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FDA Should Have Banned LABAs Five Years Ago

December 10, 2008

Analysis of:FDA: Long-Acting Asthma Drugs Increase Asthma Risks | online.wsj.com

The "news" that long-acting beta agonists (LABAs) increase asthma-related morbidity and mortality is not news at all -- this has been known at least since 2002.  When the news of this originally emerged earlier this decade, there was lots of spin put on the dangers of LABAs, both by drug companies and pediatric pulmonologists.  The first spin was that LABAs are only dangerous in a specific ethnicity -- African-American -- which has turned out to be false.  The second spin was that LABAs were only dangerous to those who used them as needed and sporadically, as opposed to those who used them daily and preventatively -- this, too, has been proven false.  And then the third spin was that these LABAs were only dangerous in those who did not use them in combination with an inhaled corticosteroid -- an illogical claim that finally seems to have been dispelled with all the others.  It is difficult to predict the FDA's reaction, however, since it has rejected evidence for the last five years.

When Your Neighbor Takes an Antibiotic, So Do You

October 13, 2008

Analysis of:C. Difficile And Antibiotics Not Necessarily Linked, Study Finds | www.sciencedaily.com

This study did not conclude that antibiotic use does not precipitate C. difficile infections.  What it found was that the individuals who are infected with C. diff did not necessarily take antibiotics in the six weeks preceding their infection.  In my mind, rather than demonstrating that C. diff is not necessarily antibiotic-related, it suggests two things that we sort of already knew: 1) the C. diff problem is so bad that individuals not treated with antibiotics are still at some risk for the disease if their community contacts have been exposed; and 2) in many cases of C. diff, there is not a neat and immediate connection between administration of antibiotics and development of symptoms -- a person can take antibiotics and not become symptomatic from C. diff infection for several weeks or months.

Published Evidence Bias: Approved Drugs Are Just the Tip of the Iceberg

September 29, 2008

Analysis of:Many Trial Reports on FDA-Approved Drugs Go Unpublished | www.washingtonpost.com

This study looked at drugs that were eventually approved by the FDA, and found that only 43% of early phase (non-"pivotal") trials were published in the medical literature.  But imagine what this means for drugs that ultimately fail: if drugs that are destined for success are withholding 57% of their early phase data from the peer-reviewed public domain, I would imagine that biotech companies with drugs that ultimately fail publish even less about their investigational therapies.  This probably has less of an effect on patients and doctors, since the vast majority only have access to drugs that are already approved -- but think of the impact this has on investors in the biotech space.  Drugs that ultimately go nowhere probably publish their uninspiring data at a rate well below the 43% seen in drugs that succeed, and so the relative bias that colors these drugs is even greater. 

At What Cost Prevention?

August 6, 2008

Analysis of:Researchers Look to Pill, Taken Daily, to Avert H.I.V. | www.nytimes.com

There is already a bounty of data to support anti-retroviral (and other) HIV medications in post-exposure prophylaxis, be it in infants born to HIV-positive mothers; intra-partum prophylaxis to HIV-positive women in active labor; and to healthcare workers (and others) exposed to HIV from accidental needlesticks and other exposures.  Pre-exposure prophylaxis is simply a broadening of post-exposure prophylaxis -- it is simply the a priori administration of HIV medications to those who might have an exposure, so that post-exposure prophylaxis is assured and begun immediately -- and so it is reasonable to assume that it will have the same infection reduction rates as current post-exposure protocols.  What will be different is the risk-benefit and cost-benefit analysis: with pre-exposure prophylaxis, you will expect a higher cost per infection prevented, and you would expect a greater side-effect toll per infection prevented.

No One is Paying $30K For One More Month

June 2, 2008

Analysis of:Erbitux Slightly Boosts Survival in Cancer Study | online.wsj.com

Or whatever the total cost of Erbitux is that is required to get you four more weeks of life.  This is basically what it comes down to.  Most cost-benefit analyses will justify up to $60K spent per year of life in amortized costs, but not above that.  So the total costs of Erbitux to justify one more month on this planet could not exceed $5K to justify extending life by one month.  And by total costs of $5K, I am not talking only about the costs of Erbitux for one month: I am talking about the cost of Erbitux for the entire interval required to get you one more month, PLUS the cost of the standard chemotherapy to which it is being added (or at least one month of that cost), PLUS the cost of taking care of a dying patient for one more month, much of which will be spent in a hospital setting (but not a hospice which, by definition, would not accept anyone looking to squeeze out four more weeks with active treatment).

Aclasta, or How to Make a Market Where There is None

April 21, 2008

Analysis of:Study Shows Once-yearly Aclasta Better Than Risedronate at Increasing Bone Mass in Patients with Osteoporosis Caused by Glucocorticoids | pharmalive.com

Aclasta, an IV bisphosponate known generically as zoledronic acid, seems to do one thing consistently: it has an uncanny knack for showing an absolute risk reduction of about 1-2% in whatever endpoint is being measured, and against whatever control it faces head-to-head.  It has been shown to have a 1-2% absolute risk reduction in hip fractures when put up against placebo in post-menopausal women, and it has shown to have a similar effect in patients hospitalized for a hip fracture.  Now it has been shown to improve a clinical radiographic marker (bone mineral density) in patients on steroids when compared to risedronate, at about an absolute risk reduction of 1-2%. So let's ask: As effective oral bisphosphonates such as risedronate and aledronate come off patent and become extremely inexpensive, is anybody going to pay for an IV infusion that will give you three days of fever for the 1-in-a-hundred chance that it will be better than a pill you have to swallow once a week?

Rotarix will all come down to cost

April 9, 2008

Analysis of:FDA Approves ROTARIX(R) Rotavirus Vaccine | www.pipelinereview.com

Rotavirus vaccination is already widely accepted by pediatricians, and Merck's Rotateq has been a medical and commercial success, so ultimately this will not change the primary care strategy of infants.  The question is whether or not pediatricians will change from Merck's Rotateq to GSK's Rotarix, and that will all come down to cost.  Rotarix is only two doses, as opposed to Merck's three-dose vaccine: since it is an oral vaccine, and not injectable, the one-dose reduction won't matter much to parents.  But the one dose reduction might make it cheaper for pediatricians.  It all depends on how it is priced, and the effect on cash flow will have at least as much an effect on what private pediatricians will purchase as much as the reimbursement rate.

Rounding Out Lilly's Diabetes Armamentarium

March 19, 2008

Analysis of:Eli Lilly, Transition Therapeutics enter licensing, collaboration agreement | www.forbes.com

The most obvious (potential) benefit to Lilly of its collaboration agreement with Transition is that it will be adding one more potential class of diabetic therapies to its product line.  Lilly already has Humulin (longer-acting insulin), Humalog (a rapid acting insulin), Actos and exenatide (a GLP-1 hormonal therapy for diabetes).  Now it will have, in its agreement with Transition, a gastrin-based hormonal therapy for diabetes (assuming, of course, that the drug works, which is hardly guaranteed).  So the obvious benefit to Lilly is that it is positioning itself to have several different product types to offer to an exploding, epidemic disease population.  The benefit to Transition, of course, is that it now has the funding to develop this gastrin-based drug.

Public Health Agency of France Gets it Right on HPV Vaccine

January 17, 2008

Analysis of:France Backs Sanofi's HPV Vaccine Gardasil Over Glaxo's | online.wsj.com

To those of us pediatricians in the United States who have been administering HPV vaccines for a couple years now, it has long been evident that Merck/sanofi's HPV vaccine, Gardasil, is superior to GSK's offering in the same space, Cervarix. It is not because GSK has a bad product -- indeed, it is pretty good. It is just that Gardasil covers more serotypes of HPV than Cervarix does, and so will cover against more viral pathogens that infect women. GSK has countered that Cervarix' immunogenicity is superior to Gardasil's, but who cares: the question is, how much disease is prevented, and the answer is that Gardasil prevents at least as much as Cervarix, with the theoretic potential of preventing even more. I offer Gardasil to my patients for the same reason that the French government would like to: it is the best HPV vaccine on the market. In regard to how this ruling will affect EU sales, it is hard to predict whether other EU countries will fall in line with France's lead.

Drug Rep Licenses in D.C. Will Have no National Effect on Sales

January 14, 2008

Analysis of:DC passes pharma rep licensing bill | www.fiercepharma.com

OK, so now to peddle pharmaceuticals to doctors in D.C., a drug company will have to license their reps.  This will be a pain in the neck to the reps and those who supervise them, and will probably result in a small increase in the cost of doing business for detail people -- but I don't see how this will have a national effect on pharmaceutical sales. The biggest effect I envision is a little more revenue for the D.C. District Council, which stands to make a little more money by issuing licenses. Pharma is peeling back its detail forces anyway, and there has been a small trend to employ "remote detailers" or "tele-detailers" -- drug reps who get to the docs by way of the telephone and some mailed promotional material, even mailed samples. If I were a pharma company and I didn't want to deal with drug rep licenses in D.C., I'd take a tele-detail or direct-mail approach, and schedule all my drug dinners in the surrounding Maryland or Virginia suburbs, and just not deal.

Ophena is a Me-Too Drug with an Impractical Mode of Administration

January 14, 2008

Analysis of:QuatRx Pharmaceuticals Announces Positive Phase 3 Results for Study of Ophena(TM) (ospemifene) to Treat Postmenopausal Vaginal Syndrome | www.prnewswire.com

Before addressing all the practical obstacles that might face Ophena, it might be helpful to acknowledge all the problems already faced by established drugs that are similar to it. The most similar would be Evista, another selective estrogen receptor modulator used primarily for osteoporosis, which has been hounded by its association with cardiovascular morbidity. Ophena is a drug in the same class, and one would have to wonder if post-menopausal women would risk a cardiovascular toxicity profile for the benefit of a non-fatal, lifestyle condition -- my guess is no. And there are numerous drugs on the market that have different mechanisms of action than Ophena, but are used for similar post-menopausal indications. The most notable would be Premarin, which has also been hounded by its association with cardiovascular morbidity, a factor which has limited the drug's use in its oral formulation. But at least Premarin is available topically, which would reduce systemic complications.

Menveo: Good News for Novartis, but Perhaps Better News for sanofi

November 20, 2007

Analysis of:New data for Menveo(TM) vaccine show excellent immune response and broad protection for infants against meningococcal meningitis | www.pipelinereview.com

Novartis should be applauded for completing the earliest stages of a conjugated meningococcal vaccine for infants and young toddlers.  However, it is conceivable that Novartis' Menveo may be cannibalized in the market by sanofi's Menactra. Menactra is an already FDA-approved conjugated meningococcal vaccine against the exact same serotypes that Menveo covers, and it is approved for use in a single-dose regimen for ages 2 and up. It is an excellent product with good results and a track record of safety. It is true that Menactra is not approved for use down to the age of 6 months, but it is likely that sanofi is aware of the challenge from Novartis, and one would imagine that sanofi is looking to expand its indication down to an even younger age group. In addition, sanofi already has extensive data in all phases (I-IV) on Menactra, and so I imagine it could meet this challenge from Novartis rather swiftly. Menactra has developed "brand name" recognition within the vaccine space - a plus.

Innovation is not the Issue: The Question is, Does Aprotinin Improve Outcomes?

November 1, 2007

Analysis of:FDA Issues Early Communication about an Ongoing Safety Review Of Aprotinin Injection | www.medicalnewstoday.com

Aprotinin, a complex bovine protein with effects on clot dissolution, coagulation and enzymatic digestion, is without a doubt an innovative product. But innovation alone should not be the standard when the purpose of a drug is to improve patient outcomes. And so, whereas aprotinin is undoubtedly an innovation when compared to older anti-fibrinolytic agents such as tranexamic acid and aminocaproic acid, it appears to fall short of the more important standard, which is decreased morbidity AND mortality in the patients who receive the drug. Older studies that have provided aprotinin with traction have focused on intermediate outcomes: blood loss, transfusion requirements, etc. And though these are certainly important and worthy endpoints, the most important measurement should be mortality. To that end, the recent DSMB data suggests that, despite less incidence of bleeding and transfusion, Trasylol seems to contribute to greater mortality, which is ultimately the only measure that matters.

If Rikelta Works Better Than Other Epilepsy Agents, it Will Probably be Due to its Improved Toxicity Profile

October 31, 2007

Analysis of:UCB Announces Initiation of Phase III Clinical Programme for RikeltaTM (brivaracetam) as Adjunctive Treatment in Partial-Onset Epilepsy | www.pipelinereview.com

Epilepsy patients who have already failed to achieve control on two or three different regimens (be they single or multiple drug regimens) are unlikely to find success with any new regimen -- that's just the nature of the disease, unfortunately.  Failure on seizure medications is more a prognostic sign that indicates the nature of the patient's disease than a predictive sign that evaluates the potential efficacy of a medication -- failure of anti-epileptics is not so much a commentary on the inadequacy of the drug(s) being used as the complexity of the patient's disease. With that being said, there is always the possibility that a drug might work better if you could increase the dose without increasing the side-effect profile, and that's what Rikelta might be: a "newer" Keppra that allows higher dosing because of high binding affinity and thus a better toxicity profile. Perhaps this drug will work best for those who  improved but had to discontinue Keppra because of side effects.

Avandia Beware: When the New V.A. Acts, It is Usually Right

October 24, 2007

Analysis of:U.S. veterans dept to limit Glaxo's Avandia: report | www.reuters.com

The United States Veterans Administration is probably the best HMO in the country, provided you are measuring the attainment of good clinical outcomes at reasonable cost.  Believe it or not, the VA, which has the unenviable task of providing healthcare to a relatively sick and historically disenfranchised population, is consistently ahead of the curve in just about everything when compared to other health maintenance organizations: it was one of the first nationwide systems to go electronic, it streamlined its access to primary care and specialty referrals, and it has kept costs low by using evidence-based medications that are, whenever possible, generic.  The VA, which used to be a chastised laggard, is now a leader. So what does this mean for Avandia? Well, if the leader in the field has abandoned you, I would wonder what all the followers are going to do.

Different Scents Makes no Sense, While Difference in Cents Makes Most Sense

October 23, 2007

Analysis of:New Allergic Rhinitis Treatment Avamys™ Receives Positive Opinion In Europe | www.medicalnewstoday.com

From the standpoint of what is clinically practical, Avamys is not a new drug: it is fluticasone in a nasal spray, available for years as Flonase, now off patent and available in the U.S. generically and as Veramyst (the same product as Avamys). Despite claims that Avamys/Veramyst is the first drug with an indication for both allergic rhinitis and conjunctivitis (itchy eyes), doctors have been using Flonase/fluticasone for both for years already: the specific indication for itchy eyes doesn't tell us anything we didn't know already.  Nobody is going to stop using Flonase or generic fluticasone because it doesn't have the formal FDA indication for itchy eyes: doctors already know it works for that and, despite differences in Avamys/Veramyst's formulation (scentless), most will view the different formulations as equivalent. The choice between the different formulations of fluticasone is an easy one: they all work more or less the same, so you might as well go with the cheapest.

Do Adults Having Their Blood Drawn Need an Anesthetic, or an Anxiolytic?

October 23, 2007

Analysis of:Anesiva Announces Pivotal Phase 3 Trial of Zingo(TM) Meets Primary Endpoint and Significantly Reduces Venous Access Pain in Adults | www.bio-medicine.org

Certainly Zingo has the potential to be used in adults, and falls into the category of old, safe drugs with new, clever formulations. But how necessary is this drug in adult practice? It appears to me that there is often confusion between the pain caused by venipuncture and the anxiety and phobia that it generates. Whereas this lidocaine product has been shown to be an effective anesthetic for adults and children, I don't see how it can overcome the more cumbersome issue of needle phobia, other than by a placebo effect. The adult patients I see are all 18-21 (I am a pediatrician), and the issue is almost never the pain associated with these mildly invasive procedures -- it's the pulse-quickening anxiety that leads up to the needlestick. Surely there are patients that have just about had it with blood draws -- oncology patients, those with chronic disease -- and they might need a break, but do a significant number of adults need anesthesia for their yearly cholesterol check?

Antidepressants: A Rising Tide Does Not Lift ALL Boats

October 11, 2007

Analysis of:Boehringer Ingelheim News Page -- 5th Bullet Point | www.boehringer-ingelheim.com

Flibanserin is, at its root, a molecule with antidepressant activity.  Decreased libido is, at its root, a cardinal symptom of depression.  So the notion that an antidepressant drug might increase the sexual desire in those who have lost it is not so far-fetched, and pre-clinical trials in animal models seem to demonstrate some effect of flibanserin against anhedonia (inability to experience pleasure).  The problem with the selective serotonin reuptake inhibitors (SSRIs), which are currently a very safe and effective class of drugs used for depression (Prozac, Zoloft, Paxil), is that one of their biggest side-effects is decreased sexual drive, even when it is successfully treating the other aspects of depression. Flibanserin apparently is only a partial serotonin agonist (and has some dopamine effects, too), and thus might offer relief of some depressive symptoms (decreased libido) without also causing it as a side-effect. Of note: this is very early, preliminary, phase zero, unproven.

Fluorosis-stained Teeth are Still Preferable to Cavities; Perhaps Supplementation Guidelines Might Change in Future

October 10, 2007

Analysis of:Some babies get too much fluoride | www.mlive.com

Since dental disease remains one of the most common to affect both American children and adults, it is unlikely that the cosmetic issues associated with fluorosis would result in a recommendation against the fluoridation of public water systems.  Fluoridation is a valuable public health measure against the development of tooth decay.  Perhaps, however, in light of recent findings, the guidelines for fluoride supplemenation (in tablet or suspension) for children might change: perhaps dosages will be lowered in light of recent findings.  Likewise, it might be deemed unnecessary to use a fluoride-containing toothpaste if the local water supply is fluoridated.

Risedronate (Actonel) Trial Likely to Promote a Monthly Regimen

September 21, 2007

Analysis of:New Phase III Data Presented For Once Monthly Dosing Regimen Of Risedronate To Treat Postmenopausal Osteoporosis | www.medicalnewstoday.com

The design of this trial, which compares daily 5 mg Actonel (risedronate) to a monthly 150 mg dosage, is likely to demonstrate equivalence. First, the study uses risedronate 5 mg as an active control, without a placebo arm: this is appropriate, as the purpose of the study is not to demonstrate benefit, but non-inferiority - it's a true head-to-head design. Second, the measured end-point is bone mineral density (BMD) of the lumbar spine, and not a clinical outcome (for example, fractures): this makes the study both easier to measure and complete, because clinical events are not being measured, just a diagnostic test value. However, this study will not be able to make conclusions about Actonel as compared to other osteoporosis treatments, or even to placebo: it can only compare Actonel to itself in different dosing protocols. The study appears to be designed in a way that will endorse a monthly risedronate regimen as equivalent to a daily regimen, as the 12 mo. BMD data is non-inferior.

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