Research and Reporting Methods Annals of Internal Medicine Net Reclassification Improvement: Computation, Interpretation,and ControversiesA Literature Review and Clinician's Guide Maarten J.G. Leening, MD, MSc; Moniek M. Vedder, MSc; Jacqueline C.M. Witteman, PhD; Michael J. Pencina, PhD;and Ewout W. Steyerberg, PhD The net reclassification improvement (NRI) is an increasingly pop-
Forum.lingvo.ruFocus on Life Science Compliance: The Evolution of Medical Affairs DepartmentsBy Krist Werling, Hol y Carnel , and Drew McCormick. McGuireWoods LLP, Chicago, IL This article addresses the evolution of medical
variety of medical communications with prescribers, the provi- affairs departments and a variety of key issues that sion of grants to fund investigators studies, as well as various
are relevant to pharmaceutical and medical device
additional research and other tasks.1 Communications over- manufacturers that are establishing or maintaining seen by a medical affairs department may include responding
medical affairs departments. The first section considers
to requests for information about off-label usage, publications, the question, "what is medical affairs?" and attempts to safety information, and independent medical education. define this relatively amorphous function. The second section As discussed in the following section, while the govern- provides an overview of regulatory and subregulatory guid- ment has encouraged the formation of independent medical ance applicable to medical affairs departments. The third affairs departments (sometimes referred to as "clinical affairs" section discusses several evolving issues that are important departments), there is not a rigid set of requirements that for medical device and pharmaceutical companies to consider dictate how a medical affairs department should look or when evaluating their medical affairs departments. Lastly, this operate. As such, the industry has developed a wide variety of article discusses five medical affairs best practices for medical models over the past 20 years, all seeking to address the inten- device and pharmaceutical companies.
sified public and regulatory scrutiny applied to the pharma- ceutical and medical device industries.2 "What Is Medical Affairs"? Generally, medical affairs departments are staffed with "Medical affairs" is the broad term that describes the depart- personnel that have advanced degrees that enable them to ment within a pharmaceutical or medical device company that understand and effectively communicate the science behind a interacts with physicians and other healthcare professionals who device or pharmaceutical product. Medical affairs directors are utilize or are involved with research related to the companies' commonly doctors of medicine (MDs) or doctors of pharmacy products. Medical affairs departments typically handle a wide (Pharm Ds) and medical affairs departments typically are staffed with medical science liaisons (MSLs) who have advanced masters degrees, Pharm Ds, or MDs to enable them to interact with physi- cians and healthcare professionals on a professional level.3 Are Medical Affairs Departments Required by Law?As indicated above, medical affairs departments are not the creature of any statutory or regulatory requirement. Instead, they have been developed by industry and encouraged by the Food and Drug Administration (FDA) and the U.S. Department of Health and Human Services Office of Inspector General (OIG) to facilitate effective and legally compliant communications and interactions between life science companies and healthcare professionals. The convention of creating and maintaining a medical affairs department is clearly endorsed by the OIG and the FDA as evidenced in agency guidance and various corporate integrity agreements (CIAs). The establishment and maintenance of a robust medical affairs department is considered a defense against intent-based One of the earliest agency guidance releases to address separation between sales and marketing and various medical affairs functions is found in the OIG's 2003 Compliance Guidance for Pharmaceutical Manufacturers (Compliance Guidance).4 According to the OIG, separation The convention of
of sales and medical affairs is critical with respect to research, consulting, and grant funding.5 For instance, the OIG recog- creating and maintaining
nizes that "many grant-funded activities are legitimate and beneficial," but notes that "contracts that originate through the a medical affairs
sales or marketing functions—or that are offered to purchasers in connection with sales contacts—are particularly suspect."6 department is clearly
Furthermore, the OIG advises that compliance with applicable healthcare regulations requires that pharmaceutical manufac- endorsed by the OIG
tures ensure that grant funding is totally independent from physician referrals for manufacturer products.7 and the FDA as
In addition to the Compliance Guidance, the OIG and Department of Justice (DOJ) have included recommenda- evidenced in agency
tions for the establishment of medical affairs departments, or the performance of certain functions by medical affairs guidance and various
departments, in a variety of CIAs entered into between the OIG and specific pharmaceutical companies. The September corporate integrity
2008 Cephalon CIA, related to Cephalon's alleged off-label drug promotion, required that the manager of medical affairs, in addition to the managers of other high-risk departments, certify as to the department's compliance with federal health- care program requirements, FDA requirements under the Food, Drug, and Cosmetics Act (FDCA), and attendant regula- finding certain provisions of the FDCA as amended by the FDA tions, and the obligations of the CIA.8 Modernization Act (FDAMA) unconstitutional. However, the More recently, the August 2010 Allergen CIA, related to District of Columbia Circuit found the case moot after FDA alleged off-label marketing of Botox, required Allergen's sales argued that the FDAMA provisions regarding off-label promo- representatives to refer all requests for information about tion operate only as a "safe harbor" and do not create any new or off-label use of Allergen products to Allergen's medical affairs independent enforcement rights.12 department, and also required that any materials distributed While the FDA cannot regulate scientific exchange, it by the medical affairs department related to off-label drug is important for medical device companies to distinguish use are consistent with FDA statutes, regulations, and written scientific exchange from marketing activities. This can best be directives.9 While CIAs do not set forth binding regula- accomplished through the implementation of formal policies tory obligations with general applicability to pharmaceutical and procedures that create a firewall between the medical and and medical device companies, they do constitute the OIG's commercial functions—this is discussed in more detail below. concept of "best practices" for the industry and shed light on what the government believes is necessary to be compliant. Evolving Issues for Medical Affairs Departments An additional source of government guidance can be found As discussed above, the lack of clear regulatory requirements in the FDA's distinction between the "marketing of medical for a medical affairs department, combined with the evolving products" and conducting "scientific exchange." In guidance state of the life science industry, has led to a number of issues for on industry-supported scientific and educational activities, medical device and pharmaceutical companies to consider when the FDA has stated that while it does regulate marketing of establishing and maintaining a medical affairs department. medical products, it does not have the authority to regulate the full scientific exchange of information with healthcare profes- Medical Science Liaisons. The increased use of MSLs or sionals.10 This means that the FDA cannot prevent physicians regional medical liaisons to engage in scientific exchange with from asking about off-label uses of products and unapproved physicians, including key opinion leaders (KOLs), necessitates uses of products nor can the FDA prevent pharmaceutical and robust policies and procedures, and comprehensive training of medical device companies from responding to these questions MSLs and sales and marketing employees. KOLs are physicians and engaging in scientific exchange. who influence their peers' medical practice, including but This issue was heavily litigated in the Washington Legal not limited to prescribing behavior. Over the past ten years, Foundation (WLF) series of cases with the FDA, in which the sales forces employed by pharmaceutical and medical the WLF challenged the FDA's restrictions on manufacturers' device companies have decreased substantially. According to dissemination of off-label, peer-reviewed scientific articles and consulting firm ZS Associates, by the end of 2008, the number support for continuing medical education.11 The U.S. District of U.S. sales representatives dropped to 90,000 from a peak Court for the District of Columbia issued an injunction limiting of about 106,000 in 2006.13 This trend is expected to continue certain aspects of FDA's restrictions on off-label speech and as the life science companies' marketing efforts shift away from mass marketing campaigns and move toward targeted off-label promotion. UCB Pharmaceuticals allegedly promoted marketing for specialty products.14 At the same time, the Wal Keppra, a drug approved as an anti-epileptic, for use in the Street Journal reports that the number of MSLs employed by life treatment of migraines. The UCB CIA builds upon UCB's science companies has increased steadily, totaling 1,970 in 2008, existing compliance program. up 48% from 1,335 in 2003, according to data for 12 major phar- Specifically, the CIA requires that UCB develop policies maceutical and biotech companies compiled by PharmaForce related to the way it will handle requests for off-label uses of International, a market-research firm.15 Further, recent data its products and the manner and circumstances under which suggest that medical affairs departments are spending as much its medical affairs department participates in interactions as 19% of their budgets on MSL programs.16 Thus, companies with healthcare professionals and healthcare institutions. The are reallocating a significant portion of their marketing budget OIG also addressed potential concerns that grant funding by to fund medical compliance through MSL programs. pharmaceutical companies could also constitute an induce- As the use of MSLs increases, the compliance issues ment for referrals, running afoul of the federal Anti-Kickback surrounding such practices increase. For example, MSLs must Statute (AKS). In response to this concern, the CIA requires be constantly assessed to ensure they are remaining compliant UCB to implement written policies and procedures relating with the array of regulations affecting scientific communica- to the appropriate ways to conduct promotional and product tion. Here, it is important that MSLs not revert to the role of services-related functions, such as grant funding, in compli- sales personnel and engage in off-label promotion of medical ance with the AKS. Further, the CIA requires UCB to establish a grant monitoring program to conduct audits of medical education grants to ensure compliance with applicable UCB FDA Off-Label Publications Guidance. The FDA recently policies, such as UCB's policy that the sales and marketing has issued final guidance on the dissemination of off-label departments have no involvement in, or influence over, the communications, off-label journal articles, and enduring review and approval of medical education grants.21 materials.17 Many pharmaceutical and medical device manu- facturers engage in the dissemination of these materials to Globalization of Medical Affairs. As life science companies prescribers. The FDA recognizes this practice and the "impor- are increasingly becoming global entities, the medical affairs tant public health and policy justification supporting dissemi- department also must develop capabilities to support the nation of truthful and non-misleading medical journal articles company's operations in the countries in which it is operating. and medical or scientific reference publications on unapproved It is common for global drug companies to have medical uses of approved drugs and approved or cleared medical affairs staff on the ground in most countries where their devices to healthcare professionals and healthcare entities."18 products are marketed. However, a 2008 study that surveyed The guidance limits the types of materials that should be pharmaceutical companies about the structure of their disseminated to scientific or medical journal articles that are medical affairs departments revealed that only about 26% of peer-reviewed, published by an organization with an edito- participating companies had global medical affairs functions rial board that utilizes reviewers with expertise in the subject in place.22 The same study determined that most drug manu- of the article under review, and are not be written for or at facturers are expanding medical affairs responsibilities world- the request of a drug or device manufacturer or otherwise wide to enhance communication with medical professionals significantly influenced by a drug or device manufacturer.19 and develop better treatments.23 Companies must success- With regard to the manner of dissemination of materials, the fully coordinate medical affairs functions between all of the scientific or medical information distributed should be in the countries in which the company operates. Furthermore, as form of an unabridged reprint or copy of an article or reference the European Union develops more standardized regulations publication, accompanied by the approved labeling from the for clinical trials and marketing communications, medical drug or medical device, distributed with any existent publica- affairs teams are preparing to develop more integrated policies, tions that reach contrary or different conclusions regarding the guidelines, and strategies to incorporate European markets.24 unapproved use, and distributed separately from material that is promotional in nature.20 Best Practices for Establishing and Maintaining One of the primary tasks of most medical affairs depart- a Medical Affairs Department ments is to oversee the dissemination of materials that discuss With these issues related to medical affairs departments in off-label uses. The recent guidance offers a safe process for mind, there are several key best practices that can be imple- medical affairs departments to facilitate this form of scientific mented by pharmaceutical and medical device manufacturers.
❯❯ Independence of Medical Affairs. The OIG has made it clear that a medical affairs department must have meaning- Funding of Independent Clinical Trials. The OIG is increasing ful separation from commercial departments within a scrutiny on the funding of investigator-initiated studies by pharmaceutical or medical device company.25 This does pharmaceutical grants. As demonstrated by the government's not mean that medical affairs personnel are not allowed recent settlement with UCB Pharmaceuticals, the use of grants to interact with the other employees. However, a company to fund investigator-initiated research can pose risks if the should work to establish meaningful separation from com- outcomes of the research are utilized improperly to engage in mercial departments. For example, interactions between commercial personnel and MSLs should be appropriately managed and safeguards should be implemented to ensure While the FDA cannot
that interactions do not run afoul of the company's culture of compliance. Moreover, sales personnel should not have regulate scientific
the ability to use grant programs to incentivize purchases exchange, it is important
❯❯ Reporting Structure. Medical affairs departments should report up to an organization's C-suite, compliance officer, for medical device
or research and development, rather than to a commercial department. Further, the OIG believes it is generally not advisable for the compliance function to be subordinate to companies to distinguish
a manufacturer's general counsel, or comptroller or similar financial officer.26 scientific exchange from
❯❯ Funding. A medical device or pharmaceutical company cannot establish meaningful separation between its com- mercial organization and medical affairs if the medical affairs department is reliant on sales to provide all or a por- tion of its funding on a periodic basis. Therefore, separate line items in budgets should be established for medical affairs and this funding should not be dependent on the sions of the sales organization. Medical affairs programs achievement of sales or marketing targets. Although some should keep documented evidence of MSL training. Such flexibility based on growth is acceptable, the funding deci- documentation should include retention of materials sions should not be sales driven. Further, funding should discussed, training logs that reflect the attendees, train- be adequate to appropriately staff the compliance aspects of ing session times, and the results of any tests or quizzes conducted during training. In the event of an investigation, an organization's ability to produce such documentation ❯❯ Off-Label Literature. Although not all life science compa- nies have elected to fully comply with the FDA's final guid- will demonstrate a commitment to compliance, and may ance for dissemination of off-label literature, it is important provide evidence of individual rather than organizational that companies establish a policy that governs the dissemi- nation of off-label materials. The policy should elect and ❯❯ Compliance with Federal and State Marketing Laws. Fol- implement the risk option that best suits the individual. For lowing the passage of the Patient Protection and Afford- example, some medical device and pharmaceutical compa- able Care Act of 2010, pharmaceutical and medical device nies permit unsolicited dissemination of publications that manufacturers must report any payment or transfer of discuss off-label uses. Others limit dissemination of these value made to healthcare professionals and academic medi- materials only to situations where a healthcare professional cal centers. In addition, several states have adopted market- affirmatively requests the information. Regardless of the ing transparency laws applicable to pharmaceutical and risk determination made by the company, a policy should medical device companies. These reports include research memorialize the acceptable practice to ensure guidance is grants and honoraria for participating in medical educa- available for all personnel. tion programs. Such laws generally require some combina- tion of the following elements (1) adoption of a compliance ❯❯ Grant Review Boards. If the medical affairs department is charged with providing medical education funding or plan, (2) registration with a state agency, (3) disclosure of investigator-initiated trial funding, education grant and certain payments or transfers of value, and (4) prohibitions trial grant boards should be established. The board should on certain transfers, including samples. Medical affairs de- be comprised of primarily medical affairs and research partments often are responsible for compliance with these and development staff and should be provided with clear various laws and should maintain state-specific policies guidance related to its decision-making protocol when and procedures, and implement tracking mechanisms to evaluating study funding applications and grant requests. track and report all transfers of value. While grants and studies may support medical education ❯❯ Establishing and Maintaining an Active Compliance Pro- or trials on off-label or unapproved uses, the grant board gram. A medical affairs department should have current itself should have the guidance on how it should be making policies and procedures to support a culture of compliance, its decisions.
and should ensure employees and organizational leadership ❯❯ Medical Science Liaisons. Medical affairs departments undergo training on the same. The department should have should establish clear guidance for the role of MSLs within policies that address the dissemination of off-label litera- the company. Specifically, MSLs should know how the ture, responding to solicited and unsolicited requests for organization expects them to respond to off-label use information regarding off-label usage grant funding, medi- inquires and how to respond to grant, medical education, cal letters, screening consultants, MSL relationships with and investigator-initiated trial grant requests, as well as physicians and KOLs, disclosure of payments to healthcare a variety of other issues. Establishing clear guidance for professionals, and any other activity that falls under the MSLs can help to ensure that MSLs do not become exten- purview of the medical affairs department. As the law changes, policies and procedures also should be updated, and employees affected by such changes should be trained 1 Maurice Wolin, et al., The Emerging Role of Medical Affairs Within the accordingly. Policies and procedures that are nothing more Modern Pharmaceutical Company, Drug InformatIon J. Apr.-Jun. 2001, available at than dust collectors on a book shelf will be inadequate to 2 Best Practices LLC, Medical Affairs Excellence: Structuring, Aligning and defend the organization in the event of an OIG or FDA Funding for Global Success, 1. 3 Pharmaceutical Drug Manufacturers, Medical Science Liaison, (last visited Sept. 14, 2011).
It is vital for pharmaceutical and medical device companies to 4 According to the OIG, the Pharmaceutical Compliance Guidance applies stay abreast of ever-changing regulations and "best practices" similarly to medical device companies. See general y OIG, Pharmaceutical Compliance Guidance Program for Pharmaceutical Manufacturers, Apr. in the area of medical affairs. Doing so can help avoid viola- 2003 (68 Fed. Reg. 23731 (May 5, 2003) . tions of law and ensure a culture of compliance. 5 Id. at 23735-36.
6 Id. at 23736. 7 Id. at 23735. About the Authors 8 Corporate Integrity Agreement between the Office of Inspector General of Krist Werling () concen- the Department of Health and Human Services and Cephalon Inc., avail- trates in corporate healthcare transactional work and regu- latory matters for all participants in the healthcare and life 9 Corporate Integrity Agreement between the Office of Inspector General of sciences industry. His experience includes representation the Department of Health and Human Services and Al ergen Inc., available of healthcare providers including hospitals, health systems, ambulatory surgery centers, specialty pharmacies, dialysis 10 62 Fed. Reg. 64074 (Dec. 3, 1997).
facilities, home health agencies, durable medical equip- 11 See Washington Legal Found. v. Friedman, 13 F. Supp. 2d 51 (D.D.C. ment suppliers, home infusion providers, and large medical 1998) (WLF II); Washington Legal Foundation v. Friedman, 13 F. Supp. 2d 51 (D.D.C. 1998) (WLF II ); see also FDA Releases Draft Guidance on practices. Mr. Werling is also Vice Chair of AHLA's Life Dissemination of Off-Label Journal Articles, Sciences Practice Group. Mar. 4, 2008).
12 Washington Legal Found. v. Henney, 202 F. 3d 331 (D.C. Cir. 2000) (WLF IV).
13 Shirley Wang, Drug Firms' Medical Staffs Say What Salespeople Can't, Holly Carnell () focuses Wall St. J., June 26. 2009, available at, on corporate healthcare transactional work and regula- tory matters. She provides guidance to clients regarding 14 Anthony Veccione, Pharma Sales Forces Will Shrink, Clinical Skil s in Demand, meD. marketIng & meDIa, Feb. 25, 2009. various issues, including the HIPAA Privacy and Security 15 Wang, supra note 13.
Rules, the HITECH Act, and legal issues related to elec- 16 Interaction With Leading Members of the Medical Community tronic health records. Ms. Carnell also represents pharma- is a Large Part of Medical Affair's Mission, Market Wire, June 17, 2008, available at ceutical, biotechnology, and medical device manufacturers in the drafting and negotiation of clinical trial agreements, 17 FDA, Good Reprint Practices for the Distribution of Medical Journal Articles contract marketing agreements, and a variety of compli- and Medical or Scientific Reference Publications, Jan. 2009, available at ance and regulatory issues.
18 Id. at Section II .
19 Id. at Section IV(A).
20 Id. at Section IV(B).
21 See Corporate Integrity Agreement between the Office of Inspector focuses on corporate healthcare transactional work and General of the Department of Health and Human Services and UCB, Inc., regulatory matters. She provides guidance to clients regarding available at various issues, including the HIPAA Privacy and Security 22 Global Medical Affairs: 26% of Pharmaceutical Companies Employ Global Teams, PR Newswire, Rules, the Stark Law, and the Anti-Kickback Statute.
(last visited Sept. 15, 2011).
23 Medical Affairs Responsibilities Continue to Expand as Budgets Shift to Global Focus, Market Wire, June 15, 2011.
24 Global Medical Affairs, supra note 22.
Thanks go to the leadership of AHLA's Life
25 Compliance Guidance, supra note 4.
Sciences Group for sponsoring this feature: Thomas
J. Quinlan, Reed Smith LLP, San Francisco, CA (Chair); Daniel B. Bailey, Via Christi Health, Wichita, KS (Vice Chair – Membership); Maryam Khotani, Sutter Health, San Francisco, CA (Vice Chair – Educational Programs); Paul A. Seltman, Smith & Nephew Inc., Washington, DC (Vice Chair – Strategic Activities); David S. Wein-stock, Weston, CT (Vice Chair – Research & Website); Kristian Andrew Werling, McGuireWoods LLP, Chicago, IL (Vice Chair – Publications).
Echos de Pharmacovigilance Chers lecteurs, Il semble que notre bulletin interrégional vous plaise et nous en sommes fort aise… Nous vous proposons cette fois un bulletin de pharmacovigilance très orienté vers l'hémos-tase et la coagulation ! Tout d'abord une mise au point sur le risque thrombotique associé aux neuroleptiques, un effet connu, souvent négligé et encore mal compris. Puis la synthèse de deux études récentes sur le risque hémorragique des anticoagulants oraux qu'ils soient anti-vitamine K ou à action directe ; à lire et surtout à suivre… Enfin, un cas clinique de mé-norragies chez une patiente traitée par un inhibiteur de recapture de la sérotonine pour nous