The Big Red Biotech Blog

A White House White Paper On Drug Approvals - Helpful?

It's Election time.  Time for another terrific "white paper" from a Blue Ribbon panel of experts outlining several recommendations as to how the federal Government (e.g. FDA and others) can speed drug approvals.

A White House White Paper On Drug Approvals // Pharmalot.

Like most such august panels, their recommendations in a robust 110 page report is long on advice and short on specifics. Some of these include:

• More funding for National Center for Advancing Translational Sciences (Francis should be happy)
• Create "broad-based" partnership to improve clinical trials and provide the FDA with more input on developing a pathway for "innovative medicines"
• Have the FDA do more to grant accelerated approval for drugs meeting the standard for addressing an "unmet need" for a serious life threatening condition
• Create a new pathwy for initial approval of drugs aimed at specific subgroups, dubbed Special Medical Use approvals
• Have the FDA run pilot studies to look at "adaptive approval mechanisms".  Congress should pony up $40 million annually to pay for this
• FDA should enact a "range of reforms', including the use of pre-market review leaders to oversee drug applications from investigative stages to final approval
• USDHHS should commission a study of economic incentives to promote innovation, i.e stimulate companies to chase drugs like treatments for Alzheimer's or antibiotics

So all we have to do is follow the advice -- blah blah blah blah -- and figure out how to put it into concrete actions. 

White paper + Blue Ribbon panel = Red Herring.  Will it get the Green light?

Posted by Bruce Lehr Sep 29th 2012.

 

Towards Pharmageddon?

More salvo's in the battle over whether the "innovation crisis" in pharma is due to inherent difficulties and costs in bringing new drugs to market or whether it is caused by pharma companies choosing to pursue more "sure thing" me-too products. 

The pharma shoots-too-low crowd, Donald Light from the University of Medicine of New Jersey and Joel Lexchin from York University in Toronto, opines in the most recent British Medical Journal that the situation has remained the same for 50 years. The incentives for drug development are wrong and have skewed the behaviour of the industry.

They claim more is spent on marketing (25 per cent of revenues) than on discovering new molecules (1.3 per cent). Drug industry claims that the cost of bringing a new drug to market is £1bn and is unsustainable are exaggerated, they claim. Research and development costs did rise substantially between 1995 and 2010 by $34.2bn (£21.9bn), they concluded, but revenues increased six times faster – by $200.4bn.

Towards Pharmageddon? The last (lost) decade .

They add that up to 80 per cent of drug spending is used by the industry on promotion. The authors call for licensing authorities around the world to stop approving new drugs of little therapeutic value. They suggest large cash prizes should be awarded for genuinely new therapeutic agents in lieu of patent protection.

In a second paper, researchers from the London School of Economics in the UK argue that drug manufacturers should be made to demonstrate that their products are superior to existing treatments before being granted a licence, rather than, as now, superior only to a placebo.  In other words, comparative effectiveness should be used to justify adding new drugs to the approved menu. 

With regard to magnitude of costs/profits, I believe the truth lies somewhere in between.  Drugs do cost a lot to discover and bring to market.  But drugmakers do spend on lot on marketing to justify me-too drugs -- and could channel some of this toward developing more novel therapies with better patient benefits. 

I suspect we will see a coorection as more regulatory and 3rd party payer incentives are put in place toward getting novel drugs to treat unserved diseases.  Economics is going to prevent us from continuing down the me-too route as these drugs increasingly will find it toughter to gain approval and to get reimbursement consideration. 

Do we really need 17 beta blockers or just one new Alzheimer's drug that actually works?

Posted by Bruce Lehr Aug 8th 2012.

KV Sinks Slowly into Oblivion

In July 9th post, I commented on KV's decision to sue FDA over the latter's non-enforcement of compounders competing with KV's Makena. I said it was only a matter of time before KV goes out of business.

KV sink .

We're one step closer now as KV filed for bankruptcy protection today. KV said the FDA's lax enforcement has prevented it from realizing its "full value" for Makena -- i.e. they couldn't charge $1500 per dose for a product that previously cost the patient $10.  So now they are left with $728 M in debts and only $237 M in assets.

Boo hoo-hoo.

Posted by Bruce Lehr Aug 6th 2012.

To QbD or not to QbD?

Back on July 17th, I related the results of a survey conducted by BioProcess Technology Consultants on industry attitudes toward QbD and its use (or expected use). The avowed attitudes seemed mixed and this seemed to stem from confusion at both the regulatory and user level.

FDA mixed messages create QbD confusion; consultant.

The link above seems to suggest that the confusion stems from variable responses potential users have experienced with regulatory personnel.  And not surprisingly, this could vary widely depending on the specific regulatory person/source. Many industry respondents felt the level of understanding at the reviewer level was variable and uneven. In other words, like most regulatory topics!

To QbD or not to QbD, that is the question

Whether tis nobler in the mind to suffer

The vagaries and confusion of FDA reviewers

Or to take arms with a massive CMC filing

To supplement QbD to avoid delays. And not to die,

Or lose precious time on the critical path to approval

To follow QbD -- perchance to gain flexibility with FDA

And cut manufacturing and regulatory costs

Or to suffer variable agency understanding and mixed response

That makes a calamity of one's pursuit and creates delay

For who would bear the percieved lack of risk assessment and justifications

But the applicants, and not the agency reviewers

Thus QbD uncertainty does make cowards of us all

 

Posted by Bruce Lehr Jul 26th 2012.

 

 

 

Quality By Design: Just a Buzz Word?

Maybe not a buzz word, but apparently not embraced if the results of this survey are taken at face value. In this bioPULSE survey, 80% of industry respondents said they have used QbD methods at least once, and only 5% say it is worthless, but............only 29% say it is used routinely in their job in biopharmaceutical development.  Only 3% in tech transfer jobs reported using it (though that may reflect low participation by tech transfer functions in this survey) 

Quality By Design: Just a Buzz Word?.

Lack of training may be one reason for low use. Many respondents (20%) believe that use of QbD will delay regulatory filings and 15% actually believe it will delay approvals.  If the FDA isn't an advocate of using QbD who is?  Only 26% of respondents believe use of QbD will expedite approvals.

The survey conductors believe that many respondents don't fully understand what QbD is. Perhaps, even more educational efforts are needed toward what QbD means to biopharm development and how it can help.

Posted by Bruce Lehr Jul 17th 2012.

Another Way to Block Uptake with Biosimilars

You have to admit the innovators are doing a good job for their investors by pursuing every avenue at their disposal to block the quick introduction of biosimilars.  You have arguments for clinical trials, you have arguments against the FDA accessing info in BLAs (see Abbott) and now you have naming conventions.

What’s In A Name? A New Fight Over Biosimilars // Pharmalot.

The PhRMA and BIO trade groups are petitioning the FDA to require each biosimilar to have a unique non-proprietary name, purportedly to aid in pharmacovigilance. These groups say they want to be able to distinguish between the original drug and the biosimilar to insure patient safety.  But they really appear to want to put another hurdle in place that would prevent direct substitution or interchangeability - which of course should slow uptake of the biosimilar.

The GPA disagrees of course.  It wants biosimilars to follow existing drug-naming convention which is used globally. It further notes that the same international non-proprietary name (INN) has been given to biosimilars in other countries and regions. They note that medical knowledge of biologics and safety information is associated with the INN and a unique name woudl cause decoupling -- and ironically potentially hurt patient safety. Plus, they note.  There have not been a raft of safety issues with biosimilars in other geographies outside the US.

This debate boils down to money.  And clearly, from a policy standpoint, if biosimilars are delayed in their introduction in the US, much of the cost savigs that patients (and the healthcare system) might derive will be blunted.  Undoubtedly, successful launch of biosimilars will decrease prices for biologics (by how much?), but it should also increase uptake (volume) of these traditionally very expensive medicines in many parts of the world.  The net effect remains to be seen...........

Posted by Bruce Lehr Jul 13th 2012.

 

As Last Ditch Effort KV Pharma Sues FDA Over Makena

KV Pharma in an apparent act of desperation has filed suit against the FDA to compel the agency to take action against compounders of KV's approved drug, Makena. If you remember, KV raised a howl last year when Makena was approved by FDA and then proceeded to use its market exclusivity as a lever to raise prices on Makena from $10 (for the similar compounded drug) to $1500 per dose.  OUCH!

KV Pharma Sues FDA Over Makena Compounding // Pharmalot.

As a result of the ensuing brouhaha from patients, their advocates and payers, the FDA refused to stop compounders from making their unapproved versions of Makena unless there was a know problem.  This leaves KV with lots of price competition and not much they can do to stop it.  So they sued!  It's only a matter of time before they go out of business though.

I will comment that it is tough for the FDA to justify its current stance relative to safety on this one.  Normally, they would prevent compounders from operating when an approved alternative was available.  Unfortunately, they happened to approve KV who abuse their trust by pricing its product at astronomical levels to try to repay investors quick.  Oops! Must have been absent during Marketing 101 as well as failed to heed government concerns about cost control in health care.   

Live by the gouge, die by the gouge I always say.

Posted by Bruce Lehr Jul 9th 2012.

FDA Approvals: ‘We Are Back On Track’

The FDA patted itself on the back for meeting its PDUFA review cycle targets (>90%) on New Drug Applications (NDAs) and Biologics License Applications (BLAs) for the past two years.

FDA Approvals: ‘We Are Back On Track’ // Pharmalot.

With PDUFA V just waiting to be signed by the President, the agency is supremely confident in its ability to keep the ball rolling.  Through June 18th this year, CDER has approved a higher percentage of NME applications (12/15) - one third of these for rare diseases continuing a strong trend.

The median approval time for NMEs and NBEs reached 9.9 months in 2011 slightly bettering 10 months in 2010 and beating the 13 months seen in 2009 and 2008.  Faster is better.

Posted by Bruce Lehr Jun 28th 2012

India launches 'similar biologics' guidelines

The Indian Government launched its biosimilars guidelines at this year's BIO meetings. The guidelines are aimed at providing a "clear" regulatory pathway for manufacturers of biologic similars and will be applied to new filings now.

India launches 'similar biologics' guidelines at BIO2012.

Manufacturers must prove similarity to a reference product -- either an innovator drug in licensed in India or approved elsewhere.  There is also a requirment for 4 years post-market surveillance on safety data.

The motive for India to promote these guidelines is to encourage more domestic and foreign investment in biosimilars in India with an idea to increase product access and to reduce4 goverment spending on drugs.

Dept of Biotechnology secretary, Maharaj Bhan,  said,  "India needs drugs at reasonable prices so we have to worry about the issue of access so we have to spur innovation and manufacturing in India.  We also need to create an environment where International companies will be interested in using India as a place to manufacture drugs."   The latter comment relates directly to the previous blog post on India's need to raise GMP compliance.

Posted by Bruce Lehr Jun 25th 2012.

Indian Drugmakers Need to Bolster GMP Compliance

Both CARE Research and ICRA (India) credit agencies report that more stringent enforcement of GMPs by the FDA represents a significant risk to the revenue growth of Indian pharma companies -- if they do not raise their game. 

Tighter GMPs a significant risk for Indian drugmakers; CARE.

Companies like Ranbaxy and Aurobindo have had quality and compliance issues that are stunting their current revenue growth.  Closing of manufacturing units, delisting products and other woes have stricken these companies.

Indian companies are taking notice and responding by investing more in quality. This may be a short term increase in their costs and decrease in profits, but in the long run will make it easier for them to compete in more regulated Western markets.

The increase in FDA scrutiny is of course also happening in the US and elsewhere, and the India response of more investment in quality is just what the agency wants to see.  Companies that invest in quality will only become more competitive in the future.

Posted by Bruce Lehr Jun 25th 2012.

Quick Senate Passage Puts House Under Pressure to Act on FDA User Fee Legislation

The Senate passed the FDA Safety and Innovation Act (FDASIA) authorizing the collection of some $6.4 billion in user fees to fund FDA.  The pay day was enough to halt partisan bickering and bring Senate Democrats and Republicans together quickly. The legislation, approved just before Memorial Day, reauthorizes hefty user fees from drug and medical device companies, along with a host of new requirements that will govern FDA operations over the next five years.

PharmTech Talk » House Under Pressure to Act on FDA User Fee Legislation Following Speedy Senate Approval..

The House is now under pressure to pass their version of the Bill.  And, lo and behold, they did so today in overwhelming fashion. The bill includes a section to "fast-track" review of new drugs that potentially treat serious or life-threatening diseases that have no good alternatives.  The FDA will also be empowered to pull drugs from the market that have been fast-tracked but don't live up to after market review requirements. See Fierce Biotech.

The House and Senate versions now need to be reconciled, but the biopharma industry should be happy that their lobbying effort has paid off. The reconciled bill should be ready for a vote by October 1st. Then it will be up to the FDA to act.

Posted by Bruce Lehr May 31st 2012.

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.