What are all those drug ads saying?

Why are all those smiling people talking about bad drug side effects on TV?
We are now all familiar with seeing drug ads on TV that talk about all the benefits and risks of prescription drugs. These commercials have become the common butt of many jokes to see a bright smiling attractive-looking face talking so openly about the diseases and medical problems they're suffering from and the medications they're taking. The commercial actors speak so comfortably about the various potential side effects the drug may cause such as nausea, vomiting, muscle aches, burning sensations, etc., etc. Each prescription drug commercial is almost formulaic: 1) Smile at camera, 2) mention what illness you have, 3) talk about how this drug has helped you, 4) tell people about a list of potential side effects, and 5) tell people to ask their doctor about more information.

The reason these commercials are so formulaic-looking is because they are. There is actually a set of rules that tell drug advertisers what they can (and can't) say in prescription drug advertisements. So who makes these rules and what are they? That is the topic of this blog.

Who makes the rules?
There are 2 types of drug classifications based on how you are able to obtain the drug. Prescription Only drugs (which I'll simply refer to as prescription drugs) can only be obtained by prescription from your health care professional (makes sense given the name). This is in contrast to Over-the Counter drugs that can be purchased at pharmacies or other stores without a prescription. The Food and Drug Administration (FDA) regulates the manufacture, distribution, and sale of both classes of drugs in the US. However, the FDA only regulates prescription drug ads. Advertisements for Over-the-Counter drugs are regulated by the Federal Trade Commission (FTC). Our focus is on prescription drug ad rules and regulations, therefore we will focus on the FDA.

The FDA's main goal regarding prescription drug ad regulations is to ensure that drug companies provide information in their advertisements that is truthful, accurate, and balanced regarding the positive and negative drug effects. Remarkably, the FDA typically does not require prescription drug ads to be reviewed and approved prior to their public use. Rather, the FDA often reviews these ads after they have already started being used. There is an FDA division called the Division of Drug Marketing, Advertising, and Communications (DDMAC) that monitors these prescription drug advertisements. This job was a lot easier prior to the mid-1980s when the drug advertisement landscape drastically changed.

How do drug companies advertise their drugs?
Prior to the mid-1980s, drug companies advertised prescription drugs only to health care professionals (HCPs), such as doctors and pharmacists. The HCPs then relayed that information to their patients to whom the drugs were being prescribed. However, during the 1980s, some drug companies started to advertise directly to the public, an approach refered to as Direct-to-Consumer (DTC) advertising. DTC ads changed everything. They were and continue to be highly controversial. Because of the controversy, many drug companies abide to a moratorium on DTC advertisements for six months after a new drug comes to market. The US Congress is currently asking drug companies to agree to a two year moratorium on DTC ads, but no companies have taken them up on the offer.

With the advent of DTC ads, drug companies now have multiple ways of marketing their drugs. A few things they need to consider are:

Who is the target audience of the ad?
Drug companies now have 2 different audience groups to consider: 1) the HCP (e.g., the doctor), and 2) the patient (i.e., the consumer). There are different FDA rules based on which of these audiences is being targeted.

When will the ads be used?
The drug company can choose to advertise the drug before the actual FDA approval to sell the drug. These ads are known as pre-approval ads. Drug ads that are used after the actual FDA approval to sell the drug are known as post-approval ads. There are different FDA rules for pre-approval ads versus post-approval ads.

Where will the ads be used?
Drug companies can advertise in many locations. Pamphlets and brochures can be placed in the doctor's office. This type of media distribution is part of what's called promotional labeling which is often treated differently from advertisements. Drug advertisements tend to be either in print (e.g., magazines, newspapers) or broadcast media (e.g. TV, radio). There are different FDA rules for print ads versus broadcast ads.

Will the ad mention the drug's name?
This may seem like a strange question? Why wouldn't the ad mention the drug's name? Well, for reasons we'll address in a moment, the drug company may not want or, as we'll see, may not be allowed to mention the drug's name. An advertisement that does mention the drug's name is called a branded ad. An advertisement that does not mention the drug's name is called an unbranded ad. (As a side note, pre-approval drug ad campaigns cannot use both branded and unbranded ads, so marketing departments must carefully plan their promotions.)

Product Claim Ads
A familiar type of branded ad is the Product Claim Ad. Product Claim Ads not only name the drug but also discuss its benefits and risks. This is the type of ad that probably comes to mind when you think of a TV drug ad. The FDA requires that Product Claim Ads not be false or misleading and must be understandable by the average person
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Product Claim Ads, whether they appear in print or on TV, must include the following key components:
1) The drug's name. This must include both the brand name (i.e., the drug company's proprietary name) and the generic name (the non-proprietary name).
2) The drug's FDA-approved use
3) The drug's most significant side effect risks. These risks must be stated in a balanced manner relative to the drug's benefits.
4) a statement that the drug is obtained by prescription only (remember, we are dealing with prescription drugs. Over-the-counter drugs are regulated by the FTC).

Drug companies are prohibited from advertising any drug benefits that have not been approved by the FDA for that drug. Interestingly, doctor's are allowed to prescribe a drug for uses other than the FDA-approved use. This Off-Label prescribing is a highly controversial issue, but will await a future blog.

In Product Claim Ads, drug companies must provide the consumer access to lots of details about the FDA-approved usage of a drug. These FDA-approved drug details are contained in the drug's Prescribing Information. This information can be found as a document in the drug's container known in the US as the Package Insert (PI).

The prescribing information includes lots of details about the drug including:
1) the drug's chemical description
2) the FDA-approved drug use (i.e., what medical condition does the drug help)
3) the drug's method of action (i.e., how it is believed to work)
4) the drug's interactions with other drugs, health supplements, or foods
5) who should not use the drug (e.g., children, pregnant women)
6) the drug's side effects, both serious and non-serious risks even if they may be rare. Risks that may lead to death or serious injury may have the warning information displayed within a black-bordered box. Such a warning is referred to as a Boxed Warning or a Black Box Warning.

So how does the drug company put all of this information into its ad (and still get you to be interested in buying the drug)?
The FDA ad rules for Product Claim ads are slightly different depending on whether the ad is printed or broadcasted

Print ads must include a Brief Summary of all the prescribing information listed above. The Brief Summary is usually on a separate, but adjoining page to a nice colorful ad page with lots of pretty graphics to catch your eye. Check this out next time you see a Product Claim ad in a magazine and you'll find this Brief Summary page next to every main drug ad page (if you don't, you can report it to the FDA because it would otherwise be illegal). The Product Claim ad will often also provide sources of further drug information, such as a website and toll-free telephone number. In addition to the Brief Summary, the FDA requires that all print media Product Claim ads include the exact statement "You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088." (again, look for this next time you see a Product Claim ad in a magazine...go ahead, it will be fun.)

Broadcast Product Claim ads must meet what the FDA calls Adequate Provision when providing drug information. Broadcast Product Claim ads do not have to state as much drug information as print ads do. This makes sense because it would be costly, time consuming, and not very welcoming if the broadcast ad had to tell you all the Brief Summary details. Believe me, you would turn the TV channel before the actor even got close to being done.

Instead of a Brief Summary, broadcast ads just have to provide what's known as the Major Statement. The Major Statement presents just the most important risks that the drug presents. The Major Statement may be provided as text in the TV video, but it must be spoken. So this is why that smiling actor on TV is telling you about the drug's main side effects. They are giving you the requisite Major Statement of the drug. This Major Statement helps the drug company fulfill the FDA's Adequate Provision requirement, but it is not sufficient. In addition to the Major Statement, the drug company must provide ways that the listener (radio) or viewer (TV) can find the drug's FDA-approved prescribing information. This may include a toll-free phone number, a website, a magazine containing the print version of the ad, or a recommendation to ask your doctor. So now you know why the actor keeps recommending you speak to your doctor ... they are fulfilling the Adequate Provision requirement.

So that's a lot of information that drug companies need to know about advertising their drug. But that just covers Product Claim ads. There is another type of Branded Ad that doesn't need so much detailed information. This is known as the Reminder Ad.

Reminder Ads
Reminder ads give the name, but not the use, of the drug. Remember, the Product Claim ad claimed how the drug is to be used. So why in the world would a drug company spend the money on an ad that doesn't even tell people what to use it for?

The Reminder Ad is used when the drug company assumes that the consumer already knows what the drug is for and simply needs to be reminded of the drug's name. Reminder Ads do not contain any drug risk information since they do not discuss the use for the drug. In fact, Reminder Ads cannot suggest in any way (graphically or in words) what the drug's use is. If they do, they become Product Claim ads and must follow the rules outlined above.

Like Product Claim ads, Reminder Ads must include both the brand name and the generic name of the drug. Reminder ads cannot be used for drugs with a Black Box Warning.

Coming Soon Ads
While Reminder Ads are released post-approval to remind a consumer about a drug, Coming Soon Ads are used pre-approval to let healthcare providers know that a drug is coming to market (assuming it gets FDA approval). Coming Soon Ads, like Reminder Ads, do not contain any drug use information, but may contain the drug's name, logo, and company. They are used to start getting doctors and pharmacists familiar with a drug's name, even if they don't know yet how it will be prescribed. Since the drug has not yet been FDA-approved, Coming Soon ads are limited to healthcare providers as a target audience and cannot be targeted to consumers.

Help-seeking Ad
As mentioned before, some ads are unbranded ads, namely they do not mention the drug's name. You can imagine that if you don't even mention the drug's name, you don't have to provide the drug's prescribing information or risks. One such unbranded ad is known as the Help-seeking Ad. A Help-Seeking Ad describes a disease or medical condition but does not recommend or identify any specific drug to help the condition. Help-seeking Ads can include the drug company's name and provide a telephone number or website to contact for more information. The FDA does not regulate these ads (as long as they obey the simple rules mentioned). Instead, they are regulated by the FTC.

And Now You Know:
So now you know some basics of drug advertisements and how they are regulated. You now can be on the lookout for ad components such as the Brief Summary and FDA contact wording in print Product Claim ads. You can listen for the Major Statement, "ask your doctor", and other Adequate Provision components the next time you see a Product Claim ad on TV.

I hope this blog has given you a little insight into the wizard behind the curtain. So next time you see a drug ad, look or listen a little longer than you did before and revel in the joys of knowing a bit more about why all those smiling actors are so happy to share their medical risks with you.

Generic Drugs: Discounted cost, Discounted ethics?

I have been frequently asked why generic drugs are cheaper than brand name drugs. Are they cheaper because they’re of “cheaper” quality or do not work as well? The answer is no (in theory at least). In spite of many people who will swear that generics don’t work as well as their brand name counterparts, generics are cheaper in cost because they required less financial investment for the company that makes them. How is that?

I want to address this question because it raises some interesting ethical issues that have come to light in the press recently and promise to continue…but I’ll get to those later. First, let’s look at why generics are cheaper in cost. To do that, we have to understand a little bit about how drugs are developed.

When a company wants to sell a drug in the US, they need the approval of the Food and Drug Administration (FDA). The company must file an application to the FDA that proves that the drug is 1) safe, and 2) effective. This is referred to as the drug’s Safety and Efficacy profile. In order to get the data to prove this, the company had to go through 6 major hurdles:

1) Identify a chemical or molecule with the desired effect. This involves a lot of screening through candidates to find the one or several that look promising. This is the research phase of R&D.

2) Show that the chemical or molecule (I’m just going to call it a drug from now on) can be manufactured in large enough amounts to not only test it in drug trials, but also be able to sell it. This is often referred to as the commercialization phase of the development portion of R&D.

3) Show that the drug is likely to be safe in humans. This involves testing it in animals. It must be shown to be safe in an animal (usually several species of animal) before it can be allowed to be given to a human. This and the next step belong to the Non-clinical phase of drug development.

4) Show that the drug is likely to be efficacious (i.e., beneficial) in humans. Again, this involves animal testing.

5) Show that the drug IS safe in humans. This is the Clinical phase of the drug testing. This starts by giving the drug to healthy people and measuring the results to make sure no damage is done.

6) Show that the drug IS efficacious in humans. This is when the drug is given to patients who have whatever the condition is the drug is trying to help. This can involve testing the drug in thousands of people to make sure enough data is gathered to know if the drug works.

If all of these steps are successful, the company can put all the data together and send it to the FDA to prove that the drug should be approved for sale. Going through the 6 steps above can often take 15 to 20 years to complete and cost greater than $1 billion (yes, that’s with a “b”) dollars. That’s a lot of time and money. To make it worse for the company involved, over 80% of drug candidates fail to make it all the way through all 6 steps and get approved. So in short, it costs lots of money to look for and develop new drugs.

So when a drug does make it all the way through, the company sells it at a high price to recoup their investment costs and make a profit to keep the company going and fund future research to find the next new drug. The company can be helped in keeping it’s price high if they can get a patent on their new drug. If their drug is awarded a patent, the company is given exclusivity for selling it, usually for 17 years from the time the patent is granted. This means no one else is allowed to sell that drug until the patent expires. (Hint: this leads to the first ethical dilemma that I’ll get to in a moment).

So why are generic drugs a lot cheaper? They are a lot cheaper, because when a company applies to the FDA for approval to sell the drug, a lot of the hurdles that the FDA puts in place have already been cleared by the company that made the original brand name drug. In fact, even the name of the application sounds easier. The brand name drug maker had to file what’s known as a New Drug Application (NDA) to the FDA to get approval. The generic drug maker files what’s known as an Abbreviated New Drug Application (ANDA). As you can guess, the “abbreviated” NDA is quite simpler. The generic drug maker doesn’t have to start from scratch and toil through laboratory, animal, and human screens to find a winner. The winning drug candidate has already been chosen for them. They don’t have to redo all the lab testing that the original company did. Instead, they just have to prove that their generic drug is identical to the brand name drug. This is known as bioequivalence, namely that the generic drug has the same chemistry and biology that the brand name drug has with identical effects on the human body.

In other words, the generic drug is physically and behaviorally identical to the brand name. (Hint: this leads to the second ethical dilemma that I’ll address). This is still quite a lot of work to prove bioequivalence, but nowhere near what the research and development costs of the original brand name were. So because it was a lot cheaper to develop, the company can charge less for it. Also, because they had to prove bioequivalence, the generic drug is (hopefully) just as good as the brand name.

OK, so what are the ethical dilemmas I’m interested in that have resulted from this scenario?

The first involves the issue of granting patent exclusivity to a company that makes a new drug or method of using the drug. This legal protection is a huge incentive for a drug company. Knowing that they will have this exclusivity is what allows them to take the huge risks of research and development to find new drugs. Without this protection, a company could spend billions of dollars in developing a drug and as soon as it gets approved, another company could start selling the same drug at no prior development cost of their own. If you were the original company, you’d probably think twice before developing another new drug any time soon.

So patent protection is a very good thing to motivate companies to invest in the future and create new drugs and medicines. However, as you may have been hearing about in the news recently (OK, probably not if you’re watching CNN or your local evening news), generic drug companies in countries with large amounts of people living in poverty want to ignore these patents. They’re claim is that getting cheaper drugs now to poor people who otherwise cannot afford them outweighs the legal issue of patent infringement and they should not have to wait until the patents expire. This issue has come up several times in the recent past in several Asian countries such as India and Thailand. So is this a bad thing?

I wholeheartedly believe in getting drugs to the people who need them, especially the poor, but I have several problems with this. First, ignoring patents can greatly damage the business incentive to develop new and better drugs. Second, allowing companies to create generic drugs in violation of patent law is likely leading down a path where legal regulations can be too easily dismissed. This can lead to the dangerous situation in which the drugs are being massed produced with the focus on low cost rather than quality manufacturing with regulatory and legal oversight. Even if the “ethical” generic drug manufacturer who ignores the patent protection for the sake of the poor maintains good quality, they have opened the door for counterfeit manufacturers to get into the action. This may too easily lead to less potent, or worse, tainted or contaminated generic drugs.

If you think this problem would be restricted to the poor countries, think again. I would guarantee that as soon as cheap generic drugs became available in poor countries while only the brand name drugs (because of patent protection) are available in the wealthier countries, a black market distribution would be set up almost overnight by some unscrupulous distributors.
So my worry is that while the idea of breaking the legal patent rules for the sake of the poor may be idealistic, breaking patent laws under the guise of a Robin Hood hero may do a lot more than rob from the rich and give to the poor. It could very well lead to hurting both drug companies and patients. In fact, they could be giving a double negative whammy to patients. In the short term, patients may suffer from “cheap” generic drugs of poor quality that could jeopardize their health. In the long term, patients may suffer from the lack of new, better drugs because companies weren’t willing to take the investment risk.

But before you decide that I’m totally in defense of the brand name drug companies, let me now talk about the second ethical dilemma. Let’s assume now that a generic drug company respects the patent laws and waits it out for a patent to expire on a brand name drug. Now that the patent has expired, the company can get approval to sell the generic drug. Remember, to do so, it must prove to the FDA their generic drug is bioequivalent to the brand name drug. Well now is when the maker of the brand name drug can start playing some “is it ethical” games.

One game they can play is to strike a deal with the generic drug maker. Basically, they can make a deal that the generic drug maker will not make a generic drug to compete with their brand name drug in return for whatever favors can be negotiated. This may be cash payments or partnerships on other drugs.

Is that unethical?…probably not, but it’s not exactly great from a patient standpoint. However, there is another thing the brand name company can do that is even more controversial (I think). The brand name company can file a patent infringement lawsuit against the generic drug maker. A government statute known as the Hatch-Waxman Act stipulates that such a lawsuit delays any FDA approval of the generic drug for 30 months or until a court rules in favor of the generic drug maker (unlikely to happen quickly). This gives the brand name drug company extra time to sell their drug at full price. For brand name drugs, some bringing in greater than $1 billion dollars a year in revenue if it’s a real blockbuster, this can be some serious cash!

The Hatch-Waxman Act is definitely not bad or itself unethical. In fact, it has been a terrific law for getting generic drugs approved while providing a nice protection to make sure patents are not infringed upon. But what the brand name drug company does during those 30 months could get a little sketchy. A brand name company may use those 30 months to change the nature of their approved drug. Maybe change the dosing, change a tablet to a capsule, etc. Now what happens? The brand name drug company can try to get their patent extended if their new formulation or drug activity can be shown to be superior to the original version.

Now don’t get me wrong. If the new version is truly better, than the patent extension is deserved. What’s not so clear cut is when the change is slightly (or arguably not) better. Does an incremental increase deserve patent protection and therefore protected high drug costs versus the benefit a patient population may get from having lower costing generic versions? Or think about this one… remember the concept of bioequivalence? The generic drug maker had to show their drug was identical to the brand name drug. However, they may have just had the target moved on them while they were in legal limbo. The brand name drug is now in a new format, different from what they were trying to compare with and be identical to. The brand name drug maker may try to claim that their new improved drug is no longer bioequivalent to the generic drug trying to get approval.

Improving a drug is a wonderful endeavor and should be pursued. What is less wonderful is if the brand name drug company improves it’s drug but waits to apply for approval of the improved version and subsequently the patent extension only at the last moment of patent life, trying to maximize the full amount of total patent protection. That may be good business and profit protection, but it can be terrible for the financial burdens on patients and health care payors.

So you can see the ethical issues I raise center on the same general issue: At what point is the financial burden on the patient more important than the patent protection of the high cost drug? Unfortunately, like most major problems facing the world today, the answer is neither simple nor clear.