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Mark DuVal, J.D., is president and managing partner of DuVal & Associates. DuVal counsels pharmaceutical, medical device, biotech, food and nutritional supplement companies and regularly advises clients in all areas of FDA law and regulation.
Bradley Merrill Thompson, Esq. is a shareholder in the law firm of Epstein, Becker & Green. P.C. There Thomson counsels medical device and drug companies on a wide range of FDA regulatory, reimbursement and clinical trial issues.
Presented by:
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Agenda: Off-label Promotion—Avoiding Off-label Pitfalls
The Big Picture and a brief overview of advertising & promotion law
Permissible forms of off-label promotion Foundations for lawful off-label
dissemination Permissible forms of off-label
communication
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The BIG Picture: The Real Promotional
Issues Are Here Today
Off-label information
False Claims Act
Anti-kickback
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“…Mr. Louck’s [U.S. Attorney Boston] team is interested in whether Schering-Plough pushed doctors to prescribe its drugs for unapproved, or ‘off-label’, purposes by offering the doctors clinical trial grants or other incentives.”
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Spotlight on CME
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False Claims Act theories: alleged marketing of off-label uses through medical science liaisons, medical education, clinical trials etc.
The Neurontin Whistleblower Case
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“It is reasonable to anticipate that the same kinds of cases brought against pharmaceutical manufacturers for kickback are going to be out there for device manufacturers because the industries are similar.”
—Jim Sheehan, Associate U.S. Attorney May 2005
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FDLI’s UPDATE magazine Jan./Feb. 2004
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Subpeonas issued:October 27, 2005
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General vs. Specific Use Issues
The Biliary Stent FDA Compliance Meeting—Spring 2007
The Spineology Warning Letter—Fall 2007
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Hot off the press:Still further pressure on off-label uses by Senator GrassleyLetter to Comm’r FDA Nov. 30, 2007
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FDA’s New Guidance document October/September 2007
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“[This] does not mean that people will never be mislead or offended even by truthful advertisements. Nor does such a principle guarantee that people will always make the right decisions. But…the American people must be trusted with a free flow of ‘commercial information’ unhindered by concern about government interference.”
—Dan Troy, Former Chief Counsel, FDA
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Brief Overview of
Advertising &
Promotion Law
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FDA Regulatory Authority
At base, FDA regulates information about products, i.e. “claims”
Claims must truthful, not misleading, fairly balanced and substantiated
The areas of general vs. specific indication/claims and dissemination of off-label information present special issues
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Under 21 CFR 801.4, the words “intended uses” … refer to
the objective intent of the persons legally responsible for the labeling of devices. The intent is determined by such persons' expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised. …
Concept of “Intended Use”
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Off-Label Use Rules
If promoted off-label, a device may be deemed “misbranded” or “adulterated”
The uses promoted are “intended uses” under 21 CFR 801.4 If an intended use is for other than the approved
indication, the lack of approval and inadequate labeling make device “adulterated” and “misbranded”
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Three Types of Information Flow
Lawful on-label promotion “Dissemination” of scientific
information Off-label “communication”
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Off-Label Promotion
The legal basis for FDA’s objection The evolution of the law over the
last decade
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Evolution of the Legal Landscape
Where FDA was:of Strict regulation off-label promotionFDA Guidances
Guidance on Dissemination of Reprints and Reference Texts (1996)
Guidance on Industry Supported Scientific and Educational Activities (1997)
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Then First Amendment Litigation
Washington Legal Foundation WLF brought action challenging 1996/1997
Guidances (and later, FDAMA) as unconstitutional under the First Amendment
WLF won at trial On appeal, when FDA asserted they were not
mandatory, but created only safe harbors, the court held the matter was not ripe for determination—a technicality
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WLF Trial Court Holding
Trial court suggested restrictions of its own, which many manufacturers have adopted Articles from bona fide peer-reviewed journals or text
books published by a bona fide independent publisher Product must be cleared or approved for at least one
indication False and misleading materials still open to FDA
enforcement Must disclose off-label nature of a use Must disclose any relationship between
the company and product or authors
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FDAMA Section 401 (1997)
Set forth process for disseminating off-label information
Required disclosure statements & labeling Required later filing for approval of any
unapproved uses in the materials Set forth audience restrictions Limited to dissemination of certain
reference journals Codified in regulations (Part 99)
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First Amendment Status
US Supreme Court decided Western States case Involved pharmacy compounding provisions of FDAMA
FDA cannot infringe on the right of medical device companies to promote their products if other, less restrictive measures can achieve FDA's objectives, such as: Disclaimers and warning labels Disclosures Limitations on non-speech related activity Narrowing of speech restrictions
On May 16, 2002, FDA requested comments on its authority to regulate communications — more than 730 comments received
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What the Law is NOW—a Void
FDCA sections on misbranding are still in effect
FDAMA 401 provisions on dissemination of off-label materials and regulations sunset
CME guidance is still in effect Constitutionally speaking, FDA cannot infringe
on promotion of products if it has other options FDA’s proposed Guidance document is in the
works
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Types of Promotion
Sales activity Trade shows Company controlled medical education
(non-CME) Contracts for the sale of unapproved
equipment Promotion before approval
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Sales
Should be controlled by “Good Promotional Practices”
Training essential to managing risk and ensuring compliance
Sales pitches and materials need to be on label
Companies need to tightly control what sales reps hand out
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Trade Shows
What standards apply to information disseminated at trade shows? Labeling regulations do apply
FDA frequently cites companies for their trade show activities.
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Trade Shows (cont’d)
Best practices: Train marketing personnel extensively in
permitted disclosures Consider having clinical personnel present to
respond to questions that are off-label Maintain a separate space for
international uses
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Trade Shows (cont’d)
Special Rules—510(k) Pending For 510(k) pending devices, special accommodation to
account for infrequent trade shows Show demo model, with conspicuous statement that not
cleared, 510(k) pending No performance claims Can explain intended use and existence of basic features Can collect business leads But do not take orders, or be prepared to take orders, that
might result in contracts of sale for the device unless limited to research or investigational use (e.g. no discussion of commercial price)
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Meetings – Two Types
“Controlled” - speakers under the control of the manufacturer (e.g., employees, consultants) Company-organized educational sessions Speaker’s bureaus Trade show booths
“Supported” - speakers are not under the manufacturer’s control but manufacturer provides financial support, i.e. grants, for the program speakers Commercially supported, accredited CME, e.g., ACCME Mark will address CME later
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Promotional Meetings
Controlled Communications Regulated as promotional material Remarks should:
Be consistent with approved intended use Conform to rules applicable to unsolicited requests
Also consider rules applicable to: Written promotional materials Appropriate locations Interactions with healthcare professionals
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Meetings
Best practices: Controlled speakers Respond to questions openly, but follow
guidelines for responding to unsolicited questions on off-label uses
Focus prepared remarks and materials on cleared or approved uses, or disease state
No “back-up” slides on off-label uses
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Contracts for Future Generations
Some provisions marketers may want: Option to purchase at unspecified price Option to purchase as specified price Commitment to provide by certain date Commitment as to features or performance of next
generation Commitment to notify when available Commitment to upgrade as part of the contract price Lease agreement that includes any future generations over
the course of the lease Clause subject to obtaining regulatory approval/clearance
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Contracts for Future Generations (cont’d)
FDA’s policy concerns Rush to develop/design, less quality Temptation to ship before approval/clearance Company loss of control Promise that the company can’t fulfill Premature promotion that creates intended uses that
may not be suitable Freedom of choice among healthcare providers/patients Rationale—this is where interstate
commerce begins
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Contracts for Future Generations (cont’d)
The Law, or Some Rules of Thumb Can’t sign, or perhaps even negotiate, a contract
where successful performance (e.g. delivery) would require FDA approval/clearance Some believe this is true even if the contract conditions
performance on FDA clearance or approval (penalty free) Note that exempt devices or changes that do not require a new
510(k) would not be included
Can’t pre-promote except in compliance with the rules for pre-approval communication
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Contracts for Future Generations
Some provisions marketers get Option to purchase at unspecified price Option to purchase as specified price Commitment to provide certain features by certain date Commitment as to features or performance of next
generation Commitment to notify when available Commitment to upgrade as part of the contract price Lease agreement that includes any future (unspecified)
generations over the course of the lease
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A blend of both phase 2 and 4.Cleared and investigational5
A whole slew of restrictions apply, including limits on off-label promotion, truth in labeling, adequate directions for use, and a number of affirmative requirements related to name, quantity, etc...
Cleared or approved4
According to FDA CPG section 300.600:“Although a firm may advertise or display a device that is the subject of a pending 510(k)--in the hope that FDA will conclude that the device is substantially equivalent to a pre-amendments device--a firm may not take orders, or be prepared to take orders, that might result in contracts of sale for the device unless limited to research or investigational use.”
510(k) pending3
IDE regulation places explicit restrictions. For example, no promotion is allowed beyond what is necessary for its use in investigations (e.g. recruiting subjects). Here, no clinical performance claims are permitted.
Investigational (Human use)2
As a legal technicality, none on promotion until introduced into interstate commerce. See CPG 300.600. Remember design control requirements that will apply to labeling. But customers and FDA will remember what is said.
Early Development1
Requirements Related to PromotionRegulatory Category
Phase
Development Phases
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Basic Rules For Pre-approval Promotion—Go Back to First Principles
Thou Shall Not Promote Beyond the anticipated Approved Label Whatever the company says now about its upcoming
product will create an impression in the minds of the customers who may ultimately be asked to purchase that product.
If the company describes uses that do not ultimately get approved, the company will be creating an off-label promotion situation once the product is introduced into commercial distribution.
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Basic Rules For Pre-approval Discussion
Thou Shall Tell the Truth in Promotional Materials Both FDA and FTC would have difficulty proceeding
against the company for statements made in advance of any product being placed in commercial distribution. (But other laws may still be relevant.)
However, once the opportunity to acquire the product exists, any prior statements made would be evaluated for their truthfulness. Being truthful means, among other things, the statements made are adequately supported by valid scientific evidence at the time they are made.
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1. Contracts for future generations2. Investor communications about clinical trials3. Medical meeting discussions of clinical trials4. Peer reviewed articles about marketed devices
Cleared and investigational5
1. Contracts for future generations2. Investor communications about clinical trials3. Medical meeting discussions of clinical trials4. Peer reviewed articles about marketed devices
Cleared or approved4
1. Trade shows2. Investor communications about clinical trials3. Medical meeting discussions of clinical trials4. Peer reviewed articles about marketed devices
510(k) pending3
1. Trade shows2. Investor communications about clinical trials3. Medical meeting discussions of clinical trials4. Peer reviewed articles about marketed devices
Investigational (Human use)2
1. Investor communications about researchDevelopment1
Special settings and issuesRegulatory Category
Phase
Issues by Development Phase
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Three Types of Information Flow
Lawful on-label promotion “Dissemination” of scientific
information Off-label “communication”
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Dissemination of Scientific Information
Unsolicited requests Dissemination of peer reviewed articles
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Unsolicited Requests
When may off-label information be provided? In response to an unsolicited request of a health care
provider Best Practices: Unsolicited Requests
Make sure unsolicited Keep the discussion objective, non-promotional in
nature, and fairly balanced Confine responses to the specific question asked,
narrowing broad questions before responding Clearly disclose that the device has not been
cleared or approved for the discussed use Document all responses to unsolicited requests
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Medical Affairs
Long recognized by FDA as a position that has additional freedom to engage in medical and scientific exchange
Must not report to marketing or sales—must remain independent
Must maintain its credibility May affirmatively disseminate off-label
information
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Proactively Disseminating Peer Reviewed Articles About Marketed Devices
FDAMA Process—Part 99 Dozens of requirements, including a commitment to
file a supplement Although it has sunset, it does provide a conceptual
approach Common law process
Undefined by FDA, relies heavily on WLF FDA seems to give it some deference
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Factors to Consider For Peer Reviewed Regulatory Status—510(k)
or PMA or investigational Type of Off-Label Content:
Any new indications for use, or intended use?
Any difference in directions for use?
Any difference in performance claims made?
Public Health Value Ability to Avoid Off Label
Content
Regulatory History Health Risk Evidence Quality Author Ties Peer Review Process
Robustness Fair Balance Disclosures and
Disclaimers Other marketing practices
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Level Of Restriction For Peer Reviewed
Don’t use Medical fulfillment of unsolicited request Sales fulfillment of unsolicited request Sales dissemination with restrictions Sales dissemination without restriction Remember all options require training
to do well
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Three Types of Information Flow
Lawful on-label promotion “Dissemination” of scientific
information Off-label “communication”
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What is Role of CME Programs?
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Three Types of Medical Education
Company-sponsored promotional programs
Independent educational programs Hybrid programs
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Independent Educational Programs
Accreditation is key Company is “commercial interest” or
“commercial supporter” Independent needs assessment done No control over content, speakers, venue Does not run program, control invitations No selling or marketing in meeting
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Hybrid Programs
Tougher analysis—has aspects of independent and promotional programs
These are symposia at credible institutions, grand rounds, medical society meetings, etc.
Accreditation may or may not be involved If speaker sponsored, must advise about making off-
label remarks, Q&A is ok No control over content, speakers, venue Does not run program Often commercial supporters sponsor meal No selling or marketing in meeting
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Supporting Medical EducationMajor Issues
CME as a “safe harbor”—ACCME accreditation, AdvaMed Code of Conduct; but ACCME not the only way—new ACCME rules out since Sept. 2004
Can support non-CME too—symposia, round table discussions, medical society meetings, grand rounds, etc.—level and type of support is fact intensive, usually stay on-label
Company speaker’s bureaus—the main message belongs to the company (Q&A treated differently)
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ACCME on CME
The standards are:1. Independence2. Resolution of Personal Conflicts of Interest3. Appropriate Use of Commercial Support4. Appropriate Management of Associated
Commercial Promotion5. Content and Format without
Commercial Bias6. Disclosures Relevant to Potential Commercial
Bias
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North American Association of Medical Education Communication Companies
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CME and Non-CME—Life As We Know It Will Change How does the organization support the inquiring
needs of customers and the advancement of medicine through CME and non-CME programs?
How are ideas for CME initiated? Does the CME provider work only with the company? Have you audited their performance (adherence to ACCME)?
What role does the company play (e.g., financial sponsorship, invitations, speaker materials, presence of employees, availability of marketing materials)?
Does the organization have a standard procedure on how to handle this topic? Has it been updated?
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Clinical Trial Recruitment of Physicians Under Notices of Availability (NOAs)
Can place ads in appropriate scientific and medical journals; calculated to reach qualified potential investigators
Do not make claims No comparisons Limit information to FDA guidance State investigational nature of product
Must direct to an audience of appropriate size and qualifications
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Direct Advertising: Be Creative
For example, while you can’t talk about safety and effectiveness of a product pre-approval, in a recruiting ad you can describe the study protocol and what you hope the trial will demonstrate
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Investigator-Initiated Trials
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Supporting Investigator-Initiated Trials—Major Issues
Can support off-label studies Anti-kickback issue is big
Is it bona fide or a “seeding” trial Is it a way to compensate a high-volume prescriber? What is a “study”
False Claims Act issue is bigger —reimbursement for off-label investigational uses
Cannot be end-run around IDE regs—issue who is truly the “sponsor”
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ANS argued the $1000 they paid physicians was an initiative to collect data to compare the efficacy of competing devices
Wall Street Journal, Feb. 2005
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Indicia of Sponsorship
Initiation of idea Providing the protocol or paying someone else to write
the protocol Reserving the right to exercise some control over study,
e.g. acceptance of the trial design (design input, suggested edits to the protocol), payment milestones, requiring right to review publication, etc.
“Loaning” employees to work on study, e.g., monitoring, auditing, data management, analysis, etc.
Requiring the physician to use a particular CRO, regulatory group
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Investigator-Initiated Trials
How are grant requests handled? What is included and excluded (mostly from an anti-kickback standpoint)?
Has the company established criteria for the support of trials? Is the trial calculated to generate meaningful, actionable clinical information? Is it overly duplicative of other studies?
How is financial disclosure handled? Does the organization have a standard procedure
on how to handle this topic?
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Patient Registries
Beware of them—FDA advertising, Anti-kickback and False Claims Act issues too
Did the government ask you to collect the data
Why are you collecting it, what use will it be and how much are you paying for it?
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We Can Conduct/Probably Cannot Disseminate— Permissible “Background Noise” Activities
Non-peer reviewed articlesPhysician-initiated trialsAbstractsCME outflowMD newslettersConsumer newslettersOpinion editorialsLay media articlesThird party letters to editorPress releases
Publication Planning— What Can We Do?
Website/Investor Relations Website/internet strategies— “Research
Focus” section on Company site; “hot links” to other sites
Private sector (e.g. Mayo) or Government (NIH, CDC, WHO, VA) treatment protocol, algorithm or practice guidelines Product/technology assessment committees, newsletters, and mailings Non-CME programs
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Consultancies
Provides good feedback on clinical trials, marketing messages, development priorities, new product ideas, etc.
Comes in many formats: advisory boards, focus panels, speaker’s bureaus, etc.
Anti-kickback Statute/OIG Safe Harbor Bona fide services Fair market value Are you extracting or imparting information?
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Physician Training
FDA tolerates some training pre-approval FDA now allows specific uses to be taught
when clearance is general Cannot train on off-label uses
Difficulty is knowing the difference between legitimate specific use within a general clearance and off-label use
Consult FDA guidance documents:
“General/Specific Intended Use” and “Determination of Intended Use for 510 (k) Devices”
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Market Research
Are you extracting or imparting information?
How many do you have involved to get necessary feedback?
Legitimate exercise under FDA regulations and anti-kickback statute—follow Personal services Safe Harbor
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Co-Marketing Practice/Product
Anti-kickback issues predominate—cannot underwrite business expenses for physician
Cannot pick just high volume prescribers Physician must have “skin in the game” Cannot promote off-label Can answer unsolicited/unscripted off-label questions Company must view this as promotional channel for
itself Meet personal services safe harbor/review ads
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Compliance—Process and Procedure
Appoint a compliance person Putting Policy and Standard Operating Procedures
(SOPs) and policies in place and someone in charge of them
Establish and use a promotional review process
Training our sales reps, medical science liaisons, reimbursement personnel and marketers on the company’s: Position on off-label dissemination SOP’s/policies/approval procedures
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Compliance—Process and Procedure (cont’d)
Education on the law—rights and responsibilities
Compliance—ensuring adherence to policies, SOPs and procedures by dealing swiftly and fairly with offenders
Audits—in-house and the field Regular management review
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