Off-Label Communications: Is More Less?

Allergan corporation has filed a law suit against the Federal government challenging the FDA’s limits for companies discussing or promoting off-label uses of approved medicines.  This is not a new issue, but the news reports indicate that Allergan is going very old school and basing their legal challenge on Constitutional freedom of speech rights.

The issue is not can doctors and patients use approved medicines for conditions, (or in ways), which are not specifically approved by the FDA, but can companies discuss these off-label uses with physicians or provide them with published information about these off-label uses?

Competing Risk-Benefit Perspectives
The competing risk-benefit perspectives that surround this issue are nearly identical to the trade-offs that all stakeholders in biomedical research and development face – including the FDA, companies, patients, clinicians, and legislators:

  • Creating a landscape that protects individuals and public safety
  • Being flexible enough to provide clinicians and patients access to the best available treatment possibilities
  • Providing companies a reasonable market environment that creates incentives for developing new treatments and investigating new uses for already approved medicines, which also has marketing rules that are as clear as possible so companies can conduct business without being excessively concerned about straying into regulatory gray zones

Off-label use is common in clinical practice – particularly for disease areas like cancer – because it often represents the standard of care.  And in situations where a medicine approved to treat a common condition has an off-label use for a rare condition, the company has very little incentive to conduct the expensive and time-consuming clinical research to get the FDA to approve that rare off-label use.

There are a few key points underlying the issue of communicating information about off-label uses:

  1. The Constitutional freedom of speech rights for a company are not as expansive as for an individual
  2. The FDA’s regulatory authority focuses on the approval for sale and marketing of medicines, (and some other product areas), and not their use in clinical practice – with some very rare exceptions
  3. The FDA’s position about companies disseminating information about off-label uses has not be fixed in stone

On this last point, the 1997 FDA Modernization Act included a provision to expand the ability of companies to give physicians journal articles and similar material about off-label uses of approved medicines.  After that the Washington Legal Foundation brought a law suit seeking to expand off-label information dissemination.  And when the FDAMA provisions expired in 2006, the FDA proceeded with rule-making guidance to replace the FDAMA provisions, and this final guidance became effective in January 2009.

Not having read the details of Allergan’s legal challenge – and since the FDA doesn’t comment on current suits – it’s hard to assess the specific pros and cons of their positions.  But considering the extensive legislative and case law involving this issue, the company certainly seems to have a very steep hill to climb.  On the other hand, it would seem unusual that they would spend the time and money to bring a legal challenge unless they felt they had a chance to prevail. However, Allergan’s suit may have implications for the FDA, industry, clinicians, and patients for several or many years – even if they lose – because they may be making a pretty big splash in the policy pond with such a public challenge to change the rules for off-label promotion, and this will likely alter the landscape for any future actions.

I was involved with a somewhat analogous situation in the mid-1990s where a lot of groundwork had been done to prepare for a substantive debate about reforming a fundamental life sciences policy issue.  However, one company had an urgent and particular need for a legislative change, and they proceeded to pursue every reasonable and extraordinary avenue for getting the change they wanted.  The end result was that all our subsequent discussions were short-circuited because every policy stakeholder’s response upon raising this issue, was “Oh, I know about THAT issue,” with the implication that it was something they wanted nothing to do with because of the controversy the one company had stirred up with their expansive activities.  (I’ve purposefully not named the issue so as to not perturb anyone or any company about something that happened years ago.)

Collective Sausage Making
The moral of this story is that to make productive changes stakeholders within and across groups frequently need to work together. And if they don’t, the well can easily get polluted for everyone when policy makers avoid any action because they connect the issue to a nasty smell.  This may be another manifestation of the old adage, “the two things that shouldn’t be seen being made are laws and sausages.”

Happy Sausage Making - 2009

Groups Seeking Funds in Health Reform

With all the anticipation about health reform happening soon, many groups are expecting increased Federal funding for different things, e.g. electronic medical records, expansion of SCHIP and Medicaid (or at least great funding assistance to States), more emphasis on personalized medicine, more resources for FDA to help them with their expanding domestic and international responsibilities, closing the donut hole in the Medicare outpatient prescription drug benefit, fixing Medicare’s physician payment formula, etc.

Another area looking for increased emphasis and funding – both as part of health reform and economic/jobs stimulus – are biomedical researchers.  The Boston Globe and Mass High Tech had articles last week describing how the Massachusetts Life Sciences Collaborative is lobbying for more NIH grant money.  The reason for this being particularly important for Massachusetts is the state’s leadership in receiving NIH funding, receiving NIH funding of $344 per resident in 2007.  The Boston Globe’s on-line article contains these numbers, but the print edition also had a great graphic – the data from which is in the chart below:

NIH State Funding 2007 Source: Boston Globe/National Institutes of Health.  “Note: Data is preliminary and excludes some research contracts.”

NIH supporters were successful in doubling the NIH budget over 5 years, (from ~$13B to ~$27B from FY1998-2003), and this resulted in a significant increase in the number of researcher grants and the likelihood of grants proposals being funded. However, since then, the increases have not been as significant – See chart below:

NIH Funding 1993-2008
Source: National Institutes of Health (Years are Federal Fiscal Years)

The challenge of the new Congress and Administration will be to allocate dollars for both the stimulus package and health reform to have the greatest effect in the shortest amount of time.  Fortunately, the last Congress deferred many funding decisions e.g., the SCHIP program authorization expires in March, and the Continuing Appropriations law (PL 110-329) funds large parts of the government – including the NIH – until March 6, 2009.  Therefore, this Congress will need to – and have the “opportunity” – to address many funding issues sooner rather than later.

Personalized Medicine – Fulfilling the Promise of Genetic Research

It has been 55 years since the discovery of the structure of DNA, and 40 years since James Watson published his account of that discovery in his book, “The Double Helix.”  (A picture of my autographed copy is below.)

Double Helix - James Watson - Signed Copy

Ever since DNA was discovered to code for the structure of most living things, there has been the hope that understanding abnormal genetics would lead to the ability to treat or cure a vast array of illnesses.  Unfortunately, that progress hasn’t been as rapid as originally hoped.  But medical science is now beginning to put genomic research discoveries into actual medical practice, and start customizing medical treatments based upon each individual patient’s genetic makeup – the fundamental concept of “Personalized Medicine.”

What are genetic tests and how are they used?
The simplest genomic tests are those that inform a clinician about the choice and/or dosage for a medicine to treat an individual patient.  This type of test is generally easy for clinicians understand and use since it provides information that it is very similar to antibiotic resistance testing – a test that clinicians have used for decades.  Currently, this type of genetic testing to guide pharmaceutical treatments is being used to guide chemotherapy for cancer – where the genomic make-up of the cancer cells can indicate susceptibility or resistance to certain medicines.  It is also being used in a few other ways, including identifying individuals whose genetic make-up indicates that they should receive lower (or sometimes higher) dosages of certain medicines.

New Reports on Personalized Medicine
Several publications and reports have come out recently about advances in Personalized Medicine.  The most recent of these was three articles in the November/December issue of Health Affairs.  These articles point out the challenges for turning scientific advances into better clinical and economic outcomes.  In discussing this very broad issue these articles emphasize the progression from the laboratory, to clinical research tools, to clinically useful tests that can provide information to guide medical care, to actual treatments designed to interact with or alter the individual’s genetic makeup.

There are obviously many additional facets and nuances to this progression, and it is a very challenging road on which reimbursement plays a very important part in determining speed of development and research priorities.  That is, reimbursement amounts and policies not only influence access to genetically-based tests and treatments, but they also create incentives that guide the development of future tests and treatments.

Another recent publication is from FasterCures, titled “Patients’ and Consumers’ Interests and Perspectives in Personalized Healthcare.”  This paper provides patient perspectives – which are not overtly addressed in the Health Affairs articles.   To present a broad picture of patients’ perspectives, FasterCures surveyed various groups and individuals, and they found that:

  • Patients are just beginning to understand the concept and potential of “personalized medicine” – although the term may not be recognized or fully understood by many people.
  • Many see personalized healthcare as an advancement that should be consistent with and support “patient-focused care,” and that it should help improve the quality and cost-effectiveness of healthcare.  However, many also recognized that new tests and treatments have the potential for increasing total healthcare costs – at least in the short-term.
  • Patients want to be educated and involved, not only in their direct clinical decisions, but also in the research and development process that relates to their particular health concerns.  And there was also a recognition of the tension between genetic testing being available, and the results of those tests being meaningful and useful.  (This tension was also discussed in the Health Affairs papers.)
  • And of course, patients are concerned about the privacy of their genetic information.

The FasterCures paper concludes with a 4 point Action Plan for speeding the process of making personalized healthcare a reality:

  1. Involve Patients in Medical Research
  2. Transform the Drug Development Process
  3. Protect Patient Privacy
  4. Focus on and Deliver Patient-Centered Care

Growing Interest and Meeting Information Demands
Interest in applying genomic research to clinical medicine is clearly growing, and genetic tests and treatments will increasingly become standards of care.  For this to happen, clinicians, patients, and other key stakeholders will need a greater understanding of these tests and treatments, and their proper role in clinical care:

Clinicians will need to keep up-to-date about the latest clinical applications involving genetic tests and treatments so they can educate patients in their role as “learned intermediaries” – the term sometimes used to describe how clinicians explain to patients what is causing their medical problems and what are the best treatment options.

Patients will need to be educated about the value and meaning of possible genetically based tests and treatments. And while physicians can do some of this educating, they have limited time.  This gap has begun to be filled by Genetics Educators – a masters level clinician who can work with patients to help them understand the implications of the results of any genetic tests or family history. While there is currently a shortage of Genetics Educators, in the future they may fill a role much like nutritionists do for diabetics, but for a wide range of genetically based tests, treatments and conditions.

And lastly, recognizing that there is a rapidly expanding need to educate other key stakeholders about genomic issues, the Personalized Medicine Coalition (PMC) was formed just over 4 years ago to “to foster understanding and adoption of personalized medicine for the benefit of patients.”  The PMC was started by a couple of dozen biotechnology, pharmaceutical and information technology companies and groups, but has grown into a much larger coalition that includes academic institutions, government agencies, patient advocacy groups, payers, clinical testing companies, and others.  Collaboration among these types of groups that will be necessary for developing, validating, determining appropriate uses and reimbursements for genetically based tests and treatments so that Personalized Medicine will become part of the solution for increasing the quality and cost-effectiveness of healthcare.

Communicating Health Information and this Blog’s Goals

Noting that I’ve written about a wide variety of health and biomedical research issues, someone recently asked me about the focus of this blog.  My response was that my goals are two-fold:  First, to present synthesized information – created by combining different sources and analyses – in ways that provide new perspectives on important issues so that people have both broader and deeper understanding of these issue.  And second, to reach multiple audiences with this information and perspectives so that the spectrum of healthcare stakeholders can better communicate and understand each other.  Which is just stating in a different way what I wrote in my first posting, that the reason I started this blog was “to provide stakeholders of all types, (such as patients, clinicians, administrators, payers, researchers, regulators, legislators, etc.) a forum for discussing healthcare policy issues. The focus of these discussions will be about how the development and use of innovations can effect clinical and economic outcomes.”

I view these two goals are complimentary, since together they help people crystallize insights about issues and make them more able to consider what specific actions would be most productive.

Sometimes my analyses take the form of questioning how information is presented to different stakeholder groups, and how that could be done more effectively.  For example, in the last two days I saw that the FDA notified a company about selling two unapproved over-the-counter medicines (asprin plus nutritional supplements), and issued a warning about a banned ingredient in a food product (Mexican “vanilla”). The challenge for the average person is to first hear about this information, so they can be aware of any risks, and second, to put it into a context useful for them –  such as the potential problem with “Mexican vanilla” if they are taking blood thinning medicines.

For both these situations the FDA issued a press release and notices intended for consumers.  Newspapers generally pick up these stories, and print them in ways that appropriate for the scope of the issue – usually a few inches on an inside page.  My concern is that some people who should know this informaiton might not be made aware of it because the FDA’s very broad mandate and limited resources means that different outside advocacy groups and the media need to spread the word.  Certainly better internet communications and increased FDA funding should help improve this, but as I’ve said before, I think there needs to be broader evaluations of how people get their health informaiton and what they do with it.

We clearly have a health information gap this country – and if this gap was in medical technology or military capabilities then the general public, the media, and politicians would be more engaged and upset.  Thus, the challenge for our country is to expand our discussion of the development and delivery of useful, (some would say actionable – but I don’t like that word), information to people so they can change the decisions they make that affects their health and wellness.

Another example of communications challenges involved the start of Medicare’s new system for paying physicians in the early 1990s.  While the methodology was very complicated – and is still somewhat contentious – the communications issue that rankled many physicians was how the new system was described as distinguishing between what were called “cognitive” and “non-cognitive” services. What this really came down to was differentiating between health care delivery involving a procedure, (like an operation), and testing, talking and prescribing.  As you might imagine, surgeons were not too pleased to be told that what they did was “non-cognitive.”  The reason I raise this old example, is that one of the major challenges facing the US healthcare system is the shortage of primary care clinicians.  And I can imagine that there will be some communications challenges with both patients and clinicians about how to improve this situaiton in the future.  While any policy changes might not pit surgeons v. non-surgeons, it very well might find specialists and primary care clinicians at odds over terminology, status, and of course….. money.

So those have been my goals for this blog, and a couple of examples of the challenges of communicating health related information to different stakeholder groups.  I hope that my postings have at least partly fufilled my goals, and from the comments left here, the emails I’ve received, and direct feedback from readers, I think there’s been some success.  I will continue working to build on those successes, and if you have any comments or suggestions, please let me know – either as a comment here, or via email.

Direct to Consumer Advertising: Drugs, Hospitals, Research….

A very contentious health policy issue is that of advertising.  Usually the specific topic is the advertising of medicines directly to patients – known as “Direct to Consumer Advertising.”  There have been proposals to limit or ban this activity, and some states have, (or have proposed), limiting or requiring disclosure of other marketing activities by pharmaceutical companies – such as marketing directly to doctors and hospitals.

However, I’ve found it intriguing that many other components of the healthcare industry advertise directly to patients.  For example, the Boston area free daily paper, Metro, contains lots of ads recruiting people to participate in medical research trials.  There are also many ads in the newspapers and on the radio about local hospitals – generally touting their expertise in one area or another that is lucrative for the hospital, such as joint replacement surgery.  And unlike pharma products, these other types of advertising aren’t regulated by the FDA – although they may be overseen by other Federal or State agencies.

Another very large vat of health related advertising is done by the herbal and nutritional supplement industry. This is a huge area of medical related advertising.  It is overseen by the FDA and FTC, but I have an entire talk about how this type of advertising fits in with the other information patients receive about their illnesses.  So I’m not going to expand upon this area here – perhaps in another blog posting.

And of course physician advertising was generally seen as unethical until about 10-20 years ago. But now, while still uncommon, (I’m not counting web-sites for physicians offices that tell people the address and phone number, and describe the clinical service the practice offers), it is not unknown for physician practices to advertise.  (Some physician related advertising is also probably partly incorporated into that done by hospitals and others.)

Issue Advertising
Another form of advertising that is quite prolific is issue advertising directed toward policy makers.  Although health care can’t seem to break out of 3rd place in the public opinion polls about the Presidential election, the healtcare industry is still paying about $10,000 per page for advertising in publications like National Journal.  And while the pharmaceutical industry certainly accounts for a portion of these ads, many other groups with healthcare interests are doing this too.  For example, flipping through some recent issues of National Journal I found ads from the following organizations (in alphabetical order) with these headers:

  • American Academy of Family Physicians – “If you health care isn’t working, neither are your employees”
  • American Health Care Association – “Home is not just where you live.  It is where people care for you”
  • American Vetinary Medical Association – “Isn’t a child’s health worth more than a penny?”
  • AstraZeneca – “What does AstraZeneca stand for? Patients”
  • BlueCross BlueShield Association- “When you cover one in three Americans you don’t just offer coverage, you offer solutions”
  • National Association of Realtors – “Soaring Health Care Costs Have America’s Small Businesses on Life Support”
  • Novartis – “People say driving a truck is dangerous.  What about high blood pressure?”
  • Office of National Drug Control Policy – “Rebuild After Meth”
  • Pfizer – “Working together to improve the health of individuals, and the health coverage of the nation”
  • Pfizer helpuful answers – “Prescription assistance for uninsured Americans, from sea to shinging sea”
  • Science Applications International Corporation – “He tells cancer cells to starve themselves to death”
  • SEIU & Greater NY Hospital Association – “Our Nation’s Teaching Hospitals”

I wish I had a simple set of solutions for what troubles people about about both issue advertising and healthcare organizations advertising directly to consumers.  My one overarching conclusion is that assessing the impact of paid advertising directed at patients and policy makers needs to be done in the context of what other information they are being bombarded with from healthcare professionals, the media, family, friends, academic and policy researchers, and others.  Examining the influence of one area of information without evaluating what other types of information may be effecting patients’ and policy makers’ attitudes and actions is like blaming the ocean for hurricane Katrina’s  devastating flooding – I’m not a meteorologist, but I think the wind and atmospheric pressure had something to do with it too.

Stem Cells, Cancer, and Politics

The cover of this week’s Economist magazine caught my eye because this weekend I was talking with people about stem cell issues in the context of the Presidential election.

Economist Stem Cells and Cancer, September 13, 2008

Part of our discussion was how the selection of Sarah Palin as John McCain’s Vice Presidential nominee will effect the Republican ticket’s position on stem cell research.

Doing a quick search on the internet, it appears that John McCain is refining in his position to support research on adult stem cells, while maintaining a foundation that doesn’t alienate the conservative base of his party.  Specifically, the only reference to stem cell research that I could find on the campaign’s web-site is:

Addressing the Moral Concerns of Advanced Technology

Stem cell research offers tremendous hope for those suffering from a variety of deadly diseases – hope for both cures and life-extending treatments. However, the compassion to relieve suffering and to cure deadly disease cannot erode moral and ethical principles.

For this reason, John McCain opposes the intentional creation of human embryos for research purposes. To that end, Senator McCain voted to ban the practice of “fetal farming,” making it a federal crime for researchers to use cells or fetal tissue from an embryo created for research purposes. Furthermore, he voted to ban attempts to use or obtain human cells gestated in animals. Finally, John McCain strongly opposes human cloning and voted to ban the practice, and any related experimentation, under federal law.

As president, John McCain will strongly support funding for promising research programs, including amniotic fluid and adult stem cell research and other types of scientific study that do not involve the use of human embryos.

Where federal funds are used for stem cell research, Senator McCain believes clear lines should be drawn that reflect a refusal to sacrifice moral values and ethical principles for the sake of scientific progress, and that any such research should be subject to strict federal guidelines.

I also found other articles and analyses concerning his earlier positions on stem cell research which seem less equivocal than his current campaign position.

Q: Would you expand federal funding of embryonic stem cell research?

A: I believe that we need to fund this. This is a tough issue for those of us in the pro-life community. I would remind you that these stem cells are either going to be discarded or perpetually frozen. We need to do what we can to relieve human suffering. It’s a tough issue. I support federal funding.

Retrieved from

Source: 2007 GOP primary debate, at Reagan library, hosted by MSNBC May 3, 2007

New Ad
Our weekend discussion also turned out to be a bit prescient, since my internet search turned up information about a new radio ad the McCain-Palin campaign is running that touts all the benefits of stem cell research without making any qualifications about what types of research would be allowed, or any of the moral issues raised on his campaign’s web-site.

Stem Cells Probably Not a Defining Campaign Issue
While stem cell research is certainly a sub-issue of the abortion/choice debate, and would not likely be a deciding factor for many voters, it is an issue of particular interest for biomedical researchers and some patient groups concerned with the development of better treatments and cures for cancers, (as discussed in the Economist), and degenerative diseases like Parkinson’s and Alzheimer’s.  It will be interesting to see how this issue plays out in the next few weeks and if it is raised during any of the debates…. Stay tuned.

E-Prescribing – Good? E-Dispensing Bad!!

With two notable government actions in the last couple of weeks there has been significant movement towards increasing the use of e-prescribing.

DEA Proposed Rule
The Drug Enforcement Agency (DEA), proposed regulations on June 27th that would make it possible for controlled substances to be prescribed electronically. Interestingly, this was released right after a National Journal article on this topic.

The DEA’s proposed rule is very important, because while it is appropriate to place stronger safeguards on medicines that are likely to be abused (which is the criteria for being a DEA scheduled medicine), having controlled medicines prescribed by pen and paper while all other medicines are e-prescribed would be a logistical problem and obviate many of the potential benefits of e-prescribing.  And technologically, if banks and others can provide secure login systems and other security measures, I would think that e-prescribing systems could be similarly secure to make sure that unauthorized people aren’t electronically writing themselves prescriptions for thousands of narcotics pills using a legitimate doctor’s DEA number.  (See more about this in the e-quackery section below.)

Medicare Bill Contains Carrots and Sticks for E-Prescribing
The Medicare bill which passed Congress yesterday included a provision to increase the incentives for physicians to use e-prescribing technologies.  These incentives are a small percentage add-on to allowed Medicare charges for physicians who are e-prescribing starting in 2009, and a cut to payments for allowed Medicare charges starting in 2011 for physicians who are not e-prescribing.

Movement in a Good Direction
Together these actions move the US healthcare system towards greater e-prescribing, something that if done right, should increase efficiency (with lower administrative costs), and improve quality of care and patient safety by creating a better system for detecting and preventing adverse drug reactions from known drug allergies and drug-drug interactions.  The use of computerized prescription order systems for patients in hospitals has been shown to accomplish both of these improvements, but how e-prescribing will work in the outpatient world remains to be seen.

Challenges to Making E-Prescribing Increase Efficiency and Improve Quality
There are many challenges for e-prescribing in clinicians’ offices.  Like electronic medical records, they have to buy and install the systems, learn how to use them, and then keep them updated – since new prescriptions keep getting approved etc.  Because of these challenges, it is estimated that only about 6-7% of physicians’ offices are currently using e-prescribing systems.

Optimally e-prescribing systems should be an integrated part of the office’s electronic medical records system so that it could identify potential problems with drug allergies, or the need to alter dosages for patients with impaired kidney or liver function.  And at a minimum, a free standing e-prescribing system should be able to keep track of each patient’s prescriptions to flag drug-drug interactions, otherwise it may become nothing more than a sophisticated fax machine – which some could argue (but I wouldn’t) is a rudimentary form of e-prescribing.

While, e-prescribing systems should provide alerts about drug-drug interactions,  potential allergic reactions, and the need for dosing adjustments, systems that constantly flash up reminders for such things when they’re not relevant, leads users to ignore them altogether. I take a lesson about this hazard from my brother who works on designing aircraft information systems. Clearly pilots need to know certain things at the right time, but I doubt any pilot would fly better or more safely if they kept getting an alert about it being unsafe to land the airplane because the wheels were up – even with the plane at 30,000 feet.  OK – that may be a bit of an extreme example, but if the e-prescribing system doesn’t know anything about the patient, it may send similarly useless alerts and lead those using it to ignore all alerts – which could be worse than having no alerts at all, since it having them pop-up and be ignored could provide a false sense of security.

This illustrates what most people involved with healthcare reform recognize – improving the quality and efficiency of healthcare in the US requires making the systems work better since our practitioners are generally already pretty good.  But giving these good people flawed systems won’t help them, their patients (i.e. us), or our overall healthcare system.

This brings me to one last point.  How many e-prescribing systems will each clinician’s office need?  I certainly hope that every pharmacy chain/group won’t require their own version of an e-prescribing system, nor will each payer, insurer or regulator require a different electronic or paper output of the prescription information for reimbursement or quality auditing purposes.  If that becomes the case, then e-prescribing will face even greater hurdles.

Since they do good work in this area, I also want to include the eHealth Initiative’s  summary of the challenges for e-prescribing systems:

  • Financial burdens – Physician practices face varying financial burdens related to e-prescribing, including covering the implementation, training and maintenance costs.
  • Workflow changes and change management – Although e-prescribing efficiencies and time savings are gained in the long run, introducing e-prescribing, and electronic health records (EHRs), can be difficult, time consuming, and requires adequate planning, training, and support, particularly in the beginning.
  • Continued needs for greater connectivity – The infrastructure exists for connectivity among pharmacies, physician practices, payers and pharmacy benefit managers (PBMs), but some pharmacies, payers/PBMs and mail order pharmacies are not yet connected.
  • Medication history Although e-prescribing is an improvement over relying on paper medical records and patients’ memories, the information that is available may not always be comprehensive or accurate and therefore tools to adequately reconcile medication histories from multiple sources are needed.

E-Dispensing – Bad!!  And E-Quackery – Bad Too!!!
One of the other challenges for e-prescribing may be the practical and policy interactions between physicians’ e-prescribing and internet sites that sell medicines directly to a patient without a prescription.  While e-prescribing potentially can improve efficiency and quality, e-dispensing can lead to bad fiscal and clinical outcomes from patients getting fake, adulterated or dangerous pills and potions.

Information on the worst examples of e-dispensing is in a recent report from Columbia’s National Center on Addiction and Substance Abuse (CASA).  Their recent annual report found that the number of web-sites selling controlled medicines without a prescription has decreased from the start of 2007 to the start of 2008 – from 581 to 365.  The CASA report also found, “Of those sites not requiring prescriptions, 42 percent explicitly stated that no prescription was needed, 45 percent offered an “online consultation,” and 13 percent made no mention of a prescription.”

I’m not sure if anyone knows what the total number of patients using these sites is, or the number of prescriptions they are filling, so it’s unclear if this reduction represents a real decline in the “industry,” or just its consolidation and maturation.  What CASA also found – and that I find especially worrisome – is “an emerging practice of Internet sites selling prescriptions for controlled drugs that can be filled at local pharmacies. The report also found sites selling online “medical consultations” which enable Internet users to get controlled drugs online without a proper prescription.”  I call this e-quackery, because this is physicians acting inappropriately, or non-physicians acting in the role of a physician and practicing medicine without a license by writing prescriptions.

Other notable findings from the CASA report include:

  • Of the few sites that require prescriptions, half permit the prescription to be faxed, allowing significant opportunity for fraud.
  • Benzodiazepines (like Xanax and Valium) continue to be the most frequently offered drugs for sale with 90 percent of sites selling them; followed by opioids (like Vicodin and OxyContin) at 57 percent of sites, and stimulants (like Ritalin and Adderall) at 27 percent of sites.
  • According to DEA estimates, in 2007 eleven percent of prescriptions filled by traditional pharmacies were for controlled substances compared to 80 percent of prescriptions filled by Internet pharmacies.
  • There are no controls blocking access to these sites by children and teens.

Just to bring things full circle – clearly e-dispensing and e-quackery are bad, so perhaps the greater use of legitimate and appropriate e-prescribing will help to clamp down on these illegal and dangerous activities.  And from a personal perspective, I can also only hope that it will reduce the ongoing flow of spam emails for on-line medicines – and the similar onslaught of spam blog comments to this blog that you never see because I delete them, but which like spam emails, just chew up time from every day.

p.s. Sorry about the long post – but this is an important and complicated topic.

Cracking Down on Fake Cancer Cures

The FDA announced today that they have sent letters to 25 companies to stop selling fake cancer cures. That is, things that the companies claim cure cancer, but have never been tested, or approved by the FDA. The FDA has a web-site with more information about this, and a sub-page that lists 125 Fake Cancer Cures.

I know the FDA gets lots of flack for not doing enough – and not doing it fast enough – I applaud the FDA for taking this action, and encourage them to do more because I have found the advertisement and selling of these non-medicines troubling for a long time.

Cancers are serious diseases by anyones definition, and real medical science is making great strides in developing better treatments and cures, and in overall improving the lives of people living with cancer – both through traditional drugs and biologics, as well as with complementary therapies. But those profiting from selling fake medicines are selling false hope.

I would like the FDA go after more of these people who are profiting from selling fake medicines marketed as cures for other diseases and conditions – particularly ones that may be for symptoms of serious conditions. For example, every time I see the plastic-faced grinning guy on TV hawking a non-FDA approved “natural male enhancement” product, I wonder about all the men who may still be too embarrassed to talk to their physician about their erectile dysfunction problem – which unknown to them is being caused by a serious medical problem, like cancer. And of course for men who are buying this stuff who don’t have ED, then it would be nice if they could talk to their physician about therapy to address the route causes of their feelings of sexual inadequacy.

But of course, the FDA currently has insufficient resources to cover all of it’s multiple priorities – which is why Congress and the Administration are discussing how to provide more funding. Until that happens, I hope the FDA continues being vigilant and stops as many of these purveyors of false hope as they can – at least so these people don’t get the idea that because the FDA’s resources are stretched a bit thin, that the FDA won’t bother them.

Biomarkers Improving Regulatory Reviews and Drug Development

The FDA announced yesterday that both the FDA and the European Medicines Association (EMEA) will accept seven biomarker tests for early kidney damage. These animal based tests were developed by a public-private collaborative and will be a voluntary part of the regulatory applications for new drugs. However, it is believed that companies will benefit by doing these test because they will both be able to detect toxicity problems earlier in a drugs development, and enable the approval of more powerful drugs, “because health care professionals could closely monitor patients and halt the drug if early signs of renal toxicity appear.”

“The development of these and other biomarkers can result in important tools for better understanding the safety profile of new drugs,” said Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research. “We hope these biomarkers will lead to human tests that detect drug-induced kidney injury in people earlier than is now possible, and help health care professionals better manage potential kidney damage from drugs.”

This advanced use of biomarkers represents a quantum leap in our understanding of molecular toxicities and organ damage – these tests detect cellular damage in a matter of hours rather than the actual kidney dysfunction which had occurred over several days by the time the traditional tests of blood urea nitrogen (BUN) and creatinine have become elevated.

The development of these types of biomarkers was also predictable. Over 10 years ago – with prompting by senior industry scientists – I had several discussions with Congressional and NIH staff about the potential value of government support for validating these types of biomarkers. It was important that the government take the lead in developing these tests since all companies would benefit once the biomarkers were validated, and thus the research was beyond the scope of any single company. This reality led to the formation of the public-private coalition to conduct the research to validate specific biomarkers. However, the formation of this consortium is somewhat remarkable because of the structural/cultural barriers between the industry and the regulatory and scientific agencies, and the extreme public scrutiny and criticism of any collaboration between the pharmaceutical industry and its regulatory agencies – no matter how valuable the public benefits.

The development of the kidney related tests is not an isolated advancement. The non-profit organization managing this initiative is working on similar tests for cardiovascular diseases, cancers, and other diseases. Patients and clinicians certainly hope that similar tests are developed quickly for these conditions, and that they will improve the speed and quality of developing and approving new and better medicines.

Accelerating these advancements will depend on how Congress funds the FDA to increase its scientific capabilities and modernize its information technology, as well as how much attention the next President gives to the FDA’s activities – which he should since they touch every American and affect ~25% of the US economy.

People in Clinical Trials: Patients or Subjects?

Are people who participate in clinical trials patients or subjects? This may seem like a minor rhetorical difference, but I believe it has tremendous implications for health and biomedical research policy. Let me explain why –

Clinical trials are experiments to discover new knowledge. Their intent is to see if a new way of treating a specific disease or condition is better than, the same as, or worse than, another option – either a placebo or an established treatment. Therefore, when people agree to participate in a clinical trial they are participating in this experiment, and their fundamental goal for participating should be to help future patients by expanding biomedical and/or clinical knowledge. As part of their participation, they may receive some benefit – IF the experimental therapy does prove to be beneficial. Therefore, they are not patients; they are subjects within the clinical trial.

I often see phrases like “clinical trial patients” or “patients in clinical trials,” and I understand what they are talking about, since for many patients with serious conditions that lack good treatment options, clinical trials offer some hope. However, I think that the term muddles the distinction, and can lead to conflicting responsibilities for the clinician-investigators conducting the trials and the patient’s primary physicians. This is one reason that I believe that patients who elect to participate in clinical trials should maintain a relationship with their primary care physician during the clinical trial – even if the researcher in charge of the clinical trial is responsible for all their clinical care. This also means that the clinical investigator and the primary care physicians for the subjects in the clinical trial need to have regular communications – both before and during the person’s participation in the clinical trial.

When the person’s primary care physician is also the clinical investigator in the clinical trial, these lines are easily blurred, and this can lead to problems – something that all clinician-investigators struggle with. This is why clinical trials have protocols that are pre-approved by at least one Institutional Review Board (IRB) that is charged with protecting the rights and welfare of subjects in the clinical trial. (IRBs are also involved with monitoring the clinical trials and modifying the protocols as needed during the course of the trial.)

I was reminded about this issue by an article in the May 1st issue of American Family Physician that discusses when and how it is OK to use a placebo in clinical practice, i.e. for patients rather than clinical trial subjects. The article lays out a bright line for physicians – “do not lie” – as well as referencing an older article* that lists five conditions that should be met before giving a placebo to a patient:

  1. There is a well-established, durable physician-patient relationship
  2. There is a concrete diagnosis that does not mandate or support the use of other “active” interventions
  3. The patient specifically requests that the physician provide some form of intervention
  4. The use of such agents is a consideration of last resort
  5. The use of such agents does not substitute for, or interfere with, diagnostic and therapeutic diligence

The distinction here is between using a placebo clinically, and using it in a clinical trial. For someone to become a subject in a clinical trial, they need to first give their informed consent so they are aware of the risks involved with their participation. Having a physician give such informed consent in clinical practice when using a placebo might actually undermine the placebo effect, and thus remove any benefit the patient might receive from the placebo. The AFP article specifically counsels that if a patient asks about a recommended treatment that is a placebo, that an appropriate response from their physicians should be something like – this may not directly affect your condition, “but it may turn on other mechanisms that might be important for your health and make you feel better.”

Any additional thoughts on this issue?

* Bok, S., “The ethics of giving placebos,” Sci. Am. 1974; 231 (5): 17-23