Latest Drugwonks' Blog
Strombeek-Bever, Belgium, November 30, 2010 – Reliable Cancer Therapies (RCT) is a Swiss non-profit organization that provides research-based information on cancer therapies and selectively funds the development of promising therapies.
RCT today launched a global online database (www.reliablecancertherapies.com) that provides scientifically checked information on cancer treatments. With this online database, RCT hopes to broaden the reliable treatment options for cancer for patients.
“Our online database provides patients and medical professionals with free and qualitative information on cancer treatments, guidelines and clinical trials s” states Lydie Meheus, PhD, executive director of RCT: “This website is an answer to the growing need for a comprehensive repository of reliable, trustworthy information on cancer treatments and investigational drugs. We give specific, verified information on as well conventional as non-conventional cancer therapies, and we want to focus on the resulting patient outcomes. We hope that this database will help people find their way through overwhelming, confusing and way too often unverified information. However, it should be emphasized that RCT does not provide medical advice and that our website does not replace a medical consultation.”
Executives at 50 medical companies think FDA has improved it relationships with them, but say the agency is not keeping up with advances in technology, the survey by PricewaterhouseCoopers LLP and Biocom, an association of 550 California life sciences companies, found.
PwC and Biocom interviewed 1,000 adults and executives at 50 drug, device and diagnostics companies of varying sizes for the report, available at www.pwc.com/us/fdasurvey.
Among the companies, 80 percent said FDA is providing better guidance about its expectations but just 38 percent said the overall working relationship with FDA has improved over the past two years.
Only 8 percent of drug and device makers said FDA is doing enough to advance personalized medicine.
While 93 percent of U.S. consumers are confident about the safety and effectiveness of drugs and medical devices approved by the FDA, 56 percent said they would be willing to use drugs and devices approved outside the United States.
More than 50 percent of consumers said they think FDA does a good job, but 36 percent said they have lost confidence in the FDA over the past two years as a result of high profile safety concerns and product recalls.
"Consumers want safer, more effective drugs and devices and access to the latest medical innovation. Industry wants fast and efficient product approvals," PWC's Michael Mentesana said in a statement.
"But the promise of faster product development has yet to be realized and the quality and productivity of the FDA-industry relationship would be better on both sides if there was more collaboration and clarity around expectations."
One of the most misunderstood areas is the Prescription Drug User Fee Act or PDUFA, which requires companies that make drugs pay up to $1.25 million per drug application.
FDA says this cash has helped speed up drug approvals but the survey found that 46 percent of company executives do not believe approvals are any faster.
And 70 percent of consumers disapprove of having companies help pay for FDA's work. Only 36 percent knew that industry helps pay for FDA and just 68 percent fully understood the agency is paid for by taxes.
“Defensive REMS” May Be Needed To Appease Advisory Committees
Sponsors facing an FDA advisory committee should be prepared to discuss Risk Evaluation and Mitigation Strategies, even if FDA tells a company that a REMS need only have minimal elements or is not necessary, to avoid a negative vote, industry experts say.
Egrifta Approval Suggests Evolution In FDA Thinking On Role Of REMS
FDA’s decision not to require a Risk Evaluation and Mitigation Strategy for Theratechnologies’ HIV lipodystrophy drug Egrifta (tesamorelin) suggests the agency is becoming more circumspect in how it applies its drug safety powers under the FDA Amendments Act more than two-and-a-half years after they took effect.
Wither predictability?
Maybe PDUFA should stand for the Predictability Deposit User Fee Act.
As negotiations for PDUFA V get serious, there seems to be a widening gap between what FDA wants (more resources) and what industry wants (more predictability).
Of course there are many, many other things – all of them important (and the devil is certainly in the details), but it’s the conjoined issues of resources and predictability that is driving the debate.
PDUFA V is turning into a battle over First Principles. And it’s about time.
Industry has (IMHO) turned the corner relative to a well-funded FDA. Regardless of whether or not some members of the 112th Congress believe that the agency should receive less funding, a well-funded FDA is in the best interest of the both the public health and a robust biopharmaceutical industry.
A properly funded FDA will be able to do more things with greater ability and alacrity. And this will (among other things) help to further bolster the agency’s reputation with the public, thought leaders and elected officials. And, as research has demonstrated, a well-regarded FDA leads to greater trust in the safety and efficacy of the products it regulates. A properly funded FDA will be able to more aggressively pursue the 21st century regulatory science so essential for 21st century drug development. The Critical Path doesn’t come cheap – but it’s worth it.
Better, more current and predictable scientific research and standards must be developed and devoted to streamlining the critical path. Investment in basic research is not enough. Specifically new development tools are needed to improve the predictability, speed and quality of the drug development cycle and, on the flip side of that coin, lower the cost of research by helping industry identify product failures earlier in the clinical trials process.
25 years ago, the success/approval rate for a new drug was about 14%. Today, a new medicinal compound entering Phase 1 testing—often after more than a decade of preclinical screening and evaluation—is estimated to have only an 8% chance of reaching the market. For very innovative and unproven technologies, the probability of an individual product’s success is even lower. We have got to work together to turn that around.
When Thomas Edison was asked why he was so successful he responded, “Because I fail so much faster than everyone else.” Consider the implications if FDA could help companies to fail faster. Using the lower end of the Tufts drug development number ($802 million):
* A 10% improvement in predicting failure before clinical trials could save $100 million in development costs.
* Shifting 5% of clinical failures from Phase 3 to Phase 1 reduces out of pocket costs by $15-$20 million.
* Shifting of failures from Phase 2 to Phase 1 would reduce out of pocket costs by $12-$21 million.
What the FDA can do with more money is a long list. But nothing's going to happen unless recognition on the part of the agency that times are changing.
Industry cannot accept, as Abba Eban famously said, “We give and they take,’ as a negotiating strategy.
There are different dimensions when it comes to “predictability.” Of course there’s the “PDUFA Date” deliverable – the driving force behind the user-fee concept in the first place. That’s broken. Then there’s the predictable and reportable allocation of funds. That’s absent. There’s a lack of consistency in agency decisions within the same therapeutic category. A poverty of best science practices that can be used to both develop and review drugs. A frightening lag relative to best practices in qualified methodologies. And a dearth of common data elements and standards.
That’s for starters.
Other items include biomarkers, REMS, a less byzantine diagnostics development and approval pathway, social media guidance, DTC and DDMAC issues, a non-BLA FOB pathway, generic bioequivalence, clinical trial design, development and use of non-US data, safe use, early safety signal communications and building an effective and proactive safety surveillance system, pediatric exclusivity, orphan disease drug development, paperless labeling, stakeholder engagement, EU harmonization, enhanced transparency and communications, etc.
It’s in this context that you have to consider the FDA’s proposed four-stage review cycle that would allow the agency to suspend the review clock in mid-review to address application problems and amendments (the infamous “time out” provision) and, if you’re still counting, the issue of “non-binding advice.”
It would be useful for the 112th Congress to clarify some of the limitations on FDA’s authority to command the payment of user fees. For example, CDER has interpreted the system to allow requests for user fees according to the number of data sets rather than applications/supplements, contrary to its own guidance.
There are some rogue elements within industry that are ready to at least (or at last) discuss the “nuclear option” – no PDUFA fees at all. Why pay for the privilege of regulatory ambiguity? Why reward a lack of consistency? After all, they say, how much worse could it get? Well – the answer is “a lot worse.” But the fact that this is even being discussed points to the need to return to First Principles. And the very first principle of PDUFA is predictability.
Industry seeks clarity. They want bright lines. They want to know the rules. They want predictability. This may sound simple and fair, but inside the FDA it has proven to be a fractious bureaucratic kulturkampf. “Change is not required,” as management guru W. Edwards Deming once said. “Survival is not mandatory.” And that doesn’t mean change for show, for politics – it means thoughtful, timely, strategic change that enhances the public health. And that kind of change requires not walking on egg shells – but breaking them.
Without a PDUFA “Predictability Deposit,” there’s not going to be much public health return. It’s a long road to September. Predictability is power in pursuit of the public health
Terry Vermillion, head of the FDA’s Office of Criminal Investigations (OCI) is “retiring” after the latest round of criticism directed at his department by congressional investigators.
The truth is that he’s taking a bullet for the team. And the public is not better off for it.
"I hope that with new leadership, this office will contribute more to the FDA's overall mission of protecting public safety," said Senator Charles Grassley (R, IA) in a statement Tuesday evening.
That’s a shameful comment.
Senator Grassley previously stated that the priorities of the criminal investigations unit shouldn’t be drug abuse or counterfeiting cases, but rather on misconduct by large companies.
When politics trumps public health, we are going in the wrong direction. Terry is an unfortunate sacrifice to a political agenda.
OCI pursues cases that present a danger to the public health and have an FDA nexus. The diverse background of OCI agents gives the FDA the ability to aggressively address issues ranging from mail and financial fraud, to smuggling, forfeiture, and counterfeiting. OCI agents do this with talent, devotion, skill – and success.
OCI is a career destination of choice for the cream of the crop of Federal law enforcement agencies such as the FBI and the Secret Service – and they come to the FDA with an average of 12.5 years of Federal law enforcement investigatory experience. That’s why Terry Vermillion, the director of OCI and a former Secret Service agent himself, refers to his agents as “a taskforce of talent.” And they play a crucial role in protecting the safety of America’s prescription medicines and food supply.
In a typical year, FDA's Special Agents will investigate about 1,000 criminal cases resulting in the arrests of hundreds of suspected violators of public health laws.
On average, 200 criminal suspects are convicted each year as the result of OCI investigations. From 1993 to present, OCI has made 4,593 arrests that resulted in 3,546 convictions and more than $5.7 billion in fines and restitutions.
Consider the words of Teddy Roosevelt:
“It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood, who strives valiantly; who errs and comes short again and again; because there is not effort without error and shortcomings; but who does actually strive to do the deed; who knows the great enthusiasm, the great devotion, who spends himself in a worthy cause, who at the best knows in the end the triumph of high achievement and who at the worst, if he fails, at least he fails while daring greatly. So that his place shall never be with those cold and timid souls who know neither victory nor defeat.”
Stand tall Terry.
A three-judge panel of the U.S. Court of Appeals for the 2nd Circuit said Vermont’s law that restricts companies' use of information about the drugs doctors prescribe is unconstitutional on free speech grounds.
In a 2-1 ruling, the New York appeals court said the law doesn't achieve what Vermont wants to achieve and that a more limited restriction would be better.
"The state has not demonstrated that its interests in protecting public health and containing health care costs could not be as well served by a more limited restriction on speech," the majority opinion said.
But there’s more to this issue than Free Speech. There’s also a crucial safety component.
When FDA-directed safety warnings are issued, they're communicated via "Dear Doctor" letters to the physicians who have prescribed the drug in question. This is accomplished quickly and precisely because the industry has access to accurate data. And when safety issues arise, that same data helps define the scope of the problem. Because of this data, for example, the FDA can determine how many patients were taking a specific drug and for how long each patient had been taking it.
Further, FDA-mandated risk management plans - developed for physicians who prescribe higher-risk therapies - are physician-targeted through the use of prescribing data. These records are also an important tool in clinical trial recruitment, allowing doctors who are treating targeted patient populations to focus their efforts.
According to the American Medical Association (AMA), "Restrictions on the use of prescription information will disrupt health care research and its corresponding benefits for patients, government agencies, health planners, academicians, businesses and others."
Relative to physician concern that their prescribing data will be used for aggressive marketing campaigns, the AMA has a web-based program specifically designed to address physician concern over inappropriate use of prescribing information. Known as the Prescribing Data Restriction Program (PDRP), the program also ensures that prescribing-data remains available for all the reasons previously mentioned. In fact, all companies that purchase data from the AMA will be contractually required to adhere to the PDRP program.
The safeguards offered by the AMA's program offer a much more reasonable and targeted approach to protecting both patients and physicians from unwanted disclosures. And those safeguards come with far fewer unintended consequences than any ill-considered state legislation.
Senator John Barrasso, M.D.: “I am thankful to have 13 new Republicans in the Senate to help repeal and replace Obamacare.”
Nancy-Ann DeParle: “I’m thankful for my wonderful family, having more time to see them and the chance to implement a law that is delivering real relief to millions of Americans.”
From the pages of Medical Marketing & Media:
Patients taking a medication and looking online for health information tend to avoid pharmaceutical company sites, according to an online survey conducted by Accenture.
Just over two-thirds of surveyed respondents said they go online for health information, according to the data. Of that group, nearly half (48%) said they use medical websites like WebMD most often, and just 6% said they use social media sites like Facebook or Twitter most often for health information. Eleven percent of the respondents said they use a pharma company website most often – the same percentage that reported using an online community, like a disease-specific patient site, most often.
Tom Schwenger, global managing director for Accenture's Life Sciences sales and marketing practice, said he “acknowledges the regulatory hurdles that exist in two-way dialogue” between pharmaceutical companies and patients, but that “the gap between the hurdles and what we're seeing represents a large opportunity” for pharma marketers. “What's ironic is that industry cost pressures are greater than ever before, so it makes sense to reevaluate digital and online strategies” with respect to patient communications, said Schwenger.
The survey also found that 69% of respondents “expect pharmaceutical companies to provide information about an illness or condition,” and only 28% of respondents said they are more likely to ask their doctor about a drug after seeing an advertisement. However, 46% of respondents said drug ads increased their awareness of symptoms and possible treatments. Ten percent of respondents said their drug choice had been influenced by coupons, and 47% said it had not, but could be in the future, according to survey data.
The survey's sample was 852 adults in the US, and was conducted between August 30 and September 3, 2010.
At a recent meeting of the Generic Pharmaceutical Association, CDER Director Janet Woodcock said that the FDA is discussing tightening the equivalence limits of generic medicines "so there is less variability.”
In April, the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, voted 11-2 that the agency’s equivalence requirements aren’t’ sufficient for certain medicines. They didn’t offer an alternative, and suggested the FDA list “critical dose drugs or drugs where a small difference in concentration can change patients’ reaction, that may need new standards.
The Pharmaceutical Science and Clinical Pharmacology Advisory Committee voted unanimously, with one abstention, that critical dose drugs do constitute a distinct group and voted unanimously that FDA should develop a formal list of those drugs - although the terminology of "narrow therapeutic index" may be more appropriate. And in an 11-2 vote, the committee concluded that current bioequivalence standards are not sufficient for drugs in the narrow therapeutic index group.
Critical dose drugs have a narrow therapeutic index, meaning that "small changes in blood concentration have the potential to result in serious therapeutic failures and/or serious adverse drug reactions." FDA is consulting the committee on the need to establish separate bioequivalence criteria for these drugs given continuing debate about whether critical-dose drugs require special consideration, the agency explained.
(Currently, the "sameness" of a brand product and a generic version is evaluated based on two-treatment crossover study to prove bioequivalence, the aim being to show that the 90 percent confidence intervals of the geometric mean test/reference ratios for both maximum plasma concentration and the area under the plasma concentration-time curve fall within a range of 80 percent to 125 percent.)
Last month the FDA responded to a request from New Jersey State Senator Joseph Vitale concerning pending New Jersey state legislation that, if enacted, would require pharmacists to dispense epilepsy drugs from the same manufacturer as previously dispensed for certain patients, unless otherwise prescribed.
In its response to Senator Vitale, FDA comments that “[t]o date, we have not seen any scientific evidence that demonstrates a problem with therapeutic equivalence for this group of products or any other class of generic drug products. Those who are questioning the quality of generic epilepsy products have produced only anecdotal evidence.”
And, further:
“[W]e believe that the concerns of some of those raising questions (in particular, physician groups) cannot be dismissed lightly. Because of FDA’s respect for these groups and the concern that patients may lose confidence in their prescribed medications, we have sought to conduct further study. Our decision to further study this issue does not stem from doubt within the agency about data we currently have on approved generic epilepsy products. Rather, it is based on a desire to obtain further independent scientific evidence that might address these concerns.”
Condescending? I suppose it depends how you choose to read it. Does the agency really mean to dismiss the concerns of practicing physicians who see these problems first hand? Maybe PDUFA V funds should be earmarked for FDA staff to attend more neurology conferences to hear about the "scientific evidence” first hand.
More peculiar still is that such statements seem at total counterpoint to the comments of Dr. Woodcock and the unambiguous votes of the advisory committee.
This strikes a very personal note for me. One of my sons has Juvenile Myoclonic Epilepsy. His condition is wonderfully controlled via his meds – and I’d like it to stay that way.
"This drug doesn't work. Period. It just doesn't work," said Steven Nissen, head of cardiology at the Cleveland Clinic. U.S. Rep. Bart Stupak, a Michigan Democrat helping to lead a congressional investigation of the study, said, "It is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data." Investors voted with their feet, pushing Schering-Plough (nyse: SGP - news - people ) shares down 8% and Merck (nyse: MRK - news - people ) shares off 1%. "
www.forbes.com/2008/01/14/enhance-merck-schering-biz-healthcare-cx_mh_0115bizenhance.html
Oops that was 2008, when Nissen was leading the charge and making charges that a study about Vytorin was flawed and that the two companies were engaged in -- what else -- a coverup of the shoddy research and its conclusions. At least that was the narrative shaping the stories from Matt Herper, Steve Nissen's Boswell... Here is a laundry list of Matt's articles regarding the 'coverup' of the Vytorin debacle.
| Sept. 3, 2008: Top Statistician Says Vytorin Cancer Risk 'Not Ruled Out' |
| May 19, 2008: Should Schering-Plough's Chief Give Back His Bonus? |
| April 15, 2008: Vytorin's Man In The Middle |
| March 30, 2008: Vytorin Backlash |
| March 25, 2008: More Questions About Vytorin Panel |
| March 21, 2008: Vytorin On Trial |
| Jan. 11, 2008: Inside Schering And Merck's Secret Panel |
| Nov. 19, 2007: The Vytorin Question |
Herper went so far as to misconstrue Eric Topol's measured response to the study: One person who won't be convinced by ENHANCE: Eric Topol, the noted chief of translational medicine at Scripps Health in La Jolla, Calif. He still wants to see clear data on how Zetia affects heart attacks, strokes and deaths, and doesn't understand why it took so long to embark on a big study to prove it. Doctors have been "hanging in suspense for years, unnecessarily," Topol says. "It's still conceivable there would be improvement in outcomes. Until we have that data, the jury is out."
Dr. Topol emphasized the need for a larger study with outcomes data. The recent study about Vytorin is consistent with Topol's broader work on genomics and heart disease:
That driving down LDL alone is not sufficient for reducing the risk of stroke or invasive procedures in both primary care and high-risk populations. Further, the mechanism by which Vytorin did achieve a reduction in plaque build up and stroke are still not completely clear. LDL levels fell but it will be interesting to see how that decline is biologically linked with the clinical outcomes observed. Finally, linking hard clinical endpoints to reductions in plaque remains an exciting and interesting area of research in cardiology when paired with genomic research that can tailor treatments to populations with different forms of the disease.
And what did Nissen say about the SHARP results? Matt Herper channel's him:
"Without a group of patients who received just Zocor, it’s impossible to determine whether Vytorin worked any better than Zocor would have alone, says Steven Nissen of the Cleveland Clinic, another critic of the drug. "blogs.forbes.com/matthewherper/2010/11/20/finally-a-win-for-vytorin/
But let's repeart what Peter Kim said:" the investigational use of the drug significantly reduced the risk of these events in a spectrum of patients with chronic kidney disease -- and this was the first demonstration that an LDL-cholesterol lowering medicine could do so."
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
