The Big Red Biotech Blog

FDA Tilts Positively Toward Accelerated Approval of "Breakthrough" Drugs

From Fierce Biotech (via Reuters), a new law is expected this year to allow the FDA to approve breakthrough drugs more quickly by allowing applicants to conduct speedier trials with fewer patients. The system would be modeled on the speedy approval process used for HIV treatments decades ago.

The FDA has approved several drugs recently in accelerated fashion, including Vertex' Kalydeco for CF, Pfizer's Xalkori and Roche's Zelboraf for skin cancer. Dr. Woodcock, the FDA's director, has been vocal in her advocacy for giving the agency the latitude to make fast approvals for drugs that show breakthrough promise in the clinic -- particularly for serious diseases with few treatment options.  The drugs, of course, would have to pass safety muster as well.

Posted by Bruce Lehr May 9th 2012.

 

First mAb Submitted to EMA for Biosimilar Approval

A biosimilar version of Remicade (anti-TNF drug) is the first mAb to be submitted to the EMA for review.  Celltrion is believed to be the company making the submission, although this has not been formally revealed.  Celltrion has conducted clinical trials with its version of the drug in 19 countries over the past 2 years. There are 16 -- yes 16 -- approved indications for Remicade.  It is not known if Celltrion is seeking approval for only the RA indication (matching trials) or going for additional indications as well.  Extrapolation of safety and efficacy data from one indication to others is allowed potentially so it is a pertinent question.

First Monoclonal Antibody Submitted to EMA for Biosimilar Approval.

 The anti-TNF market is estimated to be worth $21 B. Analysts are torn as to whether a biosimilar version is a bigger threat to J&J's Remicade or whether a (humanized) biobetter version of the antibody will more likely prevail.  J&J has its own humanized replacment called Simponi. Celltrion is betting on gettig share however and is submitting its application well ahead of Remicade's 2014 patent expiration date. Celltrion will also go to Korea and other emerging markets in Asia and Central/South America where Remicade is not under patent.

Now, we all wait to see how Celltrion's application does at EMA.  More mAb biosimilar applications are expected to be submitted to EMA this year.  Whether these have a huge impact on the market, depends upon how easily they are approved and whether companies like Celltrion (or Samsung) can make good on their promise to drop prices by 40-50% over the reference product. The race has begun in earnest now.

Posted by Bruce Lehr May 2nd 2012.

PhRMA Criticizes Biosimilar Flexibility

PhRMA has weighed in with its comments to the FDA guidelines on biosimilars.  In those, the trade group says that the FDA should not allow biosimilar manufacturers potential flexibility in delivery devices and formulations -- and still regulate it as a biosimilar.

PhRMA speaks out against FDA biosimilar flexibility.

A spokesman for PhRMA said, "Intentionally introducing differences to the molecule or the finished product will increase the level of uncertainty regarding the proposed biosimilar's similarity to the reference product. The statute imposes a scientifically rigorous standard that each product must be highly similar to its reference product.  Statutory considerations therefore cousel that FDA guidance should recommend that applicants minimize controllable process and design differences."

Several Big Pharma and BIO have weighed in with similar comments. 

Posted by Bruce Lehr Apr 30th 2012

BIO Voices its Comments on Biosimilars to FDA

BIO's response to proposed FDA guidelines is covered nicely in the Patent Docs blog. 

BIO asks FDA to publish specific statistics and/or ranges acceptable  for a determination of biosimilarity following the European model. BIO advocates for a more extensive clinical trial requirement to establish biosimilarity, including animal toxicity and human clinical trials. BIO also suggests a "cautious approach" to the extrapolation of data to other indications and patient populations without trials. BIO also asks for prominent labeling of the biosimilar to highight differences in route of adminsitration, presentations and conditions of use (presumably will inhibit switching) between biosimilar and reference product.

BIO also had comments related to quality and access to confidential information. On the quality front, BIO aks that any intentional differences from the biosimilar in host cell type, primary structure, formulation, or immediate package from the reference product result in immediate need to follow the BLA pathway and not ABLA.  BIO cites patient safety as the reason for this standard.

BIO requested explicit acknowledgement from the FDA that certain information within the reference BLA, including manufacturing facilities, be treated as confidential (see Abbott response to FDA in earlier blog post).  BIO disfavors comparison of a biosimilar to a non-US licensed product but wants to be particularly protective of manufacturing information in this instance. Trade secrets from all BLA must be protected from disclosure in biosimilar application process. The ABLA must stand on its own merit, supplemented with only public information.

In general, BIO suggests changes that will make it more difficult to gain ABLA (abbreviated biosimilar) approval.  These would appear to enhance patient safety and to also protect the competitive advantage of its BLA holder members.

Posted by Bruce Lehr Apr 26th 2012

Amgen warns biosimilar draft a threat to production innovation

The FDA is currently soliciting feedback to its recently published biosimilar guidelines.  Understandably, many among innovator pharma have comments to provide.  In its recent comments, Amgen asks the FDA if manufacturers are going to have to "maintain biosimilarity after approval."  If so, Amgen warns this requirement over time would stifle upgrades in manufacturing and quality improvements -- which would be bad for patients and a burden to the industry.  This could apply equally to innovators and biogenerics producers post-approval.

Amgen warns biosimilar draft a threat to production innovation.

Amgen suggests that a biosimilar applicant make its comparisons to the innovator product during a limited period of time and then establish a reference standard. Amgen then wants the FDA to treat the innovator product and the biosimilar as separae drugs from that point forward. Then each can make changes to their manufacturing or quality based on the mertis of their own data.

Industry commentators note however this would have implications on interchangeability -- likely the above approach would prevent these products from ever being considered interchangeable. Of course, Big Pharma and BIO have their reasons for not wanting to see interchangeability adopted anytime soon.

Posted by Bruce Lehr Apr 25th 2012.

 

 

 

 

Biosimilars: If You Can't Beat 'Em Block 'Em

The Alliance for Safe Biologic Medicines urges the FDA to adopt "steps to ensure patient safety is at the forefront of the biosimilars pathway."  Further, the FDA needs to "make clear that clinical studies will be necessary for the foreseeable future due to the complexity and diversity of human biology and the limits of scientific knowledge today."  The Alliance is a trade organization composed of biopharma companies and individuals that has set up to advise the FDA on biosimilars policy while it is under discussion (i.e. a trade lobby).  Company's like Novo Nordisk and Roche (Genentech) are members.  See in-Pharma Technologist and Fierce Biotech here and here.

They appear to be asking the FDA to make its proposed regulations less flexible than they are currently written and to impose more strict guidelines requiring clinical trials, as well as sterner traceability measures and a pharmacovigilance system that "distinguishes a biologic reference product from its biosimilar."

I've written before that I think delay tactics to make it harder to get biosimilars to the market (and at a higher cost) are so much whistling past the graveyard (see blog post).  To me, the economic and government forces favoring the implementation of biosimilar guidelines and subsequent approval of these products is a given.  Governments want to save on healthcare costs, it's that simple.  Will they compromise safety to do so?  No.  But, I think they will try to set up flexible approval systems that give the regulatory bodies some latitude to approve some biosimilar applications faster than others with more or less clinical data support needed depending on the situation. The FDA seems to be giving itself some flexibility.

I don't see innovators trying to delay implementation and market competition as a very effective strategy.  It's ironic that many of the innovators themselves are likely to be among the first biosimilar applicants (with a competitor's drug of course).  I'm further amused that many of these same companies are simultaneously in favor of other legislative efforts underway (FAST, TREAT, etc.) to speed the drug approval process.  In that instance, they've suggested only safety data is needed and a "case by case" consideration of drug licenses -- particularly for diseases without other good treatment options -- is just the way to go (see blog posts here and here).

I think we should get on with it.  Get biosimilar guidelines in place and get the process toward approval started. Biosimilars ARE coming.  If innovators want to be innovators, then innovate. If they want to be biosimilar competitors, then compete -- but don't block or slow the process down.

Posted by Bruce Lehr Apr 18th 2012.

 

Bio Drug World is a Changin'

Nothing Earth-shattering here by any means, but a couple interesting reads in the blogs by Derek Lowe (via Matthew Herper) and an article by Luke Timmerman dealing with CHANGE in the world of drug development and commercialization.

The Herper/Lowe, piece to a degree, laments that the heads of drug companies may not value the "human capital, i.e. scientists" involved in the drug discovery process.  And as the economic gap widens between the number of new drug approvals (bringing in much needed revenue) and the high cost of developing and marketing new drugs -- well at present it looks like R&D scientists are paying for it with their jobs. The observation is made that maybe this isn't the best strategy to employ in a research/discovery driven business.  Nevertheless, there is also a hard economic reality and SOMETHING different clearly has to be done -- as the current model isn't sustainable any longer.

The Timmerman piece talks about some of the changes that are taking place on the commercialization of drugs that contributes to lower sales and higher costs - exacerbating a potential need to cut R&D staff (though that response is a choice).  On the comercialization side, it is not good enough to just get your drug to the market anymore.  You actually need to show it meets an unmet need and quite frankly works better than exisiting alternatives -- otherwise me, you, the insurance companies and the government don't want to pay for it. The whole concept of "comparative effectiveness" is bringing a new discipline to drug development -- and sets a higher bar too.

The two articles demonstate the World has changed.  An for an industry to survive in response to meaningful change -- it has to adapt or head for extinction (in this case layoffs or ceasing to exist as an independent business).  It has always been thus.  Just not in the (bio)pharma industry up till now.

Posted by Bruce Lehr Apr 2nd 2012.

 

Faster FDA Go Faster to Approve New Drugs

Pharmalot reports on the latest new bill introduced in Congress aimed at speeding the FDA approval process.  This one -- called Advancing Breakthrough Therapies for Patients Act --will ask the agency to speed the approval of "breakthrough drugs". 

Yet Another Bill To Speed FDA Drug Approvals // Pharmalot.

What's a breakthrough drug?  One aimed at a serious or life-threatening illness that has demonstrated preliminary clinical efficacy that suggests a substantial improvment over currently available treatments. The bill would let sponsors apply for breakthrough status and the FDA would need to rule Yea or Nay in 60 days.

The drug sponsor could still also apply for fast-track designations, accelerated approval or priority review status as well.  Now we have ABTPA, FAST and TREAT all sitting before various parts of the legislature looking to speed drug approvals in the FDA.  And, as PDUFA legislation needs to be renewed (lest the FDA run out of its user fee funding), Congress watchers think that at least parts of any or all of these Bills may have a chance to be added to the new PDUFA reauthorization proceedings.

Charge!

Posted by Bruce Lehr Mar 27th 2012.

Big Pharma Blocks Accelerated Approval Pathway?

Earlier this week, I made a post based on an Xconomy article covering the FAST and TREAT bills in the congress presently aimed at speeding up the drug approval process. In a nutshell, these bills would create a pathway for drugs for to be approved more quickly (after small phase II studies) for serious conditions without better treatment options.  It is essentially taking the idea of the AIDs drug approval model and applying it more widely.  Companies would have to do serious post-market follow up as well and drugs could be pulled from the market if they didn't live up to their pre-approval billing.

Now BIO has come out for the bills, but PhRMA has NOT.  Some observers and analysts are viewing this very cynically with regard to Big Pharma behaviour and are essentially accusing them of scuttling the bill for their own purposes.  Namely? Big Pharma wants to keep Biotechs as a novel drug producing farm system from which they can acquire new drugs, rather than give the Bio's the possible ability to launch drugs on their own. 

"Sen. Hagan's proposal would have been devastating to the big pharma R&D oligopoly," writes Roy. "If small biotech companies could get their drugs tentatively approved after inexpensive phase II studies, they would have far less need to partner those drugs with big pharma. They could keep the upside themselves and attract far more interest from investors. Big pharma, on the other hand, would be without its largest source for innovative new medicines: the small biotech farm team."

Pretty strong words and sounds a bit too true to just dismiss doesn't it?  Let's hope not.  I hope that Big Pharma can stand on its own two feet to develop its own products if it has to do so. If not, they should become investment bankers not drug developers. See Fierce Biotech and In the Pipeline.

Posted by Bruce Lehr Mar 16th 2012.

Bad (even worse) Week to be a Fabry's Patient

Fabry patients got more bad news yesterday -- as if it weren't bad enough already, given shortages of Genzyme's Fabrazyme in the US due to that company's well chronicled manufacturing problems. In fact, last week an Idaho woman filed a lawsuit against Genzyme, charging that a long-standing shortage of its Fabrazyme treatment for Fabry disease led to the death of her husband two years ago. He would still be living, she claims, if the biotech had not experienced severe and persistent quality control problems that led to a subsequent rationing program. 

On the heels of this, Shire had been encouraged by patients and the FDA itelf to file a BLA to get its Fabry drug Replagel approved in the US.  Now,  Shire says that the FDA has told them they will require more clinical data despite the fact that Replagal has been on the European market for more than 10 years.  

However, Shire says that recent meetings with the FDA indicated additional controlled trials will be required for approval, although safety was not an issue. This comes after the drugmaker last November filed its application with the agency, anticipating a speedy review. However, the added trials will cause “a significant delay” and approval would not occur until “the distant future.”

Analysts called the move "a surprise setback for Shire," according to Bloomberg. A new trial, they added, "would take at least two years and is probably not economically justifiable."  All in all, not good news for Fabry patients.  See Fierce Biotech, Pharmalot, and PharmaGossip.

The only one who may be cheered by this news is Genzyme and its investors as its new US manufacturing facility to produce Fabrazyme was recently approved.  The company can now go back into large scale production.  One might wonder about the timing of the FDA decision given that set of circumstances.

Posted by Bruce Lehr Mar 16th 2012.

Is it Safe to go FAST with Drug Approvals?

Xconomy's Luke Timmerman wrote a post today in his blog about the FAST (Faster Access to Specialized Treatments) legislation that is currently in the House. Advocates of FAST are pushing for more drugs to be approved sooner by FDA for serious diseases -- that is after they've been shown to be safe and likely with some sort of surrogate endpoint data pointing to their possible effectiveness. Proponents liken this to speedier approvals given to AIDs drugs during the early days of that crisis.

The conundrum for regulators of course is if they approve drugs more rapidly without as much efficacy data, there is a possibility that the drugs may not perform as advertised in real (and usually larger) patients populations (ala Avastin for breast cancer).  The quid quo pro for this type of program therefore has to be the industry's diligence in doing and reporting post-market follow up.  Less than sterling drugs could then have their approval revoked.

The post also quotes people like Alnylam's CEO, John Maraganore, as being an advocate as it may offer his company a way of getting drugs to market faster and at less expense in more abbreviated clinical trials. Maraganore argues this in turn woudl make investing in smaller and mid-sized biotech's more attractive -- due to lower costs and heightened regulatory predictability. 

An In the Pipeline piece this week, points out the problems the drug industry has had with it's productivity as fewer and fewr drugs are introduced at greater and greater expense -- a sort of reverse Moore's law or Eroom's Law as th epost explains.

In addition to FAST in the House, the Senate has its version too, known as TREAT (Transforming the Regulatory Environment to Accelerate Access to Treatments). It looks like this idea's time may have come - and with desires to reduce health care costs, and boost the health of the US Biotech industry momentum is building to give this idea a try.

Posted by Bruce Lehr Mar 12th 2012.

Of the FDA, Biosimilars and Elephants

The Patent Doc blog covered a recent FDA presentation (Dr. Rachel Sherman, Feb 15th) on the biosimilar guidance documents issued earlier this month.

This FDA used entertaining analogy to demonstrate the thinking process in this determination.  The presentation contains a line drawing of an elephant (below), where each line represents an analytical or clinical study performed by the biosimilar applicant.  The FDA will have to compare the reference product (figure A) with the biosimilar products (figures B-E) to determine what level of detail is required for a determination of biosimilarity (whether the drawing is an elephant or not).  The biosimilar applicant will attempt to draw the minimum amount of lines such that the FDA can make a finding that the biological product is biosimilar to the reference product (elephant).  The FDA will not permit any "tracing" of the lines in the drawing, as these attributes of the biosimilar are already known.  Each test or study must add something to the whole body of evidence.  This elephant analogy is also used to define "fingerprint" studies, which may tell the biosimilar applicant at an early stage that its product will not qualify for approval under 351(k) (e.g., if early lines in the drawing show a beak or fins).

This got me to thinking about the old Jain proverb of the Six Blind Men and the Elephant.

The story says that six blind men were asked to determine what an elephant looked like by feeling different parts of the elephant's body. The blind man who feels a leg says the elephant is like a pillar; the one who feels the tail says the elephant is like a rope; the one who feels the trunk says the elephant is like a tree branch; the one who feels the ear says the elephant is like a hand fan; the one who feels the belly says the elephant is like a wall; and the one who feels the tusk says the elephant is like a solid pipe.

A king [FDA] explains to them:

"All of you are right. The reason every one of you is telling it differently is because each one of you touched the different part of the elephant. So, actually the elephant has all the features you mentioned."

This resolves the conflict, and is used to illustrate the principle of living in harmony with different beliefs and that truth can be stated in different ways.

 

Here's hoping the FDA can harmonize its biosimilar elephants by using a process "where each analytical study required of biosimilar applicants will advance the field of knowledge regarding the molecule of interest."

Posted by Bruce Lehr Feb 28th 2012.

GAO Report Places Primary Blame on Manufacturing Failures for Drug Shortages

New supplies of two unavailable cancer drugs will be allowed by the FDA.

Dow Jones Newswires(DJN) reports that the FDA will allow the temporary importation of Lipodox as a substitute for Johnson & Johnson’s Doxil. The drugs have the same active ingredient.  Doxil has been in short supply since about mid-2011. New supplies of Lipodox are “expected to end the shortage and fully meet patient needs in the coming weeks,” the FDA says.

The FDA has also approved a new manufacturer, APP Pharmaceuticals, of preservative-free methotrexate, a drug that is used to treat a type of children’s leukemia and has also been in short supply. The drug should be available in March.  The agency “is actively working with other manufacturers … including Mylan and Sandoz Pharmaceuticals” to meet patient needs.

DJN notes that both shortages can be traced back to the closing of a Ben Venue Laboratories plant in Ohio. Ben Venue, a unit of Boehringer Ingelheim, shut down the plant to deal with manufacturing issues. See here.

The GAO just issued a report that stated the majority of drug shortages now being seen were due to manufacturing problems. See WSJ article. 

While the Pharmalot blog reports that more than two dozen patients who suffered due to drug shortages filed a lawsuit today in DC federal court against the US Dept of Health and Human Services (DHHS), the FDA, and NIH.  The suit argues that FDA licenses to drugmakers that cuase shortages should be invalidated and their patents declared unenforceable (how did they miss the patent office in suit too?).

The poster boy for this suit is Genzyme with its celebrated manufacturing issues at the Allston plant which caused repeated delays in the supply of both Cerezyme and Fabrazyme (which is still not back to normal).

Posted by Bruce Lehr Feb 21st 2012.

 

 

Biosimilars are Progressing by the 'Totality of Evidence'

Two more blogs weigh in on the FDA guidelines published for the Biosimilar approval route last Thursday.  The Patent Doc blog seems a bit underwhelmed by the lack of specificity of the guidelines but acknowledges the FDA had a relatively short time line to issue their guidance.  It does acknowledge the guidelines will likely evolve in practice and the FDA gave itself maximum flexibility in interpreting them. The FDA will use a "totality of evidence" standard similar to that adopted in Europe.

The BioProcess Blog for its part seems a little more upbeat that the FDA put guidelines out there to get the process rolling.  In general, it was positive about the fact the FDA will allow the possibility of formula changes and different delivery devices from biosimilar to the reference product without either being an automatic block to taking a biosimilar path. The blog authors were also happy that the FDA will accept data from non-US licensed products in considering the "totality of evidence" in support of a biosimilar application.

To date the FDA has received 31 requests for meetings to discuss company plans for their biosimilars, and 21 of those had been held by the end of December 2011.  There have also been 9 INDs for biosimilars filed to date and the agency is expecting a full 351(k) application soon.  The process is well underway and there is still 60 days for interested parties to comment and suggest changes to the Draft guidelines just issued.

Posted by Bruce Lehr Feb 15th 2012.

Biosimilar Guidance Is A Pandora’s Box: Pan Explains

This is a really interesting short interview from Pharmalot with Jonathan Pan, a manager at the Scientia Advisors consulting firm on his view of what the FDA draft guidelines on biosimilars could mean.

Biosimilar Guidance Is A Pandora’s Box: Pan Explains // Pharmalot.

I excerpted a part I found very interesting concering how the FDA is [apparently] setting up to judge biosimilarity. And how this might open up opportuntities for pharma to get drugs to market as "biosimilars" instead of new entities.

Pharmalot: So was there anything surprising here?
Pan: The major surprise I see here is that FDA is creating a path of similarity versus a path of replication. Effectively, what they’re doing, because of the complex nature of these products, is they’re saying that, for any biologic agent, anybody can create a biosimilar, but that it may not be an identical product. At the end of the day, it’s creating a great way of making a ton of non-inferior products to a particular reference product.

Pharmalot: Aren’t they going go to go on a case-by-case, though?
Pan: Obviously, they leave that language open and, of course, no guidance from FDA is set in stone, but at the end of the day, it’s interesting how they worded this to mitigate the fact that compounds are very complex and because of that, there’s more opportunity for companies to move their products to market. I think if a drugmaker wanted to pursue a biosimilar path versus the new molecular entity, they make take the biosimilar path, because it’s a quicker route to market.

Look, take the rheumatoid arthritis market. If we have one anti-TNF inhibitor, all I have to do is show it’s equivalent to how one of them works… I just have to make a decision to make a biosimilar and go to FDA and say I’ll run a trial to show that it’s safe and my antibody is going to be non-inferior. The FDA, according to the guidance, would say the product is non-inferior and, therefore, it will be approved as a biosimilar.

That’s versus going through a Phase I trial and recruiting patients, and a Phase II trial and recruiting patients, and a Phase III showing superiority for standard of care… They won’t have to go through the regimented process. It’ll be more abridged. As long as they can show in standard pharmacokinetic and pharmacodynamics tests that the product is non-inferior to the reference products. They’ll be going head to head. They’ll still have to go through safety checks and efficacy checks through clinical development plan, but what most pharmaceutical companies do is cherry pick… in this process, they’ll simply try to compare to reference products.

Pharmalot: What, if anything do you see as potentially troubling?
Pan: There is a Pandora’s box here. If implemented in its current state, I imagine there will be some interesting maneuvering. If I’m a pharmaceutical company and any product is at Phase I, I may not want to go through the full development process and instead say that I have a biosimilar and get to market as fast as possible. It’s a new thought process pharma may or may not want to embrace. It’s good for the pharmaceutical industry as a whole because it allows them to get products on the market that may not get on there otherwise.

OK do we have a new way to get similar biologic products to a licensed drug to market?  Or do we have a way to get a new entity to market faster by calling it biosimilar?  Or do we have both?

Posted by Bruce Lehr Feb 10th 2012.

FDA Unveils Guidance for Biosimilar Development Today

The FDA posted its draft guidance document for biosimilars on its website today.  You can read a summary below outlined in the PharmTech Talk blog.

PharmTech Talk » It’s Here: FDA Unveils Guidance for Biosimilar Development.

Or you can go see the full document yourself on the Agency's site.

The FDA site notes that comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the availability of the draft guidance. Many comments are expected. Everyone - Have at It.

 

 

Posted by Bruce Lehr Feb 9th 2012.

 

 

FDA Gives Biosimilars Update

Rachel Sherman, Associate Director for Medical Policy, within CDER gave an update on biosimilars today. Protein biosimilars (but not chemically synthesized polypeptides) will be regulated under Public Health Services Act section 351. 

PharmTech Talk » FDA Gives Biosimilars Update.

The 351 (k) approval route will require the FDA to consider:

• Analytical studies to show th ebiosimilar is highly similar to the reference product
• animal studies (including toxicology) as needed
• clinical studies to establish safety, purity and potency in one or more conditions of use for the reference product

To assess biosimilarity, Sherman explained that each study adds a piece of information to understand what a biosimilar product is and is not, and what other information is needed. The FDA may also adopt the European approach to "use the totality of the evidence" to address biosimilarity.

To date, there have been 35 Pre-IND meeting requests for proposed biosimilars to 11 reference products, 21 Pre-IND meetings held and 9 INDs received at FDA. The line is rapidly forming.

FDA guidance has not appeared as yet, and is still in "final stages" at the agency.  No timeline for publication has been issued.

Posted by Bruce Lehr Feb 3rd 2012.

 

Study says Speedy FDA Approvals Associated with More Safety Questions

A recent study by Harvard and Stanford researchers seems to indicate that FDA approvals made closest to the review deadline have higher post-market safety problems.  While no cause and effect is yet claimed, the researchers do note a positive association and suggest the deadlines link to funding may have unintended safety consequences.

FDA Review Deadlines Caused Safety Issues: Study // Pharmalot.

PDUFA which links FDA funding to its ability to meet drug application review deadlines may be altering FDA review behavior.  The study indicates that more reviews now pile up around the 6 month deadline than before PDUFA existed as legislation. Drugs reviewed and approved less than 2 months before the deadline is reached experience higher post-market safety issues than drugs approved more than 3 months before the deadline or after the deadline was reached. A new black box warning is 3.27 times more likely for a drug approved within the 2 month window, and safety related withdrawl is 6.92 times more likely for these drugs.

The study was published at a time when Congress is conducting PDUFA hearings looking at renewal of the legislation. How are we going to choose to balance risk and reward?

 

 

Posted by Bruce Lehr Feb 2nd 2012

 

FDA Challenged to Make Rules of the Game Clear

Sanofi's CEO Chris Viehbacher, speaking in his role as leader of PhRMA, says the FDA needs to clearly state what drug makers have to meet when it comes to risk-benefit analysis with new drugs.  The uncertainty of FDA rulings is making it unattractive for Big Pharma to develop products for the primary care diseases, like obesity and diabetes, according to Viehbacher.  Both obesity and diabetes treatments have taken more than their share of lumps in recently agency rulings leading to a lot more work to get these treatments approved. See Fierce Biotech.

Clearly, I think it is fair for the industry to get transparent guidance on what it is going to take to get certain types of therapies approved.  Everyone working on a project should know what "success looks like".  I think we all expect that in our daily lives. Why not drug makers too?

I would think that the FDA and the US Goverment would want to provide this -- and I'm not saying they don't.  Diseases like obesity and diabetes have to cost US taxpayers and patients billions in treatment costs. These are diseases that have a major impact on the health of our citizen's and healthcare costs.  There should be ample motivation to get treatments out there that work (although eating better and exercise wouldn't hurt either). 

These are important areas of health where we do want to see continued improvement with treatments because of the high social and economic impact.  These would seem to be areas that are ripe for the FDA and drug makers to work together to come up with expectations on future therapies that are reasonable and safe.  The US governement also has a vested interest in helping to reach such a conclusion.

Posted by Bruce Lehr Jan 23rd 2012.

 

 

2011 Final FDA Drug Approval Statistics

The FDA approvals for full year 2011 can now be formally tallied.  The agency did approve more drugs this year than it has for any of the past seven.  Some points include 30 new drugs approved, including many novel applications that were approved in the US first.  Both J&J and GSK each achieved 3 new approvals.

Analysts attribute the higher approval numbers to such things as pharma's improved data packages being submitted with drug applications, specifically with more safety data.  Pharma companies also appear to be picking better candidates that represent more novel treatments as drug they preferential push toward approval.

The agency for its part says it is trying to streamline the approval process -- a process that heretofore has been under heavy criticism by pharma company's, industry analysts and investment groups. It remains to be seen if 2012 will be as rosy -- but we can start 2012 optimistically can't we?  See Fierce Biotech.

Posted by Bruce Lehr Jan 6th 2012.

BMJ Plays Clincal Data "Hide and Go Seek"

Several sources today reported on British Medical Journal articles that show that not all human trial clinical data is being reported.  Apparently, this is shocking to many clinicians and the public -- but also reflects charges critics have made for years (without the needed proof).

The BMJ is one of a number of journals to take developers to task on their data reporting practices. But despite the new mandates, there's no evidence that the pharma industry is drawing any closer to achieving true transparency. The BMJ concludes that some developers are purposefully keeping some data under lock and key, or publishing it on obscure sites. They want an end to what they call a "culture of haphazard publication and incomplete data disclosure."

These articles confirm the fact that a large proportion of evidence from human trials is unreported, and much of what is reported is done so inadequately. The absence of the data about harm in trials can harm patients, and incomplete data about benefit can lead to wasted costs to health systems. Moreover, researchers or others who deliberately conceal trial results breach their ethical duty to trial participants.

In BMJ, one paper examined unpublished evidence of existing meta-analyses of nine drugs approved by the FDA in 2001 and 2002, but found identical estimates of drug efficacy in only three of 41 cases, or 7 percent.  In the remaining cases, estimates of drug efficacy were evenly split between more (19/41) and less (19/41). Missing data did not always reduce estimates of drug benefits, as this study shows that “publication bias” can cut both ways. Each increment of data can change the overall picture, but in most cases with no certainty that the picture is complete.

Prior registration of all trials became a condition for later publication in 2005.  Yet, a survey of NIH funded research in the United States between 2005 and 2008 shows that only 46 percent of studies were published in a peer reviewed biomedical journal indexed by Medline within 30 months of trial completion. And three years later, one third still remained unpublished.  The law calls for publication of all Government sponsored trial data in 12 months.  Apparently, that doesn't mean much in terms of behavior.

Meanwhile, another paper found that at least 3,000 records of randomized controlled trials entered into Medline between 2006 and 2011 were NOT indexed, which means that many trials will be missed when entering the commonly used research term - randomized clinical trial - into the database. As the authors noted, important evidence in searches - design and methods, baseline characteristics, long term follow-up, and secondary data analyses - can be missed

It's like playing Hide N Seek -- searching all over through documents in regulatory bodies and drug companies to piece data together that should have been freely available. Even when data on individual participants are made available, they only form part of the picture, and Ahmed and colleagues describe the problems of fitting in such data when the whole picture is not known.

Past failures to ensure proper regulation and registration of clinical trials, and a current culture of haphazard publication and incomplete data disclosure, make the proper analysis of the harms and benefits of common treatments almost impossible for systematic reviewers. Patients will have to live with the consequences of these failures for many years to come.

The main challenge is to ensure better systems for the future. This may require the global organisation of a suitable shared database for all raw data from human trials— perhaps the next job for the World Health Organization. Concealment of data should be regarded as a serious ethical breach, and clinical researchers who fail to disclose data should be subject to disciplinary action by professional organisations. This should serve as a wake-up call to both the NIH and the FDA to restrict grants to researchers who receive government funds, but violate the rules. This may achieve quicker results than legislation in individual countries, although this is also desirable. 

See PharmaGossip, Pharmalot and Fierce Biotech reports.

Posted by Bruce Lehr Jan 4th 2012

 

Ben Venue Labs Pisses Off FDA

I saw this unusual story in the Aspen Brook Alert concerning Boehringer Ingelheim's Ben Venue operation. According to the story, during the most recent inspection of the facility a 38 liter stainless steel mixing vessel was found to contain an "unknown liquid".  Subsequent creatine testing identified it as urine. 

A related dusting for fingerprints found nothing, and DNA testing was inconclusive due to contamination. Briefly, there was consideration to polygraph the staff with access to the area but when it was determined that 700 exams may be required that concept was rightfully dismissed.

 Ben Venue did not follow its SOPs to invesitgate the "unknown substance" in the 30 days required and therefore was cited by the FDA for being past due. So now, we apparently have a pot to piss in but no hard suspects.

Posted by Bruce Lehr Dec 14th 2011.

FDA Inches Towards a Biosimilar Approval Pathway

In addition to the FDAs plan to solicit pharma input on proposed user fees for biosimilars, the FDA has also published proposed performance goals and procedures for the review.

PharmTech Talk » FDA Inches Towards a Biosimilar Approval Pathway.

The draft performance goals outline the following:

• timelines for review of applications
• timelines for review of proprietary names 
• procedures for resolving disputes.
• the procedure a sponsor should follow to get specific questions answered about protocol design, or about scientific or regulatory questions pertaining to their submission
• timeline for the agency’s response.
• there is an explanation of the types of meetings the sponsor should schedule with FDA
• the information required by FDA before scheduling the meeting 
• the timeline or conditions during the submission process that would require scheduling each type of meeting

As stated in the previous post, we're edging closer to getting a functional biosimilars process in the US to bring this important new class of drugs to the market.

 

 

 

 

 

 

Posted by Bruce Lehr Dec 12th 2011

PhRMA backs FDA plans for biosimilar fees

 Biosimilars are coming! Biosimilars are coming! in the USA and the FDA is planning to seek pharma industry input to design a set of users fees to defray costs and help expedite review of these new class of medicines.

PhRMA backs FDA plans for biosimilar fees discussion.

PhRMA says it is on board with this proposal and is eager to provide input at the hearings.  It is also in favor of a "science-based, separately funded regulatory program for biosimilars that is supported by appropriate dollars and user fees."

We're getting closer all the time.  Now if the FDA can just issue their guidelines.

Posted by Bruce Lehr Dec 12th 2011

Info Clearinghouse May Clear Way in Fight Against Adulteration

Here's an interesting idea from the GAO.  They are advocating for the creation of an information clearinghouse to combat intentional product adulteration -- based on FDA comments that getting information from industry about potential instances of economic adulteration is crucial to addressing the problem. Up to now, companies have been reluctant to share this information. 

The clearinghouse would allow companies to share information anonymously on adulterated ingredients with FDA and other companies. It could help FDA disseminate information about adulterated products quickly and enable the agency and industry to respond to adulteration rapidly. The creation of a clearinghouse managed by a third party could further ensure that the information did not identify specific companies.

PharmTech Talk » Let’s Fight Adulteration with Information.

This strategy could help allay industry’s concerns about sharing information when an adulterated ingredient has not entered into commerce. Companies are afraid that they may be sued if they reported that a supplier intentionally adulterated a product and the accusation is later found to be baseless.

Because potential adulterants often are unknown or unidentified, it can be hard for FDA to detect them, as was the case in the recent heparin adulteration. Industry may be the best source of tests to detect adulteration because companies develop such tests to monitor the products they receive from their suppliers; however, industry officials indicated that they are often reluctant to share such information because it is proprietary. The clearinghouse might solve the fears surrounding sharing proprietary information -- which in turn could help the FDA do its job better and better protect the consumer.

It seems like an idea worth exploring.

Postd by Bruce Lehr Nov 29th 2011.