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I was recently interviewed by Context Matters on Expedited Reviews and the Current State of Drug Development. Here’s Part One of the conversation
Regardless of what you want to call it, whether it’s expedited review or special protocols, limited use medicines, the theory is, “How can the FDA help bring important therapies to the market faster?” And, there are a lot of pieces to that puzzle.
At the end of the day, the agency still has to meet with the sponsor, who still has to have data. They have to meet and decide how to move forward.
There are two issues that also have to come into this conversation:
- The patient voice
- Benefit / risk profile
Those are two things that really are not usually discussed. Generally speaking, in this type of conversation what comes about in the discussion is time. How quickly can something happen? Obviously faster is better than slower, but you don’t want to ever sacrifice proper review.
Blood From a Stone: Expedited or Standard, It’s All the Same FDA Resources
A key issue not being widely talked about is that the FDA isn’t hiring a whole new team to deal with expedited reviews. It’s the same people. So does an expedited review take precedence over a non-expedited review? How does the agency determine who gets the resources at what point in time?
Obviously, if you’re going to file a regular old-style NDA, you get a PDUFA (Prescription Drug User Fee Act) date and the agency is responsible for that. How do you weigh that against “critical medical need”?
The answer is it’s on a case-by-case basis. You can’t say, “Hey, we’re not going to make the PDUFA date because we’re reviewing someone else’s drug,” that’s a non-starter. You have to view expedited review situations in the broader context of everything else the agency has to do.
And then the agency is then going to define (on a case-by-case basis) what it feels is most important to the public health. Here’s an example: MS (multiple sclerosis) or IPF (Idiopathic pulmonary fibrosis) – Are either of those more or less important from an expedited review / resources perspective than a new anti-infective? It depends who you talk to. If MRSA issues are on the top of your agenda, then it’s one thing. If it’s orphan diseases, it’s another or if it’s pain-mitigation it’s something else again. Where you stand on these issues depends on where you sit.
I don’t really think having people specifically tasked to working on expedited reviews is the way to go, unless you have more people. And then the question is, where do they come from and do you take the best and brightest away from standard review, to put them there? How do you weigh the general importance of staff time and agency resources? Do you want it to be for a disease that is not an orphan disease that’s an important therapy, or do you want it to be on an orphan disease that can have a profound difference on people’s lives? Those are really philosophical questions, but it comes down to resources. I don’t think you can have dedicated teams when you don’t have people that can dedicate their time exclusively, otherwise it is just rhetoric. It’s just another committee on which the same people sit.
Comparing the Agencies
What might be interesting (and is generally not part of this conversation) is a move towards greater FDA / EMA harmonization on certain disease categories. There’s been a lot of chatter on this issue, but at the end of the day nothing really happens. I think the EMA would be interested in that, probably more than the FDA, because one of the main differences is the type of data accepted by the EMA. The EMA casts a wider net in terms of the types of data they accept for any given application.
One of the reasons the EMA has gone beyond the FDA is that their national economies are so much more financially strapped than we are here. It is important to remember that EMA decisions are only the first part of gaining market access. After the EMA, drugs go on to be evaluated by different country Health Technology Assessment (HTA) agencies to determine reimbursement and pricing in various markets. And from a reimbursement perspective, the HTA agencies are moving away from the QALY (quality-adjusted life year) towards a more value-based insurance design.
From a review proposition, from the FDA’s perspective, obviously they don’t get involved in cost issues, only clinical issues. I think what innovator companies are going to find out (especially with the expedited review pathways) is that the risk of getting a drug yanked quicker (meeting a quick death) rises. So they are going to have to understand, from a business perspective, the risk of asking the FDA for these special medical use reviews – it could backfire unless you understand what you are asking the FDA to do. The FDA is trying to signal that there are multiple ways to get an important new therapy to market quicker, but that has to be based on a public health need and not on a marketing strategy.
Governor Deval Patrick wants to ban Zohydro in Massachusetts.
That's what he wants, but what he needs is an intro level course in federal jurisdiction -- and he's about to get one.
US District Court Judge Rya W. Zobel would not grant an immediate restraining order as requested by drugmaker Zogenix, but scheduled a followup hearing for Monday, saying it appeared that Zogenix would have a likelihood of winning the case.
“I think, frankly, the governor is out of line on this,” Zobel said..”
She urged both sides to discuss the issue before Monday.
“I do not expect this to be a very long hearing,” he said.
Returning to the subject of expanded access to developmental medicines (When Compassion Isn’t Enough), I want to be clear that it wasn’t me who coined the term “expanded access.” As one of my former FDA colleagues commented, “In March 1990 the IOM Roundtable for the Development of Drugs and Vaccines Against AIDS held a workshop “Expanding Access to Investigational Therapies for HIV Infection and AIDS.” FDA staff, including me, participated in the Keystone national policy dialogue (Expanded access to promising therapeutic drugs for HIV infection and AIDS with implications for other life-threatening diseases) in the early 1990s. Also in the early 90s, FDA used the term expanded access at advisory committee meetings and at meetings of the National Task Force on AIDS Drug Development.”
Naming issues aside, this remains a highly contentious issue – and for all the wrong reasons. A new paper from the Goldwater Institute, “Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of their Treatment,” points the finger at the FDA as a roadblock to access, “Sadly, over half a million cancer patients and thousands of patients with other terminal illnesses die each year as the bureaucratic wheels at the FDA slowly turn.”
Nothing could be further from the truth.
What the paper presents a libertarian platform, “The burdens imposed on a terminal patient who fights to save his or her own life are a violation of personal liberty.” Maybe so, but the Supreme Court has ruled otherwise. In January 2008, the U.S. Supreme Court, without comment, opted not to accept an appeal of Abigail Alliance v. von Eschenbach. In other words, the federal appeals court ruling that patients do not have a constitutional right to experimental drugs stands
The paper continues, “Such people should have the option of accessing investigational drugs which have passed basic safety tests, provided there is a doctor’s recommendation, informed consent, and the willingness of the manufacturer of the medication to make such drugs available.”
I don’t think that anyone of those constituencies has any argument on that point. But should the FDA be cut out of the process? According to the paper, “… bureaucratic impediments violate an individual’s fundamental right to try to save his own life.”
But that’s consistent with the author’s libertarian philosophy. She believes that the “vast new granting of power (of the Kefauver-Harris Amendments) “was unwarranted.” So, consider the source of the argument.
Alacrity is important, certainly. But process is important too, as is collecting data on expanded access use.
The paper does raise important questions, such as at what point in the drug development process should an investigational product be available to patients? The author argues for Phase I. That’s an aggressive position, but one worth debating.
One item that paper ignores is that for the FDA to address single patient INDs with both more careful attention and speed is funding. That’s more than the 800-pound gorilla sitting in the room – it’s the 800-pound gorilla sitting on the chests of desperately ill patients who want access to investigational medicines.
The author quotes Patty Delaney. Patty (who passed away in 2008) was the FDA’s main liaison to the cancer community and a tireless soldier for “doing the right thing.” She was a pit bull on behalf of patients.
According to the paper, “As Patty Delaney, the former director of the FDA’s cancer liaison program explained in 2007, “the patient has a right to be heard, but in the end, it’s the data that matters. FDA opinions about safety and efficacy are always based on data.”
I’ll side with Patty.
Much chatter about Janet Woodcock’s Energy & Commerce Subcommittee on Health testimony last week. Much of it ill-informed.
Dr. Woodcock stood firm that separate labeling for generic drugs will advance the public heath by advancing 21st century drug safety. Subcommittee Chairman Joe Pitts (no relation) didn’t agree. His comment, “The only outcome I see is confusion,” demonstrates his own confusion.
“I’d like to dispel the notion that labels are the same now with respect to safety information,” said Janet. Representative Pitts was not mollified, moving on to suggest the agency’s motives were other than for advancing the public health – specifically that “trial lawyers” were to blame for the agency’s actions.
Trial lawyers? Clearly he’s met with representatives of the GPhA.
Janet made it clear that the decision to move forward on the labeling change rule was CDER and no one other than CDER. “The personnel in the Center for Drugs did not meet with the trial layers.”
Mr. Pitts’ suspicions were not assuaged. Whatever.
(PS/Representative Waxman commented that he found the GPhA’s report that distinct labeling would increase consumer spending on generic drugs by $4 billion annually “highly invalid.”)
Dr. Woodcock also clarified that the discussion about generics labeling did not extend to biosimilars.
Per Janet, “This rule does not apply to that because those would be under the Pubic Health Service Act – and they’re not considered generics, so that’s a separate issue.”
Much consternation over this last remark. Some see it as a nod and a wink that the agency is going to allow biosimilars to have the same name and labeling language as innovators. I disagree for two reasons:
(1) Janet was precisely correct in stating that generic drugs and biosimilars are two distinct things. Biosimilars are not generic drugs.
(2) The fact that the FDA has made distinct generic drug labeling such an important policy initiative certainly does not send a signal that they will view biosimilars in a more laissez faire manner. Au contraire.
So, for people trying to read too much into Janet’s statement that generic drug labeling is different from biosimilar naming and labeling, relax. If anything, the news is good.
Prediction is very difficult, especially about the future. – Niels Bohr
As a wise man once said, “He who tooteth not his own horn, that horn shall go untooted.
This is a valuable lesson that the FDA has learned to be true. And it couldn’t have happened at a better time. Specifically, I refer to opioids.
The FDA has taken the bit out of its mouth and taken hold of the reins of pain.
While scene-stealing members of Congress, some governors, and a gaggle of state attorneys general are trying to run roughshod over science-based regulation to great attention from the media, the FDA has been quietly doing the right thing without anybody noticing.
But when you do the right thing and don’t tell anyone about it, the assumption is that you’re not doing anything. That began to change with FDA Commissioner Hamburg’s aggressive testimony in front of the Senate HELP Committee defending the agency’s October approval of Zohydro ER.
And it continued yesterday with the agency’s approval of EVZIO™ (naloxone hydrochloride injection) for the emergency treatment of known or suspected opioid overdose. Smartly, the FDA used the approval to speak, more broadly, to the topic. There was a lot to say – and it’s about time the FDA said it.
Peggy’s complete remarks can be found here.
During the stakeholder teleconference the Commissioner laid it all on the table. It turns out that the FDA is doing a lot to mitigate opioid risk after all! Most importantly, they are doing so while understanding the need to ensure appropriate access for the tens of millions of Americans suffering from chronic pain.
She got specific:
Combatting the serious public health problem of misuse, abuse, addiction and overdose from opioid analgesics is a high priority. Since 2001 the FDA has taken a number of actions designed to help address prescription opioid abuse and to encourage the development of new drug treatments for pain. These actions include:
Revising the labeling for opioid medications to foster their safe and appropriate use, including recent changes to the indications and safety warnings of extended-release and long-acting opioids.
Requiring that manufacturers conduct studies of the safety of long-term use of prescription opioids.
Improving appropriate prescribing by physicians and use by patients through educational materials required as a part of a risk mitigation strategy for extended-release and long-acting opioids.
Using the agency’s expedited review programs to advance development of new non-opioid medications to treat pain with the goal of bringing new non- or less-abusable products to market.
Working with other federal agencies and scientists to advance our understanding of the mechanisms for pain and how to treat it, including the search for new non-opioid medications for pain.
Recommending that hydrocodone-containing combination products have additional restrictions on their use by rescheduling them from Schedule III to Schedule II.
Strengthening surveillance efforts to actively monitor the changing nature of prescription opioid abuse and to identify emerging issues.
And, importantly, encouraging the development of medications to treat opioid abuse, such as buprenorphine for use in medication-assisted treatment, and to reverse opioid overdoses, such as naloxone.
I can’t say I agree with all of these things. (Upscheduling impacts appropriate access), but it’s a pretty powerful list.
And, it seems, recalling drugs that are currently on the market isn’t on the agenda.
In the immortal words of Don Draper, “If you don't like what is being said, then change the conversation.
Peggy returned again and again to the role the FDA must play in facilitating physician education, not only through labeling language but physician education. She specifically mentioned CME and working to develop (with a broad constituency) validated tools for physicians to use in determining which patients may be more prone to slide into abuse so they can choose their therapeutic recommendations more precisely.
“It all comes back to provider education,” she said. Amen.
Provider education – the Hamburg Manifesto.
That’s not regulatory mission creep; it’s the appropriate application of the agency’s Safe Use of Drugs initiative. The way you make a drug “safer” is to ensure that it is used by the right patient in the proper manner.
Importantly, the Commissioner regularly referred not to “abuse” but to “misuse and abuse.” That’s more than a rhetorical flourish since it recognizes that misuse is a gateway to abuse.
Joining Dr. Hamburg on the call were Michael Botticelli, Acting Director, Office of National Drug Control Policy, Douglas Throckmorton, M.D., Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research, FDA, Melinda Campopiano, M.D., Senior Medical Officer, Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, and Wilson Compton, M.D., Deputy Director, National Institute on Drug Abuse, National Institutes of Health.
Oh, and HHS Secretary Kathleen Sebelius, who never mentioned the word “recall” either. It looks like the specter of Secretarial interference is off the table. Kudos to Secretary Sebelius for making it clear this is a cross-departmental priority.
The take away message was loud and clear –misuse and abuse of opioids is a serious issue that must be addressed in an appropriate manner.
And, per today’s teleconference, “appropriate” means science-based and patient-centric.
Media Inquiries: Sandy Walsh, 301-796-4669, sandy.walsh@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA Commissioner Margaret A. Hamburg Statement on Prescription Opioid Abuse
For more than a decade, the U.S. Food and Drug Administration has been working to address the important public health problems associated with the misuse, abuse, addiction and overdose of opioid analgesics, while at the same time working to ensure continued access to effective and appropriate medications for millions of Americans currently suffering from pain. I firmly believe that these goals are compatible, and that actions to address one should not be at the expense of the other.
Tragically, the most recent data shows that more than 16,000 lives are lost each year due to opioid-related overdoses. In fact, drug overdose deaths, driven largely by prescription drug overdose deaths, are now the leading cause of injury death in the United States – surpassing motor vehicle crashes. We know that the illegal diversion, misuse, and abuse of prescription opioids are often fueled by inappropriate prescribing, improper disposal of unused medications, and the illegal activity of a small number of health care providers. This highlights the important role that education of prescribers and patients can play in addressing this epidemic. The FDA has taken steps to address this but more work remains to be done.
Combatting the serious public health problem of misuse, abuse, addiction and overdose from opioid analgesics is a high priority. Since 2001 the FDA has taken a number of actions designed to help address prescription opioid abuse and to encourage the development of new drug treatments for pain. These actions include:
Revising the labeling for opioid medications to foster their safe and appropriate use, including recent changes to the indications and safety warnings of extended-release and long-acting opioids.
Requiring that manufacturers conduct studies of the safety of long-term use of prescription opioids.
Improving appropriate prescribing by physicians and use by patients through educational materials required as a part of a risk mitigation strategy for extended-release and long-acting opioids.
Using the agency’s expedited review programs to advance development of new non-opioid medications to treat pain with the goal of bringing new non- or less-abusable products to market.
Working with other federal agencies and scientists to advance our understanding of the mechanisms for pain and how to treat it, including the search for new non-opioid medications for pain.
Recommending that hydrocodone-containing combination products have additional restrictions on their use by rescheduling them from Schedule III to Schedule II.
Strengthening surveillance efforts to actively monitor the changing nature of prescription opioid abuse and to identify emerging issues.
And, importantly, encouraging the development of medications to treat opioid abuse, such as buprenorphine for use in medication-assisted treatment, and to reverse opioid overdoses, such as naloxone.
Today’s FDA approval of Evzio (naloxone autoinjector) provides an important new tool in our arsenal to more effectively combat the devastating effects of opioid overdose, which is one part of our comprehensive work to support opioid safety. Reflecting the FDA’s commitment to encouraging important new therapies, the FDA’s review of Evzio was granted priority status, and the application was reviewed by the FDA in just 15 weeks.
This product is the first auto-injector designed to rapidly reverse the overdose of either prescription or illicit opioids. While the larger goal is to reduce the need for products like these by preventing opioid addiction and abuse, they are extremely important innovations that will help to save lives.
The FDA will continue to work to reduce the risks of abuse and misuse of prescription opioids, but we cannot solve this complex problem alone. A comprehensive and coordinated approach is needed; one that includes the White House Office of National Drug Control Policy, the Drug Enforcement Administration and many of our sister agencies within the Department of Health and Human Services, as well as state and local governments, public health experts, health care professionals, addiction experts, researchers, industry, and patient organizations.
I am confident that this can be accomplished, but we will all need to work together to invest in strategies and responsible approaches that deter or mitigate the effects of abuse while preserving access to pain medicines for the patients that need them the most.
On Tuesday I appeared on Al Jazeera America program, “The Stream.” The episode was titled “Inside the medicine cabinet,” and here’s how it was described:
Nearly 70% of Americans are on at least one medication. But for millions, combining too many of them could lead to dangerous consequences – even with safeguards in place to protect patients. We’ll explore what you need to know about your medicine cabinet.
Hosted by Lisa Fletcher, my fellow panelists were
Michael Carome
Director, Health Research Group at Public Citizen
Dr. Natalie Boulware
Naturopathic Physician, Tulsi Holistic Living
Dr. Caleb Alexander
Co-Director, Johns Hopkins Center for Drug Safety and Effectiveness
David S.H. Lee
Assistant Professor, Oregon State University College of Pharmacy
Good topic. Good panelists.
Click here for the full video.
According to a new study from Adherent Health, a mobile health engagement advisory focused on medication safe-use, adherence, and health outcomes attainment, nearly three-quarters of prescription-takers use mobile apps, including most older adults and seniors.
Mobile app adoption rates are high across all medication-taking adult age groups: 93% (age 18-24), 90% (age 25-34), 88% (age 35-44), 80% (age 45-54), 66% (age 55-64), and 50% (age 65+).
Among other study findings, prescription-taking patients using mobile apps were similar to their non-app using counterparts in terms of annual income, education level, and geographic region.
Conducted in the first quarter of 2014, the 2014 Patient Preference Study surveyed the mobile app behaviors and medication support preferences of 2,216 prescription-taking patients aged 18-65+.
"This is a high rate of mobile app use among prescription-taking patients of all ages, including those 65+" remarked Michael A. Weber, MD, Professor of Medicine at the SUNY Downstate College of Medicine in Brooklyn, and Editor-In Chief of the Journal of Clinical Hypertension. "Apps represent an attractive communications medium to better support patient understanding, medication adherence, and medication safe-use."
Approximately half of America's 187 million prescription-takers are non-adherent, meaning they do not take their medications as prescribed.
App-using patients prefer a privacy-protected single app (such as Adherent’s Mobile Health Library system) by a factor of 11 to 1 over email programs often offered by medication manufacturers. This high preference for a privacy-protected single app, customized to a user's needs for medication education and support services, was observed across all adult age groups.
"I'm not surprised that most patients would prefer a single privacy-protected app that supports medication dosing reminders, ongoing education, and co-pay and affordability needs" said Amy C. Sidorski, MS, CRNP, BSN, RN of Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, and member of the ONS:Edge Oncology Nurse Experts Panel. "Especially one they receive from their physician or nurse."
A very important series of stories in this week’s issue of BioCentury (authored by Steve Usdin) addressing the thorny, urgent (and too frequently ignored) topic of expanded access to experimental medicines. The articles generally refer to “compassionate use” and “compassionate access.” That’s the wrong terminology – and a good place to begin the conversation.
In January 2008, the U.S. Supreme Court, without comment, opted not to accept an appeal of Abigail Alliance v. von Eschenbach. In other words, the federal appeals court ruling that patients do not have a constitutional right to experimental drugs stands.
This is a tough, emotional issue and, with such heated rhetoric on both sides, it's easy to lose sight of the fact that everyone wants the same thing -- expanded access to drugs under clinical investigation.
For me this issue began (when I was Associate Commissioner for External Affairs at the FDA) during a meeting with Theresa Toigo (then the Director of the agency’s Office of Special Health Issues) and Frank Burroughs (founder of the Abigail Alliance for Better Access to Developmental Drugs). The meeting centered on Frank’s assertion that the FDA could do more to expand its parameters for patient access. We all agreed more could be done. Frank left. Terry stayed – and I asked her why we (the FDA) used the term “compassionate use.” Her answer was simple – “It’s what we’ve always called it.”
I said, “Let’s change what we call it." Allowing desperately ill patients into clinical trial programs shouldn't be an act of noblesse oblige it should be an act of civil society. We decided to work towards changing the term to “expanded access.” And we did. It’s one of the things I am most proud of accomplishing during my time at the FDA.
But it has to be more than rhetoric. The words have to mean something – and what they have to mean is that more patients get more access to more experimental medicines more expeditiously. In many cases it is, literally, a life-or-death situation.
When it comes to pharmaceutical safety, pure libertarianism isn't in the best interests of the public health. Expanded access to experimental drugs simply can't and shouldn't morph into total, unfettered access.
That doesn't mean the status quo is working. What it means is that the FDA needs to figure out a way to dramatically broaden and facilitate expanded access to experimental drugs under its review. And the Abigail Alliance and its supporters need to keep up the pressure to improve the current system.
This is best done in a spirit of collegiality rather than a confrontational courtroom or in Congress. Should expanded access design and development planning discussions be binary conversations between a sponsor and the FDA? What about the patient community? Perhaps, as part of the FDA’s current initiatives to enhance both the timeliness and weight of the patient voice, expanded access plan development and execution should involve patient organizations.
In the BioCentury articles, Usdin speaks to the phenomenon of social media and the pressures it can (and does) bring to bear on sponsors. Maybe it’s time to harness that power to make the process both more inclusive and better.
It’s time.
A new analysis by the Alliance for Integrity and Reform of 340B indicates that a substantial portion of hospitals enrolled in the 340B program provide only a minimal amount of charity care; as such, they may not be fulfilling Congress’ expectations.
The study, compiled from newly available public data analyzed by Avalere Health, noted that the 340B drug discount program was designed by Congress to help safety net providers improve access to prescription medicines for uninsured, vulnerable patients in the outpatient hospital setting. Yet, the analysis shows, most hospitals that benefit from the program provide less charity care than the national average for all hospitals, and charity care in about a quarter of all 340B hospitals represents 1% or less of total patient costs. A small number of 340B hospitals provide the lion’s share of all charity care delivered by 340B hospitals.
The analysis raises questions about whether the current 340B eligibility criteria specifically used for DSH hospitals are serving the spirit and intent of the law in that they may be overly broad and not just target those entities that serve high numbers of vulnerable, uninsured patients. Specifically, the new research shows:
• More than two-thirds of hospitals that receive 340B drug discounts provide less charity care as a percent of patient costs than the national average for all hospitals, including for-profit hospitals which do not qualify for 340B under current eligibility criteria.
• For approximately a quarter (24%) of 340B hospitals, charity care represents 1% or less of the hospitals’ total patient costs.
• Approximately one-fifth (22%) of 340B hospitals provide 80% of all charity care delivered by 340B DSH hospitals.
Currently, hospitals that qualify for the program claim 340B discounts for most outpatient prescription drugs, for both insured and uninsured patients. And while the 340B program lowers outpatient drug costs for qualifying hospitals on the presumption that it will help significant numbers of vulnerable, uninsured patients, participating hospitals currently see no restrictions on the way they spend the revenue generated if they charge both insured and uninsured patients higher prices than the 340B-discounted price.
This stands in contrast to many other covered entities that participate in the 340B program as a result of a specific grant (often referred to as “grantees”) from the U.S. Department of Health and Human Services. The grant-approval process typically requires these providers to demonstrate that they provide services to certain specified vulnerable populations, at times based upon the patients’ “ability to pay”, and that the entities reinvest resources into services for those populations.
340B's broad eligibility criteria for hospitals have led to an explosion in the number of hospitals that have come into the 340B program. Today, one-third of all hospitals in the country participate in the 340B program and get 340B discounts; that number is expected to grow, particularly absent an effort to tighten eligibility requirements. Drug purchases through the 340B program will almost double, from $6 billion in 2010 to $13.4 billion by 2016, though little of the billions of dollars in discounts has been directly tracked to or linked with charity care for vulnerable indigent patients.
The complete report, “Unfulfilled Expectations,” can be found here.
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.
