“The alternate approach to medical marijuana distribution,” an op-ed by Kate Greenwood featured in The Record

[Ed. Note: This op-ed piece was featured in The Record's Sunday Editorial Page and on North Jersey.com. It was written by Center for Health & Pharmaceutical Law & Policy Research Fellow and regular Health Reform Watch blogger, Kate Greenwood]

WE FEEL there is no question about it: The careful, legal distribution of medicinal marijuana to those in need is a good thing. The New Jersey Legislature agreed and passed legislation permitting distribution last January. Then-Gov. Jon Corzine signed the measure before leaving office.

But Governor Christie has requested a delay in its implementation, and a proposal to modify the system of distribution is cause for concern.

More than a year ago, Seton Hall Law’s Center for Health and Pharmaceutical Law and Policy distributed a position paper to New Jersey lawmakers urging passage of the marijuana measure, called the “New Jersey Compassionate Use Medical Marijuana Act.” The center did so citing the inclusion of “multiple measures designed to reduce the risk of abuse or diversion” and noting that “the medical literature supports the conclusion that smoked marijuana can provide relief to patients suffering from debilitating medical conditions for whom conventional treatments have failed.”

Implementation delayed

The act was to have taken effect this month, but, in response to a request from Christie, the Legislature pushed back the effective date to October.

As passed, the act provides that medical marijuana be grown and distributed by six not-for-profit “alternative treatment centers.”

But now, the New Jersey Council of Teaching Hospitals has proposed that the act be amended — before it is even implemented to provide that medical marijuana instead be grown by Rutgers University and distributed by the state’s teaching hospitals.

While hospitals are, as the Council of Teaching Hospitals points out, experienced dispensers of medicine, the act should not be rewritten to require them to dispense medical marijuana.

The passage of the act affects the rights and responsibilities of patients and providers of medical marijuana under New Jersey law; it does not change the fact that distribution and use of marijuana are illegal under federal law.

Although Attorney General Eric Holder has pledged not to prosecute patients and providers who comply with applicable state laws, and hospitals could thus dispense medical marijuana without fear of criminal prosecution, they would still be violating federal law.

Condition of participation

This is a problem because compliance with federal law is a condition of participation in the Medicaid and Medicare programs. Hospitals depend heavily on Medicaid and Medicare funding; the Compassionate Use Act’s alternative treatment centers would not.

Read More

Possible Repeal of Massachusetts Ban: A Gift to Prescribers, Patients or Industry?

Next month marks the second anniversary of the enactment of the Massachusetts Pharmaceutical and Medical Device Manufacturer Code of Conduct, a law requiring pharmaceutical and medical device manufacturing companies to designate a compliance officer and implement a compliance program reflecting the commonwealth’s regulations on meals, CME sponsorship, use of non-patient identified prescriber data, gifts and other payments, etc.  The law, which went into effect on July 1, 2009, builds upon the Pharmaceutical Research and Manufacturers of America’s revised Code  on Interactions with Healthcare Professionals (”PhRMA Code“) and the Advanced Medical Technology Association’s revised Code of Ethics on Interactions with Healthcare Professionals (”AdvaMed Code“), two voluntary codes intended to eliminate any influence — perceived or otherwise — of the industry over healthcare professionals with respect to gifts, entertainment, recreation, educational programs, professional meetings, scholarships, and the like.

The Massachusetts law is more restrictive, however, than its PhRMA and AdvaMed counterparts.  It prohibits companies from sponsoring continuing medical education programs that do not meet Accreditation Council for Continuing Medical Education guidelines.  The PhRMA and AdvaMed Codes do not.  It prohibits any company employee from providing meals outside of a hospital or office setting.  The PhRMA Code only restricts sales representatives and their immediate supervisors to a hospital or office setting.  The AdvaMed Code does not impose any restrictions on the location of meals.

Furthermore, starting on July 1, 2010, the law requires companies to annually certify their compliance with commonwealth regulations and, among other things, to disclose any gifts or payments valued over $50 and given to anyone who can prescribe, purchase, or dispense drugs or devices.  Effectively, it’s a ban on all gifts to prescribers (and in so doing goes a step further than the PhRMA and AdvaMed Codes which make an exception for educational gifts).  Companies must also submit $2,000, payable to the commonwealth’s Department of Public Health, with each annual disclosure report.  Violations can result in penalties up to $5,000 per occurrence.  The first round of disclosures were due 16 days ago and covered activities for the July 1, 2009 to December 31, 2009 period.  Next year companies will be expected to report on their activities for the January 1, 2010 to December 31, 2010 period.  Or will they?

The Massachusetts House recently passed an economic development bill that repeals the disclosure requirement/gift ban (the bill also establishes a sales tax holiday and consolidates commonwealth economic agencies).  The Senate version of the bill does not include the repeal.  It’s a wait-and-see as to how the two chambers will work out the final bill through their conference committee.

Opponents of the gift ban claim it has adversely affected pharmaceutical clinical research as well as the restaurant and convention industries.  Almost two years ago, PhRMA Senior Vice President Ken Johnson expressed his disappointment over the law, saying:

[it is] very likely damaging for medical partnerships, clinical research and patients in Massachusetts….

Public disclosure of a pharmaceutical company’s arrangements with principal investigators of its clinical trials also could reveal sensitive, proprietary business information to a company’s competitors.  This could erode the independent decision-making of companies trying to bring science from research facilities to patient care setting….

The disclosure requirements subjects all of the physicians, academic institutions and hospitals involved in such trials to publicity in a form that may be difficult to understand and likely will generate unwanted and unnecessary public scrutiny.  This could make Massachusetts an unattractive place for academic scientists to live and work — and for pharmaceutical research companies to do business.  Such a policy clearly is not in the best interest of public health — and it flies in the face of the ongoing efforts to further cultivate the life sciences industry within Massachusetts.

Indeed, the Wall Street Journal and Boston Herald report that some medical groups either have threatened to take their annual meetings elsewhere or have actually done so in protest of the law.

Supporters of the law say otherwise.  Health Care For All, a Massachusetts-based advocacy organization, views banning gifts as a step in the right direction.  According to the organization:

[t]he pharmaceutical industry gives gifts to promote their drugs and make a higher profit.  Under the guise of promoting welfare for all, the industry maximizes their own revenue….

Experts living within the guidelines of the gift ban find that it is not interfering with their work or professional relationships according to Dr. David Coleman, Boston University School of Medicine.

‘The Massachusetts Gift Ban legislation is an important step in the process of reducing both biases in therapeutic decision-making and healthcare costs.  The Ban has not adversely impacted the important relationships of our physician-faculty with the pharmaceutical and device industries….’

Health Care For All also maintains there is no connection between the decrease in restaurant revenues and the law as:

[t]he Massachusetts Prescription Reform Coalition has researched the decrease in restaurant profits, and found sales are down across the country — including in states without a gift ban.   According to the trade paper, Restaurants & Institutions, sales at the nation’s top 100 independent restaurants were down 10% in 2009….

Massachusetts Senators, who recognize the value of the gift ban legislation, also see that these lost profits mirror similar recession-caused losses in the restaurant industry across the country.

Georgia Maheras, Private Market Policy Manager at the Massachusetts Prescription Reform Coalition, considers the current House bill to be a “significant step backward” in the fight to curb medical costs.

Massachusetts is not alone in attempting to reform pharmaceutical and medical device marketing practices.  Neighboring Vermont has a similar, and in fact more stringent, law which even allows the Attorney General’s office to track free samples given to physicians (though a reporter for the Times Argus, a Vermont newspaper, worries how a repeal in Massachusetts might have a ripple effect).  California, the District of Columbia, Maine, Minnesota, Nevada, and West Virginia also have some form of a marketing code.  The federal government’s Patient Protection & Affordable Care Act includes the Physician Payment Sunshine Provision (”Provision”) requiring disclosure of payments made to physicians and teaching hospitals by manufacturers of products covered under Medicaid, Medicare, and SCHIP (click here to read a summary).

So who has it right?  It would seem as though PhRMA and AdvaMed opened the door for state and federal government to codify modified versions of these industry codes.  From a compliance perspective, it must be quite inefficient — and headache inducing — to wade through state marketing disclosure laws that lack uniformity.  Starting January 1, 2012, the Provision will preempt state disclosure laws except for where the state requires additional information.  Maybe this will help, maybe it will add to the headache, or maybe this particular episode will no longer matter.   For now, though, from a patient perspective, a repeal of the Massachusetts disclosure requirement/gift ban, or that of any other state, would feel more like a gift to the industry and prescribers than a service to the “best interest of public health.”

The Center for Health & Pharmacy Law & Policy here at Seton Hall Law has issued two white papers addressing these issues: Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight,” in which the Center proposes legal and policy changes to address conflicts of interest in the relationships between industry and doctors that can create unwarranted risks to trial participants and to the scientific integrity of research; and Drug and Device Promotion: Charting a Course for Policy Reform,” in which the Center proposes legal and policy changes to address conflicts of interest in the relationship of medicine and industry– including the recommendation “that industry funding for continuing medical education should be phased out, and replaced by an educational process driven by physicians.”

The Center has also recommended “the adoption of federal legislation to ban the use of gifts, meals, and other perks to promote drugs and devices. The states have taken the lead to date–Massachusetts, California, Minnesota, and the District of Columbia have passed laws to limit or ban gifts and meals that are now routine in marketing practices. Concluding that industry self-regulation is not sufficient, the Center calls for national legislation to create uniform practices by industry and physicians. As urged by Professor Boozang, ‘the benefits of drugs and devices should drive promotion and physicians’ decision to prescribe, not a marketing model that depends on gifts and meals.’”

Obviously, the adoption of additional federal standards in this regard will lessen the ability of industry to pit one state against another and make compliance easier. The Physician Payment Sunshine Provision is a step in that direction, the Massachusetts development bill is a step back.

Prescription Drug Abuse Up– Dramatically

I wrote the other day that I was “generally suspicious of the pharmaceutical zeitgeist. And terribly so as it concerns myself.” The following, I suppose, is that zeitgeist’s underbelly. Reuters reports:

U.S. officials reported a 400 percent increase over 10 years in the proportion of Americans treated for prescription painkiller abuse and said on Thursday the problem cut across age groups, geography and income.

The dramatic jump was higher than treatment admission rates for methamphetamine abuse, which doubled, and marijuana, which increased by almost half, according to figures from the Substance Abuse and Mental Health Services Administration.

They said 9.8 percent of hospital admissions for substance abuse in 2008 involved painkillers, up from 2.2 percent in 1998. The percentage of people admitted to treatment for alcohol dropped by 5 percent and for cocaine dropped by 16 percent over the same period.

The report, which is brief and chock full of interesting charts and graphs, can be found here.

Are GPO’s Suppressing Safer Devices?

S. Prakash Sethi has called group purchasing organizations (GPO’s) an “undisclosed scandal in the U.S. health care industry.” Mariah Blake’s article in the Washington Monthly on GPO’s is a sobering “must-read” for those concerned about the future of health care in the US. She writes about the entrepreneur Thomas Shaw, who’s invented a syringe that drastically reduces the risk of bloodstream infections for patients and healthcare workers. (According to Barry Lynn, who’s also written on the issue, “each year about 6,000 medical workers come down with HIV or infectious hepatitis from such accidents, and dozens end up dead.”) Shaw’s brilliant innovation “added only a few pennies to the cost of production,” but it’s rarely used today. Blake traces the non-diffusion of this innovation to a complex set of deregulatory decisions relating to GPO’s.

GPO’s are supposed to use purchasing clout on behalf of buyers (like hospitals) to drive down prices from sellers. But it appears that these intermediaries, like large Wall Street firms, are often more interested in fees and payments from the sell-side than they are in helping the buy-side. As one analyst testified before the DOJ and FTC, “the compensation of most GPO management is almost always based on . . . fee income [from suppliers] rather than on the real savings to hospital members.”

Shaw’s bad luck was to enter the market shortly after a massive GPO, Premier, struck a multiyear deal with supplier Becton Dickinson. As Blake notes, “Premier signed a $1.8 billion, seven-and-a-half-year deal with Becton Dickinson [whereby its 1700 member hospitals] had to buy 90 percent of their syringes and blood collection tubes from” Becton Dickinson, which also “landed similar deals with all but one major GPO.” Lynn says that “many hospital buying agents won’t even dare to talk to Shaw for fear of upsetting their more powerful suppliers.”

How did the GPO-Supplier nexus grow so strong? Blake does a terrific job explaining developments that transmogrified many cost-cutting intermediaries into self-serving middlemen:

To keep costs in check, in the 1970s many medical facilities began banding together to form group purchasing organizations, or GPOs. The underlying idea was simple: because suppliers generally give price breaks to customers who buy large quantities, hospitals could get better deals on, say, gauze or gloves, if a group of them came together and bargained for ten cases, rather than each hospital buying a case on its own. . . . By decade’s end, virtually every hospital in America belonged to a GPO.

Then, in 1986 Congress passed a bill exempting GPOs from the anti-kickback provisions embedded in Medicare law. This meant that instead of collecting membership dues, GPOs could collect “fees”—in other industries they might be called kickbacks or bribes—from suppliers in the form of a share of sales revenue. (For example, in exchange for signing a contract with a given gauze maker, a GPO might get a percentage of whatever the company made selling gauze to members.) The idea was to help struggling hospitals by shifting the burden of funding GPOs’ operations to vendors. To prevent abuse, “fees” of more than 3 percent of sales were supposed to be reported to member hospitals and (upon request) the secretary of [HHS].

[This shift] turned the incentives for GPOs upside down. Instead of being tied to the dues paid by members, GPOs’ revenues were now tied to the profits of the suppliers they were supposed to be pressing for lower prices. This created an incentive to cater to the sellers rather than to the buyers. . . . Before long, large suppliers began using “fees”—sometimes very generous ones—along with tiered pricing to secure deals that locked GPO members into buying their products. . . .

This situation only grew thornier in 1996, when the Justice Department and the Federal Trade Commission overhauled antitrust rules and granted the organizations protection from antitrust actions, except under “extraordinary circumstances.” . . . Within a few years, five GPOs controlled purchasing for 90 percent of the nation’s hospitals, which only amplified the clout of big suppliers.

There are a few lessons here. Within the confines of competition law, the message should be clear: Einer Elhauge was right to state in 2003 that “Serious antitrust concerns remain about exclusionary agreements that charge higher prices to GPOs or hospitals that won’t commit to limiting purchases from rivals of dominant manufacturers to a small (often 5-10%) percentage of their purchases.” The broader lesson is that intermediaries in many fields are often tempted to put their own profits ahead of the entities they’re ostensibly serving. In the endless battle for compensation between providers, hospitals, and insurers, there are many profitable opportunities to shift alliances. Meanwhile, entrepreneurs like Thomas Shaw, patients, and thousands of medical workers are enduring unsafe conditions that could easily be remedied.

Pharmaceutical Outsourcing: Trading Quality for Lower Costs?

With the waning economy, outsourcing has never been a more popular route for businesses to take.  Why pay more when you can get a similar product or service for less overseas?  Traditionally, outsourcing has been limited to low-end, back-office type of work. However, in the recent years, more companies have been outsourcing complex services such as medical diagnostics.

So it should be no surprise that India, a country with an abundance of cost effective labor, has emerged as a hot spot for pharmaceutical companies to outsource their drug manufacturing.  The NY Times reports,

India’s drug industry — on track to grow about 13 percent this year, to just over $24 billion — was once notorious for making cheap knockoffs of Western medicines and selling them in developing countries. But India, seasoned in the basics of medicine making, is now starting to take on a more mainstream role in the global drug industry, as a result of recent strengthening of patent law here and cost pressures on name-brand drug makers in the West.

Not limited to just manufacturing, India is projected to further expand into more sophisticated aspects of drug making such as pharmaceutical research and development. Due to its cheap labor, Indian drug companies are able to “discover new drugs at a tenth of the cost” incurred in the United States, according to Ajay G. Piramal, the chairman of Piramal Healthcare.

This pharmaceutical boom in India has been relatively recent.  Initially, pharmaceutical companies were hesitant to outsource their internal operations.  Sujay Shetty, an associate director with PricewaterhouseCooper in Mumbai, described pharma as  “an incredibly arrogant industry” and predicted that “everything in the value chain will move to different parts of the world that are cheaper.”

But, what risks are these pharmaceuticals companies taking?  Outsourcing, in general, can be riddled with quality problems and pharmaceutical outsourcing to India has been no exception.  According to the NY Times,

Recent growth, though, has been shadowed by quality problems. The F.D.A. cited Ranbaxy [India's largest pharmaceutical manufacturer] for manufacturing violations several times in recent years, and in February ordered a review of the company’s global manufacturing operations.

In May, Sanofi-Aventis recalled vaccines made by Shantha Biotechnics that were distributed to the World Health Organization after users complained about white sediment in the vials. In June, after floating matter was found in some plastic IV bags, Pfizer recalled injectible drugs made by Claris Lifesciences and sold in the United States.

Maybe pharmaceutical companies were justified in being cautious, even to the point of arrogance, in deciding whether to outsource in the past.  Drug manufacturing is a complex process that needs proper review practices to prevent errors.

Fortunately, the Food and Drug Administration (FDA) has taken note of India’s growing influence in the drug industry and has been cracking down to prevent substandard and contaminated drugs from entering the United States.  In the past two years, the FDA has opened two new offices in India, one in Delhi and the other in Mumbai.  And just last month, as reported by The Wall Street Journal, the FDA stated that “it will propose stronger regulation for pharmaceutical companies that outsource manufacturing, putting more responsibility on the companies to ensure the purity and safety of the products…”

Whether or not the FDA’s crackdown improves the quality of the outsourced drugs remains to be seen.  But, with lower costs and regulation avoidance said to be the primary motivation behind pharmaceutical outsourcing, it’s uncertain whether the quality problems mentioned by the NY Times will be the last.

Bad Ads and Doctor Deputies

Earlier this month, the FDA launched a new initiative — the Bad Ad Program — to “help health care providers recognize misleading prescription drug promotion and provide them with an easy way to report this activity to the agency.”  In an article appearing earlier this week in Advertising Age, advertising executives and others decry the program as a “publicity stunt” with the potential to lead to physician “vigilantism” and to become “unbridled and messy.”  Also quoted in the article is PhRMA Senior Vice President Ken Johnson, who states that PhRMA views the Bad Ad Program as “another step to help educate — and receive feedback from — healthcare providers about prescription drug advertising and promotion.”  The Advertising Age article, correctly I think, characterizes this statement as offering only “tepid support.”

There appear to be two central criticisms of the Bad Ad Program: (1) that it is not as low-cost as it seems because it will take up physicians’ time and create more work for the FDA’s already overburdened Division of Drug Marketing, Advertising, and Communications (DDMAC) and (2) that it will be an ineffective compliance tool either because doctors cannot tell the difference between compliant and noncompliant advertising or because doctors will “go on personal jihads on ads they don’t like - ads that very well might be in perfect compliance.”

Both concerns seem overblown.  Doctors do not have to participate if they do not have the time or inclination — it seems likely that most will not — and pharmaceutical companies have been reporting each other’s marketing abuses to DDMAC for years, so the Division has experience sifting through more and less credible information.  Doctors may well have difficulty discerning which ads are compliant and which are not — see, e.g., this study revealing that doctors could not accurately identify the FDA-approval status of a significant percentage of the drugs they prescribe — but this is not an argument against the FDA’s effort to educate them.

The bottom line is that while pharmaceutical companies track what happens in physician offices in multiple ways, including through sales rep call notes and sales message recall studies, they do not, at least not consistently and/or voluntarily, use the information gathered in service of compliance, as opposed to sales, goals.  In the words of Arnie Friede, to the extent that the FDA’s Bad Ad Program creates “an additional incentive for a company to closely monitor and control communications by their sales people” it is “an understandable, perhaps even brilliant move.”

Surety Bond Requirements for Durable Medical Equipment, Prosthetics, Orthotics and Supplies (DMEPOS)

By Rachel Jones

The final rule implementing surety bond requirements for DMEPOS became effective March 3, 2009.  The regulation implemented the surety bond requirements for DMEPOS set forth in section 4312(a) and (c) of the Balanced Budget Act of 1997 (BBA).  The Centers for Medicare & Medicaid Services (CMS) proposed a rule on January 20, 1998 (63 FR 2926) reflecting the BBA’s surety bond requirements and solicited comments.  Comments were solicited for advisability with respect to Section 4312(c) of the BBA, which further allowed CMS to require a surety bond from some or all providers or suppliers who furnish items or services under Medicare Part A or Part B and not solely Durable and Medical Equipment (DME) suppliers.  A substantial amount of comments were received and in the final published rule on October 11, 2000 (65 FR 60366), CMS decided to delay the final rule with respect to surety bond requirements for suppliers of DMEPOS in order to further study the issue.  However, in 2003 Congress enacted section 902 of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (Pub. L. 108-173) (MMA) which prohibits the Secretary of Department of Health and Human Services from finalizing a proposed rule related to Title 18 that was published more than 3 years earlier except under exceptional circumstances.  In response to this CMS proposed a rule on August 1, 2007 (72 FR 42001) to implement the statutory surety bond requirements set forth in the BBA.  CMS received approximately 200 comments that were considered before they published the final rule on January 2, 2009. (FR 30802)

Surety bonds are a financial guarantee whereby a first party (obligee) contracts with a second party (principal) to perform duties in a contract that will benefit a third party (surety).  The first party guarantees that the second party will fulfill its obligation(s) under the contract and in the event that the obligations are not met, the first party will recover its losses via the bond.  CMS has imposed the rule in order to deter fraud and abuse by Medicare suppliers of DMEPOS.  CMS believes a surety bond requirement will (1) limit the Medicare program risk to fraudulent DMEPOS suppliers; (2) enhance the Medicare enrollment process to help ensure that only legitimate DMEPOS suppliers are enrolled or are allowed to remain enrolled in the Medicare program; (3) ensure that the Medicare program recoups erroneous payments that result from fraudulent or abusive billing practices by allowing CMS or its designated contractor to seek payments from a surety up to the penal sum; and (4) help ensure that Medicare beneficiaries receive products and services that are considered reasonable and necessary from legitimate DMEPOS suppliers.  CMS has also instituted other measures– including requiring accreditation for DMEPOS suppliers to deter fraud.

Who is affected by the surety bond requirements?

The regulation affects many healthcare providers; generally any DMEPOS supplier that is registered with the National Supplier Clearinghouse (NSC) may be subjected to the surety bond requirement.  Every DMEPOS supplier to Medicare patients must register with the NSC.  There are several exempt DMEPOS suppliers under the regulation:

I.      Government-owned suppliers,

II.       State-licensed orthotic and prosthetic personnel in private practice making custom made orthotics and prosthetics if the business is solely-owned and operated by said personnel and is billing only for orthotic and prosthetics, and supplies,

III.      Physicians and non-physician practitioners if the DMEPOS items are furnished only to his or her patients as part of his or her professional service, and

IV.      Physical and occupational therapists if: (1) the business is solely-owned and operated by the therapist, and (2) if the DMEPOS items are furnished only to his or her patients as part of his or her professional service.

The economic impact on non-exempt healthcare providers is significant since the regulation requires a minimum of $50,000 surety bond.  This bond amount is required for each National Provider Identifier (NPI).  Since DMPEOS suppliers must obtain an NPI by practice location, this amount can become quite significant for a supplier with multiple locations.  The estimated cost to DMPEOS suppliers is approximately $1200 per $50,000 surety bond, depending on the company’s financial stability.  The regulation also permits an additional $50,000 surety bond for high risk DMPEOS.  For example, if a DMPEOS supplier has an adverse legal action within the last ten years preceding enrollment, revalidation, or re-enrollment then an additional $50,000 surety bond is required per adverse legal action.  An adverse legal action includes: Medicare imposed revocation of any Medicare billing number, suspension of a license to provide health care by any State licensing authority, revocation or suspension of accreditation, a conviction of a Federal or State felony offense or an exclusion or debarment from participation in a Federal or State health care program.

CMS believes that the surety bond will deter fraudulent activity because a fraudulent DMEPOS supplier will not likely post a surety bond.   However, it is more likely the basis for this new requirement is to more easily allow CMS to recoup lost funds due to fraudulent activities.  In addition, the bond requirement allows CMS to track and reprimand those DMEPOS suppliers that have continuously violated the law and stayed in the Medicare

Allergan v. FDA: Where Does Disseminating Safety Information End and Promotion Begin?

In the Fall of 2009, the drugmaker Allergan made waves when it sued the FDA alleging that the ban on off-label promotion was chilling its “First Amendment right to share truthful medical information with physicians about how to safely use Botox off-label [to treat muscle spasticity] to achieve a benefit while minimizing risk of serious adverse events.”  Allergan was back in the news last week when the LA Times reported that trial was set to begin in a case brought against Allergan by the mother of Kristen Spears, a seven-year-old girl with cerebral palsy who died after being injected with Botox to treat muscle spasticity in her legs.

Allergan manufactures two FDA-approved botulinum toxin products, Botox Cosmetic, the well-known anti-wrinkle treatment, and Botox, which is approved to treat, among other conditions, cervical dystonia, “a movement disorder that causes [the muscles of the neck and shoulders] to contract and spasm involuntarily.”  Botox is also frequently used “off-label” for conditions it is not approved to treat, including muscle spasticity.  Per the NIH,  locally-injected Botox “has become a standard treatment for overactive muscles in children with spastic movement disorders such as cerebral palsy.”  The FDA agrees.  An agency physician describes Botox as a “commonly used” and “very effective” treatment for spasticity, which he characterizes as a “significant disability[y.]“  Per the LA Times, Botox can “sometimes help young patients walk without surgery.”

While the NIH’s website states that the undesirable side effects of Botox are “mild and short-lived,” the FDA’s informs physicians that “a Boxed Warning has been added to the prescribing information to highlight that botulinum toxin may spread from the area of injection to produce symptoms consistent with botulism,” “that swallowing and breathing difficulties can be life-threatening and there have been reports of deaths related to the effects of spread of botulinum toxin,” and “that children treated for spasticity are at greatest risk for these symptoms[.]”

In addition to requiring the addition of the black box warning to the Botox label, the FDA has ordered Allergan and other manufacturers of botulinum toxin products to adopt a Risk Evaluation and Mitigation Strategy (REMS) which includes “a Medication Guide [for patients] and Communication Plan, including a Dear Health Care Provider letter, and a timetable for submission of assessments.”

In its complaint against the FDA, Allergan alleges that while “the boxed warning and REMS materials identify the risk of potential distant spread of toxin effect, … they do not give physicians using Botox for spasticity specific guidance about how to further minimize that risk while still obtaining an acceptable therapeutic effect.”  Allergan wants to provide physicians with specific information about treating spasticity including “proper dosing, patient selection, and injection technique.”  Allergan argues, with good reason I believe, that if it were to, say, develop a slide deck about dosing, patient selection, and injection technique in treating spasticity and present it to physicians it would be exposing itself to criminal liability for promoting an off-label use.  In its brief in opposition, the FDA disagrees — sort of — arguing that disseminating safety information about unapproved uses is “not necessarily” promotion and that Allergan has “ample room” “to disseminate truthful, non-promotional information about dangers associated with unapproved uses of Botox.”  (I will have more to say about the parties’ legal arguments in a subsequent post.)

In an interesting twist, the LA Times reports that Kristen Spears’ pediatrician and his nurse practitioner wife testified in depositions that they “learned to use Botox on children with cerebral palsy at Allergan-sponsored seminars in 2000 and 2001″ and that “Allergan’s sales agents discussed the use of Botox for juvenile cerebral palsy patients … repeatedly, visiting the practice about 50 times over several years.”  They also claimed that they were told by sales representatives that other doctors were using “in range of 10 to 15 units” of Botox per kilogram to treat their pediatric patients.  Dr. Mitchell Brin, Allergan’s Chief Scientific Officer for Botox, testified that fifteen units per kilogram, which is the dose given Kristen Spears, is nearly twice the maximum dose that the company considers safe for children.  He also testified that, because of the ban on off-label promotion, Allergan did not disseminate its maximum dosage information to physicians.  If it is true that Allergan’s sales force was providing doctors with dosing information gleaned from anecdotal reports from other doctors they called on while the experts in the company’s medical department kept their dosing knowledge to themselves, it is an example of an all-too-common disconnect between the field and headquarters that in this case may have had tragic consequences.

Financial Remuneration of Clinical Study Investigators

In November 2009, the Center for Health & Pharmaceutical Law & Policy, in its White Paper, Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight, explored payments to investigators — and other potential motivators — to conduct research.  A study in this month’s IRB: Ethics & Human Research explores the impact payments may have on researchers to conduct and complete studies.  In Motivated by Money? The Impact of Financial Incentive for the Research Team on Study Recruitment, Sharon Unger and her colleagues examine the effect financial remuneration has on researchers in a neonatal intensive care unit (NICU).

Taking advantage of a “fortuitous set of circumstances” in which two separate clinical trials with nearly identical inclusion criteria were conducted simultaneously in an NICU in Canada, the authors looked at two issues: 1) whether financial remuneration impacted the rate at which the research team approached parents about research participation, and 2) whether financial remuneration impacted the rate at which parents provided consent to participate.

In the first study (Study A), a placebo-controlled trial involving a medication that was the standard of care for treatment of newborns nearing extubation to prevent apnea of prematurity, members of the research team were financially compensated for their time if they were successful in obtaining parental consent (parents were unaware of this arrangement).  In the second study (Study B), which involved two different forms of noninvasive respiratory support following extubation, there was no financial compensation of the research team.  Both studies had the same recruiting team.  Study A was federally funded, multicentered and high-profile, while Study B was a single-center, unfunded trial.

The payments in Study A were per capita, which, while creating a direct incentive to recruit individual enrollees, is usually not problematic as long as the payment is not excessive.  The Center recommends “that the benchmark for compensation for physician services for research should be comparable payment for time and services for treatment. This will compensate physicians fairly for their time and services, and will assure that there are no hidden bonuses or incentives for physicians to recruit patients into research or to refer them to research rather than treatment.”  As noted in the study, finder’s fees are increasingly considered “ethically problematic;” the Center recommends a wholesale bar on finder’s fees because they can create conflicts of interest that can incentivize investigators to recruit and retain individuals who do not meet the study’s inclusion and exclusion criteria.

As the authors noted, and as acknowledged in the Center’s White Paper, potential enrollees are increasingly vulnerable as increasing numbers of individuals seek to participate in research either as a primary means of access to treatment or as a form of income.  The results of this study indicate a much higher likelihood of approach when there was a prospect of financial remuneration.  These results are concerning, and were anticipated by the Center’s White Paper, which noted the potential for poor compliance with inclusion and exclusion criteria and pressure to enter or remain in a clinical trial.

However, surprisingly, the authors found that, despite the much higher likelihood of approach for Study A than Study B, parents were much more likely to actually agree to enroll their newborn in Study B — for which there was no financial remuneration of the research team.  The authors explored various explanations for this result, including that the research team was overly cautious about giving the appearance that their approach for consent was motivated by financial compensation, or that parents chose to withhold consent  due to the research team’s  increased pressure.

The authors do acknowledge other potential factors — beyond financial remuneration –  that could have affected the study’s results.  For example, parents’ hesitancy to enroll their newborn in a placebo-controlled drug trial could explain the discrepancy between enrollment in the studies.  Likewise, the authors consider that parents may not have been able to differentiate between the two modes of support being investigated in Study B.  In addition, the recruiting team, when presented with the results of the study, did not recall feeling influenced by the financial arrangement of Study A, but did “recall being highly motivated to ensure the success of Study A as it was part of a high-profile, multicentered trial.”

The authors concluded by noting concerns that “there may be a point at which the amount of the financial remuneration or the manner in which it is assigned could negatively impact the ethical conduct of the researcher,” but cautions that these concerns should be balanced with the value of conducting research in patients’ best interests.  This balancing act is considerably important.  As the Center notes,

Research is critical to the advancement of medical treatment and health. It must be structured to produce high quality data that facilitates the assessment of safety and efficacy in the population for whom the treatment will be used. The good of the enterprise requires that the clinical trial system sufficiently balance the costs and benefits to physicians and prospec­tive trial participants to ensure the continued sufficient supply of researchers and subjects. The system must also be imbued with actual and perceived integrity — so that it produces scientifi­cally reliable results, participants are safe, and people trust the system sufficiently to be willing to participate.

Medical Marijuana Act Signed Into Law: Some Chronically Ill New Jerseyans Rejoice While Others Continue to Wait

As expected, on January 18, 2010, Governor Jon Corzine signed the New Jersey Compassionate Use Medical Marijuana Act into law, making New Jersey the 14^th state to legalize marijuana for medical use.  Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy endorsed the Act in a position paper distributed to key lawmakers in June 2009.

The Act’s backers celebrated its passage with “hugs and tears,” while its opponents expressed continued concerns, including that the for-profit “alternative treatment centers” that the Act will allow to grow and distribute marijuana will have negative effects on the neighborhoods where they are established.  An interesting abcnews.com article by Susan Donaldson James highlights a third constituency: New Jerseyans with chronic illnesses that are responsive to treatment with marijuana but who are not considered to have debilitating medical conditions under the Act.

The article profiles Jack O’Brien of Laurel Lake, New Jersey who was born without fingers and toes and suffers from “crushing neuropathic pain.”  He wakes up to shooting pain in his arms and legs and can only walk short distances on his deformed feet.  According to O’Brien, smoking marijuana is “like having a valve on the forearm, turning it and having the coolness of relief through my extremities. … I try to walk on these feet and I can go four or five blocks, with my wife. With marijuana, I can go forever.”  State Assemblyman Reed Gusciora, who was a prime sponsor of the Act, explained that while he had empathy for O’Brien and others in his position, the legislature “had to do a measured approach,” citing fears that New Jersey could become another California, where medical marijuana “seemed to be spiraling out of control.”   Assemblyman Gusciora promised that in two years the legislature would “revisit the issue and add ailments.”

Addendum:

While Jack O’Brien’s case provides only anecdotal evidence of marijuana’s efficacy against neuropathic pain, as the Center noted in its position paper, “in the past two years, three placebo-controlled, randomized, double-blind clinical trials published in the medical literature have demonstrated that smoked marijuana is effective against neuropathic pain, including for patients who have tried the available conventional treatments and are still in pain.”   The existence of this evidence is remarkable because, as recent articles in the New York Times and Wall Street Journal explain, researchers must surmount formidable hurdles to study marijuana’s potential medical uses.

For those who are curious, under the compromise version of the Act which was signed into law January 18^th, “debilitating medical condition” is defined to include the following:

• Seizure disorder, including epilepsy, if resistant to conventional medical therapy;
• Intractable skeletal muscular spasticity, if resistant to conventional medical therapy;
• Glaucoma, if resistant to conventional medical therapy;
• HIV or the treatment of HIV, if it causes severe or chronic pain, severe nausea or vomiting, cachexia, or wasting syndrome;
• AIDS or the treatment of AIDS, if it causes severe or chronic pain, severe nausea or vomiting, cachexia, or wasting syndrome;
• Cancer or the treatment of cancer, if it causes severe or chronic pain, severe nausea or vomiting, cachexia, or wasting syndrome;
• Amyotrophic lateral sclerosis;
• Multiple sclerosis;
• Terminal cancer;
• Muscular dystrophy;
• Inflammatory bowel disease, including Crohn’s disease; and
• Terminal illness, if the physician has determined a prognosis of less than 12 months of life.

New Jersey Legislature Passes Medical Marijuana Bill

Yesterday, the last day of its 2008-2009 legislative session, the New Jersey legislature voted to legalize the use of medical marijuana by New Jersey residents suffering from debilitating medical conditions.

The version of the New Jersey Compassionate Use Medical Marijuana Act passed yesterday represents a compromise between the version that the state Senate passed in February of 2009, which Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy endorsed in a position paper distributed to key lawmakers, and the Assembly version, which included a number of amendments intended to bolster the Act’s already strict safeguards against abuse and diversion.  (The differences between the Assembly and Senate versions are outlined here; a summary of the changes made in the final legislation is posted here on the Legislature’s website.)   Governor Corzine is expected to sign the Act into law before he leaves office next week.

Among other changes, the final legislation:

• revises the definition of “debilitating medical condition” to specify that severe or chronic pain, severe nausea or vomiting, and cachexia or wasting syndrome qualify a patient to use medical marijuana if they are symptoms of cancer, HIV/AIDS, “or the treatment thereof.” The new definition also adds inflammatory bowel disease, including Crohn’s disease, muscular dystrophy, and terminal illnesses expected to cause death in 12 months or less to the list of debilitating conditions;

• deletes the Assembly provision that allowed patients to designate an individual to transport marijuana to them in an emergency, and reverts to the Senate language allowing patients to designate a primary caregiver to assist them with their use of medical marijuana on an ongoing basis; and

• preserves the Assembly version’s requirement that patients obtain their marijuana from “medical marijuana alternative treatment centers,” i.e., that they not be allowed to grow their own, but increases the amount of marijuana that patients can be dispensed in a 30-day period from one ounce to two ounces.

Interestingly, the final legislation also requires that the system the Division of Consumer Affairs in the Department of Law and Public Safety establishes to monitor the dispensation of marijuana for medical use must “serve the same purpose as, and be cross-referenced with” the Division’s system for monitoring the dispensation of certain prescription drugs with the potential for abuse.  This is further evidence that marijuana is slowly but surely, as Fordham Law Professor Kimani Paul-Emile writes, “migrating from the criminal regulatory regime into the public health regulatory regime.”

Of Electric Eyes, $20 Knees & Flying Cars

CNN recently featured what it called the Top 10 Health Innovations of 2009. From a $20 knee joint replacement developed by Stanford students (which may in time at least partially replace the titanium versions currently marketed with price tags from $10,000 to $100,000), to a microchip developed by MIT researchers which may, as an “electric eye,” help blind people to regain partial sight. There’s also a smart stethoscope which can transfer monitored data directly to a computer where that which has been transmitted can be further analyzed; a new found process which uses pieces of wood to regenerate broken bones; and a Transcranial Magnetic Stimulation Therapy System which has shown promising results in treating the depression of those who have not been able to obtain relief through anti-depressants. The electromagnetic headpiece “pulses magnetic fields into a patient’s prefrontal cortex, the part of the brain that regulates mood” and “stimulates the neurons to make more mood enhancing chemicals.”  The technology may offer relief to millions of people who suffer from depression. Amazing really.

The award winning New Jersey Journalist Paul Milo has just published a fascinating book entitled “Your Flying Car Awaits: Robot Butlers, Lunar Vacations, and Other Dead-Wrong Predictions of the Twentieth Century.” Milo has produced what Harper Collins has aptly referred to as an “insightful compendium of the most outrageous and completely ridiculous predictions of the 20th Century.” And as I, having grown up in the late Sixties and Seventies, ponder this present dire lack of flying robot cars (we were veritably promised), I can’t help but be amazed that we’ve reached a point where machinery may offer sight to the blind and knees to the poor.

And if still upset about the flying robot cars, there’s always the Transcranial Magnetic Stimulation Therapy System.

The CNN graphic showing the Top 10 Health Innovations is well worth a quick look.

Pharma Marketing, Advanced

With the Senate’s bill clearing late night hurdles, the coverage in the mainstream media is, at least for the moment, broad. But there was a segment on NPR’s All Things Considered in the midst of all that Health Reform bill coverage that is well worth a listen. The segment, “How A Bone Disease Grew To Fit The Prescription,” (transcript linked, audio below) functions as a sort of biography of the evolution of both a drug and a disease– which was not, it seems, an entirely independent process.

The drug is Merck’s Fosomax, the disease is Osteopenia. Fosomax had sales in 1996 of $281.8 million; by 2005, on the heels of what qualifies as a comprehensive and wildly successfull marketing effort, the drug had sales of $3.2 billion.  Osteopenia derives its origin as somewhat of an afterthought, when in 1992 “a group of osteoporosis experts gathered under the auspices of the World Health Organization” and drew a somewhat arbitray bright line to determine what level of bone mass loss was normal and what amount constituted a disease. The term “Osteopenia” was coined, on the spot, to give clinical researchers a term which described those whose bone loss was considered normal, but was close to the line. They never imagined that Osteopenia would come to be considered a disease in itself, but it did. Millions of women are said to have it; millions treat it with Fosomax. The story of how this came to be (and the implications regarding the role of Pharma in health care) is fascinating.

The FDA Steps In: Regulating Prescription Drug Promotion on the Internet

The FDA has been widely criticized for not providing guidance for drug companies eager to promote their products on the internet.  Earlier this year, the FDA expressed the view that the message was what was important, not the medium, meaning that companies should simply apply the rules governing prescription drug advertising in print media to the internet.  On April 2, 2009 the agency issued Notice of Violation letters to 14 companies who sponsored links on internet search engines advertising their products; the links gave the name of the drug and, in some cases, its indicated use, without including the required “fair balance,” i.e., safety information such as contraindications and potential side effects.  In reliance on the so-called “one-click rule” — which had never actually been adopted by the FDA — the companies had put the required safety information one click away on a separate page.

In recent months, the FDA has indicated that it is open to providing internet-specific marketing guidance.  Yesterday and today (November 13^th) the agency is holding a hearing on “Promotion of FDA–Regulated Medical Products Using the Internet and Social Media Tools.”  Representatives from advertising agencies, consumer groups, health-related websites, pharmaceutical companies, and search engines are scheduled to testify.

In written testimony released before the hearing, PhRMA, the pharmaceutical industry’s trade group, proposed that the FDA approve a standard universal warning: PhRMA suggests “All drugs have risks.  Click here for more information from the manufacturer.” — for use “in places throughout the Web where there is not enough room for complete disclosure of all warnings, indications, and contraindications (e.g., search results and microblog posts.)”  Such a warning would, PhRMA argues, allow companies to take advantage of sponsored links, make full use of Twitter, etcetera, while also providing easy access to safety information.  PhRMA even suggests that the warning incorporate the FDA’s logo, arguing that this could mitigate against “the dangers posed by illegal Internet drug sellers.”

It will be interesting to see whether and how the proposals of the other groups represented at the hearing differ from PhRMA’s, and, of course, whether the FDA in the end decides that its “fair balance” requirements should be modified for the web.  Among the other interesting issues FDA may address is companies’ responsibility for web content they do not control.  Google’s introduction of Sidewiki, which allows anyone visiting a pharmaceutical company’s website to leave a comment, has brought this issue to the fore, raising, for example, the prospect of doctors discussing a product’s off-label uses on the manufacturer’s site.

Anyone who wishes to comment on these or other internet-specific promotion issues may do so through February 28, 2010.

ACCME: Showing Some Teeth?

This week, the New York Times reported on efforts by the Accreditation Council for Continuing Medical Education (ACCME) to step up its enforcement of its Standards for Commercial Support.  Drug and device companies spent over a billion dollars on accredited continuing medical education (CME) courses in 2008; ACCME’s Standards for Commercial Support are meant to ensure that industry funding does not translate into commercially-biased content.  ACCME’s new focus on enforcement comes in the wake of a Senate Committee on Aging hearing over the summer at which Dr. Steven Nissen of the Cleveland Clinic testified that ACCME should be abolished because it is a toothless watchdog, “uninterested or incapable” of enforcing its Standards.  And that was not the first time ACCME’s oversight of CME has attracted congressional attention.  A 2007 Senate Finance Committee investigation uncovered numerous cases in which drug and device companies violated ACCME’s Standards and expressed concern about ACCME’s years-long delays in imposing penalties for compliance failures.

While noting that medical education is largely self-regulated, Dr. Murray Kopelow, ACCME’s head, told the New York Times that, relative to years past, ACCME was active in 2008 and 2009, investigating twelve complaints and finding five courses to be commercially biased.  In addition, the organization will soon post to its website a list of CME courses and providers found to be biased.  ACCME will also consider a proposal that providers whose courses are found to be commercially biased be required to alert the doctors who attended and provide them with corrective materials.

While these efforts are salutary, an effective enforcement program would require a significant commitment of time and resources (in 2008, there were just under 50,000 accredited CME activities), which ACCME may not have.  Well-known critic of industry-funded CME Daniel Carlat (author of “Dr. Drug Rep,” a fascinating piece about his experience giving paid promotional talks for a drug company) had this  to say about the prospects for effective enforcement:

…if the Atypical Antipsychotic program is bad enough to be pulled for commercial [bias], my conservative estimate is that at least half, probably more, of all industry funded psychiatry CME will also need the retraction treatment. The problem is, who on earth has the time to police these things? Certainly not ACCME. Dr. Carroll and I try to keep on top of the worst of the worst, but we have other things to do in order to make a living. The best and simplest solution would be to end industry funding of medical education altogether.

Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy has recommended just that — that industry funding be ended altogether, on the grounds that drug and device industry funding too often leads to bias and that such bias is incompatible with CME’s educational aims.  Dr. Nissen makes the additional argument that ending bias in CME would reduce inappropriate prescribing of branded prescription drugs, which would in turn yield significant cost savings.  As Dr. Nissen told the Senate Committee on Aging, “That’s one of the ways we can pay for healthcare reform.”

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