Last week, Amgen announced their third quarter earnings which included a $780 million charge related to a legal settlement they entered into with the federal government and a number of states concerning “illegal sales and marketing practices”. Now $780 million dollars is a large amount of money by anyone’s measure, but if you read the third quarter report, it sounds like there were some “questionable” actions on the part of Amgen, but it’s all worked out now and we can get on with business, right?
If you read the Massachusetts whiteblower lawsuit court documents, it appears that Amgen committed some very serious crimes which weren’t the action of just one or two employees, but rather an intentional marketing tactic that involved a large number of Amgen employees all the way up to senior management. And if you live in the US and pay taxes, you should be very, very mad.
The product in question is Amgen’s Aranesp, a erythropoetin analogue, which stimulates the production of red blood cells in the body. It is used in patients undergoing chemotherapy (since many anti-cancer drugs damage bone marrow, where red blood cells are made) and patients with chronic kidney disease (since erythropoetin is made in the kidneys) to boost their levels of red blood cells. It’s a very profitable drug for Amgen, with total sales just north of $2.5 billion dollars in 2010. Now this is where things get a little complicated… Aranesp is a longer-acting version of another Amgen product, Epogen, the first erythropoetin analog that was originally used for dialysis patients. When Epogen was developed, Amgen outlicensed the rights to Epogen, outside of use in dialysis, to J&J, which sells it’s version as Procrit. So as you can imagine Amgen’s current strategy: get patients who use Epogen or Procrit to use Aranesp, since why would you want to share the market with J&J?
Now that we have the background laid out, we can get down to the details of the case. Aranesp is sold in either vials (as pictured above) or as prefilled-syringes. Since it’s impossible to to get all of the liquid out of a vial, or inject all of the liquid in a syringe, manufacturers of injectable drugs often “overfill” their products, or basically add a little bit more of the drug to the vial or syringe, so that when a physician or patient administers the drug, they get the full dose. How much do they need to overfill? Less than 10% typically.
Well, someone at Amgen had a smart idea that they could overfill the vials or syringes of Aranesp by more than 10%, then “hint, hint, nudge, nudge”, let doctors know that they are actually getting more drug than what they paid for. Why would they do that you ask? Well, doctors can bill insurance companies and Medicare for each dose of Aranesp they give patients (they actually bill in 5ug increments). So if a doctor orders 5 vials of Aranesp (each one overfilled by 20%), they can actually bill for the 6 doses of Aranesp they actually gives patients (basically pooling the extra 20% until it adds up to a full dose). Amgen was giving physicans a kick-back for using Aranesp, paid for by YOU, the taxpayer (in the case of Medicare/Medicaid patients).
Now you might be thinking this was a scheme devised by a few rogue Amgen employees, working on their own accord. Well, you’d be wrong. Nevermind the fact that sales reps don’t have any control over how much “overfill” is included in each vial or syringe of Aranesp (that’s a decision made by manufacturing), there is also the fact that information on how much the vials were overfilled and how much extra money physicans could make charging insurance companies for the overfill amount was sent out by Amgen’s medical affairs department (document below is from this link).
And to top it all off, it appears that Amgen’s CEO, Chris Sharer, knew about the overfill scheme the entire time. An email from a Senior Manager of Medical affiars reads as follows…
… an email dated January 6, 2006 from Edwin Mar, Senior Manager of Medical Information, to Helen Torley, Vice President and General Manager of Nephrology, and Leslie Mirani, Vice President of Sales, states: “In regards to your request to provide EPOGEN overfill historical information to [CEO] Kevin Sharer, these are the information I have available so far regarding EPOGEN 1.0 mL vial fill volumes.” The email goes on to provide the overfill amounts for Epogen from 1993 through January 2006:
(1993-Q4/2002) – 1.168 mL
(Q4/2002-Q1/2004) – 1.144 mL
(Q1/2004 – present) – 1.111 mL
Yup, you read that right, the older erythropoetin analog that Amgen wanted patients to stop using? They started to reduce the overfills in that product to ensure that doctors were only getting a kick-back for Aranesp.
I’m literally at a loss for words. The pharmaceutical industry has taken a lot of heat (rightly so) for their off-label marketing of drugs and other nefarious activities, but this takes the cake. This is not some sales rep promoting a drug for an unapproved condition (in that case, at least the patient is getting what they paid for), this is a deliberate, organized scheme to defraud both private insurance companies, Medicare/Medicaid and in the end, you, the American taxpayer. Honestly, I think anyone associated with this scheme, from the CEO down to the account managers needs to be fired and the whole organization rebuilt, from the ground up. I mean, how else do you rid a company of the mentality that thinks this is OK?
This is something I’ve been thinking about for a while. The cost of health care is rising everywhere, but it seems to be a particularly critical issue in the US. While the cost of drugs is a approximately 10% of total health care spending in the US, it is increasing, albeit more slowly than total health care spending.
This is related to a previous post, where I commented on how it seems like every pharmaceutical and biotech company is jumping on the oncology bandwagon. One of the big reasons for this trend is that the pricing pressure on oncology drugs is relatively low. Insurance companies consider oncology relatively “untouchable”, that is, telling a mother of three that you won’t pay for her cancer drugs will cost you far more in terms of public relations than it will ever cost in terms of dollars. This is why we now have drugs like Yervoy ($120K/treatment) and Provenge ($93K/treatment). And these high prices aren’t limited to cancer. There are drugs that cost over $10,000/year in areas such as asthma, multiple sclerosis and lupus, to name just a few. Is this strategy really sustainable? The answer is no, it’s not. But what will stop this trend of ever increasing drug prices?
The answer is you. You’ll simply stop paying for these drugs.
You’re probably thinking “Come on! I never pay full price for my drugs! The worst case scenario is that I pay a $25 or $50 co-pay, not my problem!” That’s probably true right now, but might not be true in the future if the trend towards high deductible health plans (HDHP) continues. The number of Americans covered by HDHPs has more than doubled since 2008 and continues to rise (see chart below). Why? The premiums on HDHPs are often a fraction of what HMO or PPO coverage is. It not only reduces costs for your employer, but it also reduces the premiums that are deducted off your paycheck every month.
What are HDHPs? Well, under typical HMO or PPO coverage, you only pay a co-pay on your prescription drugs. Depending on if it’s a generic or a branded drug, your co-pay might be $5, $10 or even $50, but that’s all you’ll pay whether or not the drug’s actual cost is $5 or $5000. Under a HDHP, you pay the full amount of your drug costs, up to the annual deductible limit (the limit includes all health care expenses). These plans are almost always paired with a health care saving account (HSA), where you (or your employer) make tax-free contributions that you can use to pay for your out of pocket expenses.
So let’s say you visit your physician and he says “Mr. Smith, it looks like you’ve got a bacterial infection, might be serious, let’s put you on Zithromax.” Under the HMO or PPO plan, you might say, “Sounds good doc! Thanks!” and then run to your pharmacy and complain about the $25 co-pay. Under the HDHP plan, you’ll likely repsond “Really? How much is Zithromax? $200?!?!? Is there anything else I could take that isn’t so expensive? Amoxicillan? $4 at Walmart? Thanks Doc!!”. Of course, this isn’t a likely scenario if you have cancer, but for non-life threatening diseases, it’s a conversation I could see happening.
As medical costs in general, and prescription drug costs in particular, continue to be shifted towards the patient, there will be an increased awareness on the part of patients of the costs of drugs and choices will have to be made, hopefully through consultation with physicians.
So what does this mean for drug companies? The strategy of shifting from $200/month drugs for large patient populations, to $10,000/month drugs for smaller patient populations, won’t work forever. Eventually patients will start to say “This is coming out of my pocket, is there anything cheaper?” and drug companies will be facing real pricing pressure, across the board.
It’s a challenging situation to be in for drug companies since producing safe, effective drugs is an expensive process. However, eventually another strategy (lower priced drugs) will have to replace the current one. That’s going to require more than just a shift in strategy by the drug companies, it will require a complete reappraisal of how patients, physicans, insurance companies, the FDA and drug companies view value and risk.
I’ll be honest and say I have no idea what the drug industry will look like in 10 or 20 years. However, I do know that the drug companies that will be on top are the ones planning for this future right now.
In an earlier post, I promised to provide updates about the on-going saga to get an obesity drug approved by the FDA and surprisingly, there is some news on that front from Vivus.
Despite the FDA’s rejection of Qnexa back in October of last year, Vivus has decided to go for broke and give it another try. If you recall, Qnexa is a combination of phentermine and toperimate, two drugs that are already FDA-approved. The problem is that mothers who take toperimate during pregancy may have a greater risk of delivering a child with a cleft palate. Due to the anticipated widespread use of any approved obesity drug (including use by pregnant women), the FDA has set very high standards in terms of safety (some would say ridiculously high standards). Needless to say, an obesity drug that causes birth defects would not meet those standards.
In their latest press release, Vivus announced that the FDA has accepted an early resubmission of their NDA based on three recently completed studies…
“Topiramate teratogencity data published and presented since our last meeting with the FDA in April 2011 includes two case-control studies….In addition, a birth defect study from Denmark on newer generation antiepileptic drugs including topiramate was published in JAMA. In all of these studies, the authors concluded that topiramate was not a major teratogen,” commented Wesley Day, vice-president clinical development.”
I wish Vivus all the best, but I’m a little concerned about this resubmission. First off, the quote “the authors concluded that topiramate was not a major teratogen” (the emphasis is mine) doesn’t exactly instill confidence in terms of the drug’s safety for pregnant women and the children they are carrying. However, it appears that Vivus will be pursuing an indication that excludes pregnant women, at least for the initial NDA…
“In this initial indication, we plan to include a contraindication for women of childbearing potential. We believe this is a sound approach that, if approved, will potentially allow early commercialization in a higher-risk population with a significant unmet medical need. The FORTRESS study remains important in our plan to more precisely define the teratogenic potential of topiramate and may enable us to expand the indication to include obese women of child-bearing potential. If the FORTRESS results are favorable, we expect to file for the full indication in late 2012.”
You might be thinking “What’s the problem? They just won’t give it to pregnant women!”
Well, the issue is two-fold:
- Vivus included a contra-indication for pregnant women with their initial NDA and it was rejected. You can say that pregnant women shouldn’t take Qnexa, but it’s difficult to convince the FDA that they won’t. Unless Vivus can institute a very rigid REMS program to ensure that pregnant women won’t have access to the drug, I feel that the FDA is not going to play along. Since the FORTRESS study results are expected in late 2012, and I assume that it is a very comprehensive study of the teratogenicity of toperimate, the FDA may say “Still too risky, let’s just wait until the FORTRESS date comes in.”
- If Vivus does offer an acceptably rigorous REMS program to keep pregnant women from getting access to Qnexa, it will severely curtail the launch of the drug. A rigid enough REMS program will likely mean that only certain doctors can prescribe Qnexa, only certain pharmacies can fill these prescriptions and for each patient who takes the drug, an extensive tracking system will have to instituted to collect all the follow-up safety data. Not exactly conducive to big revenues, now is it?
However, the FDA did agree to the early resubmission, so I assume that the agency sees some validity to Vivus’ data and amended NDA. This story will definitely be worth keeping an eye on and if Vivus is successful, it may pay off handsomely for them, but I feel that they still have a long road ahead of them.
In early August, the FDA sent Adventrx Pharmaceuticals a Complete Response Letter (CRL) for their drug Exelbine which basically said “Hey, thanks for the NDA, but based on what you sent us, we’re not going to approve your drug.” Now CRLs can take many forms, all the way from “we have some concerns about your manufacturing controls”, which can often be resolved in a matter of months, to “your trial design is so mess up that you’ll have to repeat the whole thing”, which is often a death knell for biotech start-ups who don’t have a lot of cash.
Whenever I read about a company receiving a CRL, I’m always interested learn why their application was rejected. CRLs are not publically released (this is a bit of a hot topic lately, since many think they should be), but companies always issue press releases when they receive them since the information they contain is obviously very material to the value of the company. When I read Adventrx Pharmaceuticals’ press release, I cringed:
The FDA determined that it could not approve the Exelbine NDA in its present form. In particular, the complete response letter noted that, based on inspections at clinical sites, the authenticity of the drug products used in the pivotal bioequivalence trial (Study 530-01) could not be verified, which placed the results of the trial into question. The letter stated that the bioequivalence trial will need to be repeated to address this deficiency.
Ouch! Basically what the letter is stating is that the data from the clinical trial in question (Study 530-01) is being thrown out because the FDA doesn’t believe that the trial sponsors could tell the drugs they were using apart. After doing some searching on clinicaltrials.gov, I found the trial here. This was a bioequivalence study where the company’s product, Exelbine, was being compared to a reference product, Navelbine, to make sure that they both behaved the same way in patients. The reason this trial was run is that if bioequivalence could be proven, Adventrx Pharmaceuticals could use Navelbine data in support of its application.
The reason why this is so painful to see is that it can be so easily avoided. The FDA has very strict guidelines concerning what type of testing is required to prove what you say you are giving patients is actually what you are giving patients. It goes further than just making sure you ordered the right drug; trial sponsors are usually required to test a cetain percentage of the packages they receive (be it vials or bottles) to ensure that what is written on the label is actually what is in the bottle. And following that, once the drugs are taken from their packaging and prepared for administration to patients, they need to be carefully tracked so that no mix-ups occur. It appears that the clinics running this trial failed to do that.
What makes it even more painful, is that it’s likely that nothing is wrong with the clinical trial. In the press release, the company states:
Of note, Exelbine and the reference product come in different package presentations, require different preparation procedures and have different physical characteristics. Based on the different characteristics between the study drugs, the Company believes it is unlikely that study sites would confuse the two study drugs or fail to recognize which drug was being administered to a patient.
The company’s arguement is pretty weak (“hey, we didn’t follow procedure, but come on! only an idiot would mix those two drugs up”), but they are most likely right. However, it doesn’t matter (and it shouldn’t matter). If you don’t follow FDA guidelines for trial design you can be guarenteed you won’t be getting approval.
The only solace I can provide is that it was relatively a small phase I trial. With an estimated 28 patients enrolled, it would likely cost the company only a few hundred thousand dollars and a year or so of their time to repeat it. However, it appears they may not bother:
“In the meantime, our resources and focus are on ANX-188 and ANX-514, which we believe are the long-term value drivers for our company. Our cash and equivalents of $40.7 million at July 31, plus cost savings from delaying or potentially discontinuing the Exelbine program, will provide us the capital to continue to advance both of these programs,” Mr. Culley added.
Lesson learned I guess…
Xconomy.com just posted an interview with Dennis Purcell of Aisling Capital and while reading it, a comment by Dennis caught my eye:
So the clinical trials, the understanding of FDA regulations, the patent protection all came together for us. We made about a 15x return on Adams.
The “Adams” he’s talking about is Adams Laboratories, Inc., the company that brought you Mucinex and this guy..
Aisling Capital had invested in Adams Laboratories and that 15x return came about when Reckitt Benckiser (a maker of a number of OTC healthcare products) acquired Adams Laboratories for 2.3 billion dollars in 2007. So what made Mucinex and Adams Laboratories so valuable? Mucinex is nothing special, just an extended-release version of the drug guaifenesin, an expectorant (it helps loosen mucus so you can expel it) that has been on the market for decades. This isn’t a “new” drug by any means and it makes you wonder, is there really that much value in an over-the-counter cold medicine? If you read the press release about the acquisition, you should carefully note this part:
Mucinex, the No.1 OTC expectorant in the USA, is a long-acting guaifenesin product and the only FDA approved 12-hour expectorant.
Hmm…. the only FDA approved 12-hour expectorant? What’s going on here? Well, after a little digging a very interested story came to light (I got much of the background from this excellent Harvard Law paper by Tammy Muccio).
First, we need a little context concerning drug regulation laws in the US (I’ll try to keep it short and to the point): The Food, Drug and Cosmetic Act (FDCA) was first passed in 1938 as a means to ensure that consumers were not exposed to unsafe (you guessed it) foods, drugs or cosmetics. The regulations only concerned unsafe drugs, not ineffective drugs. It wasn’t until 1962 that the FDCA was amended and drugs were required to be both safe and effective. Great, right? Well, now the problem was, what should we do with all the drugs that were currently on the market that don’t have efficacy data? To address that question, the FDA decided to initially grandfather these drugs and in the meantime initiated the Drug Effectiveness Study Implementation (DESI) program which would examine the available data and hopefully help the FDA classify the drugs as either safe and effective or not (not a small task in the least). For OTC products, the FDA initiated the “OTC Monograph Program” in which the FDA evaluated current OTC ingredients for safety and effectiveness on a class-by-class basis. If you were an OTC drug manufacturer, you could continue to sell your product as long as you registered with the FDA and complied with the monograph and manufacturing standards. It wasn’t a perfect solution, but considering the task at hand, it was a pretty good compromise.
Fast-forwarding to 1983, E-Ferol, an unapproved IV preparation of vitamin-E for premature babies results in the death of a number of newborns. This reinvigorated the FDA and made them take a second look at all those grandfathered drugs, guaifenesin included because, at the time, it was a Category III drug (“insufficient data to establish safety and efficacy”). Eventually in 1989, guaifenesin was moved to Category I (“generally recognized as safe and effective and not mis-branded”). So everything is fine, right? Not quite. A few years later the FDA got on a new kick and started targeting extended-release drugs of all kinds (and with good reason). Guaifenesin extended-release products were now on the FDA radar.
At this point in time, Adams Laboratories entered the scene. In 2000, they submitted an NDA for extended-release guaifenesin and in July 2002 it was approved and made available OTC (they also got a patent for their formulation). Shortly after approval, they requested that the FDA remove all of the “unapproved” extended-release guaifenesin products from the market and subsequently, the FDA sent out 66 Warning Letters to all of Adams Laboratories’ competitors that stated “either get an ANDA or stop selling your product.” Honestly, what more could you ask for than to have the government come in and shutdown every single one of the your competitors? Just to put this in context, take a look at what a 2006 10-Q filing from Adams Laboratories had to say:
Based on data from IMS Health—NPA TM , we estimate that, for the 12 months ended June 30, 2003, there were approximately 10.5 million prescriptions filled for long-acting, single-ingredient guaifenesin products. After November 2003, we believe that a majority of prescriptions written for long-acting, single-ingredient guaifenesin resulted in OTC sales of our Mucinex SE product. Humibid SE is now also available to meet this demand in a maximum strength formulation.
Basically, Adams Laboratories saw a huge Rx and OTC market, created a couple products, got FDA approval and then eliminated all of their competitors using the heavy hand of FDA regulators. Wow. The amazing part is, the FDA didn’t even bat an eye at this maneuver. Here is what a director from the FDA’s CDER group said in 2007 about the FDA’s continued enforcement against unapproved extended-release guaifenesin products:
“Today’s action is another example of our commitment to ensure all drugs marketed in the United States that require FDA approval have that approval,” said Steven K. Galson, M.D., M.P.H., director of the FDA’s Center for Drug Evaluation and Research (CDER). “This benefits consumers because drugs that skirt the approval process may be unsafe, may not work, and often have inadequate labeling or are improperly manufactured.”
So it all starts to make sense at this point. Adams Laboratories simply figured out how to help the FDA with their goals (getting unapproved drugs off the market) and at the same time turn a profit. Pretty remarkable if you ask me.
As a final point, I’ll leave you with this: If you think this is a smart business model to emulate, tread carefully. A few other companies have tried the same thing. URL Pharma did it with colchicine (Colcrys) and most recently, KV Pharmaceuticals did it with a progesterone (Makena) and it didn’t turn out quite so well. A quick google search will give you the story on those drugs. I think the window closed a long time ago on this business model.
The trashing of Dedreon’s stock price happened less than 24 hours ago and a lot of speculation is underway as to why they missed their revenue target. Ed Silverman over at Pharmalot just posted an interview he did with a Los Angeles urologist where he tried to find out if reimbursement concerns are the real issue behind the lagging sales. It’s an excellent article and I encourage you to read it.
I won’t spoil the punchline from Ed’s article, but it appears that Dendreon’s mistake is one that a lot of start-ups make. It’s a hard lesson to learn, but I think we can all benefit by reminding ourselves: “It’s not about the product, it’s about the customer.” It’s something that we often forget about in biotech where the “wow!” factor of a new drug can overshadow the fact we still have to get the drug to the patient.
Matthew Herper’s “The Medicine Show” blog on Forbes.com has a new series of posts on fixing pharma’s R&D machine. One post in particular caught my eye, “Seven Steps to Medical Innovation”, which lists Bernard Munos’ strategic plan to fix what ails pharma. Munos came up with this list from his observations during a 30 year career in sales at Eli Lilly and his own personal research on the issue (more on Munos here).
Let’s take a look at the list…
1. Regain the trust of physicians, regulators and payers.
I can’t argue with this point. Pharma has a bad reputation among all of these constituents, physicians most of all. A friend recently did a sales rotation and he said the tension (with many, but not all physicians) is palpable. For the most part, they would prefer to never see another sales rep again, but they do, mainly for the free samples. Many physicians are quite cynical about anything big pharma companies say and are always looking for the “catch”, assuming that drug companies have no qualms about bending the truth to increase sales. Improving the reputation of drug companies probably wouldn’t go far in fixing the R&D problem, but it’s an important goal, nonetheless.
2. Stop chasing blockbusters, which help lots of people a little bit, and start chasing breakthroughs, which help patients a lot.
Hmm… not so sure about this one. Blockbusters “help lots of people a little bit”? I think one could argue that the statins have helped lots of people a lot. Just take a look at the long-term clinical trials and the reductions in cardiac events and death. Norvasc? Enbrel? Blockbusters too and huge steps forward in treating hypertension and arthritis, heck one might even call them “breakthroughs”.
3. Do what works. Stop trying to manage drug discovery with Six Sigma processes.
Not sure how helpful “do what works” is, since if companies knew what worked, they’d probably be doing it. However, I can throw my support behind the disdain for big pharma’s attempt to industrialize R&D. I won’t say anything further on it, since it’s a widely recognized issue and has been commented on many times.
4. Lower costs with collaborative research.
Hmm… again, not so sure about this point. I can agree that collaborative research has a lot of positive aspects: access to experts who are familiar with the nuances of a biological target, access to creative thinkers who don’t come from big pharma, etc. However, I’m not sure how much it will reduce costs. The expensive part of R&D is the “D” part and the numerous clinical trials that are run (I’ve seen numbers that breakdown R&D costs about 1/3 “R” and 2/3 “D”). Doing the pre-clinical work (where most collaborations occur and discoveries are fleshed-out) isn’t what’s driving up R&D costs.
5. Mitigate risk by developing lots of potential breakthroughs, not by trying to develop projects that seem low-risk. History says the risk is never low.
6. Don’t move anything into human trials unless it is a potential breakthrough.
I’m combining these two points because I think they are related. I have a problem with Munos’ argument that developing lots of “potential breakthroughs” mitigates risk. What is the risk he speaks of? In R&D terms, it’s investing money in a project that fails to generate a positive return. The problem with his point is that even if you developed a lot of “potential breakthroughs”, they are just that potential breakthroughs. What makes or breaks a new drug are the clinical trials which is where most of the risk (and cost) lies. Pharma companies have plenty of “potential breakthroughs” (just listen to any pipeline presentation), what they don’t have is the money to send each one through the gamut of clinical trials. So choices have to be made. If Munos is arguing that the choices should be in favor of “potential breakthroughs” versus low-risk, incremental improvements, he’ll get no argument from me.
7. Cut research and development.
If nothing else, Munos knows how to get people’s attention, and I think that was the purpose of how this point was worded. Delving a bit deeper, Munos suggests that pharma companies should cut their R&D by outsourcing it to small, independent research labs that don’t suffer from the “big pharma” mentality. This is already happening to some extent through the academic collaborations that almost every big drug company has (or is planning to) set up. Munos argues that this should go further and that big pharma should open up their R&D organizations to the outside, offering up their internal resources to outside researchers. Pfizer plans to do this with their academic collaborations where they provide access to internal Pfizer technology. It will remain to be seen how beneficial it is.
So what’s the verdict? Munos makes some good points, but is a little lean on the details. My biggest concern is that this is being pushed as a “solution” to the problems of big pharma R&D and reeks of “if only these companies do X, Y and Z, everything will be better.” It’s that sort of thinking that got big pharma into the mess it is in today, with a top-down approach to R&D management. However, I do commend Munos for trying to change the system, because it certainly does need to change.