Vivus vs. the FDA: Round Two

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:

  1. 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.”
  2. 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.

Biosimilars: A little more complicated than we thought…

Most people are familiar with generic drugs and how big the cost savings can be.  Typically, once a branded drug goes off patent, the price drops precipitously, usually somewhere in the range of 80-90% (excluding the 180 days of market exclusivity that the first company to produce the generic gets).  Now that biologics have become such a large part of the drug market (estimates are the will be the top 6 selling drugs by 2014), the most obvious question to ask is “when will generic versions of biologics be available?”

The answer to that question is important to a lot of people, namely  insurance providers who pay tens of thousands of dollars a year for each patient who takes drugs like Avastin, Epogen and Rituxan.  The issue is so important in fact, that the Congressional Budget Office conducted a study that estimated that the government could save up to $25 billion dollars over 10 years from the introduction of biosimilars.

The problem was, until the Health Care Reform Act was passed last year, there was no regulatory process to approve biologic drugs.  With the passage of the bill, the FDA was given a mandate to create such a regulatory process.  Problem solved, right?  Not so fast.  There are two specific issues that seem to be taking the wind out of the sails for those promoting biosimilars.

The first issue is the approval pathway.  Back in August, Janet Woodcock (director of CDER at the FDA) and others published an article in the New England Journal of Medicine outlining the FDA’s view of a potential biosimilar approval pathway (keep in mind that the health care bill simply told the FDA to create a pathway, it didn’t actually lay out how to do it).  The article is worth reading, but the best way to summarize it is “We’ll figure it out as we go.”  Yikes.  Not exactly what companies want to hear when it comes to estimating the risks of investing in the development of a biosimilar.  Now, I’m not blaming the FDA for saying what they said; biologic drugs are incredibly complex compared to small molecule drugs (see figure below) and until the FDA has had a chance to “test” the approval pathway, they can’t really come out and say “Do X, Y and Z and we’ll approve you drug.”  So what does this mean?  For the most part, the only players in the biosimilar market will the big biopharmaceutical companies who have both the expertise and more importantly, financial backing, to forge an approval pathway.  Think of the process less like hiking in the Rockies with a compass and more of using a machete to cut a path through the dense jungles of South-East Asia.

Image taken from ICON Insight, Vol 18, March 2010

 This image gives you some idea of just how complex biologics are.  On the right is a molecule of aspirin and on the left is an antibody (a number of biologics are antibodies).

The second issue is physician and patient perception of biologic drugs.  Small molecule generics are literally the exact same drug as the branded products, at least to the degree that we can tell (which is really well).  Not so with biologic drugs.  Heck, it’s not uncommon for a company that produces biologic drugs to have difficulty producing consistent batches of them in their own plants.  In light of this, physicians will likely be very wary of switching a patient from a branded biologic to a generic, especially since biologics are often used to treat conditions where drug efficacy can be a matter of life or death/debilitation (cancer, MS, etc).  In fact, Decision Resources recently release a report where a majority of surveyed physicians said they would hesitate to prescribe a biosimilar for a patient, unless the biosimilar had gone through phase 3 trial for that indication.  Ouch.  Phase 3 trials are typically the most expensive part of drug development and their costs can easy run into the tens of millions of dollars, if not more.  If a company is required to conduct such trials, the likelihood of a biosimilar being 80-90% cheaper than the branded generic is pretty much zero.

Prediction: Once biosimilars hit the market (and they will, eventually), I can almost guarantee that the companies who own the branded biologics will conduct a marketing campaign, targeted at both physicians and patients, where they hammer away at the “similar” part.  I can see the commercials now “Biosimilars are not like your generic Lipitor, they are only “similar”, not identical.  Do you really want to risk your health on something “similar”?”

So all in all, biosimilars have a pretty rough road ahead.  The big biopharmaceutical companies are already making serious investments in the area since there is a lot of money at stake, but it’s not a task for the faint of heart.  Most likely we’ll start to see biosimilars of the relatively simpler biologics like the insulins, where the cost of development is more predictable and less costly.  Either way, it’s an interesting area to keep an eye on because I have no doubt that there will be some spectacular successes in the area and some spectacular failures.

A very small, but incredibly expensive mistake…

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, 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…

Can the DMV innovate? Why yes it can!

This post is a little off-topic, but I thought I would share…

Since nearly everyone has experienced the frustration of visiting the DMV, I’ll spare you the details of my latest visit.  It was no better and no worse than the DMVs I’ve visited in other states.  The only thing that helps keep me sane during these visits is identifying all the inefficiencies and imaging the numerous ways that service could be improved.  I liken it to what world peace would be like: a pleasant though, but something impossible to achieve.

Or is it possible?  Well, let me share with you what happened in my hometown almost 20 years.  In Canada, the province of Alberta (prior to 1993) had a system very similar to the DMV system that you see in many states.  Just like in the US, it was a painful process to get a driver’s license or register your vehicle.  In Calgary, a city of about 800,000 people at the time, there were a grand total of two registry centers (the equivalent of DMVs).  The hours were terrible, customer service was non-existant and the waits were long.  In 1993, the Alberta government decided to privatize the registry system, or at least the front-office part.

What happened?  Well, this map show one change that occurred.  Nearly everyone of those red dots is a registry services business.  I’m sure google picked up a few other businesses by accident, but right now there are 25+ registry services businesses in a city of just over one million.  Talk about options!

Before I left the city, I had a chance to experience the new system.  I needed a copy of my long form birth certificate.  So I looked up the closest registry services business (less than 2 miles away!).  But will they be open?  Why yes!  Their hours, Monday through Friday are 9am to 9pm (no need to leave work early!) and they are open on the weekend too.  I drove over, parked the car and walked in.  There were 2 people in line.  After a 3 min wait, I walked up to the counter and inquired about gettting a copy of my birth certificate.  No problem!  After filling out a form, the very pleasant lady entered my information into the computer, asked me a few questions to confirm my identity and said the birth certificate would be delivered by mail in less than a week.  Great!  I don’t remember what it cost me, but I do know they accepted credit cards.  I was in and out in less than 10 minutes.  I had a similar experience when I renewed my driver’s license a couple years later.

Today, the registry services businesses allow you to do the following quickly, painlessly and with great customer service: get a driver’s license (including the test), register a vehicle, register your business, get a marriage license, do a land title search, put a lien on property, change your name, get an Alberta healthcare card and even obtain a raffle license for your fundraiser.

So what’s the point of this post?  Well, it’s mostly a rant, but one take away is that innovation is possible, even in those areas of our lives where we’ve grown to accept inefficient, archaic systems.  Now to just get the California government to buy into the idea…