Category Archives: Pharma

Book Reviews: Global Politics & Pharmaceutical Industry Practices

Two books on the ethics, politics and practices of the global pharmaceutical trade. Reviewed are: The Global Politics of Pharmaceutical Monopoly, Power, Drug Patents, Access, Innovation and the application of the WTO Doha Declaration on TRIPS and Public Health by Ellen F.M. ‘t Hoen (AMB Diemen, 2009) and Global Pharmaceuticals: Ethics, Markets, Practices, edited by Adriana Petryna, Andrew Lakoff, & Arthur Kleinman (Duke University Press, 2006).

The Global Politics of Pharmaceutical Monopoly, Power, Drug Patents, Access, Innovation and the application of the WTO Doha Declaration on TRIPS and Public Health by Ellen F.M. ‘t Hoen (AMB Diemen, 2009. ISBN 97890-79700-06-6)

In her new book, The Global Politics of Pharmaceutical Monopoly, Power, Drug Patents, Access, Innovation and the application of the WTO Doha Declaration on TRIPS and Public Health, Ellen ‘t Hoen, former Director of Policy Advocacy for the Medecins Sans Frontieres (Doctors Without Borders) Access Campaign, outlines progress made in increasing access to medication and medical innovation. She also identifies critical unresolved issues in development and distribution of new medical technologies for the treatment and prevention of disease in the developing world. Specifically, this book describes how access to medication in the developing world is affected by the current global rules for pharmaceutical patents. The book highlights recent alternative mechanisms to encourage medical research and development in a way that also ensures access to the product—by separating the cost of research and development from the price of diagnostics, medicines, and vaccines.

Link to reviews of this book:

Knowledge Ecology Studies
European AIDS Treatment Group

Link to this book:

AMB Press (where you will find link to an on-line version of this book)

 

Global Pharmaceuticals: Ethics, Markets, Practices by Adriana Petryna, Andrew Lakoff, & Arthur Kleinman (eds.) (Duke University Press, 2006. 312pp. ISBN 082233741X)

This edited volume, a collection of ethnographies, tackles a timely topic- the inequalities produced by the current global pharmaceutical system that of the anthropologist. This collection provides insights into the burgeoning international pharmaceutical trade and the global inequalities reinforced by market-driven medicine. From an examination of how popular and professional understandings of psychiatric illness in the Western world to the experience of African families faced with the financial burden of AIDS treatment for its members, this book brings together experiences of individuals and communities and the roles they play along with organizations, corporations, and governments in the market-driven game of global pharma. This work is an important step in bringing the moral and ethical issues inherent in every phase of pharmaceutical production to the forefront of the social science research agenda.

Link to review of this book:

British Journal of Psychiatry

Link to this book:

Amazon.com

The Depression Epidemic: The “Medication-alization” of Sadness

Is there really an epidemic of depression or is it, as some have suggested, forces of medicalization at work? This article looks at pharma’s direct-to-consumer advertising practices of marketing antidepressants and the health insurance industry’s influence on the perception of depression prevalence.

Surviving America’s Depression Epidemic, “Depression: Epidemic for a Postmodern Age,” “Depression: The Hidden Epidemic.” These kinds of titles lamenting or questioning the popular lay and professional conception of depression as increasingly widespread have become more and more common in recent years. It is true that depression is understood by many as a major public health problem of epidemic proportions. The United States Surgeon General’s 1999 report, “Mental Health: A Report of the Surgeon General,” stresses the widespread nature of mental illness, with one in five Americans affected by mental illness each year. The World Health Organization describes depression as an epidemic that will, within the next 20 years, be second only to cardiovascular disease in terms of disease burden worldwide.1

But what is an epidemic? And for that matter, what exactly do we mean when we say “depression?” The U.S. Centers for Disease Control defines an epidemic as: “the occurrence of disease within a specific geographical area or population that is in excess of what is normally expected.” The term depression is used regularly in our everyday lexicon to refer to a variety of concepts relating to weather patterns to the state of our economy. We also use the word depression to describe a fleeting mood state—the disappointment after failing a test or a feeling resulting from a particularly sad or “depressing” movie. However, increasingly over the last few decades, the general public uses depression as physicians and mental health researchers do—to refer to a mental illness called “major depressive disorder (MDD),” which, as described above, seems to be affecting more and more of us each year.

If depression is an epidemic then, according to the CDC definition, depression is a disease. It also means that depression is occurring “in excess of what is normally expected.” But what is a “normal” amount of depression? Is the number of people found to be depressed in U.S. higher than what should be expected? Are those diagnosed in epidemiologic studies as depressed experiencing disease or just plain old sadness resulting from the normal ups and downs of life?

There is no doubt that depression is a serious, debilitating condition for sufferers, who can be helped immensely by professional interventions, including medication. But it remains the case that there is no definitive test—no blood test or x-ray—to confirm or deny someone has MDD. This uncertainty about cause and the widespread nature of depression “symptoms” makes depression diagnosis malleable and suggestible—offering opportunity to the pharmaceutical industry to expand sales by expanding what is considered treatable “illness.”

Medications work on our biology and therefore pharmaceutical companies depend on biological definition of depression to sell their products. Because of the difficulty in identifying clear cut biological mechanisms for the diagnosis of various mental disorders, the degree to which the mental is medical remains contested.

Medicationalization—DTCA

The medicalization of “sadness,” as it is called by critics of the depression as epidemic perspective, points to direct to consumer (DTC) advertising of antidepressants by pharmaceutical companies as a major vehicle in the expansion of depression diagnoses.2,3 “Medication-alization” seems more like it. In 1997, The Food and Drug Administration approved the use of DTC drug advertisements in broadcast media (TV and radio); before that, advertising was relegated to publications targeted at physicians.4 By 2000, the pharmaceutical industry was spending more than $2 billion on DTC advertisements.

DTC ads for antidepressants typically feature the DSM defined symptoms of major depressive disorder in conjunction with explicit reference to biological etiology, defining depression as a “chemical imbalance” or lack of normal levels of the neurotransmitter serotonin in the brain. While this was once a promising theory, science has not borne out the truth of the “chemical imbalance” theory.5 Today’s science increasingly depicts depression as resulting from a highly complex interaction of human biology, genetics, psychology, and social and physical environments. But even though psychiatry shies away from direct claims about cause, the pharmaceutical industry is sticking with what works—and the result is continued sales. SSRIs have come to be some of the best selling drugs of all time, and the success of these drugs has lead to a proliferation of new antidepressants on the market for depression and a variety of other mental health problems.

Managed care and mental health treatment

Around the time that SSRI antidepressants came on the market in the late 1980’s to early 1990’s, managed care was expanding. Managed care prefers the quickest, least expensive treatment alternatives. In the case of depression treatment that means medication over psychotherapy. The result—patients seeking care for depressive symptoms were more than four times more likely to receive medication for depression in 1997 than in 1987.6

What doctors can diagnose and prescribe as treatment is subject to the approval of a patient’s health insurance companies and what it defines as acceptable diagnosis and treatment. To the degree that patients are unable or unwilling to pay for service out of pocket, they must seek the services covered by their health insurance carrier, all of whom employ at least some managed care practices these days. With recent mental health parity legislation, insurance companies being forced to provide increased psychotherapy benefits, but most still have strict limits on coverage, ironically requiring a mental health problem to be deemed “biologically-based” by the provider to get reimbursed for psychotherapy treatment services.

Protecting the healthy

The number of people experiencing the “symptoms” of Major Depressive Disorder may be plenty. No doubt, the symptoms of depression are common and widespread human experiences. We may have a lot of depression going on, but that there’s “disease” in excess of what’s normally expected in this case is less certain.

Contrary to popular sentiment, while lots of people may be experiencing symptoms of depression, it’s not clear that this is occurring at higher rates than in the past, nor is it the case that everybody who goes to their doctor is clamoring for medication. But with Pharma, physicians and health insurance industries telling us that yes, our experience is very common, but no, it is not normal, and that medication is our best option for feeling better, it’s no wonder that we’ve got a society ripe for viewing depression as an epidemic.

No question society needs to make the protection of the rights and interests of persons with mental illness a priority since they have in the past often been ignored and trampled on. But convincing people who are sad or live in difficult circumstances that the only way they can get better is to take a powerful drug carries its own dangers. Only by critically analyzing the social forces that have created the “epidemic” of depression can we chart effective policies to recues its burdens.

 

References

1 Summerfield D. Depression: epidemic or pseudo-epidemic? Journal of the Royal Society of Medicine. 2005: 99: 161-1.

2 Horwitz A, Wakefield J. The loss of sadness: How psychiatry transformed normal sorrow into depressive disorder. Oxford: Oxford University Press; 2007.

3 Conrad P. The shifting engines of medicalization. Journal of Health and Social Behavior. 2005: 46(1): 3-14.

4 Conrad P, Leiter V. From Lydia Pinkham to Queen Levitra: DTCA and medicalization. Sociology of Health and Illness. 2008: 30: 825-838.

5 Lacasse JR, Leo J. Serotonin and depression: A disconnect between the advertisements and the scientific literature. PLoS Medicine. 2005: 2(12): 1211-1216.

6 Olfson M, Marcus SC, Druss B, Elinson L, Tanielian T, Pincus HA. National trends in the outpatient treatment of depression. JAMA. 2002;287:203-209.

 

Photo Credits:
1. angelinawb 

Sara Kuppin, DrPH, is a postodoctoral fellow in Urban Public Health at Hunter College.

Off-label marketing: Good for business, bad for health

Off-label marketing has been illegal since 1938 but continues despite major lawsuits because expanding market share leads to hefty industry profits. And now, a last minute Bush administration policy push inside the FDA may be giving this practice of off-label marketing the official thumbs up.

Pharmaceutical companies are spending big bucks to settle suits for illegally promoting drugs for off-label uses and harming customers in the process. The practice, called off-label marketing, has been illegal since 1938 but continues because expanding market share leads to hefty industry profits. And now, a last minute Bush administration policy push inside the FDA may be giving this practice of off-label marketing the official thumbs up.

Most recently, Eli Lilly, the maker of Zyprexa, pled guilty to off-label marketing in a federal suit settled in January and has been ordered to pay a $1.4 billion settlement—the largest in Department of Justice history.1 The FDA approved the use of Zyprexa (olanzapine), for treatment for schizophrenia and bipolar illnesses in 1996 but the drug has been used off-label for generalized anxiety disorder, panic disorder, post-traumatic stress disorder, conduct disorders in children and dementia among elderly patients.

After the ruling, Laurie Magid, the Department of Justice acting attorney in the case, severely criticized the industry for endangering consumer health and ignoring federal law by marketing drugs for off-label uses. In a Philadelphia Inquirer op-ed Magid said, “These cases should send a clear message to the entire pharmaceutical industry: This conduct must stop.”2

Industry profits eclipse potential fines?

In the past five years, almost all major pharmaceutical companies have been involved in lawsuits for off-label marketing offenses, resulting in over $6 billion in settlements.3 Industry documents disclosed in these cases show companies knowingly promoted off-label uses for drugs that had unknown or undisclosed health effects for the express purpose of increasing market share and boosting sales.

Neurontin (gabapentin), an adjunctive antiepileptic made by Warner-Lambert (now part of Pfizer), was marketed off-label for epilepsy monotherapy (for use by itself), as a treatment for migraines, bipolar disorder, restless leg syndrome and attention-deficit/hyperactivity disorder (ADHD). That case settled for $430 million.4 Actiq (fentanyl), a painkiller 80 times more potent than morphine made by Cephalon, was approved by the FDA to treat cancer-related pain but was marketed off-label as a general pain reliever.5 Zyprexa, an antipsychotic approved to treat schizophrenia and some events related to bipolar I mania, was illegally marked. In each example, companies marketed their products for more common conditions than those approved by the FDA. And in each case, patients taking these medications for off-label uses experienced significantly more adverse health events, including death, than those taking the drugs for approved uses. All three companies have pleaded guilty to their charges, and the settlement monies are headed to consumer and state restitution funds and whistleblower compensation.

Unfortunately, however, settlement fines seem scarcely enough to successfully curb the practice of off-label marketing when compared to industry profitability. In 2007, the pharmaceutical industry was the nation’s third most profitable industry out of all Fortune 500 firms, with drug sales over $286.5 billion.6 When Lilly’s Zyprexa was leading company sales, the drug brought in over $1 billion per quarter,7 vastly exceeding the recent settlement fine ($1.4B). Today, the company’s total annual revenue is more than $20 billion.

Why off-label marketing is off limits

Much like direct-to-consumer (DTC) advertising, off-label marketing influences prescribing habits which, in turn, drives drug utilization and sales. DTC ads on TV or in magazines are only allowed to promote on-label uses of drugs and are subject to FDA penalties if guidelines are not met. However, off-label marketing, which targets doctors, is illegal because use of a drug for any indication other than the one on the (FDA approved) label carries unknown risks.

Historically, the FDA has served to protect consumers against those risks. Banning the marketing of drugs for unapproved uses was an issue of consumer protection when first addressed as a federal concern. Since 1938, when the Food Drug and Cosmetics Act established new rules for drug makers, off-label marketing was recognized as a serious threat to consumer health. Sulphanilamide, an elixir marketed for the treatment of infection, was the catalyst for this Act. Having never been tested, and containing what is now recognizable as anti-freeze, the “elixir” killed more than 100 people, most of them children, before being taken off the market. Public outrage led to the establishment of what was to become the defining feature of drug regulation: safety and effectiveness as determined by the independent, peer-reviewed clinical trial.8 Theoretically, FDA approval of a medication is granted for specific use(s) and it is for those uses only that the drug can be marketed.

Side effects

Ten years after being on the market, Zyprexa was given a black box warning that states, “Not approved for the treatment of patients with dementia-related psychosis.” Independent studies revealed these patients have almost two times the risk of death compared to those taking a placebo (non-theraputic control drug).9 But the company had already made a global marketing blitz, advertising the drug as a good treatment for dementia-related symptoms. Their “five at five” campaign championed 5 milligrams at 5 PM to subdue disruptive elderly patients with dementia.

Zyprexa also causes weight gain and diabetes, side effects that are particularly pronounced in children and youth. According to the drug’s label, more than half of people taking Zyprexa as a long-tem treatment gain 12 or more pounds. Additionally, “safety and effectiveness in pediatric patients have not been established.” Despite the warnings, the dramatic increase in the number of antipsychotic prescriptions written between 1996 and 2005 was due, one study found, to a “remarkable increase in the rates of use for off-label conditions and use among youth.”10 The authors singled out “drug company marketing effects” and the “dominance of industry-funded trials” as two potential sources for the profusion of antipsychotic prescriptions.

Beyond drug safety; health spending and ‘manufactured’ evidence

To be clear, off-label prescribing is both legal and common—it is off-label marketing that is illegal. Doctors can prescribe any medication they believe will be helpful as long as that drug is FDA approved. Radley et al. reported in the Archives of Internal Medicine that according to a large nationwide sample of prescriber reports collected in 2001, 21% of all prescriptions were for off-label uses.11

Many argue off-label drug prescription is necessary in situations where clinical trials have not included vulnerable populations, for example children and elderly adults, due to ethical guidelines. So off-label prescribing is not necessarily a bad idea, but it does carry extra known and unknown health risks and costs to health care.

There are other concerns about off-label marketing. First, blockbuster drug sales driven by marketing campaigns contribute to skyrocketing health care spending. Prescription drug costs account for $1 out of every $10 spent on health care in the U.S. and that number is expected to increase rapidly over the next 10 years, in part due to rising drug utilization rates.6 In 2007, 3.8 billion prescriptions were filled, up 72% since 1997.6 The U.S. spends $792 per capita on pharmaceuticals, more than all other OECD countries, and nearly twice the OECD median.12 One might expect this kind of spending to translate in to real health benefits, but U.S. health status, as measured by WHO indicators, only slipped further behind developed nations since 1997 with the highest mortality from causes considered amenable to health care.12

Second, conflicts of interest between drug researchers, the pharmaceutical industry and the FDA, leave consumers vulnerable to untested, scientifically unsound medical practices, the health care system to pay for the billions of dollars spent on medications used for off label purposes, and treatments for their untoward side effects. In an interview with McClatchy Newspapers, Arthur Caplan, Professor of Bioethics, University of Pennsylvania called it a “fox in the hen house situation.”13 The research available to doctors regarding off-label drug treatments is heavily biased by pharmaceutical industry interests—one recent study found 73% of medications prescribed for off-label use had “little or no scientific support.”11 Additionally, FDA drug advisory panels that make recommendations about which drugs should be approved are populated with drug company consultants who have financial ties to the drugs reviewed. In a report published in JAMA in 2006, Public Citizen’s Health Research Group found conflicts of interest occurred in 73% of advisory meetings in 2001-2004.14

As Marcia Angell, former editor of The New England Journal of Medicine and author of The Truth About Drug Companies, recently wrote, “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines.”15

Marketing matters—expanding the target audience

When a drug’s specific indication is narrow and therefore appropriate for a relatively small group of patients, pharmaceutical companies can expand potential user groups and boost sales legally by adding new indicators that have been demonstrated to respond favorably to this medication, using scientifically valid testing procedures. This approach, however, requires FDA approval. As the recent court cases reveal, many drug companies chose to sidestep regulatory authorities and expand their drug’s market share by off-label marketing to doctors.

src=”uploads/images/old_archives/img/Cocktailofdrugs.png” alt=”Cocktailofdrugs” hspace=”10″ vspace=”5″ width=”250″ height=”167″ align=”right” />Blockbuster sales of a product approved for a very limited audience is less likely a measure of drug efficacy than the outcome of powerful marketing campaigns directed at doctors. Whether a medication’s use is expanded legally with FDA approval (as GlaxoSmithKline did with Paxil when its use was extended from treatment of depression to social anxiety disorder), or illegally with off-label marketing (as was the case with Neurontin, Actic, Zyprexa and many others), the result is more people receiving a prescription and consequently sales soar. In the words of Barry Brand, Paxil’s product director at GlaxoSmithKline, “Every marketer’s dream is to find an unidentified or unknown market and develop it.”16

For example, in the case of Zyprexa, indicated uses (for schizophrenia and some bipolar symptoms) occur relatively rarely—between 1-3% of the general population. But when the company began marketing the drug as a treatment for other off-label symptoms, the potential market share was greatly expanded. Documents used as evidence in a Zyprexa court case indicate this was the result of a targeted off-label marketing agenda. In a company meeting, Zyprexa brand manager Mike Bandick said the company “intends, quite simply, to redefine the way [primary care physicians] treat mood, thought, and behavioral disturbances.”17 Eli Lilly’s efforts to convince prescribers that Zyprexa was a good treatment for dementia (and several other disorders) launched the drug into a top selling position—with a total of $39 billion in sales since it hit the market.18

FDA industry ‘Guidance Doc,’ new cause for worry

Before a solution to the above concerns can take shape, there is a new monkey wrench in the off-label drug promotion conflict. In January, during the last days of the Bush administration, policy makers at the FDA issued a ‘Guidance Document’ for the pharmaceutical industry.19 Despite recent court rulings, the document appears to give pharmaceutical companies the thumbs-up to market “unapproved new uses” for FDA approved drugs to doctors. In other words, drug sales reps have the legal ‘ok’ to send prescribers medical articles their company has funded, directly benefiting from the evidence they have produced.

Several health and consumer groups strongly criticized an earlier draft of this FDA guidance. In a 2008 statement,20 the Patient and Consumer Coalition, comprising such organizations as Center for Science in the Public Interest, Consumers Union, National Physician’s Alliance, Our Bodies Ourselves, the Prescription Project and others, asserted that it “strongly opposes this draft guidance, which would allow the promotion of off-label use of prescription drugs and medical devices by giving manufacturers the right to distribute reprints of poorly regulated journal articles with minimal federal oversight.” In the Coalition’s view, “the draft guidance is much too lenient, has no enforcement tools, undermines the Food and Drug Administration’s prohibition on off-label marketing, and lowers incentives for drug and device makers to complete clinical trials or seek FDA approval for new uses.”

Proposed solutions

As the FDA comes under new leadership, several solutions to the problem of off-label marketing warrant consideration.

  1. Enforce existing federal laws and drop the exceptionalism in the new ‘Guidance Document.’ As U.S. Attorney Magid from the Zyprexa case wrote, “Off-label marketing is a sales strategy that ignores the basic purpose of the federal drug-regulatory program, which is to protect the consumer… Off-label-marketing cases are not easy to bring. They can take years and involve the review of millions of documents by an alphabet soup of federal agencies, state regulators, and law-enforcement officers. But we will keep bringing them until this practice stops.”2
  2. Pass new laws that require full disclosure of all drug company payments to physicians. Senators Grassley (R-IA) and Kohl (D-WI) have introduced “The Physician Payments Sunshine Act” that would require pharmaceutical companies to report all marketing and payments to doctors to the Department of Health and Human Services. With increased attention to the need for corporate transparency under the Obama administration and a Democrat led Senate, the bill may have a chance to pass this year.
  3. Provide new incentives and penalties to encourage physicians to report off-label promotional campaigns. Fugh-Berman and Melnick suggest increasing fines, increased marketing regulations and more culpability for physicians. “Perhaps financial incentives could be provided to reward physicians and others who report off-label promotions,” the authors suggest.

 

References

1 Pharmaceutical company Eli Lilly to pay record $1.415 billion for off-label drug marketing. U.S. Department of Justice. Jan 15, 2009. Available at: http://www.usdoj.gov/usao/pae/News/Pr/2009/jan/lillyrelease.pdf

2 Magid L. Keeping us safe from drug reps. The Philadelphia Inquirer. Jan. 27, 2009. Available at:http://www.philly.com/inquirer/opinion/20090127_
Keeping_us_safe_from_drug_reps.html

3 Adams C. Bush admin opened door to controversial off-label marketing of drugs. McClatchy-Tribune News. Feb 1, 2009. Available at: http://bulletin.aarp.org/yourhealth/policy/articles/bush_administration
_opened_door_to_controversial_offlabel_marketing_of_drugs.html

4 Warner-Lambert to pay $430 million to resolve criminal and civil health care liability relating to off-label promotion. U.S. Department of Justice. May 13, 2004. Available at: http://www.usdoj.gov/opa/pr/2004/May/04_civ_322.htm

5 Attorney General Announces $6.15 Million Settlement For Illegal Drug Marketing. Connecticut Attorney General’s Office. September 29, 2008. Available at: http://www.ct.gov/ag/cwp/view.asp?a=2795&q=423868

6 Prescription Drug Trends – Fact Sheet. Kaiser Family Foundation. Sept 2008.

7 Ackerman R. Eli Lilly’s Zyprexa sales are depressing. Forbes. April 21, 2008. Available at:http://www.forbes.com/2008/04/21/elililly-pharma-diabetes-markets-equity-cx_ra_0421markets10.html

8 Goozner M. The $800 Million Pill: The Truth behind the Cost of New Drugs. University of California Press; 2004.

9 Patient information sheet: Olanzapine (marketed at Zyprexa). FDA Center for Drug Evaluation and Research. Sept 2006. Available at: http://www.fda.gov/cder/drug/InfoSheets/patient/olanzapinePIS.htm

10 Domino ME, Swartz MS. Who Are the New Users of Antipsychotic Medications? Psychiatric Services. 2008;59(5):507–14.

11 Radley DC, Finkelstein SN, Stafford RS. Off-label Prescribing Among Office-Based Physicians. Arch Intern Med. 2006;166:1021-1026.

12 Towards a High Performing Health Care System: An International Perspective. The Commonwealth Fund. Presentation by Robin Osborn. October 20, 2008.

13 Adams C. Late move on drugs by Bush FDA could be dangerous. McClatchy-Tribune News. Feb 1, 2009. Available at:http://www.mcclatchydc.com/244/story/61113.html

14 Lurie P, Almeida C, Stine N, Stine A, Wolfe S. Financial Conflict of Interest Disclosure and Voting Patterns at Food and Drug Administration Drug Advisory Committee Meetings. JAMA. 2006;295:1921-1928.

15 Mossakowski KN. Is the duration of poverty and unemployment a risk factor for heavy drinking? Soc Sci Med. 2008;67(6):947-55.

16 Vedantam S. Drug Ads Hyping Anxiety Make Some Uneasy. Washington Post. July 16, 2001; Page A01. Available at:http://vedantam.com/socialanxiety07-2001.html

17 Zyprexa Primary Care Presentation. Eli Lilly National Sales Meeting. Mar 13, 2001. Available at:http://www.furiousseasons.com/zyprexa%20documents/
ZY100041630.pdf

18 Levine B. The Case for Giving Eli Lilly the Corporate Death Penalty. AlterNet. March 3, 2009. Available at:http://www.alternet.org/workplace/129709/eli_lilly_and_the
_case_for_a_corporate_death_penalty/

19 Good reprint practices for the distribution of medical journal articles or medical scientific reference publications on unapproved new uses of approved drugs and approved or cleared medical devices. Department of Health and Human Services. Food and Drug Administration. Office of the Commissioner. Jan 2009. Available at:http://www.fda.gov/oc/op/goodreprint.html

20 Comments of the Patient and Consumer Coalition to the U.S. Food and Drug Administration “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices DRAFT GUIDANCE Docket No. FDA-2008-D-0053.” April 18, 2008. Available at: www.cspinet.org/new/pdf/20080421_group_comments_on_fda_off-label_draft_guidelines.doc

21 Fugh-Berman A, Melnick D. Off-label promotion, on-target sales. PLoS Med. 2008;5(10):e210.

 

Photo Credits:
1. hughelectronic 
2. dust
3. hippie

Tracking on Corporations and Health

Those seeking to modify corporate practices that harm health often have to track changes in corporate or government policy to assess their progress. Here, Corporations and Health Watch describes a few databases and websites useful for tracking local and nation policy and the social responsibility performance of major corporations.

Tracking local policies:

Looking for policies to propose to solve a local problem related to food industry practices that reduce access to healthy food? Visit Prevention Institute’s Local Policy databasean online resource of local policies that can improve opportunities for healthy eating and physical activity. For example, a search for policies on unhealthy foods located 21 specific local policies, mostly in California, enacted to reduce promotion of unhealthy foods.

 

Tracking federal legislation:

Open Congress tracks legislative proposals and bills on various issues and industries. Its website explains different ways to use the site. For example, OpenCongress bill pages bring together news coverage, blog buzz, insightful comments, and more. Linking to OpenCongress thus gives readers access to the big picture as well as the official details on specific legislative proposals. If you write a blog post about a bill and include the official title (for example, H.R.800), then a link to your blog post will appear on that bill page. Another section shows the most-viewed bills, or hot bills by issue area. The site includes one-click sharing to Digg, StumbleUpon, Facebook, e-mail a friend, and more. It also allows visitors to find their members of Congress and to track their actions and what people are saying about them.

To illustrate topics of interest to Corporate and Health Watch readers, visitors can track legislative proposals on the following topics, among many others:

Alcohol taxes
Automobile industry
Firearms
Food industry
Pharmaceutical research
Tobacco industry

 

Tracking corporate responsibility:

Several organizations have ranked corporations on their social responsibility.

Fortune Magazine ranks 100 of the Fortune 500 on business responsibility.

The Ethics & Policy Integration Centre provide a user-friendly resource for tracking US and emerging global standards in corporate responsibility. It includes sections on environmental and human righs standards, but not health or consumer protection standards.

Corporate Responsibility Index The British group Business in the Community’s CR Index is the United Kingdom’s leading benchmark of responsible business. It helps companies to integrate and improve responsibility throughout their operations by providing a systematic approach to managing, measuring and reporting on business impacts in society and on the environment. Each year the CR Index lists and rates the top 100 companies in the UK.

 

Fixing the FDA: Options for the Next President

The last several years have not been kind to the Food and Drug Administration (FDA). Critics have accused the agency of being inefficient, failing to meet its mandates and of complicity with the pharmaceutical industry. The FDA has come under attack by Congress, health and medical professionals and the pharmaceutical, tobacco and food industries. One director was forced to quit and the current director has repeatedly been summoned by Congressional committees to respond to criticisms.

With the 2008 presidential election quickly approaching, the topic of health care, including the safety of pharmaceuticals, has gained increasing attention. The next United States President will face great pressure to reform the FDA and will need to simultaneously attend to issues of efficiency, drug and food safety, tobacco and funding. How the President and Congress choose to respond to industry calls to make the FDA even more business friendly and advocates calls for restoring the FDA’s public health mandates will shape how a key federal agency will regulate corporate practices that influence health in the next four years.

This Corporations and Health Watch story begins a series examining recent conflicts about the FDA, the positions of the presidential candidates on the agency and options for 2009 and beyond. This report’s focus is on the FDA and the pharmaceutical industry. Future reports will examine the role of the FDA in regulating food and tobacco.

Drug Safety

Vioxx

The FDA’s recent troubles with Vioxx, Avandia and Heparin illustrate the range of problems the agency faces in premarket testing, oversight of foreign industries and on limiting industry influence on its decisions. In Fall of 2004, pharmaceutical giant Merck began the largest and most expensive drug recall in history by pulling its drug Vioxx off the market after studies showed that chronic use was associated with an increased risk of heart attacks and strokes. Approved in 1999 based on data submitted to the FDA but not reviewed through the standard scientific peer review, Vioxx is reported to have caused as many as 139,000 heart attacks.1

Although Merck was initially praised for its voluntary withdrawal of the product, critics later charged that Merck had known about the risks involved with long-term use far earlier than it had gone public with them.1 Merck was eventually shown to have ignored research published three years earlier, which found that long-term Vioxx use increased risk of cardiovascular events, and to have planted studies in medical journals that were attributed to independent researchers.2 Whistleblower and 20 year employee of the FDA David Graham later testified that the agency’s role in the Vioxx scandal was far from innocent, stating: “What happened with Vioxx is really a symptom of something far more dangerous to the safety of the American people. Simply put, the FDA and its Center for Drug Evaluation and Research are broken.”1

Avandia

In June 2007, the New England Journal of Medicine published a meta analysis of 42 clinical trials for Avandia that showed that the drug was associated with increased risk of myocardial ischemic events.3 It wasn’t until five months later that the FDA announced additional warnings on the Avandia product label. In addition, an advisory committee voted to keep the product on the market despite a later study published in the Journal of the American Medical Association which concluded that Avandia was associated with increased risk of acute myocardial infarction, congestive heart failures and mortality in older patients undergoing diabetes treatment.4

Heparin

Earlier this year, the FDA was criticized for failing to protect Americans against a contaminated supply of the blood thinner Heparin. At least 19 people died and hundreds became sick after consuming the contaminated product that had been imported from China. The Heparin case raised questions about the agency’s ability to regulate and inspect a growing flow of imported drugs and drug ingredients.

Compounding the problem of limited resources for plant inspections, FDA policies do not extend to the foreign study sites that produce more than 20% of clinical trial data submitted to the FDA.5 Moreover, at present, 80% of all active drug ingredients are imported.6 Finally, the FDA has reported an 800% increase in the number of cases of counterfeited pharmaceutical ingredients between 2000-2006.7 Exacerbating the already flawed foreign inspection process is the fact that the FDA does not bring its own translators or hire independent ones but rather relies on English-speaking representatives of the plants it visits to translate during the inspection process.

The Government Accountability Office stated that in order for the FDA to complete full inspections of foreign plants, it would require more than $56 million in additional funds with $15 million required to inspect Chinese plants every two years.8 The New York Times reported that at the current inspection pace, the FDA would need “at least 27 years to inspect every foreign medical device plant that exports to the United States, 13 years to check every foreign drug plant and 1,900 years to examine every foreign food plant.”8 Though the Bush Administration stated there were plans to improve the FDA’s ability to conduct foreign inspections, no funds were allocated for this purpose in President Bush’s yearly budget.

In order to apply for approval, drug companies must conduct clinical trials of products under development. However, the FDA does not require that these clinical trials be published and are therefore not subject to peer review. Mandated by the 1997 Food and Drug Administration Modernization Act (FDAMA), in 2000 the FDA created a national clinical trial registry for pharmaceutical corporations to submit clinical trial data. FDAMA required manufacturers to register their clinical trials at clinicaltrials.gov and to give a detailed account of both their experiments and eligibility requirements for research subjects. However, the FDA neither enforced compliance nor encouraged use of the clinical trial registry. While some manufacturers, such as Merck, did register their clinical trials, they only reported results that favored their products as they are not required to submit raw data. This led to suppression of full information about the efficacy and safety of new products under development.1

The FDA seems to be increasingly entangled with industry in ways that affect the process of review and regulation. For example, the Agency has frequently delayed the release of information about potential health effects of approved medical products. In the case of the Ortho Evra birth control patch manufactured by Johnson & Johnson that was linked to increased risk of blood clots and strokes and resulted in 50 deaths, the FDA did not make public these risks until six years after Johnson & Johnson’s own study showed such an association.9 After numerous lawsuits were filed against the manufacturer, Johnson & Johnson utilized the legal argument of pre-emption, claiming it could not be sued because the FDA had approved the patch and warning label. Testifying at a trial over the schizophrenia drug Zyprexa, former FDA scientist Dr. John Gueriguian who worked at the agency for two decades stated that the FDA did not always pursue strong warnings on products considered potentially dangerous, in part, because the pharmaceutical industry objects to warnings: “We at the FDA know what we can obtain and what we cannot obtain – and what we can’t obtain we will not ask.”9 By withholding negative findings, then using the FDA approval based on this limited information to preempt litigation from those harmed, the drug industry has made the FDA its ally in avoiding liability.

Under-funded, Understaffed and Overtaxed

Responsible for the safety of the nation’s food and drug supply, it might strike the American public as odd that the FDA budget is less than that of the school board of Montgomery County—the county in which the FDA is located.10 The FDA, particularly under the Bush Administration, has been chronically underfunded while at the same time it has been saddled with increasing responsibility.

The Prescription Drug User Fee Act (PDUFA) has been the source of both funding and controversy for the FDA. Adopted in 1992, the act requires pharmaceutical and biological products makers to pay fees for product applications and supplements. These fees are used to hire staff to assist in reviewing product applications, thus accelerating the process of drug approval. Though some have argued that user fees provide a vital source of revenue for an already underfunded agency and have suggested their application to overseas producers, a widely cited New England Journal of Medicine study suggested that PDUFA deadlines affect the safety of approved drugs with those approved right before a deadline being less safe than drugs approved at other times.11 By rushing through product applications, the FDA opens itself to the potential for an increase in recalls. PDUFA must be renewed every five years and over time has become more controversial. Public health critics of the PDUFA argue that it makes the FDA increasingly susceptible to industry pressure. Industry officials have critiqued user fees as unfair as the government is responsible for safety reviews.

Given these uncertainties about both the ability of the FDA to regulate the drug industry and the influence of Big Pharma on the agency through the use of such fees, the agency lost funding for a direct-to-consumer advertising fee provided by the FDA Amendments Act (FDAAA). Legislators also axed $1 million in funding for the new Reagan-Udall Foundation, a foundation created by Congress to work independently from the FDA to enhance product safety and innovation.

With a woefully inadequate budget and what many FDA staff characterize as a demoralizing work environment, the agency faces staff shortages that limit its ability to carry out inspection and regulation tasks properly. In 1997, Congress gave the FDA funding to support more than 9,000 scientists; today the number actually employed is less than 1,000.10 Further, the FDA is not able to match salaries in the private sector making it difficult for the agency to attract top candidates. Under the Bush Administration, the FDA has faced reduced funding and has lacked consistent leadership, often operating without a confirmed commissioner. Drug scandals and low morale have also lead to increased resignations, with many former employees citing pressure to express status quo scientific opinions and a belief that their work supported marketability more than health as reasons for leaving.12 A 2006 Union of Concerned Scientists survey of 5,918 FDA scientists found 1 in 5 reported that they experienced pressure from top-level FDA employees to gear their work according to political and corporate interests.13 Understaffing is also linked to slowdowns in drug approval rates with 19 new drugs being approved in 2007 compared to 53 approved in 1996.14

During this same period, Congress and the President gave the FDA more responsibility. For example, in the fall of 2007, Congress gave the agency increased power to regulate drug safety and data disclosure. However, the ability of the FDA to take on additional responsibilities is hindered not just from lack of adequate funding and high rates of turnover but also by an inefficient organizational climate. As a case in point, the FDA currently uses more than 300 non-compatible databases and has not created a centralized system which would allow researchers, medical professionals and the general public to access clinical trial information efficiently.1 The Office of the Inspector General (OIG) in the Department of Health and Human Services (HHS) has stated that the lack of an efficient FDA information system has hampered its ability to properly oversee research. Because of this, the FDA inspects less than 1% of clinical trials and less than 300 Institutional Review Boards (IRB) each year.14

Challenges from Across the Political Spectrum

The FDA has been a frequent target on Capitol Hill, in the press and from public health advocates. Democratic lawmakers have called for increases in user fees in order to improve surveillance and inspections. Earlier this year Representative Bart Stupak (D-MI), the chairman of the House Energy and Oversight and Investigations subcommittee, called for acting FDA commissioner Andrew von Eschenbach and other FDA officials to resign due to their “total lack of leadership.”14 Referring to scandals over Sanofi-Aventis’ antibiotic Ketek which caused liver damage and other serious side effects, Senator Charles Grassley (R-IA) stated, “There were sirens, red flags, and bullhorns, but it looks like the company and the FDA kept ear plugs and blinders on.”7

Public health advocates commonly critique FDA review and regulatory procedures as serving industry at the expense of public health. Consumers Union, Consumer Federation of America, US PIRG and others have repeatedly argued that the FDA has not adequately protected the American public from dangerous medical and food products and has charged the Bush Administration as crippling an already weak system. In a March 2005 joint letter to the committee charged with reviewing Dr. Lester Crawford to be the Commissioner of the FDA, the three agencies noted that the FDA suffers from a lack of adequate authority to regulate the pharmaceutical industry, from conflicts of interest which prohibited the public release of important research findings, and from the data reporting procedures which favor industry at the expense of peer review and open information.15 Similarly, in April 2008, the Prescription Project, Community Catalyst, National Physicians Alliance, Prescription Access Litigation, Community Catalyst and US PIRG gave comments urging the FDA not to adopt the draft guidance that would have allowed pharmaceutical representatives to distribute single studies to medical providers on the benefits of off-label drug use.16 The coalition called for hearings on what circumstances, if any, should allow for such practices but noted that as the draft guidance was currently constituted, it would benefit industry at the expense of good science and public health and safety. Also in April, Consumers Union Policy Counsel Ami Gadhi testified before the US House of Representatives Subcommittee on Health, Energy & Commerce Committee that “the call for a major overhaul of the FDA has now become a roar.”17

In March of 2005 the Center for Medical Consumers, Center for Science and the Public Interest, Command Trust Network, National Research Center for Women & Families, National Women’s Health Network and US PIRG launched a media campaign including a now defunct website www.FixTheFDA.org, television and print ads detailing the flaws in the FDA regulation system. On one campaign flyer, the groups argued, “Unfortunately, the FDA is broken. The public’s health is being compromised to the point of negligence. The current Vioxx controversy is just the latest symptom of a system in crisis. It’s not all the agency’s fault. Congress has reduced the FDA’s authority, slashed enforcement budgets, and weakened its legal powers.” The groups then called for Congress to close loopholes and fix the FDA before further scandals occurred.

Conservatives arguing from a free-market perspective have suggested that the FDA cannot be reformed and should be abolished. Libertarian new source The Freeman, a publication of the Foundation for Economic Education, has argued that the FDA operates as a legally protected monopoly and that increasing the powers of and funding for the FDA will only exacerbate problems with the fledgling agency. In July of 2005 Freeman author Arthur E. Foulkes claimed that overcautious regulatory and review practices at the FDA kept important medications from market and from helping those who might be benefited by them: “How free is a land in which bureaucrats and politicians decide which health-care options are legal and which is not? No one is made better off by having peaceful options in life denied him. The FDA is beyond being reformed. It should be abolished.”18 In a later Freeman piece, author Larry van Heerden echoed the critiques of public health advocacy groups, noting the impact of user fees and corporate influence on the ability of the FDA to operate efficiently and objectively. However, rather than calling for increased reform and stricter standards to reduce corporate influence, van Heerden argued for abolishing the FDA in support of a free-market system and the responsibility of consumers to be self-informed: “In a system without such gate keeping, where drugs were available along with all the information on risks and benefits, the market would sort out the wheat from the chaff, dramatically lowering the financial stake in any single drug and reducing the tendency for drug companies to engage in fraud and deception.”19

Conservative critiques of the FDA are not new. In the early 1990s a coalition of conservative organizations raised concerns over the FDA regulatory process, particularly questioning agency restrictions on off-label use of medication and the slow rate of new drug approval. Industry leaders and conservative commentators continue to point to the slow down in approval rates as signs of ineffectiveness and an overly-cautious regulatory environment caused, in part, by a bevy of recent scandal over approved pharmaceuticals such as Vioxx. Though the FDA argues that new drugs will have to show marked safety or efficacy advantage over existing drugs in order to gain approval, industry officials claim that slowdowns increase development costs and inhibit competition by blocking new drugs from entering the market and taking market share away from established drugs. Despite overall arguments defending current approval procedures for new drugs, even the FDA’s own Science Board acknowledges that slowdowns in approval for new medical technologies and pharmaceuticals has a negative impact and “means that American lives are at risk.” 20

The FDA responds to its critics

The FDA has both defended itself against its critics and acknowledged deep structural issues that prohibit it from functioning properly. Facing increasing criticism, in 2005 the FDA asked the Institute of Medicine (IOM) to assess the safety of the U.S. drug system. The IOM released its report, “The Future of Drug Safety: Promoting and Protecting the Health of the Public” in September 2006 noting that the “perception of crisis” has compromised the credibility of the FDA and of the pharmaceutical industry;” that there is widespread agreement amongst stakeholders to improve the drug safety system; that the current system is currently hindered by “serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety” as well as a less than optimal organizational climate and insufficient and unclear regulatory authority; and a lack of transparency on the part of both the FDA and the drug industry to communicate safety concerns in a timely and appropriate manner.21 In response to the report, the FDA stated it would take steps to improve the integrity of the science behind the entire process of medical product safety; to improve risk communication policies and procedures; and to strengthen management and operations in order to ensure an effective U.S. drug safety system.22

The 2008 Presidential Election and the Chance for Reform

In their review of the history of the FDA, Borchers et al (2007) note that the “evolution of the FDA can be described as a series of ‘crisis-legislation-adaptation’ cycles: a public health crisis promoted the passage of congressional legislation, which was then followed by implementation of the law by the FDA.”23 Though this pattern reflects the history of the FDA at large, the authors note that current crises and challenges facing the FDA are so severe that only “strong and permanent leadership willing to redefine the role and procedures of the FDA” will be successful in getting the agency back on track. With the 2008 presidential campaign approaching and the state of the FDA in near permanent crisis, neither Democratic candidate Barack Obama nor Republican challenger John McCain have staked out strong positions on the FDA.

Senator Obama’s website offers some information about his stance on prescription drugs. His primary focus is on reducing the cost of prescription drugs by increasing the amount of safe pharmaceuticals imported from the developing world and increasing the amount of generic medications available on the market. While Obama notes the importance of breaking up insurance monopolies that drive up premiums, he does not call for similar moves in the pharmaceutical industry. Further, Obama takes no official stance on the FDA at large, plans to increase the safety of imported drugs or prescription drug marketing.

By comparison, in her campaign, former Democratic challenger Hillary Clinton, commented at more length on FDA issues. On the need for FDA reform, Clinton stated on her website: “Recently, concerns have been raised about the ability of the FDA to ensure the safety of drugs marketed to American consumers. I believe there is a clear need for post-marketing monitoring.”24 Like Obama, Clinton proposed to lower prescription drugs through the promotion of generic medicines and the importing of safe drugs from developing countries. To reduce prescription drug prices, Clinton argued for breaking up pharmaceutical monopolies to create generic competition. On the safety of drug imports, Clinton critiqued the Bush Administration for its failure to protect the American people from unsafe pharmaceutical imports:

If George Bush won’t start that process now, I will when I am President. As I laid out in my import safety agenda, I will require that foreign drug makers produce a certification that they have met American safety standards as a condition of import into the United States, confirmed by independent testing and inspection. I will open permanent FDA oversight offices in at-risk countries like China so that episodes like this one are not repeated. I will require foreign drug makers to accept random, surprise inspections, rather than notifying them in advance – and giving them a chance to clean up their act — as we do now. And I will stiffen civil and criminal penalties for violators. It is a basic obligation of government to protect its citizens. Americans can count on me as President to protect the food we eat, the toys our children play with and the drugs we take to make us healthy, not sick.25

Finally, Clinton noted that for every direct-to-consumer marketing dollar spent, pharmaceutical sales increased by $4.20. To address this issue, she suggested limiting such advertising, instituting a reporting requirement for financial arrangements between providers and industry, and protecting information about the prescribing practices of medical providers from being sold to drug manufacturers.

Senator McCain offers little information about his views on the FDA and the need for its reform on his presidential website. Like the Democratic challengers, McCain calls for increased imports of pharmaceuticals and faster genetic drug approvals. On McCain’s Senate website, transcripts of statements given to the Senate provide more information. In July 2002, McCain urged the Senate to pass the “Greater Access to Affordable Pharmaceuticals Act.” In his testimony, McCain argued against current pharmaceutical monopolies and for increased generic competition. In order to effect such a change, McCain argued: “This should not be done by imposing price controls or creating a universal, government-run health care system. Rather, a balance must be found that protects consumers with market-based, competitive solutions without allowing those protections to be manipulated at the consumers’ expense, particularly senior citizens and working families without health care insurance.”26 In support of the “Pharmaceutical Market Access and Drug Safety Act of 2004,” McCain specifically addressed the safety of drug imports noting, “To ensure the safety of this new system, the FDA would be required to regularly inspect Canadian exporters as well as domestic importers. The legislation also would require all importers and exporters to maintain a full chain of custody, or pedigree, for the drugs imported into the U.S.”27 Finally, in February 2005, McCain supported the “The Pharmacy Market Access and Drug Safety Act of 2005,” which would lower the cost of imported prescription drugs. He stated: “None of us have any illusions that enacting drug importation legislation will easy. Powerful special interests will continue to try to block us every step of the way. However, this is a battle worth fighting and winning for American consumers.”28

In a February 2008 blog entry from EyeOnFDA.com, Mark Senak of marketing and communications giant Fleishman-Hillard, briefly compared the positions of presidential candidates at that time on the FDA. He noted,

All of the candidates also tend to agree that they want to bring in new technology and devices to manage information, cultivate more prevention programs and to improve the quality of healthcare. But what was perhaps most surprising was the fact that as much as the candidates differ on the details of these reforms, they were nearly all in favor of two changes that would have a hefty impact on the pharmaceutical market place – Medicare Part D reform and the importation of prescription drugs. In other words, change with this election cycle is of course, inevitable, but it is also highly possible, if not probable, that candidates from both political parties will embrace these two reforms. To me, that was news. 29

Certainly it seems then that regardless of the winner of the next US presidential election, Americans can expect increased attention to the lowering the price of pharmaceutical products by increasing imports and access to generic medicines. However, neither Obama nor McCain have articulated their positions on the necessity for deep structural reform within the FDA and the need for creative solutions for both a source and level of funding that would allow the agency to properly review and inspect domestic and foreign food and drug applications, data and manufacturing plants.

In the coming months, health advocates may want to press the candidates to explain in more detail their positions on the FDA. More generally, the presidential candidates and those running for Congress will need to articulate how they propose to change the cozy relationship between the pharmaceutical industry and the FDA in order to allow the agency to fulfill its original mandate. Unless the next US President and Congress take a strong stand on the need for FDA reform and a transformation of the relationship between the FDA and the industries it regulates, it is likely that the trends of the past, crisis—legalization—adaptation, will continue at the expense of American health and public safety.

References

1. Dohrman, AJ. Rethinking and Restructuring the FDA Drug Approval Process in Light of the Vioxx Recall. Journal of Corporation Law. 2005;31(1):203-223.
2. Mukherjee, D; Nissen, SE; Topol, EJ. Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors. JAMA. 2001;286(8):954-959.
3. Nissen, SE; Wolski, K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. New England Journal of Medicine. 2007; 356(24):2457-2471.
4. Lipscombe, LL; Gomes, T; Lvesque, LE; Hux, JE, MSc; Juurlink, DN; Alter, DA. Thiazolidinediones and Cardiovascular Outcomes in Older Patients With Diabetes. JAMA. 2007;298(22):2634-2643. Wechsler, J. FDA Hit for Poor Clinical Oversight. Applied Clinical Trials. 2007;16(11):30-35.
5. Wechsler, J. FDA Hit for Poor Clinical Oversight. Applied Clinical Trials. 2007;16(11):30-35.
6. Washington Post. Fixing the FDA: Lack of funding inhibits crucial drug inspections abroad. Friday, March 7, 2008; A16.
7. Loewenberg, S. US FDA Feels the Heat from Congressional Hearings. The Lancet. 2008; 371:1565-1566.
8. Gardiner, H. U.S. Identifies Tainted Heparin in 11 Countries. New York Times. April 22, 2008.
9. Harris, G; Berenson, A. Drug Makers Near Old Goal: A Legal Shield. The New York Times. April 6, 2008.
10. Hubbard, W. The Overwhelmed FDA. The Boston Globe. June 3, 2007.
11. Carpenter, D; Zucker, EJ; Avorn, J. Drug-Review Deadlines and Safety Problems. New England Journal of Medicine. 2008;358(13):1354-1361.
12. Ross, W. What’s Up with the FDA? Medical Marketing & Media. 2008. Accessed at: http://www.mmm-online.com/Whats-Up-with-the-FDA/article/104861/
13. Union of Concerned Scientists. FDA Scientists Pressured to Exclude, Alter Findings; Scientists Fear Retaliation for Voicing Safety Concerns Public Health and Safety Will Suffer without Leadership from FDA and Congress. 2006. Accessed at: http://www.ucsusa.org/news/press_release/fda-scientists-pressured.
html
14. Wechsler, J. Attacks on FDA Escalate. Pharmaceutical Technology. May 2, 2008. Accessed at: http://pharmtech.findpharma.com/pharmtech/Washington+Report/
Attacks-on-FDA-Escalate/ArticleStandard/Article/detail/515161?context
CategoryId=484
15. Consumers Union; Consumer Federation of America; US Public Interest Group. March 15, 2005. Accessed at: http://www.pirg.org/consumer/pdfs/crawfordfda.pdf
16. Prescription Project; Community Catalyst; National Physicians Alliance; Prescription Access Litigation; Community Catalyst; US PIRG. Comments Concerning the United States Food and Drug Administration Draft Guidance for Industry “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.” Docket No. FDA-2008.D.0053. April 21, 2008.
17. Consumers Union. Statement of Ami Gadhia Concerning Discussion Draft of “FDA Globalization Act” Subcommittee on Health, Energy & Commerce Committee U.S. House of Representatives. May 1, 2008. Accessed at: http://www.consumersunion.org/pub/core_product_safety/005598.html
18. Foulkes, AE. The FDA Cannot be Reformed. The Freeman. July 1, 2005.
19. van Heerden, L. Abolishing the FDA. The Freeman. March 1, 2007.
20. Harris, G. Advisers Say F.D.A.’s Flaws Put Lives at Risk. The New York Times. December 1, 2007.
21. Institute of Medicine. The Future of Drug Safety: Promoting and Protecting the Health of the Public. September 22, 2006. Accessed at: http://www.iom.edu/?id=37339
22. Food and Drug Administration. The Future of Drug Safety: Promoting and Protecting the Health of the Public. FDA’s Response to the Institute of Medicine’s 2006 Report. Accessed at: http://www.fda.gov/oc/reports/iom013007.pdf
23. Borchers, AT; Hagie, F; Keen, CL; Gershwin, ME. The History and Contemporary Challenges of the US Food and Drug Administration. Clinical Therapeutics. 2007; 29(1):1-16.
24. Clinton, H. Accessed at: http://clinton.senate.gov/issues/health/
25. Clinton, H. Clinton Responds to FDA Tripling Its Estimates For Heparin-Related Deaths. April 9, 2008. Accessed at: http://www.hillaryclinton.com/news/release/view/?id=6989
26. McCain, J. McCain Urges Senate to Pass Generic Drug Bill Quickly. July 17, 2002 Accessed at: http://mccain.senate.gov/public/index.cfm?FuseAction=PressOffice.
Speeches&ContentRecord_id=aa8ace59-666d-4d42-aad7-caab
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27. McCain, J. Pharmaceutical Market Access and Drug Safety Act of 2004. April 21, 2004. Accessed at: http://mccain.senate.gov/public/index.cfm?FuseAction=PressOffice.
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28. McCain, J. McCain Continues to Fight for Lower Prescription Drug Costs. February 9, 2005. Accessed at: http://mccain.senate.gov/public/index.cfm?FuseAction=PressOffice.
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29. Senak, M. Where the Candidates Stand – A Side by Side Comparison and Conclusion. January 02, 2008. Accessed at: http://www.eyeonfda.com/eye_on_fda/2008/01/where-the-candi.html

Photo Credits:

1. MooN
2. goodmosconi
View CHW’s coverage on Corporations, Health and the 2008 Presidential Race:

Part 1: Following the Money
Part 2: Clinton, Obama and McCain on the Role of Corporations
Part 3: Clinton, McCain, Obama and the Food Industry

“Because You Want More Life to Live:” BiDil, a Heart Failure Prescription for “Self-Identified Blacks”

In June 2005, the US Food and Drug Administration made history by approving the patented pharmaceutical BiDil to treat African American patients suffering from congestive heart failure. BiDil, whose generic name is isosorbide dinitrate/hydralazine hydrochloride, is not the first race-specific pharmaceutical (that distinction may belong to Travatan, a brand of eye drops marketed to black patients1) — but it is the first race-specific pharmaceutical to be awarded federal approval.

Its appearance sparked controversy in the medical and bioethics communities, as some lauded the drug’s development and others deemed it a designer drug that sanctioned racial profiling in medicine2 and loaned credibility to the concept of race as biology. This flurry of excitement was matched in the market: anticipation of the drug’s release caused the value of shares in NitroMed, the company that owned the patent to BiDil, to more than triple in the months leading up to the FDA’s announcement.

Citing the medical establishment’s historic neglect of African American patients, NitroMed has promoted BiDil as a bold step by the pharmaceutical industry and a path-breaking effort to reverse long-standing racial health disparities in heart failure. The drug’s development was also hailed by the NAACP and the Association of Black Cardiologists. But in an article written forScientific American, Jonathan Kahn, expert on race and bioethics, lambasted BiDil’s passage to market as a tangled tale of inconclusive studies, regulatory hurdles and commercial motives.3 Kahn pointed out that BiDil is not a new drug, nor was it initially designed for use in black patients. It is a combination of two generic vasodilators, hydralazine and isosorbide dinitrate (ISDN), which increase the bioavailability of nitric oxide, relax blood vessels, and relieve stress on the pumping heart. H/I was patented as BiDil after a series of pharmaceutical trials appeared to confirm its worth as an improved therapy to treat congestive heart failure in self-identified black patients. This claim rests on three assumptions, each to be examined here. First, the claim asserts that the drug is more effective in black patients than in other patients; second, it posits that heart failure is overrepresented among black patients; and finally, it assumes that black is a meaningful category in medicine. The critique of Bidil challenges these assumptions and argues that they promote structural inequalities in health care and misrepresent sociological determinants as biological facts.

1. Shown to Save the Lives of Black Heart Failure Patients

BiDil’s designation as a race-specific drug results from an attempt to justify the patenting of generic drugs, and in order for this to be accomplished, its innovator was required to manipulate the research design of the pharmaceutical trials that appeared to prove H/I’s efficacy in only certain patients. Jay Cohn, a University of Minnesota cardiologist who began using hydralazine and ISDN in combination to treat heart failure, was unable to secure a patent on the two generics, and also failed in an early attempt to secure FDA approval of the H/I combination. Retrospectively reviewing data from earlier trials, Cohn sought to prove that a sub-population had shown strong response to treatment. Leveraging the results of a prior trial which had enrolled just 49 African Americans, Cohn applied for a patent on the use of H/I to treat heart failure in black patients. Approved in 2000, the patent will last until 2020.3

Subsequently, Cohn organized the African American Heart Failure Trial (A-HeFT) in 2004 with a study population of 1,080self-identified black heart failure patients4 at 150 different study sites, including Morehouse Medical School and other historically black institutions.5 The study’s early results were remarkable: the active arm of the study experienced a 43% reduction in mortality, and the data and safety monitoring board of the study determined that it would be unethical to deny the drug to participants who were receiving only standard contemporary modern care. The trial was halted at the 8-month mark to provide H/I to all participants.5

At the conclusion of the African-American Heart Failure Trial, the investigators filed a new application for the therapy’s approval with the FDA. In just months, the FDA decided to approve BiDil, satisfied the drug had been shown to decrease mortality, to reduce hospitalization, and to improve patients’ functional status, and to slow the progression of heart failure in self-identified blacks.5 But because the A-HeFT included only self-identified black patients, it could not confirm whether BiDil is more effective in black patients than in any other population. The frequently cited hypothesis that H/I would yield similar results in patients of other racial groups remains untested.

2. African Americans: At High Risk for Heart Failure?

A fact sheet from NitroMed’s public relations office states that an estimated 750,000 African Americans are currently diagnosed with heart failure, with the number expected to increase to nearly 900,000 by 2010.6 Elsewhere, NitroMed claims that African-American heart failure patients are disproportionately over-represented in the North American heart failure population and that African Americans aged 45-64 face a mortality risk more than twice that of white heart failure patients.7

While these statistics appear to confirm the popularly held belief that African Americans are prone to suffer cardiac conditions more than other racial groups, NYU sociologist Troy Duster argues that NitroMed’s use of these data is misleading. The age group 45 to 64 only accounts for about 6% of heart failure mortality, and for those over 65, the statistical differences between ‘African Americans and Caucasians’ nearly completely disappear.8 This statement is backed up by CDC data showing that heart-failure-related mortality among African Americans has actually declined since 1988, and that this rate of decline outpaces the decreasing level of heart-failure-related death rates in the Caucasian population.9 Apparently, NitroMed is culling data to create the impression that all African Americans are at high risk for heart failure and premature death.

In the Common Questions portion of its website, NitroMed answers the question Why are African Americans at greater risk for heart failure? in two sentences:

Two well-known contributors to the increased risk are much higher rates of high blood pressure and diabetes in the African American community. Other potential risk factors being explored are African Americans’ lower access to and use of health care services, greater exposure to environmental pollutants, and greater tendencies to be overweight and to get less exercise.10

Interestingly, this statement does not mention genetic risk factors, although NitroMed is currently supporting research to isolate gene sequences related to heart failure. However, heart failure is not a genetic disease. As NitroMed correctly states in its own FAQ, the etiology of heart failure is shaped by multiple inputs. As anthropologists W.W. Dressler and colleagues propose, attempts to link hypertension rates in African Americans to single variables (genetic factors, higher rates of obesity and smoking, and socioeconomic status) have failed to explain race-bound health disparities completely.11 And as Troy Duster has argued, the role of racism in the heart health of African Americans may represent the most meaningful link between race and disease prevalence.12 In short, the marketing of BiDil is a misguided – or cynical – attempt to medicalize the stress of racism, and to convert a social problem into profit.

3. Target Markets and Self-Identified Blackness

Finally, the FDA’s approval of BiDil raises a practical problem: How are doctors to determine who is black? Though BiDil’s legally approved patient population consists of self-identified blacks, Bidil.com uses the term African-Americaninterchangeably with black, and company personnel are slippery on the issue of who is eligible for the prescription. In response to a query, a NitroMed representative wrote:

If a multiracial or a dark skinned individual decides that they are a self identified black and a physician believes that BiDil is an appropriate option for their heart failure, then they would be an appropriate candidate for BiDil.13

Self-identified black is a catch-all category that could include patients whose origins are African American, Melanesian, or South African, but the A-HeFT’s study design recognized no distinctions between such populations: a patient might have joined the A-HeFT on the basis of ancestral, regional, genetic, phenotypic, or even cultural blackness. Sidestepping responsibility for racing its participants, the study design of the A-HeFT did not require researchers to confirm that a study participant conformed to any given definition of blackness: though subjects were meant to be screened in on the basis of diagnosis and race, the trial was administered colorblind.14 This point was pressed home at an FDA advisory committee meeting, when a woman of apparent Asian ancestry asked whether she would have been admitted to the study if she’d self-identified as black. The study investigators responded ‘Yes.’14 By refusing to define who may be reasonably considered blackin clinical trials, NitroMed also maximized its market of potential patient-consumers.

Despite early enthusiasm about BiDil, its high public profile, and its strategic efforts to appeal to as many patients as possible, the drug ultimately faced a challenging capital marketing environment. In BiDil’s first year on the market, physicians only wrote 84,000 prescriptions, due partly to insurers’ reluctance to reimburse.14 NitroMed was criticized for the drug’s high cost, which at $1.80 a pill (or $5.40 a day) equaled 4 to 7 times the price of generic isosorbide plus hydralazine. Some physicians prescribed patients to the two generics, despite the difficulty of establishing the correct ratio in a dose.15

In its first year, BiDil turned profits of only $11M, far short of the $100M that analysts anticipated. By January 2008, NitroMed had ceased corporate expenditure for the sales and marketing of BiDil, cut staff from 90 to 20, and retained an investment bank to explore strategic alternatives.16 Roughly translated, NitroMed is for sale.

Though BiDil’s disappointing performance might come as a relief to its critics, its probable disappearance from the market represents a setback for the 5 million Americans who face an incapacitating and potentially fatal disease, and for whom the value of this therapy has barely been realized. The development of race-based therapies or, beyond that threshold,personalized medicine may allow pharmaceutical corporations to create and corner target markets that provide more effective therapies for people with specific conditions, creating an opportunity for improved health for some and higher profits for drug companies. Though pharmaceutical companies often cite these advantages to justify the development of designer therapies, such endeavors siphon resources from research that will address the needs of the greatest number of patients, produce more expensive drugs that may not be affordable to those most in need, and encourage the confusion of sociological factors with biological facts. BiDil’s short-lived moment on the market illustrates the perils of leaving decisions about drug development in the hands of corporate managers whose bottom line is their balance sheet, not public health.

 

Martha Lincoln is a doctoral student in the PhD Program in Anthropology ay the CUNY Graduate Center, New York, New York.

 

References

1. Rose N. 2006. The Politics of Life Itself: Biomedicine, Power, and Subjectivity in the Twenty-First Century. Princeton, New Jersey: Princeton University Press. 2006, p. 181.
2. Schwartz R.S. Racial Profiling in Medical Research. New England Journal of Medicine 2001; 344:1392-1393. 
3. Kahn J. Race in a Bottle. Scientific American. 2007; 297(2): 40-45. 
4. A-HeFT. 2007. A-HeFT.org: The Web site of the African American Heart Failure Trial (A-HeFT.) Available at: http://www.aheft.org/. Retrieved October 30, 2007.
5. Kramer J, Vice President of Corporate Communications, NitroMed, personal communication, October 6, 2007.
6. . Heart Failure Backgrounder. Available at: http://www.nitromed.com/pdf/Heart%20Failure%20backgrounder.pdf, retrieved October 8, 2007.
7. NitroMed. 2007. African Americans and Heart Failure. Available at: http://www.nitromed.com/ pipeline/aaheart.asp, retrieved December 8, 2007.
8. Duster T. Race and Reification in Science. Science 2005; 307: 1050-1051. 
9. Haldeman, G.A. et al. 1998. Changes in Mortality from Heart Failure – United States, 1980-1995. Morbidity and Mortality Weekly Report. 47(30): 633-7. Available at: http://www.cdc.gov/MMWR/preview/mmwrhtml/00054249.htm, retrieved March 19, 2008.
10. NitroMed. 2007. Common Questions. Available at: http://www.bidil.com/pnt/questions.php#18, retrieved December 13, 2007.
11. Dressler WW, Oths KS, Gravlee CG.Race and Ethnicity in Public Health Research: Models to Explain Health Disparities. Annual Review of Anthropology 2005; 34: 231-252.
12. Dreifus C. 2005. A Sociologist Confronts ‘The Messy Stuff.’ New York Times, October 18. 2005. Available at :http://www.nytimes.com/2005/10/18/science/18conv.html 
13. Neil J. (BiDil Product Manager, personal email, 11/28/2007)
14. Kreimer S. 2007. BiDil not Widely Prescribed. DOC News 4(7): 23. 
15. Brody H, Hunt L. BiDil: Assessing a Race-Based Pharmaceutical. Annals of Family Medicine 2006; 4:556-560.
16. NitroMed Reports on BiDil XR(TM) Progress Following FDA Meeting, Announces Restructuring and Suspension of BiDil(R) Sales Force, and Retains Investment Bank to Advise on Strategic Options. 2008. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c= 130535&p=irol-newsArticle&ID=1096799&highlight= retrieved January 21, 2008.

Corporate Targeting and the Impact of Corporate Practices on Socioeconomic, Racial/ethnic, Gender and Age Inequities in Health

Selected Peer-reviewed Articles

A small but growing number of studies examine how corporate practices influence health inequities. Studies have described and analyzed how corporations target selected populations for marketing of unhealthy products, assessed the impact of these practices on differences in health behavior and health, and explored other ways that corporate decisions maintain or exacerbate health disparities.

Here Corporations and Health Watch summarizes a few of these recent reports and invites readers to submit additions to the list for subsequent posting.

 

Baker EA, Schootman M, Barnidge E, Kelly C. The role of race and poverty in access to foods that enable individuals to adhere to dietary guidelines. Prev Chronic Dis.2006; 3(3):A76.

Analyzes the results of an audit of community supermarkets and fast food restaurants to assess the location and availability of food choices that enable individuals to meet the dietary guidelines established by the U.S. Department of Agriculture. The researchers used supermarket and fast food restaurant audit tools to assess the availability of healthy food choices in the urban area of St. Louis, Missouri. The researchers found that two factors (race and income) are associated with the location of food outlets and the selection of foods available. Individuals living in mixed or white high-poverty areas and in primarily African American areas are less likely to have access to foods that would enable them to make healthy food choices. The researchers recommend collaborations with the business community and political structures to make it economically viable to provide equal access to healthy food choices.

 

Brody H, Hunt LM. BiDil: assessing a race-based pharmaceutical. Ann Fam Med. 2006; 4(6): 556-60.

Analyzes scientific evidence on BiDil, the first drug approved by the Food and Drug Administration to be marketed to a single racial-ethnic group, African Americans, for the treatment of congestive heart failure. The authors discuss the problems that can arise when race is viewed as a biological-medical construct, leading to an overly simplistic assumption of a racial and hence presumed genetic difference while obscuring the “economic, social, cultural, and ethical issues lurking in the background.” The authors predict that the manufacturer will launch a publicity campaign targeting African Americans, and that family medicine doctors will be asked by their patients for the new “for blacks only” medication.

 

Freudenberg N, Galea S, Fahs M. Changing corporate practices to reduce cancer disparities. J Health Care Poor Underserved. 2008; 19(1):26-40.

Reviews data on disparities in cancer morbidity and mortality in the United States, and reviews evidence on corporate practices contribute to cancer risk behavior, incidence, and cancer disparities. The authors propose that the practices of the tobacco, alcohol and food industries be considered as modifiable social determinants of health. The authors conclude with recommendations for research, practice, and policy that would lead to what they term “less carcinogenic” corporate practices.

 

Kwate N O A. Fried chicken and fresh apples: Racial segregation as a fundamental cause of fast food density in black neighborhoods. Health and Place 2008;14:32-44.

Analyzes pathways by which racial segregation contributes to higher density of fast food outlets in Black neighborhoods in US. The author proposes that population characteristics, economic characteristics, physical infrastructure and social processes of Black neighborhoods each contribute to creation of “localized geographic areas for targeting by fast food corporations and operators.”

 

Kwate NO, Lee TH. Ghettoizing outdoor advertising: disadvantage and ad panel density in black neighborhoods. J Urban Health. 2007;84(1):21-31.

 

Investigates correlates of density of outdoor advertising in predominantly African American neighborhoods in New York City. Authors found that that black neighborhoods have more outdoor advertising space than white neighborhoods, and these spaces disproportionately market alcohol and tobacco advertisements. By linking census data with property data at the census block group level, investigators found that two neighborhood-level determinants of ad density were income level and physical decay.

 

Macdonald L, Cummins S, Macintyre S. Neighbourhood fast food environment and area deprivation-substitution or concentration? Appetite. 2007l;49(1):251-4.

Investigates associations between area deprivation and the location of the four largest fast-food chains in Scotland and England. The authors report statistically significant increases in density of outlets from more affluent to more deprived areas for each individual fast-food chain and all chains combined. They conclude that these findings support a “concentration” effect whereby environmental risk factors for obesity appear to be ‘concentrated’ in more deprived areas.

 

Monsivais P, Drewnowski A. The rising cost of low-energy-density foods. J Am Diet Assoc. 2007; 107(12): 2071-6.

Discusses the results of a study on the energy density and retail prices of 372 foods and beverages in major supermarket chains in the Seattle, WA metropolitan area in 2004 and 2006 (energy density and prices were calculated in terms of $/100g and $/1,000 kcal). The researchers discuss the role of lower energy-density foods as a strategy for managing overweight and obesity. The two-year price change for the least energy-dense foods was +19.5% whereas the price change for the most energy-dense foods was -1.8%. The researchers suggest that the lower price of energy-dense foods and the resistance of energy-dense foods to price inflation may help explain why the highest rates of obesity in the United States are observed among those with limited economic means.

 

Morrison MA, Krugman DM, Pumsoon P. Under the radar: smokeless tobacco advertising in magazines with substantial youth readership. Am J Public Health. 2008; 98(3): 543-48.

Reviews the level of advertising of smokeless tobacco products before and after the Smokeless Tobacco Master Settlement Agreement (STMSA). The researchers determined that the STMSA appears to have had a limited effect on adolescents’ exposure to the advertising of smokeless tobacco in magazines with high youth readership. The researchers determined that adolescent boys (aged 12-17) are at greatest risk for exposure to smokeless tobacco advertisements.

 

Primack BA, Bost JE, Land SR, Fine MJ. Volume of tobacco advertising in African American markets: systematic review and meta-analyses. Public Health Rep. 2007; 122(5): 607-15.

Reviews the peer-reviewed literature on the density of pro-tobacco media messages. Of the studies identified for inclusion, 11 met the eligibility criteria for the current review. The researchers pooled the results of these studies in a meta-analysis and conclude that African Americans are exposed to a higher volume of pro-tobacco advertising. The researchers also cite evidence demonstrating that African Americans bear the greatest morbidity and mortality burdens due to smoking, and that exposure to pro-tobacco media messages predicts cigarette smoking.

 

Schor JB, Ford M. From Tastes Great to Cool: Children’s Food Marketing and the Rise of the Symbolic. Journal of Law, Medicine & Ethics. 2007; Spring issue on Childhood Obesity: 10-21.

Discusses the increasing participation of children in the consumer markets, their heavy media use and exposure to high levels of advertising. The researchers discuss deteriorating diets and rising obesity, as well as the shift in children’s food advertisements from product attributes to symbolic messages. The researchers cite studies that demonstrate that exposure to junk food marketing is much higher for low-income children as well as racial and ethnic minority children, groups that also have higher rates of obesity.

 

Thompson DA, Flores G, Ebel BE, Christakis DA. Comida en venta: after-school advertising on Spanish-language television in the United States. J Pediatr. 2008; 152(4): 576-81.

Analyzes the content of food and drink commercials aired during after-school hours (3 to 9 p.m.) on two Spanish-language television stations in the United States. The researchers found that children viewing Spanish-language television in the United States after school are exposed to food and drink commercials, mostly advertising unhealthy foods, including fast foods and sugared drinks. The researchers propose that food and beverage advertising to children via Spanish-language television may contribute to the high rates of obesity among Latino children.

 

Yerger VB, Przewoznik J, Malone RE. Racialized geography, corporate activity, and health disparities: tobacco industry targeting of inner cities. J Health Care Poor Underserved. 2007; 18(4 Suppl): 10-38

Reviews more than 400 internal documents from the tobacco industry to explore the ways in which the tobacco industry targeted inner cities populated predominately by low-income African American residents in the 1970s-1990s. The authors cite studies demonstrating that smoking rates remain higher among the poor, the less educated and other underserved populations, despite significant reductions in the overall smoking rate in the United States. This archival analysis demonstrates how the tobacco industry’s promotion activities and the “menthol wars” fought by tobacco companies in America’s inner-cities have contributed to the tobacco-related health disparities that we observe today.