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.

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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.

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For a Suboxone marketing probe, 2019, here.

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For an earlier blog on sublingual buprenorphine alone, here.

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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.

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

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

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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.

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

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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.

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Mental health letter here.

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For links to September 2019 status of Senate health funding:

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

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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.)

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*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.

Prior Authorization Notepad

There have been a number of intersections of CMS and prior authorization over the years.  I noted a number of them (many I wouldn't have remembered) right on my own blog. 

In July 2019, Medicare proposed preauthorization in the annual Medicare outpatient rulemaking, although for targeted surgeries like blepharoplasty and liposuction. 

In parallel this summer, on the Hill, legislation was proposed for controlling prior authorization inside Medicare Advantage (links below). 

Also on the Hill, in September 2019, a House hearing on the burdens of preauthorization on small providers.

A note pad of some relevant links below. 

2015 Budget (released March 2014) flags pre auth ideas for CMS.
http://www.discoveriesinhealthpolicy.com/2014/03/the-presidents-fy2015-budget-medicare.html

2017, United Healthcare boosts pre authorization for genetics. (This is a pop-up headline that comes and goes for various payers year by year.)
http://www.discoveriesinhealthpolicy.com/2017/06/united-healthcare-may-be-widening-pre.html

2018-2019:
AMA has a dedicated website for prior authorization & burden issues.
https://www.ama-assn.org/amaone/prior-authorization

News: AMA Says Payers Dragging Their Feet (March 2019)
https://healthpayerintelligence.com/news/ama-payers-moving-too-slowly-on-prior-authorization-fixes

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2018 OIG Report on Medicare Advantage Denial Rates Etc.

OIG Report 9/2018

Medicare Advantage Appeal Outcomes and Audit Findings Raise Concerns About Service and Payment Denials
https://oig.hhs.gov/oei/reports/oei-09-16-00410.asp

Trade articles on the above

https://healthpayerintelligence.com/news/oig-finds-profits-to-blame-for-denied-medicare-advantage-claims
https://revcycleintelligence.com/news/medicare-advantage-plans-overturn-75-of-their-own-claim-denials
https://www.kff.org/medicare/issue-brief/prior-authorization-in-medicare-advantage-plans-how-often-is-it-used/


February 2019 AAFP/AMA letter to Seema Verma on Prior Auth
https://www.aafp.org/dam/AAFP/documents/advocacy/legal/administrative/LT-CMS-PriorAuthMedicareAdvantage-021919.pdf
https://www.aafp.org/news/government-medicine/20190308mapriorauth.html


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April 2019:  Prior Auth Bill Coming
https://www.medpagetoday.com/practicemanagement/reimbursement/79314

June 2019:  Prior Auth Bill Imminent
https://www.medpagetoday.com/practicemanagement/reimbursement/80194

June 2019: HR 3107, DelBene et al.  Prior Auth should be less burdensome... in Medicare Advantage.
https://www.congress.gov/bill/116th-congress/house-bill/3107/text

August 2019: Hospitals burdened by prior auth, want overhaul
https://www.modernhealthcare.com/payment/hospitals-call-overhauling-medicare-advantage-prior-authorization-rules

August 2019:  Myriad says it's lost $50M due to tighter edits, especially on CYP genes, meaning Genesight; due to lab benefit managers (LBMs); similar to prior auth...
http://www.discoveriesinhealthpolicy.com/2019/08/very-brief-blog-myriad-genetics-unusual.html

August 2019:  Medicare Outpatient/OPPS Policy Introduces Prior Auth Procedures
http://www.discoveriesinhealthpolicy.com/2019/07/july-20-2019-cms-releases-cy2020-pfs.html

House Hearing September 2019

September 2019, House Committee on Small Business: Pre Auth burdens physicians.  Hearings and testimony.
https://smallbusiness.house.gov/calendar/eventsingle.aspx?EventID=2794

For the Hearing, testimony from Dr. Harari, Oncology, University of Wisconsin; from Dr. Walega, Anethesiology & Pain Management, Northwestern; Dr. Cullen, family practice, Arkansas; Dr. Rogers, dermatologist, Amer Acad Dermatology.

   House Committee Info as ZIP File
   I've put all the House Hearing testimony PDF files, agenda, and an "only here" transcript in one cloud Zip file here.

Follow up press generally about the House hearing:
Modern Healthcare, September 2019:
https://www.modernhealthcare.com/politics-policy/house-committee-throws-spotlight-prior-authorization-burden
Medpage, September 2019:
https://www.medpagetoday.com/practicemanagement/reimbursement/82104
Health Payer Intelligence (playing defense!), September 2019
https://healthpayerintelligence.com/news/payers-providers-spar-over-proposed-prior-authorization-regulation
Becker Hospital Review, September 2019
https://www.beckershospitalreview.com/supply-chain/prior-authorizations-making-it-as-difficult-as-possible-for-patients-to-get-necessary-medical-supplies.html

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In other payer-provider news, Anthem rolled out steep cuts to anatomic pathology payments, see Dark Report, July 2019, here.


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This is a brief link posting. For my regular blog see Discoveries in Health Policy.

Cedars Sinai vs Quest - Trade Journal; Original Court Docs; Patent and Secrets and NDA

MedTechDive on the Cedars v Quest court case.  September 17, 2019.
https://www.medtechdive.com/news/quest-didnt-steal-cedars-sinai-blood-test-in-trade-secrets-row-jury-says/562909/

Original Complaint 11//2017, 24pp
https://www.documentcloud.org/documents/6407574-CedarsSinaicomplaint2017.html

Quest says no: 09/2019, 31pp

https://assets.documentcloud.org/documents/6407575/Questmemoranduminsupportofjudgmentasamatteroflaw.pdf

Sound bite from MedTechDive:

As to the trade secrets claims, Quest said Cedars-Sinai not only failed to prove it had any ownership interest in the claimed trade secrets but also had failed to prove any of the trade secrets were actually secret. Quest said the information was never actually secret because the hospital had been actively shopping its test to multiple companies at the same time it was in discussions with Quest.

The jury ultimately rejected Cedars-Sinai's trade secret claims.

Quest Diagnostics' senior director of external engagement Dennis Moynihan told MedTech Dive the company was pleased with the verdict.

Meanwhile, Cedars-Sinai is still committed to protecting Pimentel's innovations, Laura Coverson, senior communications specialist at the hospital, told MedTech Dive.

Lab Fees and Payments on a Doctor's Bill

Got an explanation of benefits from BCBS today for a doctor's visit (routine GYN).

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Office visit, Well Care (annual), 99396, Charge $250, payment $97.41.

Pap smear, obtaining, and transmitting to lab, Q0091, Charge $100, payment $0.

Lab test, bacteruria, other than culture or dipstick (?), 81007, Charge $50, payment $1.07.
   (Medicare CLFS, 81007, $29.98).
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This is an in-network physician so BCBS charges/copays represent payment in full.

The Unimpressive FDA Clinical Labeling for Sublingual Buprenorphine

Update: For a later blog that adds depot injection and adds the context of Medicare OTP rulemaking, here.
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It is a truism today that medication-assisted management is best for opioid disorders.  One common form is sublingual, once-a-day buprenorphine (Subutex).  What does the FDA labeling say regarding clinical trials? See the current, online FDA labeling -  Here.

The initial US approval is stated as 2002, labeling updated in 2017 and 2018.   SUBUTEX buprenorphine sublingual tablets is "indicated for the treatment of opioid dependence."   Also, use "should be part of a complete treatment plan that includes counseling and psychosocial support."

I'm used to seeing fairly complete clinical trial descriptions on drug labeling (or device labeling) including graphs, outcomes, etc.  Not here.   Three studies are briefly and incompletely described.
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It looks like in total, across three studies, 575 patients got Suboxone (buprenorphine/naloxone), and 2450 got Subotex (sublingual buprenorphine).  All trials used comprehensive therapy with psychosocial counseling.

In a double blind placebo and active-control study, 326 heroin addicts got Subotex or placebo or Suboxone.  Clinic dosing was provided M-F and home dosing on weekends.  Both drugs had "statistically higher" negative urine tests than placebo.   The degree of difference and the time course don't appear to be stated.

A second study provides time course information.  162 patients were randomized to (a) ethanolic sublingual buprenorphine, or (b) low dose active control, with a 16 week maintenance phase and a 7 week detox (withdrawal) phase.   Doses were tapered 20-30% per week during the taper phase.  " buprenorphine was  more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use  of opioids while in  treatment."  The degree of difference isn't stated.

A third study also provides time course information.  731 subjects were randomized to one of four doses of "ethanolic buprenorphine solution," at 1, 4, 8, 16 mg.  Maintenance for 16 weeks.   Based on "retention in treatment and percentage of negative urine samples," they found that "the three highest tested doses were superior to the 1 mg dose."   No degree of difference is stated.   Doses used here should be crosswalked to slightly higher sublingual-tablet dosing (e.g. 16 mg ethanolic = 24 mg sublingual tablet).

Analysis

The on-label FDA data, usually considered a gold standard for drug approvals, is very weak.

• In some studies, patients had daily attendance at a clinic, something that wouldn't happen with real-world buprenorphine scrips.   
• All patients were in controlled clinical counseling environments that were funded and tracked as part of the drug study. 
• None of the labeled clinical studies reported the scale of outcome at all. 
• (Were there 50% more clean urine samples ... or 5% pr 1%?)  
• The largest of the three studies involved 16 week therapy and then a 7 week taper down to zero; nearly all popular press I read emphasizes long-term use of buprenorphine.   

There may be other data on the effectiveness of long term buprenorphine, and on modern real-world outcomes in clinical use, but it's completely absent from the FDA labeling.  The lack of any meaningful outcome data, including scale-of-impact, in the drug labeling was surprising.

Medicare's Listed Preventive Services at SSA 1861 and Open-Ended UPSTF Option

Medicare has enumerated benefits (health benefits defined; preventive benefits defined) at SSA 1861.

For example, the Act covers "medical and other health services," of which 1861(s)(1) are "physician services," 1861(s)(1)(2)(B) are "hospital services incident to a physician" (e.g. hospital surgicenters and ERs).  1861(s)(2)(J) covered prescription services for transplants before there was a Medicare Part D benefit. 

Then you get a handful of screening services, like mammography, PSA testing, colonoscopy, PAP smears, and some others.  For example, 1861(s)(2)(P) covers "prostate screening services" as defined at "subsection (oo)" and so on.  It goes on for pages.

Some Preventive Services Are Easier to Add Than Others

One take home lesson from reading 1861 carefully is that new modalities for prostate and colorectal screening can be added by CMS (probably via an NCD), whereas outside that, any kind of other preventive services can be added IF and AFTER the service is approved by USPSTF. 

For example, liver cancer screening or ovarian cancer screening would have to be approved first by USPSTF. 

(One other pathway, hypothetically, would be a demo program to screen for something under the Innovation Center (CMMI).)

Examples of Statutory Definitions of Some Preventive Benefits

Prostate Screening
Defined at subsection (oo) as a test for early detection of prostate cancer in a man over 50, to include DRE, and PSA, and "such other procedures as the Secretary finds appropriate" including for effectiveness, costs, and other factors the Secretary finds appropriate.  (Note: cost effectiveness clause here at (oo).)

Colorectal Screening
Defined at (pp) to include fecal occult blood test, sigmoidoscopy, colonoscopy, and "such other tests or procedures as the Secretary determines appropriate, in consultation with appropriate organizations."    (Note: no cost effectiveness clause here at (pp).)

Bone Mass Measurement
Defined at (rr) as "radiologic or radioisotopic procedure or other procedure" approved by FDA for the purpose of identifying bone mass or detecting bone loss or determining bone quality.   There are exactly five indications, estrogen-deficient woman, vertebral anomalies, steroid therapy, hyperparathyroidism, and osteoporosis drug therapy.

Cardiovascular Blood Test
Defined at (xx) as cholesterol and other lipid/triglyceride levels, May include other indications and blood tests if approved by USPSTF.

Additional Services Added by NCD After USPSTF Approves

After the enumerated services (above just a sample), additional services at (ddd) can be added IF:

• Reasonable and necessary to prevent or early detect an illness or disability AND
• Recommended A/B by USPSTF, AND
• Appropriate for persons in Part A or B, AND
• Determination made by NCD process.

If CMS does look at a USPSTF benefit, and consider converting it via an NCD to a Medicare benefit, CMS can consider cost effectiveness.  We read under the USPSTF clause, "The Secretary may conduct an assessment of the relation between predicted outcomes and the expenditures for such service and may take into account the results of such assessment in making such determination."

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The Colorectal NCD.   The Colorectal NCD has been revisited three times under 1861(pp):

1. To add the FIT test, 
2. To non-cover virtual CT colonography, and 
3. To cover the Exact Science Cologuard test.  
1. These are each under NCD 210.3, here.

Claims and Codes for Preventive Services

Medicare has a special Claims Processing Manual (rulebook) for preventive services, Claims Processing Manual, Chapter 13, here.   For CRC, codes include 82270 (Guaiac), G0328 (FIT), Cologuard 81528 (temp code had been G0464).. 

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Gray Areas.

There are some gray areas.  For example, Medicare has a smoking cessation benefit, and USPSTF has a preventive service Smoking Cessation that it approved.  However, these two things do not interact.   Medicare approved the Smoking Cessation Benefit in 2005 via an NCD, ruling that for smokers, smoking cessation was simply part of necessary medical care.   USPSTF also has a preventive category benefit called Smoking Cessation.  Today it could be the basis of the NCD, but in 2005 the NCD stood by itself as a "necessary medical benefit"  and was not linked to USPSTF or prevention.

I believe when CMS created the Smoking Cessation benefit in 2005, it was classed as "medical care" and therefore had a 20% copay, but a later law said that USPSTF-covered services have no copay at Medicare, so I suspect today it is also classified as a no-copay service since it is also endorsed by USPSTF.

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All this may add up to a more complex system for preventive services in Medicare than in private healthcare or in some other countries.  E.g. an OncImmune test for high risk lung cancer screening might have a faster path in the UK than USA; see here.

Medicare's General Authority to Implement the Act: SSA 1102 and 1871

As noted in new fraud regulations released 9/5/2019. 

These same two sections of Medicare law were also used in a 2018 proposal, finalized in 2019 but delayed in court, to require TV ads to display prices. 

S. 1871 was also used in June 2019 to delay the expiration of a proposed rule about antibiotic stewardship programs.

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Fraud law inspection copy: https://s3.amazonaws.com/public-inspection.federalregister.gov/2019-19208.pdf

"Sections 1102 and 1871 of the Act, which provide general authority for the
Secretary to prescribe regulations for the efficient administration of the Medicare
program."

1102 grants a general authority to create regulations and places some rules regarding impact on rural hospitals.

1871 also grants a general authority, while providing a timeline (3 years), and other factors.  Comment periods must be 60 days.  A final regulation must be a natural evolution ("logical outgrowth") of a proposed regulation; if not, it itself should be a proposed regulation.  Rules shall not be retroactive.  Clipped below. 

At bottom, see some legal links on the concept "logical outgrowth," a legal term of art.

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https://www.ssa.gov/OP_Home/ssact/title11/1102.htm

Sec. 1102. [42 U.S.C. 1302] (a) The Secretary of the Treasury, the Secretary of Labor, and the Secretary of Health and Human Services, respectively, shall make and publish such rules and regulations, not inconsistent with this Act, as may be necessary to the efficient administration of the functions with which each is charged under this Act.

Sections 1102(b) (1,2,3) deal with impact of any rule on small rural hospitals.

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https://www.ssa.gov/OP_Home/ssact/title18/1871.htm

Sec. 1871. [42 U.S.C. 1395hh] (a)(1) The Secretary shall prescribe such regulations as may be necessary to carry out the administration of the insurance programs under this title. When used in this title, the term “regulations” means, unless the context otherwise requires, regulations prescribed by the Secretary.

(2) No rule, requirement, or other statement of policy (other than a national coverage determination) that establishes or changes a substantive legal standard governing the scope of benefits, the payment for services, or the eligibility of individuals, entities, or organizations to furnish or receive services or benefits under this title shall take effect unless it is promulgated by the Secretary by regulation under paragraph (1).

(3)(A) The Secretary, in consultation with the Director of the Office of Management and Budget, shall establish and publish a regular timeline for the publication of final regulations based on the previous publication of a proposed regulation or an interim final regulation.

(B) Such timeline may vary among different regulations based on differences in the complexity of the regulation, the number and scope of comments received, and other relevant factors, but shall not be longer than 3 years except under exceptional circumstances. If the Secretary intends to vary such timeline with respect to the publication of a final regulation, the Secretary shall cause to have published in the Federal Register notice of the different timeline by not later than the timeline previously established with respect to such regulation. Such notice shall include a brief explanation of the justification for such variation.

(C) In the case of interim final regulations, upon the expiration of the regular timeline established under this paragraph for the publication of a final regulation after opportunity for public comment, the interim final regulation shall not continue in effect unless the Secretary publishes (at the end of the regular timeline and, if applicable, at the end of each succeeding 1-year period) a notice of continuation of the regulation that includes an explanation of why the regular timeline (and any subsequent 1-year extension) was not complied with. If such a notice is published, the regular timeline (or such timeline as previously extended under this paragraph) for publication of the final regulation shall be treated as having been extended for 1 additional year.

(D) The Secretary shall annually submit to Congress a report that describes the instances in which the Secretary failed to publish a final regulation within the applicable regular timeline under this paragraph and that provides an explanation for such failures.

(4) If the Secretary publishes a final regulation that includes a provision that is not a logical outgrowth* of a previously published notice of proposed rulemaking or interim final rule, such provision shall be treated as a proposed regulation and shall not take effect until there is the further opportunity for public comment and a publication of the provision again as a final regulation.

(b)(1) Except as provided in paragraph (2), before issuing in final form any regulation under subsection (a), the Secretary shall provide for notice of the proposed regulation in the Federal Register and a period of not less than 60 days for public comment thereon.

(2) Paragraph (1) shall not apply where—

(A) a statute specifically permits a regulation to be issued in interim final form or otherwise with a shorter period for public comment,

(B) a statute establishes a specific deadline for the implementation of a provision and the deadline is less than 150 days after the date of the enactment of the statute in which the deadline is contained, or

(C) subsection (b) of section 553 of title 5, United States Code[502], does not apply pursuant to subparagraph (B) of such subsection.

(c)(1) The Secretary shall publish in the Federal Register, not less frequently than every 3 months, a list of all manual instructions, interpretative rules, statements of policy, and guidelines of general applicability which—

(A) are promulgated to carry out this title, but

(B) are not published pursuant to subsection (a)(1) and have not been previously published in a list under this subsection.

(2) Effective June 1, 1988, each fiscal intermediary and carrier administering claims for extended care, post-hospital extended care, home health care, and durable medical equipment benefits under this title shall make available to the public all interpretative materials, guidelines, and clarifications of policies which relate to payments for such benefits.

(3) The Secretary shall to the extent feasible make such changes in automated data collection and retrieval by the Secretary and fiscal intermediaries with agreements under section 1816 as are necessary to make easily accessible for the Secretary and other appropriate parties a data base which fairly and accurately reflects the provision of extended care, post-hospital extended care and home health care benefits pursuant to this title, including such categories as benefit denials, results of appeals, and other relevant factors, and selectable by such categories and by fiscal intermediary, service provider, and region.

(e)[503](1)(A) A substantive change in regulations, manual instructions, interpretative rules, statements of policy, or guidelines of general applicability under this title shall not be applied (by extrapolation or otherwise) retroactively to items and services furnished before the effective date of the change, unless the Secretary determines that—

(i) such retroactive application is necessary to comply with statutory requirements; or

(ii) failure to apply the change retroactively would be contrary to the public interest.

(B)(i) Except as provided in clause (ii), a substantive change referred to in subparagraph (A) shall not become effective before the end of the 30-day period that begins on the date that the Secretary has issued or published, as the case may be, the substantive change.

(ii) The Secretary may provide for such a substantive change to take effect on a date that precedes the end of the 30-day period under clause (i) if the Secretary finds that waiver of such 30-day period is necessary to comply with statutory requirements or that the application of such 30-day period is contrary to the public interest. If the Secretary provides for an earlier effective date pursuant to this clause, the Secretary shall include in the issuance or publication of the substantive change a finding described in the first sentence, and a brief statement of the reasons for such finding.

(C) No action shall be taken against a provider of services or supplier with respect to noncompliance with such a substantive change for items and services furnished before the effective date of such a change.

(2)(A) If—

(i) a provider of services or supplier follows the written guidance (which may be transmitted electronically) provided by the Secretary or by a medicare contractor (as defined in section 1889(g)) acting within the scope of the contractor’s contract authority, with respect to the furnishing of items or services and submission of a claim for benefits for such items or services with respect to such provider or supplier;

(ii) the Secretary determines that the provider of services or supplier has accurately presented the circumstances relating to such items, services, and claim to the contractor in writing; and

(iii) the guidance was in error;

the provider of services or supplier shall not be subject to any penalty or interest under this title or the provisions of title XI insofar as they relate to this title (including interest under a repayment plan under section 1893 or otherwise) relating to the provision of such items or service or such claim if the provider of services or supplier reasonably relied on such guidance.

(B) Subparagraph (A) shall not be construed as preventing the recoupment or repayment (without any additional penalty) relating to an overpayment insofar as the overpayment was solely the result of a clerical or technical operational error.

(f)(1) Not later than 2 years after the date of the enactment of this subsection, and every 3 years thereafter, the Secretary shall submit to Congress a report with respect to the administration of this title and areas of inconsistency or conflict among the various provisions under law and regulation.

(2) In preparing a report under paragraph (1), the Secretary shall collect—

(A) information from individuals entitled to benefits under part A or enrolled under part B, or both, providers of services, and suppliers and from the Medicare Beneficiary Ombudsman with respect to such areas of inconsistency and conflict; and

(B) information from medicare contractors that tracks the nature of written and telephone inquiries.

(3) A report under paragraph (1) shall include a description of efforts by the Secretary to reduce such inconsistency or conflicts, and recommendations for legislation or administrative action that the Secretary determines appropriate to further reduce such inconsistency or conflicts.

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[502]  See Vol. II, 5 U. S.C. 553.

[503]  As in original. No subsection (d) has been enacted.

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* Logical Outgrowth.   

Google search results here.

https://law.lclark.edu/live/files/10039-administrative-law-outline-funk-fall-2010

https://www.foreffectivegov.org/node/2585  (logical outgrowth test)

https://scholarship.law.nd.edu/cgi/viewcontent.cgi?article=4697&context=ndlr   Law article by Lifton, 2017.