Lily must pay up: pharma and illegal drug promotion

I first came to understand the link between the responsibility of pharma to closely follow FDA marketed drug regulations and related pharmaceutical company lawsuits with the landmark Merck settlements. The Vioxx claims of increased cardiac events in patients and the cover-up of data implicating these conditions reminded me of the power pharmaceutical companies have affect the lives of millions of people. For me, that opened up a whole world of knowledge of the area of pharmaceutical litigations, especially with the rising number of lawsuits dealing with illegal drug promotions. Bristol-Myers Squibb had to pay $389 million for illegal promotion of the use of Abilify (aripiprazole) to children. Purdue Frederick had to pay $700 million in connection with the resolution of charges on the promoting of the opioid analgesic, OxyContin, which opium-related side effects were not delved. And now Lily must pay over $1.4 billion across various states in the US, the highest sum for any case perpetuated by a whistle-blower, for the illegal promotion and the use of schemes to increase the number of prescriptions of the drug Zyprexa to vulnerable populations.

One of the big news reports in the pharmaceutical word right now is the criminal and civil law suits against Eli Lily surrounding the marketing of Zyprexa, an atypical antipsychotic commonly used to treat schizophrenia and biopolar disorder. For instance, research has shown that the use of Zyprexa is associated with increased mortality from heart failure in elderly patient populations, especially those being treated for various forms of dementia. However, Eli Lily use methods to market to these special population of people beyond FDA regulations. Scandal also arised from this cases due to the lack of scientific evidence that this generation of agents is significant better than older generation of anti-psychotics. Eli Lily could possibly lose the rights to participate in Medicaid and Medicare, one of the biggest finanical support for prescriptions in the US, because of the charges against the company. This, however, is unlikely due to the essentialness of Lily products to elderly patients who depend of government programs.

Since it is not illegal for physicans to prescribe drugs off-label for new indications, pharma has learn to exploit the use of physicans in getting around FDA marketing laws. One way pharmaceutical companies have been involved in illegal promotion is through the use of drug representatives to inform physicans about additional indications drugs can be used for. This is where scandal arises since it is illegal to do so. Additonal, pharmaceutic companies have been known deceive the FDA in the beginning stages of clinical trials. By clinical testing for an indication route that can easily get fast approval, pharma can then promote to healthcare professionals for a wide variety of indications.

Though these practices are illegal, pharma breaking scientific and medical ethical codes is not uncommon in this environment of captalism and big profits. Truth is, even if they are caught in the act, these companies with settle out of court or plead guilty and pay a fine that, though in the millions, are sometimes only a small percentage (1% or less) of annual revenues. In the case of the Zyprexa, there hasn't been a dramatic change in total monetary sales for the product, attributed to the raising of drug prices. Honestly, this unethical practices may even be cost effective when you compare the billions gains from illegal promotion. So don't expect any change anytime soon.

References:
Lily said to be near $1.4 billion U.S. settlement
How drug companies covertly promote off-label drug use

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Efficacy and Safety of Incretin in Type 2 Diabetes

Currently available hypoglycemic agents are not able to successfully lower the hemoglobin A_1c (HbA_1c) level to less than 7% in the majority of type 2 diabetics. If not from ineffective usage, the lack of efficacy is majorly due to a decrease in pancreatic beta cell function. Efficacy is also limited by adverse effects such as weight gain, edema, hypoglycemia, or lack of targeting of postprandial hyperglycemia. New treatment options aside from the conventional antidiabetic agents are being considered for nonpregnant adults with type 2 diabetes.

One recent therapeutic approach is to exploit the role of incretins, intestinally derived peptides which are released in the presence of glucose in the gastrointestinal tract and act to stimulate the secretion of insulin. The two major incretins are glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are active in decreasing blood glucose when levels are less than 55 mg/dL but are quickly degraded by the enzyme dipeptidyl peptidase 4 (DPP4). Because the incretin pathway is disrupted in patients with type 2 diabetes, incretin-based therapies have been developed and used clinically to decrease hyperglycemia. Current therapies include the injectable GLP-1 analogue exenatide which is resistant to degradation by DPP4 and sitagliptin, a DPP4 inhibitor used as a single agent or in combination with metformin or thiazolidendione.

The purpose of this study is to evaluate the efficacy and safety of incretin-based therapies using data collected from 29 randomized controlled clinical trials comparing incretin-based strategies with non-incretin-based agents (placebo or other antidiabetic agents). Each of these pharmaceutical industry-sponsored studies were double-blind except those including insulin which were open-label. Data from clinical studies were gathered from MEDLINE, Cochrane Central Register of Controlled Trials, and other relevant websites and included information from unpublished abstracts since results were found to be consistent with published data. Additionally, only trials lasting at least 12 weeks were included in the analysis to ensure the accurate assessment of efficacy.

Glycemic efficacy was determined primarily by noting the changes in HbA_1c from baseline between treatment groups. Fasting plasma glucose and postprandial glycemia following a mixed-meal test were secondary indicators of efficacy. Assessment of safety was determined by evaluating changes in body weight, lipid profile, and hypoglycemia. Any information on the levels of circulating antibodies to the incretin analogue was also noted. Importantly, the description of each trial and method of analysis was also evaluated in order to ensure the quality of the study. For all continuous variables, the weighed mean differences were calculated with a 95% confidence interval (CI) for comparisons across treatment groups while for dichotomous variables, the risk ratios and 95% CIs were calculated.

Results of the meta-analysis showed the GLP-1 analogue exenatide were efficacious in decreasing HbA_1c from baseline compared to the placebo and was as effective as insulin in open-label studies. In evaluating postprandial glycemia, exenatide reduced this parameter to a greater extent than insulin glargine or biphasic aspart. Significant weight loss was reported with GLP-1 analogues verses non-incretin-based treatments. Data on the effects of GLP-1 analogues on lipid profiles showed that insulin improved HDL over exenatide but exenatide treatment induced a small decrease in LDL compared to placebo. Mild to moderate nausea and vomiting with some instances of diarrhea was the most common adverse effect and was a major reason for trial withdrawal. These gastrointestinal complications were thought to be due the effects of GLP-1 analogues in reducing gastric emptying and only occurred in the initial weeks of the studies. A high incidence of antibodies raised to these analogues was also noted, but this did not specifically lead to any negative outcomes.

The DPP4 inhibitors sitagliptin and vildagliptin were found to similarly lower HbA_1c compared to placebo but were less efficacious compared with other hypoglycemic agents. Fasting plasma glucose was also reduced with DPP4 inhibitors over placebo. In terms of adverse events, there was a very low incidence of hypoglycemia similar to other treatment groups, and no significant change in lipid profile. There was no risk of gastrointestinal complications as with GLP-1 analogues. However, an increased risk of infections, such as urinary tract infections and nasopharyngitis, as well as headaches was noted with the DPP4 inhibitors sitagliptin and vildagliptin, respectively.

When considering the clinical use of incretin-based therapy, it is important to note that the efficacy of these agents in lowering the HbA_1c is highly dependent on the baseline levels. Though these agents were associated with a low risk of hypoglycemia, other potential adverse effects reported in these studies should be taken into consideration, especially since all trials did not go beyond 30 weeks. Combining these agents with other therapies may also increase unwanted effects. Additionally, the clinical data gathered in this study did not consider differential effects in various ethnic populations and in children. Further investigation into the efficacy and safety of incretin therapy is warranted to accurately determine their benefit over currently available treatments for type 2 diabetes.

References:
Efficacy and Safety of Incretin in Type 2 Diabetes: Systematic Review and Meta-analysis

Drug discovery: forward or reverse pharmacology?

Drug discovery is a very complex process which entails discovering new agents for the treatment or prevention of diseases and disorders. Despite the high level of advances in the understanding of the human body, from basic human physiology to the smallest level of the human genome, a potential agent still takes an upward of 15 years from pre-clinical study in the lab to the patient lying in a hospital. Only in understanding the various strategies that have been implemented for the development of clinically successful agents can one find the best approach for effective drug discovery. Recently, new terms have been coined to describe two approaches to the study of the interaction between organisms and chemical molecules used to alter the biochemical function of molecular targets: forward and reverse pharmacology.

Much of the drug discovery and development that is carried on today is based on forward pharmacology. In this approach, a molecular target instrumental in modulating an abnormal biological process is first identified. One then searches for a molecule that can either positively or negatively modulate this target, depending on the desired clinical outcome. Then is often through the use of high-throughput screening of compound libraries, using the molecular target as "bait" to "hook" the potential therapeutic agent. Forward pharmacology is thus simply a target-based strategy.

Conversely, in reverse pharmacology, agents that have a history of therapeutic activity are used as a starting point for drug discovery. Documented medicinal compounds, often from traditional natural sources, have their active ingredients isolated, and these molecules are the basis for drug discovery. Reverse pharmacology often operates on three consecutive levels: experiential, exploratory, and experimental. Pharmacoepidemiology, or the study of the effects of drugs in a large human population, constitutes experiential reverse pharmacology. Information on traditional medicine including the illness or disease it is used to treat and any potential side effects are gathered. In exploratory reverse pharmacology, extensive scientific study is conducted on these compounds to learn the mechanism of action and the targets of these agents. Human dose determination studies are also sometimes conducted. Experimental reverse pharmacology involves the opitmization of these chemical entities using computational chemistry to maximize activity, potency, or water solubility.

There are many advantage and disadvantage to forward and reverse pharmacology approaches. Forward pharmacology is often attractive due to the advances in the technology associated with high-throughput screening and the large compound libraries that have been constructed. However, an inherent disadvantage of forward pharmacology is that drugs are discovered exclusively on their ability to target specific cellular molecules. Billions of dollars are spent within the pharmaceutical industry developing potential drugs which be successful in pre-clinical models but fail in clinical studies due to toxicity, unfavorable pharmacokinetics, or lack of target validation. Because of this, a large number of drug candidates may be identified in the pre-clinical discovery period but only 1-5% reaching the end phases of clnical trials due to numerous bottlenecks. Additionally, the big pharmaceutical industry sometimes only focus on discovery agents that modulate long established targets instead of new targets because of the risk of failure. These are some areas where reverse pharmacology is favorable. Since agents with therapeutic success is studied in the reverse approach, a sense of the pharmaceodynamic and pharmacokinetic properties are known and new targets have the potential to be validated. This can also lead to a shorter duration between drug discovery and drug marketing. Also, due to these factors and the use of computational chemistry, there is a great chance for there to be a greater number of compounds entering clinical trials compared to those in pre-clinical study. There are some drawbacks to reverse pharmacology, however. Often times, these agents may have multiple targets that are never identified and assays to validate these compounds are often phenotypic (i.e. pain reduction, decrease in blood pressure, reduction of tumor size).

All in all, both forward and reverse pharmacology approaches have a place in drug discovery. However, all factors must be taken into consideration to determine which approach is best.

References:
Pharmacology at a reverse
Chemical complemenation: A definitive phenotypic strategy

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