Notepad: FDA Labeling and Outcome Data on Buprenorphine in OUD

If there is one unanimous tsunami in health policy, it may be the use of Medication Assisted Therapy in opioid use disorder (MAT/OUD).

• In the Annals of Internal Medicine, see Beetham (2019) on buprenorphine access in high OUD mortality areas here, see Martin (2018) on "next stage of buprenorphine care," here, see  Chou (2019) on buprenorphine and opioid tapering here.
• See also in AIM, Barocas (2019) on policy and therapy in OUD, here.  Paired with a cost effectiveness article by Murphy et al. (2019) here.
• In NEJM, see Wakeman (2018) on "myths and realities," primary care and buprenorphine here, see Saloner (2018) moving buprenorphine to mainstream here.
• In JAMA, see Mark (2019) on CMS, FDA, and prior authorization policies for buprenorphine here, Roy (2019) on over the counter non-Rx buprenorphine here, Petz (2019) on nurse practitioner Rx for buprenorphine here.   See Olfson (2019) on trends in buprenorphine prescriptions 2011-2018 here.
• In JAMA Psychiatry, see Fiscella (2019) on the urgent need for buprenorphine deregulation here.
• In Health Affairs, see Harris (2020) on gaps in opioid treatment access for Medicare patients; defines opioid treatment access = MAT.  Here.
• In NEJM, see Haffajee (2020) on delayed competitors to Suboxone here.  Includes citations to November 2019 FDA action to revoke orphan status.  As is my point with this selection of articles, Haffajee takes effectiveness for granted, with one citation to a short-term observational study, Larochelle 2018; for example, you can't assume patients entering methadone clinics for five months and patients declining to start them, are the same.  (For another observational study see Morgan 2019.  Morgan 2018 found drug effectiveness but discontinuation rates are very high.)

The above are for-example-only, easily picking obvious articles from a few top-ranked medical journals.

See similarly a high-profile lead editorial at New York Times, 2019, here.  Although it's about methadone, not buprenorphine, see also Health Affairs, 2019, here.

Pivoting to FDA Labeling

CMS New Policy for OUD Payments.

In rulemaking for new OUD benefits in opioid treatment programs (OTPs; a term of art currently usually meaning methadone centers), CMS proposed separate payment levels depending on the patient's MAT (see CMS, 84 Fed Reg 40529, 8/14/2019, PFS CY2019 rulemaking proposal).  

There would be one code for methadone per week; one code for oral buprenorphine per week; one code for injectable buprenorphine per week, one code for monthly depot injection buprenorphine.   Pricing for drug is found on Table 15 (page 40537) and ranges from $22 for methadone to $4791 for buprenorphine monthly implant insertion.   

FDA Labeling for Buprenorphine Formulations: Clinical Studies  On-Label

Often FDA labeling is taken as a gold standard.  Claims and usage that are "off-label" may be decried in various public policy forums.   

It's easy to find the FDA labeling for buprenorphine sublingual tablets (e.g. SUBUTEX; approved 2002; label updated to 2018) label here.   It's easy to find the FDA labeling for buprenorphine depot injection; (e.g. SUBLOCADE; approved 2002 (original drug), updated 2017); label here.   See the FDA press release for SUBLOCADE, 2017, here.

The FDA-labeled clinical data for SUBUTEX is very weak, and non quantitative, with no charts, graphs, or tables of outcome data (such as percent change in any outcomes.)

The labeled clinical data for SUBLOCADE includes two studies.  One is an observational study of self reported opioid high while on drug (drug-liking analog visual scale) in non-treatment seeking opioid patients.   

The second SUBLOCADE study was an RCT against placebo with a 24 week trial period and follow-on data to 24 months.   Data is shown in Figure 12.   SUBLOCADE depot markedly raised the opioid-free weeks in the first six months of treatment (about 60% instead of about 5-10%).  Good.  However, by two years, the two groups are about the same.   

And note two things: SUBLOCADE was compared to placebo, not methadone or oral buprenorphine; and SUBLOCADE had only a very small differential effect at two years.   If you based your decision-making on this FDA table alone, SUBLOCADE does not look like a very good treatment for 2, 3, or 4 years or longer.   Yet many of the articles above are about the need to get people on buprenorphine for a long time, most often by comparing OUD as a chronically medicated disease like diabetes.

FDA label, SUBLOCADE (for link see text)

Comment

Medicare proposes to pay $115,000 for each two years of SUBLOCADE treatment.  If you used FDA labeling as a gold standard, it's impossible to make a clinical or pharmacologic argument for why this is better than generic buprenorphine.   

FDA itself uses FDA labeling as a gold standard, as in 2019 actions against labs doing pharmacogenetic testing that was not included in FDA labeling.  Here.  If you used FDA labeling as a gold standard, you would not be doing much pharmacogenetic testing, but you would not be giving much depot buprenorphine, either.

___

The SUBLOCADE advisory committee meeting in 2017, here.  See the actual data links for two 2017 meetings here.   On October 31, FDA reviewed depot buprenorphine; on November 1, FDA reviewed injectable buprenorphine.  At the link, which is a long page of many links, look for the actual data at the term "Briefing Materials" for each day.

Per FDA's press release, the SUBLOCADE product had priority review and fast track designations.  INDIVIOR holds the drug license.

___

For a Suboxone marketing probe, 2019, here.

___

For an earlier blog on sublingual buprenorphine alone, here.

___

In its own press release for SUBLOCADE, FDA refers to off-label data.  In stating that buprenorphine-assisted treatment may cut death rates in half, FDA does not refer to its own drug labeling but to NIH data.  Here.

___

For a 2005 report on MAT, still online at ASAM, here.

___

For a general 2019 review,  Bell & Strang, Biol Psychiat here.  See Rosenthal 2017 for advances in buprenorphine delivery formulations, here.

___

For a rare example of medication-assisted therapy getting negative press, see an FDA warning letter to Alkermes in December 2019 regarding improper marketing of Vivotrol (depot naltrexone) - here.

____

One good article on the value of MAT is Wakeman et al., comparative effectiveness, real world evidence, JAMA Network Open 3:e1920622 here.  Effectiveness of MAT vs non-MAT was assessed for 3 months and 12 months; the AHR (adjusted hazard ratio) at 12 months was .74 relative risk in harm.   The authors note, "The most common treatment pathway was nonintensive behavioral health (24 258 [59.3%]), followed by inpatient detoxification or residential services (6455 [15.8%]) and buprenorphine or methadone (5123 [12.5%]). Not receiving any treatment was more common (2116 [5.2%]) than naltrexone (963 [2.4%]) or intensive behavioral health (1970 [4.8%])."
\
____

ICER published a negative cost effectiveness review of advanced MAT drugs, in December 2018, here.

____

THere is a very complex story about the legal marketing status of MAT drugs and special formualations, reviewed in Health Affairs in March 2020 here.

Mental Health Groups Protest FDA Actions against PGX (Politico Subscription)

2019/09/26

https://www.politico.com/newsletters/politico-pulse/2019/09/26/how-impeachment-push-is-shaking-up-health-agenda-759972

FIRST IN PULSE: Mental health groups pan FDA's genetic testing stance. Advocates urged HHS Secretary Alex Azar and acting FDA Commissioner Ned Sharpless to reverse FDA's position on using genetic tests to inform treatment for depression and other mental health conditions, POLITICO's Brianna Ehley reports.

The FDA last year warned that genetic tests couldn't predict patient responses to antidepressant medications and moved to crack down on developers making those claims.

But advocacy groups — including the National Council for Behavioral Health, Mental Health America, the National Alliance on Mental Illness, and the Depression and Bipolar Awareness Alliance — argued in their letter to Azar and Sharpless that FDA's actions could "inflict greater harm on patients and impede innovation" given the potential of genetic information and some early, positive results.

##

Mental health letter here.

##

For links to September 2019 status of Senate health funding:

https://www.thenationalcouncil.org/capitol-connector/2019/09/senate-health-appropriations-language-released/

##

For an open access Politico article on September 12, 2019, on the Executive Branch's 2020 health agenda, here.

Notepad: Andrew Vickers at MSK: Prognostic Markers and Clinical Utility

One of the drawbacks of prognostic biomarkers is that clear decisions about their "clinical utility" are often difficulty.  (Separately, Frueh & Quinn have argued that clinical utility is not one linear thing, but has a more complex cognitive structure - here.)

One issue with MAAA-type prognostic tests is that we can a group of patients - say, patients with PSA of 4 to 10 - and put them into a bucket (like putting marbles into a barrel and not being able to see their colors.)   Then, we take the marbles out of the barrel one at a time, and apply the new prognostic test, and classify them as lower and higher risk.  The obvious problem is you already KNEW that the PSA 4 patients had much lower risk than PSA 10 patients (and, for example, PSA 11 patients have such high risk you wouldn't even consider them for this test.)   Yes, the new test may re-stratify the patients somewhat better than PSA=4 and PSA=10; but how much better can be difficult to decide.*

Andrew Vickers of Memorial Sloan-Kettering has worked on this issue in a number of very interesting papers.

• See a 2009 interview about his ideas on prognostic test clinical utility, in Cancer Network, here.
• For three open access articles on predictive/prognostic tests and separating value from hype, here, here, here.
• For all Vickers AJ articles at PubMed, here.
• For his MSK web page, here.

For another example of Vickers' critical thinking, see "Validating Patient Reported Outcomes: A Low Bar," 2019, here.  (Discusses in part this article here.)

____

*Another issue is when the MAAA test contains age and perhaps quite a bit of other clinical data in the algorithm.   On the one hand, this probably makes the MAAA test more accurate in absolute terms.  That's good, in that viewpoint, it's a bad idea to leave out info that makes the test more accurate.   On the other hand, you already knew that patients age 75 have more chance of (say) coronary disease than patients 45, if there's a part of the test that's worth $1500, it's not that.

E.g. see Panoptic test in LDCT screening for lung cancer, here. Op Ed here.

SUPPORT Act Section 6032: RFI and Public Meetings Required

Subtitle D—Opioid Addiction Action Plan

{Note:  See also HHS Action Plan Report, May 2019, here.}


SEC. 6031. SHORT TITLE.

This subtitle may be cited as the “Opioid Addiction Action Plan Act”.

SEC. 6032. ACTION PLAN ON RECOMMENDATIONS FOR CHANGES UNDER MEDICARE AND MEDICAID TO PREVENT OPIOIDS ADDICTIONS AND ENHANCE ACCESS TO MEDICATION-ASSISTED TREATMENT.

(a) In General.—Not later than January 1, 2020, the Secretary of Health and Human Services (in this section referred to as the “Secretary”), in collaboration with the Pain Management Best Practices Inter-Agency Task Force convened under section 101(b) of the Comprehensive Addiction and Recovery Act of 2016 (Public Law 114–198), shall develop an action plan as described in subsection (b).

(b) Action Plan Components.—The action plan shall include a review by the Secretary of Medicare and Medicaid payment and coverage policies that may be viewed as potential obstacles to an effective response to the opioid crisis, and recommendations, as determined appropriate by the Secretary, on the following:

(1) A review of payment and coverage policies under the Medicare program under title XVIII of the Social Security Act and the Medicaid program under title XIX of such Act, including a review of coverage and payment under such programs of all medication-assisted treatment approved by the Food and Drug Administration related to the treatment of opioid use disorder and other therapies that manage chronic and acute pain and treat and minimize risk of opioid misuse and abuse, including in such review, payment under the Medicare prospective payment system for inpatient hospital services under section 1886(d) of such Act (42 U.S.C. 1395ww(d)) and the Medicare prospective payment system for hospital outpatient department services under section 1833(t) of such Act (42 U.S.C. 1395I(t)), to determine whether those payment policies resulted in incentives or disincentives that have contributed to the opioid crisis.

(2) Recommendations for payment and service delivery models to be tested as appropriate by the Center for Medicare and Medicaid Innovation and other federally authorized demonstration projects, including value-based models, that may encourage the use of appropriate medication-assisted treatment approved by the Food and Drug Administration for the treatment of opioid use disorder and other therapies that manage chronic and acute pain and treat and minimize risk of opioid misuse and abuse.

(3) Recommendations for data collection that could facilitate research and policy-making regarding prevention of opioid use disorder as well as data that would aid the Secretary in making coverage and payment decisions under the Medicare and Medicaid programs related to the access to appropriate opioid dependence treatments.

(4) A review of Medicare and Medicaid beneficiaries’ access to the full range of medication-assisted treatment approved by the Food and Drug Administration for the treatment of opioid use disorder and other therapies that manage chronic and acute pain and treat and minimize risk of opioid misuse and abuse, including access of beneficiaries residing in rural or medically underserved communities.

(5) A review of payment and coverage policies under the Medicare program and the Medicaid program related to medical devices that are non-opioid based treatments approved by the Food and Drug Administration for the management of acute pain and chronic pain, for monitoring substance use withdrawal and preventing overdoses of controlled substances, and for treating substance use disorder, including barriers to patient access.

(c) Stakeholder Meetings.—

(1) IN GENERAL.—Beginning not later than 3 months after the date of the enactment of this section, the Secretary shall convene a public stakeholder meeting to solicit public comment on the components of the action plan described in subsection (b).

(2) PARTICIPANTS.—Participants of meetings described in paragraph (1) shall include representatives from the Food and Drug Administration and National Institutes of Health, biopharmaceutical industry members, medical researchers, health care providers, the medical device industry, the Medicare program, the Medicaid program, and patient advocates.

(d) Request For Information.—Not later than 3 months after the date of the enactment of this section, the Secretary shall issue a request for information seeking public feedback regarding ways in which the Centers for Medicare & Medicaid Services can help address the opioid crisis through the development of and application of the action plan.

(e) Report To Congress.—Not later than June 1, 2020, the Secretary shall submit to Congress, and make public, a report that includes—

(1) a summary of the results of the Secretary’s review and any recommendations under the action plan;

(2) the Secretary’s planned next steps with respect to the action plan; and

(3) an evaluation of price trends for drugs used to reverse opioid overdoses (such as naloxone), including recommendations on ways to lower such prices for consumers.

(f) Definition Of Medication-Assisted Treatment.—In this section, the term “medication-assisted treatment” includes opioid treatment programs, behavioral therapy, and medications to treat substance abuse disorder.

Links: Surrogate Markers Don't Add Up to OS in Cancer

September 2019
Endpoints essay on weak correlation of surrogate markers with OS.
https://endpts.com/cancer-trials-aimed-at-surrogate-targets-miss-bigger-mark-study/

New BMJ study by Naci et al. of EMA approvals 2014-2016.
Surrogate Markers have poor correlates to outcomes
https://www.bmj.com/content/366/bmj.l5221

With Op Ed by Mintzes
https://www.bmj.com/content/366/bmj.l5399

With Essay by Naci themselves
https://blogs.bmj.com/bmj/2019/09/18/gauging-the-validity-of-cancer-drug-trials-a-call-for-collaboration/

With Trackback to 2018 article in JAMA Internal Medicine by Kovic et al.
(PFS not correlated to QOL)
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2705082

The Statutory Requirements for Explanation in an NCD; SSA 1862

https://www.ssa.gov/OP_Home/ssact/title18/1862.htm


This text is not clearly numbered but appears just prior to 1862(b).  Congress writes:

"In making a national coverage determination (as defined in paragraph (1)(B) of section 1869(f)) the Secretary shall ensure consistent with subsection (l) that the public is afforded

• notice and opportunity to comment prior to implementation by the Secretary of the determination; 
• meetings of advisory committees with respect to the determination are made on the record; 
• in making the determination, the Secretary has considered applicable information (including clinical experience and medical, technical, and scientific evidence) with respect to the subject matter of the determination; 
• and in the determination, provide a clear statement of the basis for the determination (including responses to comments received from the public), the assumptions underlying that basis, and make available to the public the data (other than proprietary data) considered in making the determination."

Subsection 1862(l) [ el ] defines LCD and NCD processes, while section 1869(f) simple defines LCD and NCD.

Link Collection: Scott Gottlieb Joins Board of AETION: RWE

Scott Gottlieb has been joining boards both large and small.  (Joins Pfizer board; here.)

In a Linked In blog, he announced he has joined the board of startup AETION, which is created to help pharma and others build and manage RWE.

in February 2019, AETION raised $27M from Sanofi, McKesson, and others.    Total funding > $70M.

See a 2019 Aetion funding announcement here:

https://www.aetion.com/press-release/global-health-care-leaders-back-aetion-with-27-million-strategic-investment

Trade press on funding, here.

See Aetion website here: https://www.aetion.com/

Some trade press this summer on Aetion here.  Partnership with Horizon, here.  FDA, Brigham, and Aetion, here.  (Syapse also announced a link with FDA; here.).

Gottlieb blog at Linked In:

https://www.linkedin.com/pulse/real-world-evidence-future-drug-development-scott-gottlieb/

The health care system is enabling more effective ways to leverage electronic tools to gather and use vast amounts of health-related data. These tools offer new opportunities to use data collected during the routine care of patients to advance healthcare delivery, and to improve the development of new medical innovations. The supporting science and technology have advanced to a point where we can quickly and reliably analyze real-world data to generate evidence, and ultimately, make better health care decisions.

That’s why I’m delighted to be joining the Board of Directors at Aetion, a health care technology company that delivers real-world evidence for life sciences companies, payers, and other stakeholders. More efficient and effective application of evidence derived from practical settings can improve health care delivery, lower its cost, and make the development of new treatments more efficient. My work with Aetion will allow me to continue to advance goals I’ve championed over many years, in private and public roles.

Aetion is at the forefront of many important efforts in this burgeoning field. As one example, the company is working with Brigham and Women’s Hospital to help inform the use of RWE in drug development through the RCT DUPLICATE demonstration project. Brigham and Women’s Hospital researchers are running RWE studies in the Aetion platform to attempt to replicate the results of 30 completed randomized controlled trials, and to predict the results of seven ongoing Phase IV trials. 

As part of this effort, researchers recently analyzed claims data via the Aetion Evidence Platform to predict the findings of the CAROLINA clinical trial. The real-world data analyses took 16 weeks. They reached the same conclusion as the 43-country, eight-year clinical trial. This study joins a growing body of evidence that demonstrates the potential for RWE in supporting post-market safety and efficacy studies.

This work is a recognition that new approaches and new technologies can expand the evidence we use, bring clinical research closer to more settings of care, and help inform better and faster decisions. RWE can complement and contextualize how we understand clinical interventions — answering not just do they work, but how they best work, and for which people. I’m thrilled to advise Aetion as we advance these opportunities for patients.