2019 Regulatory Update

The presenter(s) for today’s educational program is/are:

Disclosure Statement

David Vulcano

I have no relevant financial relationship(s) in connection with this educational activity.

Disclaimers

• Presentation is a high level overview. There are lots of additional details, “only ifs” and “except whens”.

• Presentation is a combination of lecture and slides. Neither are intended to be construed as a stand-alone presentation or taken out of context.

• Any opinions put forth in this presentation are not to be construed as the opinions of any particular entity or person (including being the speaker’s own opinions).

3

EHRs

• Maintains no Part 11 requirements for EHRs.

• “Sponsors should include in their data management plan a list of EHR systems used by each clinical investigation site in the clinical investigation. Sponsors should document the manufacturer, model number, and version number of the EHR system and whether the EHR system is certified by ONC.”

• For those not certified by ONC, Sponsor must consider the following:

• Policies and processes for the use of EHR systems at the clinical investigation site are in place, and there are appropriate security measures employed to protect the study data.

• Access to electronic systems is limited to authorized users.• Authors of records are identifiable.• Audit trails are available to track changes to data.• Records are available and retained for FDA inspection for as

long as the records are required by applicable regulations.

New FDA Guidance on EHRs in Clinical Trials

1) WEBSITE: https://chpl.healthit.gov/#/search

Is the EHR ONC Certified? The Certified Health Product List (CHPL)

2) SEARCH

3) RESULTS

Miscellaneous Privacy Actions

• HIPAA: Old Rule But New Audits

• Revised 42CFR2 (Privacy of Substance Abuse Treatment Information)

• 21st Century Cures Act• Section 2012: Expands Certificates Of Confidentiality For Certain Research

Participation/Data Privacy

• NIH Policy (October 1, 2017):

- “Certificate” is essentially default for federal-funded applicable research

- Can be applied for non-federal-funded applicable research

• EU’s General Data Protection Regulation (GDPR)

• California Consumer Privacy Act of 2018

Make Identifiable Data More Private….

• 42CFR11 (2016) + NIH Policy (2017) For Federally Funded Clinical Trials

• New ICMJE Requirement For Data Sharing Plan (July 2018) For All Clinical Trials• Individual Level Data with Dictionaries• What Other Documents Will Be Available• Who/What/When/Where/Why/How’s of Access

• De-Identified Individual Patient Data (IPD) Made Public As A Condition Of Product Approval• EMA Policy 0070/Phase 2 (Preparations In Place Now)

- Requires (Re-Identification) Risk Evaluation

• Health Canada’s Public Release of Clinical Information (Draft, Dec 2017)

…But Make De-Identified Data More Public…

• Trusted Exchange Framework and Common Agreement (In Development)

• Result of 21st Century Cures Act (Sec. 4001-4006) and Executive Orders 13812, 13771, & 13777

…and then, there’s TEFCA

Interoperability: The Past

HIN HIN

HIN

Interoperability: Today

QHIN QHIN

QHIN

Interoperability: Under TEFCA

QHINBroker

QHIN

QHIN

QHIN

QHIN

2. Matching Challenge

• Patient• Provider• Third Party

Source: https://www.healthit.gov/sites/default/files/nprm/ONCCuresNPRMUSCDI.pdf

The U.S. Core Data for Interoperability (USCDI)- Version 1

• Able to exchange EHI with, and use from, other health IT without special effort on the part of the user.

• IT developers must publish their APIs (Application Programming Interface)

• Providers and vendors prohibited from “Information Blocking” unless meeting one of 7 defined exceptions

• Does not override existing privacy laws• For HIPAA covered entities: HIPAA Authorizations or IRB Waiver of

HIPAA Authorizations still apply for disclosure of identifiable data for research

• All other laws that affect research privacy also apply: e.g. Common Rule, SAHMSA, FTC, State privacy laws, GDPR etc.

Basic TEFCA Rules

• Recent Action (2019) on Timeliness (First Official OIG Case):• $85k settlement with OIG (plus a Corrective Action Plan) for not providing

a mother records timely access to records about her unborn child.• https://www.hhs.gov/about/news/2019/09/09/ocr-settles-first-case-hipaa-right-access-

initiative.html

• Recent Action (2019) on “Reasonable Costs”• $35.4M civil settlement from Wisconsin hospital and their third party

processor for overcharging ($22.58 fee) for copies of medical record requests (from 2011-2019).

• https://www.beckershospitalreview.com/legal-regulatory-issues/wisconsin-hospital-ciox-health-to-pay-35m-for-medical-records-overcharges.html

Legal Actions are Starting To Take Place

• Quicker and easier to get AE and Con-Med information from disconnected providers

• More notification between disconnected providers that “Patient Is On A Clinical Trial” (i.e. Z00.6 code)

• Enhanced remote source data verification monitoring

• Improve direct connection between patent and sponsors• Patient contacted for trials

• Patient able to “sell” their data for research

Some Potential for Research/Trials Industry

For example, ONC and NIH’s S4S Pilot…

Other 21st Century Cures Act Updates

21st Century Cures Act | Sec. 2034: Reducing Administrative Burden For Researchers

• Within 2 years, HHS is to harmonize and eliminate duplicative Conflict of Interestreporting.

• Examine the varying minimum thresholds

• Consider allowing for “Just-In-Time” reporting

• Consider redefining which investigators and sub-investigators need to report.

• HHS is to minimize the burdens of an NIH prime recipient’s monitoring of subrecipients’ funding.

• Note, the prime recipient is still responsible for sub-recipient behavior.

• Endorses the creation of “multiple primary awardees”.

• Office of Management & Budget to establish a “Research Policy Board” (a public-private advisory board of 9-12 members) to identify negative or adverse consequences of regulations, identify regulatory gaps and make actionable recommendations by September 30, 2021.

20

Note: Not quite the Research Policy Board yet but…..2017 American Innovation and Competitiveness Act (AICA) Sec. 201

• Create a government-wide annual standard set of assurances for grant applicants and recipients

• Create a Centralized Researcher Profile database• Using ORCID for identifying researchers• Universal CrossRef to create grant identifiers (think

“Funding DOI”)• Using SciENcv for researcher biosketches

• Create a Uniform Grant Application (building off of SF424RR work in 2003)

• Create standard progress report (building off of RPPR report in 2010)

• Clarify responsibilities for monitoring SubRecipients• Improve/Harmonize Financial Conflict Of Interest (FCOI)

Regulations

“The working group shall: (1) establish a centralized database for documents relating to researchers, (2) establish a central repository for all assurances required for federal research grants, and (3) conduct a comprehensive review of the mandated progress reports for federally funded research.”

FDA PHS Patient Protection & Affordable Care Act (PPACA)

“Ownership” Any amount (if value cannot be readily determined through reference to public prices) OR >$50,000 in a publicly traded corporation

Any equity interest earned (e.g., stock, stock option, or other ownership interest) >$5000 (in preceding 12 months)

Any amount (other thanstock options received as compensation, untilthey are exercised) but excludes publically traded securities

Significant Payments of Other Sorts (SPOOS)

$25,000, exclusive of the costs of conducting the clinical study or other clinical studies

$5,000 (in preceding 12 months)

$10 (unless >$100/yearin aggregate) adjusting for inflation since 2010

Major Differences Between FCOI Thresholds

The “Immediate Family”: by FDA (21CFR54) & PHS (42CFR50)

Only Dependent ChildrenOnly Dependent Children

(1) Spouse.(2) Natural or adoptive parent, child, or sibling.(3) Stepparent, stepchild, stepbrother, or stepsister.(4) Father-, mother-, daughter-, son-, brother, or sister-in-law.(5) Grandparent or grandchild.(6) Spouse of a grandparent or grandchild

The “Immediate Family”: by PPACA Sec: 6002 (a.k.a. “Open Payments” or “Sunshine Act”)

Only Dependent ChildrenDo NOT have to be dependent

NIH “Reminder” on COIs Posted July 10, 2019…other support [in grant applications] includes all resources made available to a researcher in support of and/or related to all of their research endeavors, regardless of whether or not they have monetary value and regardless of whether they are based at the institution the researcher identifies for the current grant.

List all positions and scientific appointments …relevant to an application …whether or not remuneration is received, and whether full-time, part-time, or voluntary (including adjunct, visiting, or honorary).

The FCOI regulation acknowledges that an applicant/recipient’s policy on financial conflicts of interest may have standards that are more stringent than those in the regulation, … in which case the institution shall…provide FCOI reports to NIH … in accordance with its own standards and with the protocol specified in the regulation.

21st Century Cures Act | Sec. 3021-3024: “Subtitle C: Modern Trial Design and Evidence Development”

• FDA Is To…

• Issue Guidance On The Use Of Complex Adaptive Or Other Novel Clinical Trial Designs For Drugs/Biologics

• Develop A Program For Potential Use Of Real World Evidence.

• To Include For New Indications Or An Alternative Way To Conduct Post-Approval Studies.

• Issue Guidance On When/How They Will Accept Real World Evidence In Lieu Of (Or As A Supplement To)

Controlled Clinical Trials

• Issue Guidance On Appropriate Standards And Methodologies For The Collection/Analyses Of This Data

• HHS To Reevaluate OHRP And FDA Regulations To Support The Elimination Of Barriers To Research And

Eliminate Duplication Of Regulations.

• This Process Should Allow For FDA Waivers Of Consent For Research Of No More Than Minimal Risk, Assure

Adequate Protection Of Vulnerable Populations And Assure Ability Of Single Central IRB Review For

Multicenter Studies.

• [What Is Interesting About That Last Item Is That The Law Goes On To State That It Is Protecting A Facility To

Use An “IRB Other Than The Sponsor’s” Which Is Seemingly Counterintuitive To The Nature Of The NIH

Having The Sponsor Pick The Single IRB.]

26

FDA’s Response To 21st Century Cures: General and Waiver of Consent

• Real-World Evidence (RWE) is the clinical evidence about the usage and potential benefits or risks of a medical product derived from analysis of RWD.

• RWE can be provided instead of (i.e. observational studies) or in hybrid with clinical trials (e.g. “pragmatic design”, RWD Control arms, “cluster randomization” etc).

• FDA will evaluate use of RWE with…• RWD fit for use?

• See Guidance “Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data”

• Adequate scientific design?• Meets regulatory requirements?

• risk-basedand central monitoring for clinical trials that are integrated into the health care system

• FDA inspections, recordkeeping, and record retention requirements

• Non-FDA regulations (i.e. HIPAA)

FDA’s Response To 21st Century Cures: Real World Evidence

• Not (Currently) Required But Not Inconsistent If Adopted

• Changes to Consent Requirements

• Single IRB (not in this guidance but addressed in others)

• Not (Currently) Adoptable• Changes to Expedited Review

• Changes To Continuing Review

FDA’s Response To 21st Century Cures: Harmonization with Common Rule

Update on “Right To Try” vs Expanded Access

30

“Right To Try” Status Summary

• 41 States Passed A Variant Of The Law Over Past 4 Years• A Few More States’ Versions In Various Pending Stages

• Purports No FDA IND Is Needed (I.E. No Expanded Access Approval)

• No National Law Allowing Until May 2018 (But Only References “Drugs”…”Devices” were removed in final law)

• The “Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017”

31

• “Eligible Patient” under the law• Life-threatening disease or condition defined as:

• (1) …where the likelihood of death is high unless the course of the disease is interrupted; and

• (2) …with potentially fatal outcomes, where the end point of clinical trial analysis is survival.

• Exhausted approved treatment options

• Unable to participate in a clinical trial involving the eligible investigational drug

• The above is certified by a physician, who:• (i) is in good standing with the physician's licensing organization or board; and

• (ii) will not be compensated directly by the manufacturer for so certifying.

• Provided (themselves or via their legally authorized representative) written informed consent

Key Components of National Right To Try Act

• Definition of Eligible Investigational Drug• Completed Phase 1 Clinical Trials, Still Under Active IND Development and Not

Currently Under A Clinical Hold

• Labeled with "Caution: New Drug--Limited by Federal (or United States) law to investigational use."

• Labeling shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated

Key Components of National Right To Try Act

• FDA may not use a RTT clinical outcome to delay or adversely affect the review or approval of an IND unless—

• Certifies as critical to determining the safety of the eligible investigational drug; or

• The sponsor requests use of such outcomes.

Key Components of National Right To Try Act

Core Comparisons of State LawsCO LA MO MI AZ

WY

AR SD UT IN VA MSMT

ND OK MN TN NV AL FL TX NC IL OR ID WV ME GA SC NH CT CA OH WA KY IA MD PA WI NE AK

Requires More Than 1 Physician To Diagnose

Terminal Illness*

1

Additional Requirements (Beyond State Licensure)

Of Physician To Be Qualified To Diagnose

2 2 2 23,

44 2 3

Additional Criteria ForEligible Product Above Completing Phase One

Clinical Trial(s) And Still Under Development

5 5 5 5 5 5

There are (N)o Other Treatment Options or they

only had to have (C)onsidered All Other

Options

C N C C N C N C N N C C C C C C C N C C C C C 6 C C C C N N C C N C C C C C6 N C C

Clinical Trials (with limitations) Must Be

Considered As “Other Options”

7 8 7 8 8 7 7 7 7 7 7 7 7 9 8 7 8 8

Excludes (H)ospitalized or (U)nder 18 Patients As

“Eligible Patient”

H H H U H H U H H

• *Note, Indiana allows for non-terminal illnesses if there is no unreasonable risk• 1: If the eligible patient is incarcerated, the DOC’s Medical Director must also approve. • 2: Second physician must be board certified in the appropriate specialty (LA, FL) or excludes/limits primary care (AZ, OH) or specifies the physician cannot have been previously involved in the patient’s care (VA)• 3: Patient must be resident of the state (in Oregon, physician must verify residency by viewing drivers license, voter registration, property ownership or state tax returns).• 4: Must verify eligibility to give consent (in Oregon, if physician sees a psychiatric or psychological disorder, they must refer to a counselor to clear for informed consent, in CA, the second physician must verify ability to give consent).• 5: Disallows Schedule 1 Controlled Substances (MO, MS, OH); Includes cannabis by state approved grower (UT); excludes investigational drugs for assisted suicide (OH, IA); requires state medical licensing board to develop protocols for non-hospital settings and

states physician can be disciplined for not following the protocol (IN)• 6: Mentions that the patient may be eligible for FDA’s expanded access. • 7: No Trial Within 100 Miles or not accepted within 1 week of their “application” to be in the trial (TN is 50 miles; ME is just 1 week, no distance; CA is 1 week or the trial nearest to their home unless physician certifies condition does not allow participation; OH is

100 miles or “application” was denied).• 8: No Trials In-State (Virginia is no reasonable opportunity, regardless of distance or in-State) or general Ineligible or unable to participate in a clinical trial (MD, WI and AK)• 9: Multiple subjective criteria, such as the physician having to have prsonally contacted one or more PIs in the practice area

35

Core Comparisons of State LawsCO LA MO MI AZ WY AR SD UT IN VA MS MT ND OK

MN

TN NV AL FL TX NC IL OR IDWV

ME GA SC NH CT CA OHWA

KY IAMD

PA WI NE AK

Informed Consent Required In Writing

Requires Items In Addition To Those Expected Of FDA For

Expanded Access 2 3 4 5 2 5 6 6 2

Consent Form Requires Witness 7

8

Specifies requirement of physician to cosign consent

form 9 9

Requires Ethics CommitteeReview/Approval of Consent

Form

Requires Disclosing Of Updates From Safety Findings (i.e.

DSMB) OF Same Product In Clinical Trials

• 1: Not really additional but more descriptive than FDA• 2: TN and OR require what FDA generally considers exculpatory language in that it requires a release of liability towards providers, hospitals and manufacturers for providing the product. AK just requires a statement

that the physician/medical team & manufacturer are not liable for damages when acting in good faith.• 3: Requires disclosure that future benefits under the policy of insurance covering the patient may be affected by the patient’s use of the product• 4: No requirements by law but states HHS Commissioner may adopt a consent form which has not been done to date.• 5: Requires physician to provide documentation to the patient that includes an attestation from the treating physician that they (the treating physician) were consulted in the creation of the written, informed consent.• 6: Form must be based on a State Medical Board (Ohio @ http://www.med.ohio.gov/Portals/0/DNN/PDF-FOLDERS/PRESCRIBER-RESOURCES-PAGE/Informed%20Consent%20to%20Treatment.pdf) or Office of Attorney

General (MD, under development) template• 7: specifies witness does not have to sign and must be 18 years of age• 8: Requires 2 witnesses, one witness must be independent of the patient/family, physician and healthcare facility. Neither can be the physician.• 9: Patient must sign a 3-way written agreement with both physician and manufacturer

36

CO LA MO MI AZ WY AR SD UT IN VA MS MT ND OKMN

TN NV AL FL TX NC IL OR IDWV

ME GA SC NH CT CA OHWA

KY IAMD

PA WI NE AK

Expressly States It Is Illegal For A State Official To Block Access

Protection Of Actions Against Physician’s License

Promise Immunity Of Physician’s Medicare Certification

Protections Of Manufacturer

Protections Of Other Healthcare Providers/Institution

Requires IRB Oversight 1 2 2 3

Requires Manufacturers To Provide

4 4

Requires Private (I)nsurers or (S)tate Insurers (i.e. Medicaid) To

Cover Cost5

6, 7

5 6 5 5 7 7

Allows For Patient’s Estate to Not Be Liable For Associated Debts In

Case Of Patient Death8 8 8 87

• 1: Does not mention “IRB” but if done by a hospital, requires the governing board or their appointed “committee” that approves “experimental or nonconventional” treatments• 2: No IRB oversight/preapproval but in TN, the physician must report adverse events to the manufacturer (TN) and in OR, physician must file report afterward to Oregon Health Authority detailing outcomes,

adverse events, cost to patient and demographic information.• 3: Yes to IRB oversight, and the IRB must additionally report biannually to the state a report containing 1) # requests, 2) status, 3) duration of treatment, 4) cost paid by patients, 5) “success or failures” and 6)

adverse events for each product.• 4: If provided, the manufacturer must provide to the eligible patient without receiving compensation (TX) or the patient cannot be compensated for receiving (OR)• 5: In fact, expressly allows insurance to deny all coverage while on the drug and up to 6 months after, generally except for pre-existing conditions• 6: No obligation to pay but does require insurance company to be notified by day of treatment. • 7. Allows insurer potential to deny coverage if the patient dies (CA) or to cover costs to treat harm caused by the product (WA, UT)• 8: In SD and NE this only applies to estate’s associated debt to the manufacturer only, not the providers. NOTE: In WV, the consent form requirement seemingly contradicts this by requiring disclosure that the

estate is potentially liable for costs.

37

Core Comparisons of State Laws

• Pilot Started June 2019 For Oncology

• Physicians and Patients Can Call FDA First Requesting Expanded Access

FDA’s “Project Facilitate” To Expedite Expanded Access

Miscellaneous

• Is set forth in a policy applied uniformly and consistently

• Cannot publicly market or advertise & no marketing during the ride

• For medically necessary items and services only

• Must be an “established patient”, meaning• Had previous appointments at center, or

• Patient initiated contact to schedule an appointment

• Within 25 miles of the health care provider or supplier to or from which the patient would be transported, or within 50 miles if the patient resides in a rural area

• Pharmaceutical companies are excluded as an eligible entity in the safe harbor

https://www.gpo.gov/fdsys/pkg/FR-2016-12-07/pdf/2016-28297.pdfIS IT THE SITE’S OR THE SPONSOR’S

TRANSPORTATION PROGRAM?

Offering “Free or Discounted” Travel- OIG Safe Harbor

• SUPPORT Act = “Substance Use–Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act”

• Passed 2018

• Extends Open Payments Reporting (Including research payments reporting) to include those to:

• physician assistant,• nurse practitioner, • clinical nurse specialist, • certified nurse anesthetist, and• certified nurse-midwife

• Removes restriction for CMS to post NPI numbers on Open Payments website

SUPPORT Act’s Sec 6111: “Fighting The Opioid Epidemic With Sunshine”