrid, or decomposed substance. That is fairly intuitive. The next--prepared, packed or held under unsanitary conditions where it may have been contaminated with filth or rendered injurious to health. The key word here, which is italicized, is may. And what I mean by that is that the FDA will never have to prove that something is adulterated before removing it from the market. It’s out there as a general concern. If anything happened where a drug may have been adulterated, well then, in fact it would be considered adulterated. So, for example, if you had a drug that was packed in your back storeroom at the pharmacy and in the back room it was subject to extraordinary heat or cold, then you don’t know if the product was rendered injurious to health. But you have to assume that drug would be adulterated. Another example of adulteration is if a product was developed not in conformity with good manufacturing practices. Or if the container of that product is composed of any poisonous or deleterious substances which, again, may contaminate the drug. It doesn’t need to be shown to have contaminated the drug-just that the prospect is there. Or if it contains an unsafe color additive. Or if purports to be a drug in an official compendium, like the USP, and the strength differs or quality or purity is below the compendial standard, unless it’s plainly stated on the label. Or alternatively, if a drug is not listed, for example, in the USP, and the strength differs, or quality or purity is below what is stated on the label that would be another example of adulteration. And then finally, and this is another intuitive example of adulteration, where the product is mixed with any substance which reduces its strength or quality, or the drug has been substituted in whole or part. A good example of this is what you see a lot of times in drug dealings where they cut down heroin or cocaine with some other product. But I do want to draw your attention to the two of the last three bullets where it says it purports to be a drug in an official compendium, but the strength differs or quality or purity is below the compendial standard, and let’s assume that difference is not stated on the label. Intuitively, if I were looking at this definition, I would be thinking that it might be adulteration, but my first thought that would come to mind would be that that would be a misbranding because the label would not be correct. And similarly, the next bullet point, where it’s just simply a product where the strength differs or quality or purity is below what is on the label. Again, that to me would be a classic example of misbranding – meaning the label is wrong. And in fact, here’s where you must be very careful. Whenever you have a situation where you are debating if it is adulteration or misbranding, I think I have a simple formula to try to work that through. If you are presented with a scenario, ask yourself the following question: Is the strength, quality or purity of this product affected by whatever the scenario involves? And if the answer is yes, then likely it could be considered adulteration and misbranding. So I would really suggest that you think that through to understand the importance of identifying in a lot of cases where a product is both adulterated and misbranded. This slide reinforces what I had said on the previous slide about a situation where a product may have been adulterated. What this slide indicates is that it’s just a practical measure. It’s so much easier for the regulation of a facility than the product per se. In other words, it’s easier for the FDA to inspect the plant rather than undergo the expensive process of individually looking at every single product. If they walk into a manufacturing plant and see that it’s dirty, they don’t have to go any further and inspect any product. They could shut down that plant immediately and call all the products existing in that plant as adulterated. And the reason behind that is that the health and safety risk to the public is much lower by allowing the FDA to take this measure and not having to prove adulteration. So even in a situation where a product may be adulterated, the FDA is allowed to call it adulterated in the interest of protecting the health and welfare of the community. This slide addresses Good Manufacturing Practices (GMP’s). Even though we alluded to the topic of GMP’s in prior slides, we really haven’t talked about them too much. GMP’s are really a set of regulations that establish minimum requirements used in the manufacture, processing, packaging, or holding of a drug product. And perhaps the easiest way to understand it is to provide a couple of examples. The first example is, in a typical manufacturing plant when a product is being added in the manufacturing process, it typically requires that two individuals sign off on witnessing addition of that new added ingredient. That would be one example. Another one might be where a product in the sterilization process required so much time in an autoclave. And maybe the GMP’s associated with that might mandate that the actual autoclave time chart be included, indicating that the desired temperature was reached for the time that was required. That would be another good example. And again, GMP’s, for the most part, pharmacists don’t have to worry about unless they are engaged in large scale compounding and/or in repackaging activities beyond the individual pharmacy (i.e., where they’re repackaging for other entities). The next Act that you need to be familiar with is the Tamper Evident Packaging Act. In 1982, there was widespread contamination of over-the-counter Tylenol capsules that were being laced with cyanide. Following that, Congress enacted the Tamper Evident Packaging Act, making it a federal offense to tamper with consumer products. And they define tampering as an act of improper interference with the product for the purpose of making objectionable or unauthorized changes. Typically, most over the counter drugs are affected by this Act. In addition, cosmetic liquid oral hygiene products, vaginal products and contact lens solutions and tablets are also required to be packed in tamper evident packaging. Exceptions to this requirement exist for dermatologicals, dentifrices, insulin and lozenges. One interesting aspect of this Act, and perhaps it was based on the initial cyanide contamination of Tylenol capsules, is that if you have a two-piece hard gelatin capsule, that’s an over- the-counter product, in addition to the packaging, the actual capsule itself must be sealed using an acceptable tamper-evident technology. If there is a violation of this Act, it would be considered either adulteration or misbranding or both. The definition of tamper-evident packaging means having one or more indicators or barriers to entry, which if breached or missing, can reasonably be expected to provide visible evidence that tampering has occurred. This is typically accomplished in one of two ways. The package can be distinctive by design meaning that the package can’t be duplicated with commonly available materials or processes. An over- the-counter inhaler might be a good example of that, or through the use of one or more indicators or barriers to entry that employ an identifying characteristic, for example, a pattern, name, trademark, logo or picture or something else that if altered, would be easy to see that the product had been tampered with. Finally, the most important thing is not to confuse the Tamper Evident Packaging requirements with those of the Poison Prevention Packaging Act. The Poison Prevention Packaging Act, which we will be going over next week, imposes a child-resistant requirement. The Tamper Evident Packaging rules simply aid us in figuring out if a product has been tampered with. So, in other words, it’s not a tamper proof packaging requirement, it’s just tamper-evident, meaning all we want to know is if someone was tampering with the product, not trying to prevent them from getting into the product. Another added requirement of the tamper evident packaging rules is related to its labeling. The labeling needs to identify all tamper evident features on the package, including if a capsule is involved, the features that are on the capsule to make it tamper evident. The labeling must be prominently placed on the package and most importantly, unaffected if the tamper evident feature is breached or missing. Now moving to a discussion of misbranding. Misbranding, for the most part, is intuitive as identified in the first bullet point, meaning that the labeling is false or misleading in any way. And if you look at the remainder of the bullets, for the most part, the misbranding definition comports with that. For example, if the drug is listed in an official compendium but not labeled and packaged according to compendial standards. That would be a classic example of misbranding. It also requires that the name and location of manufacturer, packer, or distributor be included as well as an accurate statement of the quantity. The container can’t be any way misleading. It can’t be an imitation of another drug or offered for sale under the name of another drug. For example, you couldn’t label the prescription vial Lasix and then dispense to the patient generic furosemide. If a drug is subject to deterioration, the label needs to state the appropriate cautionary statements. The label can’t be dangerous to health when used in the manner suggested by the labeling. The product can’t be packed or labeled in violation of the Poison Prevention Packaging Act (PPPA). And finally, if a pharmacist sells a drug without a prescription, or refills a prescription beyond the number of authorized refills, that would be considered misbranding. That is probably the one example where you would pretty much just have to memorize this as a misbranding offense because it’s not as intuitive as the other definitions, meaning that the label on its face is improper or misleading because it’s basically a bogus prescription, but again, not as intuitive as some of the other definitions, like offering for sale under another name of a drug. So just keep that in mind and even the one about the Poison Prevention Packaging Act (i.e., if you dispense a drug in an easy open container when a child resistant container was required). Again, that’s not as intuitive that that’s a misbranding offense. You just have to memorize that. Some additional misbranding provisions are: That the label has to state the quantity and/or proportion of any active ingredient of prescription drugs and over the counter drugs and a specific mention of alcohol and certain other drugs whether they’re active or not. There is a very long list of very obscure drugs listed in the text that you may want to look at. You won’t be responsible for them other than knowing it’s important to note that you have to mention the presence of any alcohol in the product. So again, the primary purpose of that bullet is just to identity that you need to have the quantity and/or proportion of any active ingredients both for prescription drugs and over the counter drugs. Secondly, the product needs to list inactive ingredients as well. Again, this applies to both prescription drugs and over the counter drugs and they need to be listed alphabetically. For the next three bullets, these are requirements that would be required for over-the-counter products, and they would be: Adequate directions for use Adequate warnings against use by children and others for whom it might be hazardous. All conditions, purposes and uses intended and commonly used. Let’s turn our attention now to the requirements for an over-the-counter drug label and we’ll see where some of the misbranding provisions bear out in the requirements for the label. First of all, on an over-the-counter label you need: An identity of the actual product, obviously the name of the product, and the pharmacologic property for which it’s being sold.  The name and address of the manufacturer, packer, or distributor Net contents Cautions, warnings that are needed. Adequate directions for use and A drug facts panel A drug facts panel includes a listing of: Active ingredients, including the dosage unit and quantity/dosage unit. (i.e., capsule, tablet, or whatever dosage form it might be and the quantity per dosage unit) The purpose for which it is intended. The uses and indications of the product Any applicable warnings Directions And any other information as required by a monograph. A listing of inactive ingredients, (which we saw in the misbranding provisions) Then there’s an optional section if the lay person purchasing the product wants to ask a question where they can telephone to have their question asked When trying to understand and memorize the contents of a drug facts panel, the easiest thing to do in my opinion is simply have a drug facts panel illustrated like we have here. And to me it would be a whole lot easier to memorize it that way. Each of the arrows designated there represents one of the requirements of a drug facts panel label. You can see the active ingredients, purpose, uses, warnings, directions, other information, listing of inactive ingredients. So, if you familiarize yourself with an actual drug facts panel, I don’t think you will have any issues identifying any questions related to a drug facts panel on your exam. This slide lists some additional adequate directions for use requirements for an over-the-counter product, which of course would be expected to be on the label. The normal dose for each intended use and doses for individuals of different ages, frequency, duration of administration or application, administration, or application in reference to meals, onset of symptoms like take one before meals or after meals, the route of method of administration or application and any required preparation for use. For example, shake well before using, etc. This slide lists a miscellaneous misbranding provision as it applies to advertising. Any drug advertising needs to include basically a balance between the benefits of the drug and the side effects and contraindications, etc. Also, the established name of the drug must be prominently in place on the label and the type has to be half as large as that used for the actual brand name. And, of course, a quantitative listing of each active ingredient. And then finally a summary of side effects, contraindications, and effectiveness. In essence, all this is trying to do is say is that you can’t just tout the benefits of a drug. You must list the side effects, contraindications, etc., to provide a fair balance to the person that’s being influenced by the advertising. This is an important slide that discusses a situation where drugs can be both over the counter and prescription yet be the same drug. The import here is that if a drug can be labeled with adequate directions for use for a certain indication, then it could arguably be sold over the counter. On the flip side, if it can’t, then that drug would be a prescription product. These are a couple of examples that are listed here. Certainly, there are more, but just to give you a flavor. Meclizine can be sold over the counter if it’s marketed for nausea, vomiting and dizziness associated with motion sickness. However, if one is treating vertigo, then meclizine would be a prescription product. And again, the doctor’s directions would dictate how the person would take it. Same for ibuprofen. Ibuprofen is sold over the counter for mild to moderate pain but in the treatment of rheumatoid or osteoarthritis, it is a prescription product. This slide list the requirements that must be on a bulk prescription container label. I’m not going to go through each of these individually. They are intuitive and do in fact comport with what we’ve already seen in terms of the misbranding provision of what needs to be on a label. For example, the quantity and/or proportion of each active ingredient and the names of the inactive ingredients. And again, everything else is straightforward like lot number, control number, expiration date. But the interesting thing about bulk prescription container label requirements, if you look at this slide, everything that you see pretty much makes sense except there’s one item that I would think that you expect to see here that in actuality is not a requirement. And we’ll see that on the next slide. The item that you would expect to see as a requirement for a bulk prescription label would be the NDC number. The NDC number is only requested, but is not required, on all over the counter and prescription drug labels and labeling. And even when you see an NDC number, the presence does not necessarily indicate that a drug has received an approved NDA from the FDA. It’s just assigned in the beginning by the FDA more for housekeeping purposes and it doesn’t reflect on an NDA status at all. The FDA issued a compliance policy guide to impact manufacturers producing unit dose containers and the requisite labeling for those unit dose containers. The FDA currently requires the: established name of the drug the quantity of the active drug in each dosage unit the expiration date lot and control number name and location of manufacturer, packer or distributor any compendial statements that are required. if there is more than one dosage in the package, the number of dosage units that are contained and the strengthen per dosage unit warning message: warning-may be habit forming, if that’s applicable and the controlled drug symbol if required by the DEA. The requirements for the package inserts were revamped in 2006 to prevent adverse effects by making the package insert basically more user friendly. Before that, it was unwieldy and as a result of that, a lot of health care professionals weren’t even using it as a primary source of drug information. Part of the updates to the package insert were a Highlights section that was included in the beginning, and which contains the most important information about a drug product including any boxed warnings, the indications and usages of the product, dosage and administration. For ease of use, it now includes a Table of Contents, full prescribing information and a patient counseling section. Fairly recently, the FDA revised drug labeling requirements for drugs that were taken during pregnancy. Previously, drugs were classified according to an archaic system where they were rated A, B, C, D or X, and it was confusing because the classification was not meant to imply that A rated drugs were ok and then getting less and less ok with the B, C, D, and X. And sometimes these ratings were based on animal studies, and sometimes they weren’t. So basically, what the FDA decided to do to make it more meaningful for prescribers and those intending to take these drugs was to divide the labeling into pregnancy and a lactation sections, and each of them would have three principal components section: a risk summary, clinical considerations, and a data section. The risk summary starts with a high level one-sentence statement that summarizes the potential of the drug to increase the following risks: structural abnormalities fetal and infant mortality or any impaired physiological function or alterations to growth The summary will also state if animal or human data was used. If it was human data, the summary is going to go into greater detail. The clinical considerations section of the labeling will address situations in which a woman was inadvertently exposed to the product, the effects the medication is going to have in labor and delivery, other clinical decisions that clinicians are going to have to make, including any dosing adjustments during pregnancy, adverse reactions that might be unique to pregnancy, and any interventions that may be required. And finally, the data section of the labeling. All available drug data will be included here where it was involved pregnant women and with an obvious precedence of human data over animal data. It will include the type of studies that were completed, what animals were used, dosages, any adverse events that were reported and the relationship between drug exposure in animals and humans if it was applicable. Bar codes are required for the following drugs: Prescription drugs Biological products Over the counter drug products that are dispensed pursuant to an order, meaning in a hospital and which are packaged or labeled for hospital use or are marketed, promoted, or sold to hospitals. A bar code can contain a lot of information. But for now, the minimum information that a bar code needs to contain is the NDC number. Notice the subtle distinction from a previous slide where we mentioned that NDC numbers are strongly encouraged but not required to be placed on prescription and otc drug containers. That slide was discussing being able to visualize the NDC number on the product if you were to pick up the container. For a package requiring a bar code, the NDC number is not always visible, and you need a scanner to read the NDC number. So, these slides are not contradictory. Now shifting gears to the drug approval process. The general rule is that no new drug can be marketed in interstate commerce unless the product has an NDA. The drug must be proven to be safe and effective under that NDA. And new drug is defined as “not generally recognized by qualified experts as being safe and effective for use under the conditions recommended in the drug’s labeling”. So, what this slide is implying is that if the scientific community had a drug that was deemed generally recognized as safe and effective, it would not require an NDA. But I can assure you that’s really in name only. The most recent example about 15-20 years ago was when the manufacturer of Synthroid tried to convince the FDA that they were a grandfathered drug not subject to an NDA (i.e., generally recognized as safe and effective). The FDA responded that all of the levothyroxine products on the market were exhibiting a wide variety of concentrations for the same microgram quantity on the label and they insisted that all manufacturers of levothyroxine obtain an NDA. Ultimately, that’s what happened. Any manufacturer who manufactured levothyroxine was required to get an NDA. So the bottom line is that there are really no drugs that are generally recognized as safe and effective which do not require an NDA. We also need to discuss when a previously approved drug becomes a new drug. That can happen if a drug contains a new substance. Obviously, a new active ingredient would do it, but even an excipient, carrier or coating would make that drug a new drug subject to approval by the FDA. Often, too, we will see a new combination of approved drugs. How many times have you seen a drug put in combination with hydrochlorothiazide? Or if a proportion of ingredients in combination is changed? Again, using that same hydrochlorothiazide example, sometimes it might be 25 milligrams, sometimes it might be 50 mg. in combination with another drug. Or if there is a new intended use of the drug. This has come back to haunt the manufacturing community many times over. If there is a new intended use of the drug, it’s perfectly permissible for a physician to prescribe that drug for off-label use, but for the manufacturer to promote a drug for a new use, they need to go through the drug approval process. And then finally, an already approved drug would become a new drug if the dosage, method, duration of administration or application is changed. For example, a drug going from an oral dosage form to a rectal suppository. So, how does an investigational new drug application work? An investigational new drug application would be submitted to the FDA when a manufacturer, based on preliminary studies, believes that they have a drug that they can market with the FDA’s approval. So in essence, what the manufacturer does is submit to the FDA all the information from all of the animal and laboratory studies that were already conducted regarding the pharmacological, pharmacokinetic and toxicology evaluations of the drug. Also, in anticipation of testing the drug on humans, the manufacturer needs to submit the experience and qualifications of the investigators who are to conduct the human clinical studies. Also, the FDA wants a complete outline of how the manufacturer is going to conduct those clinical studies. And this is a case of “no news is good news”. If the FDA doesn’t contact the manufacturer back within 30 days, then human testing can begin. Once the clinical testing begins in humans, informed consent of the patient is required for all 3 phases of testing and the consent needs to be in writing for phases I and II. The institutional studies that are conducted need to be approved by the Institutional Review Board which basically acts as a monitoring agency or group to protect the health and welfare of the subjects that are in the research study. And just a quick refresher of the different phases which I’m sure you had in other classes. Phase I is really designed to test the pharmacological activity of the drug on a small number of healthy individuals. And just by way of refresher, this means that if a diabetes drug is being tested, the individuals in Phase I do not have diabetes. Again, they are healthy volunteers. Phase II the testing begins on a limited number of individuals who have the disease at issue. Efficacy and safety testing is done on these individuals. Phase III is simply a larger scale of Phase II study, where again, continued safety and efficacy studies but on a larger number of patients. You should be familiar with the FDA drug rating and classification system. If, for no other reason, than when the FDA is going through the NDA approval process or even when a drug first comes on the market, drugs are often referred to by their chemical type and therapeutic potential. A number indicates chemical type and we’ll go through those numbers in a minute and a letter, either P or S, indicates the therapeutic potential. P would represent a priority drug which appears to represent an advance over an existing therapy in any number of ways. For example, there could be no other effective drugs that are available, or this drug might be more effective or safer than a current drug on the market or it might provide advantages such as greater convenience, reduced side effects, improved tolerance or usefulness. While on the other hand, an S classification for therapeutic potential would simply be for a drug that appears to have therapeutic qualities similar to a marketed drug. Now for the numbering that’s associated with a chemical type: 1 would represent a new molecular entity. 2 would be for a chemical derived from an active ingredient that’s already marketed. 3 would be for a new dosage form. 4 is a new combination of two or more compounds that weren’t previously marketed together (i.e., the example I gave before about hydrochlorothiazide being marketed in combination with a drug that was already on the market). 5 already marketed but simply a new manufacturer. 6 already marketed but for a new use. This slide illustrates when a supplemental NDA might be submitted to the FDA. There are 3 different procedural categories when a manufacturer would be required to submit a supplemental NDA. You won’t be required to know in which situations the different procedural categories apply, but just to go through the categories quickly: That require pre-approval from the FDA when the manufacturer is engaging in any change in production ranging from the synthesis of the drug or the manufacturing process and most of the labeling related to the drug. Again, that would require pre-approval.  There’s another situation where the manufacturer would simply be adding strengthened warnings to the label, dosing information or certain changes in manufacturing methods that would require the manufacturer to simply notify the FDA that the change is being affected. And then finally, any minor editorial changes to the labeling or container size. The manufacturer simply needs to include that in the annual report. And obviously for the scope of the course that you’re taking, you wouldn’t have to know which changes in manufacturing methods would require that the FDA be simply notified that a change was being affected compared to the manufacturing process changes in bullet #1. It’s certainly beyond the scope of this course, but rest assured the drug manufacturers know quite well when they must notify the FDA either for pre-approval or after the fact. Post marketing surveillance is also known as Phase IV studies. Phase IV studies occur after a drug has received NDA approval from the FDA. And as part of the post marketing surveillance, once a drug comes on the market, the FDA is still keenly interested in the manufacturer submitting reports to the FDA basically regarding the safety of the drug as it exists on the market. The FDA wants the manufacturer to report any serious adverse drug reactions. They also want the manufacturer to report any new information relating to the drug’s safety and efficacy, including information about current clinical studies. Clinical studies in Phase IV can occur basically in one of two ways. Sometimes when the FDA accelerates a drug approval, it might mandate that the manufacturer continue to conduct clinical studies as part of that Phase IV study. Or the manufacturer itself may conduct Phase IV clinical studies of its own to support a new proposed indication for approval on the part of the FDA. As mentioned in an earlier presentation, the medical device amendments give the FDA much more control and authority over the regulation of devices. Initially, under the medical device amendments, devices were classified, and controls were put in place based on the evaluation of the function of the device. Pre-market approval is typically required for any life-sustaining or life-supporting devices and manufacturers are required to report any death or serious injury associated with the use of the device. Class I devices are the simplest types of devices, where the traditional FDA controls over adulteration, misbranding and manufacturing are sufficient to provide reasonable assurances of safety and efficacy. In essence, this is saying that if a manufacturer is just simply abiding by or complying with GMP’s, that the product is likely not to have any issues and can be deemed a Class I. Some examples of a Class I device would include needles, stethoscopes, scissors, toothbrushes, tongue depressors. You can see that there’s not much required beyond abiding by GMP’s with these types of devices. On the other hand, with Class II devices, we see the concept of performance standards introduced. For Class II devices, performance standards are required to provide reasonable assurances of safety and efficacy. And if you look at the examples given, (i.e., insulin syringes, thermometers, diagnostic reagents, contact lenses for daily use and electric heating pads) every one of those devices has some type of measurement involved to assure that the device is working properly, like the gradations on a thermometer or the lines on an insulin syringe. It’s critical that they get measured to make sure that they are up to standard and that’s why Class II devices need to comply with performance standards. Class III devices are the most serious and require pre-market approval because they are either life- supporting or life-sustaining or they may present a potential unreasonable risk of illness or injury. And the examples here bear that out (Pacemakers, replacement heart valves and soft or hard contact lenses for extended use). Contact lenses for extended use fit the definition under pre-market approval under the potential unreasonable risk of injury or illness. Surely, if a contact lens for extended use is worn improperly, it can present a very real risk of injury or illness. Keep in mind that a soft or hard contact lens for daily use would fit the definition for a Class II device. So make sure you understand that distinction. Under the Safe Medical Device Act of 1990, we see another safety wrinkle introduced. When the medical device amendments were first introduced, the requirement applied to the manufacturer to report any death or serious injury related to a device use. What this amendment does is require device user facilities like hospitals to report any serious injury or illness caused by the device within 10 working days to the manufacturer. Or if the manufacturer isn’t known, then the requirement is to notify the FDA within 10 days of any serious injury or illness. In the event of a death, the requirement is to report that device that’s suspected of causing a death to the FDA and the manufacturer within 10 working days. Under the Safe Medical Device Act it also requires the manufacturer, for any permanently implantable or life-sustaining device, to implement a tracking mechanism to ensure that patients can be notified if necessary if there is a recall or something wrong with the product. The Medical Device Amendments of 1992 impose similar tracking requirements on distributors. Now on this closing slide for this presentation today, just a few words about cosmetics. Cosmetics are unique in that they don’t require pre-market approval. The manufacturer doesn’t have to register with the FDA and doesn’t have to conform to GMP’s. The FDA will get involved, however, if there’s any cosmetics that are adulterated or misbranded or that are deemed a health hazard. It is reminiscent of what we saw earlier with dietary supplements. The FDA has little control over dietary supplements unless the dietary supplements have been deemed unsafe for whatever reason.