Pharma’s Cutting Edge

Following FDA’s non-approvable decision for rimonabant (Acomplia) last year, I referred to Sanofi-Aventis’ pursuit of an indication for the metabolic syndrome as “kakameyme”.  Seems like FDA’s Metabolic and Endocrine Division (DMEDP) agrees with me.

DMEDP this week released its long-awaited revision of its 1996 clinical guidance for development of weight-loss drugs.  Most of the changes were expected, based on a 2004 advisory committee hearing to discuss the topic.  Highlights of the new guidance include delineation of the recommended exposure to active treatment (3,000 subjects for at least 1 year) in placebo-controlled studies and tips for getting claims of obesity-related complications into the label.

I hadn’t necessarily expected FDA to provide specific guidance for making metabolic syndrome claims.  They surprised on the side of logic and scientific evidence; good for them.  Here’s the relevant paragraph:

The term metabolic syndrome represents a cluster of laboratory and clinical findings that serve as markers for increased risk for cardiovascular disease and type 2 diabetes, and, depending upon the definition used, is prevalent in as much as 25 percent of the adult American population. The FDA does not necessarily consider the metabolic syndrome to represent a distinct disease entity. At present, there is no single etiological factor or central pathogenetic abnormality identified as mediating the constellation of excess visceral adiposity, abnormal lipids, elevated blood pressure, and insulin resistance that comprise the metabolic syndrome. Nonetheless, in addition to lifestyle modification, a host of drug therapies now exist to address individual or multiple components of the syndrome (e.g., lipid altering agents, antihypertensives, insulin sensitizers). Ideally, a therapeutic product intended to treat metabolic syndrome should normalize or improve all components of the syndrome, independent of weight loss (see section VIII), and ultimately be shown to prevent the development of type 2 diabetes and reduce cardiovascular morbidity and mortality.

As S-A investors will undoubtedly recall, S-A has emphasized for the last two years that Acomplia benefits patients with metabolic syndrome (see this for instance).  But it looks like FDA is demanding a demonstration that a drug improves each of the metabolic syndrome components and/or improves cardiovascular morbidity/mortality independently of weight loss before it will allow the use of the phrase “metabolic syndrome” in a drug’s indications for usage.  S-A made it clear that it was hoping to get an indication for metabolic syndrome, presumably because it believed that drugs targeting metabolic syndrome would be viewed more favorably by third-party payers than drugs targeting weight loss and secondarily improving obesity-related complications  But this type of thinking is highly speculative over mid-range timeframes, even if supported by quantitative market research, because the attitudes of third-party payers change over such timeframes in response to environmental factors, such as prevailing academic medical opinion, political pressure and public opinion.

Bottom line for now is that investors and drug developers should not expect to get a claim for metabolic syndrome until they are willing to spend the money needed to establish the validity of such a claim.  For those seeking claims for obesity and its complications, the new FDA guidance provides a clear blueprint for approval in the U.S.  Most of its teachings will also transfer directly to the EU and elsewhere.

I try to stick to topics of broad interest to the life sciences industry.  I rarely get personal.  Today, I’ve decided to break my rules to honor a friend to many of us in the industry.

Last week, Mary Gallagher of New Hope, PA died after a brief but horrific battle with cancer.  Her death at age 50 came as an unnerving shock to her many friends and co-workers who knew only that she had taken a leave of absence from work in December.

Mary was one of those people whose work you rarely read about.  Her job promotions weren’t celebrated in press releases.  She wasn’t a recipient of national awards.  She didn’t edit a journal or write a blog.  All she did was make sure that the work got done.

After a couple of decades in the business, some people take their jobs for granted.  They assume roles of entitled elder statesmen who pass off mundane jobs for others to do while taking credit for successes and pawning off failures. 

Not Mary.  She grew into her role as a clinical operations leader gracefully, becoming a genuine expert while remaining virtually egoless.  She was a supervisor but was available to perform any task without complaint if she felt it needed her personal attention.  She gave credit to others freely and shied from the spotlight herself. 

At her funeral, Mary’s co-workers described her as gentle and kind, hard-working and confident.  They mentioned her infectious smile, broad and literally glowing, her fair skin becoming erubescent with little prompting.  They reflected on her empathy and her eagerness to listen and to mentor.

Mary Gallagher will not be remembered in textbooks of pharmaceutical medicine.  Her story will not be learned by college students.  But the world needs to know about Mary, because she made a difference.  She was all that any of us can aspire to be–a decent human being who shared love and kindness and served as an example for others to emulate.  The pharmaceutical industry, indeed all of humanity, has lost a brightly shining star.

The story Study Finds Flaws in Cancer Clinical Trials reports on a study designed to examine the adequacy of Phase 2 oncology clinical study design.  Sophisticated investors won’t be surprised by the conclusions of the study–that Phase 2 oncology studies frequently fail to describe and account for historical clinical data used for efficacy comparison.  In fact, sophisticated hedge fund investors frequently capitalize on this unfortunate fact, by shorting the stocks of selected small companies when their oncology candidates reach Phase 3.

Heck, even non-sophisticated investors can profit.  Just short equal dollar amounts of the stock of every small company whose oncology drug reaches Phase 3 based on an historical efficacy comparison.  If you sell when enthusiasm is high and hold the position long enough (and the commissions or interest rates you’re paying aren’t excessive), you’ll come out ahead, because these companies fail in Phase 3 more often than they succeed.  And when they fail, their stocks usually fall through the floor.

But if profiting from the misery of cancer patients isn’t your cup of tea, perhaps you, the activist investor, could simply demand greater due diligence of the management teams responsible for these flaws? 

FDA and the US Veterans Administration (VA) announced signing a Memorandum of Understanding (MOU 225-07-4300) that would enable the agencies to share information for the main purpose of: “build[ing] infrastructure and processes that meet the common needs for evaluating the safety, efficacy, and utilization of drugs, biologics, and medical devices.”

The MOU is far too wishy-washy to satisfy me, let alone Congressional critics of FDA’s drug safety oversight policies.  Consider Item 3(d) of the MOU, which reads more like a guideline for avoiding progress than achieving it:

3d. FDA and VHA agree that either may decide not to share information or expertise in response to a particular request for information made according to the procedures established under Section 3.b., or to limit the scope of information and expertise sharing in response to a particular request. A decision not to share information in response to a specific request may be based on several factors, including, for example, the amount of resources necessary to fulfill the request, the reasonableness of the request, the responding Federal partner’s priorities, or legal restrictions. In the event both partners can not reach consensus on a decision to share or not share information, the issue will be referred to the FDA Deputy Commissioner for Operations and the VHA Under Secretary for Health for a final decision.

Federal agencies like the VA and CMS (Medicare/Medicaid) are responsible for acquiring and maintaining a treasure trove of therapy utilization and medical claims data.  Getting at these data in a way that is useful for monitoring the safety of therapeutics by FDA should be a cornerstone of any national therapeutics safety-monitoring policy. 

What is needed is a genuine alliance between these federal agencies, formed by a dedicated group of experts, who have dedicated resources to support them, and led by an upper-level management committee whose main role is to ensure continued support of the agencies and Congress.  A promise for agency liasions to hold quarterly meetings and for the parties to respond to specific requests for information (as opposed to a provision for open information exchanges) is not nearly good enough.

It increasingly looks like Congress is going to have to legislate a mechanism for sharing data that holds individuals responsible and accountable for making progress.  It’s clear from the language in this MOU that Congress must also make such data sharing a priority of all involved agencies and that it must earmark funds to support it.