Off-Label or Off-Limits?

08/11/2008 12:05 PM |

Very comprehensive feature article in the August issue of Nature Biotechnology of the issue of off-label prescribing and off-label promotion. Jerry Avorn and Steve Nissen perform according to their usual scripts -- but once you get beyond the preening and posturing there's a lot of good information, facts and figures and perspectives from both the US and the EU.

Two issues that are touched on but not really pursued (not surprisingly considering the readership of the journal) are that of (1) the fundamental freedom of free speech and (2) the fact that if drug companies overplay their hands when it comes to off-label promotion there is no shortage of liability lawyers ready to go after them. (Although this article does contain a list of selected healthcare-related fraud cases involving off-label use.)

The complete Nature Biotechnology article can be found here.

Important and timely reading for all of you drugwonks out there as well as for folks like Mr. Waxman.  Read More & Comment...

Commercial Confidentiality: What Goes Around Comes Around

08/08/2008 12:41 PM |

The ample chatter (instigated by the smart and feisty Matt Herper at Forbes) on the subject of the FDA and “classified” information speaks to two larger issues –transparency and honesty.

First let’s talk about transparency.

As John Jenkins (aka, “Dr. Wry”) appropriately pointed out, communications the agency has with sponsors is commercial confidential. That’s the law. The agency’s hands are tied. Period.

Why? Many reasons, but the most important is, well, commercial confidentiality. Trade secrets. Intellectual property. And when it comes to drug development, that’s core business, intelligence other companies would love to see.

But they can’t. And that’s appropriate. It’s at the very heart of a market-based system. The system that has driven unprecedented advances in pharmaceutical development.

The alternative, the so-called “patent-free” idea advocated by Jamie Love and Senator Bernie Sanders (aka, “the Senator from Ben & Jerry’s") was last applied in the former Soviet Union -- and it didn’t work. The Soviet experience was characterized by low levels of monetary compensation and poor innovative performance. The US experience isn’t much better. The federal government paid Robert Goddard (“the father of American rocketry”) $1 million as compensation for his basic liquid rocket patents. A fair price? Not when you consider that during the remaining life of those patents, US expenditures on liquid-propelled rockets amounted to around $10 billion.

Intellectual property rights are the fertile soil that facilitates the tree of pharmaceutical innovation to grow in the first place. To borrow an over-used adjective from the world of global climate change -- we must protect "sustainable" innovation. Jamie Love and Company may very well say, "A world without patents, amen." And they're right, because minus pharmaceutical IPR we'd all better start saying our prayers -- because that's the only way we're going to battle disease and improve the health of our global fraternity. That's a Silent Spring we cannot afford.

The question of honesty, however, is a more difficult issue. “Difficult” because honesty is often in the eyes of the beholder.

If you’re a journalist or pundit, you want as much information as possible. If (post August 11th 2008) the FDA issues a “complete response” letter, you want to see it so you can fully understand and report on the issue. If you’re the sponsor, you don’t want to share it because of both intellectual property considerations – but also because of how the contents of the communication might impact (among other things) how Wall Street views the value of your stock.

Which brings us to the issue of “spin.” Since the sponsor controls what is and is not shared, the sponsor controls what is and is not known. And let’s face it, that can quickly slip/slide into spin. Is not telling the whole truth a lie? It depends on which side of the information divide you reside. At a certain point the sponsor has to make a tough call – is less information better? There’s no hard and fast rule. But one rule is crystal clear – misleading information is just plain wrong.

It’s a fine line.

And speaking of honesty, the news out of Parklawn/White Oak is that 2008 is likely to be one of the slowest years for new drug approvals in the last five years.

Some in Big Pharma (and small pharma and biopharma) blame this on the FDA’s renewed “obsession with safety.” But how can the FDA take action on applications it hasn’t received? The real question is whether or not the FDA has helped or hindered new applications.

Going down this path leads to a discussion of the importance of the Critical Path. And, unfortunately, at present that’s more of a political conversation. Hello Ms. DeLauro. FDA can (indeed must!) be a facilitator – but the main responsibility for 21st century drug development resides with innovator companies.

And hence the importance of intellectual property protection and the need for (yep, you guessed it) commercial confidentiality.

What goes around comes around.  Read More & Comment...

"Going Medieval" on Cancer Patients

08/07/2008 11:50 AM |

Cancer Research UK, the leading voice of cancer patients in the UK, is asking for patient comments on NICE preliminary decision on whether the National Health Service (NHS) should use four new cancer drugs - bevacizumab, sorafenib, sunitinib and temsirolimus - to treat people with kidney cancer that has spread (‘metastatic renal cell carcinoma’).

Why? Because, despite clinical evidence that these drugs can actually help, NICE has decided that they’re too expensive. In essence, NICE doesn’t think that these four drugs are value-for-money for the NHS.

Currently, the only available treatment for metastatic renal cell cancer is immunotherapy. This halts the disease’s progress for just four months on average. But if people are unsuitable for immunotherapy, or it doesn’t work, that’s it. There’s no other treatment option.

So doctors urgently need new treatments for this disease. And the four drugs NICE has rejected have shown considerable promise in clinical trials.

These four drugs are part of a new generation of cancer drugs, developed after years of painstaking research. They target key processes within the body that get hijacked when cancer develops.

In fact, several of the trials were stopped early, to allow those people not receiving the new treatment to have it. Other trials showed that some of these drugs could stop the cancer from growing for several months more than immunotherapy alone. That doesn’t seem much, but when you’re trying to beat cancer, those extra months can mean a lot. And NICE’s assessment contains details of several such trials.

NICE agreed that patients tended to live longer when they were given these drugs. But they felt that the evidence wasn’t sufficiently robust. And when they put the data from the trials into their computer models, they found that the drugs cost a lot (£20,000 - £35,000 per patient per year) compared to the benefit they brought patients - too much for them to recommend that the NHS prescribe these drugs.

Doctors don’t have a lot to offer people with advanced kidney cancer. If these drugs can help them - and the clinical trials show that they do - shouldn’t they be made available?

The full statement from Cancer Research UK can be found here.

And according to an article in today’s Daily Mail, “Thousands of kidney cancer patients have been handed an 'early death sentence' under plans to ban life-extending new drugs.”

British kidney specialist Tim Eisen, professor of medical oncology at the Cambridge Research Institute, said, “Patients here are receiving medieval treatment. Together these drugs are the single greatest advance for kidney cancer patients in the last 20 years, yet I and my colleagues face the prospect of being unable to offer treatment that is absolutely standard in every other western European country.”

According to the Daily Mail, “… kidney specialists believe this proposal is a watershed because it requires them to act unethically, offering a lower standard of care than elsewhere in western Europe and the US. Instead doctors will be forced to offer interferon - a medication of such limited use that it is prescribed for just one in ten patients in some cancer units.”

The full Daily Mail story can be found here.

And here’s what our London correspondent, Antoine Clarke, has to say on the matter:

“It means that a rare disease will be neglected by the NHS, in a brutal reversal of the complaint made about poor countries where diseases are untreatable because of a lack of available drugs. Here the research has been done, clinical efficacy demonstrated by the ‘greedy’ drugmakers, but no one will get the medicines because the UK government has decided not enough people die of the disease: ‘only’ 3,600 people out of the 7,000 who are stricken by metastatic renal cell carcinoma. And if you dare buy it out of your own pocket, you will be denied ANY treatment by the NHS, including emergency care, but still have to pay for it in national insurance taxes. Welcome to universal healthcare! America’s tort lawyers will love it!”

And to add to that point consider this additional fact: Nexavar (denied to NHS patients in England and Wales) has been cleared in China.

Welcome to "universal" healthcare.  Read More & Comment...

Pocket Watch

08/06/2008 01:53 PM |

Just exactly who's in whose pocket these days?

Consider the headline from this week's BioCentury on the new ESA label, "FDA the enforcer."

Authored by the thoughtful and no-nonsense Steve Usdin, the article calls the agency's action, "a dramatic example of how the FDA is willing to use its new powers ..."

And while this isn't a Clark-Kent-Fortress-of Solitude denouement, it is significant -- and as much for the obvious reasons as for some interesting unintended consequences.

The obvious conclusion is that label changes will happen with greater alacrity. An intended consequence of the FDAAA. On this issue, where you stand depends on where you sit. We think it's a good thing because it does away with delaying tactics that served more of a marketing purpose than a public health one. At the end of the day, intelligent people can disagree -- but it's the FDA's job to make the ultimate call.

A less obvious consequence is enhanced transparency in the label discussion process. Usdin writes:

"FDA has been unusually transparent about its interactions with Amgen over ESA labeling in the cancer setting. The agency has released correspondence with the company that describes labeling negotiations, detailed points of disagreement and explained its position in interviews with BioCentury and other news media, and posted redlined copies of the label that highlight changes."

We think that enhanced transparency is a good thing too.

Further, according to Usdin, "The disclosures suggest it would have taken longer to negotiate the changes, and the final language would have been different, in the absence of the new authorities."

Faster? Yes. Different? Maybe. But we now know who wanted what and why. And that's important.

Consider Amgen's statement:

"Amgen has worked closely with the FDA to develop the new label and has no plans to appeal. Although we may have disagreed on specific points, we are pleased that the final label permits physician discretion and recognizes the known benefit:risk profiles of ESAs at this time."

Well, so much for FDA being in the pocket of those it regulates.

We'll give Richard Pazdur the last word (because that's the way he likes it):

"This is a journey and we have not completed it."

  Read More & Comment...

Dry Run of Comparative Effectiveness: No Prostate Screenings for Seniors

08/06/2008 02:45 AM |

  Read More & Comment...

A Cheesehead worth heeding

08/05/2008 10:41 PM |

Congressman Paul Ryan (R,WI) has a lot to say about reforming American healthcare.

(And he's worth listening to.)

See for yourself on our latest vidcast here.  Read More & Comment...

The Cost Containtment Dirty Work Bill

08/04/2008 06:40 PM |

  Read More & Comment...

Vytorin Prevents Dementia?

08/04/2008 02:03 PM |

  Read More & Comment...

Dogmatic Day Afternoon

08/04/2008 11:41 AM |

Much hand wringing and speculation over the FDA’s recent Vanda decision. And the big question being asked is:

Is this the end of the dynamic duo of safety/efficacy and the beginning of a new Holy Trinity that includes comparative effectiveness?

Most reporting went something like this (courtesy of the Washington Post):

“Vanda Pharmaceuticals' stock tumbled 73 percent Monday after federal regulators rejected the Rockville biotech's schizophrenia treatment, saying it was similar to a drug already on the market.” (My italics.)

In fairness, the FDA didn’t actually say anything. This is how Vanda chose to represent the communications it received from the agency.

But rather than looking at this through the lens of comparative effectiveness – perhaps a better way to think about it is via comparative safety. Should inferior performance in some settings (for example if you won't know about it for weeks) be a molecule killer? The debate isn’t only (or primarily) whether it's bad to be worse – but also whether it can be easily monitored.

A tough situation for the FDA and a potential opportunity for those who would exploit this situation to call for a NICE-like system in the U.S. – such as Senators Baucus and Conrad and their “Comparative Effectiveness Research Act of 2008”

But it’s really just the latest example of why dogmatic approaches to drug regulation don’t work -- and why the Critical Path program is so essential.

Nobody said the FDA’s job was an easy one.

  Read More & Comment...

Giving Drug Enforcement a New Meaning and Mission

08/01/2008 12:26 PM |

"The government could start paying impartial experts to visit doctors to talk about the safety, effectiveness and cost of prescription drugs and other treatments.

The idea would be to give presentations along the lines of those given by company drug reps. But the federally funded presentations would provide a counterweight to the industry messages on specific drugs.

A bill to that end is likely to be introduced today in both houses of Congress, according to the Prescription Project, a nonprofit that backs this sort of thing."

Impartial? Hardly. Right off the bat bias is built in...the government subsidized detailing will reduce drug costs..or else? Already a conflict of interest is introduced..the federal drug reps will be beholden to Senators Kohl, Grassley who have one objective...using detaiing to restrict the use of brand drugs.

And who will benefit? I noticed the Prescription Project supports the measure. No coincidence that Jerry Avorn who runs his own academic detailing company and contracts with state Medicaid agencies is an advisor to the Prescription Project, which in turn benefits from suing drug companies. And Avorn using ALLHAT as an example of conflict free prescribing. Problem is, ALLHAT undertreats most African Americans who have stroke.

This is beyond academic medicine rent seeking behavior as the previous post pointed out...this is a power grab that punishes patients. Worse, can you imagine have federal drug reps reporting on the who, what and where or what doctors are doing... Talk about a pharmaceutical police state..Don't like what docs are prescribing, call in DEA 2.0

  Read More & Comment...

EBM? More than "a feeling"

08/01/2008 11:26 AM |

A new study in the Journal of Public Health shows that German physicians have "a feeling" when evidence-based medicie is being used as a cost containment tool rather than a clinical tool to improve patient outcomes. The study also indicates that for certain disease states (i.e., diabetes) EBM may play a greater role than in others (i.e., CNS ).

Here’s the abstract:

Background

In Germany, evidence-based medicine (EBM) is increasingly used to standardize medical decision making and patient treatment. As a consequence this development leads to a shift of influence in health care decision making from physicians to institutional representatives, payers and health care policy makers. However, EBM’s practical role in day-to-day patient care is less clearly defined.

Aim

The aim of this study was to evaluate a potential difference between EBM assessment of therapy benefits and empirical judgment by prescribing physicians and their patients.

Methods

Interviews were conducted with practicing physicians to evaluate reasons for selecting treatments and attitudes towards EBM. The physicians’ view was complemented by a patient telephone survey evaluating treatment satisfaction in selected indications.

Results

The findings of the physician survey suggest that many general practitioners (GPs) as well as specialized practitioners in Germany do not share EBM’s paramount concern with clinical effectiveness, but see it as one aspect in a wider concept that also includes patient-oriented concerns such as patient satisfaction, minimal infliction on patients’ day-to-day life and incompatibility with other needs or treatments. Another important finding is the notion that EBM is misused by health care policy aimed at restricting clinical practice options by focusing entirely on clinical effectiveness without considering the complex physician-patient interaction required for implementing a successful treatment process. Results from the patient survey reveal the patients’ expectation that their individual needs as well as their personal experiences with a given therapy are being considered and that a dialogue between patient and physician shall guide the course of treatment with the aim of finding an optimal balance between EBM-derived therapy effectiveness and individual, patient-based assessment of a particular treatment approach with respect to entirely subjective impressions and judgments.

Discussion

The results of this study demonstrate that practicing physicians consider not only evidence-based information, but also patient-oriented criteria to achieve adequate patient care and compliance. Patients wish to discuss disease and personal therapy experiences with their physician and emphasize their intention to actively participate in the treatment process. Therefore, the concept of patient-based medicine is proposed as an extension of current EBM practice in everyday patient treatment as well as for regulatory decision making regarding health care services.

Here is a link to the article

  Read More & Comment...

Mr. Deats Goes to (London) Town

07/31/2008 10:51 AM |

From a recent press release issued by our regulatory cousins over at the MHRA:

LONDON MAN FINED FOR ILLEGAL INTERNET SALE OF MEDICINES

Mr Hafid Essadki (39) formerly of 341 Boardwalk Place, Trafalgar Way, London, E14 5SQ was fined £1,000 and ordered to pay £1,500 costs at Snaresbrook Crown Court for the illegal online sale and supply of Viagra and Cialis. The sentencing followed a prosecution by the Medicines and Healthcare products Regulatory Agency (MHRA).

The MHRA started investigating Mr Essadki in January 2006 after receiving information from Pfizer that customers had complained about two websites advertising Viagra and Cialis for sale. On March 2006 MHRA enforcement officers, accompanied by representatives from Pfizer and Eli Lilly together with the Metropolitan Police, went to Mr Essadki’s home address and found a quantity of Viagra and Cialis tablets. These were seized along with computers, mobile phones and a laptop.

Mick Deats, Group Manager of Enforcement at the MHRA said, “The MHRA will not hesitate to take action against those who undermine public health. There is considerable risk to the public from obtaining medicines through unregulated websites. A medicine bought in this way has no guarantee of safety, quality or effectiveness. It could be counterfeit. It may not contain the right amount of medicine. At worst it may cause a severe side effect."

Jolly good work, right?  Well let’s look at this operation a little more closely.

First – the operation began in March 2006 – over two years ago. 

Second – the penalty is a total of £2,500.  And that includes “costs.”  Could the entire 15+ month-long investigation have cost Her Majesty only £1,500?  Such a deal!

Third – no jail time.  What kind of message does this send?

Answer:  It sends a very strong message which goes as follows, “Selling counterfeit drugs is a low risk/high reward business.”

Is that really the message we want to send?  Obviously not, since the MHRA’s Mr. Deats appropriately points out the real dangers of unsafe and unregulated products being sold over the Internet.

  Read More & Comment...

Not Quite Human, So Let Her Die

07/30/2008 05:38 PM |

  Read More & Comment...

Grassley and Dingell Introduce Anarchy

07/30/2008 04:36 PM |

  Read More & Comment...

Nasty Rhetoric and Sloppy Reporting

07/30/2008 04:17 PM |

According to the Wall Street Journal, “Powerful members of Congress want to remake the Food and Drug Administration by giving it broad powers to levy fines, order drug recalls and restrict drug-industry advertising. Leading the drive are Rep. John Dingell (D., Mich.) and his longtime friend in Congress, Sen. Chuck Grassley (R., Iowa).”

“The lawmakers say an FDA restructuring should build a much taller wall between the agency and the industry it regulates. The FDA would gain authority to recall drugs, which it can't do today, and to impose significant fines on drug companies for safety violations. The lawmakers also want the FDA to inspect generic-drug makers before approving a new product. Perhaps most importantly, they want the next president to appoint a tough FDA commissioner completely independent from the industry.”

Can anyone out there think of even one drug that the FDA wanted recalled that was not “voluntarily” recalled?

No – I didn’t think so.

(Also, isn't the FDA already an entirely independent government agency?)

FDA officials "are too cozy with the companies they regulate," Mr. Grassley said, adding that new leadership must "fix the culture."

What does “too cozy” mean? Really, what does it mean?

Senator Grassley believes the FDA Office of New Drugs, which he said has been compromised by its relations with industry lobbyists, among them former top FDA officials.”

And what does that mean? Any evidence to back up such blowhard accusations?

Too boot, here’s some really shoddy reporting by the Journal’s Alicia Mundy,

“Some current and former FDA safety reviewers have opened a whistleblower Web site to air their concerns that FDA leaders are pushing them to approve some drugs”

She is referring to www.thoreau-fda.com/index.php.

This site defines itself as “a website launched and operated by current and former US Food and Drug Administration staff who believe public health is being put at unnecessary risk. These concerned civil servants and ex-civil servants have either experienced or are aware of wrongful directives by US FDA upper management – directives that put public health at avoidable risk.”

That’s nice. But when you check out to whom the site is registered, it turns out to be Jim Dickinson of FDAWeb.com – long-time FDA antagonist -- and no former FDA employee.

Oops.

But who needs facts when you have red-hot rhetoric and a gullible reporter who's willing to take a leak anywhere?

  Read More & Comment...

Ringing the Federal Register

07/30/2008 01:16 PM |

Ya gotta love gov-speak. Bureaucrat-ese has its own unique and lovely lilt.

Consider the Federal Register notice announcing the August 14/15 meeting of the FDA's Risk Communications advisory committee:

"The committee will meet for presentations and discussion of the scientific basis for translating principles of risk communication into practice in situations of emerging and uncertain risk."

And this is the committee that's mandated to create clear ways to discuss risk communications (or as it's cool to say in DC "Plain English").

I think it was Albert Einstein who said something along the lines of, "If you can't explain a complicated topic in a simple way -- then you don't really understand it."  Read More & Comment...

Next Time Just Let Her Die and Don't Send A Letter

07/30/2008 02:38 AM |

  Read More & Comment...

A Gaggle of Wonks. Another Step Towards Patient-Centric Care

07/29/2008 11:44 AM |

What happens when you put Mark McClellan (Chairman of the Reagan/Udall Foundation), Michael Weber (Chairman of the Center for Medicine in the Public Interest), Ralph Snyderman (of Duke reknown), Tevi Troy (Deputy Secretary of Health and Human Services), Jeff Cossman (President of the Critical Path Institute) and other leaders in progressive healthcare policy together in a room?

What happens is the meeting of the Patient-Centric Health Leadership Forum.

This new report shares the cutting edge thinking of the folks mentioned above along with other similarly talented leaders. And the key phrase is patient-centric.

The report can be found at the top of this page or here, the first item under "reports."

A worthwhile and important read.  Read More & Comment...

The Last Lecture and Comparative Effectiveness

07/29/2008 06:29 AM |

  Read More & Comment...

Maggie Mahar Makes It Up As She Goes Along

07/29/2008 06:20 AM |

  Read More & Comment...