Caroline Hroncich was associate editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International from 2015 to 2017.

Caroline Hroncich

	The pharmaceutical industry has been under scrutiny recently for raising the cost of drugs extraordinary amounts. 

, who hiked the prices of older drugs that lacked generic competition, are perhaps the most notable examples. 

indicates that while Turing and Valeant may be outliers, they are far from the only US pharmaceutical companies that have considerably raised prices over the past five years.

report released on April 5, 2016 reviewed the nation’s top 10 most widely used drugs and found that four of the top 10 drug’s prices increased 100% since 2011, while the other six increased 60%. Overall sales of the top 10 drugs went up 44% to $54 billion in 2014 from 2011, 

reported, while prescriptions for the medicines fell 22%. Steve Miller, chief medical officer of Express Scripts, told 

he thinks the level of drug price increases are “not sustainable.”


	Humira (adalimumab), AbbVie’s blockbuster rheumatoid arthritis drug, surged more than 126%, 

found. According to the report, Humira was the most widely used drug in the US in 2014. In November 2015, AbbVie 

, said the company has 70 patents protecting the drug from biosimilar competitors and doesn’t expect any biosimilars for the drug to reach market until 2022.

	Amgen, the maker of ABP 501, the first biosimilar submitted to FDA for Humira, challenged multiple claims on Humira’s ‘157 formulation patent. The US Patent and Trademark Office 

 to review the patents in January 2016.  While this may be a setback for the biosimilar maker, the company said they hope to have their first biosimilar on the market between 2017 and 2019. It is still unclear how the approval of a Humira biosimilar may affect the drugs price.

report is Enbrel (etanercept), marketed by Amgen and Teva in the US, with a price increase of 118%. A spokesperson for Amgen told 

 “after most discounts, the average sales price for a dose of Enbrel is at least $200 less than list.” It is important to note, Eli Lilly’s Taltz (ixekzumab), which was recently 

 at the end of March 2016, is expected to be a direct competitor to Enbrel.

found Johnson & Johnson’s drug Remicade (infliximab) price increased 63%. Caroline Pavis, a spokesperson for the company, told the news organization “average selling price increases were closer to 5.4% per year.” Celltrion and Pfizer’s Inflectra, an infliximab biosimilar, was 

 for all of Remicade’s indications except for pediatric ulcerative colitis. Jay Siegel, MD, chief biotechnology officer at Johnson & Johnson, said the company plans to protect its patents for Remicade, which are enforceable until September 2018.

. By prioritizing generic approval, FDA hopes to increase market competition, and decrease drug prices. It is still to be determined how the approval of biosimilars may affect the prices of biologic drugs like Remicade, Enbrel, and Humira.

Peter Bach, an oncologist at Memorial Sloan Kettering Cancer Center, told 

he estimates Enbrel added up to approximately $1 billion in care costs. Amgen spokesperson Kristen Davis told 

it would be “impossible to infer revenue growth from list price increases because of other factors, including rebates and discounts.”

analysis “failed to capture negotiated discounts and rebates.” Drug companies told 

they set prices in order to recoup investments in failed drugs, support R&D efforts, and to pay for clinical trials. In the report, 

said they shared findings with the eight companies that sold the top 10 drugs. None of the eight companies disputed findings in the report.

Articles

A report by Reuters found that four of the top 10 most widely used drugs increased 100% since 2011, while the other six increased 60%.

Report Examines Price Increases on Most Widely Used Drugs in US

 on the labeling of biosimilar products on March 31, 2016. The guidance states that information concerning a clinical study of a biosimilar should only be included in the products labeling if it is “necessary to inform safe and effective use by a health care practitioner.” This will only be required in certain situations, FDA wrote, since studies done on biosimilars are generally meant to show there are no clinically meaningful differences between the biosimilar and the reference biologic, and may not be relevant to prescribers.

	FDA recommends that information on a biosimilar product label should incorporate the relevant data from reference product’s labeling with “product-specific modifications.” These modifications may differ depending on the indications for which the biosimilar is approved. Information related to administration, preparation, storage, or safety should also be included in the biosimilar label if different from the reference product, wrote FDA.

	FDA notes the biosimilar product name should only be used on the label if the text is referring solely to the biosimilar. When clinical studies or information related to the reference product is described in the label, the reference product’s name should be used. FDA writes when the risk associated with taking a biosimilar is also relevant for the reference product, “it would be appropriate to use the core name of the reference product followed by the word ‘products.’”

 on FDA’s website, Leah Christl, PhD, associate director for Therapeutic Biologics and lead of the Therapeutic Biologics and Biosimilars Staff in the Office of New Drugs

 discusses FDA’s reasoning behind the guidance. Christl writes that including comparative clinical data in biosimilar product labeling would be “confusing or potentially misleading to health care providers.” While this data may be important for determining biosimilarity, it may not be applicable when prescribing the drug, she said.

	“However, I want to point out that these comparative data generally will be available to the public,” Christl writes. “Health care providers and others who want to delve more deeply into the product-specific data supporting a demonstration of biosimilarity, including the comparative clinical data, may find this information in FDA’s product reviews, on our Drugs@FDA website.”

	In an investor report from Evercore ISI discussing the guidance, Umer Raffat, senior analyst of equity research, specialty pharmaceuticals, notes, “pharma sponsors had asked FDA to move away from the type of labeling format it had used for the first biosimilar, Sandoz’s Zarxio,” which was labeled similarly to generic drugs. Raffat says sponsors encourage FDA to describe the clinical data for the biosimilar on the label, and to “also describe differences [versus] the brand’s data.”

	In May 2015, multiple physician groups submitted an 

 to FDA on biosimilar labeling, urging the agency to take into consideration the needs of physicians. The groups cited the “lack of prescriber education” on biosimilars, saying physicians may mistake an identical label as a representation of interchangeability between the biosimilar and reference product.

 to FDA in August 2015 discussing FDA policy on biosimilar naming. The biopharmaceutical company was concerned with an explanation FDA gave the Senate Committee on Health, Education, Labor, and Pensions (HELP Committee) on interchangeability in biosimilar labels. In the letter, AbbVie expressed concern that FDA told the HELP Committee information on interchangeability could be found in The Purple Book, and did not need to be included in the biosimilar product label. The company also said it would be misleading to include study information from another drug in a biosimilar label without acknowledging the studies were not done on the biosimilar itself.

	It is important to note that FDA did not make any definitive statements about interchangeability in new draft guidance. The agency writes, “FDA continues to consider the types of data and information that would support a demonstration that a biological product is interchangeable with a reference product.” FDA says it will cover interchangeability recommendations in a future guidance.

The draft guidance states information concerning a clinical study of a biosimilar should only be included if it is necessary to demonstrate the safety and efficacy of the drug.

FDA Releases Draft Guidance on Labeling of Biosimilars

	Researchers at the University of Pittsburgh School of Medicine and Arts and Sciences say they have designed a more potent version of the FDA-approved epilepsy drug retigabine. A 

compares RL648_81 (RL-81), the experimental agent developed by Pitt researchers, with retigabine, and SF0034, a KCNQ2/3 activator being developed by 

 for suppressing neuronal hyperexcitability.

	The researchers assert the new compound may not only be more potent than both SF0034 and retigabine, but it may also reduce the incidence of common side effects that are associated with antiepileptic drugs, including retinal abnormalities, skin discoloration, and urinary retention. According to the study

while there are more than 20 antiepileptic drugs available; 25–40% of those available are “refractory to the treatment” and are not without adverse side effects.

	In comparison to other antiepileptic drugs, RL-81 is the “most potent KCNQ2/3-specific channel activator known to date,” according to researchers. The researchers add, “due to its higher, yet selective agonism on KNCQ2/3 channels, [RL-81] is expected to be more effective at a lower dose than retigabine and its analog, SF0034, in preventing seizures.” RL-81 does not activate the KCNQ4 or KCNQ5 channels, unlike retigabine, which adds to its specificity, and may mean it will have fewer side effects. The researchers note, RL-81 showed to be 15 times more potent than retigabine, and three times more potent than SF0034. The compound could also potentially be used to treat 

, a disorder that causes ringing in the ears.

	“At this point, the new compound is ready to be studied further in animal models of epilepsy and tinnitus and for other preclinical assessments,” said Peter Wipf, PhD, distinguished university professor of chemistry at Pitt. “RL-81 appears to have great potential for the treatment of these challenging neurological conditions.”

	RL-81 is not the only drug being tested for its effectiveness at treating epilepsy. 

, a London-base biopharmaceutical company recently released results from clinical trials with its drug Epidiolex (cannabidiol or CBD), an investigational drug meant to treat Dravet syndrome, a rare form of epilepsy. Phase III clinical trial results showed the drug achieved median reduction in monthly convulsive seizures of 39% over a 14-month treatment period.

 released by Pharmaceutical Manufacturers of America and the Epilepsy Foundation said the drug pipeline to treat neurological disorders included 420 medicines under review by FDA. The list includes drugs to treat epilepsy, in addition to Alzheimer’s disease, chronic pain, brain tumors, multiple sclerosis, Parkinson’s disease, migraine, spinal cord injury, neurological genetic disorders, and stroke.

University of Pittsburgh School of Medicine

Researchers at the University of Pittsburgh say the compound may be more potent and selective than drugs currently available to treat epilepsy.

Antiepileptic Experimental Compound May Reduce Side Effects Associated with Conventional Treatments

	FDA released draft guidance on abuse deterrence for solid oral opioid drugs in March 2016. The draft guidance, titled 

General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products

is intended for those submitting abbreviated new drug applications (ANDAs) for generic opioid drugs with abuse deterrent properties.

, it is estimated that 2.1 million people in the US abuse opioid prescription pain relievers, resulting in addiction and, in some cases, death. The institute says the number of unintentional overdose deaths has more than quadrupled since 1999. In the past year, US regulatory agencies have prioritized addressing prescription drug dependence. Sylvia M. Burwell, secretary of the Department of Health and Human Services, released a 

 on the topic in March 2015, and Robert Califf, PhD, FDA’s deputy commissioner, called for a “

” of FDA opioid policy in February 2016.

 in early February 2016, stating a plan to combat opioid abuse, dependence, and overdose. In the plan, FDA said it had plans to “fundamentally re-examine the risk-benefit paradigm for opioids.” Releasing draft guidance on the abuse-deterrent formulations (ADF) was a “high priority” for the regulatory agency, which said it hoped the guidance would spur more generic ADF development.


	FDA defines abuse deterrence in opioid drugs in seven distinct categories. These categories include physical/chemical barriers, agonist/antagonist combinations, aversion, delivery system, new molecular entities (NMEs), prodrugs, and combinations and novel approaches. FDA recommends that ANDA applicants follow a tiered approach when conducting comparative 

studies of generic solid oral opioid products. The guidance suggests following tiered levels of solvents in chemical manipulation tests to determine the possibility of extraction of opioid for oral abuse. FDA says level one tests should be conducted with water; level two with commercially available food-grade vinegar, 0.2% baking soda, 40% ethanol, and carbonated drink; and level three with cooling oil, isopropyl alcohol acetone, 0.1 N HCl, and 0.1 H NaOH.

testing methodologies, FDA suggests using pharmacokinetic (PK) studies to evaluate the abuse deterrence of the generic product in comparison to the reference. FDA also says the “applicant may provide supportive data to demonstration compositional proportionality across difference strengths of R [reference] and T [generic] products as justification for not conducting studies” to evaluate strengths.

	FDA outlines a tier-based approach for comparing abuse deterrence in generic opioid drug products. These steps involve comparing the percentage of opioid extraction between a reference product, generic product, and control. The guidance notes there may be times where the tier-based approach “cannot adequately capture the complete profile” for the generic product due to inclusion of novel inactive ingredients, use of new technology, and formulation design.

	The guidance also provides a detailed outline for ways solid oral opioid products may be mechanically manipulated using household equipment, in addition to ways they may be abused through injection, insufflation, inhalation, and oral ingestion. The agency provides testing methods to combat these types of abuse through comparison of reference and generic products, allowing applicants to more accurately determine abuse deterrence.

The draft guidance outlines ways applicants can test for abuse deterrence in solid oral opioid drugs.

FDA Releases Draft Guidance on Evaluating Abuse Deterrence of Generic Solid Oral Opioid Drugs

	On March 11, 2016, the Center for Drug Evaluation and Research (CDER) released a revision of the Manual of Policy and Procedures (MAPP) on the 

Prioritization of the Review of Original ANDAs, Amendments, and Supplements

. In the revision, CDER cites submissions for “sole-source” drug products as an additional circumstance under which abbreviated new drug applications (ANDAs) for new generic drugs may be prioritized.

	In the revised MAPP, CDER says “submissions for drug products for which there is only one approved drug product listed in the Prescription Drug Product List of FDA’s 

Approved Drug Products with Therapeutic Equivalence Evaluations 

and for which there are no blocking patents or exclusivities may receive expedited review.” This applies except where the approved drug product was approved “pursuant to a suitability petition.”

House Oversight and Government Reform Committee hearing

 in early February 2016 that focused on hikes in drug prices. The committee called upon executives from Turing Pharmaceuticals, who raised the price of Daraprim (pyrimethamine) nearly 5000%, and Valeant, who raised the price of Nitropress (nitroprussid sodium) 212% and Isuprel (isoproterenol) 525%, to give reasoning for the price jumps.

	Part of the issue, the committee noted, was a decrease in market competition, particularly for older drugs like Daraprim, the only available treatment for toxoplasmosis. Turing purchased the 62-year-old drug and later raised the price from $13.50 per pill to $750. The lack of generic equivalents for Daraprim, the committee said, allowed the company to monopolize the market and may force patients to pay high out-of-pocket costs.

	Recently there has been a call for a faster review process of ANDAs by FDA, to prevent a single drug from monopolizing the market. In February 2016, Steven Ostroff, acting commissioner of food and drugs at FDA, published a blog for the agency on 

modernizing the generic-drug review process

. Ostroff cited the Generic Drug User Fee Amendment (GDUFA) as a potential method for increasing patient access to affordable generics. He says the agency is working to improve the process and recently cleared an ANDA backlog of 1100 that had accumulated since August 2014.

	The most recent revision to the MAPP may be an important step towards modernizing the generic-drug review process. Prioritizing review of generics drugs for which there is only one approved drug product listed may be a method of combatting the decrease in market competition. This may also speed up FDA review process of generics. 

, Sandy Walsh, a spokesperson for FDA said the agency expects the change in prioritization to expedite review of 125 generic drug applications. Whether or not the revision will have a significant impact on the ANDA review process is yet to be determined.

	In another effort to improve generic review, FDA announced that it is holding a 

 on regulatory science initiatives for generic drugs. The agency is asking for public input for the meeting, which it will take into account while developing the 2017 fiscal year Regulatory Science Plan.

CDER is now prioritizing review of generic drug products for which there is only one approved drug product on the market.

CDER Revises MAPP on Prioritization Review of ANDAs

	GW Pharmaceuticals, a London-based biopharmaceutical company focused on the development and commercialization of therapeutics derived from its cannabinoid product platform, announced on March 14, 2016 that it had successfully completed a Phase III study of its investigational medicine Epidiolex (cannabidiol or CBD) for the treatment of Dravet syndrome. Epidiolex is derived from cannabidiol, a component present in marijuana. 

, if approved, the drug will become the first prescription drug in the US extracted from the plant.

	Dravet syndrome is a rare form of epilepsy that affects patients from infancy. 

According to the Dravet Syndrome Foundation

, individuals suffering from Dravet syndrome often experience frequent seizures, poor seizure control, and developmental delays. Treatment options for the syndrome are extremely limited, and there are currently no approved drugs for the disease in the United States.

	The results of GW’s Phase III clinical trial with Epidiolex showed that the drug achieved a median reduction in monthly convulsive seizures of 39% over the 14-month treatment period compared with placebo, which demonstrated a 13% decrease. The study was completed with 120 patients, who were given Epidiolex or a placebo, in addition to regular anti-epileptic treatment regimens. The 120 patients participating in the study averaged 10 years of age, with 30% of patients under the age of six.

	While there have been reports prior to this study of marijuana-based products reducing frequency of seizures, the 

says experts have been “cautious about anecdotal reports, saying that such treatments needed to be compared with a placebo to make sure they work.” Orrin Devinsky, MD, of New York University Langone Medical Center Comprehensive Epilepsy Center, said in a statement that this trial represents the first placebo-controlled evidence to support CBD’s “safety and efficacy” in children.

	Epidiolex has also received Fast Track designation and Orphan Drug designation from FDA for the treatment of Dravet syndrome. The agency referenced the drug in a 

 as an example of an investigational drug derived from marijuana being studied for clinical efficacy. In the statement, FDA says, “If there is any future for marijuana as medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives.” These components, the agency says, will produce more reliable results than crude plant mixtures. More than 300 American children are currently taking Epidiolex under FDA’s expanded access program, according to the 

	Recently, the use of CBD has been a popular topic of discussion in the pharmaceutical industry. In March 2016, 

 the import of pharmaceutical grade cannabidiol by Catalent Pharma Solutions and Kannalife Sciences for feasibility studies. In February 2016, 

FDA issued eight warning letters to CBD sellers

 who, the agency said, were marketing dietary supplements as new medications, although they had not been tested by FDA. 

GW Pharmaceuticals released Phase III trial results on Epidiolex, which was shown to decrease monthly convulsive seizures in children by 39%.