Pembrolizumab and nivolumab: PD-1 inhibitors for advanced melanoma

This article looked at the progress of two new drugs for advanced-stage melanoma that target the PD-1 receptor. They were recently approved by the FDA for treating patients with unresectable or metastatic melanoma. Pembrolizumab and nivolumab are antibodies that prevent the PD-1 receptor, a programmed cell death receptor, from interacting with its ligands by binding with the receptor. This allows the body to have a better anti-cancer immune response.

This is a breakthrough treatment option, because usually surgical resection is only possible in early-stage melanoma. Chemotherapy is the most common option for patients with advanced-stage unresectable melanoma. Other medication options offer only moderate benefit and significant toxicity. Immunotherapy is an effective treatment for melanoma and other cancers, and even though only about 20% of patients respond to this type of therapy, they usually have long-lasting responses. Adverse reactions experienced from PD-1 inhibitors can usually managed with corticosteroids.

Clinical trials tested the safety and efficacy of Pembrolizumab, and a Phase I open-label trial of 135 patients found that 38% showed an objective response and a progression-free survival time of at least 7 months. 79% of patients had an adverse reaction, but only 13% had a serious adverse reaction. The cost of a single dose for a 70 kg patient is estimated to be $7500, and it is administered via IV every 3 weeks.


Clinical trials tested the safety and efficacy of Nivolumab, including a Phase I open-label trial of 296 patients, 107 of which with advanced, unresectable melanoma. 30.8% of the 296 patients showed an objective response, with an estimated duration of 2 years for the response. The median overall survival time for patients was 16.8 months. 84.1% of the 107 patients with melanoma experienced an adverse reaction, but 22.4% were serious effects. The cost of a single dose for a 70 kg patient is estimated to be $7000, and it is administered via IV every 2 weeks.

It is encouraging to see new targets and treatment alternatives for different types of cancers, although the cost is very high. With more oral and IV medications emerging as valid treatment options, do you think this can have a significant impact on treatment for the disease? Do you think it is likely that more patients would opt for a treatment option like this over chemotherapy?

Ivashko, I, and Kolesar, J. Pembrolizumab and nivolumab: PD-1 inhibitors for advanced melanoma. Am J Health-Syst Pharm. 2016; 73:193-201.


Liver injury caused by herbal and dietary supplements on the rise

Over the last ten years, liver injury caused by herbal and dietary supplements has almost tripled, raising from 7% of liver injury causes up to 20%. From these liver injuries, some have even resulted in liver transplant or death. In 2014, the Drug-Induced Liver Injury Network (DILIN) did an analysis evaluating cases of liver injury between the years of 2004 and 2013. Out of more than 800 cases, 85 were caused by nonbodybuilding supplements and 45 to bodybuilding supplements (709 due to medications). The study also showed that nonbodybuilding cases were more severe, with several of them resulting in liver transplantation or death.

Pharmacy Today’s article discussed how it is hard to monitor these liver injuries and failures because the supplements are often over the counter and can be purchased and used without a physician’s consent. Additionally, they are not as monitored by the FDA and do not go through the same efficacy and safety processes that prescription medications do. Some herbal and dietary supplements interact with medications if taken at the same time that will cause adverse effects, such as hepatotoxicity. Once the liver is experiencing injury, it is then hard to figure out what is causing the problems because most dietary and herbal supplements are composed of several vitamins and substances, making it hard to pinpoint the issue.

So what can pharmacists do for this problem? First off, they can inform patients and customers that they are not as highly monitored and regulated, so they should be more cautious taking the products. Going off of that, they should talk to their physicians about the safety of the products and should ask if the supplements are recommended to be taken with their current medications. I feel that this is an important issue when looking at how many livers are damaged by these products that are supposed to be used for improving health. The fact that the numbers are rising makes me feel that pharmacists and physicians should pay extra attention to the dietary and herbal supplements their patients are using. It does have me wondering though – could the FDA be doing more to regulate dietary and herbal supplements?

Navarro VJ et al. “Liver injury caused by herbal and dietary supplements on the rise.” Pharmacy Today. 20.11 (1 November 2014). 24. Web. 29 February 2016.

Lack of efficacy prompts citizen petition to remove phenylephrine from OTC market

In November 2015, two university professors submitted a petition to the FDA to remove phenylephrine from the OTC market due its apparent inability to effectively alleviate nasal congestion. Data from numerous clinical trials indicate that when taken orally, it is no more effective than a placebo, even when taken at four times the FDA-recommended dose. This is due to its extensive first-pass metabolism in the liver, before it enters the blood.

According to the article, phenylephrine was discovered in 1927 and categorized as an analog to adrenaline. It was approved by the FDA in the 1970’s as part of a rushed drug monograph approval process, which allowed it to be approved as an ingredient due to its relationship to adrenaline, without thorough examination of data regarding its safety and efficacy, the majority of which was unpublished.

Alternatives to phenylephrine are available over-the-counter, such as oxymetazoline for nasal stuffiness from a cold, which is available as a topical medications (eye drops and nasal spray). However, if these are used for more than three days, they can actually cause rebound congestion. For patients with allergies, OTC intranasal steroids such as fluticasone or triamcinolone, were recommended as alternatives by the pharmacist cited in the article. Oral pseudoephedrine is also an option, available behind the pharmacy counter, but is still shown to be less effective than topical medications at alleviating symptoms.

Phenylephrine is effective at lowering blood pressure when given intravenously, and is also effective when used topically. Many common OTC medications for nasal congestion contain phenylephrine, such as Sudafed, Theraflu, and Tylenol Cold. I know I have heard complaints many times from friends, family, and patients about these medications not really working effectively for them. I found the information in this article about the quick approval process and clinical studies indicating its ineffectiveness when taken orally to be very interesting. Because its inefficacy stems from its extensive first-bypass metabolism, I feel that it is important for it to remain available as a topical medication. Furthermore, as future pharmacists, we can be aware of the clinical evidence and even make suggestions about topical medications to treat nasal congestion as the best treatment option. I am interested to see how the FDA responds to this petition about the ineffectiveness of phenylephrine in the upcoming future.


Tanzi, Maria G. Lack of efficacy prompts citizen petition to remove phenylephrine from OTC market. Pharmacy Today. 2016; 22.



Characteristics of FDA drug recalls: A 30-month analysis

This article describes the Food and Drug Administration (FDA) recalls for a period of 30 months (June 20,2012 – December 31, 2014). The FDA is in charge of regulating many types of drugs including prescription, nonprescription, dietary supplements, and biological products. The analysis of the recalls were based on the following data: product type, recalling firm, country, voluntary/involuntary recall, how the recall was communicated, FDA classification, product availability, reason of recall, recall initiation, and recall report date. There were 21,120 products recalled during the time frame and only 14.4% of them were analyzed based on meeting the inclusion criteria. The main reasons for recalled drugs were due to contamination, adverse reaction, incorrect potency, defective product, and mislabeling. There was a total of 348 manufactures involved in the recalls, and the top 5 manufactures accounted for 1,014 out of the 3,045 recalled drugs (33.3%). The majority of the contamination occurred at compounding firms rather than non-compounding firms.

I believe that these results are not entirely surprising. It makes sense that more contamination would occur at compounding firms because they deal with physically making the products they dispense rather than dispensing medication that is already ready to be dispensed. What is surprising is that 33.3% of the drugs that were recalled came from only 5 manufactures out of the 348 manufactures. In my opinion, there should be specific regulations regarding how many drugs can be recalled from the companies. If there is a high recall rate from a specific company, there is probably an error in their processing. Intense monitoring should be implemented in order to minimize the risk of contamination and mistakes during production. It is almost scary that 5 companies were responsible for so many recalls. If a patient took a medication that was not formulated correctly, it could seriously affect a patient’s health. What types of regulations do you think could be implemented to ensure the minimization of risks?

Hall K, Stewart T, Chang J, et al. Characteristics of FDA drug recalls: A 30-month analysis. Am J Health Syst Pharm. 2016;73(4)235-240.

FDA’s Role in Regulating Generic Drug Affordability

This article from The Journal of the American Medical Association makes some suggestions to the FDA on how to manage the affordability of off-patent pharmaceuticals.  Historically and currently the FDA stays away from making decisions based on the economics surrounding drugs and drug-pricing.  However, this has led to exacerbated issues when it comes to drug cost for generics in non-competitive markets.  The article details how in a competitive market if one generic manufacturer dramatically increases the price of their product, another manufacturer can sell the product at a much lower cost and do well in the market.  However, in a non-competitive market, if the sole manufacturer of a generic drug decides to increase the price, people have to pay the price set by the manufacturer in order to get the medication.  Additionally, when there have only been one or two manufacturers of a drug historically, a drug shortage can easily occur.  If those one or two manufacturers fail temporarily or increase their prices drastically, the United States is unable to obtain their specific drug product and get it to patients affordably except by importation from other countries.  The article asserts that it would do the drug industry good in the U.S. if the FDA began involving itself in issues of drug-pricing regulation and management.  Suggestions from the article include changing the FDA’s generic drug application review process by prioritizing drugs that would fall into a non-competitive market if approved, temporarily permitting compounding of drugs that are facing shortage issues due to manufacturer failure or dramatic price increase, and permitting importation of drugs from reputable sources in the instance of a shortage.

I believe I am of the same opinion as the article: that it is the FDA’s duty to protect the public, and the service of regulating drug-costs falls under that category.  If a life-saving drug’s price skyrockets for the benefit of the manufacturer and a patient is no longer able to purchase the ridiculously high-cost medication, the FDA has failed in one way.  If the FDA were to change their ways it could have an incredible impact on the drug market in the United States, for better or for worse.  Do you think the FDA should play a role in drug price regulation?  Or do you tend to think that drug companies are companies like any other and should be able to price drugs how they please?

Greene JA, Anderson G, Sharfstein JM. Role of the FDA in Affordability of Off-Patent Pharmaceuticals. JAMA. 2016;315:461-462.

Link to Article

Peak in Drug Approvals in 2015

In 2015 the FDA approved 45 drugs, a notable high in almost two decades. However, due to increasing research and development costs and decreasing sales, rate of return has been declining. According to the consulting firm Deloitte the average rate of return dropped from 10.1% in 2010 to 4.2%. The recent merger of DuPont and Dow Chemical reflects the increasing R&D costs since they cut the 2016 R&D budget by about $300 million and laid off 200 R&D employees.

About one-third of the approved drugs were biologics, an increase from about one-quarter in 2014, but there was a smaller percentage of novel mechanisms of action, 36% down from 42% in 2014. Also notable in 2015 was that some form of expedited approval by the FDA was granted for 60% of the drugs and 87% of drugs were approved on their first NDA application. The FDA credits this increase in speed that drugs are reaching market to more drugs for rare diseases where greater risk is tolerated, more targeted therapies, fewere me-too drugs, and better interactions with companies during early development. The “breakthrough therapy designation” introduced in 2012 for innovative drugs has also helped to expedite the approval process. About half of the drugs approved in 2015 were for “orphan diseases” with a small affected population. Due to the smaller demand, these drugs carry larger price tags. For example, some of the approved cancer drugs have an annual cost of $110,000 to $310,000.

How do you think costs should be distributed between pharmaceutical companies, government, insurers and patients?

Jarvis, Lisa M. The Year in New Drugs. Chemical & Engineering News. 2016;1(1):12-17.

Potential Bias of Speakers on Behalf of New Cancer Drugs

The number of cancer cases throughout the world is clearly on the rise, requiring an ever increasing need for a cure and more effective treatments. Many speculate that a cancer cure has already been discovered but it is being hidden because of all the money cancer as a disease generates. Others question why cancer is so prominent now but was not spoken of this often in their childhood. With so much confusion abound about the treatment of cancer and its widespread effects, an article delving a little into the processes of the FDA when it comes to cancer and possible conflicts of interest may be helpful.

The authors of this article decided to search into the meetings held by the Oncologic Drugs Advisory Committee, the advising committee to the FDA concerning cancer treatments, to determine what other influences may be at play when deciding if a drug should go to market. They reviewed twenty-eight meetings between 2009 and 2014. The main investigation for this study was to determine what biases may be present within these extra speakers, who usually have taken the drug discussed or represent an organization. The researchers recorded what the speakers’ affiliations may be as well as their financial association or lack thereof.

It was found that amongst the 103 speakers present at the 28 meetings, 58 were representing an organization associated with the type of cancer being potentially treated, 46 were diagnosed with the specific type of cancer, and 31 had taken the drug. Almost all of the speakers throughout these twenty-eight meetings (92%) supported the approval of the drug. Thirty percent of the speakers revealed that they did indeed have financial associations with the company seeking approval while two speakers did have associations but did not disclose them when asked.

The authors concluded that the FDA committee should consider possible financial associations and personal biases of speakers when reviewing a cancer drug company’s marketing approval. When we look at how huge of a problem cancer has become and how much it could affect both us and those around us, does this potential bias matter so much? If the drug trials show that the drug works, should a small financial association hold this FDA committee back from approving their marketing?

Reference: Abola MV, Prasad V. Characteristics and conflicts of public speakers at meetings of the Oncologic Drugs Advisory Committee to the US Food and Drug Administration. Jama Intern Med. Published online February 1, 2016. Accessed February 6, 2016.