FDA and Off-Label: A Very Betamax Approach

01/23/2017 11:50 AM | Peter Pitts

From Inside Health Policy ...

Attorney: FDA's Firm Line On Off-Label May Be Bid To Avoid Judicial Review

A controversial FDA memo released Wednesday (Jan. 18) defending the agency's oversight of off-label communication and raising concerns over the public health impact of such communication could be used as a tactic to stall potential future litigation against the agency, according to one key attorney. However, FDA argues the memo was written instead to follow up on, and further discussions, that occurred during a November 2015 public meeting on off-label communication.

The memo, issued in the final days of the Obama administration, reasserts FDA's stance against off-label communication, which has been opposed by industry and First Amendment advocates for years and which is expected to be revisited by the incoming administration.

The release of Wednesday's memo, “Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products,” prompted strong reaction from both industry and patient advocates, reminiscent of the debate during the public meeting held late last year.

Off-label communication advocate, Peter Pitts, president of the Center for Medicine in the Public Interest and former FDA associate commissioner, had harsh words for FDA.

“I wonder if this memo was written on an electric typewriter -- since it seems to represent thinking from the 1980s,” Pitts wrote to Inside Health Policy.

However, public health advocate, Diana Zuckerman, president of the National Center for Health Research, called the memo “a great summary of the issues,” which she argued “clearly explains how destructive off-label communication is to patients and to the health of all Americans.”

FDA cited discussions of First Amendment issues during its public meeting as an impetus for releasing Wednesday's memo.

“At our November 9-10, 2016, public meeting, a number of speakers addressed First Amendment considerations...To further this discussion, this section describes the different ways that courts and commentators have addressed the intersection of the FDA Authorities and the First Amendment,” FDA wrote.

However, others argued FDA had underlying motives for publishing the controversial memo.

Coleen Klasmeier, partner at Sidley Austin, told IHP that the memo was likely a litigation tactic, by which FDA could give the appearance of ongoing activity that would make it appear premature for a court to weigh in, possibly avoiding more blows against FDA's regulation of off-label communication.

FDA was recently dealt key blows over the constitutionality of its enforcement on off-label communication. Jurisprudence has shifted so significantly in recent years that one health law expert recently cautioned that restrictions on direct-to-consumer marketing of off-label uses could be loosened should the current First Amendment jurisprudence around commercial speech be taken to its logical end.

Pitts argued that the Obama administration may have put pressure on FDA to take a final stance on the issue. “What's most surprising about this memo is that it is so contrary to the spirit of what Drs. Califf and Woodcock have been saying over the past few months. My only conclusion is that the Obama HHS leadership gave the agency explicit direction as to tone, context and conclusions,” Pitts told IHP.

Lisa Dwyer, partner at King & Spalding and former senior policy advisor at FDA, also saw FDA's recent dump of documents on off label as the Obama administration’s last stand, but said the agency's arguments were not surprising.

“The series of documents that FDA issued this week related to the provision of off-label information to health care practitioners and the provision of healthcare economic information to payors are effectively the Obama’s Administration last statements defending their positions on those issues. The documents are helpful to the extent that they green light the sharing of certain information with health care practitioners and payors, which may have resided in gray areas previously. But, they do not articulate major policy shifts,” Dwyer wrote.

The agency stuck to its guns in laying out what it believes are the legal precedents protecting its current enforcement regime. Namely, FDA cites U.S. Supreme Court case Wisconsin v. Mitchell and district court case Whitaker v. Thompson to argue that FDA can use speech to establish a crime.

“Courts have held that the government’s reliance on speech as evidence of intended use under the FD&C Act does not infringe the right of free speech under the First Amendment based on Supreme Court precedent establishing that '[t]he First Amendment . . . does not prohibit the evidentiary use of speech to establish the elements of a crime or to prove motive or intent'...Under these rulings, the FDA Authorities do not directly prohibit or restrict speech by a firm about unapproved new uses of the firm’s medical products. Instead, the FDA Authorities regulate the introduction of unapproved, adulterated, or misbranded medical products into interstate commerce and the speech of firms may be relevant to establishing an element of a violation of those provisions,” the memo states.

The government had failed to convince a court of a similar argument in the high-profile case United States v. Caronia -- namely that the defendant's speech was used as evidence of intent, not that the defendant was being prosecuted for his speech. The court disagreed, vacating the conviction of the defendant and dealing a key blow to FDA's regulation of off-label speech.

“[T]he government's assertion now that it used Caronia's efforts to promote Xyrem for off-label use only as evidence of intent is simply not true. Even if the government could have used Caronia's speech as evidence of intent, the district court record clearly shows that the government did not so limit its use of that evidence. See Mitchell, 508 U.S. At 489-90,” the Caronia decision states.

Klasmeier similarly argued that Wisconsin v. Mitchell does not save FDA from their off-label woes. That case dealt with the use of speech as evidence of a crime, which does not offend the First Amendment, however, using speech as the source of illegality, rather than an element of the crime, does offend the First Amendment, explained Klasmeier.

FDA also took on the Caronia decision Wednesday -- namely the court's interpretation of a the key commercial speech case, Central Hudson Gas & Electric Corp. v. Public Service Commission, which laid out a four-part test for determining whether restrictions on commercial speech violate the First Amendment.

“There are several points worth noting regarding the Central Hudson evaluation conducted by the Second Circuit panel majority in United States v. Caronia. First, the panel majority limited its analysis to addressing the constitutionality of a specific ‘construction of the FDCA’s misbranding provisions to prohibit and criminalize off-label promotion’… rather than evaluating FDA’s implementation approach. Second, the panel majority did not consider multiple components of public health interests advanced by the FDA Authorities and FDA’s implementation approach,” the memo states.

FDA also argues that if the court had the opportunity to review a recently published study on adverse events tied to unapproved use, it may have come to a different ruling.

However, Klasmeier points out that the agency already brought up its issues with the Central Hudson interpretation in Caronia during another high-profile off-label case, Amarin v. FDA, and the judge in that case had dinged FDA for not appealing Caronia when it had a chance.

The agency also took on Wednesday what it saw as the public health risks associated with off-label use. First, FDA argued that unapproved uses increase risks to patients and lack evidence of effectiveness.

“More recent studies have similarly found that the majority of unapproved uses for which drugs are prescribed lack adequate evidence of effectiveness, and that the risk of adverse events is higher for unapproved versus approved uses, and even higher when the unapproved use is not supported by reliable scientific data,” the memo states.

FDA also disputed arguments that health care professionals can adequately discern an appropriate level of substantiation for off-label claims.

“Research has also shown that marketing of drugs toward health care providers drives prescribing practices, including prescribing for unapproved uses, and that commonly used marketing techniques can influence prescribing decisions in a manner that is not in the patient’s best interest. Studies have found that health care providers overestimate their knowledge of what uses are FDA-approved for drugs and assume that many unapproved uses are supported by sound scientific evidence when they are supported by uncertain or no evidence,” FDA continued.

Next, the agency expressed concern over protection of patients subject to off-label uses, highlighting comments made during the agency’s November public meeting.

“The same protections are not routinely provided when approved/cleared medical products are prescribed to patients for unapproved uses as part of their medical care. Several presenters at the November 9-10, 2016 public hearing who experienced adverse events associated with the unapproved use of approved or cleared medical products noted that they did not know, prior to using the product, that the use for which they were prescribed the product was unapproved,” the memo states.

Unapproved uses could also discourage clinical trial participation and programs, such as the Orphan Drug Designation and priority review programs, FDA argued.

“With regard to maintaining incentives for clinical trial participation, firms’ actions to promote widespread use of approved/cleared medical products for unapproved uses may undermine the clinical trial process, and thus ultimately impede the development of robust and reliable scientific data to better support medical decision-making,” FDA writes.

Zuckerman highlighted FDA's explanation of the potential research disincentives as a strength of the new memo.

“It makes it clear that off label communication takes away a company’s incentive to do needed research and therefore undermines the very fabric of the FDA as an agency designed to protect patients and consumers from unsafe and ineffective medical products,” Zuckerman wrote to IHP. “[I]t is a huge disincentive for companies -- why do research to see if the 'off label' use has benefits that outweigh the risks if the product can be promoted and widely sold without approval for that use? It’s not a coincidence that studies have found that off label uses are often ineffective and cause many complications,” Zuckerman continued.

However, Pitts slammed FDA for its critical view of the impact of off-label communication.

“The memo is written to show that allowing the truthful, accurate, and non-misleading of information will cause the earth to stop spinning on its access, research into new indications to cease, malpractice cases to explode, and misleading and misbranded communications to proliferate,” Pitts wrote.

FDA, however, also outlines how it believes off-label communication could advance public health, including supporting informed decision making for patient treatments and furthering scientific research, provided the information is scientifically valid and presented in a truthful, complete, balanced, transparent and objective fashion.

Some question whether FDA's newly hardened stance will survive a change of administrations.

“The FDA’s Memo on the First Amendment lays out the best case possible defending the current FDA policies on off-label. Indeed, it appears to be a statement that current policy is constitutional and FDA is prepared to continue to defend it in court. So far, that hasn’t worked. Meanwhile, we will have a new President and a new administration starting Friday. This is definitely not the last chapter in this novel,” John Kamp, ‎executive director at Coalition for Healthcare Communication, wrote to IHP.

Pitts also told IHP that the memo runs contrary to the philosophy of the incoming administration and that he is curious to see what impacts a change in leadership will have. 
   Read More & Comment...

Bad Ad Program a Waste of FDA Time and Resources

01/23/2017 11:42 AM | Peter Pitts

From the pages of Inside Health Policy ...

Some Health Policy Experts Question FDA's New Deceptive Ad Studies

A former FDA associate commissioner and a free-speech advocate question two proposed agency studies to determine the extent to which health care professionals (HCPs) and consumers can detect and report deceptive prescription drug promotion. The experts also raise concerns about the agency's plan to create a program for consumers to directly report deceptive advertising to the agency. However, another former FDA official saw the announcement as par for the course for the agency's drug promotion office's growing research program.

FDA announced Jan. 4 its intention to conduct two studies to determine the ability of HCPs and consumers to identify deceptive advertising.

"Prescription drug promotion sometimes includes false or misleading (i.e., deceptive) claims, images, or other presentations; for instance, representations that a drug is more effective or less risky than is demonstrated by appropriate evidence. A number of empirical studies have examined the occurrence and influence of deceptive promotion, both in regard to prescription drugs…and other products...No research to our knowledge, however, has investigated the ability of consumers and healthcare professionals (HCPs) to independently identify deceptive prescription drug promotion," FDA wrote in the Jan. 4 agency notice.

The proposed project involves two studies, both of which will entail subjects viewing websites promoting fictitious drugs.

Study one will examine how the level of deception in promotion affects subjects' perceptions and behavior. The level of deception will be varied over three levels, which the agency defines as: none, fewer, and more.

The study will attempt to answer: the proportion of subjects that can identify a promotional piece as deceptive and whether the ability to identify deceptive promotion varies depending on the level of deception; whether the degree of deception affects consumers' and HCPs' actions, including reporting the advertising; and whether people who recognize information as deceptive adjust their "attitudes and intentions toward the product."

Study two will compare the impact of implicit deceptive claims, which "suggests or implies an unstated piece of information," versus explicit deceptive claims, which "fully and clearly expresses information and leaves nothing to be implied," according to the agency notice.

Subjects in study two will be shown three websites: an explicitly false web site, a factually true but implicitly misleading site and a website with no misleading information. The study will explore whether the ability to identify deception varies depending on the type of deception; if the type of deception affects subjects' behavior, including reporting to authorities; and if detection of deception impacts a person's actions.

The agency argues that people's ability to detect deception affects public health.

"The ability to identify such promotion has important public health implications. If unable to identify deceptive promotion, consumers may ask their HCPs to prescribe specific drugs that they would not otherwise request. Likewise, HCPs unable to identify deceptive promotion may prescribe specific drugs that they would not otherwise prescribe. In the case that consumers and HCPs are able to identify deceptive promotion, then they may instead be equipped to incorporate such information into their medication decisions, and perhaps even report deceptive promotion to appropriate government regulators who can take corrective action," the agency writes.

However, Peter Pitts, president of the Center for Medicine in the Public Interest and former FDA associate commissioner, questioned the usefulness of the planned studies. "I don't think the OPDP studies will make a difference to anything whatsoever," Pitts told IHP.

Pitts also told IHP he doesn't see the value in FDA studying fake ads, because actual ads already are reviewed by FDA. The agency's resources would be better spent looking at the impact direct-to-consumer ads play in patient and physician education, argued Pitts.

The former FDA official also maintained that FDA should be looking at marketing of dietary supplements, which he argued often cross the line into drug claims. "That needs to be slammed shut," Pitts told IHP.

Richard Samp, chief council at the Washington Legal Foundation, argued the new studies likely don't signal FDA will step up its enforcement of off-label communication. It's likely that FDA is instead trying to provide clearer guidance for companies to be in compliance with FDA regulations, Samp argued.

Samp, who recently urged "FDA to abandon its current, overly restrictive view of what constitutes truthful speech and to limit its speech-suppression efforts to speech that is truly false or misleading," told IHP that he applauds FDA for doing the studies. Samp maintained that the agency has recently been "[asking] a lot of very good questions."

Heather Bauelos, counsel at King & Spalding and a former associate chief counsel in the FDA's Office of the Chief Counsel, argued that the studies aligned with OPDP's ongoing research efforts.

"FDA's research on identifying deceptive drug promotion could potentially be related to these ongoing efforts, but strikes us as par for the course for OPDP. OPDP has a very active research program, which has been a growing area in recent years. The announcement and focus of this new study appears to fit neatly among other research priorities, particularly since the ability of consumers and HCPs to identify deceptive promotion is an area that OPDP has yet to investigate," Bauelos wrote to IHP.

When asked by IHP if the studies may impact FDA's regulation of off-label promotion, Bauelos argued that any enforcement activities that come out of the study would instead likely deal with issues such as risk minimization or unsubstantiated claims.

"Any use of the results of this research in enforcement activities would likely be related to misleading promotion and advertising, which might encompass off-label communications, but typically extend to issues of risk minimization, overstatements of efficacy and other unsubstantiated claims. Overall, the study results may likely provide more information about whether FDA oversight of prescription drug promotion and advertising is protecting the public health and related government interests," Bauelos wrote.

FDA also raised the possibility Jan. 4 of creating a deceptive advertising reporting program for consumers, similar to the "Bad Ad" program currently created for HCPs

"The FDA Bad Ad program, for example, encourages HCPs to report deceptive prescription drug promotion…a goal which requires that HCPs successfully identify such promotion when it appears in the course of their duties. Likewise, similar programs could be implemented for consumers to report deceptive prescription drug promotion to FDA. Reports of deceptive promotion are useful to FDA because they allow investigators to focus their efforts in an era where the amount of promotion far exceeds the resources available to monitor everything," the agency wrote.

Samp questioned whether a similar program for consumers would be worthwhile. "I suspect [consumers] are not in a position to identify so called bad ads," Samp told IHP. Samp also maintained that nothing currently prevents a consumer from contacting FDA if they feel they've been deceived.
Pitts called the original bad ad program "a complete waste of time," maintaining that FDA never really determined what was a bad ad, and that FDA should instead be focusing on regulating safety and efficacy. "FDA does not regulate creativity," Pitts added.  Read More & Comment...

An Off-Label Regualtory Temper Tantrum

01/23/2017 09:53 AM | Peter Pitts

FDA memo rebuffs many suggestions for expanding off-label marketing
By ED SILVERMAN @Pharmalot

After weeks of anticipation, the FDA has issued a lengthy memo about the extent to which so-called off-label information about medicines may be disseminated to physicians, one of the most contentious issues to roil both the agency and the pharmaceutical industry. But rather than spell out possible solutions to this particularly thorny topic, the 63-page missive essentially summarized key points framing the long-running debate and carefully rebuffed many of the suggestions made by drug makers and others that support expanding pharmaceutical marketing. Meanwhile, the agency continues to seek comments while working to develop a final guidance.

Drug company “communications that are designed to cause the audience to reach safety or efficacy conclusions independent of, or not supported by, the available data are misleading, have the potential to harm patients, and lead to a waste of health care resources,” the agency declared.

The memo follows a public meeting held last November to explore off-label promotion, which refers to materials that describe unapproved uses of a drug. Doctors are allowed to prescribe a medicine for an unapproved use, but drug makers have battled restrictions on their ability to distribute such information — such as reprints of medical studies — and have lobbied Congress and the FDA to loosen regulations.

The FDA has, so far, avoided doing so.

The agency has regularly voiced concern that public health could be jeopardized if a drug maker distributes information about an unapproved use that has not been proven safe or effective. For its part, the pharmaceutical industry argues that its free speech rights are being restricted, but has won significant court rulings that say truthful and non-misleading speech is protected. These court battles have placed the agency on the defensive.

But in its memo, the FDA recounts why drug makers must provide evidence of safe and effective medicines, and why certain marketing restrictions exist. “The history of public health tragedies caused by medical products demonstrates that there have been some unscrupulous players in the marketplace who have made deceptive or unsubstantiated claims about medical products,” the memo states.

And the agency pointed to concerns that physicians are not always well positioned to discern the information they receive. “Studies have found that health care providers overestimate their knowledge of what uses are FDA-approved for drugs and assume that many unapproved uses are supported by sound scientific evidence when they are supported by uncertain or no evidence,” the agency wrote.

The FDA then reiterated its concerns about the aftermath of unapproved uses of drugs: “More recent studies have… found that the majority of unapproved uses for which drugs are prescribed lack adequate evidence of effectiveness, and that the risk of adverse events is higher for unapproved versus approved uses, and even higher when the unapproved use is not supported by reliable scientific data.”

To underscore the point, the FDA assembled two appendices replete with examples in which unapproved uses led to patient harm.

The agency also shot down several suggestions from the meeting, notably one that would permit drug companies to actively promote unapproved uses so long as disclosure is made. The FDA essentially rejected this out of hand by writing that patients may be harmed by a “return to an environment” where the public encounters claims based “conjecture or extrapolation from limited data, most of which is later found to be false or misleading.”

“They’re pulling out all the stops in pointing to the price to be paid from expanding off label use,” said Dr. Sid Wolfe of Public Citizen Health Research Group, who spoke at the meeting last November against industry efforts to widen off-label marketing.

At the same time, the FDA did acknowledge that there is virtue in sharing some off-label information.

“The reality remains at any point in time that, for some patients, approved or cleared therapies are not available or have failed,” the agency wrote, adding that reliable scientific information about unapproved uses may help further scientific research into new or existing medicines.

Nonetheless, industry supporters were miffed.

“This memo is a regulatory temper tantrum,” said Peter Pitts, a former FDA associate commissioner who heads the Center for Medicine in the Public Interest, a think tank that is funded, in part, by industry. “The memo is written to show that allowing the sharing of truthful, accurate, and non-misleading of information will cause the earth to stop spinning on its axis, research into new indications to cease, and misleading and misbranded communications to proliferate.”

Yet another observer, whose research was cited by the FDA throughout the report, praised the effort.

“It appears to be extremely well-researched and well-argued defense of the importance of the FDA in protecting patients and promoting accurate flow of information about approved medical products, among other outcomes, by maintaining its current oversight of off-label communications,” said Aaron Kesselheim, an associate professor of medicine at Harvard Medical School who also heads the regulation, therapeutics, and law program at Brigham & Women’s Hospital. “And it’s probably not a coincidence that it’s being published now, since the three names I’ve seen all be associated with a possible change in FDA leadership after Jan. 20 all have a very anti-regulatory ideology, and may look to change the FDA’s approach to regulating off-label marketing.”  Read More & Comment...

JAMA Publishes Fake Science Study of Industry Influence of Patient Groups

01/20/2017 08:11 AM | Robert Goldberg

A report published in JAMA Internal Medicine entitled “Patient Advocacy Organizations, Industry Funding, and Conflicts of Interest” Susannah L. Rose, PhD1,2; Janelle Highland, MA3; Matthew T. Karafa, PhD4; et al  is a textbook example of fake science.
 
Here’s the article abstract:
 
Question What is the nature of industry funding of patient advocacy organizations (PAOs) in the United States?
 
Findings This survey study found that 6 percent of a national sample of patient advocacy organizations, virtually all of which were not for profit, reported receiving funding from for-profit companies. Twelve percent received more than half of their funding from industry; a median proportion of 45 percent of industry funding was derived from the pharmaceutical, device, and/or biotechnology sectors.
 
Why is this fake science?
 
 The authors skew the survey results to prove that industry contributions to patient advocacy organizations are a conflict of interest.   Here’s how the survey results are presented in the article: 


 
 
At first glance, the results do not reflect the assertion that “evil company” money is corrupting patient groups.  In fact, less than 20 percent of groups reported receiving ANY funding from evil private companies.   Here’s the survey data formatted to reflect this fact.
 

 
As the chart below shows, most of the patient advocacy organizations received less than 25 percent of their revenue from companies.
 

 
 
The authors then go on to conclude from this data that companies have undue influence on patient groups.  Yet the survey shows that only 7.7 percent felt pressure to conform to a specific policy position (which are not provided by the survey). 
 
From this anthill of evidence, the authors conclude:
 
“Such dependence on the financial support of companies whose interests may not always align with those of the organizations’ constituents has important implications for PAO.”
 
Nowhere do the authors identify what those interests are and how they may diverge with industry positions.  Rather, the proof they provide is this claim:
 
Some groups have “been the focus of media investigations regarding their ties to industry and the integrity of their activities.” 
“Their large numbers and credibility with policymakers and the public likely give even small PAOs extensive influence in specific disease areas. At the other end of the spectrum, large PAOs that receive considerable for-profit support and have sophisticated public relations and government affairs departments likely have a substantial effect on policies relevant to their industry sponsors.” 
Again, no evidence.
 
For instance, the 21st Century Cures Act was developed by Fred Upton and Diane Degette.  Only after the legislation was drafted did the two legislators seek out the support of a small group of patient organizations.  Where is the evidence that patient groups took their lead from evil companies?  And how statistically significant is that association given that more than 80 percent of funding for all groups comes from bake sales, individual contributions, etc.?
 
No matter.  The article concludes that: “Financial relationships between PAOs and industry demand effective steps to ensure that these groups serve their constituents’ interests while minimizing risks of undue influence and bias. “
 
The JAMA article is fake science AND fake news.  It is an exercise in confirmation bias against industry support of patient groups.  It is not evidence.  It is closer to libel than it is truth.   Read More & Comment...

Off Label back on the table

01/19/2017 12:56 AM | Peter Pitts

Much more on this to come (much more!), but for starters …

FDA has released two new documents that address off-label communications about medical products. A draft guidance outlined questions and answers regarding communication with payers about healthcare economic information, including information concerning unapproved uses of medical products. A separate memorandum described the agency's position on sharing information about off-label use of approved drugs.

In the guidance, FDA described "truthful and non-misleading" healthcare economic information that is acceptable for product sponsors to share with payers or formulary committees. The agency said it is acceptable to share information that "relates to" a product's approved indication, with some variance allowed about factors such as dosing, patient subgroups, and practice settings beyond what is included in the product's label. The guidance said certain other information, such as analyses of patient populations not included in a label, would not be acceptable. 
The document said economic analyses provided to payers should specify the type of analysis performed, including modeling techniques, patient populations, outcome measures, cost estimates and any underlying assumptions. 
The guidance said terms of value-based contracts between manufacturers and payers lie outside the scope of FDA regulation.

It said FDA "does not intend to object" to sharing certain information with payers prior to products' approval, including factual and non-misleading statements about product information, indications sought, estimated approval timelines, and clinical or preclinical results. 
In separate draft guidance released Tuesday, FDA recommended ways to convey truthful, non-misleading information that is "consistent with" a product's label, but not included in the label.
In the memorandum, FDA outlined its concerns regarding promotion of unapproved uses of approved drugs. The agency said it must balance public health needs with First Amendment protections, and described potential approaches to doing so. The agency asked stakeholders to comment on the memorandum's proposals, as well as both draft guidances.  Read More & Comment...

FDA marches towards interchangeability

01/17/2017 11:45 PM | Peter Pitts

The FDA’s new draft guidance on interchangeability of biosimilars will require most biosimilars' sponsors to conduct studies showing that switching between a biosimilar and its reference product poses no greater risk than continuing to use the reference product. The guidance recommended designs for switching studies, as well as integrated trials to show that a compound is both biosimilar to and interchangeable with its reference biologic.

Per a report in BioCentury, the agency said it will "generally" require switching studies to show interchangeability between any biological products that are dosed more than once. Switching studies should evaluate pharmacokinetic and pharmacodynamic measures as primary endpoints, while also assessing immunogenicity and safety. The agency specified that the studies should include at least three switches between a reference product and proposed biosimilar; the last switch should be a transition to the proposed biosimilar from its reference product.

FDA emphasized that an imbalance in adverse events or immune responses reported at any point during a switching study will "raise concerns" as to the biologics' interchangeability, because it may be difficult to determine which product caused the event. The agency also encouraged powering studies to accommodate patient dropouts, noting that an imbalance in dropout rates may also suggest that compounds are not interchangeable. The agency encouraged companies to first seek a candidate's approval as a non-interchangeable biosimilar if there is "residual uncertainty regarding interchangeability" based on adverse events. The sponsor could then conduct postmarketing studies to show interchangeability.

FDA suggested a two-part study design for sponsors seeking evidence of both biosimilarity and interchangeability. The agency said that after an appropriate measure of clinically meaningful differences between two biologics, a second stage of an integrated study could re-randomize patients into a switching study. The study should be powered to adequately measure both PK and PD, as well as clinical effectiveness.

The guidance said sponsors seeking to extrapolate data supporting interchangeability to additional indications "need to provide sufficient scientific justification" that addresses factors such as immunogenicity risk, PK and mechanism of action.

FDA will accept comments on the draft guidance through March 19. In a Federal Register notice accompanying the guidance, FDA asked stakeholders to address how the agency should consider additional indications approved for a reference product after approval of its interchangeable product, and if the agency should change or add to its comparability assessments for post-approval manufacturing changes of interchangeable products.  Read More & Comment...

Trump Can Reduce Drug Prices Without Price Controls

01/17/2017 11:33 AM | Robert Goldberg

President-elect Trump once again made it clear that he wants to make good on his promise to reduce drug prices. Drug stocks tumbled as investors understood Mr. Trump’s assertion that "we're the largest buyer of drugs in the world and we are going to bid properly” as code for price controls. 
 
Price controls would kill innovation, which would kill people just as rent controls in New York City hurt development.  What Trump wrote in The Art of the Deal about rent control applies to government limits on drug prices.  (Rent control) forced landlords to subsidize tenants. The costs of fuel, labor, and maintenance rose steadily, but the city refused to let landlords raise their rents to keep pace with inflation, much less the market itself. When landlords simply couldn’t make ends meet anymore, they began abandoning—or torching—their buildings. Between 1960 and 1976, approximately 300,000 housing units in New York were abandoned. Whole neighborhoods in the South Bronx and Brooklyn turned into ghost towns. The city, in turn, lost hundreds of millions of dollars in real-estate taxes.
 
Price controls would create a similar wasteland in our healthcare system.  And contrary to claims that drug companies can charge the government whatever they want,  Medicare, Medicaid (including ACA enrollment), VA, the Public Health Service have negotiated an average reduction in list drug prices by up to 60 percent.   Unfortunately, for the most part, these discounts are not passed onto consumers.
 
However, it is possible to reduce what Americans pay for medicines now and in the future by changing the way new drugs are created and financed.
 
First, cash rebates that drug companies give to discount products are now pocketed by insurance companies or used to subsidize other line items should go directly to patients.  Rebates now make up 30 percent ($115 billion) of total drug spending.  Indeed, 77 percent of the retail price increase in drugs since 2006 goes to rebates.
 
When auto companies offer new car rebates, the cash is applied to reduce the price of the car in the dealership.  In our health care system, the cash rebates go to the insurance companies and pharmacy benefit management firms.  And when we pay for our prescription at the drug store, we are charged the list price.  
 
That’s because PBMs and insurance companies use their control over our drug choices to maximize rebates and discounts. Most of the rebates are generated by medicines for about 5 percent of Americans (including seniors fighting cancer, multiple sclerosis, Parkinson’s and other complex diseases).   Most, if not all, Obamacare and Medicare drug plans place most or all drugs that treat such patients on the highest cost formulary tier.  So the sickest patients wind up paying up to 50 percent of the retail price of the drugs they depend on even as billions of rebate dollars are being racked in. This targeting is profitable, but it is also discriminatory.
 
 President Trump could sign an executive order banning such discrimination and allow companies to directly pass through rebates and out of pocket assistance to patients for any drug doctors prescribe as part of a broader.  The goal should be to eliminate cost sharing completely and encourage health plans to compete on the quality of care. The over $100 billion in rebates and discounts could be used to make this possible.
 
Second, he can encourage different ways to pay for medicines.  Many new medicines generate value and reduce spending over a long period of time.  Yet much of the cost is either upfront or recurring.   To address this problem drugs could be financed as are cars, college education, homes and construction projects, etc.   Drug companies could use cash flow to set up such long-term financing or create financial instruments backed by profits and savings generated by medicines to increase liquidity. 
 
Third, drug discounts the government negotiates on behalf of hospitals in poor communities are pocketed by the institutions instead of going directly to those in need.  These discounts (called 340 B discounts for the section of the law creating the program) are as high as 60 percent.   Hospitals now receive these 340B discounts on almost half of their drug purchases. In turn these institutions markup drug prices and pocket the profit.  The 340B statute doesn’t require that the discounts go directly to their customers.  That must change.
 
Finally, Mr. Trump should remove reduce barriers that limit competition between companies.  During his press conference, Trump noted “We have to get our drug industry coming back. Our drug industry has been disastrous. They're leaving left and right. They supply our drugs, but they don't make them here, to a large extent. “Nearly $350 billion in biopharma profits are held overseas because the 35 percent US corporate tax rate can be five times higher than elsewhere. 
 
That’s in part because pharmaceutical research and development efficiency, measured by the number of new drugs brought to market, has declined compared to the amount of money invested.  Thanks to regulation, the cost and time needed to developed new medicines have climbed to $1.5 billion over a decade.  And a Deloitte study concludes that the pharmaceutical industry's return on its current portfolio of approved products has declined from 10.1 percent in 2010 to 3.7 percent in 2016.   The industry's cost of capital is about 8.4 percent.  That is not sustainable. 
 
Fracking reduced the time and cost of discovering and safely producing new sources of energy.  New biomedical tools and technologies can yield the same benefits in biomedical innovation.  He can encourage the return of profits and investment with regulatory reforms of the Food and Drug Administration needed to unleash such potential.
 
Without new medicines, our lives would be shorter, more painful, less productive.  Our economy would be smaller, and health care would be less efficient and more expensive.  We need to produce more medical innovations more quickly and at a lower cost.  Price controls won’t make it happen.  Instead, the way medicines are developed and paid for has to be changed.  

The question for companies is not whether they must do so, but when and how.    The rebate system is rigged against consumers.  The FDA cannot keep up with the geometric pace of change.  Failure to address these challenges will, I'm afraid, will lead to the kind of regulation that will undermine innovation.   Read More & Comment...

And the word on biosimilar nomenclature is ... Suffix

01/13/2017 08:09 AM | Peter Pitts

We've called for this from the start and now it's reality. In final guidance released Thursday on naming of biologic drugs, FDA reiterated that each biologic should receive a non-proprietary "core name" plus a unique four-letter suffix that is devoid of meaning. Each biologic and biosimilar would receive a hyphenated "proper name" joining the core name with the suffix.

The convention is designed to differentiate among non-interchangeable reference products and biosimilars.
The agency said it is also still considering the suffix format for interchangeable products.

In an agenda released Wednesday, FDA said it plans to publish guidance this year addressing "considerations in demonstrating interchangeability with a reference product."
FDA said it intends to apply the naming system prospectively, and will "communicate with companies that have pending applications to discuss implementation."


In the final guidance, FDA said it is "continuing to consider" how to implement the naming convention for existing biologics, and "in the near term, intends to assign distinguishing suffixes to a limited group of these products."
FDA said the unique suffixes should prevent "inadvertent substitution" among biologics and clarify adverse event reporting. The agency encouraged "routine use" of designated suffixes in ordering, prescribing, dispensing and pharmacovigilance of biologics, independent of a product's approval pathway or time of approval.

Well done FDA.

  Read More & Comment...

Trump’s Anti-Vaccine Views Rooted in Media's Fake Science

01/12/2017 01:55 PM | Robert Goldberg

Donald Trump has been vilified as anti-science for asking Robert F. Kennedy Jr. – who has been peddling the long discredited claim that vaccines (or ingredients in the shots) cause autism—to chair a commission on the connection.  

Trump is not the only celebrity who buys into the vaccine-autism link.  But he is also going to be President.   Asking Kennedy to chair a panel to ‘study’ the issue who claims drug companies are covering up what he called a vaccine holocaust for the sake of profits is troubling.  

But Trump is not alone in his unscientific anti-vaccination views.  Dozens of celebrities and politicians have continued to promote unfounded assertions about vaccine safety for years.   And we can thank the same media outlets that now are condemning the president elect for vaccine denialism for promoting fake science peddled by what infectious disease expert Paul Offit calls autism’s false prophets.  

From 2005 to 2011 CBS aired nearly a dozen stories that included extremist views of vaccines and autism.   In 2015 Kennedy cited a CBS Atlanta segment that reinforced the claim that the government was covering up the truth about vaccine dangers. The Huffington Post, which pontificated about Trump’s anti-science views yesterday has been the soapbox of anti-vaccine types – Kennedy included --  for several years. 

But the irony does not end there.   Recently, Kennedy has been claiming that recent research  links industrial exposures of lead, mercury and arsenic to the prevalence of autism spectrum disorder (ASD).   But he is not alone,  dozens of mainstream outlets have published these claims –– as settled fact.  

For instance the Fox News website published uncritical article about the connection headlined: “Number of chemicals linked to autism and other disorders doubled in past 7 years, study shows.”

The piece quotes Dr. Philip Landrigan, of the Icahn School of Medicine at Mount Sinai in New York City the co-author of the study: “the increase of later diagnoses of these disorders tracks very nicely with increased production and release into environment of synthetic chemicals over last 40 or 50 years,” Landrigan said. 

Except that, the amount of heavy metals, fertilizers and air pollution in our food, water, air, consumer goods have been falling for 20 years.  Moreover, as Emily Willingham, the co-author of "The Informed Parent: A Science-Based Resource for Your Child's First 4 Years notes about claims air pollution cause autism: “ You can see an overall decline, sometimes steep, something that doesn’t fit with the increased autism prevalence over the same period, whether you consider the mounting numbers an “epidemic” or a more accurate reflection of primarily stable values over time. Turn to some of the world’s most air-polluted cities, and you will fail to find autism rates that correlate.”   The same goes for chemicals alleged to cause autism. 
Why is claiming vaccines (or how we administer them) cause autism anti-science but asserting that climate change and pollution have the same impact is unchallenged?

Asking if the president-elect’s views on vaccines and autism are based on fake science is more than fair.  But the same questions should be raised when media outlets run uncritical stories claiming (declining) pollution levels damages infant brains. 

We all choose the information that confirms our view of the world.   Science is shaped by the exact opposite impulse. 

The media did not report on the science of vaccines decades ago and it isn’t doing so now. Removing preservatives from vaccines was intended to calm fears, but it only led to more concern and less immunization. 

Our children have been endangered by this hijacking of science.  In 2013, 87 percent of pediatricians surveyed said they encountered vaccine refusals from parents of their patients, up from 75 percent of pediatricians who said the same in 2006.

After Andrew Wakefield’s claims about vaccines causing autism were finally retracted: The British Medical Journal observed: “The damage to public health continues, fueled by unbalanced media reporting and an ineffective response from government, researchers, journals and the medical profession.”

Mr. Trump’s trust in Robert F. Kennedy Jr. is a product of this fake science. 
  Read More & Comment...

Deadly Swap: PBMs, Health Plan Drug Switching To Save Money

01/09/2017 10:57 AM | Robert Goldberg

Sometimes PBMs and health insurers don't even bother with step therapy or high cost-sharing to limit access to drugs that give them the biggest rebates.

Now they are just switching what drugs they cover without telling consumers. 

Swapping drugs to save money is unsafe and unhealthy:

Patients who were switched to another SSRI for non-medical reasons after being stabilized on escitalopram used more resources and had higher health care costs within 3 months of switching than patients who did not switch.

Non-medical switching of drugs for patients treated for heart conditions, diabetes, rheumatoid arthritis, ulcers, menopause, and pain "was more often associated with negative or neutral effects than positive effects on an array of important outcomes. Among patients with stable/well-controlled disease, non-medical switching was associated with mostly negative effects."

 Switching may expose heart patients to a higher risk of therapy discontinuation or substitution.

This isn't just a case of switching from a brand to generic or from one brand to another.  Switching from one generic to another can cause problems:

After switching their generic phenytoin, 33 out of 80 patients with epilepsy (41%) suffered from increasing seizure events. The number of medical visits for acute seizure significantly increased in the post-interchange period. 

These are just a few of the studies that associate when insurers and PBMs switch drugs to save money, they can hurt patients.

Incredibly,  the Medicare part B study was going to non-medically switch the cancer drugs seniors gets without telling them.   Proponents failed to acknowledge the risks of such a study.  In this content, it should be pointed out that ICER's decision to limit access to new drugs based on how it affects the bottom line of health plans is non medical drug switching writ large.   

It's not enough to be against step therapy.   All that will do is increase the amount of dangerous non-medical drug switching taking place in the dead of night, without notifying patients or worrying about whether such a switch will do more harm than good.





   Read More & Comment...

The Perennial Political Poppycock of Drug Importation

01/05/2017 08:10 AM | Peter Pitts

A new president, a new Congress with a new agenda, lots of new ideas -- and then there’s drug importation. This regularly resurrected bad idea is likely to be tagged onto the budget resolution. This perennial populist poppycock is an ill-considered sound-bite solution to drug pricing that won’t offer lower prices but will result in a public health calamity. The truth does not cease to be the truth because it isn't politically expedient.

Importing drugs from Canada is exceedingly dangerous for a number of reasons. For starters, many Internet pharmacies based up north are stocked with drugs from the European Union. And while many people wouldn’t hesitate to take medicines purchased from countries like France, Germany and Great Britain, there’s plenty of risk involved.

The EU currently operates under a system of “parallel trade,” which allows products to be freely imported between member countries. This means that any drugs exported from the United Kingdom to Canada could have originated in an EU country with significantly less rigorous safety regulations, like Greece, Portugal, Latvia or Malta.

Just last year, EU officials seized more than 34 million fake pills in just two months. And in May, Irish drug enforcers confiscated over 1.7 million pounds of counterfeit and illegal drug packages. So if American customers start buying drugs over the internet from Canadian pharmacies, they could easily wind up with tainted medicines of unknown European origin.

It’s also important to note that drugs from anywhere in Europe aren’t even legal for sale in Canada. So when politicians say we can get “the same drugs” that Canadians get, they’re just plain wrong.

Even more worrisome is outright fraud — many “Canadian” pharmacies are actually headquartered somewhere else. Far too often, importing drugs of unknown quality from sketchy pharmacy websites ends in tragedy. Consider the case of one Texas emergency-room doctor, who suffered a stroke after importing what he thought was a popular weight-loss drug. The online pharmacy had actually substituted the doctor’s ordered drug for a counterfeit, stroke-inducing medication shipped in from China. If medical professionals can’t tell the difference between real and counterfeit drugs, regular patients don’t stand a chance.

A 2005 investigation by the Food and Drug Administration (FDA) looked at 4,000 drug shipments coming into the United States. Almost half of them claimed to be from Canada. Of those, fully 85 percent were actually from countries such as India, Vanuatu and Costa Rica.

As part of another investigation, FDA officials bought three popular drugs from two internet pharmacies claiming to be “located in, and operated out of, Canada.” Both websites had Canadian flags on their websites. Yet neither the pharmacies nor the drugs were actually from Canada.

The on-the-ground reality of state and local importation schemes has been dismal and politically embarrassing. Remember Illinois’ high profile “I-Save-RX” program? During 19 months, only 3,689 Illinois residents used the program — that’s .02 percent of the population.

Programs like this wouldn’t do any better on a national basis. A study by the nonpartisan Congressional Budget Office showed that importation would reduce our nation’s spending on prescription medicines a whopping 0.1 percent — and that’s not including the tens of millions of dollars the FDA would need to oversee drug safety for the dozen or so nations generally involved in foreign drug importation schemes. And generic drugs (which represent more than 85 percent of the medicines dispensed in the U.S.) are cheaper here at home than in Canada.

Calling foreign drug importation “re-importation” is a clever way to sell the idea to the American people. But the term simply doesn’t fit with the facts. In reality, in addition to importing foreign price controls, Americans would end up jeopardizing their health by purchasing unsafe drugs while not saving money.

A better policy for our new President and Congress to focus on is the issue of increasing insurance company co-pays. American patients who head up north or online are motivated by the cut-rate prices they see on the web. Health insurers could help patients avoid this temptation by reducing their co-pays for drug purchases, particularly for low-income patients.

Dropping drug co-pays would also help patients stick to their prescribed treatment regimes. All too often, people skip a dose, don’t get a refill, or stop taking their drugs prematurely in order to save money. In the long run, though, not adhering to a drug regimen leaves patients less healthy — and increases national medical expenses by an estimated $300 billion annually.

When consumers say, “My drugs are too expensive,” what they mean is that their co-pays and co-insurance are too expensive. And they’re right. Major insurance companies and pharmacy benefit managers (PBM) receive significant discounts from the manufacturers. So why doesn’t this result in lower co-pays for consumers? That’s a good issue for our new political leadership to debate.  Read More & Comment...

Keep the Feds out of Drug Pricing

12/20/2016 07:32 AM | Peter Pitts

From the pages of USA Today ...

Keep the Feds Out of Drug Pricing

Allowing the federal government to negotiate drug prices, as suggested by Minnesota Sen. Amy Klobuchar’s column “Let’s work with Trump to reduce drug prices,” would result in prices going up and patient choice going down.

According to the Congressional Budget Office, allowing Uncle Sam to negotiate Medicare drug prices would have a “negligible effect” on Medicare drug spending. Its report from 2009, reiterated this view, explaining that such a reform would “have little, if any, effect on (drug) prices.”

Allowing the feds to negotiate prices for the Medicare Part D drug benefit would likely have a negative effect on the program. The CBO predicts that when Health and Human Services forces pharmaceutical firms to lower the cost of a particular drug, this tactic brings “the threat of not allowing that drug to be prescribed.” In other words, price controls equal choice controls.

When consumers say, “My drugs are too expensive,” what they mean is that their co-pays and co-insurance are too expensive. And they’re right. Major insurance companies and pharmacy benefit managers (PBM) receive significant discounts from the manufacturers. So why doesn’t this result in lower co-pays for consumers? That’s a good issue for Sen. Klobuchar to take up with President-elect Donald Trump.

Peter J. Pitts, Center for Medicine in the Public Interest; New York  Read More & Comment...

Solving for Drug Prices Exacts A High Human Cost

12/16/2016 11:43 AM | Robert Goldberg

 
Elaine Schattner, a courageous and compassionate cancer survivor, physician and advocate has written a blog for Forbes entitled: “We Need To Tame The Price Of New Cancer Drugs” In the post she reports  on a presentation by Peter Bach (who she calls a drug pricing theorist!) about the clear and present danger of cancer drug prices and how nothing short of government set prices will make medicines affordable.   (I disagree with him on pricing but Dr. Bach is smart, articulate and creative.  And he is a Red Sox fan.  No one’s perfect.)

 Dr. Schattner writes that: “U.S. healthcare costs will approximate $3.41 trillion. Drug prices are a big part of that, Bach emphasized.”
 
Not really.   Even though cancer drugs are a bigger part of spending on cancer care, cancer spending as a percent of total health care spending has remained about 4.6 percent since 1965. 
 
If drug prices are a big part of the rise in overall health care spending, why has the percent spent on cancer care remained the same over time?  Similarly, spending on drugs as a part of all health care spending spiked in 1990 to about 11 percent (15 percent if you add drugs used in hospitals and outpatient settings) and has remained the same since then (with another spike due to Hep C drug spending in 2013).  The retail spending amount in 2014 is about $429 billion according to IMS.  Rebates and other discounts from drug prices are about $130 billion.  Most of that does NOT go to patients. 
 
Back to Dr. Bach:
 
“Although prescriptions drugs account for only 10% of national health expenditures, their prices are rising disproportionately. Bach showed a graph of cancer drug prices at the time of FDA approval, from 1965 to the present, demonstrating a 100-fold increase. “The y-axis is exponential,” he reminded the audience. The same graph indicates that since 1990, price tags for newly approved cancer drugs have gone up 10-fold.”
 
Two points. 
 
First, Prices are NOT rising disproportionately.  Especially when you back out rebates.  The chart below shows how most of the increase in drug prices driving Bach batty is in the form of rebates and discounts that do NOT go to patients.
 

 
In a reply to a tweet I sent to her about this trend, Dr. Schattner asked if it really made a difference if the price was set by insurers or drug companies. 
 
It does.
 
Schattner writes: “Bach referred to data from the Kaiser Family Foundation on rising premiums and high deductibles that affect 150 million non-elderly Americans who get insurance through employment. Many can’t afford out-of-pocket cancer drug costs until they meet their insurance deductibles, so they don’t take their meds, skimp on doses or wait before filling prescriptions. Even then, when companies charge over $100,000 per year per drug, and insured patients with cost-sharing plans are expected to pay some fraction of that, steep prices limit use.”
 
But as the chart below shows, Insurers are not only pocketing rebates and using them for everything other than reducing patient out of pocket costs.  They are increasing what patients have to pay as a percent of the retail drug price! 
 
 

 
Second, Dr. Bach’s comparison of cancer drug prices in 1960 and today is out of context and made to make an impact vs. making a substantive point.
 
For instance, Harvard tuition has increased by 145 percent from 1970 until today.

Or more to the point, the cost per cancer hospital discharge has increased (in unadjusted dollars) from $1778 in 1970 to $73379 in 2014.   That’s a 445 percent increase.
 
Hospitalization is a bigger contributor to health care cost.  But the interest and moral outrage about inpatients costs is nil compared to the time and emotion devoted to drug prices.

The reason for that is we pay more of the retail price of a drug on a regular basis than we pay for hospitalization on a less routine basis. 
 
Ironically, the use of new drugs has reduced the hospitalization (along with mortality rates and lost productivity) due to cancer as the
charts below demonstrate:

 

Schattner observes that “Prices are problematic at the group level, too. They’re a burden for public insurers such as Medicare. “These are serious numbers,” Bach said. In recent years, Medicare has been paying an increasing fraction of prescription drug costs. In private insurance networks, high medication prices drive up premiums and tend to reduce coverage for all participants. “Health insurance, although it’s been extended in the U.S., has beenstripped down in terms of what it delivers.”

Not true.   The share of the decline in hospitalization is due to the shift to outpatient procedures and most of it comes from substituting medicines for surgery, a trend that is associated with an increase in cancer survival and life expectancy.  
 
So how much could cancer cost if we had the same hospitalization rates in 2014 that we had in 1970 and at current charges per cancer hospitalization?   (I use charges vs costs because Dr. Bach uses retail drug prices.)   About $1 trillion dollars vs $100 billion:

Over time Frank Lichtenberg and others have shown that new cancer medicines explain from 60 to 90 percent of the decline in cancer death rates and is the main reason hospitalization costs have decline.   If Dr. Schattner or anyone can provide evidence of another reason, I’d be happy to see it.
 
Finally, the increase in cancer costs matched the overall increase in medical expenditures during the last 20 years.   The Bureau of Economic Analysis concluded that new medicines for cancer reduced the cost of treatment between 1990-2010.  One can only imagine what insurance premiums would be if we were spending $1 trillion on cancer hospitalizations alone.   So add profitability and lower insurance costs to the benefits new medicines generate.
 
Given what Bach presented, Dr. Schattner favors governments deciding what to pay for drugs based on a robust measure of value.  Well, it turns out that when the value parameters she believes Dr. Bach’s estimate of drug value (as well as ICER’s) are counted it would increase the cost per QALY threshold to about $250-300K.   That would make most, if not all cancer drugs a bargain, especially when rebates and discounts go to patients.  
 
I haven’t done all the math, but I also estimate that the rebates and discounts on the $18 billion or so spent on the kind of targeted drugs Bach believes will drive us into bankruptcy are about $2.4 billion.   Estimates derived from a recent Millman study of the drivers of cancer costs done for the Community Oncology Alliance suggest about 1.25 million people with cancer undergo active treatment each year.  I assume that half of these patients are likely to get targeted or immunotherapy and that $2 billion of the rebates are generated from such products.   That’s about $3800 per patient, enough to eliminate all but a few hundred dollars of out of pocket costs for those not protected from such a burden.
 
Yet, my guess is people still would want to solve for price by having the government negotiate prices. They support government price control (the euphemism is negotiation) of drug companies in the same of economic justice and are impelled by the feeling the industry as a whole generates excessive or windfall profits it doesn’t deserve.  As I pointed out in my last blog, price competition does not lead to lower prices in the long run since innovation – which requires more investment and higher costs – is the kind of competition that matters.
 
In any event, it should be noted that at present the government already negotiates drug prices through the VA, Medicare, Medicaid, the Public health service and the Defense Department.    (Average discount: 60 percent) And it should also be noted that such negotiations are always paired with limits on access (as they are in Europe) and that such limits on access such as cost sharing, step therapy and outright caps increase death and morbidity. 
 
If Dr. Schattner wants a kinder, gentler version of the cancer Abacus, she should bear in mind that there is no value framework in the world that does NOT limit access to reduce prices and does not reduce the pace of innovation.   Indeed, in the past Bach has argued against using higher priced drugs because they do not add more average survival to patients than older, less expensive drugs developed decades ago.
 
As the last chart shows, the impact of solving for price would be hundreds of thousands of additional cancer patients dying that are alive today.  Note that the steep decline in life years lost began as targeted medicines were introduced compared to what would have happened without new drugs.
 

 Source: The Impact of Pharmaceutical Innovation on Premature Cancer Mortality in Canada, 2000-2011
 
Solving for price exacts a high cost on society. 
 
 
   Read More & Comment...

New FDA Commisioner: Change Agent, not Bomb Thrower

12/15/2016 08:21 AM | Peter Pitts

From the pages of the Washington Examiner ...

Potential FDA chiefs eye faster drug approvals

Donald Trump's potential choices to lead the Food and Drug Administration have called for the agency to ramp up approval of new products, though in drastically different ways.

Two people have been floated as being under consideration to lead the agency: agency veteran and physician Scott Gottlieb and libertarian and investment firm director Jim O'Neill.

Both candidates reflect a desire by President-elect Trump to speed up approval of new products, albeit through different approaches. Trump didn't talk a lot about the FDA during the campaign, but he has said that the agency needs to cut red tape to get new products approved.

O'Neill is the managing director at the investment firm Mithril Capital, which was co-founded by Trump donor and Silicon Valley billionaire Peter Thiel. O'Neill also served as the deputy administrator in the Department of Health and Human Services during President George W. Bush's administration.

He previously has called on the FDA to approve drugs based solely on safety and not on effectiveness, a radical departure from the current approach.
The agency currently approves drugs based on whether they are safe and effective. However, it threads a fine line at times, balancing the risk of a drug versus the expected benefit, especially if it is a new or experimental treatment.

The agency this year approved an experimental therapy called Sarepta for the rare and deadly disorder Duchenne Muscular Dystrophy, but came under fire from consumer advocacy groups who say the agency should have rejected it because of serious safety concerns.

Gottlieb has called for a different regulatory approach at the agency, but hasn't gone to the same extremes as O'Neill.

In July, he advocated for clinical trials for drugs that treat rare diseases. He pointed to the 21st Century Cures Act, which Obama signed into law on Tuesday and would enable the agency to approve drugs using a different clinical endpoint called a surrogate measure.

"These are interim endpoints that can be used to more quickly gauge a medicine's benefit, such as measuring its ability to shrink a patient's liver rather than having to wait for kids to accrue enough disability to see if a drug can help them walk or breathe better," he wrote in the Chicago Tribune.
He also said the law nudges the FDA to make wider use of "adaptive" trials that test a drug on a smaller group of patients.

An agency veteran who worked with Gottlieb said that having support from the agency's career staff is vitally important to getting goals accomplished.
"It is important for the commissioner to be a change agent, not a bomb thrower," said Peter Pitts, a former associate commissioner at the FDA and the president and CEO of the Center for Medicine in the Public Interest. "If you bring in someone who is aggressively contrary to agency culture, those [career staff] will simply wait him out."

However, if a commissioner can get buy-in from career staff who actually review products, it can "help him accomplish it," Pitts said.

Public Citizen, a consumer advocacy group, has problems with both potential picks.

"I don't know if there is any reason to guess that the president has a real vision for the FDA besides the broad brush deregulate," said group President Robert Weissman. "I think that both of these potential candidates are in line with that. Both of them on the pharma side particularly aim to lower the standard of review for new drugs, presumably for existing drugs as well."

It is not clear who Trump will pick for the FDA. However, several other Cabinet picks have shown that Trump is willing to tap people who aim to radically shake up the agencies they are set to lead.

For instance, Trump tapped former Texas Gov. Rick Perry to lead the Energy Department, an agency he pledged to eliminate while running for president in 2012.

He also chose Oklahoma Attorney General Scott Pruitt to lead the Environmental Protection Agency. Pruitt sued the agency on multiple occasions over several regulations and said that people "are tired of seeing billions of dollars drained from our economy due to unnecessary EPA regulations."

Whomever Trump chooses, Pitts said that he is heartened that names are at least being floated early in the transition.

"A lot of times it is left as an afterthought," he said.
   Read More & Comment...

​21st Century Cures could be the tipping point for Alzheimer’s research

12/14/2016 05:35 PM | Robert Goldberg

Note:  Today's blog is from the very talented Nicole Gray, formerly a reporter for BioPharmaDive and now an independent journalist who is covering and commenting on the passage and implementation of the 21st Century Cures Act in terms of how it will affect the patient groups that supported it.   Of note is the role The Critical Path Institute will play in ensuring that many of the objectives enshrined in the legislation are realized. 



Yesterday the Alzheimer’s Association was one of hundreds of patient/disease advocacy groups celebrating passage of the Cures Act. From the beginning, when Representatives Fred Upton and Diane DeGette introduced the bill in May 2015, the association rallied long and hard for this legislation, driven by the sense of urgency around Alzheimer’s disease (AD)—the leading cause of death from a disease that can’t be prevented or cured; the most expensive disease in the U.S. and a disease associated with a tremendous personal burden borne by patients and their families.

When Lilly canceled the solanezumab development program last month, it was disappointing, but not a complete surprise. Unlike oncology, AD drug development has been a battlefield where there have been very few victories. 

Between 2000 and 2012, there were 413 AD trials, including 83 phase III trials. While some of these studies tested disease-modifying or immunologic drugs, most focused on treating symptoms. The overall failure rate was 99.6%. There hasn’t been a new drug approved for AD since 2003 when Namenda was approved for symptomatic treatment of moderate-to-severe AD. 

Despite the high level of risk associated with AD drug development, committed companies continue to pursue R&D in this space, but it’s still not enough. As of December 2016, there are 23 drugs in phase 3 development for AD and 134 active trials---a mere pittance compared with oncology in which there are close to 5,000 active drug trials in process, and more recruiting. 

As Jeffrey Cummings from the Center for Brain Health at the Cleveland Clinic noted earlier this year, “Overall, the ecosystem of AD drug development must be altered to yield more targets and more candidate therapies if a robust pipeline of therapies is to be established.”
That’s where the Cures Act comes in. The AD research community stands to benefit in many ways from this eleventh-hour bipartisan feat, especially from the $1.6 billion Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative and the funding of the EUREKA prize competition to spur innovation in AD research.  

Cures is being hailed as groundbreaking legislation, but for AD researchers, many of the law’s built-in initiatives reflect current best practices in Alzheimer’s R&D---large-scale data-sharing, innovative trials design and mega-collaboration. The day after Cures passed in the Senate, the AD research community convened in San Diego at CTAD to listen to a post-mortem recap from Lilly on sola, as well as more encouraging updates from companies like Biogen, which presented phase 1B data showing that adacanumab successfully reduced beta-amyloid plaques in the brains of AD patients; EIP Pharma, which highlighted positive phase 2A data on neflamapidmod in patients with mild cognitive impairment; Eisai with positive phase 1B data on its BACE inhibitor and Sangamo Biosciences, which presented positive, very early-stage data on its gene therapy.

On the last day of the conference, Anavex Life Sciences, a small company with a first-in-class small-molecule, sigma-1 receptor agonist in phase 2A development for mild-to-moderate AD, presented safety and exploratory efficacy data from a 32-patient study on ANAVEX 2-73.  Phase 2A, 57-week data demonstrated a favorable safety and tolerability profile, in addition to positive functional and behavioral outcomes. There were significant improvements in insomnia, depression and agitation, and patients reported feeling happier, being able to play golf again, enjoying international travel and even having more compassion for children.

The presentation’s high point was the cognition data. The data showed early signs of a disease-modifying effect when ANAVEX 2-73 was compared with the current standard of care, with drug-related improvements in attention, working memory, verbal learning and other cognitive domains, compared with declines in the standard-of-care population. And when treated patients were tracked based on MMSE/ADL/CogState scores, after 57 weeks, the scores hovered right around baseline, suggesting cognitive stability.

“This is the first drug to demonstrate statistically significant improvement in cognitive domains. We were able to learn from the vast data available from other AD trials,” said Christopher Missling, PhD, CEO of Anavex.  “We learned from others’ failures and we were able to factor everything that we know about this disease into our development process.”

As a small company, Anavex has been able to leverage data made available through the Critical Path Institute’s Coalition Against Major Diseases (CAMD) to inform clinical trial design. CAMD facilitates sharing of precompetitive patient-level data from legacy clinical trials, and supported development of a clinical trial simulation tool for AD. 

Because of collaborative culture of the AD research community, and the groundwork laid by CPI and other stakeholders, Anavex was able to successfully use adaptive clinical trial design to test their drug in 32 patients and show a statistically significant effect sufficient to justify moving into phase III. 

The Cures Act is intended to create more opportunities for companies to find methods to determine early on whether a drug has what it takes to cross the finish line---and when a drug shows real potential, and meets rigorous safety standards, new drug-development tools will be available to make the pathway to approval more straightforward. 

“I think the legislation is extremely important because it helps to allocate resources. Time is always lost in the interfaces between companies and the FDA. Every day counts,” said Missling.

In reality, implementation of Cures will be slow-moving. Nonetheless, the additional funding and adoption of more innovate trial design could move the target 2025 date for approval of a disease-modifying AD treatment up a year or two, possibly more. 
That’s what twenty-first century victories are made of---pragmatic, collaborative and relentless research that uses new technologies and reserves of knowledge to accelerate drug development and approval. 
  Read More & Comment...

Gray Goose

12/14/2016 09:08 AM | Peter Pitts

My letter to the NY Times ...

To the editor:

Clyde Haberman, in Lives and Profits in the Balance: The High Stakes of Medical Patents (NYT, December 11, 2016) raises an important issue – and then gets it wrong. Patents save lives and enhance the value of medicines. As Abraham Lincoln said, “Patents add the fuel of interest to the passion of genius.” Mr. Haberman points to the Bayh/Dole Act, and suggests that the innovator pharmaceutical industry is getting a free ride on R&D but, according to an article in Health Affairs, drugs with public-sector patents accounted for only 2.5 percent of US prescription drug spending. Also, Haberman refers to the Hepatitis C medicine Sovaldi as costing $1000 per pill. This is incorrect. Every major insurance company and pharmacy benefit manager (PBM) receives significant double-digit discounts from the manufacturer and now, with competition from other innovator companies, prices are dropping even further. That's the power of patents in a free market. The more important question is, why doesn't this result in lower co-pays for consumers? “Facts,” as John Adams said, “are pesky things.”
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"Elusive" RWE

12/08/2016 10:10 PM | Peter Pitts

Pre PDUFA and post 21st Century Cures vote, BioCentury reports that ...

FDA cautious about real-world evidence

A great deal of work will be required to pave the road for the use of real world evidence in regulatory decisions, wrote FDA Commissioner Robert Califf and 14 other FDA staff members in a commentary published Thursday in the New England Journal of Medicine. The article sets a tone of caution just as the 21st Century Cures Act and PDUFA reauthorization goals commit the agency to create a framework for the use of real-world evidence to make decisions about post-approval studies of drugs and their approval in supplementary indications.

The article describes the definition of real-world evidence as “elusive.” The authors believe it refers to healthcare information "derived from multiple sources outside typical clinical research settings, including electronic health records (EHRs), claims and billing data, product and disease registries, and data gathered through personal devices and health applications.”

It warns that the “allure of analyzing existing data may lead to flawed conclusions," and says this “concern is especially salient in light of the growing proliferation of precision molecular medicine and treatments for rare diseases, many of which are anticipated to undergo review in accelerated approval programs.”

Real-world evidence could play an important role in reviewing such applications, the authors note, which adds to the urgency of developing rigorous methods for collecting and analyzing such information. The authors express optimism about "long-term prospects for the evolution of mature, robust methodologic approaches to the incorporation of real-world evidence into therapeutic development and evaluation," but emphasize that "caution is still needed, and expectations of 'quick wins' resulting from the use of such evidence should be tempered accordingly.  Read More & Comment...

So-called Progressives vs Medical Progress

12/08/2016 10:05 PM | Robert Goldberg

Progressives Against Patients



This week the House and Senate overwhelmingly passed the 21st Century Cures Act.  The legislation increases National Institutes of Health funding, maintains the Cancer Moonshot and Precision Medicine initiatives and provides additional funding for the Food and Drug Administration to support the greater use of information from precision medicine and patient reported outcomes in determining the benefits and risks of new medicines and medical devices.

According to an article by Ed Silverman at STAT: “some consumer advocates and academics warn the legislation contains a provision that may usher in a new era of lower approval standards. 

Here’s why: The bill requires the Food and Drug Administration to develop a program for evaluating the use of so-called “real world evidence” for approving additional uses of medicines, as well as for any follow-up studies that may be required.”

Huh?  How does capturing evidence about the actual clinical risks and benefits of medicines in specific groups of patients translate into lower approval standards.  

Let’s give those who opposed the bill a bit of credit and presume they are uninformed instead of just crazy.  They have no evidence to show that randomized controlled trials guarantee safety or are better at demonstrating effectiveness.  On the contrary, most safety problems are discovered in a haphazard way through adverse event reporting after thousands of uses.  And real world use of medicines provides not information that can be matched against thousands of other data points that randomized trials do not capture.  

In opposing the bill, Public Citizen proclaimed “later-stage “Phase III” trials that have long been the gold standard for drug approval. Well-designed randomized controlled Phase III clinical trials are critical for weeding out bad drugs; more than a third of the drugs that enter Phase III testing fail to gain FDA approval.”

But the “failure” of Phase III trials have little to do with whether or not the drug is safe or even effectiveness at time.  On the contrary, “failure” is a product of being unable to identify reasons for ineffectiveness that would be more accurately and quickly discovered in observational studies.  

Public Citizen has used the gold standard as apolitical tool when convenient.  Michael Carome, MD director of Public Citizen's Health Research Group opposed the approval of Exondys 51 for Duchenne Muscular Dystrophy claiming “It would be a mistake for the FDA to approve this…. It would be giving in to political pressure and essentially eviscerating their standard for approval.... To put out a drug that’s not effective isn’t helping anyone.”   This from a group that has recommended not use ANY new diabetes drug introduced over the past 20 years. 

Ironically, Public Citizen, which now claims randomized trials are the gold standard had fought against their use in testing the effectiveness of HIV drugs in pregnant women living in developing countries.  And some of the groups that were part of the anti-Cures act cabal like Annie Appleseed have pushed for using alternative treatments for cancer that of course undergo no FDA testing at all.  

Similarly, Cures opponents deliberately mislead and misrepresented the truth when they claimed surrogate endpoints -- physical changes or measures that are reasonably likely to predict clinical benefit – leads to ineffective drugs.  Such surrogates are used mostly in a serious or life-threatening disease that lacks good therapies.  As FDA’s Janet Woodcock noted in congressional testimony: “During the last five years (2010-2014), out of a total of 197 novel drugs and original biologics approved across FDA, 84 (43 percent) relied upon a surrogate endpoint for approval. Most of these surrogates have gone on to be well-established tools for measuring drug response or the foundation for biomarkers.”   The talking about weaker standards is as devoid of evidence as it is full of malice. 

The newly found support of randomized trials has nothing to so with watering down FDA standards. It has everything to do with the belief that real world evidence and patient involvement will lead to an increase in the development and use of new medicines and – by extension – benefit drug companies who have a financial interest in getting drugs approved.  

Diane Zuckerman, the President of the far left foundation and trial attorney funded National Center for Health Research -- a woman with little insight and even less expertise about drug development -- pretends to stand up for patients.   She is part of a smear campaign against the hundreds of patient groups that supported Cures Acts, accusing them of being tools of the drug industry.   I will write more on this slander in a future blog.  But for now, let me note that Zuckerman and others like her believe patients can’t be trusted to make such decisions because hope (or pharma funding) clouds their judgment. 

Increasingly medical advances determine not only whether we live or die, but how we will live and die.  Ordinary citizens, those who are potential patients and the friends and relatives of such have as much of a right to determine a drug’s approval as any trial attorney or far left funded lobbying organization.   The anti-Cures Act cabal is more interested in hurting drug companies than in saving lives.   
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Who's next for the White Oak corner office?

12/07/2016 10:09 PM | Peter Pitts

Via Stat News …

President-elect Donald Trump is weighing naming as Food and Drug Administration commissioner a staunch libertarian who has called for eliminating the agency’s mandate to determine whether new medicines are effective before approving them for sale.

“Let people start using them, at their own risk,” the candidate, Jim O’Neill, said in a 2014 speech to a biotech group.

O’Neill, has also called for paying organ donors and setting up libertarian societies at sea — and has said he was surprised to discover that FDA regulators actually enjoy science and like working to fight disease.

A source close to the Trump transition team told STAT that Peter Thiel, the billionaire Trump donor who is helping shape the new administration, is pushing for the FDA appointment for O’Neill, his managing director at Mithril Capital Management.

Trump’s focus on O’Neill was first reported Wednesday morning by Bloomberg.

O’Neill would be an unusual choice. He is not a physician, and lacks the strong science background that nearly all former commissioners have had in recent years.

A graduate of Yale University, with a master’s degree from the University of Chicago, O’Neill went to work at the Department of Health and Human Services in 2002, after a stint as speechwriter at the Department of Education. He worked his way up to principal associate deputy secretary, where he advised the HHS Secretary on all areas of policy, according to his LinkedIn page.

O’Neill first worked with Thiel at Clarium Capital Management, and also ran the Thiel Foundation and Breakout Labs, which funds early-stage companies in areas ranging from food science to biomedicine to clean energy. He is a promoter of anti-aging treatments and technology.

O’Neill also serves on the board of the Seasteading Institute, an organization that aims to create its own sea-based floating communities, on the theory that existing governments are woefully ineffective. “Obsolete political systems conceived in previous centuries are ill-equipped to unleash the enormous opportunities in twenty-first century innovation,” the Seasteading website notes.

O’Neill is not well known in Washington, but has been a frequent speaker on the biotech circuit.

In 2014, in a talk to a group gathered to discuss regenerative medicine, he recalled his days at HHS and expressed disdain for the FDA’s process.
“As a libertarian, I was inclined to believe that the regulatory costs that the FDA impose kill a lot of people and provide a lot of harm to the economy, and I don’t deny that… but one thing that surprised me is that the actual human beings at the Food and Drug Administration like science; they like curing disease and they actually like approving drugs and devices and biologics.”

The problem, O’Neill told the group, is the overall structure and incentives of the regulatory system.

“Every time the FDA commissioner approves something and someone gets sick who used it, the commissioner is summoned to a congressional committee that also controls his budget and forced to testify under oath, why he made this rash decision…It’s a miserable process,” O’Neill said.

O’Neill has proposed that the FDA only require companies to prove drugs are safe before they are sold – not that they actually work.

O’Neill has also said that organ donors should be allowed to be paid. “There are plenty of healthy spare kidneys walking around, unused,” he said in a speech at a 2009 Seasteading conference.

His participation in the Seasteading movement might be a sensitive topic, too. The video of his speech was available on The Seasteading Institute’s website in the afternoon, but by evening, it had disappeared.

In the speech, which is still available elsewhere, O’Neill said that “we can all wish that existing governments will somehow stumble into freedom, but if we want to achieve freedom, seasteads are by far the best prospect.”

Neither O’Neill, Thiel or Trump transition team staffers returned calls seeking comment.

Also under consideration for the FDA job: Dr. Scott Gottlieb, a former FDA deputy commissioner.

Gottlieb, a resident fellow at the American Enterprise Institute, was a senior adviser to the presidential campaign of Wisconsin Governor Scott Walker.  A clinical assistant professor at the NYU School of Medicine, he is a venture partner at the venture capital firm New Enterprise Associates, and a senior principal at TR Winston, a healthcare focused merchant and investment bank. He has testified before Congress 18 times on health and regulatory issues.

Gottlieb was recently named to the transition team.  Read More & Comment...

WSJ Gets It Half Right On Drug Prices

12/07/2016 11:25 AM | Robert Goldberg

Thomas Sowell observed: “A cynic is said to be someone who knows the price of everything and the value of nothing. The same could be said of economic illiterates, many of whom are in politics and the media”.

But often what is perceived as illiteracy is really confirmation basis or just not understanding.  An example of the latter is WSJ reproter Jonathan Rockoff’s article “Drugmakers Find Competition Doesn’t Keep a Lid on Prices”.  Rockoff's article does transcend the usual narrative:that drug prices don’t decline in the face of competition because only drug companies can defy market forces and pass added costs onto consumers.  Rockoff acknowledges that drug companies are not the only culprits.  In making this point, he still implies competition should reduce drug prices without regard to the costs associated with producing goods or services.   In doing so, he perpetuates the meme that drug companies are so profitable they can cut prices and generate new medicines. 

Rockoff apparently has not looked at the relationship between competition, prices and production costs in other industries.

For example, when has Apple or Microsoft or Google engaged in a price war leading to lower prices over the long run? Have cable rates fallen in response to other ways of watching movies, tv shows, etc?   On the contrary, they have not.  Similarly, has Netflix or Amazon or Hulu reduced their prices as the battle for broadband viewership heat up?  

Have the prices hospitals and insurance companies charge fallen?  How about the cost of college? Or closer to home, why has the Wall Street Journal continued to raise its newsstand and digital subscription prices?  Heck, WSJ is laying off a bunch of high paid writers. Shouldn't prices go lower, not higher?   And why is the renewal price higher than the introductory price.  Shouldn't the $99 price be standard? 

The fact is prices are more than a response to competition.  And competition is rarely only about prices.  WSJ increases prices because the costs of staying in business and putting out a good product increase.   Netflix could have continued to charge 6.99 if it didn’t want to invest in new movies and original programming.  Would people be satisfied watching reruns of Law and Order?  

This dynamic is separate and apart from the increase in list prices that fuel higher rebates for insurers and PBMs.    But not totally.  List prices rise in response to the added cost of rebates and other discounts drug companies must give to get market share.  

As Sowell points out (should he really have to?) “Costs are not just prices arbitrarily put on things. Whether the economic system has prices or not, there are real costs for everything. Whether under capitalism, socialism, feudalism or any other system, the real cost of building a bridge are all the homes, factories and other structures that could have been built with the same labor and materials that went into building the bridge.’

To be sure, rebates and discounts don’t mostly flow to the consumers of the drugs generating rebates and discounts.  But that is due to the control insurers and PBMs have over retail pricing.  This is a huge problem as I have pointed out time and again.  Until recently most reporters were unaware of how rebates worked.  (Credit due to me and Peter for doing the explaining!) 

None of the above changes the fact that lower prices can often lead to less innovation across industries or that prices do reflect value in market economies. Generic drug companies don’t innovate and often stop producing essential medicines that go off patent because prices are often drop below increasing production costs. 

Rockoff, like many of us, seek explanations when competition doesn't lead to lower prices.   The key is to look deeper into how competition sustains innovation.  Companies compete on quality, on novelty and on value.  Prices reflect what those qualities or values are as well as the cost of making them.   If we want 1990s prices for anything, college, cellphones or drugs, be prepared for 1990s technology.  
A footnote:  Rockoff’s piece is featured in a WSJ weekly business ethics course reviewed by OC Ferrel, a professor of business ethics at Belmont University.  Ferrel writes: “Students should understand that 'fair' competition should result in competitive or lower prices. This phenomena (sic) is causing increased burden on the health care system and should have public policy consequences.”

Maybe Sowell was not tough enough.  Read More & Comment...