Latest Drugwonks' Blog

War Against the Orphans

  • 09.20.2017
  • Robert Goldberg
Great piece in the Weekly Standard by former HHS General Counsel Mike Astrue about the well-organized war against people with rare diseases.  What Mike doesn't note is that the war is being financed largely by the Laura and John Arnold Foundation.   More on this connection after Rosh Hashana.  

Gottlieb Gets Real ... World Evidence

  • 09.20.2017
  • Peter Pitts
Yesterday, at a National Academy of Sciences workshop on Real World Evidence, FDA Commissioner Scott Gottlieb expressed the agency’s commitment to advancing the use of RWE, defended the idea that data from clinical experience should be incorporated into regulatory decisions, and acknowledged that the agency won’t have the last word when it comes to interpreting real world evidence.

BioCentury reports that Gottlieb took on critics who say FDA should only consider data from randomized, controlled trials. “For those who’d challenge the suitability of our effort to incorporate real world evidence into our regulatory model, I’d challenge you with the opposite intention: Should a product be marketed based on a data set that speaks to a limited and rigidly constructed circumstance, when the clinical use, and in turn the evidence we might have to evaluate the product, could have been far richer, far more diverse, and more informative?”

RWE is essential to making FDA’s decisions relevant to entire healthcare system, Gottlieb said. He noted that data gathered from routine clinical experience is already being used to make medical, payment and coverage decisions. “We need to close the evidence gap between the information we use to make FDA’s decisions, and the evidence increasingly used by the medical community, by payers, and by others charged with making healthcare decisions.”

In a move that is unusual for a regulator, Gottlieb acknowledged that FDA’s policies on and interpretation of RWE may not be definitive. “FDA needs to think of itself as a curator of information, not just an arbiter, where a single truth standard is secured to a fixed orthodoxy.” He added: “There’s often no single truth standard when it comes to the evidence used to support medical decisions.”

Gottlieb placed RWE in the context of a regulatory life cycle that extends well beyond product approval. “No product is all risky and uncertain one day, and completely safe and effective the next,” he said. “We can’t allow our need for a point of regulatory accountability to prevent us from looking across the line we have to draw, at practical information that’s collected both before and after our point of demarcation, when a product gains a license for initial market entry."

Getting more reliable RWE will require changes in the way clinical data is collected, Gottlieb said, including a shift from electronic health records designed primarily to support billing to records that routinely capture information about what is happening with patients. He also committed FDA to take steps to provide more clarity about the requirements for using RWE in regulatory submissions.

Vinay Prasad's Fake Pharma Numbers

  • 09.19.2017
  • Robert Goldberg
Attempting to discredit the $2.6 billion drug development cost a developed by Joseph DiMasi is a long-standing tradition among those who think that pharma is too profitable and greedy. [i]

But why contend with the DiMasi numbers and submit your analysis to a leading economic journal when you can just fabricate your own lowball estimates and get published in a second-tier medical journal run by your friends and allies in the war against Big Pharma?

That’s what Vinay Prasad and Sham Mailankody did when they published Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval in JAMA Internal Medicine.  The study looks at 10 small biotech companies that successfully developed a cancer drug over the past 15 years, The authors conclude that on average it costs $648 million (not including capital costs) to develop a drug to generate an average of $7 billion in revenue.   They also claim that “sales of these 10 drugs since approval was $67.0 billion compared with total R&D spending of $7.2 billion.” 

In a shot at DiMasi, Prasad and Sham claim “this analysis provides a transparent estimate of R&D spending on cancer drugs and has implications for the current debate on drug pricing.”

In fact, the article consists of falsehoods, carefully constructed to fit that narrative. And that’s not including many of the study’s methodological flaws such as inflating all prior spending and revenues to 2017 dollars and using a low cost of capital (7 percent) when the cost of capital for biotech is closer to 16-20 percent.

Far worse is the outright distortion of data to reach a preordained conclusion. To get to $67 billion in revenues from $7.2 billion in R&D, the authors had to count the proceeds of acquisitions as product sales. They included Pfizer’s acquisition of Medivation for $14 billion, Takeda’s purchase of Ariad for $4 billion, Abbie Vie’s acquisition of Pharmacyclics for $22 billion.   

Next, the authors understate R&D expenditures. (To find that data and other information the authors “reviewed publicly available SEC 10-K filings, available at the SEC website ...and all expenses listed as R&D were totaled for the cumulative duration of R&D for each drug.”)

In fact, after reviewing the same 10-K filings it is clear the authors deliberately exclude R&D for expanded uses of the approved drug, post-marketing studies and trials needed for approvals in other countries.  They also exclude any R&D spending for new projects even though the revenues of the approved drug were being used to fund those efforts.

The charts below take the data from the 10K reports of the companies the authors surveyed and states it as reported to the SEC. Absent the Enron style accounting of the authors, the data is a more truthful representation of the total R&D and profits (or losses) the companies generated individually and as a ‘portfolio’.  


Whereas the authors want you to believe there is a $60 billion profit from R&D in fact, only 2 of the 10 companies had cumulative profits. As a ‘portfolio’ the group lost money and spent 66 percent of gross profits on R and D. Prasad and Sham claim that it’s only 10 percent of revenues.

Further, the authors are conspicuously uninterested about what companies did with revenues from approved products. In fact, every company increased R&D and spent more on production facilities over the years reviewed. As I noted, much of the added spending went to finding new therapeutic uses for their products, as well as completing post-marketing studies and trials to obtain approval overseas. Ignoring that R&D investment is also hypocritical since the purchase price of the companies that the authors misleadingly count as revenue were based on the pipeline and the platform producing the each firm's approved drug.

Indeed, an objective editor of a journal of economics would have caught this intellectual malfeasance. More broadly, an editor might have if developing new drugs is anywhere from 75 to 90 percent cheaper than reliable and reproducible estimates of about $2 billion, why haven’t more companies jumped in? If these activists have cracked the code of drug development set up a company and sell drugs at their “just price” (slightly above the cost of production) why haven’t venture capitalists funded their startup? Because the model the authors construct is based on lies that promote a fiction that cannot be found in the real world.

But that’s the point. The depiction of profitability especially among the smaller companies that are the largest source of new medicines is deliberately deceptive. It is designed to replace objective truth with a narrative and hard evidence with soft propaganda.

The article should be retracted, but that’s unlikely. Prasad discloses that he receives funding from the Laura and John Arnold Foundation. So does ICER. That connection is important because Rita Redberg, the editor of JAMA Internal Medicine is also working for ICER and her position is largely possible because of Arnold funding as well. Moreover, Redberg wrote an article with Prasad to support ICER’s position on the price of specific medicines and supports Prasad’s assertion that most cancer drugs are not really that effective.

The Prasad and Redberg collaboration, including the use of medical journals as outlets, is part of a bigger effort and group of activists funded by the Arnold Foundation.  In addition to Prasad and ICER (and others), the Arnold Foundation is funding media outlets to spread these mistruths once they are placed in medical journals friendly to the cause. The goal is to replace objective truth with a narrative in which the enlightened Arnold acolytes tell the rest of us what drugs should cost, what medicines we should use and what lives are worth saving. 

Where is the FDA going with off-label speech? Here’s what Commissioner Gottlieb had to say last week:

“It’s very clear right now that the courts recognize commercial free speech as constitutionally protected, and it’s very clear that the agency has lost a series of First Amendment challenges … What I want to make sure is that we have a legally enforceable set of rules that we’re operating from that we’re able to use to promote our public health goals. So we need to have clear regulation that is legally sustainable and we need to enforce against that vigorously.”

“To the extent that we have certain regulatory parameters that either we feel or others feel is in conflict with the court’s interpretation of what constitutes commercially protected speech and the cope of FDA’s ability to regulate that, we need to resolve that. We can’t be operating from a platform where our regulations might be in perpetual conflict with the courts and then we are reluctant to take action for fear that we might run afoul of the courts. We need to have clear regulation that is aligned with the interpretations of the courts around what is and what isn’t permissible and we need to enforce vigorously against that.”

Key phrase, “We need to have clear regulation.” That’s as welcome news as it is unusual since (when it comes to regulating speech), the agency’s default proposition has been vigorous ambiguity.

The Commissioner’s statement also seems to throw onto the dustbin of history, the agency’s memo (issued in the waning days of the Obama administration) Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products, which asserted FDA's stance against off-label communications.

Gottlieb-watchers understand his support of making sure physicians and patients have access to truthful accurate and non-misleading information about FDA-approved medicines –- both on and off-label. Time marches on and regulatory practices must evolve to better serve the public health.

Off-label communications is about getting the right medicine to the right patient in the right dose at the right time.  Off-label communications advances both the practice of medicine and the safe and effective use of medicines.

Stay tuned.
Amid Opioid Crisis, Insurers Restrict Pricey, Less Addictive Painkillers

Drug companies and doctors have been accused of fueling the opioid crisis, but some question whether insurers have played a role, too.
by Katie Thomas, The New York Times and Charles Ornstein, ProPublica

At a time when the United States is in the grip of an opioid epidemic, many insurers are limiting access to pain medications that carry a lower risk of addiction or dependence, even as they provide comparatively easy access to generic opioid medications.

The reason, experts say: Opioid drugs are generally cheap while safer alternatives are often more expensive.

Drugmakers, pharmaceutical distributors, pharmacies and doctors have come under intense scrutiny in recent years, but the role that insurers — and the pharmacy benefit managers that run their drug plans — have played in the opioid crisis has received less attention. That may be changing, however. The New York State attorney general’s office sent letters last week to the three largest pharmacy benefit managers — CVS Caremark, Express Scripts and OptumRx — asking how they were addressing the crisis.

ProPublica and The New York Times analyzed Medicare prescription drug plans covering 35.7 million people in the second quarter of this year. Only one-third of the people covered, for example, had any access to Butrans, a painkilling skin patch that contains a less-risky opioid, buprenorphine. And every drug plan that covered lidocaine patches, which are not addictive but cost more than other generic pain drugs, required that patients get prior approval for them.

In contrast, almost every plan covered common opioids and very few required any prior approval.

The insurers have also erected more hurdles to approving addiction treatments than for the addictive substances themselves, the analysis found.
Alisa Erkes lives with stabbing pain in her abdomen that, for more than two years, was made tolerable by Butrans. But in January, her insurer, UnitedHealthcare, stopped covering the drug, which had cost the company $342 for a four-week supply. After unsuccessfully appealing the denial, Erkes and her doctor scrambled to find a replacement that would quiet her excruciating stomach pains. They eventually settled on long-acting morphine, a cheaper opioid that UnitedHealthcare covered with no questions asked. It costs her and her insurer a total of $29 for a month’s supply.

The Drug Enforcement Administration places morphine in a higher category than Butrans for risk of abuse and dependence. Addiction experts say that buprenorphine also carries a lower risk of overdose.

UnitedHealthcare, the nation’s largest health insurer, places morphine on its lowest-cost drug coverage tier with no prior permission required, while in many cases excluding Butrans. And it places Lyrica, a non-opioid, brand-name drug that treats nerve pain, on its most expensive tier, requiring patients to try other drugs first.

Erkes, who is 28 and lives in Smyrna, Georgia, is afraid of becoming addicted and has asked her husband to keep a close watch on her. “Because my Butrans was denied, I have had to jump into addictive drugs,” she said.

UnitedHealthcare said Erkes had not exhausted her appeals, including the right to ask a third party to review her case. It said in a statement, “We will work with her physician to find the best option for her current health status.”

Matthew N. Wiggin, a spokesman for UnitedHealthcare, said that the company was trying to reduce long-term use of opioids. “All opioids are addictive, which is why we work with care providers and members to promote non-opioid treatment options for people suffering from chronic pain,” he said.

Dr. Thomas R. Frieden, who led the Centers for Disease Control and Prevention under President Obama, said that insurance companies, with few exceptions, had “not done what they need to do to address” the opioid epidemic. Right now, he noted, it is easier for most patients to get opioids than treatment for addiction.

Faced with competition, some pharmaceutical companies are cutting deals with insurance companies to favor their brand-name products over cheaper generics. Insurers pay less, but sometimes consumers pay more. Adderall XR, a drug to treat attention-deficit hyperactivity disorder, is a case in point.
Leo Beletsky, an associate professor of law and health sciences at Northeastern University, went further, calling the insurance system “one of the major causes of the crisis” because doctors are given incentives to use less expensive treatments that provide fast relief.

The Department of Health and Human Services is studying whether insurance companies make opioids more accessible than other pain treatments. An early analysis suggests that they are placing fewer restrictions on opioids than on less addictive, non-opioid medications and non-drug treatments like physical therapy, said Christopher M. Jones, a senior policy official at the department.

Insurers say they have been addressing the issue on many fronts, including monitoring patients’ opioid prescriptions, as well as doctors’ prescribing patterns. “We have a very comprehensive approach toward identifying in advance who might be getting into trouble, and who may be on that trajectory toward becoming dependent on opioids,” said Dr. Mark Friedlander, the chief medical officer of Aetna Behavioral Health who participates on its opioid task force.

Aetna and other insurers say they have seen marked declines in monthly opioid prescriptions in the past year or so. At least two large pharmacy benefit managers announced this year that they would limit coverage of new prescriptions for pain pills to a seven- or 10-day supply. And bowing to public pressure — not to mention government investigations — several insurers have removed barriers that had made it difficult to get coverage for drugs that treat addiction, like Suboxone.

Experts in addiction note that the opioid epidemic has been changing and that the problem now appears to be rooted more in the illicit trade of heroin and fentanyl. But the potential for addiction to prescribed opioids is real: 20 percent of patients who receive an initial 10-day prescription for opioids will still be using the drugs after a year, according to a recent analysis by the CDC.

Several patients said in interviews that they were terrified of becoming dependent on opioid medications and were unwilling to take them, despite their pain.

In 2009, Amanda Jantzi weaned herself off opioids by switching to the more expensive Lyrica to treat the pain associated with interstitial cystitis, a chronic bladder condition.

But earlier this year, Jantzi, who is 33 and lives in Virginia, switched jobs and got a new insurer — Anthem — which said it would not cover Lyrica because there was not sufficient evidence to prove that it worked for interstitial cystitis. Jantzi’s appeal was denied. She cannot afford the roughly $520 monthly retail price of Lyrica, she said, so she takes generic gabapentin, a related, cheaper drug. She said it does not manage the pain as well as Lyrica, which she took for eight years. “It’s infuriating,” she said.

Jantzi said she wanted to avoid returning to opioids. However, “I could see other people, faced with a similar situation, saying, ‘I can’t live like this, I’m going to need to go back to painkillers,’ ” she said.

In a statement, Anthem said that its members have to meet certain requirements before it will pay for Lyrica. Members can apply for an exception, the insurer said. Jantzi said she did just that and was turned down.

With Butrans, the drug that Erkes was denied, several insurers either do not cover it, require a high out-of-pocket payment, or will pay for it only after a patient has tried other opioids and failed to get relief.

In one case, OptumRx, which is owned by UnitedHealth Group, suggested that a member taking Butrans consider switching to a “lower cost alternative,” such as OxyContin or extended-release morphine, according to a letter provided by the member.

Wiggin, the UnitedHealthcare spokesman, said the company’s rules and preferred drug list “are designed to ensure members have access to drugs they need for acute situations, such as post-surgical care or serious injury, or ongoing cancer treatment and end of life care,” as well as for long-term use after alternatives are tried.

Butrans is sold by Purdue Pharma, which has been accused of fueling the opioid epidemic through its aggressive marketing of OxyContin. Butrans is meant for patients for whom other medications, like immediate-release opioids or anti-inflammatory pain drugs, have failed to work, and some scientific analyses say there is not enough evidence to show it works better than other drugs for pain.

Dr. Andrew Kolodny is a critic of widespread opioid prescribing and a co-director of opioid policy research at the Heller School for Social Policy and Management at Brandeis University. Kolodny said he was no fan of Butrans because he did not believe it was effective for chronic pain, but he objected to insurers suggesting that patients instead take a “cheaper, more dangerous opioid.”

“That’s stupid,” he said.

Erkes’s pain specialist, Dr. Jordan Tate, said her patient had been stable on the Butrans patch until January, when UnitedHealthcare stopped covering the product and denied Erkes’s appeal.

Without Butrans, Erkes, who once visited the doctor every two months, was now in Tate’s office much more frequently, and once went to the emergency room because she could not control her pain, thought to be related to an autoimmune disorder, Behcet’s disease.

Tate said she and Erkes reluctantly settled on extended-release morphine, a drug that UnitedHealthcare approved without any prior authorization, even though morphine is considered more addictive than the Butrans patch. She also takes hydrocodone when the pain spikes and Lyrica, which UnitedHealthcare approved after requiring a prior authorization.

Erkes acknowledged that she could have continued with further appeals, but said the process exhausted her and she eventually gave up.
While Tate said Erkes had not shown signs of abusing painkillers, her situation was far from ideal. “She’s in her 20s and she’s on extended-release morphine — it’s just not the pretty story that it was six months ago.”

Many experts who study opioid abuse say they also are concerned about insurers’ limits on addiction treatments. Some state Medicaid programs for the poor, which pay for a large share of addiction treatments, continue to require advance approval before Suboxone can be prescribed or they place time limits on its use, both of which interfere with treatment, said Lindsey Vuolo, associate director of health law and policy at the National Center on Addiction and Substance Abuse. Drugs like Suboxone, or its generic equivalent, are used to wean people off opioids but can also be misused.

The analysis by ProPublica and The Times found that restrictions remain prevalent in Medicare plans, as well. Drug plans covering 33.6 million people include Suboxone, but two-thirds require prior authorization. Even when such requirements do not exist, the out-of-pocket costs of the drugs are often unaffordable, a number of pharmacists and doctors said.

At Dr. Shawn Ryan’s addiction-treatment practice in Cincinnati, called BrightView, staff members often take patients to the pharmacy to fill their prescriptions for addiction medications and then watch them take their first dose. Research has shown that such oversight improves the odds of success. But when it takes hours to gain approval, some patients leave, said Ryan, who is also president of the Ohio Society of Addiction Medicine.

“The guy walks out, and you can’t blame him,” Ryan said. “He’s like, ‘Hey man, I’m here to get help. What’s the deal?’”
When members of the tort bar start to salivate over a piece of legislation, it’s worthwhile to find out where the red meat resides.

In a rush to pass legislation to “lower drug prices,” lawmakers are pushing forward two pieces of parallel legislation, the Senate’s Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act and another House bill the Fair Access for Safe and Timely (FAST) Generics Act of 2017.

Both bills are being viewed by some as possible CHIP “pay for” legislation.  The Senate Finance is holding a hearing next Wednesday and the House wants a vote by end of September. It’s time to take a breath – because neither of these pieces of legislation will speed generic drugs to market or lower the cost of medicines for a single American. What they will most certainly provide is a windfall for the trial lawyers.  

Both bills aim to provide a series of new legal provisions will make it easier for drug companies to introduce generic alternatives, thus spurring competition and bringing down prices. Both are well intentioned. Unfortunately, they’re worded poorly – leading to dangerous unintended consequences. Instead of bringing generics to market sooner, these bills could endanger patients’ lives and encourage costly, needless litigation.

Both bills strip the FDA of its watchdog role. Under their proposals, generic manufacturers aren’t required to outline testing and safety protocols for the FDA to approve. Even if a generic drug maker’s proposed risk evaluation and mitigation strategies are inadequate, the FDA has no authority to reject or halt the transfer of medicines to the generic company for testing.

Both bills contain ambiguously worded liability provisions that subject innovators to unfair legal risk. Generic drug companies often obtain brand-name drug samples and ship them off to third-party research firms to perform clinical trials. If the third party is negligent with the samples, patients could get hurt. Under the bill’s terms, patients would be able to sue the brand-name drug company, even though it had no control over the testing or safety protocols.

Both bills would allow generic drug manufacturers to sue brand-name manufacturers if they fail to hand over their drug samples for testing within 31 days, or if the companies do not reach an agreement on shared risk evaluation and mitigation strategies for risky drugs. Such subjective wording is music to trial lawyers’ ears.

Both houses of Congress deserve praise for trying to bring generic medicines to market faster, relieving consumers from high drug prices. Yet good intentions don’t change the fact that the CREATES and FAST acts, as currently constructed — are deeply flawed.

Congress could help consumers by reworking the legislative language to end bad behavior without gutting safeguards for patients or enabling unscrupulous trial lawyers to file costly, pointless suits. Whether it’s the practice of medicine or the development of public healthcare policy two rules apply – first, do no harm and, second, be wary of trial lawyers bearing gifts.
Yesterday, at the annual RAPS (Regulatory Affairs Professional Society) meeting, I was pleased to speak on the timely topic of real world evidence and to share the podium with Jonathan Jarow (FDA’s point man on RWE) and Enrica Alteri (Head of EMA’s Human Medicines Research and Development Support Division).

The good news is that there was near total agreement that RWE presents important possibilities and opportunities – but the path forward is still nascent, with many crucial questions still to be addressed.

One of the most difficult items on the RWE list is causal inference (the process of drawing a conclusion about a causal connection based on the conditions of the occurrence of an effect). As both FDA and EMA continue to evolve beyond reviewing new medical products exclusively on the traditional substantial evidence standard, it’s a whole new ballgame.

Or is it?

The panel agreed that we're moving forward into a world where there will be many different kinds of reviews for both drugs and devices. Some will be of the “gold standard” large-scale RCT variety, others will be substantially truncated reviews based on dozens (or fewer) patients, and many will be hybrid models (such as using RWE for confirmatory purposes for a surrogate endpoint).

And then there’s the exciting potential in advancing Causal Inference (CI) models through the tools of Artificial Intelligence (AI).

Who said regulatory science was dull?

The panel also stressed that Real World Evidence and “Big Data” are not the same thing, and that developing interoperability (the idea that different systems used by different groups of people can be used for a common purpose because those systems share standards and approaches) must be a priority.

And not just interoperability, but interaction. When it comes to advancing the regulatory science of real world evidence, industry must become comfortable being not just a regulated entity but also a partner in development. In fact, per Dr. Jarow, the FDA is encouraging all comers to submit questions, data sets, and suggestions via a new email link,

Gentlemen and Ladies – start your engines.

The tools for appropriate validation are urgently needed – but cannot be rushed. That being said, the 21st Century Cures Act requires FDA to establish a framework for use of real-world evidence to approve supplemental indications and satisfy post-approval requirements within 2 years.

Tick. Tick. Tick.

Gottlieb: Speed Saves

  • 09.11.2017
  • Peter Pitts
But how will Pharma calculate the speed-to-price equation? And what of PBMs?

From the pages of Politico:

Gottlieb promotes FDA move away from traditional three-phase clinical trials

FDA Commissioner Scott Gottlieb on Monday laid out new clinical trial approaches and digital techniques that he said could get medicines to patients sooner and at a lower price by moving away from the time-honored, traditional three phases of clinical trials.

"We're on an unsustainable path, where the cost of drug development is growing enormously, as well as the costs of the new medicines. We need to do something now, to make the entire process less costly and more efficient. Otherwise, we won't continue to realize the practical benefits of advances in science, in the form of new and better medicines," Gottlieb said in a speech delivered at the RAPs Convergence Conference.

Although development costs aren't necessarily mirrored in treatment prices, they are an important factor, he said. The steep price of development may also be causing fewer drugs to get developed, particularly because so much of the cost burden of drug development is front-loaded at the earliest stages, he said.

He called for savings in development costs to be passed along to consumers, but gave no details on how the government might ensure savings are shared.

"We need to reduce the risk and uncertainty that makes drug development increasingly costly, he said, "and make sure that we have markets that are competitive, and let us capture those savings in the form of lower prices."

FDA is taking a number of steps to modernize how clinical data can be collected, Gottlieb said.

One approach is "seamless" trials, which already have been used to test drugs on various cancers at a single time. In such studies, instead of conducting the usual three phases of clinical trials, a company conducts one large adaptive trial where data can be observed at certain intervals. This reduces the number of patients needed in the trial and saves time and money.

"This approach is well suited" to drugs being developed now to target specific changes that can be found in different disease states, Gottlieb said.

FDA is also encouraging companies to pursue common control studies, where multiple drugs are tested against the same control arm, and large simple trials, which have large sample sizes and statistical power, thereby providing less ambiguous results and minimizing the effects of random errors.

Another new approach is the master protocol concept, in which a single trial evaluates multiple treatments in more than one subtype of a disease or type of patient. Master protocols have been used in cancer drugs and in antibiotic development, to evaluate medicines targeting pathogens in different parts of the body.

The FDA plans to issue new policy and guidance documents to help companies make better use of these approaches, Gottlieb said.

To protect patients, the agency is adapting its safety screening to these new trial types, he said. For example, informed consent documents for seamless trials need to be updated throughout the trial to reflect new safety and efficacy evidence gathered in the process.

Since these trial designs may allow an entire drug development program to take place in just one study, FDA may also need to build in new regulatory milestone meetings to check on progress and provide oversight and advice.

"This is not 'business as usual' approach. It may require a much more iterative process, with greater communication between all of the stakeholders involved in the clinical trial processes," Gottlieb said.

FDA is also modernizing its evaluation of company data, with more advanced software and sophisticated statistical and computational models. Gottlieb said he wants to increase FDA investment in high-performance computing because access to this technology at the agency is limited.

Computer modeling can help select the optimal dose of a drug or better estimate effect size to figure out the ideal number of patients needed in a clinical trial. It can also help FDA determine whether the trial endpoint a company wants to study is appropriate for the disease at hand.

The agency will convene a series of workshops, publish guidance documents and develop policies and procedures for translating modeling approaches into regulatory review, Gottlieb said. It will also conduct a pilot project to test use of these new computer tools with willing drug companies.

The agency has ongoing projects underway to use software to develop natural history models of diseases like Parkinson's, Huntington's and Alzheimer's disease. This information can make trial recruitment more efficient and help evaluate the effect of a treatment again the normal course of disease.

The agency is developing algorithms that could help speed trials. For example, its working on a lung cancer algorithm it hopes can help classify how well a tumor responds to a drug treatment.

Embedding CDER's Centaurs

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


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.


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

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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