Policy and Medicine

Physician Payment Sunshine Act: Physician Congressman Ask CMS for Changes to Proposed Regulations

Since the Centers for Medicare and Medicaid Services (CMS) announced that it would be delaying the collection of payment data under the Physician Payment Sunshine Act, there has not been a lot of activity surrounding the final regulations.  We previously reported that CMS is putting together a working group to ensure that the final regulations are issued with input from all stakeholders.  

The Sunshine act requires that all drug, medical device, and medical supply manufacturers disclose every payment or object above $10 allocated to physicians and teaching hospitals.  

While CMS is reaching out to stakeholders affected by the Sunshine Act, a group of 8 medical members from Congress recently sent a letter to Marilyn Tavenner, Acting Administrator of CMS, expressing their concerns over the proposed Sunshine rules.  

The members from the House included all physicians and one nurse, which comprise Representatives Phil Gingery, MD (GA), Michael Burgess, MD (TX), Ann Marie Buerkle, RN (NY), Dan Benishek, MD (MI), Andy Harris , MD (MD), Philip Roe, MD (TN), John Fleming, MD (LA) and Paul Broun, MD (GA).  

In their letter, the members recognized that the rule “calls for additional reporting of pharmaceutical payments to groups including continuing medical education (CME) providers, professional medical associations, patient advocacy groups, and non-profits.”  The letter expressed concern that the proposed regulations “could cause a number of unintended consequences” that if left unaddressed, will “negatively impact patient care and the practice of medicine.”  Specifically, the Representatives highlighted four concerns. 

First, the letter pointed out the overwhelming administrative burden for companies and providers to comply with the Sunshine Act.  The letter noted how the complexities such as third party payments, global companies with multiple affiliates, and accounting requirements that call for companies to track the actions of providers during meetings – such as how much food an individual ate when in a group setting in order to calculate the foods worth – “will force companies and providers to spend limited resources on compliance lawyers and administrative staff rather than strategies to improve patient care and outcomes.”  

Interestingly, the authors noted that nothing in the Sunshine Act prohibits companies from passing on the data collection to medical providers, which could create more administrative burdens for doctors, directing valuable time they have to care for patient and placing additional financial strain on fledgling medical practices. 

Second, the letter recognized that the failure to exempt accredited CME events and non-CME speaking engagements in the proposed rule will end company participation in CME events, especially when the focus on the seminar relates to advancements in medical technology.   

The members of Congress recognized the importance of CME as a “valuable source” for providers to help support “their efforts to provide the highest quality health care to their patients.  Consequently, the authors stated their fears that if company participation in CME events is decreased further, “the primary means by which medical providers keep abreast of advancements in patient care will no longer exist.” 

Accordingly, “with no equitable alternative available,” the members noted the “negative impacts on patients” this kind of change would have, especially for rural providers, whose CME opportunities are more limited than those practicing in urban areas. 

Third, the members of Congress noted that the Sunshine Act will have an adverse impact on medical research in the U.S.  They pointed to a recently survey from the Association of Clinical Research Organizations (ACRO) which found that roughly 24% of physicians who conduct research and clinical trials for industry would be less likely to participate if their payments from such work were made public. 

One reason attributed to this finding is that compliance with the regulation would provide a distorted view of provider compensation resulting from this type of work.  Specifically, the members recognized that given the way the rule is written now, a distorted view of drug and device research would result because the full payment would be attributed to a researcher, even though the individual only receives a percentage of the total payment, with the rest going towards the cost of running the trial.  This would “stifle innovation due to the appearance of impropriety.”  

In addition, the members emphasized their concern about the impact on “small manufacturing, medical device and pharmaceutical companies,” who will also face a challenge that could result in job loss and operations moving overseas as companies relocate new research development.   They recognized how CMS estimates that small manufacturers would need to dedicate 50 percent of their employee’s times just to comply with the reporting requirements. 

Finally, the letter recognizes that compliance with the sunshine act will cost billions of dollars for both industry and the federal government.  Specifically, they noted that the potential for high penalties and the low threshold for reporting will result in “high penalties” that will cause over reporting, which will also lead to greater costs for CMS.  In addition, “the threats of fines and the additional resources required of industry to be in compliance with the rule will have a dramatic impact on medical innovation as well.”  The members of Congress emphasized the fact that “accounting changes and internal controls necessary to track the actions of individual providers will create an estimated $200 million dollar burden per applicable manufacturer – costs that directly threaten medical innovation and job creation in this country.”  

Ultimately, the congressional members asked CMS to allow the appropriate congressional committees of jurisdiction to have a chance to review the proposed rule and its impact on patients and the health system before publishing any final details.  

The CME Coalition has been active in educating congressional members on the role of CME and sunshine.  

These are reasonable requests and we are hopeful that CMS will take these suggestions into serious consideration.

Foreign Corrupt Practices Act: Life Science Companies and Emerging Markets

Last year, Johnson & Johnson announced that it will pay $70 million as part of a deferred prosecution agreement (DPA) with the Department of Justice (DOJ) to resolve improper payments by J&J subsidiaries to government officials in Greece, Poland and Romania in violation of the Foreign Corrupt Practices Act (FCPA).

The Foreign Corrupt Practices Act of 1977 (FCPA), was enacted for the purpose of making it unlawful for certain classes of persons and entities to make payments to or bribe foreign government officials to assist in obtaining or retaining business. In other words, FCPA prohibits corrupt payments to foreign officials for the purpose of obtaining or keeping business. Increasingly, global drugmakers are facing new scrutiny in the U.S. under the FCPA.

For example, a recent article from Reuters noted that DOJ and the Securities and Exchange Commission (SEC) have begun to conduct extensive inquiries into nearly every major drug and medical device manufacturer for potential violations of the FCPA.  One recent investigation came after a report from lawmakers in India who alleged abuses in that country's drug approval process.  An Indian parliamentary panel recently said officials of India's drug regulator had been colluding with pharmaceutical companies to speed up approval procedures, allowing some drugs that are not permitted in other countries to go on sale.

Many probes from DOJ and SEC focus on accusations of bribery in emerging markets, such as China and Latin America, but dealings in India have yet to come under major scrutiny.  "If the Indian parliament issued a report condemning practices, then I'm sure my clients will be getting calls from the DOJ pretty soon," said one lawyer who works with pharmaceutical companies on such investigations. The lawyer spoke on condition of anonymity, as did others who represent drugmakers in FCPA cases.

Other experts familiar with the Justice Department's workings agreed.  "There is certainly going to be Department of Justice interest, said Howard Sklar, who ran anti-corruption programs for several major companies and now works at Recommind Inc, which makes software used in corporate investigations.

According to Reuters, “The 78-page report by Indian lawmakers named several major international drug companies including Eli Lilly and Co. and Novartis.  It cataloged a series of procedural failures that it said raised questions about how certain drugs were allowed to be sold in India, but it did not directly accuse the companies of wrongdoing.”

"If these Indian drug regulators were in cahoots, then it's not particularly a stretch of the imagination to say that part of the reward for their laxity was money, and that is very clearly a violation of the FCPA," Sklar said.

Clinical Trials May Draw Scrutiny

When the Justice Department and the SEC sent letters in April 2010 to several drug manufacturers including Lilly, Bristol-Myers Squibb Co. and AstraZeneca PLC in its foreign bribery probe of the industry, it requested information on countries like Brazil, China, Greece and Russia but did not include India in that list, people familiar with the matter said at the time.  According to the article, “Most of those investigations have focused on sales and marketing practices, people familiar with the investigations said, rather than the higher-level drug approval issues that were cited in India.”  Some of those cases are wrapping up, Reuters noted.  “Lilly disclosed last month it was in "advanced discussions" with the SEC to resolve foreign bribery issues in Poland and other countries.

The same factors have not been at work in India, where much of the booming medical market is privately run, and expensive, brand-name products are rarely purchased by public hospitals, the people said.  “But the Justice Department has signaled its interest in examining possible corruption in the clinical trials process, said John Kelly, a former federal healthcare fraud prosecutor now in private practice at the law firm Bass, Berry & Sims.”

"With clinical trials, you're going to have constant interaction with either foreign officials or entities that are operated by government entities," Kelly said. "If they weren't (looking at it), they will be now."  Novartis said it would investigate the drug approval irregularities alleged in the report. Lilly said it "followed all appropriate regulatory processes required by the regulatory agency in India."

White House: National Bioeeconomy Blueprint – Encouraging Collaboration

“Economic activity that is fueled by research and innovation in the biological sciences, the “bioeconomy,” is a large and rapidly growing segment of the world economy that provides substantial public benefit.”  As noted in President Obama’s recently published National Bioeconomy Blueprint, “The U.S.bioeconomy is all around us: new drugs and diagnostics for improved human health, higher-yielding food crops, emerging biofuels to reduce dependency on oil, and biobased chemical intermediates, to name just a few.” 

The public benefit gained through bio­logical research can be seen through the eyes of a patient who receives a critical medication that did not exist a decade ago.  The bioeconomy allows Americans to live longer, healthier lives, reduce our dependence on oil, address key environmental challenges, transform manu­facturing processes, and increase the productivity and scope of the agricultural sector while growing new jobs and industries. 

The National Bioeconomy Blueprint describes a number of key elements that will contribute to achiev­ing the potential of the U.S.bioeconomy.  Input from government, industry, and the public has helped to define them. They are: 

• a full spectrum of basic and applied R&D activities performed by academic, government, and private sectors
• public-private partnerships
• a supportive commercialization system for bioinventions
• innovative regulatory policies that reflect government awareness of needs for and impediments to progress
• a skilled and creative workforce
• public support for technological advances
• flexibility to accommodate the evolving needs, discoveries, and challenges 

The Blueprint has two purposes: to lay out strategic objectives that address the key elements to help realize the full potential of the U.S.bioeconomy, and to highlight early achievements toward those objectives.  The Blueprint makes several important recommendations that federal agencies, academia and industry should pay close attention to: 

1. Integrating entrepreneurship and industry involvement into the university research experience will facilitate the path from research to commercialization and help innovative ideas reach the marketplace. 
2. Encouraging federal agencies to pursue “opportunities for effective public-private partner­ships in health to leverage Federal investments and industry investments and expertise.”
3. The need for federal agencies to focus on building new, and augmenting existing, stakeholder collaborations to inform efforts, stream­line processes, and reduce costs and response times, while preserving safety and ensuring substantive benefit to public health.  We recently have seen actions such as this when the Centers for Medicare and Medicaid Services (CMS) decided to postpone data collection under the Physician Payment Sunshine Act and created a collaborative industry/stakeholder workgroup to address the challenges of implementing this section of the Affordable Care Act.  

Background 

Decades of life-sciences research and the development of increasingly powerful tools for obtaining and using biological data have brought us closer personalized medical treatments based on a patient’s own genomic information.  Increasingly, scientists and engineers are looking to augment biological research with approaches from other scientific disciplines for solutions to our most demanding scientific and societal challenges and seeing exciting options that will profoundly affect our future. 

The growth of today’s U.S.bioeconomy is due in large part to the development of three foundational technologies: genetic engineering, DNA sequencing, and automated high-throughput manipulations of biomolecules.  While the potential of these technologies is far from exhausted, a number of impor­tant new technologies and innovative combinations of new and existing technologies are emerging.  Tomorrow’s bioeconomy relies on the expansion of emerging technologies such as synthetic biology (the direct engineering of microbes and plants), proteomics (the large-scale study and manipulation of proteins in an organism), and bioinformatics (computational tools for expanding the use of biological and related data), as well as new technologies as yet unimagined.  There is also a set of emerging trends in recent research that foreshadow major advances in the areas of health, biological-based energy production, agriculture, biomanufacturing, and environmental clean-up. 

In recognition of the potential of the U.S. bioeconomy, in 2010 the Obama Administration included, in its science and technology priorities to inform Federal agency budget submissions, a priority for Federal agen­cies to “support research to establish the foundations for a 21st century bioeconomy.”  Agencies began focusing their efforts accordingly, and have made significant early progress in building a foundation for the future bioeconomy.  In addition, strategic objectives that would help to enable a future vibrant U.S. bioeconomy with potential to deliver major economic and social benefits began to emerge. 

On September 16, 2011, President Obama announced that his Administration would release a National Bioeconomy Blueprint as part of his commitment to supporting scientific discovery and technological breakthroughs to ensure sustainable economic growth, improve the health of the population, and move toward a clean energy future. 

Five Objectives of The National Bioeconomy Blueprint 

The National Bioeconomy Blueprint describes five strategic objectives for a bioeconomy with the potential to generate economic growth and address societal needs.  Although progress is being made in all of these areas, much work remains if the United States is to remain competitive in a changing world.  Summarized below (and described in more detail in the second chapter) are the strategic objectives and the next steps that will help realize the full potential of the U.S. bioeconomy. 

1. Support R&D investments that will provide the foundation for the future U.S. bioeconomy. 

Although many studies show that research provides a healthy return on investment, a major justification for government investments in science and technology is to overcome market failures; these occur when private investors invest less in technology than the socially optimal level because they cannot reap the full benefits of their investment.In this context, scientific discovery is a public good that benefits all. 

The pursuit of a greater understanding of natural systems yields knowledge, ideas, and technologies that the private sector can build on, sparking economic growth by giving rise to new products, services, and jobs.  Coordination of Federal bioeconomy-related research activities can improve the efficiency and effectiveness of those investments and is especially important when budget growth is constrained.  Coordinated strategic programs and targeted investments will accelerate progress in biological research and technology areas, and this in turn will drive discovery for an American bioeconomy.

Moving Forward: Coordinated, integrated R&D efforts will help strategically shape the national bioeconomy R&D agenda. 

Expand and Develop Essential Bioeconomy Technologies – Foundational technologies have made possible unprecedented discoveries in biological research.  Multiagency collaborations for emerging foundational technologies such as synthetic biology, biology-related information technologies, pro­teomics, and others are being fostered in order to grow the bioeconomy. 

Integrate Approaches across Fields – The complexity of modern research questions requires that traditional boundaries between fields of study become permeable and programs concentrate expertise from diverse disciplines around societal challenges where it is needed most.  The Administration will pri­oritize additional multidisciplinary efforts to enable biological research at the boundaries of fields, such as physics, chemistry, engineering, computer sciences, and mathematics, that support the bioeconomy. 

Implement Improved Funding Mechanisms – Creating or modifying funding mechanisms to support creative, high-risk/high-reward research can enable researchers to pursue daring—and potentially groundbreaking—research that may be constrained by typical funding mechanisms or approaches.  Agencies should further explore the use of new or modified funding mechanisms in and across agencies to stimulate the discovery of new bioinventions with potential to grow the bioeconomy. 

2. Facilitate the transition of bioinventions from research lab to market, including an increased focus on translational and regulatory sciences. 

If it is to be successful and thrive, the bioeconomy will be based on a steady flow of new products and services that address American needs.  To ensure this flow, policies must be developed and taxpayer dollars must be used responsibly to foster an ecosystem that supports discovery, innovation, and commercialization.  Moving Forward: A dedicated commitment to translational efforts will accelerate movement of bioinventions out of laboratories and into markets. 

Accelerate Progress to Market – An increased focus on entrepreneurship, translational sciences, regulatory science, and technology transfer can help ensure that ideas with potential for application move beyond the laboratory.  Strategic, coordinated investments in translational and regulatory sciences will accelerate progress in many sectors of the bioeconomy.  To capitalize on the promise of the newly reauthorized Small Business Innovation Research (SBIR) program, agencies should evaluate and update SBIR programs.  Some relevant objectives include reducing application response times, hiring/training program staff to enhance relevant in-house experience, and increasing the use of industry experts as peer reviewers to evaluate industry proposals. 

Enhance Entrepreneurship at Universities – Academic research is traditionally disconnected from its economic implications, making it difficult for innovative ideas to progress beyond the lab.  Integrating entrepreneurship and industry involvement into the university research experience will facilitate the path from research to commercialization and help innovative ideas reach the marketplace.  As an additional benefit, students can be exposed to the broader benefits of academic pursuits, as well as introduced to potential future careers in areas outside of academia.  Innovative programs that enhance entrepreneurial activities at universities are needed to help academic discoveries become commercial realities. 

Utilize Federal Procurement Authority – The purchasing authority of the Federal government offers opportunities to help drive some aspects of the bioeconomy.  By procuring biobased and sustainable versions of products used in agency missions, the Federal government supports markets and promotes innovation, while creating jobs in rural America where many of these businesses are located and bio­products are manufactured.  To drive the creation and growth of new bioeconomy markets, Federal agencies should prioritize procurement of biobased and sustainable products where appropriate and cost-effective. 

3. Develop and reform regulations to reduce barriers, increase the speed and predictability of regulatory processes, and reduce costs while protecting human and environmental health. 

Regulations are essential for protecting human health and the environment and reducing safety and security risks associated with potential misapplications of technology.  When they are not carefully crafted or become outdated, however, they can become barriers to innovation and market expansion and discourage investment.

Moving forward: Improved regulatory processes will help rapidly and safely achieve the promise of the future bioeconomy. 

Improve Regulatory Processes and Regulations – Agencies should improve predictability and reduce uncertainty in their regulatory processes and requirements.  To reduce costs and impediments to invest­ments but without compromising safety and efficiency, attention should be given to application review times, sequential reviews by multiple agencies should be coordinated to allow parallel reviews, and specific guidance should be issued in response to stakeholder needs.  When an emerging technology enters the regulatory process, Federal agencies must have a robust framework that identifies lead agency responsibilities, clarifies supporting agency roles, and delivers timely, specific guidance for applicants. 

Collaborate with Stakeholders – Improved agency regulatory processes rely on productive stakeholder collaborations to identify needs and impediments to progress and investment.  Federal agencies should focus on building new, and augmenting existing, stakeholder collaborations to inform efforts, stream­line processes, and reduce costs and response times, while preserving safety and ensuring substantive benefit to public health. 

4. Update training programs and align academic institution incentives with student training for national workforce needs. 

Many jobs in science and technology-related businesses remain unfilled despite high rates of local unemployment.  Opportunities exist to enhance training efforts at all levels to keep pace with chang­ing career pathways.  At the K-12 and undergraduate levels, the Administration has made significant progress in developing approaches to improve science, technology, engineering, and mathematics (STEM) education, and to increase the number and diversity of STEM students.  For example, in 2009, the President launched the Educate to Innovate campaign to move American students from the middle to the top of international rankings in STEM achievements over the next decade.  Building upon and expanding these efforts, particularly with regard to graduate-level training enhancements, would help to align academic institution incentives with training for future workforce needs.  Also needed is the development of metrics to measure progress over time.  Moving forward: Federal agencies should take steps to ensure that the future bioeconomy has a sustainable and appropriately-trained workforce. 

Employer-Educator Partnerships – Foster increased industry participation in the development of programs and in training students at all levels for the future bioeconomy workforce. 

Reengineer Training Programs – Incentives for academic institutions to enhance entrepreneurship and restructure training programs would better prepare the future bioeconomy workforce, whether individuals are bound for careers in industry or academia.Federal agencies should develop incentives for institutions to adapt training to meet the needs of the 21st-century bioeconomy workforce.Following reengineering of training programs, agencies should consider convening industry stakeholders from various sectors to assess the success of training programs to meet the needs of employers. 

5. Identify and support opportunities for the development of public-private partnerships and precompetitive collaborations—where competitors pool resources, knowledge, and expertise to learn from successes and failures. 

Partnerships enable private industry, government agencies, and academic institutions to pool resources and expertise around an idea, dramatically improving chances for success.  Many companies do not invest in early ideas because they are unlikely to pay off immediately.  This is one place where the government can play a crucial role.  The President has emphasized that the Federal government, universities and companies should work together to invent, deploy, and scale the cutting-edge technologies that will create new jobs, spark new breakthroughs, and reinvigorate America today and in the future.  Moving forward: Federal agencies should provide incentives for public-private partnerships and precompetitive collaborations to benefit the bioeconomy broadly. 

Catalyze Public-Private Partnerships – Great potential exists for partnerships and collaborations where sharing information about successes and failures is anticipated to generate transformative outcomes.  Federal agencies are encouraged to broadly pursue opportunities for effective public-private partner­ships in health, energy, agriculture, and manufacturing to leverage Federal investments and industry investments and expertise. 

Conclusion 

While the Blueprint has some notable goals and recognizes the importance of public-private partnerships as part of a broader strategy to stimulate the economy and realize the full promise of biomedical research, in practice, we have not seen much progress on this part in health care.  For example, the Food and Drug Administration (FDA) still has prohibitive policies for including members on their Advisory Committees who work with industry and the National Institutes of Health (NIH) also have significant restrictions on the involvement of investigators in clinical trials who collaborate and work with industry. 

More importantly, we have Congress passing, and CMS implementing, the Sunshine Act, which paints industry-physician/academia collaboration as inherently unethical and wrong by posting such payments publically online so that media and sensationalist critics can continue their careers bashing doctors and professionals for developing new treatments and educating their peers about them.  

How can the Obama administration be calling for more collaboration, more interaction with industry, more investment and resources to be shared with industry, while at the same time, labeling these relationships as “conflicts” and forcing doctors to disclose their work as if they should be ashamed for saving the lives of millions of patients?  The Obama administration cannot plan to recruit doctors, physicians and scientists to enter into these new collaborations and partnerships and reduce the regulatory burdens while also placing a red target on industry’s back.  

Consequently, a telling quote on page 13 sums up public and congressional frustration with the current model of life sciences R&D: “One issue that government and industry must address is that increased investment in research has not resulted in a concomitant increase in approved drugs.”  In a break from the usual call for industry and academia to align primarily along technical and scientific lines, the Blueprint repeatedly calls for deeper engagement, including academic participation in commercialization.  This document is an example of the multiple and seemingly contradictory messages emanating from various policy centers.

Moving forward, there needs to be a more consistent message throughout the Administration and federal health agencies, which recognizes the important role of industry in navigating through the Bioeconomy, one which does not send mixed messages, and demonize relationships.  Instead, the government must begin to recognize that achieving the objectives of this Blueprint will require significant involvement of industry and private stakeholders who have the patients best interest in mind, and are looking to provide important jobs to hardworking Americans and reinvest their earnings in new technologies and resources.

 

FDA: Risk Evaluation and Mitigation Strategies (REMS) Paper on Program Evaluations and Outcomes

The Food and Drug Administration (FDA) recently published an Issue Paper discussing the use of surveys to assess whether a risk evaluation and mitigation strategy (REMS) is meeting its goals related to knowledge of health care providers and patients.   

FDA often requires a REMS to include a goal to inform or educate patients or health care providers (prescribers and/or pharmacists) about the risks associated with a drug. The important messages may include information about how to use the drug safely.  REMS assessment surveys are one way to assess the extent to which patients/caregivers or health care providers understand the risks associated with the drug and/or how to use it.   

Since the initiation of required REMS assessments four years ago, FDA has reviewed numerous REMS assessments that contain survey data and has identified issues associated with the methodologic rigor of the surveys, calling to question their utility as a tool to assess whether REMS are achieving their goals.  Accordingly, FDA’s issue paper focuses on the use of surveys to assess patient and provider knowledge. 

Background  

Title IX, Subtitle A, section 901 of the Food and Drug Administration Amendments Act (FDAAA) (Public Law 110-85)2 created section 505-13 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act).  Section 505-1 authorizes FDA to require applicants submitting NDAs, ANDAs, or BLAs to submit and implement a REMS if the FDA determines that a REMS is necessary to ensure that the benefits of a drug outweigh the risks of the drug. To require a REMS for an already approved drug, FDA must have become aware of new safety information as defined in the statute. 

The majority of REMS include, as a goal, informing or educating patients or health care providers of the serious risks of a drug.  Thus, the majority of the current REMS have one or more educational components, such as a Medication Guide, a communication plan, or a communication-related Element to Assure Safe Use (ETASU).

 FDAAA requires NDA and BLA applicants to periodically assess the effectiveness of their product’s REMS.  REMS assessments generally include an evaluation of the extent to which each of the REMS elements are meeting the goals and objectives of the REMS, and whether or not the goals, objectives, or REMS elements should be modified.

For REMS containing these educational components, the assessment plan generally requires an assessment of patient or health care provider understanding of the risks of the drug and/or safe use of the drug.  The first REMS assessment was submitted on September 27, 2008. 

As of December 31, 2011, FDA has received and reviewed 144 assessments that contained surveys for 105 individual drugs (many of these assessment submissions, particularly for those associated with REMS with ETASU, represent serial assessments (e.g.., assessments every 6 months)).  A total of 55 of these REMS were of the Medication Guide-only type; 33 had a Medication Guide and a Communication Plan; and 56 were classified other, which were predominantly REMS with ETASU.

FDA requested and applicants submitted only cross-sectional surveys to evaluate patients’ or health care providers’ understanding of the risks of the drug and/or safe use of the drug. In addition, in a July 2010 public meeting on REMS, the public speakers who addressed this issue noted that surveys are the accepted methodology for evaluating understanding and knowledge. It is also important to note that the assessment of knowledge is not the entire scope of a REMS assessment; REMS assessments may contain data from sources other than surveys to inform the overall effectiveness of a program. 

FDA Practices Regarding Survey Methodologies  

To date, FDA has generally requested that applicants submit their proposed survey methodologies to FDA for comment at least 90 days before fielding the survey.  FDA adheres to general social science principles in advising applicants.  Most FDA comments on the survey proposals have related to the methods proposed and the wording of individual questions.  High-level concepts that FDA communicates to applicants are summarized below:                 

• State the purpose of the survey and how it relates to the REMS goal(s)
• Identify the key risk messages that should be understood by the group of interest (patients, prescribers, or dispensers), depending on the goal of the REMS
• Enroll a demographically diverse population that has used, prescribed, and/or dispensed the product, depending on the goal of the REMS
• Specify a survey design, including a statistical analysis plan, that meets the survey objectives, and calculate the appropriate sample size
• Construct a questionnaire that targets the key risk messages
• Minimize factors that might contribute to a biased survey (e.g., unrepresentative sampling, faulty recruitment strategies, leading questions that bias the responses in a particular direction, missing data)
• Minimize any burden imposed on participants taking the survey  

FDA’s Experience With Knowledge Assessment Surveys 

Surveys conducted as part of a REMS assessment have focused on patients’ or health care providers’ understanding of the key risks of the drug.  FDA does not expect those surveyed to recall the full prescribing information or all of the information available for patients.  For example, patient surveys are generally limited to the information included in the “Most Important Information” section of the Medication Guide.  In rare instances, prescriber surveys have included questions about prescribing behavior. 

A high-level summary of FDA’s experience with surveys to assess REMS follows (through December 31, 2011):                 

Selection criteria: Applicants have almost exclusively used convenience samples (generally defined as when respondents are selected based on the basis of what is most feasible for the researcher).  Although applicants sometimes send invitations to potential participants in a random manner, the actual survey populations generally do not represent random samples.  As described in Recruitment strategies below, generally, invitations are sent to adult, English-speaking patients who have been dispensed the drug or to prescribers who have prescribed the drug in the previous 3 to 6 months.  Responding to the invitation is voluntary, and it is possible that respondents may attend to health or prescribing information to a greater extent compared to the entire population on the drug, or respondents may be more interested in the incentives offered for completing the survey. 

Recruitment strategies:  Applicants have most commonly used the following techniques to recruit health care providers (not all inclusive): 

• Sending letters by mail, fax, or email or placing a telephone call to known or potential prescribers identified by pharmacies or national audit services
• Sending a fax or other communication to a random sample of relevant potential prescribers identified by specialty (e.g., rheumatologists for a rheumatology product) or general likelihood that an invitee may have prescribed a drug (e.g., a random sample of internists for a diabetes drug)
• Contacting prescribers using the prescriber registry (where applicable such as when prescriber certification is required by the REMS)  

Applicants have most commonly used the following techniques to recruit patients (not all inclusive): 

• Using the pharmacy or pharmacy network to identify patients dispensed drug and invite them to participate (usually by mail)
• Having the pharmacy recruit patients personally while presenting and dispensing the prescription
• Requesting that prescribers identify eligible patients and provide an invitation. Alternatively, for drugs administered in an infusion center, by soliciting all or a subset of infusion sites (when the patient presents for dosing)
• Requesting that prescribers personally recruit patients at the time of prescription writing
• Contacting patients using the patient registry (where applicable such as when patient enrollment is required by the REMS)
• Providing an invitation with materials that were supposed to have been dispensed with the prescription  

Response rates: It is not uncommon for applicants to have a low response to their survey recruitment efforts; it is not uncommon to see recruitment rates ((number completing the survey/number invited) X 100) below 10 percent. 

Sample size: For health care providers, actual sample sizes have ranged from 3 to approximately 500. For patients, the sample size has ranged from 8 to approximately 400. For surveys with a low sample size, this is usually attributed to small patient populations.

Question types: Questions are generally limited to the True/False/I don’t know or multiple-choice (either the single best or all applicable answers) types. We have seen few open-ended questions or questions related to a case presentation. 

Statistical Analysis: Some applicants have prespecified a threshold for success. Formal statistical hypothesis testing is generally not conducted.  Applicants compile and report descriptive statistics summarizing the demographics of the surveyed population and the proportion of subjects who demonstrated knowledge of the risk message (defined by us as the knowledge rate). Rarely do applicants compare the demographics of the surveyed population to the population that uses, prescribes, or dispenses the drug to determine if the sample is representative. 

Findings: Generally, the surveys submitted as part of a REMS assessment have shown:  

Patient surveys: There is evidence of limited understanding of some important risk information (in some surveys, patients had < 50% correct answers to questions about critical risks). A small FDA analysis suggests limited survey representativeness.4 For the limited number of surveys that stratify results by whether or not the patient reported reading the Medication Guide, readers tended to have higher scores. The significance of this finding is not clear. 

Health care provider surveys (predominantly prescribers): Generally, surveys show that the REMS are meeting their information goals (as defined by a knowledge rate ≥80%). In some cases, adequate performance on all but one of the risk questions has resulted in modifications to the educational materials. 

In the context of the goal of a valid, reliable, and useful knowledge/understanding assessment, our review of the REMS survey data has identified issues regarding the adequacy of some of the surveys conducted to date:                 

• Because of the limitations outlined below, surveys may not be the best methodology in all situations to assess knowledge in populations that range in size from hundreds to potentially millions.
• Sometimes the sample size achieved appears to be too low to draw conclusions with confidence.
• The surveyed population may not reflect the demographics of the target patient population.
• Because convenience samples are commonly used, surveys are likely to be biased in some way.
• The level of difficulty of the questions varies across surveys, although this is a subjective assessment that has not been formally assessed. This variability may be related to:
  • Familiarity of the information to be conveyed (e.g., the risks of a first-in-class drug may be less familiar than those of a drug that has been marketed for a substantial duration of time).
  • Wording of a question and the level of detail of knowledge tested. In some cases, the correct answer is self-evident.
  • Sometimes the wording of a question is open to interpretation, which may explain a low knowledge rate.
  • There are no objective standards for an adequate knowledge rate (i.e., the threshold for success) of the REMS educational component.
  • There may be alternatives to the knowledge rate to assess the effectiveness of the educational component of the REMS.  

Input Requested  

Most REMS require drug manufacturers to provide educational materials for health care providers, patients, or both, and FDA is seeking input on the best way to evaluate the effectiveness and utility of these requirements. 

Ideally, REMS assessments would provide information about whether health care providers prescribing or dispensing the drug and/or patients taking the drug understand the key risks and safe use of the drug (where applicable).  Having a valid, reliable, and accurate measurement of the level of understanding would answer two critical questions related to the informational goal: Is this component of the REMS working? And if not, how should the REMS be modified?  In addition, as FDA has gained experience with REMS, the following questions have taken greater prominence:  

• Is the REMS affecting health care provider and patient behavior?
• What are the effects of REMS on burden to the health care system?
• Is the REMS adversely affecting patient access to the drug?  

Accordingly, FDA is seeking public input on the following questions: 

1. What strategies can the applicant use to recruit a sample that is representative of the population that is prescribing/dispensing/taking the drug?

Given that the applicant cannot compel an individual to complete a survey, is it acceptable to enroll a relatively small (making the survey feasible) number of participants that are representative of the totality of the health care provider or patient population and make generalizations from that sample to the larger population?

What is an adequate sample size to be able to confidently extrapolate findings to the entire population prescribing/dispensing/taking drug?

2.  Is the knowledge rate (i.e., the proportion of subjects who demonstrate knowledge of the risk message) the appropriate primary endpoint for a survey?

What factors need to be considered when establishing the threshold for success for educational elements of the REMS?

Should the threshold for successfully meeting a REMS educational goal be set at a knowledge rate of 80 percent or 90 percent, or should it vary depending on the risk message? If it should vary, what should the minimum threshold for success be? Should the threshold reflect whether the product is a new molecular entity (NME) or original biologic product, or an older drug?

3.   Since most surveys use only True/False and multiple-choice questions, what are the advantages and disadvantages of using other question types (open-ended, case vignettes, fill-in-blank) to evaluate knowledge?

4.  Please discuss process issues related to these surveys: 

1.  
   1. Given issues of recall, should the lag time between the REMS communication and the survey administration be standardized?
   2. Should pretesting/validation be required to reduce the likelihood of a poorly worded question that was not recognized during survey development?
   3. On average, how long does it take to design, test, recruit participants, conduct, analyze, and report the results of a survey?
   4. Please comment on appropriate incentives for patients and health care providers to complete surveys.

5.  Given the issues with surveys that FDA has observed, what are the alternatives to knowledge surveys to assess the effectiveness of the educational elements of the REMS? If any, what are the advantages and disadvantages of the alternatives?

6.   What are the considerations in designing questions to assess the impact of REMS on patient and/or provider behavior and access to drug, as well as the potential burden of the REMS on these groups? What are alternative methods to assess behavior, burden, and access for a REMS? If any, what are the advantages and disadvantages of the alternatives?

7.   Question for industry: From your perspective, what challenges have you encountered in designing and conducting knowledge surveys?

 

 

Walgreens and Lilly Announce Diabetes Hypoglycemia Awareness Program

Lilly Diabetes and Walgreens are educating people living with diabetes about one of the most common and misunderstood consequences of diabetes: hypoglycemia (low blood sugar). 

Earlier this month, Eli Lilly and Walgreens announced the launching of a new awareness campaign at 43 Walgreens pharmacies throughout the Indianapolis area. Lilly Diabetes will provide take-home educational materials about hypoglycemia that pharmacists may use when counseling people with diabetes. 

Hypoglycemia occurs when people experience an abnormally low level of blood sugar, which is the body's main energy source. Symptoms may include shaking, sweating, tiredness, hunger, increased heart rate, confusion, blurred vision and / or headaches. It's important to recognize and treat hypoglycemia, as it can get worse and people can lose consciousness. 

“At Lilly Diabetes, we understand that managing diabetes extends beyond medicines to tools and resources that provide real, personalized solutions to improve the quality of everyday life, which is why we're excited to collaborate with Walgreens to tackle the important and sometimes overlooked issue of hypoglycemia,” said Steve Sugino, vice president of Lilly Diabetes. “This initiative will not only provide needed education, but will also ultimately help facilitate better discussions between pharmacists and people with diabetes that can lead to improved disease management.” 

The Lilly Diabetes-Walgreens approach is designed to complement the care and guidance people with diabetes receive from their health care providers. The campaign will be launched in 43 Walgreens stores in the Indianapolis area and showcase Walgreens' new approach to community pharmacy that includes making pharmacists more accessible for patient consultations.

 Based on customer feedback over the next six months, the companies will explore expanding the campaign in additional cities. 

“Walgreens, with our dedicated and highly professional pharmacists, is continually looking for ways to enhance our services to best meet the needs of our customers, particularly when it comes to their health needs,” says Walgreens Indianapolis market pharmacy director Marcel Naddaf.  “With the high incidence of diabetes and its potential complications, we're pleased to collaborate with Lilly Diabetes to provide valuable information to our customers with diabetes to help them better manage their condition.”

 

International Physician Payment Sunshine: Medicines Australia Code of Conduct

“Medicines Australia (MA) is an industry association whose members represent multinational, research-based pharmaceutical companies such as Pfizer, GlaxoSmithKline and CSL.  Their self-regulatory code of conduct governs the promotion of prescription drugs and the relationship of industry to health professionals.”

Consequently, MA recently held a Code of Conduct Consumer Review Workshop (one of three held in different cities) on behalf of CHOICE (Australian Consumers Association) in late March.  Consumer representatives and several MA staff, representatives from the pharmaceutical industry on the MA Code Review Committee and others participated.

Background

As a recent article explained, the code of conduct “refers to relevant legislation, such as the Therapeutic Goods Act 1989, which states that prescription drugs must not be promoted to health professionals.”  The code is “the oldest and most detailed of four self-regulatory codes that deal with the promotion of medicines to health professionals.”

The Generics Medicines Industry Association (GMiA), the Australian Self-Medication Industry Association (ASMI) and the Complementary Health Care Council of Australia (CHC) have their own codes.  As do a number of other industry associations involved with therapeutic devices and diagnostics.

Despite these measures, the author noted that there “are concerns about the multitude of self-regulatory codes produced by the therapeutic goods industry” because “there are great variations in their provisions, sanctions, administrative procedures and transparency and, most importantly, they do not apply to non-members who are often the worst offenders.”

As a result, the Australian government set up a “Working Party on Therapeutic Promotion” in 2010 “with the aim of achieving uniformity among the codes and addressing the problem of non-members.”  The author noted, however, that the government did not “adopt the most important recommendation of the working party – that compliance with an appropriate code should be a condition of marketing for all sponsors of therapeutic goods.” 

Meeting on Australian Industry Codes

Participants during the workshop, which the author attended, “expressed concern about the code review process.  Submission to the review (available on the MA website) was open to all and consumers appreciated the additional opportunity to attend public workshops.  But MA and its code were not well known in the community, which limited input.”

Participants expressed that it had been their experience in making previous codes “that it often took many years (and several code revisions) to make changes.”  For MA to make changes to its codes, a 75% vote is required (and some larger companies had more votes than others).  Participants noted that this “self-regulation was self-serving and could only endorse the lowest common denominator of member ethical standards.”

The sanctions imposed for Code offences were another concern.  Participants noted that the maximum fine of $250,000 (or $300,000 for multiple code breaches) was “hardly an effective deterrent to a large multinational pharmaceutical company and the average fine imposed (around $50,000) could easily be written off as a tax deduction.”

Consumers in the workshop “were not convinced that the ‘shame’ of being found in breach of the code provided any real deterrent as some companies have repeatedly violated the code over the years.”  This is not much different than the process seen in the U.S., in which pharmaceutical companies are currently under second, third and sometimes fourth corporate integrity agreements (CIAs).

The workshop also discussed “product familiarization programs, patient support programs and starter packs (free product samples for doctors).”  While some considered these to be “mere marketing strategies aimed at getting doctors to prescribe the latest and most expensive drugs,” others believed they served a useful purpose.  For example, some noted that patient-support programs “can assist patient compliance with reminders and other strategies, while free product samples could be helpful for needy patients or to see if side effects may be a problem.”

However, some participants were concerned “that free starter packs didn’t just target the indigent and were often not the drug of choice for the patients’ condition.” Others indicated that starter packs “lacked accompanying important information and labelling provided by pharmacists.”  In addition, all participants “agreed on the need for greater transparency about such programs so the benefits being advocated could be evaluated.”

Conclusion

In the end, “MA was commended for monitoring promotion, (which many other industry associations do not) and the recognition that complaints usually only represent the tip of the unethical promotional iceberg.”  Consequently, participants “suggested that MA also monitor the activities of medical representatives as they represent a significant proportion of the promotional budget and research has revealed concerns.”

The author noted that “There was support for much greater transparency in the relationship between industry and health professions,” with some even suggesting that the provisions of the Physician Payment Sunshine Act should be incorporated in the code.”  The author pointed out that there is already public support for this measure by some drug companies and the Australian Medical Association.

While we wait to see the final regulations for the Sunshine Act, which Congress has asked the Centers for Medicare and Medicaid Services (CMS) to produce this year, the Drug Information Association (DIA) will be holding a session on the Sunshine Act in anticipation of the final regulations to discuss implementation.  The panel will be moderated by John F. Kamp, JD, PhD, Executive Director of the Coalition for Healthcare Communication and includes several prominent physician-industry collaboration experts.

Evaluating New Approaches for Accelerating Clinical Trials in Cancer

A recent article from Reuters Health looked at the difficult challenges that clinical trials of cancer treatment face.  One of the main challenges to these trials is costs.  However, “a new study suggests that government-funded trials could take at least one cue from those backed by pharmaceutical companies.” 

Background 

In 2010, the Institute of Medicine (IOM) released a report saying that the U.S. system for conducting cancer clinical trials was approaching a "state of crisis."  The IOM expert panel said the National Cancer Institute's (NCI) Clinical Trials Cooperative Group program was inefficient, bogged down by red tape and underfunded.  The NCI program includes a number of collaborative groups -- academic cancer centers, researchers and community doctors that work together to conduct trials on cancer treatment.  Altogether, the program involves more than 3,100 institutions in the U.S., Canada and Europe. 

New Study 

In the new study, researchers at one Canadian cancer center focused specifically on the timing of cancer clinical trial funding.  With cooperative group trials, funding typically comes as a "modest payment up front" for each patient enrolled, explained lead researcher Dr. Hsien-Yeang Seow of McMaster University and the Juravinski Cancer Center in Hamilton, Ontario. 

Trials done by the drug industry, on the other hand, dole out money over time, as patients hit certain "milestones" -- like during treatment, and as they come back for follow-up visits after treatment ends. 

Seow's team looked at 97 clinical trials done at its center in recent years. Two-thirds of those studies were cooperative group trials, including some with NCI funding, while the rest were industry-sponsored.  Those included early- and late-stage trials of treatments for cancers including breast, lung and stomach cancer. 

The researchers found that the cooperative group trials quickly began to lose money after the initial stages because the funds were all spent early on.  That leaves nothing for study patients' follow-up, which can last for years. 

The industry trials, in contrast, had more money going in than out at multiple time points -- though any net income typically disappeared during longer term follow-up.  The study also found that “its center had fallen into a pattern of starting new clinical trials in order to pay for patients' follow-up in the older, ongoing trials.  Seow likened it to a "Ponzi scheme" -- albeit an unintentional and legal variant.  "In order to stay afloat," Seow explained in an interview, "we have to start new trials and recruit new patients." 

The money from that new-patient accrual then goes to "pay down the deficit" of earlier trials. "Obviously, that's not sustainable," Seow said.  One way to help with the larger issue of sustaining cooperative group trials could be to switch from "up front" payment, according to Seow. 

Editorial and New Approach to Cancer Clinical Trials 

The author of an editorial published with the study in the Journal of Clinical Oncology agreed with Seow. "Perhaps it is time to consider more closely following the pharmaceutical industry model of progress payments," writes Dr. David M. Dilts, of the Knight Cancer Institute in Portland, Oregon.  He noted that this could help stop the "robbing Peter to pay Paul" habit of using new trials to fund old ones. 

An alternative for individual cancer centers would be to take part in fewer and fewer cooperative group trials, and more industry-funded ones.  “A recent survey of centers in the NCI cooperative program suggested that is happening: one-third said they were going to limit their participation in NCI-funded trials in the future.” 

But non-industry trials are vital, Seow pointed out.  Drug company studies may bring us the "next blockbuster drug," he noted, but the cooperative group trials help answer the bigger questions of how to improve cancer patients' overall care.  This new analysis, Seow said, looks at just one aspect of the larger, complicated issue. 

The 2010 report from the IOM recommended an overhaul of the NCI cooperative group program. Many of its suggestions focused on efficiency: the process of simply designing a trial, for example, is lengthy and cumbersome -- taking an average of two years to complete.  It also called for more funding. The NCI's payment-per-patient has not changed in a decade, standing at about $2,000. But the actual cost is thought to be closer to $6,000, Dilts points out in his editorial. 

The NCI has said it plans to boost that reimbursement to $4,000, at least to "high performance" centers that enroll a large number of patients in clinical trials.

In an email to Reuters Health, a spokesperson for the organization said it recognizes the need for more funding going to individual study sites. 

Dilts noted, however, that centers may still end up spending more money up front because “researchers are increasingly trying to develop treatments that are "personalized" to patients' genetic makeup.”  As a result, there still may be no money left over for years of patient follow-up.  Another option, Seow said, is to finally close some of the long-running "mega-trials" that are no longer generating useful information. 

Ultimately, Seow said that multiple solutions are needed.  "There have been remarkable breakthroughs in cancer therapies," he said. "But there's a state of crisis in clinical trials right now, and there are many reasons for it."

Merck for Mothers Initiative to End Maternal Mortality

This year, it is estimated that 365,000 women will die from complications of pregnancy and childbirth.  A great many of these deaths are preventable. For every woman who dies, 20 others suffer injury, infection or disability. This toll is heartbreaking and unacceptable. 

Women who die during pregnancy is a horrible human tragedy that can unravel families and communities.  The death of a mother not only jeopardizes the lives of a surviving newborn and any other young children, but it also makes it harder for her family to obtain life's necessities and escape the crush of poverty.  This burden falls most heavily on the developing world, with the vast majority of mothers dying in sub-Saharan Africa and South Asia.  

However, certain communities in the United States and other developed nations are suffering as well.  In the United States, maternal mortality rates doubled between 1990 and 2008 and the nation now ranks 39th in the world. This dramatic shift in the wrong direction illustrates the continued disparities in healthcare access for too many at-risk mothers. 

To address these maternal health issues, Merck recently launched the “Merck for Mothers” initiative.  "Merck for Mothers" is a long-term effort with global health partners to create a world where no woman has to die from complications of pregnancy and childbirth.  The launch includes a 10-year, half-billion-dollar initiative that applies Merck's scientific and business expertise to making proven solutions more widely available, developing new game-changing technologies and improving public awareness, policy efforts and private sector engagement for maternal mortality. 

On Sept. 20, 2011, Merck President and CEO Ken Frazier announced Merck's 10-year commitment to creating a world where no woman has to die giving life.  "We are joining the fight to save women who risk their lives giving birth and making it part of Merck's mission," said Merck President and CEO Ken Frazier. “'Merck for Mothers' will help us make a difference in the lives of more people in more parts of the world." 

"By helping to address one of the world's oldest and most preventable global health tragedies, we believe 'Merck for Mothers' will have an important impact on society. We also believe it will provide valuable learnings to our business. We are in this fight for the long term," he added.  Mr. Frazier credited Merck Chairman Richard T. Clark with having a vital role in driving the development of the initiative. "Because of Dick Clark's leadership and vision, Merck now has a new way to deliver on the company's mission of saving and improving lives," he noted. "Dick's passion for creating 'Merck for Mothers' is consistent with the focus he has had on corporate responsibility throughout his five years as CEO." 

Background 

Governments, multilateral organizations and nongovernmental organizations (NGOs) have been expanding efforts and momentum is building, but more help is needed — especially from the private sector.  There is no "magic bullet" when so many women lack access to basic medical care, but dozens of life-saving technologies are potentially available to address this global catastrophe.  More than half of all deaths during pregnancy and childbirth are from post-partum hemorrhage (35 percent of all deaths) and  preeclampsia (18 percent of all deaths).  Many of these deaths can be avoided when women in need have access to quality prevention, diagnostic, and treatment services. 

In 2000, the United Nations agreed to work toward eight Millennium Development Goals (MDGs). Goal 5 focuses on improving maternal health in two ways: MDG 5a calls for reducing maternal deaths by three quarters and MDG 5b calls for universal access to reproductive health — including pre-natal care and family planning. 

In Sept. 2010, UN Secretary-General Ban Ki-moon launched the Global Strategy for Women's and Children's Health, which catalyzed $40 billion worth of new action on maternal and child health from diverse stakeholders.  While some countries are making progress, many are falling behind. The world is not on track to achieve the goals outlined in MDG 5a or MDG 5b. 

“Merck for Mothers” 

Merck's new initiative is grounded in intense listening and learning and in transparent collaboration with healthcare workers and experts on the front lines. Based on input from more than 150 experts in the field, Merck developed a strategic framework identifying where the company will focus its people and resources.  The initiative will focus on the two leading causes of maternal mortality (post-partum hemorrhage and preeclampsia) as well as family planning, which is known to play an important role in reducing maternal mortality.   

The initiative will be guided with input from both an internal steering committee and an external advisory board.  Merck will use an independent organization to monitor and evaluate its efforts.  Consequently, there are three main approaches for this long-term initiative. 

Accelerating Access to Proven Solutions:  Merck intends to improve the quality and supply of diagnostic, prevention and treatment interventions for post-partum hemorrhage and preeclampsia.  In addition, Merck will strengthen medical education for skilled birth attendants, help develop sustainable models for healthcare delivery, and expand access to family planning. 

Product Innovation:  Merck will collaborate with partners to develop game-changing maternal health technologies for widespread use in resource-poor settings.  Merck will start with an assessment of more than 30 promising existing technologies in partnership with leading donors, nongovernmental organizations (NGOs) and researchers, with a goal of developing at least three innovations that address post-partum hemorrhage, preeclampsia and family planning.

Global Awareness and Advocacy:  Merck will join leading maternal health experts to create greater public awareness of the need to reduce maternal deaths in an effort to improve global and national policy. As part of "Merck for Mothers", Merck is the first among companies to join the UN Global Compact/UN Foundation's Private Sector Task Force for Every Woman Every Child. 

"Merck is breaking new ground for women and their families.  This commitment is extraordinary in its volume, its scope and its vision for the long haul.  More than half of all deaths during pregnancy and childbirth result either from excessive bleeding, or from complications related to high blood pressure, as well as from a lack of access to family planning," said Dr. Carole Presern, a midwife, and Partnership for Maternal, Newborn and Child Health (PMNCH) Director. "While there are many proven solutions, there is no silver bullet for maternal mortality. Faster progress requires access to known solutions that can be implemented at scale; new products that can leap frog over the challenges we face today; and a relentless drive on global advocacy to reduce maternal deaths." 

On March 26, 2012, Merck announced that it was partnering with the U.S. Government and leading global health advocates to reduce the number of women who die during pregnancy and childbirth. Saving Mothers, Giving Life – a collaboration among Merck for Mothers, the U.S. Government, the Government of Norway, the American College of Obstetricians and Gynecologists (ACOG), and Every Mother Counts – aims to reduce maternal mortality in several selected regions in Africa where maternal mortality is high, and identify ways to replicate success.  Merck's contribution to the partnership, which will span five years, is valued at more than $50 million. 

Merck for Mothers will help guide the strategic direction of Saving Mothers, Giving Life, contribute to on-the-ground program implementation and evaluation, and provide management, leadership, and support for the partnership.  Coordinating the partnership on behalf of the U.S. Government is the Office of the Global Health Initiative at the U.S. Department of State.

Senate Finance Committee Reacts to Reports of Opioid Abuse and Conflict of Interests: Letters to Manufactures and Organizations

Deaths from painkiller overdoses have tripled over the last decade and led to the deaths of 14,800 Americans in 2008, exceeding those caused by heroin and cocaine combined.  More recently, a 2011 GAO report linked prescription pain killers to a 142% spike in emergency room visits between 2004 and 2009.  The increase in deaths from opioids has pushed drug poisoning ahead of automobile accidents to be the leading cause of accidental death in the United States.  Painkiller sales have increased fourfold since 1999.  Opioids, derived from the poppy plant, reduce the perception of pain by attaching to opioid receptors in the brain, spinal cord and elsewhere in the body.  

Pain doctors and patient groups say that while drug overdoses are a legitimate concern, only a small percentage of deaths involves patients who receive them from their doctors. Most deaths involve illicitly obtained drugs, statistics show.  The groups also say that patients' risk is low if they do not have addictive personalities, and that any restrictions should not punish patients who suffer from serious pain. 

The Centers for Disease Control (CDC) reports that improper “use of prescription painkillers costs health insurers up to $72.5 billion annually in direct health care costs and opioid pain medications now kill more people than heroin and cocaine combined, and accounted for almost 74% of fatal presciption drug overdoses in 2008. In response to these alarming numbers, the Food and Drug Administration (FDA) last fall released a Blueprint on opioids.  Despite these and other efforts, the difficulties and dangers associated with opioids have remained.  

According to the New York Times, “the number of prescriptions for the strongest opioids has increased nearly fourfold [over the last decade], with only limited evidence of their long-term effectiveness or risks” while “[d]ata suggest that hundreds of thousands of patients nationwide may be on potentially dangerous doses.”  In addition, allegations have arisen over the past few years that pharmaceutical companies that manufacture and market opioids may be responsible, at least in part, for opioid abuse by promoting misleading information about the drugs’ safety and effectiveness. 

Recent investigative reporting from the Milwaukee Journal Sentinel/MedPage Today and ProPublica “revealed extensive ties between companies that manufacture and market opioids and non-profit organizations” noted above.  According to the Milwaukee Journal Sentinel/MedPage Today, a “network of national organizations and researchers with financial connections to the makers of narcotic painkillers…helped create a body of dubious information” favoring opioids “that can be found in prescribing guidelines, patient literature, position statements, books and doctor education courses.”  

Due to the increased problems opioids have caused, Senators Max Baucus (D-MT) and Charles Grassley (R-IA), recently sent letters to three pharmaceutical companies, Purdue Pharma,  Endo Pharmaceuticals and Johnson & Johnson, as well as five groups that support pain patients, physicians or research: the American Pain Foundation (APF), American Academy of Pain Medicine, American Pain Society, Wisconsin Pain & Policy Studies Group, and the Center for Practical Bioethics. 

The Federation of State Medical Boards (FSMB), the trade group for agencies that license doctors, also received a letter, as did The Joint Commission, an independent nonprofit that accredits hospitals nationwide and made pain management a national priority in 2001.  The letters inquired into the nature of funding from these companies and educational materials that the patient support groups produced and gave to patients and doctors.  

The senators requested payment information from companies since 1997 (15 years) to 10 groups and eight people, including two doctors featured in ProPublica's December report. They asked about any influence the companies had on a 2004 pain guide for physicians that was distributed by the Federation of State Medical Boards; on the American Pain Society's guidelines; and on the American Pain Foundation's Military/Veterans Pain Initiative. 

Consequently, the APF closed last week, “due to irreparable economic circumstances.”  APF said it “hopes to be able to transfer content from various information, education, and support programs to other organizations so that you may continue to benefit from the value these programs have provided to thousands of individuals and families across the country.”  It is unclear whether the group's announcement was related to the Senators’ letters. 

The American Pain Foundation (APF) 

According to ProPublica, APF received “nearly 90 percent of its $5 million funding from the drug and medical device industry.”  The group had “also lobbied against federal and state proposals to limit opioid use.”  ProPublica wrote that its review of the American Pain Foundation’s “guides for patients, journalists, and policymakers play down the risks associated with opioids and exaggerate their benefits. Some of the foundation’s materials on the drugs include statements that are misleading or based on scant or disputed research.” 

APF’s patient guide discusses several treatments for pain.  It says such pain relievers as aspirin, ibuprofen and naproxen commonly cause gastrointestinal bleeding or ulcers, delay blood clotting, decrease kidney function and could increase the risk of stroke or heart attack.  And it warns patients to use these pain pills at the lowest dose and stop them unless clearly needed. 

The side effects of opioids, on the other hand, are minor, and most go away “after a few days,” the foundation’s guide says. Patients, it says, shouldn’t worry if they need more of a drug. They are not developing an addiction.  “Many times when a person needs a larger dose of a drug,” the guide says, “it’s because their pain is worse or the problem causing their pain has changed.” 

Another guide, written for journalists and supported by Alpharma Pharmaceuticals, likewise is reassuring. It notes in at least five places that the risk of opioid addiction is low, and it references a 1996 article in Scientific American, saying fewer than 1 percent of children treated with opioids become addicted.  According to the investigations, however, “the cited article does not include this statistic or deal with addiction in children.”  “I would much prefer that they would put in there something that could be substantiated by a real reference,” said Leonard Paulozzi, a CDC medical epidemiologist specializing in drug overdoses. 

APF asserts that industry money has had no effect on its advocacy.  “I’m convinced with every shred of my body that our interest is improving the lives of people affected by pain,” said Will Rowe, the foundation’s chief executive, “and we want to do that the best way we can.”  The problem isn’t opioids, Rowe and other group leaders say. It’s poorly trained doctors who prescribe them too easily or in excess.  Rowe, acknowledged that some of its publications need updating and he pointed to additional materials on the group’s new PainSAFE Web site, which includes a broader description of the risks. 

Critics, however, believe that any industry money automatically taints a patient organization—guilt by association.  Its funding makes the group “one and the same” with the pain industry said Gary Franklin, a Washington state official who tussled with the foundation over new restrictions on high-dose painkillers.  This kind of attribution, however, is unwarranted.  In America, individuals and parties are presumed innocent until proven guilty.  In the case of patient organizations who receive funding from industry, the opposite holds true.  In retrospect APF should have sought additional resources and funding outside of industry, but those resource might not have been there.  The automatic assumption that the materials they produced were biased because of industry funding is contrary to the principles of fairness America stands for. 

Media also took issue with the fact that some of APF’s board members connections to the pharma companies.  One member was paid to speak and consult, one researcher’s clinic relied on funding for survival and a public-relations executive represents them.  In ProPublica said “board members have extensive financial ties to drugmakers.”  Last year, one board member was the lead author of a study about a Cephalon drug. Cephalon sponsored the study, and its employees were co-authors. The study found that the drug, Fentora, was “generally safe and well-tolerated” in non-cancer patients even though it is only approved for severe cancer pain. 

The investigation also noted that the APF literature does not mention that the drugs “don’t work for many chronic pain sufferers” and “recent editorials in medical journals and scientific reviews cite little evidence of long-term benefit.”  Most of the clinical trials for opioids to treat chronic pain “were small, lasted less than 16 weeks and excluded patients with a history of substance abuse, psychiatric illness and depression, who are at increased risk for opioid misuse and abuse,” three physicians wrote in an editorial this year in the Archives of Internal Medicine.   

Rowe said he knows plenty of patients for whom the drugs work, “and their lives are together because they use them.”  Scott Fishman, the APF’s chairman and president and chief of pain medicine at the University of California at Davis said, he “always believed that patients in pain in the United States need strong patient advocacy, which APF has offered.”

Federation of State Medical Boards (FSMB) 

In addition, the Sentinel reported, that the FSMB, with financial support from opioid manufacturers, distributed more than 160,000 copies of a model policy book that drew criticism from doctors because “it failed to point out the lack of science supporting the use of opioids for chronic, non cancer pain.”  According to MedPage Today, the FSMB “asked Purdue Pharmaceuticals for $100,000 to help pay for printing and distribution that policy to 700,000 practicing doctors.”  That $100,000 was just a small down payment on the $3.1 million that the Federation's foundation estimated it would cost for its campaign to get out the word about "safe" use of opioid analgesics in treatment of chronic pain. 

An FSMB spokesperson said there were many reasons for it to codify a position on the prescribing of opioids, and among those reasons was a project supported by the Robert Wood Johnson Foundation (RWJ) to seek some common ground in the treatment of chronic pain.  A Journal Sentinel/MedPage Today investigation suggested that it was the $693,000 grant from the RWJ Foundation to University of Wisconsin that started the ball rolling down this slippery slope. That grant went to the UW Pain & Policy Studies Group. 

Last year, the Journal Sentinel/MedPage Today reported that the UW Pain group had received $2.5 million from Purdue and several other opioid makers between 1999 and 2010.  After the story ran last April, the UW Pain group said it had decided to stop taking money from the drug industry.  The investigation, however, still revealed several findings: 

• The Robert Woods Johnson Foundation funded project started with an advisory committee that recruited several pain experts who were experts in their field and also had done worked with makers of opioids -- a core group that included J. David Haddox, DDS, MD, then a member of the Purdue Pharma speakers' bureau, who went on to become a Purdue employee. Purdue is the maker of OxyContin.

• FSMB's involvement started with a guideline written in 1998, and then with its model policy, which was adopted in 2004. With that policy in hand, the FSMB decided to spread the word to the nation's physicians by translating the policy into a book and it delegated that task to Scott Fishman, MD, a University of California Davis physician who also works with pharmaceutical companies that market opioids.

• FSMB reached out to a total of six opioid makers requesting financial support to produce and distribute "Responsible Opioid Prescribing: A Physician's Guide," but it won't disclose how much each company contributed.

• In 2009 the University of Wisconsin School of Medicine and Public Health decided to offer an online CME course based on the FSMB book, and to fund the activity it sought and received a $119,000 grant from Endo Pharmaceuticals (one the six companies that chipped in to pay for the book's printing and distribution). As course reviewer, UW chose Aaron Gilson, PhD, a UW employee, who had been paid to help another opioid maker, Cephalon, with a new drug application to the FDA. 

Deborah Grady, MD, a professor of medicine at the University of California, San Francisco, said she believes the federation's policy as well as continuing medical education (CME) courses such as the one offered by UW contributed to the marked increase in opioid use.  That policy also helped establish the idea that denying high doses of opioids to patients is a bad medical practice, she said. 

"The sad fact is that for many patients, the pain is never controlled, despite very high, dangerous doses of opioids that may actually result in more side effects than benefit," Grady said.  The model policy, which describes how opioids should be used to treat pain, has been adopted in full or in part by nearly 30 state medical boards. 

Instead of protecting patients from over-prescribing doctors, many of those medical boards have been "duped" by the federation's "pharma-funded campaign" into encouraging aggressive prescribing, said Andrew Kolodny, MD, a New York psychiatrist, addiction specialist and critic of the opioid industry. 

In a statement, Lisa Robin, the federation's chief advocacy officer, said its efforts are not intended to advocate for opioid therapy.  "Far from encouraging opioid use, the policy and book have provided a much-needed warning to physicians that opioids are potentially dangerous, that the use of opioids for other than legitimate medical purposes poses a threat to the individual and society ... Such medications must be used with great caution." 

She said the policy urges physicians to seek balance, "recognizing the fact that millions of legitimate patients rely on these medications for pain relief, while incorporating safeguards into their practices to minimize the potential for the abuse and diversion of controlled substances. 

In a statement, UW said the book and the CME course are not clinical practice guidelines. They are a response to the issue of opioid abuse and how to reduce it, said UW spokeswoman, Lisa Brunette.  The book's content was reviewed for accuracy and balance by 20 experts, including 14 who had no financial relationships with drug companies, she said.  She said Gilson, who reviewed UW's CME course, is a widely published expert on pain policy issues.  He had no financial relationship to the Endo Pharmaceuticals, which funded the course, she said. 

In a statement, Fishman, the book's author, said he was not paid for his work on the book and does not receive royalties.  He acknowledged that when the first edition of the book was written in 2006, the science on the effectiveness of opioids "was not robust" and data on the severe risks "had yet to emerge.”  Since then, new data on risks, including unintended overdose deaths, have emerged, he said. The new risk information will be included in an expanded version of the book that will be published by the spring, he said. 

Janssen Pharmaceuticals, a Johnson & Johnson subsidiary that makes the painkiller Nucynta, said in a statement that it "is committed to the responsible prescribing and appropriate use of opioid pain medications" and has supported educational websites about safe use.  The company is reviewing the senators' letter and "will work with them to fulfill their request for information," spokesman Mark Wolfe said via email.  Purdue Pharma acknowledged in a statement that it had received the letter, was reviewing it and looked forward to "cooperating with the committee on this matter." 

Conclusion 

While companies producing opioids have made mistakes in the past, the difference with pain is that there are realistically no other options.  Therapy, surgery, and everything in between do not work for a vast majority of people and these treatments do not last very long.  Nevertheless, the risk of addiction and abuse for opioids is significant.  In addition, FDA and companies have not been successful discovering and approving new treatments for pain.  

Adding to the problems of opioids is the fact that symptoms are hard to detect and patients can easily lie and deceive physicians.  In addition, physicians need more training and CME to understand the risks and challenges of prescribing opioids.  New laws currently being proposed in several states may address some of these issues by restricting the prescription of opioids and creating new regulatory requirement for the dispensing of such drugs.   With the FDA REMS Blue print on long acting Opioids the need for companies to support pain continuing medical education has never been greater. 

With scant options to treat chronic pain, opioids have made the difference between days and nights of agony and a return to productive life for millions of patients. Critics have a hard time understanding that these patients are willing to risk serious side effects to gain relief.  “Policymakers can go to bed at night and say, ‘Well, I protected society’ ” by restricting access to a risky painkiller, Rowe said. “The person with pain or the person with cancer could say: ‘You know, I’m sorry. I’m living with this, and I want to take this chance.’ ” 

With APF gone, patients have lost a valuable resource.  Moving forward, patient groups must ensure the proper balance of industry support in their programs to prevent any appearance of conflict or impropriety.  The problems our country faces with opioids will only continue to grow and become more costly.  As a result, Congress, industry, academia, and federal agencies must begin to work together to implement real and practical solutions that alleviate the physical pain of patients without creating a burden on the way patients receive their treatment.  

Physician Payment Sunshine: Forest Labs Reports Payments to Physicians

Continuing the ongoing trend of transparency and disclosure in the health care industry, Forest Laboratories became the latest in an ever-growing list of companies to publicly report all payments it makes to physicians to develop, market, and educate colleagues on its products.  According to Q2 Metrics’ Company & Physician Aggregate Spend Solution (COMPASS), Forest Labs doled out more than $11.1 million in payments to over 63,000 US-based physicians in Q1.  

Payments disclosed by the company included those for consulting fees, speaking fees, travel expenses, educational items, meals, and independent physician research funding.  Forest has a strong compliance program in place and values physician-industry relationships.  

What is interesting about Forest Labs’ Q1 disclosure is that professional speaking fees represented a substantial 70% of Q1 payments (or $7.9M).  Conversely, other professional service fees for consulting and independent research represented less than 4% of Forest Labs’ Q1 payments (or just over $200K). This spending on professional fees is in stark contrast to the practices of competitive firms. 

In 2011, Eli Lilly (LLY) spent only 28% of its physician aggregate spend dollars on speaker fees despite spending a staggering 92% of its aggregate spend budget on professional fees.  Similarly, Pfizer (PFE) spent only 17% of its physician aggregate spend dollars on speaker fees in 2011 while spending on professional fees in general represented a staggering 87% of its aggregate spend.  The article pointed to many reasons “for the spending discrepancy on speaker fees.”   

First, Q1 2012 represents the first reporting period for Forest Labs and as such, many of the consulting and research agreements the company has with physicians may not yet be complete. Resultantly, the company may not yet be obligated to fulfill the financial obligations underlying these consulting and research agreements. 

Second, and maybe more importantly, Forest Labs is smaller than most pharma companies that are currently reporting physician payments, has a largely undifferentiated pipeline, and is not often first to market with products. Despite this, the company has demonstrated that it can successfully launch new drugs into mature markets (e.g. Lexapro, Namenda, & Bystolic), not an easy task without having a significant volume of clinicians speaking on your behalf.   

The publication of Forest’s payment also comes in anticipation of the finalized rules for the Physician Payment Sunshine Act.  However, as we recently noted, companies will not have to begin reporting payments until January 1, 2013.  Nevertheless, a recent article from MedCity News noted that complying with the law will require an average of 1.74 full-time equivalents in the first year at a cost of $195,288 per organization. 

“That amount does not include outside legal counsel or IT infrastructure,” said Sheva Sanders, a Twin Cities lawyer with Leonard, Street and Deinard, who was one of the presenters. “I think the cost has been underestimated.”  “You cannot do this on a dime,” Sanders said. “It takes big effort.”