Latest Drugwonks' Blog

Embedding CDER's Centaurs

  • 09.07.2017
  • Peter Pitts
The FDA needs centaurs – and that’s no myth.

Huh?

In the parlance of Artificial Intelligence (AI), a “centaur” is a combination of a human brain and computer intelligence. The centaur model sparked the growth of freestyle chess, a context in which Garry Kasparov concluded that “weak human + machine + better process was superior to a strong computer alone and, more remarkable, superior to a strong human + machine + inferior process.”

Now replace “weak human” with “FDA reviewer.” Get it? According to Brad Bush (COO of Dialexia), “Being a centaur in the workplace means taking advantage of the vast analytical capabilities of AI-enabled technology and adding human thinking.”

As AI innovation continues to advance, we should carefully review the centaur model in terms of the FDA review process and consider how combined human and computing power can augment the evolving methodologies for adaptive clinical trial design and statistical analytics being used to achieve approval via the agency’s various expedited review pathways.

Centaurs, far from being mythological, represent a very real opportunity for drug reviews that are both faster and more accurate – a crucial public health double play.

But isn’t AI risky? Consider this -- machines are terrible risk takers and have no capacity to make leaps of faith. It’s easy for a conversation about AI to devolve into a philosophical discussion about consciousness, because that’s what humans bring to the table — a sense of consciousness and intuition that machines don’t possess. AI isn’t about replacing reviewers, it’s about freeing them to do what they do best – think outside the box! It's precisely that kind of hiuman risk taking the FDA's senior leadership want to see from it's staff.

If you’re an FDA reviewer, ask yourself this question, which end of the centaur do you want to be? Perhaps the FDA needs a new position on its organizational chart – Centaur Director.

As Philip K. Dick wrote, “Reality is that which, when you stop believing in it, doesn’t go away.”

Fahrenheit 483

  • 09.01.2017
  • Peter Pitts
FDA Commissioner Scott Gottlieb has gotten the message – closing the loop on agency inspections is taking too long.

Per the Commissioner:

Manufacturing of drugs has become increasingly complex and global, requiring us to remodel our oversight of these tasks, to improve FDA’s efficiency and reach. As a step toward achieving these goals, FDA previously announced that we’re restructuring our field activities, to direct our focus and organization around the programs we regulate, instead of our previous structure, that organized our activities and resources based on geographic regions. This allows us to better align the expertise of our staff and make more efficient use of our resources.

As another key step towards achieving these goals, the FDA’s Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs (ORA) are implementing a new, historic concept of operations agreement to more fully integrate the drug review programs with the facility evaluations and inspections for human drugs. This new collaboration is a model for how we’ll modernize other parts of our organization to better achieve our mission.

This new agreement leverages two efforts to ensure alignment between FDA’s field professionals and the agency’s review staff. First is the use of “Integrated Quality Assessment” teams. This new, team-based approach aligns field and review staff so that we can make closer consideration of all elements that create risk including the drug substance, the drug product, manufacturing processes, and the state of the facilities we regulate.
Second, on May 15, 2017, we previously announced the structural realignment of ORA. It moved ORA’s previous geographically organized staff and management into program-aligned commodity areas, more closely mirroring the organizational model of FDA’s centers and the industries we regulate. This step enhanced the Integrated Quality Assessment, and the new concept of operations that operationalizes these approaches, by enabling better alignment between our field professionals and the review staff who evaluate the products that are being manufactured in the facilities that we inspect. The unifying hallmark of the integrated quality assessment team and the concept of operations agreement is the closer integration of the professional staff charged with inspecting facilities and the review staff involved in evaluating applications. Experts in our drug program, and our field force, will be aligning their efforts. We believe that this sort of collaboration can better inform the work done across each of these domains. Our inspectional force will benefit from insights that might be offered by the review teams who have carefully evaluated products being manufactured. Meanwhile, our review staff will benefit from the deeper understanding they will glean through more direct and regular contact with the professionals who are inspecting facilities and seeing the kinds of things that can go wrong during the manufacturing process.

Bravo.

His full announcement (and explanation) can be found here. Another victory for enhanced regulatory predictability.
 

A Real World Continuum

  • 08.25.2017
  • Peter Pitts
In a JAMA Viewpoint piece, CDER director Janet Woodcock and colleagues reinforced FDA’s stance on the incorporation of real-world evidence into clinical trials, as well as the use of pragmatic studies pre or post-market to collect data on optimal dosing and treatment effects in subpopulations.

In the piece, FDA defines real-world evidence as any data collected as part of routine clinical care, including electronic medical records and administrative claims data as well as data generated from personal electronic or “smart” devices, social media and socioeconomic tools.

The agency also notes that there is no clear dichotomy between real-world and “non-real-world” evidence and that the two exist in a continuum.

Woodcock and her colleagues reiterated what she told BioCentury in its 2016 Back to School essay about the value of studies that are randomized within the healthcare system, which can allow for the collection of data and results that are more generalizable to how the drug candidate will be used in the real world. They also noted that these studies can be cheaper to conduct and can help to address other regulatory questions post-approval, including optimal dosing, long-term outcomes and benefits in various subpopulations.

Per Woodcock, et al., “It is not feasible to answer all of these questions with traditional RCTs. Using RWE to begin to address these questions is preferable to having no evidence whatsoever.”

CRISPR Questions

  • 08.24.2017
  • Peter Pitts
Cancer survivors can carry germline mutations that will be transmitted to their progeny. Today, many of these mutations have been identified and can be tracked. With the recent development of genome-editing technologies and CRISPR (clustered regularly interspaced short palindromic repeats), the possibility of genetically modifying the human germline—gametes and embryos—has never been closer.

This perspective has sparked a controversy within the scientific community with reactions ranging from calls for a ban on germline modification to cautious approval of further research.

A new article in the DIA journal, Therapeutic Innovation and Regulatory Science, analyzes the possible adoption of CRISPR-based germline engineering to prevent the spread of cancer predispositions in the human population. Implications of CRISPR-Based Germline Engineering for Cancer Survivors discusses whether the genomic edition of human sperm and eggs would contribute to rectifying or altering the heritable genome.

The paper anticipates the emergence of a new form of liberal eugenics fueled by a logic of offer and demand from stakeholders such as cancer survivors and their relatives and offspring, but also from fertility clinics, biotech firms, insurers, and clinicians. From a regulatory perspective, validating the clinical safety and utility of CRISPR-based germline engineering is an essential step. However, with time, gradually perfecting the technology and assessing the economic benefits for stakeholders could soften society’s resistance and align opinions in support of genomic decontamination of human germlines. This progressive shift would be justified in the name of cancer prevention as well as a moral obligation to facilitate the conception of cancer-free children at a cost that is acceptable to individuals and health systems.

It’s a worthwhile read.
Up until recently, Missouri was the only state without a Prescription Drug Monitoring Program for opioids. The good news is that’s changing — sort of. Last month, Gov. Eric Greitens issued an executive order creating one.

The governor’s order directs the state Department of Health and Senior Services to build a database, which will be designed to help identify suspicious patterns of prescriptions of controlled substances — including opioids.

Good news? Seems to be, until you look into the details — where the devil resides. In every other state, doctors and pharmacists can access the database as they write and fill prescriptions, to see where else their patients are getting medications. That won’t be the case under Greitens’ order. What’s wrong with this picture?

Under the new system, dispensers will be required to submit information, but the governor’s order doesn’t give them access to the information. According to Alexandra Dansicker, a policy analyst for the Missouri Foundation for Health, “The intent is to help identify the issues from the supply side of the equation, rather than looking at patient demand and doctor shopping.”

That’s a huge problem that’s being called out by many, including U.S. Sen. Claire McCaskill (D-Mo.), “While I certainly welcome the governor’s attention to this crisis, I have serious questions about how meaningful this action will be if doctors writing prescriptions — and pharmacists filling those prescriptions — don’t have access to this database,” she said in a statement. “The welcome mat is still out for drug dealers to shop for prescriptions in our state.” Instead of an executive order, McCaskill said, state lawmakers should “get off the sidelines and pass a robust statewide program into law that gives law enforcement, pharmacies, and doctors the tools they need.”

Seems obvious, right. What’s going on? Where’s the missing piece? The Kansas City Star offers some valuable reportage: The governor’s executive order was announced “at the St. Louis headquarters of Express Scripts, a pharmacy benefits management company (PBM).”

A seemingly innocuous detail? Hardly. What you smell is the whiff of a smoking gun. It seems that Express Scripts wasn’t recipient of just a gubernatorial visit, but also of a no-bid state contract to administer the PDMP. And here’s another important detail: Express Scripts donated $10,000 to the governor’s inauguration — the PBM’s largest contribution this year and the only one it has made in Missouri.

In addition to the no-bid contract for Express Scripts, Greitens appointed Julia Brncic, the company’s vice president and deputy general counsel, to the governing board of the University of Missouri System.

The Kansas City Star pulls no punches: “The secrecy surrounding Greitens’ fundraising has translated into near constant questions about his motives. And to ethics reform advocates, who argue voters have a right know if special interests are trying to curry favor with politicians, the situation has a corrosive effect on the public’s faith in government.”

Cui bono? Why such largesse from Express Scripts? Is it just a nice gesture for their home state governor? Before you sign onto that chimera, consider this — a $10,000 donation results in a $250,000 no-bid contract. That’s a pretty good return on investment and a nice resume-padder for Ms. Brncic.
Ryan Burns, spokeswoman for the state agency that handles contracting, said data held by Express Scripts and the tools that perform analysis of that data are unique to the company. Under these circumstances, Burns said, state law permits a contract to be awarded without a full competitive bidding process.

But, according to Dr. Robert Twillman, executive director of the Academy of Integrative Pain Management, “No one has designed even simple analytics that make any sense in this arena. If they [Express Scripts] succeed, it will be a modern statistical miracle worthy of some kind of prize. But, of course, we won’t really know what goes into their analytic algorithms, because they’ll keep all that secret. They will just show up to arrest docs and pharmacists on the basis of their black box analytics.”

Now consider with whom the governor is doing business. In 2014, pharmacies sued Express Scripts over its “scheme to deny all claims” for certain customized medications. “The scheme is forcing patients to go without treatment,” the suit stated, “jeopardizing their health and causing bodily harm, or forcing them to pay out-of-pocket sums that they may or may not be able to afford for basic health care needs that have been prescribed by their doctors.”

At a 2014 meeting at the Federal Trade Commission, Dr. Steven Miller (senior vice president and chief medical officer, Express Scripts), said he had research showing that physicians don’t want information from pharmacists telling them which patients have filled a prescription. (Miller was unable to cite the source of this data point.) Well, there are a lot of things “physicians don’t want” — like having to adjust to a world where opioids prescribing must better monitored – but that doesn’t mean they need to be iced out of PDMP access. What does Missouri know that the rest of the nation doesn’t?

Why are Express Scripts and Gov. Greitens being complicit in this illogical PDMP design that is so contrary to the public health? Why the disregard and disrespect for physicians? Part of the answer must lie in the PBM’s historic distrust of doctors’ ability to prescribe what’s best for their patients — as opposed to what’s cheapest. Cui bono indeed — and at whose expense? The opioid epidemic cannot be controlled by disrespecting physicians and pharmacists.

Patients for Affordable Drugs (P4AD) is the faux patient group fronting for the Laura and John Arnold Foundation funded syndicate pushing for European style price controls on drugs.  Along with other Arnold funded academics and organizations, including ICER-  P4AD is demanding that Novartis price it’s breakthrough gene therapy for acute lymphocyte leukemia  ‘fairly’ because “of the fact that U.S. taxpayers invested hundreds of millions of dollars to develop CAR-T before your company became seriously involved.” 

The demand was part of a letter sent by P4AD founder David Mitchell (formerly an executive in a PR firm that received $12 million in drug company funding for Obamacare ads) to Novartis CEO Joe Jimenez. According to a fawning article by Arlene Weintraub in Fierce Pharma, “Mitchell requested a meeting with Jimenez, even offering to bring along two experts in drug pricing: Steven Pearson, president of the Institute for Clinical and Economic Review (ICER), and Aaron Kesselheim, professor at Harvard Medical School and head of its program on regulation, therapeutics and law.” 
Mitchell never reveals that Pearson and Kesselheim also receive funding from the Arnold Foundation.  Weintraub never mentions it either. 

This factual oversight is important since Mitchell proposes that Novartis hold its “price in the United States to the average of prices you receive in six other wealthy nations.”  Or “accepting a value price as established by an independent organization such as the Institute for Clinical and Economic Review (ICER), discounted to reflect American taxpayers’ contributions and assumption of risk.”   

Mitchell’s assertion that NIH invested $200 million in CAR-T that directly contributed to the Novartis drug is a well-crafted lie.  But before dealing with that deception we should explore why discounting the prices of newly developed products that have benefitted in some way from federal support of basic research is a bad idea:

1. It penalizes companies that are successful.

What if the Novartis drug had failed.  Most new medicines never make it to market. Should companies get an NIH rebate when companies invest in products that don’t work? 

2. Why shouldn’t this principle be applied to all successful products developed by people or organizations that at some point in time received federal funding for basic research?

The government had provided billions in support for computing research. About 40 percent goes to universities and 60 percent going to industry and government labs. 
Applying Mitchell’s logic, we should demand that Google, Facebook, Apple, Oracle, etc. should be setting prices “discounted to reflect American taxpayers’ contributions and assumption of risk”.

3. Why stop there?  The government hands out $33 billion a year in Pell Grants to college students.  Shouldn’t these kids starting salaries be “discounted to reflect American taxpayers’ contributions and assumption of risk.”  A third of students getting Pell Grants do not graduate.  Should that money be given back?

When we sell or buy houses, should the prices be “discounted to reflect American taxpayers’ contributions and assumption of risk” in the form of mortgage interest tax deductions?

4. So-called fair pricing requirements reduce private sector investment in NIH sponsored research. 

In 1989 the NIH imposed a reasonable pricing clause on drugs developed using federal basic research support.   The number of direct partnerships between NIH and biotech companies declined steadily declined from 42 in 1989 to 32 in 1995. 

In 1995, the clause was removed.  The NIH director -- Harold Varmus -- noted at the time that the pricing clause had driven industry away from many collaborations with N.I.H. scientists that could have benefited the public. "Eliminating the clause will promote research that can enhance the health of the American people," he said.

By 1997 the number of partnerships surged to 153.  (The NIH averages about 80 such agreements each year. )

Mark Rohrbaugh who ran the technology transfer office at the institutes from 2001 to 2013 and is now an adviser to the agency states that “Companies will not take technologies from us if we say the government will decide in the future what the price will be,” said Mark.  He goes on to say (as noted above) that “after the “reasonable price” clause was struck, he said, there was a threefold increase in partnership deals.”

Now let’s turn to the canard that the NIH invested $200 million in CAR-T research before Novartis dropped a dime. P4AD claims it found 356 NIH projects from1993-2017 containing the phrase “chimeric antigen receptor” (CAR) totaling $204 million. 

There are several problems with this analysis:

1. It includes NIH funding after 2012, the year Novartis began investing.  Replicating PD4D’s search and limiting to 1993-2011 generates 43 grants totaling $18.9 million.
2. Its search is overly broad. It should have at least searched for CAR therapy since CARs are engineered for a variety of research purposes apart from T cell therapy.

A search using the phrase CAR “ therapy” from 1993-2017 yields 33 projects receiving $22.9 million.  But all that funding came AFTER 2011.  Which means that the NIH spent zero dollars on zero CAR therapy projects until Novartis stepped into the picture and after the first results of the CAR-T therapy were published (in 2011). 

Indeed, the Association of Cancer Gene Therapy provided Dr. Carl June who developed the genetically engineered CAR-T approach all the initial funding. NIH provided no funding. 

Dr. June received two grants from ACGT in 2004 and 2008 for his studies in CAR-T therapy for lymphoma and leukemia, and ovarian cancers. On August 10, 2011, Dr. June’s study results were reported in the New England Journal of Medicine and Science Translational Medicine. The results exceeded everyone’s wildest expectations.”

When the FDA advisory committee approved the therapy, June noted: “The funds from ACGT sustained us. When other organizations, including the NIH, considered gene therapy too risky, ACGT believed in the science and funded us when no one else would. ACGT really kept us going and kept the research alive. Without them, we wouldn’t have had a clinical trial and I don’t think we’d be where we are today.”

In 2012, the University of Pennsylvania and Novartis announced a major partnership, in which Penn granted Novartis exclusive rights to its CAR-T therapies. In return, Novartis gave Penn $20 million to fund CAR-T research. Additionally, Novartis is spending hundred of millions of dollars to support clinical trials, manufacturing of genetically engineered T cells and the actual production of the CAR-T therapy which must be tailored to a person's specific genetic and tumor profile. An innovation is something that can be widely used.

P4AD was hoping that the public and media would accept it’s phony $200 million NIH funding estimate at face value to support its equally bogus assertion because it fits the narrative that drug companies are simply free riding off taxpayer funded research or that NIH supported the riskier part of the development process. 

Neither is true.  P4AD is running a  deceptive campaign on behalf of the Arnold Foundation to promote policies that have reduced private investment in NIH research.   If Novartis had been required to negotiate the launch price of CTL019 it would not have provided the $20 million.  It would not have spent hundreds of millions of dollars developing a pilot facility for producing genetically modified T-cells.  In short, many people who were are death’s door and who are alive today – as well as thousands of people in the future facing the same fate – would be dead.




 
Last week I started a twitter argument about narrow networks with Yevgeniy Feyman a (very nice) fellow at the Manhattan Institute.
 
He wrote that we don’t know whether narrow networks negatively impact patients.
 
I responded: BS.  Plenty of evidence.
 
Feynman asked me to show him the data.
 
So, after lobbing a couple of snarky comments (that YG swatted away) I realized I had engaged in a Twitter tantrum instead of responding to his request.  
 
I needed to become more mature and substantive to improve on my original response.  Thank you Yevgeniy for a second chance to act like an adult!
 
So here goes.
 
By narrow networks, I meant and mean excluding or restricting access to hospitals, doctors and other services based on price or cost considerations. That includes the VA, Medicaid and now many exchange plans under the ACA.  (Doug Badger doesn’t call these exchange plans “Medicaid lite” for no good reason.)
 
To be sure, consumer surveys suggest that most people are willing to forgo more choice of providers, hospitals, and medicines in exchange for lower premiums.  People have picked narrow network plans over broader options with increasing frequency and surveys show they tend to be satisfied with their choices.
 
Moreover, while research examining the quality of care provided by plans with limited networks is relatively sparse, there is some evidence to suggest that these plans have performed just as well as those that offer access to a broader range of providers. 
 
At the same time, “according to a Consumer Reports survey, 44 percent of those who bought an Affordable Care Act (ACA) plan for the first time in 2015 reported that they did not know the network configuration associated with their plan. 
 
For the clear majority of consumers, a narrow network can be a good choice and provide good care.
 
For the 5-10 percent of Americans with chronic, fatal or rate conditions narrow networks, evidence suggests, not only fail to deliver the care people are paying premiums (and deductibles) for.  They can also increase the cost and seriousness of the condition.
 
It should also be noted that restrictions go beyond access to doctors and hospitals.  Health plans restrict access to medicines in many ways such as formulary exclusions, prior authorization, high cost sharing and step therapy.  In addition, if someone receives care from a doctor outside of a network than the drug prescribed is also not covered.
 
For example, a recent examination by Harvard researchers of the network composition of health plans offered on the federal Marketplace during 2015 found that nearly 15 percent of the sampled plans lacked in- network physicians for at least one specialty
 
Narrower provider networks are more likely to exclude oncologists affiliated with NCI-Designated or NCCN Cancer Centers. Health insurers, state regulators, and federal lawmakers should offer ways for consumers to learn whether providers of cancer care with affiliations are in or out of narrow provider networks. http://ascopubs.org/doi/abs/10.1200/JCO.2017.73.2040?journalCode=jco
 
There are dozens of studies demonstrating that narrow prescription drug formularies and narrow pharmacy networks hurts patients.  (I link to those articles that review a number of these studies as well as the most impactful citations.)
 
While the ACA bars discrimination in proving coverage, health plans, and PBMs narrow choices because by doing so they can discriminate against the chronically ill.  Offering high priced drugs, hospitals and specialists will attract sicker enrollees into the plan

If plans and PBMs narrow networks to avoid adverse selection once someone is enrolled, it is hard to make a convincing case that they do not shift the burden of disease to patients in one way or another.  And the results of studies examining the impact of narrowing on patient well-being (as well as out of pocket costs) strongly suggest that for chronically ill people, such skinny choices can be sickly as well.  
 
But what if networks were limited to hospitals and medicines that provided the best overall quality and access customized to the specific needs of patients?
 
This quality and patient-focused approach to network development has guided Horizon Blue Cross Blue Shield of New Jersey’s the development of its network of providers, called the OMNIA plan.  Unlike many top-down efforts that require doctors to follow a cookbook or force people into narrow networks, Horizon Omnia has been collaborating with doctors, hospitals and health professionals to encourage wellness and patient-centered care.  About 750,000 of its members are now receiving this type of care from more than 6,500 physicians.
 
Horizon has provided the tools but it’s the doctors that are leading the change.  Primary care doctors now see their patients 3-4 times a year because keeping in touch and engaging in some coaching keeps people healthy.   Orthopedists have partnered to reduce lengthy hospital stays and replaced them with teams of physical therapists and home health aides to get people back home and on their feet more quickly.  And important, Horizon, while making these design changes have made this new arrangement one of many choices available to patients. And so far, that has translated into lower premiums and out of pocket costs.
 
In addition, HBCBS is partnering with GNS Healthcare, a precision medicine company that applies causal machine learning technology to match health interventions to individual patients, to further refine and personalize the Omnia offerings.   As Colin Hill, the CEO of GNS, notes: HBCBS and his company will analyze claims and medical records to predict the disease risks of patients and customize the best treatments.   The goal is to “know the value and efficacy of an intervention for a specific individual, as well as an entire population.”
 
So, the moral of the story is: The quality of a network is not about who you know, but what you know about who you are treating.   That's the difference between most narrow networks and the Omnia approach. 
 
 
 
 
 
 

Expanded Access Sturm und Drang

  • 08.11.2017
  • Peter Pitts
From the pages of MedPage

Will 'Right To Try' Bill Actually Help Anyone?
Little effect from state laws, and industry largely uninterested

By Shannon Firth, Washington Correspondent, MedPage

WASHINGTON -- If a new federal bill is made law, terminally ill patients anywhere in the country would be allowed to request access to experimental treatments that haven't yet received FDA approval -- and deal directly with the companies developing them.

"Patients with terminal diseases ought to have a right to access treatments that have demonstrated a level of safety and could potentially save their lives," said Sen. Ron Johnson (R-Wis.) in a press statement following the Senate's unanimous approval of his bill, "The Trickett Wendler Right To Try Act," a week ago.

The latest draft of Johnson's bill now heads to the House, where similar bills have already been filed.

Critics of the right-to-try movement say it's unsafe, exploitative, and a "smokescreen" for an anarchist agenda.

Others argue that right-to-try laws are redundant, since the FDA already has an "expanded access" pathway (sometimes called "compassionate use") that allows patients to receive investigational treatments.

The American Society of Clinical Oncology (ASCO) made this argument in stating its opposition to right-to-try legislation.

"ASCO supports access to investigational drugs outside of clinical trials, when adequate patient protections are in place," ASCO chief medical officer Richard Schilsky, MD, said in a statement in April. "We don't support right-to-try legislation, however, because these laws ignore key patient protections without actually improving patient access to investigational drugs outside of clinical trials."

Instead, ASCO backs the FDA's expanded-access program.

But right-to-try proponents view the new federal bill as a critical tool for seriously ill patients, allowing them to bypass the FDA's red tape and decide the course of their own care.

"If a patient truly is dying, and there truly is no other remedy, and they want to try for a 'Hail Mary,' and truly understand the risks and benefits, then it is hard not to offer them an opportunity -- assuming the integrity of clinical trials can be maintained. Because, if not, there can be risks to future patients," said Robert Field, JD, PhD, MPH, a professor of law and health policy at the Dornsife School of Public Health at Drexel University in Philadelphia.

The Senate Bill

As passed by the Senate, Johnson's bill requires that, to be eligible for early access, treatments must be under an active Investigational New Drug application and have completed a phase I trial. And it obliges drug companies to submit annual reports to the agency that include adverse events.
A physician must certify that patients have "exhausted approved treatment options and [are] unable to participate in a clinical trial involving the eligible investigational drug," and patients must have "written informed consent" to the referring physician. Also, current FDA regulations limiting what companies can do to promote or market investigational drugs would still apply.

But the bill also includes several protections for drugmakers who participate. They can't be sued except for "reckless or willful misconduct, gross negligence, or an intentional tort," and the FDA can't use clinical outcomes from use of investigational treatments in its regular review process, unless senior FDA staff make a documented determination that "use of such clinical outcome is critical" for judging the product's safety.

The bill does limit what patients can be charged for investigational drugs to companies' actual direct costs of providing them. (But enforcement could be difficult: companies are not required to inform regulators of what they provide to individual patients, nor the costs to patients.)

The legislation already appears to have support from the White House. Vice President Mike Pence, former governor of Indiana, signed his state's right-to-try bill in 2015.

In 2014, Colorado was the first state to pass a right-to-try law. But the movement began long before that amid the HIV epidemic of the 1980s, as portrayed in the film "Dallas Buyers Club."

In more recent years, the Goldwater Institute, a Phoenix-based libertarian think tank, has led the right-to-try movement. "There's no more fundamental freedom than the right to save your own life ... Right to Try will open new paths to treatments for many patients who are currently out of options," said Victor Riches, the institute's president and CEO, in a press statement.

If someone is desperate, "I don't think a person or agency has a right to tell that terminally ill person, 'I'm sorry I don't think I'm going to let you try this' ... It should be up to them," added Jeffrey Singer, MD, a senior fellow at the Cato Institute, another libertarian think tank.

Singer, a general surgeon in private practice in Phoenix, said passing a federal bill would prevent the FDA from simply overriding state laws.

Industry a No-Show

For the legislation to have any real effect, it will naturally require participation by industry. But that is far from assured. The bill doesn't oblige drug companies to make treatments available. And no pharmaceutical companies have come forward to embrace the bill or promise to make drugs available; some have opposed it.

"While well-intentioned, current 'Right-to-Try' legislation is not in the best interest of patients and is unlikely to help us bring forward innovative, safe, and effective medicines to all patients as quickly as possible," pharma giant Merck & Co. said in a statement issued earlier this year.

Richard Garr, formerly CEO of Neuralstem Inc., which is developing cell therapies and small-molecule drugs for a variety of neurological conditions including spinal cord injury and amyotrophic lateral sclerosis, testified in support of Johnson's bill at a September 2016 hearing.

But Neuralstem's current management disagrees. In a statement sent to MedPage Today, the company said, "We feel that providing access to our investigational therapies outside of our ongoing and critical clinical trials may delay or jeopardize the approval of therapies, by reducing the supply of study agents or adversely affecting the data collection process. By focusing on clinical development and seeking regulatory approval, it is our goal to offer our therapies to the largest number of patients as quickly as possible."

The Pharmaceutical Research Manufacturers Association (PhRMA) has issued a series of noncommittal statements about the legislation as it worked its way through the Senate, all of which stopped short of endorsing the bill.

"We appreciated the opportunity to work with Sen. Johnson on the bill and look forward to continuing to work with his office," wrote Andrew Powaleny, director of public affairs for PhRMA, in a recent email to MedPage Today. "The revised Right to Try legislation that passed the Senate includes important protections for patient safety and the clinical trial process."

Medical ethicist Arthur Caplan, PhD, of New York University, noted that early access to investigational drugs puts drug companies instead of the FDA into the role of gatekeepers, and negative publicity is among their major concerns.

If one patient has a serious adverse event following an experimental therapy, that could scare off investors, Caplan said.

"As long as you have private sector investment driving drug development, the priority is to get the drug approved and sold and not to start giving it away," he noted.

The record with state-level right-to-try laws also suggests lackluster interest from industry. "It's telling that although 37 states have adopted these laws, when asked to provide examples of success stories, one of the primary groups pushing for their adoption can only provide the testimonies of six patients who received access to experimental medicines through a single physician in a single state," Rachel Sachs, an assistant professor of law at Washington University in St. Louis, told RAPS recently.

"The net impact of state right-to-try laws has been absolutely nothing. I don't expect a federal right-to-try law will change that," said Caplan, dismissing Johnson's bill as "a feel-good" exercise.

Redundant, Fraught with Risk

"It's entirely [for] show ... This bill is not going to expedite, accelerate or ease the burden of a single patient getting access to experimental medicine," said Peter Pitts, president and co-founder of the Center for Medicine in the Public Interest, a nonprofit medical issues research group. Pitts is also a former FDA associate commissioner for external relations.

The FDA already approves 99% of the requests for expanded access that it receives, Pitts noted. In fact, in 2016 the agency introduced a streamlined pathway to further accelerate the process, and one report indicated that the agency's average response time is 4 days. An FDA official told MedPage Today that emergency requests are usually granted immediately.

"It's not as if the agency is turning people away," Pitts said.


Carolyn Engelhard, MPA, director of the Health Policy Program at the University of Virginia School of Medicine's Department of Public Health Sciences, in Charlottesville, Va., told MedPage Today that the FDA's expanded access program already offers the same options as right-to-try but with more "checks and balances."

Engelhard predicts that a federal right-to-try program won't produce a "groundswell of drugs" that couldn't have already been accessed through the expanded use program.

Critics also said the bill's stipulation that drugs must have completed phase I testing does not offer very much assurance of safety.

Most drugs entering phase II trials never make it to market, usually because they turn out to be ineffective or because of safety issues not spotted in phase I. "So it is possible that patients will be taking something of no help, or that creates new health problems," Field said.

Mat Staver, JD, founder and chairman of Liberty Counsel, a self-described "international litigation, education, and policy ministry," said he supported the right-to-try concept. But he stressed that whatever new path develops should be monitored from a cost and availability standpoint, and studied to determine whether people are being exploited and whether the pathway is effective.

Engelhard, meanwhile, called the entire effort a "political smokescreen" for anti-regulation ideologues hoping to get patients believing they can sidestep the FDA and go straight to drug companies for treatments.

"It sounds like it's pro-patient, but by removing the FDA it opens the door for greater risk for fraud and abuse," she said.

Senior Associate Editor Charles Bankhead and Managing Editor John Gever contributed to this story.

Embracing Generic Complexity

  • 08.09.2017
  • Peter Pitts
“Generic” does not mean “identical” – nor does it mean “easy.” FDA Commissioner Scott Gottlieb understands these basic tenets of drug development and has created a working group of senior FDA staff that will look for ways to increase generic competition by embracing complexity.

The working group will propose options for using FDA's existing authorities and may develop legislative proposals to respond to changes in technology and in the marketplace that have occurred since the Hatch-Waxman Act was enacted in 1984. For example, it will consider whether and how ANDAs for complex products, such as those combining a drug and a device, may include clinical data. This isn’t a simple change. It’s a revolution in generic drug labeling – recognizing what pharmacologists and physicians have known for decades – that “bioequivalent” doesn’t mean “identical” – and that for some products, that’s more important than for others.

Just as the agency recognizes that biosimilar labeling can recognize both similarity and differences, that recognition will now be used to help determine the appropriate use of generic medicines. Gottlieb has expressed concern for years that FDA policies don’t adequately support the development of generic versions of complex products. To paraphrase Dr. Harry Lever of the Cleveland Clinic, we mustn’t lose control of what patients are swallowing.

Per the FDA, “Consistent labeling will assure physicians, health professionals, and consumers that a generic drug is as safe and effective as its brand-name counterpart.” But “consistent” doesn't mean “identical” – especially when the data says otherwise. We live in the Information Age. Knowledge is power.

Working group members will include Elizabeth Dickinson, an attorney in FDA's Office of the Chief Counsel who served as the agency's Chief Counsel during the Obama administration; Grail Sipes, director of the Office of Regulatory Policy at FDA's Center for Drug Evaluation and Research (CDER); and Maryll Toufanian, deputy director of CDER's Office of Generic Drug Policy.


David Mitchell is the founder of a group called Patients for Affordable Drugs.  He claims he is a consumer advocate crusading against high drug prices.  In fact, Mitchell's organization received a large grant from the Laura and John Arnold Foundation.  P4AD is part of a syndicate of think tanks, advocacy organizations and media outlets the Arnold Foundation is funding to the tune of $25 million.  (For the record, CMPI receives funding from pharmaceutical and biotech firms. )

As for attacking drug companies, it turns out Mitchell took $12 million from pharmaceutical companies to run campaigns in support of the Affordable Care Act.   

Perhaps because he is running a political operation like he did for Obamacare, he cares little about facts or context.  But I do.  And I hope the reporters that now have Mitchell on their Twitter feed do are asked to buy his deceptive narrative do so as well. 

And the fact is Mitchell's sob story about Revlimid doesn't add up. 

He claims his co-pay for Revlimid - the myeloma drug Mitchell takes went from $42 to $250 over the last few years while the list price of Revlimid jumped from $8,000 to $10,691 for a four-week supply over the same time period.  Ergo, his co-pays climbed in response to the price increase. 

But that means the list price increased by 33 percent while the copay increased 500%.   The list price is set by Celgene, but the copay is set by health plans.  So the co-pay increase exceeded the list price increase by a factor of 15.  

Also, since Medicare covers a large portion of spending novel cancer therapies, PBMs also generate rebates and other fees not passed on to the patient.   Such Medicare rebates are about 15-20 percent of the retail price according to recent estimates. 

That means that the PBMs got another $536 per month from Celgene.  Remember that the co-pay increased to $250.  So that means the PBMs did not pass on the rebate and indeed collected more co-pays while pocketing the rebate money.   Moreover, Celgene offers copay assistance to people who can't afford the increase in out pocket cost.  In fact, a study found that "after financial assistance, 86.2% of patients had a direct cost of less than $50 per prescription. That money goes to the PBMs too.   Either way, the PBMs collect an additional $9432 a year from people in Mitchell's plan.    

And yet all Mitchell can think of doing is suing Celgene? 

Mitchell is claiming Celgene is blocking the production of a generic form of Revlimid by refusing to provide generic companies with samples to base production on.  Mitchell also claims that as a result,  his co-pays would go down. 

Let's deal with latter claim first. Indeed, if Revlimid went generic, there is no guarantee that it would reduce out of pocket costs.  PBMs have placed several generic cancer and HIV drugs on the highest cost sharing tier in the past.  Moreover, PBMs -- who set the price of generics when they sell them at drug stores -- mark up the prices.  In addition, they charge a co-pay that often exceeds the cost of the medicine.  Again, Mitchell is silent on these practices.  

Secondly, and contrary to Mitchell's claim, Celgene HAS been working with generic companies to provide their medicines.  As Erika Lietzan Associate Professor of Law, University of Missouri School of Law wrote: "Notwithstanding the rigorous REMS protocol, Celgene has provided Thalomid to generic drug companies that want to develop and test generic copies of the drug and that agree to Celgene’s risk mitigation policies. Celgene has done so when those companies provided documentation and information confirming steps and safeguards that would not only prevent fetal exposure but also minimize the risk for Celgene’s business and reputation, such as risk from products liability litigation. Mylan—one of the generic companies—has declined to provide information requested by Celgene, however, and instead filed an antitrust suit that is still pending in federal court."

Suing Celgene is just a publicity stunt to Mitchell.  But wiping out patent life  would eliminate any future investment.  Over the past few years, Celgene was investing hundreds of millions of dollars in clinical trials to demonstrate the clinical benefit of Revlimid to newly diagnosed myeloma patients.  That will stop when the product goes off patent.   Generic companies don't invest in the future, only the past.  If Mitchell were honest, he would acknowledge that and much more. 


 

CMPI

Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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