Google Sidewiki and Pharma Sites

How will pharma companies react, now that the latest Google toolbar comes with a “sidewiki” that allows users to post comments that anyone can see (as long as they have sidewiki enabled)?

There have been exceptional commentaries on what the sidewiki may mean for pharma, including John Mack’s fun and informative Pharma Marketing Blog, the Impactiviti Blog, and ePharma Rx, which may provide the best analysis of the bunch. Wendy Blackburn of ePharma Rx lays out clearly how the Google sidewiki works.

This is “crowdsourcing” or the “groundswell” at an extreme level: when a user downloads the sidewiki as part of the Google toolbar, he or she can make comments that will be seen by everyone else who visits the site and has the sidewiki installed and enabled. So far, only John Mack and a few others have gone to pharma sites and shown what you can do. Right now, the adoption curve seems to be mostly around political sites: people complaining that CNN is great, too far right, or too far left, depending on their tastes. Drudge, for example, has become a magnet for comments.

How will pharma respond? Can they legitimately claim that these comments are not a part of their site and something over which they have no control? If I talk about adverse events on a sidewiki, is it more akin to chatting on a forum, or will it constitute adverse event reporting for which pharma companies will have to develop a process? Wendy Blackburn thinks that pharma may have to put a disclaimer concerning the sidewiki on sites, but would that attempt to distance themselves from the sidewiki simultaneously constitute an acknowledgment of it? Kind of like the old joke: “You mean the dark-haired guy, about 5′10″, wearing a checked jacket and sunglasses? Nope, haven’t seen him.”

The pharma “groundswell” is here

Right now, the sidewiki comes with every download of the Google toolbar. Users have to enable advanced features (as they do with page rank), because sidewiki needs to know what page you’re on. And your Google moniker will accompany your comments–there’s no hiding behind anonymity.

But just wait: Think what happens when you search for statins or SSRIs. You get page after page of how they’re killing people, or you get psychiatry Luddites such as Peter Breggin. Now imagine those people all having adopted sidewiki a few months to a year from now.

Or what about your carefully crafted unbranded site? What happens when someone goes on the sidewiki and points out that this is bought and paid for by a pharma company? It’s not as if you were hiding the fact, but you might not want it to be the first thing people see, either.

Or people might talk about your drug–good or bad–on the NIH site, the American Heart Association, the National Alliance for the Mentally Ill (NAMI), or others. What do you do about those conversations?

Talk with your clients

I don’t claim to know what the upshot of all this will be, but ePharma Rx lists some potential possibilities. But you should think about the potential implications, and you should let your clients know. In fact, you should have your best marketing and UX minds prepare a brief of possibilities that could result from the sidewiki. They won’t be final answers, but they’ll be the start of an important conversation–especially as the FDA starts hearings this fall on the internet and social networking. Your clients may very well not have heard of sidewiki yet, but they soon will–this is Google, after all–and they’ll thank you for the early heads-up.

Biosimilars: How the EMEA Got it Right (Part 2, the Science)

In the first part of this series, we looked at where the EMEA (the EU equivalent of the FDA) got it right in terms of the regulatory pathway to biosimilars, without putting patients at risk. Their process is rigorous, testing both the structural (does the protein structure match–unlike some current US proposals, in which differences in the very amino acid structure are considered “minor”) and functional (does it work in large numbers of patients without causing immune reactions?) aspects of proteins. The attitude is “approve only if” the biosimilar meets tough standards that show that it is indeed comparable to the innovator protein.

Put simply, the EMEA  got the regulations right because they got the science right.

Certain US proposals–most notably by Henry Waxman–are tilted in favor of approval. When a biosimilar comes forward, the legislation is written in such a way that the prevailing attitude is “approve unless” some extraordinarily lenient guidelines are breached.

Biosimilars are not the same as generic drugs–not even close.

In the general guidance published by the EMEA, it is clearly stated that the generic approach is scientifically not appropriate for biosimilars. Biosimilars cannot be assumed to have the same efficacy and safety profile as the innovator protein–and neither can they be deemed identical simply by statutory fiat, as the Waxman proposal currently attempts to do.

“Due to the complexity of biological/biotechnology-derived products, the generic approach is scientifically not acceptable for these products.”

- EMEA, Guideline on Similar Biological Medicinal Products (CHMP/437/04), adopted October 2005

Many supporters of biosimilars legislation applaud the EU for having pioneered a regulatory approval pathway. However, the actual approval of biosimilars–and along with it the approbation of the U.S. biosimilars supporters–often founders on the shores of science–that is, the fact that the EU looks at the relevant science. When testifying before the Senate Committee on Health, Education, Labor, and Pensions in March 2007, Nicolas Rossignol, the European Commission Administrator, EC Pharmaceutical Legislation, testified that:

“The rationale for creating [a] new licensing route is that biologics similar to a reference product [i.e., the innovator product or brand] do not usually meet all the conditions to be considered as a generic. [emphasis in original] Although the EU ‘generic’ route remains legally open to biologics…, this is more a theoretical possibility than a practical way forward given the current state of science. It is clear for EU regulators today that the complexity of biological molecules, the fact that they are produced in living organisms and their sensitivity to changes in the manufacturing process make it virtually impossible for applicants to produce an identical copy of a reference biological product. In other words, the licensing route for biosimilars is based on the principles that biologics are not chemical drugs, [and] the generic approach is, in the quasi-totality of cases today, very unlikely to be applicable to biologics: biosimilars are not ‘biogenerics’.” [emphasis mine]

I’m sure Schumer and Waxman had expected someone from the EU to be on their side. After all, to a certain type of “intellectual,” isn’t Europe better in all things? But here was a representative of the EU all but telling them that their proposal was reckless. There were those pesky facts again, when Waxman and Schumer obviously wanted only to slap down pharma companies and tell their constituents that they had wrangled cheap drugs for them. Rossignol continued to pick apart their bill in an extremely polite way.

After elaborating on the reasons for the EU’s 11-year period of data exclusivity (Waxman recently wanted NO data exclusivity, and some proposals were as short as 5, when the break-even cost for biologics, given the cost of VC capital, is about 12 to 15 years), Rossignol continued his withering testimony, turning next to provisions in the Waxman-Schumer bill that merely overlooked–by fiat–science stating that shortcuts to biosimilars were rarely available.

“The type of amount of pre-clinical data are not predefined in legislation but are determined on a case by case basis, on the basis of the relevant scientific guidelines. This approach reflects the wide spectrum of molecular complexity among the various products concerned, ranging from relatively simple molecules such as insulin to far more complex ones. Thus, the requirements to demonstrate safety and efficacy of a biosimilar are essentially class-specific. In theory, a biosimilar application could therefore range from being almost ‘as abridged’ as a generic application (with very limited non-clinical/clinical studies), to being nearly as complete as a full stand-alone application.” [emphasis mine]

This is not what this committee wanted to hear–rather what they wanted to hear was something along the lines of, “Yeah, we make biologics in the bathtub in Europe, they’re almost free for everyone, the birds are always singing, and the sky is blue.” Instead they heard from an EU/EMEA representative that the task is difficult and requires getting scientists involved–not merely making political calculations.

Schumer introduced Mr. Rossignol with as stunning a bit of hypocrisy as can be imagined:

“As it stands today, the EU has a highly-regulated process in place that has arguably been unnecessarily burdensome to competitors and has only resulted in two approvals to date. This process was not established by the legislation that was passed by the European equivalent of Congress, however. The statute that created a pathway to biosimilars in the EU was written in broad language which gave Europe’s equivalent of the FDA discretion to flesh out the details. [in other words, they gave the damn scientists too much freedom to do that science-y thing of complicating everything...]

So when we think about this model, I agree that we should pass legislation that would give the FDA the discretion to establish a scientific approval process as they see fit. But why would the United States of America deprive the FDA of the ability to draft its own regulations [in other words, simple and one-size-fits-all], and force them to swallow a complex set of regulations that has been created by another system of government [the complexity of the regulations is a result of the science, not the whim of the government; only simplicity could be "forced" on the production of biosimilars by the whim of the government]? A system of government, I might add, that has price controls [given the healthcare debacle, which must result in rationing if passed, the hypocrisy here should leave you without words, no matter where you stand politically] and a generic drug market that is not as robust as our own.”

To be fair, it appears that Schumer has taken his name off of Waxman’s bill, but that does not change the complete hypocrisy (“we don’t want to regulate too much”) in the statement above. Waxman’s newer bill is largely the same as the one he introduced during the 2007 session; I see no substantive difference when it comes to the understanding of the science involved.

Similar is not identical.

The EU begins with the premise that a biosimilar is just that–similar to the innovator or pioneer protein, but not identical. The EU shows a proper deference to gaps in our scientific knowledge of proteins. Some simple, foundational premises are laid out in the EMEA Guideline on Similar Biological Medicinal Products (CHMP/437/04, adopted October 2005):

First, biologics are not chemical drugs.

“Biological medicinal products are usually more difficult to characterize than chemically derived medicinal products. In addition, there is a spectrum of molecular complexity among the various products…Moreover, parameters such as the three-dimensional structure [crucial to a fully functioning protein, but not well-characterized -- my note], the amount of acido-basic variants or post-translational modifications [what happens to the protein after it is formed from DNA/RNA, including various chemical reactions and folding into the proper 3D shape -- my note]…can be significantly altered by changes, which may initially be considered to be ‘minor’ in the manufacturing process. Thus, the safety/efficacy profile of these products is highly dependent on the robustness and monitoring of quality aspects.”

Second, there may be subtle differences between a biosimilar and the innovator product. The EU recognizes that:

“…it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference [innovator] products, which may not become fully apparent until great experience in their use has been established [emphasis mine].”

The EU is stating clearly that because follow-on biologics are similar, but not identical to, innovator biotech proteins, testing is needed to detect subtle differences: pre-clinical testing, clinical testing, and post-marketing testing (surveillance or Phase IV) to ensure safety and efficacy in the broader population. The EMEA guidelines are based on current science–not wishful thinking, the desire to save money alone, or statutory pronouncement.

Next time: More on getting the science right, class-specific guidelines for biotech medications, and the absolute necessity for full-on Phase III testing for almost all biotech medications.

Biosimilars: How the EMEA Got It Right (Part 1)

I don’t think anyone disagrees that:

1. Access to life-saving medications for all patients must be granted through a patient-focused, science-based application of a logical, open, and rational process, and that
2. For patients to gain the greatest possible benefits, biologics with patent protections that have expired should be subject to competition from appropriately safe biosimilars

However, despite some irresponsible bills that have been introduced in Congress (such as Waxman-Schumer), a science-based, patient-focused pathway to biosimilars is possible–but we MUST take into account:

1. Information gaps in our knowledge of these complex medications–and the complex process of manufacturing them
2. Potential threats biosimilars can pose to patients, from problems with excipients to life-threatening immunogenicity
3. Vulnerable patient populations–such as the sick, elderly, minorities, uninsured, and underinsured–who would bear the brunt of policies that shortcut appropriate safety

“Appropriately safe”: a proper, cautious regard for patient safety

What does “appropriately safe” mean? It cannot mean taking the kinds of shortcuts that some legislation is considering when it comes to patient safety. Some people may say that that simply begs a further question: What does it mean to “take shortcuts”? Basically, any regulatory pathway that does not take into account the uniqueness of biotech medicines–the unique complexities, unique difficulties in manufacturing, and unique safety issues–is taking shortcuts and putting patient safety at risk.

There are four basic principles for an responsible pathway to biosimilars. To provide some background on these principles, and to help illustrate the outcomes to which they lead in the real world, it’s instructive to take a look at the experience of the European Union and the European Medicines Agency (EMEA). They have forged a rigorous process that tests both the structural and functional aspects of biosimilar proteins.

In other words, the EMEA proceeds with a proper, cautious regard for safety when considering applications for biosimilars. EMEA regulations show that a science-based, patient-focused pathway to biosimilars is possible. There’s no need to sacrifice patient safety for cost savings, as Henry Waxman’s latest abomination of a bill does (more on that in a later article–he is still insisting that an altered amino acid sequence is a “minor difference” between proteins). There’s no need to stifle the innovation and regard for intellectual property rights that have led the US biotechnology industry to worldwide leadership.

The EU has developed a balanced approach to biosimilars that rewards companies who develop innovative products, while allowing for competition. It’s possible to develop safe and effective biosimilars in which patients and physicians can place their trust. Because if this trust is betrayed by products that are rushed to market through a less-than-responsible regulatory pathway (and to call the Waxman bill less than responsible is a massive understatement–it’s criminally misguided and obviously the result of political calculation only), it will do irreparable harm not only to patients and the healthcare system, but also to the budding biosimilars industry. It will actually move us farther from the goal we all seek: To make life-saving biologic medications available to the patients who need them.

The EU hasn’t always gotten it right.

In fact, it came to a balanced approach, focusing on science and patient safety, in large part because of a horrific event.

First, some key background on the medication involved: EPREX is the European version of Epogen, a biotech medicine developed by Amgen that relieves anemia for patients with chronic kidney failure who are on dialysis. Epogen is a biotechnology-derived version a naturally occurring protein called erythropoietin (EPO). EPO is a “signaling protein” that tells the bone marrow to increase red blood cell production. Because of our increased understanding of signaling proteins, we know that damaged kidneys don’t make enough EPO. Normally, when blood oxygen levels are low, or when someone has lost blood in an injury, the kidneys produce and release EPO to tell the bone marrow to get started producing more red blood cells. People with kidney failure, in addition to all of their other complications, don’t make enough EPO in their kidneys. As a result, they have fewer red blood cells than normal. Using biotechnology, we can now produce large amounts of EPO to stimulate the production of red blood cells and treat chronic anemia among very sick patients, including those undergoing chemotherapy and those with chronic kidney disease.

A version of EPO—called EPREX—was introduced into the European Union by Johnson & Johnson, a large innovator company that pays careful attention to patient safety. This was essentially an intra-manufacture change, since a licensing agreement gave all companies involved full access to patents, the details of the manufacturing process, and all trade secrets. When EPREX was made in Europe, a tiny change was made that was intended to improve its safety profile. There was a concern that the ingredient used to stabilize the protein could possibly contain Mad Cow Disease, so this single stabilizing agent was changed.

Everything was done in accordance with then-current EMEA quality-control regulations that guided companies in demonstrating “comparability” of biotech medicines after a change in manufacturing. But this one small change in the manufacturing process—made by a large innovator company that pays careful attention to patient safety, not a fly-by-night biosimilars company—was enough to lead to huge consequences for patients throughout Europe. There was a significant increase in patients who developed antibodies to (or rejected) Eprex—in other words, their bodies no longer accepted this foreign protein. These antibodies even reacted with the body’s own natural erythropoietin—because the biotech medicine replicates the original, natural protein. As a result, affected patients no longer made their own red blood cells, a rare condition called “pure red cell aplasia.” They became severely anemic, requiring multiple blood transfusions and dialysis.

The key lessons of the EU experience.

Spurred on by a terrible experience, the EU established a regulatory review process for biologics that focuses on patient safety.

Because such severe immunogenic reactions cannot be predicted with pre-clinical (or non-human studies)—whether laboratory assays or animal tests—the EU has determined that clinical studies among relatively large patient populations for safety and efficacy must be conducted for all follow-on biologics. Not only are clinical studies required before approval, but robust post-marketing studies (pharmacovigilance) are required post-approval to ensure the safety of the public and track adverse events. We’re not talking about the kind of 20-person pharmacokinetic/pharmacodynamic studies done for small-molecule generics (which should not be reassuring to anyone–good specialists know that many patients, especially those taking psychotropic medications, experience worsening when switched to generics; just look up bupropion or “generic sertraline” online).

In other words, in order to ensure patient safety, the EU was saying that, first, you have to get the science right.

Next time: Getting the science right, and the relationship between good science, innovation, and improved healthcare.

The EU hasn’t always gotten it right. In fact, it came to a balanced approach, focusing on science and patient safety, in large part because of a horrific event.

First, some key background on the medication involved:

EPREX is the European version of Epogen, a biotech medicine developed by Amgen that relieves anemia for patients with chronic kidney failure who are on dialysis. Epogen is a biotechnology-derived version a naturally occurring protein called erythropoietin (EPO). EPO is a “signaling protein” that tells the bone marrow to increase red blood cell production. Because of our increased understanding of signaling proteins, we know that damaged kidneys don’t make enough EPO. Normally, when blood oxygen levels are low, or when someone has lost blood in an injury, the kidneys produce and release EPO to tell the bone marrow to get started producing more red blood cells. People with kidney failure, in addition to all of their other complications, don’t make enough EPO in their kidneys. As a result, they have fewer red blood cells than normal. Using biotechnology, we can now produce large amounts of EPO to stimulate the production of red blood cells and treat chronic anemia among very sick patients, including those undergoing chemotherapy and those with chronic kidney disease.

A version of EPO—called EPREX—was introduced into the European Union by Johnson & Johnson, a large innovator company that pays careful attention to patient safety.

This was essentially an intra-manufacture change, since a licensing agreement gave all companies involved full access to patents, the details of the manufacturing process, and all trade secrets. When EPREX was made in Europe, a tiny change was made that was intended to improve its safety profile. There was a concern that the ingredient used to stabilize the protein could possibly contain Mad Cow Disease, so this single stabilizing agent was changed.

Everything was done in accordance with then-current EMEA quality-control regulations that guided companies in demonstrating “comparability” of biotech medicines after a change in manufacturing. But this one small change in the manufacturing process—made by a large innovator company that pays careful attention to patient safety—was enough to lead to huge consequences for patients throughout Europe. There was a significant increase in patients who developed antibodies to (or rejected) Eprex—in other words, their bodies no longer accepted this foreign protein. These antibodies even reacted with the body’s own natural erythropoietin—because the biotech medicine replicates the original, natural protein. As a result, affected patients no longer made their own red blood cells, a rare condition called “pure red cell aplasia.” They became severely anemic, requiring multiple blood transfusions and dialysis.

DDMAC Misses Opportunity to Clarify, Rather than Kill, Pharma SEM

In a recent series of Warning Letters, DDMAC has begun to look closely at SEM (e.g., Google AdWords) for prescription products, and they don’t like what they see.

These small ads generally include only the name of the medication–usually in the URL–as well as the indication. GSK received warnings about a boatload of SEM ads, including those for Avandia, Avandamet, Avandaryl, Avodart, Coreg CR, and Tykerb. According to the letter from DDMAC to GSK,

“The sponsored links cited in this letter are misleading because they make representations and/or suggestions about the efficacy of [the drugs mentioned above], but fail to communicate any risk information associated with the use of these drugs. In addition, the sponsored links inadequately communicate the drugs’ indications and fail to use the required established name.”

A Digression: Haiku of the Hoi Polloi

Google AdWords are the closest many people will get to writing haiku. Although there are other forms of SEM, Google Adwords are the most popular. These have four lines: an “ad title” (which is also a link), two “description lines” about your product or service, and a “display URL” (which is not a link, but could be cut and pasted).

Very roughly speaking, English-style haiku have three lines of five, seven and five syllable, respectively–although many appearing in journals have 10 to 14 syllables, without concern for line symmetry. In any case, let’s look at a typical haiku by Basho, the greatest Japanese haiku poet, and compare it to a Google AdWords ad:

the first cold shower

even the monkey seems to want

a little coat of straw

Just in terms of length, we’ve got three lines: the first is 21 characters, the second 29, and the third 22. So the writer of a Google AdWords ad has a little breathing room compared to a haiku, but not much. Google Adwords gives you an extra line of 35 characters, but it’s for the URL. Let’s now look at the example of an ad provided by Google:

Google Adwords

Effective CPC Advertising

Fast Results Within Your Budget!

Adwords.Google.com

There are other parallels between Google AdWords and haiku. Very roughly speaking, a haiku works by setting a scene and then disrupting it, with the resulting reflection leading to insight. Japanese uses a kireji–a “cutting word”–to drive the point home, while English haiku often uses ellipses or dashes to separate the elements. (At the risk of this turning into a haiku lesson, in the example given, the kireji is komino–coat of straw–which appears at the end of the second line in the original Japanese. It forces us to draw a parallel between a natural scene, with a cold spring rain and monkey, and our own human situation, needing shelter just as desperately.)

The “Cutting Word” in a Google ad

In the same way, an AdWords ad sets the scene in the “ad title” (in the example above, that would be “Google AdWords”) and continues “scene-setting” with the first of the two “description lines” (here, “Effective CPC Advertising”). And just as in an effective haiku, a good Google AdWords ad drives home a point related to the scene-setting…granted, in a somewhat less subtle manner than Basho: “Fast Results Within Your Budget!”

In other words, your moment of Zen reflection on just what might constitute “effective CPC advertising” is disrupted by an answer of sorts: “Fast Results Within Your Budget!” Here, the display URL is somewhat redundant, since it’s the same as the “ad title,” but many ads use the display URL line to provide the name of their product or service. The rules for the “sponsored links” that appear above the central column have slightly different rules, but generally about the same constraints.

Back to Pharma SEM

Let’s look at an SEM ad that was called out by DDMAC. This one is for Singulair, an effective and relatively benign medication for asthma or allergies:

Allergy Medication

Relief of Allergy Symptoms:

Learn About A Treatment Option.

www.SINGULAIR.com

Allergy medication does, in fact, relieve allergy symptoms (how about that?). That’s the scene-setting part of the ad; the “insight” comes with “Learn about a treatment option.” Not much insight–I’m certain marketing wanted “different” or “new” in there, but “different” would blow the character count (and is implied in “option”), while we’re way beyond the 6-month cut-off for using the word “new.”

In fact, there’s nothing much at all here–just the name of the medication and the indication…not even any claims. So what does the FDA say about this ad?

“According to its FDA-approved PI, Singulair is indicated, among other things, for the relief of symptoms of allergic rhinitis (seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older, and perennial allergic rhinitis in adults and pediatric patients 6 months of age and older).

Singulair is associated with a number of risks, as reflected in the Contraindications, Precautions and Adverse Reactions sections of its PI.”

In other words, DDMAC wants all this information in there. I’m not counting, but I think that would blow our character count out of the water. The FDA would also like to see the full generic name (in this case, montelukast sodium–18 characters right there; that’s most of our “ad title” and more than half of our “descriptive lines”). And normally, the generic name would go in parentheses (another 2 characters, not counting an additional space) after the drug name, which in Google SEM goes in the “display URL line.” But I have feeling that companies don’t want to send potential patients to “www.SINGULAIR (montelukast sodium).com” for any number of reasons. (Personally, it makes me feel like I’m programming in LISP again.)

Interesting aside–on its page outlining what’s allowable in AdWords, Google specifically states that advertisers should not “use excessive capitalization such as ‘FREE’ or GOOGLE ADWORDS’” and that “[c]apitalization of the first letter of each word within your display URL is also permitted.” But in deference to the bizarre pharma practice of ALWAYS CAPITALIZING BRAND DRUG NAMES,  they apparently put up with it (every single example given by the FDA has the brand name in caps in the URL). I never, ever have understood why PHARMA COMPANIES WANTED TO LOOK LIKE THEY WERE SHOUTING THE BRAND NAME AT PATIENTS AND HCPS!!! But I digress again…

The real problem

What is the difference between an SEM ad and a rich media banner that puts the Important Safety Information and PI one click away? Generally, the “one-click-away” rule has been acceptable to the FDA (and to most med/legal teams). Occasionally, on rich media banners, I’ve worked with designers to develop scrolls at the bottom of one of the rollover panels. And for drugs with a black box or other restricted information, you have to find a way to show it, even on banners, the second your drug name appears.

This is why Tysabri is not a good example. DDMAC has a point there: not only does it have a black box warning, but there are severe limitations in the drug’s labeling:

TYSABRI is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations . . . . Because TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability, TYSABRI is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate multiple sclerosis therapies.

In other words, this drug is not simply “different from the others,” as stated in the SEM ads. It’s for patients who’ve tried other medications and have had a poor response. This one really smells like a backdoor attempt to broaden the indication and cast the net wide for patients.

But DDMAC has missed a chance to bring some clarity here. By lumping Tysabri (a misleading ad for a black-box drug) together with Singulair (a straightforward ad for an effective, relatively benign drug), they’ve missed the chance to address internet advertising in general. When is “one click away” appropriate for the PI? For Important Safety Information? For SEM, how are black-box drugs different from drugs with good tolerability? How are first-line drugs different from adjunct therapy or second- or third-line drugs? How are drugs with a broad indication (asthma, type 2 diabetes) different from those for specific presentations of a disease or for patients who have failed on multiple drugs?

Basically, DDMAC, you blew it. If I was a pharma company exec looking at your examples and your letters, I would avoid SEM altogether. And I would be scratching my head wondering what the takeaway–if any–is for rich media banners. I think the answer is “not much,” and SEM dollars will go to rich media, carefully placed. Because, with this guidance, DDMAC has effectively killed SEM for prescription meds.

Hey–and Levitra, do you really want to appear within mere pixels of another sponsored ad that promises that you can “Be bigger, harder and longer for 85% cheaper”? That placement is not DDMAC’s fault. But c’mon…really?

Biotech drugs: Pushing policy boundaries

Biotech medications are beginning to attract attention and push policy boundaries in the US.

What does it mean to say that biotech products “push policy boundaries”? Well, since the passage of the Medicare prescription drug benefit (Part D), Medicare policy and pricing decisions have taken on a role normally assigned to the market: the ongoing challenge to balance access considerations, the role and strength of evidence for efficacy and safety, and the cost of new treatments. This is a role that the National Health Service (NHS) in the UK has been playing for years, performing cost/benefit analyses of new medications based partly on quality-adjusted life years (QALY). However, it’s not a role that we’re accustomed to the government playing in the US, nor are many people comfortable with it, even when they say they are.

Usual responders to cholinesterase inhibitors From: Stahl SM. Stalh's Essential Psychopharmacology: Neuroscientific Basis and Practice Applications. New York: Cambridge University Press; 2008.

A friend or coworker might say, “Hey, I’m comfortable with that. Healthcare is rationed under the current system anyway!” Tell them about the National Institute of Clinical and Health Excellence (NICE), part of the NHS in the UK. Tell someone with an older relative or friend suffering from Alzheimer’s that NICE has decided, based on a cost/benefit analysis, that patients in the UK cannot get cholinesterase inhibitors (small-molecule drugs)–at any price. Granted, most patients get little or no benefit from these medications, but there are responders, and doctors can make informed treatment decisions with patients, caregivers and family. (See figure.) But not in the UK. A 2005 decision by NICE said that they were “not good value for the money”–end of story.

Or tell them about the 41-year-old mother of four who was denied Herceptin for breast cancer based on cost/benefit analysis. Or about the woman who dared to pay on her own for the breast cancer drug Avastin–and had ALL treatment withdrawn by the NHS! Seems we wouldn’t want to create a “2-tier” system.

Whoops…scratch that. Turns out that the NHS is now considering a “top-up” plan that would create a 2-tier medical system. According to the BBC, “Patients get the right to pay for top-ups without losing their basic NHS package of care…But those paying for extra drugs will also have to cover the cost of any staff time, tests and scans associated with that treatment…Top-up care must be carried out away from NHS wards to avoid patients in beds next to each other getting different quality care…” So we have some hypocrisy to top off the top-up care! And still the amount the NHS pays for drugs has doubled in the past 10 years.

New Zealand also provides a good example of how frank cost-benefit analysis leads to perverse results and impairs patient care. A recent article in The Atlantic Monthly (“My Drug Problem”) outlines New Zealand’s attempt to ration the use of Herceptin, leading off with a stark statement: “If I lived in New Zealand, I’d be dead.” Pharmac, New Zealand’s appropriately robotically named version of the UK’s equally mordantly named NICE, evaluates the efficacy of new drugs, decides which are cost-effective, and negotiates prices. New Zealand began covering the cost of the drug for advanced (metastatic) breast cancer in 2002, but withheld it from those with early stage breast cancer, even though studies showed that adding Herceptin to standard treatment regimen for these patients could increase survival rates from 50% to 95%!

After 2007, Pharmac covered Herceptin for early-stage breast cancer, but only for nine weeks (three treatments), despite the fact that the trials that established efficacy in early-stage breast cancer were conducted over 12 months (17 treatments) among 13,000 patients. Instead, Pharmac disingenuously pointed to a small Finnish study, involving only a couple of hundred patients, that showed positive results from a nine-week regimen. In other words, we know that a year of therapy works, but Pharmac decided to go with a small, statistically uncertain nine-week trial. Why? This allowed them to conflate patient safety (potential cardiac problems from long-term use) with outright cost concerns. No agency wants to look like a heartless robot–even an agency named Pharmac–so the agency made a purely cost-based analysis while using a small study for “scientific” cover.

It’s coming to the US under the guise of “evidence-based medicine” (who’s not in favor of evidence-based medicine?). In the recent bailout/recovery/stimulus package, the FDA states that, “Funding to study the comparative effectiveness of healthcare treatments, including drugs, is part of the stimulus package Congress is considering now that lawmakers have recommended $1.1 billion to support such research. Comparative effectiveness studies that take the costs and effectiveness of drugs into account could affect sales of specific products.” Many argue that this is the first step to NHS/NICE-style cost/benefit analysis of medications, treatments, and devices.

Biotech medications: “Lightning rods” attracting attention

Biotech medications attract attention for a number of reasons:

• They draw strong patient demand, often being the only treatment for certain disorders
• They often treat rare or life-threatening diseases, so that simply withholding treatment is not an option
• They may have uncertain evidence of health benefits, especially for oncology medications used off-label
• They are often costly to Medicare, which means that they are costly to the government, meaning that they are costly to all of us

Now, the Centers for Medicaid and Medicare Services (CMS) makes individual decisions based on an “evidence-based approach” to evaluate whether a medication’s health benefits outweigh its risks. Under statutory requirements, CMS must cover treatments that are “reasonable and necessary” for diagnosis or treatment. In fact, after the Medicare Reform Act (Medicare Prescription Drug, Improvement, and Modernization Act [MMA]) of 2003 stated that the CMS must spell out coverage criteria, the CMS issued a 2006 guidance document explicitly stating that cost-effectiveness and costs would not be considered in deciding whether to cover a treatment.

In fact, for now, every time CMS has moved toward making cost more of a consideration, it has gotten its hand slapped by Congress, and its ability to invoke costs explicitly has been narrowed. For example, in 2003 the CMS said that two anemia medications, Aranesp and Procrit, were “functionally equivalent” simply because they “use the same biological mechanism to produce the same clinical result,” so they would both be reimbursed at the same, lower Procrit rate.

Before we look at why this was simply wrong in the case of Aranesp and Procrit, it’s important to take a look at that reasoning, which should scare you. Why? Because it implies that any two medications in the same class are “functionally equivalent,” because they “use the same biological mechanism to produce the same clinical result.” Companies would not be able to charge any sort of premium for incremental improvements, or even for substantial improvements (Aranesp, for example, actually represented years of work by the best researchers on the planet). Anyone who has found no relief or intolerable side effects with one SSRI, only to find efficacy and tolerability with another, should take issue with this reasoning. The same goes for those who have tried pain relievers, PPIs for acid reflux, or even antihistamines.

It’s well known among psychiatrists that different SSRIs, for example, have different profiles. Prozac is somewhat energizing, while Paxil is sedating (which is why it was used for panic disorder in the late 90s, until its weight gain and withdrawal effects became more noticeable). Beyond that, they can have different–and sometimes idiosyncratic–effects on different patients. In addition, SSRIs can have a tendency to “poop out” and stop having an effect, at which point a psychiatrist must switch to a different SSRI, or else use another drug–such as buproprion, buspirone, or others–to augment the effect of the SSRI.  When switching, there exists a body of received wisdom that you won’t find in the journals, such as that Prozac responders tend to respond to Zoloft, or that those who respond to Celexa won’t necessarily respond to its enantiomer, Lexapro (and vice versa).

The STAR*D trials represented an attempt to systematize these sorts of interventions. Over a seven-year period, the study, funded by the National Institute of Mental Health (part of the NIH), enrolled more than 4,000 patients aged 18 to 75. They eventually arrived at an algorithm or decision tree for sequenced treatment alternatives in treatment-resistant depression. If you follow the link above, you can find this decision tree. The real point is this: If the NIMH/NIH had followed the logic of the CMS, STAR*D would not have been an algorithm but rather a single sentence–”Try whatever you want, because these drugs are all functionally equivalent–0h, and try the cheapest.” They all inhibit the reuptake of monoamine neurotransmitters, generally serotonin (“same biological mechanism”) to alleviate depression (“same clinical result”). Under that definition, you could expand beyond the typical notion of “class” to include the tricyclic antidepressants, which have essentially the same MOA, but have well-known cardiac toxicity (they prolong the QT interval), problems with weight gain, and anticholinergic effects such as dry mouth and constipation.

So what’s wrong with the CMS using this criterion for payment? Without some incentive, what company is going to invest in research into improvements? As you progress through the SSRIs, from Prozac to Lexapro, you see generally increasing affinity for the serotonin receptor and less initial agitation for patients. Although doctors are well aware of individual patient reactions and happy to have a choice of medications to use for a given condition, pharmaceutical companies will not invest the time and effort without a reward in return for their risk (not every drug makes it to market, even when the receptor/target is known).

Why the Aranesp decision was so wrong-headed…and why the same thinking is found in some biosimilar legislation

It’s true that Aranesp is a modified version of epoeitin alfa, the protein that signals the bone marrow to make more red blood cells. Epoeitin alfa, due to intellectual property and licensing considerations, is sold under two names–Procrit and Epogen–so we’ll refer to it by its common name in the industry: EPO. This medication completely changed the quality of life for thousands of patients with anemia from chemotherapy or who were undergoing dialysis due to end-stage renal disease. But many of these patients had to inject themselves several times a week, and a once-a-week injection would improve their quality of life.

However, Amgen researchers were thinking a little like CMS bureaucrats; they didn’t want to spend the time developing what seemed like a merely incremental improvement as opposed to doing “real,” groundbreaking science. As George Binder, the former CEO of Amgen, put it in Science Lessons: What the Business of Biotech Taught Me About Management, “One unspoken explanation for the skepticism [regarding the development of Aranesp] was that many researchers regarded prolonging a drug in the bloodstream as ‘low-grade’ science. Making a wholly new discovery was ‘genuine’ science…But for patients who had to inject Epogen several times a week, being able to go a whole week without a single needle stick would improve the quality of their lives in a very real way.”

Some patients don’t like to inject themselves (who would?). And a long-acting EPO would provide more freedom to patients, allowing them to go on vacations or business trips without concern about their next injection, especially since EPO needs to be refrigerated.

It turns out that the decision to go ahead was based on business, but the science involved was anything but “low-grade.” After EPO had been on the market for some time, new analytic techniques had allowed researchers to see that it was actually a mixture of five EPOs. Each had the same amino-acid “backbone” in the protein, but with different amounts of carbohydrate, which connect to the backbone at various points like branches of a tree . When the five EPOs were separated, the one with the most carbohydrate turned out to be the most effective.

In order to develop a long-acting EPO, or Aranesp, the EPO protein (and the gene producing it) would have to be reengineered to contain more carbohydrate than natural epoeitin alfa would allow. However, it seemed that with each attempt, the additional carbohydrate blocked the action of the epoeitin alfa protein. A few years and 100 molecules with various amounts of carbohydrate later, one was found that worked: it prolonged the action of epoeitin alfa in the body. As George Binder states, “Far from being low-end science, this was pioneering work.” And it was work that never would have been done without market incentives.

Courts find Aranesp a new product, not merely an improvement on an existing product

In its early days, Amgen had licensed Epogen to Johnson & Johnson as Procrit. Amgen retained certain indications, such as chronic anemia due to end-stage renal disease, while J&J sold Procrit for anemia due to chemotherapy and other causes. If the drug were merely an improvement, Amgen would have to allow J&J to sell it for those indications, as spelled out in the contract. If it were a new drug, Amgen would be free to sell it to all Americans suffering from chronic anemia due to a variety of causes. In 1998, an arbitration panel ruled in favor of Amgen: Aranesp (darbopoeitin) was a new drug.

Why, then, would the CMS, 5 years after this decision, decide that Aranesp and Epogen were essentially the same drug? If you’re thinking “cost control,” you’re on track. If you’re thinking, “cost-control with a hypocritical veneer of science,” you’ve hit the nail on the head.

Next time: the EMEA experience and why THERE IS NO SUCH THING AS A GENERIC BIOLOGIC

Just this week, Bloomberg.com reported that lawmakers are once again taking a look at biotech drugs: “Obama also wants to introduce changes so generic versions of drugs made through biotechnology can be introduced to the market more quickly, the official said. Biologically based medicines with combined sales of $34.2 billion are due to lose patent protections in the next eight years…The list of drugs that could be replaced by cheaper generics include some of biggest sellers for pharmaceutical companies, such as Johnson & Johnson’s Remicade, which generated $3.75 billion last year; Amgen Inc.’s Aranesp, with $3.14 billion in sales; and Genentech Inc.’s cancer drugs Avastin, Herceptin and Rituxan.”

In the next installment, we’ll look at why there are no such thing as “cheaper generics” when it comes to biologic medications, some of the potentially damaging and industry-destroying biosimilar pathways Congress has considered (which would kill investment in biotech and endanger patient safety), and how the EMEA has it largely right.

So you want a pharma RM program? 7 questions you need answered (part 2)

In part 1, I looked at

• Barriers to adherence
• How these barriers change over time (so that you can engage in stage-based RM)
• Patient attitudes toward treatment

I also wondered aloud about why marketing, brand and product managers put so much weight on the results of the small numbers of people seen in focus groups. However, I must say that focus groups, when properly run, can give you fantastic directional, qualitative information. When I went to Adderall XR focus groups, conducted with parents (largely mothers), and saw for myself mother after mother break down into tears over seeing their child labeled at school, thinking that they were a bad parent, recounting the daily ordeal over pill-taking, or even leaving a job–out of guilt–to be a full-time, stay-at-home parent.

That provided great insight into the best way to streamline the Adderall XR program from a quarterly, tchotchke-based program to a true stage-based RM program. We front-loaded the program with patient-friendly messaging about the brain science of ADHD, as well as ADHD’s “heritability”–a measure, based largely on twin studies, demonstrating the effect of heredity vs environment. For ADHD, heritability is about 80%–among the highest for any psychiatric disorder, and the same as the heritability of height in the US! In other words, from the beginning, our message is, “You’re not a bad parent. This not your fault.”

(For those of you with an interest in genetics, yes, I know that heritability is a tricky, misunderstood concept that measures only the percentage of the variation within a given population of a particular trait attributable to genes, and only within a particular environment. For example, in the US, although the heritability of height is 80%, in cultures with more variation in access to nutrition, the environment would play a much larger role in determining final height.)

This research for Adderall XR provided insights that informed a rebranding effort focusing on the child achieving his “true” inner potential, blunted by ADHD. It also was top of mind when developing branding for Daytrana, the first patch for ADHD. In these spec ads you can see that, although the patch technology is highlighted, the way in which the patch changes family dynamics was brought to the forefront. A patch avoids the daily ordeal of getting one’s child to take a pill, which is a constant reminder of his or her “difference.” And the patch is positioned, not as mere novel delivery method, but as a way to heal emotional wounds and scars.

That brings me to one more point before moving on to the next four questions that you need answered before beginning an RM program. To make RM successful, think of everything as “relationship marketing.” Broad media advertising, even though its purpose is to gain awareness and trial, is the beginning of your relationship with your patient. The same thinking that will keep patients engaged and moving through your RM program should be employed upfront–at print, broadcast, rich media, and websites.

If you’re involved in branding, bring in your RM agency: You should create and position campaigns with patient relationships in mind. In fact, “traditional” thinking is exactly backward. You should have a vision of the relationship–the engagement–you want to have with your patients. Only then should you develop adlobs and TV storyboards. What will be the tone of your relationship with patients? What will it feel like or sound like at 2 weeks, one month, two months, six months?

Especially now that the era of blockbusters appears to be giving way to smaller brands for very specific markets–even medications that require diagnostic testing to determine whether they’ll work (personalized medicine is already here!)–you need to think about relationships and conversations. The best raconteurs don’t start out by shouting or by telling you how fantastic they are; they gradually weave you into their world as you follow their narrative. Perhaps cable spots on network catering to very specific demographics, or rich media banners contextualized to the sites on which they appear, will start a conversation, inviting patients into a like-minded community. Because a conversation in a crowded bar is a lot different from one in a quiet dining room. Even the context of your first communication becomes part of your ongoing conversation.

Engagement–the new grail

Good RM agencies have been involved in engagement for a long time because, as Charlene Li and Josh Bernoff put it in Groundswell, to take advantage of social networking technologies, “you should have a vision of the kind of conversation you want with your customers.” Once you have that, you can figure out the precise social networking technologies that may (or may not) work in pharmaceutical marketing, whether you’re listening to, talking with, energizing, or embracing the groundswell.

Can pharma tap into the groundswell, with concerns around HIPAA, adverse events, and discussions of off-label uses? So far, there’s only a toe in the water, but it will be RM thinking that eventually finds the technology that makes the groundswell work for prescription medications. That’s because RM thinking begins with the question, “What sort of a conversation do I want to have with my patients?” Because the groundswell is about listening and conversing–not pushing messages. As George Glatcz, president of Vox Medica says in a discussion of engagement, “Is the path you’ve set out on going to lead you where you said you need to be ultimately?”

Listen carefully enough, and you may just find out enough about your patients to move far beyond typical DTC, beyond even direct-to-patient marketing, to “direct-from-patient” marketing–in which the needs of patients are addressed in as close to real time as possible.

Now let’s get back to the remainder of the 7 questions you need answered before you start an RM program

4. What does your persistence curve look like?

For many medications, you can almost lay persistence curves on top of one another; most show a gradual slope from the group who fill their first prescription to about 50% to 60% by month 3, gradually decreasing over time.

However, there’s a lot beneath the surface when it comes to the apparently simple term “adherence.” A recent study in the British Medical Journal reminds us that:

“Although ‘adherence’ seems a simple construct, often reduced to a percentage of prescribed doses taken, electronically compiled dosing histories reveal variably long intervals between doses and variably short durations of treatment.” (Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008;336(7653);1114-1117)

In general, when marketers say “adherence,” they really mean “persistence”–that is, whether or not patients continue to take medication over time. However, is your case one in which patients are persistent (continue to take medication over time) but non-compliant (do not take the medication as prescribed)?

Non-compliance can affect your messaging. Is it due to a desire to make refills last longer (cost issue), skipping doses (a day or two), drug holidays or “taking a break” (three or more days), or side effects?

Non-compliance can also affect the cadence and timing of your messages. For example, if you’re attempting to push out your persistence curve, there’s going to come a time at which you’re speaking to the “worried well.” But the point at which you’re communicating with this group is not so clear if you’re looking at non-compliance–such as patients taking PPIs on as-needed basis, taking statins 3 to 4 times a week, or splitting doses to make prescriptions last longer.

I’ve known many brand managers who wanted to know at what point they were communicating with the “worried well,” because they saw it as throwing good money after bad: pure lack of ROI. However, if you’re able to measure engagement factors, the so-called “worried well” could be your best advocates–they’re taking your medication regularly and they want to hear from you. You could message them differently, perhaps going heavy on “send-to-a-friend” tools and information, depending on the disease state and demographics.

Finally, don’t forget that there can be a break in adherence between the doctor’s office and the pharmacy, or even for patients who are prescribed medications in the hospital. In one recent Canadian study, patients who had had a heart attack filled only 73% of their prescriptions within one week of leaving the hospital. The number rose to 79% by 4 months of leaving the hospital. Patients filled 82% of heart-related prescriptions and only 35% of prescriptions not related to the heart (such as anti-anxiety medications). All in all, at least one in every four patients either took no medication or only some of it.

Many of these patients said that they couldn’t afford the medication or that they didn’t understand why they needed it. Here’s a perfect space where the right communications at the right time can intervene-when patients leave the doctor’s office, they need to be convinced that they need the medication. Your messaging should facilitate doctor/patient communication, complement the doctor’s advice, and explain clearly to the patient why he or she may need the medication. For example, a Q&A, ostensibly to facilitate discussion with the doctor, may never be used for that purpose, but it helps to present branded information in a more factual, straightforward–and less promotional–manner.

In other words, adherence is not a “one-size-fits-all” problem. A given solution will not be right for all drug classes, may not be right for all medications in that class, and may not be right for patients taking a particular medication.

But still, know that persistence curve like the back of your hand. In fact, imagine it as a topography with landmarks. Some of these landmarks are large obstacles, some are small hurdles–but all are potential jumping-off points where the right message will keep your patients going.

5. What are the goals of my adherence program?

The answer here should not be simply, “To keep my patients on medication longer.” Yes, that’s absolutely true, but there are different measures you can use. Choose the one most appropriate for your situation.

If you’re looking primarily at persistence, you might say that, on average, you want each patient in your database to have one more refill, or to move, for example, from an average of 2.5 to 3 refills. (However, this also involves compliance, since if patients take medication as prescribed, they will be more likely to reach their next refill sooner.)

Patient Days on Therapy (PDOT) is a number that neatly combines compliance and persistence. Your market research team can determine the average PDOT for your patient population, and your marketing team can determine the amount by which you wish to increase PDOT-or need to increase it to achieve a given ROI.

Another important and related question: Should your adherence program also be a conversion program? In other words, is your “adherence” program open only to patients currently on your medication, or do you wish to cast the net wider, making it available to those on competitive medications-and giving you a chance to build a database of handraisers who have already gone to the doctor and been diagnosed? For medications with generic competition or which require step therapy, competitive brand users in the same category may be your low-hanging fruit, because presumably they’ve already failed on a competitor, or they wouldn’t be raising their hand.

Once you’ve decided to open up your RM or patient support program beyond your own patients in the hope of achieving switches, you have a number of questions to consider:

• Do you move beyond directly competitive medications in the same class to other classes? For example, if your patients are taking ARBs for hypertension, do you also look at those taking ACE inhibitors? This seems to make sense. But what about diuretics? Patients taking diuretics could be new to the category, or they or their doctor may be concerned about cost. Will you be able to move them from a diuretic to an ARB?
• For some categories, such as allergies and acid reflux, part of your competition involves OTCs. Do you go after those taking branded OTCs? What about generic OTCs? Or even OTCs that aren’t in the same class? For example, if you’re marketing a brand-name PPI, do you reach out to those taking brand-name OTC PPIs (Prilosec and Prevacid, which is coming in 2009)? What about the generic versions of these? And what about those taking H₂ inhibitors or antacids? Is it too much of a leap to get them to go to the doctor to get a prescription for your tier 2 or tier 3 brand-name PPI, especially with step therapy in the way?
• You soon cross over into market-expanding tactics, such as reaching out to undiagnosed patients who suspect they may have a particular condition. This begins to move you from conversion to acquisition. However, if you already have a program in place that discusses the disease state and your medication, and which includes useful tools and information, it may just be cost-effective. You and your marketing team have to make these decisions.

If you don’t have a goal, you won’t get there. Simple as that.

6. What messaging will accomplish my goals?

By this time, if you’ve answered the questions above, your messaging should be taking shape. However, there’s one more question not yet covered–does your medication generally require a caregiver? It could be a parent, as in ADHD, growth hormone deficiency, or other diseases of childhood; or it could be a spouse or grown child, as in Parkinson’s disease, Alzheimer’s, osteoporosis, or other diseases of the elderly. Make sure your communications involve the caregiver as well as the patient.

Develop a separate communication stream, put a caregiver section in newsletters, or develop a caregiver section of your website. Don’t overlook the important role-and influence-of the caregiver.

7. What can I offer patients, families and caregivers that they cannot find elsewhere?

This knowledge is important–it informs your messaging, and without unique content or tools, even the right messaging will only take you so far. With approximately 60% of people using the internet to search for health-related information, but only 10% to 15% going to product.com sites, what can you offer that they cannot find elsewhere? Because you can be assured that, right now, there is a conversation taking place about your medication, and you want to be right in the thick of it.

What reason can you give patients and caregivers to come to your site? Why should they register for and read your newsletter? Do you even want registration? It greatly suppresses use of a site, but that may be okay. You and your marketing team have to decide the optimal trade-off between number of visitors and amount of information gathered. Can you let everyone in and generate registration with offers of loyalty/discount cards or certain unique tools accessible only to registrants? Or do you require registration upfront?

For Stepping Stones, a registration-only site for patients taking Nutropin (a growth hormone), we offered an interactive tool that plotted height over time. All the caregiver has to do is key in the date and height, and a chart is created. That chart contains “growth channels” (height deciles for age) that show whether your child is staying on track (generally, sudden moves up or down are a cause for concern). We wanted only caregivers and patients taking Nutropin, and we signed up thousands in record time. We also offered information about the five indications that was not easily accessible elsewhere, generating patient-friendly content from the medical literature and conversations with our client’s on-staff doctors and nurses.

For Azilect, we offered interviews with key opinion leaders, including leading neuroscientists and clinical experts, all on the cutting edge of research into Parkinson’s disease. We also offered the perspectives of fascinating people living with Parkinson’s disease, both caregivers and patients.

Thinking of fresh content is especially important in disease states that already have advocacy associated with them–think of diabetes, for example. What can you provide that is not readily available at the American Diabetes Association or through the NIH?

Think of your RM program like a true branded product. What are its unique features? What are its benefits? How does the relative emphasis change for different segments or for different indications? What is your RM program’s reason for being? Answer these questions, and find the right messaging for your audience segments, and you’re well on the way to building an engaging, successful multi-touch, multi-channel RM program.

So you want a pharma RM program? 7 questions you need answered (part 1)

I can’t tell you how to design a CRM program. Only your patients–and their behaviors and attitudes–can do that.

It’s unlikely that they’ll be able to tell you directly, through social networking, because of HIPAA regulations and the probability that online communities will lead to discussions of adverse events and off-label uses (unless they’re carefully moderated, which defeats the purpose of a true online community). And blatant pseudo-social networking is likely to do you more harm than good.

Two sites that have done a great job of creating a community are MyAlli and QuestionEverything. However, these are both for the same weight-loss medication: Alli, which is the OTC version of Xenical. OTC regulations are less onerous that those for Rx drugs, and Alli could cover topics relating to diet and exercise, as well as common adverse events. On QuestionEverything, when the conversation strayed too far into AEs, a nurse moderator would step in gingerly to give the “correct” answer, without seeming overly authoritative or as if s/he were giving the “company line.”

But if you tread into this space with, say, a new antidepressant, you’d be up against some pretty frank discussion on sites such as Crazymeds, Breggin.com (an overtly anti-med site), and even the communities on the National Alliance on Medical Illness, which can be very frank. GSK has Depression.com, but that’s primarily a “push” site, with no self-generating interaction among users. And then there’s Dr. Bob, who has been around since the early days of the internet, allowing users to vent their frustrations with medications. Dr. Bob sums up his “all are welcome” homepage greeting with, “We are not priests with hidden holy books and a bird language which other people cannot understand.”

Focus groups? What’s wrong with secondary research?

Ah, yes… 6 people in a room, who are willing to spend time talking about medication in front of perfect strangers for a nominal fee. These are probably not your average users or caregivers, but they can give you directional insight. However, I have sat through far too many focus groups in which a single patient, caregiver or HCP says “XYZ,” and suddenly being around the brand team is like being around a friend that’s converted to the cult of “XYZ”–at least until the next focus group or IDI in the next city.

My own belief is that far too many marketers underestimate the importance of secondary research, especially when it comes to pharmaceuticals. For example, do you want to know why patients resist taking insulin, and physicians resist starting patients on it? You don’t need focus groups–there’s such an extensive literature that this situation has its own acronym: PIR, or Psychiatric Insulin Resistance. Start with the DAWN (Diabetes Attitudes, Wishes and Need) Studies, a global Novo Nordisk initiative in collaboration with the International Diabetes Federation. You’ll find the same is true for many questions you may have about patient behavior and attitudes.

It’s always escaped me as to why corporations put their faith–and their marketing dollars–in the fact that, say, 9 out of 15 people responded in the “top 2 boxes,” when massive accrued wisdom is available in secondary literature. My own best guess? Management who learned that focus groups are the be-all and end-all (maybe that’s why they call it B-school), and senior management for whom the fallback of “it tested well” is a good CYA, while secondary literature research and analysis is not.

7 questions you need answered before you start

Before you begin ramping up your CRM program, you need answers to the following questions:

1. What are the barriers to adherence?

It’s rarely simply forgetfulness, but too many marketers act as if that were their only problem. They rattle off the benefits of the medication, then add a line saying, “So that’s why you should continuing taking your medication as directed.” One thing I have learned sitting through numerous focus groups is that people don’t simply forget. When you read studies that say that forgetfulness is the reason for non-adherence, dig a little deeper, and you’ll almost always find one of the following:

• Stigma associated with the disease

When developing an adherence program for Adderall XR, it was found that mothers’ attitudes were very   important. It’s crucial to reassure them that they hadn’t failed as parents, and that medication is an integral part of treatment. And you have to do it quickly, because the drop-off in this category is steep–more than 50% of patients discontinue or switch within just 2 months.

• Stigma associated with treatment

The DAWN studies of why type 2 diabetes patients don’t want to use insulin found that moving to insulin from oral antidiabetic drugs (OADs) meant admitting failure and defeat. The needle or injection itself was low on the list of patient concerns. In fact, physicians often “threaten” patients on OADs, saying things such as, “If you don’t lose weight/eat right/exercise, I’m going to have to put you on insulin.” Look closely at stigma associated with other “lifestyle” diseases such as high cholesterol or obesity, or in psychiatric disorders (which have a biological basis, although patients may feel personally responsible or think that they have “failed” in some way).

• Lack of conviction or visceral understanding that current behavior has future consequences

With “symptomless” diseases such as hypertension, high cholesterol or even diabetes, patients may be in denial about the connection to future cardiovascular or other events–or may view these consequences as vague and far off. Think about how you can create a more visceral connection between current actions and future risks. For example, for diabetes, perhaps you could build a model in which the patient can move a slider that changes blood glucose (in mg/dl) or A1c levels. Everything else–cholesterol, blood pressure, BMI, etc.–is held steady. As A1c changes, so does a curve showing time and likelihood of neuropathy, kidney disease, eye problems, and cardiovascular disease. But be careful not to come across as fear-mongering. You want to provide the tools for your patient to experience that “ah-hah” moment, not participate in a chorus of “you’d better change your behavior” (which the patient is most likely already hearing–and blocking out–from every direction).

• Cost/Formulary position
  

In recent years, healthcare plans have responded to rising drug costs by excluding certain medications from coverage, using quantity-dispensing limits, or using step therapy more frequently (in which patients must fail on one or more “preferred” medications in a class before they can have access to higher-priced medications).

Enrollee cost-sharing amounts are also increasing, so that even patients with prescription drug plans are no longer insulated from cost increases. According to the Kaiser Family Foundation Prescription Drug Trends Report (September 2008), 75% of workers with employer-sponsored insurance coverage had a 3- or 4-tier prescription drug plan in 2007, in contrast to just 27% in 2000. (Generally, Tier 1 is generics; Tier 2 includes “preferred” or cheaper brand-name drugs; Tier 3 includes “non-preferred” or newer, higher-priced brand-name drugs; and Tier 4 might include biologics, specialty drugs, or “lifestyle” drugs such as Viagra.)

Copayments for non-preferred drugs increased from an average of $29 in 2000 to $43 in 2007. Even copayments for preferred drugs (Tier 2) increased on average from $15 in 2000 to $25 in 2007. And according to an AARP Public Policy Institute report on trends in specialty drug prices, rather than copayments (a fixed amount), many patients are now paying coinsurance for “specialty drugs”–anywhere from 25% to 32% of the total cost.

Coupons or loyalty cards can help combat poor formulary position or generic competition, but step therapy can only be overcome by delivering complementary messages to patients and HCPs. Patients must be made into advocates who will ask for your medication, while HCPs must be convinced of its superiority–or at least its unique suitability for specific patient groups.

• Side effects

You might be thinking, “Why should we bring up side effects?” Check the blogs and community sites–your patients are already talking about them. If you know that your medication can cause side effects–especially during the first weeks of treatment–be upfront with patients about it. You might offer tips on how to overcome certain problems.

2. How do these barriers change over time (from initial Rx to, say, 6 months out)?

When you know this–and communicate with your patients accordingly–you’re engaging in stage-based RM, or RM based on your patient’s lifecycle. Combined with what you know about general barriers to adherence and typical time to adherence drop-off (your persistence curve), together with psychographic segmentation (see below), you can now craft powerful, targeted messages that go far beyond simply urging patients to stay on medication.

3. What are patient attitudes to treatment?

These attitudes help form your psychographic profiles, and they usually do come from primary research, including focus groups and IDIs. Depending on the disease state, you can look at variables such as:

• attitude toward overall health and wellness
• view of the connection between current adherence/health and future risk/consequences
• feelings about the disease: “my fault,” “couldn’t be prevented,” “I can take control,” “woe is me,” “I can beat this,” etc.
• feelings about medication: For the patient, does the need to take medication represent a failure on his or her part? Is the medication itself more a reminder of disease than of health?
• attitude toward physicians and the healthcare system: Does your patient trust the advice of his or her doctor? Does he or she distrust the medical system and medication?
• views toward holistic or alternative medication. If your patients often look toward alternative or complementary medicine for help, don’t dismiss it or ignore it–acknowledge it and work with it. To the extent that your med/legal department will allow, provide your patients with credible information from the National Center for Complementary and Alternative Medicine (NCCAM), part of the National Institutes of Health (NIH). In fact, in October 2008 NCCAM added four new Centers of Excellence, drawing on highly accomplished researchers who carry out multidisciplinary work on stress-related illnesses, obesity, cancer, and other conditions. Such credible information will gain patient trust, placing your medication in a more holistic context, perhaps even taking it (to some extent) out of the realm of “big pharma.”

Next time: Questions 4-7.

And more: We’ve been discussing narrowly focused direct-to-patient marketing, as opposed to broad push marketing (typical DTC). But is it possible to find out enough about your patients and their needs that you’re engaging in what I would call direct-from-patient marketing? We’ll see.

“Do something!” How increased prescription drug utilization may lead to price controls

With rising healthcare costs, and with government expected be the payer for 37% of all drugs under Medicare Part D by 2010, the pressure is on for the federal government to do something about prescription drug costs. In fact, the Centers for Medicare and Medicaid Services issued a rule in July 2007 that would have placed limits on federal government reimbursements to states for Medicaid prescriptions. Although a US District Court issued a preliminary injunction against this change in December 2007, several similar bills are pending in Congress.

“Do something, Gromit!”

Any Wallace and Gromit fans will recognize this plaintive call for help. While Wallace, the human, is fairly capable, anytime he finds himself in a tight spot he calls out to his dog, Gromit: “Do something, Gromit!” And Gromit invariable comes up with an ingenious solution. Trouble is, Congress is nowhere near as smart as Gromit.

But Congress is hearing something similar from its constituents recently: “Do something about high drug prices!” Eventually, the government could become the single largest payer for prescription drugs. Right now, the government is prohibiting from negotiating directly with pharmaceutical companies for discounts, but there is a great deal of pressure to change that. The federal government could easily require companies who want their medications covered under Part D to provide a specified discount–creating de facto single-payer price controls, since private insurers tend to follow the precedent sent by Medicare and Medicaid. Private insurers already use physician and hospital reimbursement as a starting point in negotiations.

With increased utilization comes increased scrutiny.

Within about the past 10 years (1997 to 2007), utilization of pharmaceutical drugs and biologics has increased by 72%, according to the Kaiser Family Foundation Prescription Drug Trends Report (September 2008). The average number of prescriptions per person increased from 8.9 in 1997 to 12.6 in 2007.

It’s true that, in the early part of the decade, prescription drug spending grew at double-digit rates–from 15% annually in 2000 to 11% annually in 2003. In 2006, prescription drug costs grew at 9%. According to the Kaiser Family Foundation, “Rising costs and implementation of the Medicare Part D benefit have highlighted the need for a better understanding of the pharmaceutical market and for new approaches to address prescription drug costs.”

However, prescription drug spending was a small proportion of overall healthcare spending in 2006 (10% for prescription drugs, 31% for hospitals, and 21% for physician services). So attacking prescription drug costs is like a struggling company cutting back on travel or other perks–it makes for good PR but does little or nothing to address the root of the problem. As the kids used to say, it’s like arranging deck chairs on the Titanic. Except that nothing’s sinking. As we’ve seen, prescription drug utilization is up, and that very same increase in utilization may be responsible for preventing hospitalizations and physician visits.

So where’s the problem?

More people than ever are using prescription drugs, but this increased spending makes up just 10% of overall healthcare costs. You might rightfully ask, “Where’s the problem?” And the answer is “None, if you’re measuring increased benefit to society.”

The problem is that patients pay out of pocket for prescription drugs, but not for many other aspects of healthcare. And even though many people may have copayments or coinsurance for doctor visits or hospitalization, it’s not a noticeable, recurring expense in the way that prescription drug costs are. In addition, tiered copays–or even switching prescription coverage from copays to coinsurance–leads to increased patient out-of-pocket expense for many medications.

(Copayments are set amounts that you pay for a service or product; for example, $20 for a doctor visit or $25 for a brand-name drug. Coinsurance is when you pay a certain percentage of the total expense. Your insurance company may pay 70% – 80% of the bill, and you pay the remainder. Do a quick calculation on almost any medical expense, and you can see how coinsurance comes out higher.)

With increased exposure to price comes increased price sensitivity

Here’s the rub: Although healthcare is a public good/necessity, it responds to price pressures like a consumer good. Insulate consumers/patients from costs, and prices will rise unimpeded. Something similar has happened in higher education, where students seldom pay “full freight” because of grants, loans and scholarship programs.

Insurers know this. They’ve responded to increasing drug costs by excluding certain drugs from coverage, using quantity-dispensing limits (using the PDR maximum dosage as an absolute rather than a recommendation), increasing enrollee cost-sharing amounts (e.g., coinsurance as opposed to copayments), or using step therapy more frequently (in step therapy, patients must fail on one or more “preferred” medications in a class before they can have access to higher-priced, generally newer, medications).

In 2007, 75% of workers with employer-sponsored insurance coverage had a 3- or 4-tier prescription drug plan, in contrast to just 27% in 2000. Copayments for “non-preferred” drugs (usually newer brand-name drugs placed in tier 3 or tier 4) increased from an average of $29 in 2000 to $43 in 2007.

And according to a recent AARP Public Policy Institute report on trends in specialty drug prices, many patients are now paying coinsurance for “specialty drugs” (generally higher-priced biologics)–anywhere from 25% to 32% of the cost of the medication. For medications that can run several thousand dollars a month, that can get pretty expensive. The report states that, “This cost-sharing strategy is rapidly spreading to private insurance plans, exposing beneficiaries to a higher share of the cost.”

The result? As more and more people are exposed to higher costs for medications, the call for generics and price controls increases, and more and more people are demanding government action.

Be careful what you wish for

64% of people in the United States believe that there is not enough government regulation limiting the price of prescription drugs (Kaiser Public Opinion Spotlight, “Views on Prescription Drugs and the Pharmaceutical Industry,” April 2008).

Even when presented with the prospect that price regulation could lead to less research and development for new medications, 48% of the public overall still say that there’s not enough government regulation concerning drug prices. (Looked at another way, fully 75% of those who think that there is not enough government regulation limiting drug prices stick that view, even when told it may lead to less research and development.)

The alarming potential of less research and development–less innovation–is one of the major arguments for patent protection and market exclusivity and against price controls. Adequate reward for risk helps to attract capital and lead to the next generation of medications. However, almost half of the American public rejects that argument outright.

In other places, I’ve argued that Hatch-Waxman, the original generics law, may have led to the blockbuster craze of the 90s and the recent drying up of pharmaceutical company pipelines.

I don’t know what the answer is. As I’ve said, I believe that healthcare is a public good and cannot be treated as a consumer item. “Can’t afford a Lexus? How ’bout that Kia?” It doesn’t–and shouldn’t–work that way for healthcare. However, healthcare does respond to price like a consumer good.

There are places in the world known for their excellent generic manufacturing capabilities–but not for innovation. It would be a shame to see the US become one of them. This is a problem that calls for a surgeon’s skill–a scalpel, not a hatchet.

Soups and Sparks and SSRIs, Oh My!

Drawing of Purkinje cells (A) and granule cells (B) from pigeon cerebellum by Santiago Ramón y Cajal, 1899; Instituto Santiago Ramón y Cajal, Madrid, Spain.

You know there’s a synapse (a gap between nerve cells). I know there’s a synapse. With our ability to look at cells through electron microscropy, we take the synapse for granted. But it wasn’t always that way.

Beginning in the latter part of the 19th century, there was an ongoing “war of the soups and the sparks” (to borrow from the title of an excellent book by Elliot Valenstein). The “soups” believed that neurotransmission was chemical, while the “sparks” believed that nerves communicated via electrical impulses.

The “neuron doctrine”

The theory that the nervous system comprises nerve cells that do not join with one another physically–in other words, that there are synapses–was widely accepted by around 1900. This was known as the “neuron doctrine.” However, the gaps between neurons was not actually seen until electron microscopy became available in the 1950s.

Charles Sherrington coined the term synapse in 1897 to describe what he saw as a functional gap between neurons, or between neurons and muscle. Why synapse? Turns out he was facing a deadline to finish a textbook! In a letter to a colleague, he said, “I had begun it [the textbook], and had not got far with it before before I felt the need for some name to call the junction between nerve-cell and nerve-cell (because that place of junction now entered physiology as carrying functional importance).” A friend who was a Greek scholar (an expert in Euripides) suggested “synapse,” which according to Sherrington, “strictly means a process of contact, that is, a proceeding or an act of contact, rather than…an instrument of contact.”

In other words, Sherrington recognized that electrical conduction did not proceed across the synapse, but that there had to be some form of “contact.” He didn’t know exactly what it was, but he knew that a physiologically functional junction had to exist between nerves, because his own work showed a delay in neuronal transmission, almost as if some sort of “valve” were at work controlling nerve impulses, and because he was familiar with the careful histological work of Santiago Ramón y Cajal (see below).

“End bulbs”

In 1898, Leopold Auerbach had used silver stain to show what he termed the “end bulbs” on the surface of neurons in the facial nucleus. However, Auerbach believed that “axon terminals exert their effects…by means of close contact of the end bulbs, without intervention of any intermediate substance.”

However, the work of Santiago Ramón y Cajal clearly showed a gap between nerve cells (see illustration above).  Ramón y Cajal applied cell staining methods developed by Camillo Golgi to show that claims of contiguity, or contact, between nerve cells were based on artifacts. His work also demonstrated that if a nerve fiber is cut, the resulting degeneration of the nerve fiber stops at the boundary of the next cell.

It was Ramón y Cajal’s work that led directly (along with the research of people like Charles Sherrington) to the wide acceptance of the “neuron doctrine.” But it was still not clear how neurons communicated across the synapse.

“Neurohumoral secretions”–better known as neurotransmitters

In 1901, John Newport Langley published a paper showing that electrical stimulation of the sympathetic autonomic nervous system resulted in changes that could be mimicked by the direct application of adrenaline to a nerve. Langley would also dip threads in curare or nicotine and apply the threads to severed nerve endings. The resulting nerve action confirmed previous observations that these drugs exert their effect only at the synapse. These experiments by Langley and others at Cambridge set the stage for the discovery that nerves secrete chemical substances.

Work by Otto Loewi in 1921 provided the first direct evidence that nerve stimulation was based on the release of “neurohumoral secretions,” as they were then called. Many neurophysiologists conceded that although these “neurohumoral secretions” might account for the regulation of heart rate, this process was believed to be too slow to account for neural transmission in general–especially when it came to the central nervous system and thought. However, opposition to chemical transmission gradually faded and led to the current view of neurotransmission.

We now know that neurotransmitter release occurs through a process called exocytosis. Synaptic vesicles (small sacks) near the synapse hold neurotransmiters such as serotonin or dopamine. Within 5 milliseconds of receiving an electrical stimulus through the nerve cell, these vesicles fuse with the neuronal membrane, forming fusion pores, which open rapidly and allow neurotransmitters to enter the synapse and cross over to the downstream (or post-synaptic) neuron.

How do SSRIs really work? The nerve cell nucleus and gene expression

In the mid-19th century, Augustus Waller first outlined the role of the cell body, calling it a “center of nutritive energy.” New research is once again turning to the role of the cell body, looking beyond the “monoamine hypothesis” (the theory that depression is caused simply by a deficiency or imbalance of neurotransmitters) and the “receptor hypothesis” (the theory that depression is caused by an abnormality in neurotransmiter receptors) to the “monoamine hypothesis of gene expression.”

So what is the “monoamine hypothesis of gene expression”? Well, you know how the pharmaceutical companies always explain the action of SSRIs by saying that they correct an imbalance of neurotransmitters in the brain? It’s not that that’s not true. In fact, according to Dr Stephen Stahl, “the immediate pharmacological actions of all antidepressants have the effect of boosting levels of monoamine neurotransmitters.” (If you have any interest at all in this sort of thing–and I assume you do, if you’ve read this far–you must read Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 3rd edition, published in 2008. An intelligent layperson with an interest in neuropsychiatry will find it approachable and rewarding.)

But recent research shows that that increasing the amount of available neurotransmitters is just the beginning of a cascade of effects. That cascade leads to “second messenger systems,” which in turn form transcription factors (proteins that bind to DNA at certain sites where they can control transcription, or copying). Transcription factors cause DNA in the cell nucleus to synthesize messenger RNA (mRNA), which allows DNA to make new proteins–including new receptors and other chemicals (such as brain-derived neurotrophic factor, or BDNF). Studies have shown that BDNF acts to generate new neurons, protect existing neurons, and increase the efficiency of neurotransmission, possibly helping improve learning and memory.  In mice, BDNF has been observed to repair damaged neurons.

We are only beginning to learn about the role that these changes in gene transcription, which can persist for days or weeks, may play in depression and other mood disorders. When neurons communicate, the ultimate goal is not merely stimulus of post-synaptic receptors. In the worlds of Dr Stahl, “the function of chemical neurotransmission is not so much to have a presynaptic neurotransmitter communicate with its postsynaptic receptors as to have a presynaptic genome converse with a postsynaptic genome; DNA to DNA; presynaptic command center to postsynaptic command center.”

Or as a very wise psychiatrist once told me, “We only know that we’re blocking the reuptake of neurotransmitters, making more available. Beyond that it’s largely darkness–but we’re finding our way, and within this darkness we can do good work and help make patients better.”

Hatch-Waxman 25 years later…lots o’ (the same) cheap drugs

25 years on, was Hatch-Waxman such a great idea? Dried-up small-molecule pipelines, the endless search for blockbusters at the expense of innovation, in-licensing from smaller innovative companies–just what you’d expect from a law that had the unintended effect of shutting down innovation.

Many people point to Hatch-Waxman as a model for legislation that combined patent protection and market exclusivity (necessities for innovation) with a common-sense pathway to generics. But has that turned out to be the case? From the time a patent on a new molecular entity (NME) is filed until FDA approval can easily eat up all but 7 or 8 years of a 20-year patent life. Is it a coincidence that within a few years of Hatch-Waxman, every pharma company was looking for the next Prozac, the next statin, the next ACE inhibitor or ARB? In other words, blockbusters to recoup the hundreds of millions of dollars it takes to develop a new drug–and do it quickly.

It doesn’t help that generic companies are roughly half lawyers, poring over patents the moment they’re released, looking for problems or ways to horn in on innovator research. As a result, effective patent life is reduced even further in many cases. Is it any wonder that small-molecule pharma companies have turned to incremental improvements, enantiomers (for example, Clarinex from Claritin, Lexapro from Celexa, Nexium from Prilosec, etc.), to extended-release variations, or to metabolites (Pristiq from Effexor)?

In each case, the original was a blockbuster drug, and in many cases, the incremental improvement made a real difference for many patients. Just ask someone who couldn’t tolerate or “pooped out” on Celexa and switched to Lexapro–let alone the many patients who were able to switch to a completely different medication in the antidepressant class because of all the options available.

Part of the problem was the the HMOs and PBMs didn’t see it that way, and don’t allow patients choices in these categories. Why? Because older generics are available, and newer medications are put in higher “tiers,” with higher co-payments. According to the Kaiser Family Foundation, more and more patients now have Tier 3 or even Tier 4 medications, many with co-insurance (in which patients pay a percentage of the drug cost) rather than co-payments (in which patients pay a fixed amount per prescription).

But tiers aren’t nearly as bad as “step therapy” or “prior authorization.” By requiring patients to fail on certain drugs (usually the ones available as generics), payers are essentially practicing medicine and engaging in therapeutic substitution. Just ask a psychiatrist who had someone who couldn’t tolerate sertraline (Zoloft) but is doing fine on Celexa, or hypertensive patients kept on ACE inhibitors (with that persistent dry cough) while the ARBs weren’t yet generic.

Problem is, at small-molecule pharma companies, marketing controls R&D. Marketing can tell researchers to find the next statin or the next antidepressant, or to look into controlling obesity–in other words, look for whatever will sell, not wherever the research is leading. That’s why some of the most amazing new drugs are now coming from biotech, or from universities or smaller companies that do in fact follow the research. Nexavar, in-licensed by Bayer from the University of Georgia, is making real improvements in the lives of people with hepatic cancer, and is showing promise in a range of cancers. Tracleer, developed by a small pharmaceutical company, is turning a little-known disease (pulmonary arterial hypertension) that used to be a death sentence into a more manageable condition.

This is real progress, and despite the fact that these medications make money, it’s not “Zoloft-license-to-print-money” kind of money. But it’s a lot, and the medications help patients. Hatch-Waxman may very well have given us $4 Wal-Mart generics, but it may also very well have taken away hundreds of life-saving drugs for smaller patient populations, which became uninteresting to big pharma chasing the next blockbuster to stay profitable in the post-Hatch-Waxman era.

Next time–more on how the rise of managed care combined with Hatch-Waxman to reduce patient choice. And what does the rising cost of medicine have to do with the rising cost of higher education? Hint: In both cases, consumers are isolated from the true cost of a product that should not be treated as a commodity or typical consumer product, but which still responds to market factors like any other consumer product.