Pharma’s Cutting Edge

Try to get a hold of the article by Eichacker et al in today’s NEJM  (sub. req.) entitled: ”Surviving Sepsis: Practice Guidelines, Marketing Campaigns, and Eli Lilly”.  They give the most detailed published account that I can recall that attempts to show how industry influences clinical practice guidelines.  They do so by temporally aligning communications made at scientific events with guideline development progress, revelations of clinical trial data and pharmaceutical sales (see the supplemental bibliography to the published editorial) for their sources of information).  In this effort, the authors are assisted by Lilly’s own PR firm for Xigris (rhAPC, Lilly’s drug to treat sepsis), Belsito & Company, which published a brief account of its “surviving sepsis” campaign on the Council of PR Firms website (I’m guessing this account will be removed from the site soon, so read it while you can).

Influencing practice guidelines is part of what the industry does.  It is fiduciarily obligated to its investors do so, to the extent it is allowed, because in the age of evidence-based medicine, disease management and quality-based compensation of physicians, practice guidelines increasingly influence prescribing, and you can’t sell drugs without prescriptions.  That said, it is also in industry’s interests to behave ethically, honestly and to the benefit of its customers (both doctors and patients) as it does so.  The two goals are not mutually exclusive!  There are at least two sides to every scientific story.  To the extent that an industry member argues its side aggressively, it can hardly be blamed.  To the extent that it lies or obscures the truth when doing so, it can be.

In the case of Eli Lilly and guidlelines for the management of sepsis, Eichacker et al suggest that the whole truth was not revealed by practice guidelines.  They don’t go so far as to state that Lilly was responsible for the guideline omissions, but they imply as much.  I hope that Lilly feels the need to respond directly to this implication, as it should every similar implication, because a questioning of the integrity of a pharmaceutical company in a visible public forum such as the NEJM is always serious enough to warrant a direct response.  If Lilly did something wrong in this case, they should own up to it and make amends.  If not, they should show where Eichacker et al over-reached when drawing their conclusions or making their implications.

The practice of influencing clinical guidelines is certainly not new.  Perhaps the best-known example is also probably one of the first: when Merck influenced and then widely promulgated NCEP cholesterol guidelines to boost sales of Mevacor (Mevacor was approved in September 1987; the first NCEP guideline was published in January 1988).  See this U of Michigan case study for a very brief account.  With Mevacor, Merck showed the industry the way, and the industry has become more adept at managing guideline and thought-leader development ever since.

Eichacker et al have used the Lilly example as a reason (excuse?) to raise alarms about industry influence over medical practice guidelines generally, albeit some 15 years late.  There’s no denying that they raise some valid concerns.  However, they offer little in the way of practical suggestions for addressing them.

It’s easy to say “Ban industry funding of practice-guideline development efforts and its financial support of the individuals involved in such efforts.”  But, even if such a ban were agreed to by likely industry-fund recipients, those organizations and individuals determined to take industry money for their efforts would find a way, including through other non-banned funding mechansims (e.g. of research projects) to do so.  And this “solution” provides no alternative funding sources for such efforts that are without their own conflicts, some potentially much more worrisome than those discussed by Eichacker et al (think managed-care funding for one).

Medical science, medical education and medical practice in most of the world is inextricably linked and dependent upon pharmaceutical industry funding and will likely remain so for the forseeable future.  It is unreasonable to expect that the industry will spend money on research without some control over how that money is spent, and it is also unreasonable to expect industry to fall short on its obligations to its investors when it comes to influencing medical practice, thereby maximizing the commercial value of its products. 

Understanding this reality, responsibility falls first upon the medical community to find practical solutions to keep industry money from unduly swaying legitimate scientific debates in industry’s favor.  Avoiding taking industry money for one effort (e.g. IDSA’s refusal of industry support for its practice guidelines) and accepting it for another is merely the appearance of avoiding undue industry influence.  To minimize the potential impact of financial conflicts, it makes more sense for physician organizations to require objective guideline-development criteria that don’t favor industry-funded studies over non-industry funded studies and guideline-development procedures that involve broader swaths of the medical community working in an open environment (e.g. online).

For its part, responsibility falls on the industry to help dissuade its member companies from abusing their influence over key medical decision-makers, even when non-offenders may not be directly affected by the unethical behavior.  I have not read any suggestions from industry members how to do this.  Here’s one:  appoint a board of ethical review officers within the major trade organizations (in the U.S., PhRMA and BIO) whose responsibilities include writing industry standards of ethical behavior and policing medical practice guidelines.  If evidence of unethical behavior is found in a guideline, an inquiry is launched, and, if a member company is found to have violated ethical standards, it would face sanctions such as revocation of trade-group listing and public “outing”.  It might not be viewed as a serious solution to those who would prefer to see Pharma divorced from medical practice and policed by public governments, but to the industry it would be a huge concession to academic medicine and a huge step forward.

Dennis Nowak reports on the rampant dissatisfaction with working conditions among German doctors in the Oct 12th issue of the (”Doctors on Strike — The Crisis in German Health Care Delivery).  If you care about the future of healthcare delivery, and you’re not already familiar with the German healthcare system, read this brief and compelling account. 

In it you’ll read how most of Germany’s physician’s have recently walked out of work to protest an increasing workload and relatively low wages (the purchasing power of a German physician’s wages is now about 20% that of a U.S. physician).  It wasn’t always this way, when healthcare costs were lower as a percentage of GDP, German physicians worked relatively less and earned relatively more.  But Germany has relied on sacrifices among its healthcare workers to help constrain growth in government healthcare costs.

As result of this policy, the loss of purchasing power for physicians in Germany has been paralleled by relatively small increases in Germany’s per capita public healthcare expenditures.  According to a 2005 NBER report from Christian Hagist and Laurence Kotlikoff that compared healthcare costs in ten OECD countries,  Germany’s per capita healthcare expenditures increased at an annualized rate of 3.6% between 1970 and 2002, the lowest annualized rate among major economies.  Compare this rate with Norway’s, the highest, of 5.3%.

Despite the controlled growth in per capita healthcare expenditures, Germany’s per capita healthcare expenditures as a percentage of GDP have spiralled upwards, becoming the highest among the 10 leading economies (8.6%).  This is because of Germany’s anemic GDP growth over this period, just 1.5% annualized, again the lowest among major economies.  As a result, Germany’s per capita healthcare expenditures as a percent of per capita GDP has increased, to become the highest among the 10 major economies in 2002 (8.6%).  Compare Germany’s level of spending with the U.S. 2002 level of 6.6%, which puts the U.S. in the middle of the pack [note that I’m speaking of per capita spending in 2002; aggregate spending on healthcare as % of GDP is higher in the U.S. than in Germany: ~16% vs. ~11%].

You can quickly see how a healthcare delivery crisis can arise when the general economy weakens and a dominant proportion (80% in Germany in 2000; compare with 45% of healthcare spending from public sources in the U.S. in 2004) of healthcare expenditures are made by the government: governments restrain healthcare costs by putting downward pressure on healthcare-worker wage growth, as GDP growth stalls, but real-wage growth lags healthcare delivery needs (owing to population aging) resulting in overworked, underpaid healthcare workers who then look to other countries for better conditions, leaving less highly qualified workers, who work more, so quality suffers, etc.

Is Germany’s crisis a foreshadowing of healthcare crises everywhere?  Just wondering.

It’s been a while coming, but 2006 has finally seen the introduction of legislation to the U.S. Senate that, if passed, would create a statutory pathway for FDA review and approval of genuine generic biologic drugs.  The Act, which the sponsors have asked be called “Access to Life-Saving Medicines Act,” was read into Congress yesterday.  The Senate version has No. S.4016 and has been referred to the Senate Health, Education, Pensions and Labor Committee (Chaired by Sen. Enzi ) for review and debate.

The U.S. generic manufacturers trade association, the GPhA, immediately announced its strong support for the legislation, while PhRMA and BIO, the innovators’ trade groups remained silent.  It’s likely that GPhA personnel played a prominent role in crafting this legislation, which has been speculated to have been in the works for over a year.

The text of the Senate bill is still at the printing office, but Rep. Waxman, who will be sponsoring the unnumbered House version, published the bill’s text on his website.  As there is a reasonable chance that the version that will eventually emerge from Committee will conserve some elements of the bill as published, and as there is also a chance that a competing bill (supported by innovators) will soon be introduced, I’ve decided to devote some of my time outlining it here.  For those of you would would like to read the official summary, Rep. Waxman has published that as well.

Just a bit of background for readers who may not regularly read my blog (have a look at the generics category for related posts).  This new bill is intended to amend the Public Health Service Act.  Biologic drug products are regulated primarily by Sec. 262 of the PHS Act.  “Traditional” small-molecule drug products are not regulated by the PHS Act, but rather are covered by the Food, Drug and Cosmetics Act.  Of particular importance to this discussion is Sec. 505 subsection (b) and Sec. 505 subsection (j) of FDCA, which provide for the major pathways by which new drugs gain introduction to the U.S. market. 

Although an accelerated development/approval pathway that relies on predecessor biologic drugs per se is not found within Sec. 505 (b) or (j) of FDCA, Sec. 505 (b)(2) does provide for accelerated development/approval of new drugs that rely on another sponsor’s investigations, when the original sponsor’s patent(s) and marketing exclusivity have expired.  FDA has published a draft guidance (2001) for how and when such investigations may be used to gain marketing approval for a new drug.  As one of the examples for types of applications that would be covered in 505(b)(2), FDA wrote the following:

Naturally derived or recombinant active ingredient. An application for a drug product containing an active ingredient(s) derived from animal or botanical sources or recombinant technology [my emphasis] where clinical investigations are necessary to show that the active ingredient is the same as an active ingredient in a listed drug.

Time does not permit me to review the debate–and lawsuits–that have surrounded FDA’s application of 505(b)(2) provisions.  Suffice to say, that innovators have generally opposed use of this pathway and that generic manufacturers have generally supported it.  No surprise there.  Nevertheless, prior to 2006 quite a few drugs, including several peptides and four recombinantly made proteins, have been approved using the 505(b)(2) pathway.  Read the rest of this entry »

FDA’s crack down on compounding has apparently been dealt a setback according to this FDA News Story describing a U.S. District Court opinion.  I had previously discussed FDA’s recent crackdown on national compounders, which FDA claimed were behaving more like drug manufacturers than compounders, risking patient safety.  Let’s have a brief look at the lawsuit and opinion itself (Decision). 

A group of compounding pharmacists joined forces to sue FDA in 2004.  They sought summary judgment relief from FDA in five general areas: the practice of compounding itself, FDA inspections of compounding pharmacists, compounding from bulk ingredients for non-food animals, FDA’s compliance policy guideline 608.400 (relating to compounding for non-food animals), and injunctions against FDA.

Compounding itself:

Plaintiffs claim that compounded drugs are not “new drugs” under the United States Code.  FDA disagrees.  The Court sided with the Plaintiffs, granting summary judgment, finding that FDAMA (1997) implicitly exempts compounded drugs from the new-drug definitions.  However, the Court upheld FDA restrictions that limit compounding to “compounds which are made in reasonable quantities upon receipt of a valid prescription for an individual patient from a valid prescriber. Drugs that are compounded in large quantities before a prescription is received from a doctor do not fall with the narrow exemption this Court finds exists.”

Inspections:

Plaintiffs contended that they are exempt from inspections, beyond FDA’s general and limited inspection authority, specifically from “enhanced inspections” that include inspections of records.  FDA argued that they were entitled to the enhanced inspections.  The Court sided with the Plaintiffs, finding that since the Plaintiffs themselves met the inspection exemption requirements of USC 374(a)(1), they were exempt from inspections.  Note that the Court was careful to make this judgment applicable only to the Plaintiffs in this case, as they had demonstrated their exemption status.

Compounding from Bulk for Non-food Animals and FDA’s Policy Guideline:

The Plaintiffs argued that nothing in the law prevented them from compounding drugs for non-food animals.  FDA argued that such drugs were new drugs that were unsafe, adulterated and misbranded.  The Court again sided with the Plaintiff’s, finding that pharmacies may compound for non-food animals using legal bulk drug.  As far as the policy guideline on non-food animal compounding, the Court agreed with FDA that its policy guideline doesn’t violate the Adminstrative Procedure Act’s requirement for notice and comment, since it doesn’t contain new substantive rules.  However, the Court further found that FDA would not be premitted to enforce the portion of its policy guideline and notice which conflict with the Court’s ruling on compounding (above).

Injunctions:

Plaintiffs sought injunctions against FDA that would prevent FDA from declaring that: compounded drugs were new drugs,engaging in enhanced inspections, enforcing its compliance policy guideline,prohibiting plaintiffs and other compounding pharmacists from receiving bulk ingredients, and bringing actions against Plaintiffs for refusing to allow FDA to conduct enhanced inspections.  The Court denied these injunction requests without prejudice, opening the door for future injunctions to be granted if re-urged later.

Putting it all together, I can see how this Court ruling can be construed as a victory for compounding pharmacists.  It was clearly a victory for the Plaintiffs who swept the Court’s decisions, save for the injunctive relief sought.  And it reinforced legal support for the practice of compounding per se.  However, FDA’s recent crackdown on compounding pharmacists and their threat to go after other compounding pharmacists are not based on arguments the Texas Court defeated.  Rather, FDA is claiming that these compounders violated laws regulating new drugs and that they are not exempted by FDAMA.  Specifically, FDA is going after compounding pharmacists that it believes are acting like manufacturers of drugs, making drugs in advance of receiving a valid prescription.  The Court in the Texas case was careful to note that the Plaintiffs in this case were found not to have violated the FDAMA exemptions for compounding pharmacists, leaving the door open for rulings against compounders that do violate these exemptions.  In a nutshell, this ruling leaves allows FDA to shutter the operations of manufacturers that disguise themselves as compounding pharmacists, while allowing genuine compounding pharmacists to operate legally.  Sounds like a win-win to me.

It’s a sign o’ the times, as I’ve said countless times in these pages. Payors are attempting to squeeze every last penny from between the links of the prescription-drug value chain. I single out the case of IBX (that’s Independence Blue Cross, the Philadelphia Region’s largest insurer with coverage of ~3.5 million lives) only because I’m a customer–hurray! The same thing is happening everywhere; there’s no place to hide. Recently, IBX announced two “cost-saving” initiatives that will limit consumer choice of new drugs (by limiting reimbursement and/or raising co-pays for innovative medicines) and hit innovator Pharma in the bottom line.

The first initiative is called FutureScript. It’s a PBM run by IBX (IBX is ending its relationship with Caremark for in-person Rx purchases; they will continue using Caremark for mail-in scripts) that will initially manage IBX’s commercial Rx drug program and soon thereafter its Medicare program as well. Basically, IBX argues that having its own PBM allows it to better control costs. What that means for consumers, however, is that owning its own PBM allows IBX to offer less choices at higher co-pays for its customers compared with Caremark, which faces the pressure from a larger, less-captive customer base.

The second initiative is the Select Drug Program formulary. This is an aggressive formulary management program that automatically excludes all new branded drugs from from Tier 1 and 2 co-pays (IBX uses a three-tier co-pay structure) and subjects new drugs to pre-authorization (case-by-case; nothing new there). Generics are automatically added to the formulary at the first tier (i.e. lowest co-pay) and the innovators they replace are automatically consigned to the third tier (i.e. highest co-pay). Again, that’s not new.

What is new is a practice that IBX describes as a convenience to some consumers: shifting some self-injected meds from medical benefits to drug benefits (and from doctor’s offices and hospitals to retail drug-store shelves). These drugs can now be conveniently picked up at the pharmacy, where they might or might not be covered with a Tier 3 co-pay. How convenient (use Dana Carvey’s Church Lady voice for maximal impact when reading the foregoing).

In addition, IBX is clamping down on the practices of docs who routinely inject meds in their offices by hooking up with vendors who will monitor the use and cost of such injections to provide IBX with the most “cost-effective” purchases. If you’re a doc in the Philly area, you may read this as further invasion of your practice for the sake of saving insurers money. But don’t bother complaining, lest you risk insurers exhorting you to climb down from your big blue cross.