 Individualized treatment protocols for patients are becoming increasingly important in the management of NSCLC. Consequently, drug research and development continues to focus on regimens that select therapy according to the pathologic and molecular characteristics of the tumor, and thereby have the potential to enhance the poor patient outcomes currently associated with NSCLC. Treatment will increasingly focus on a genetic biomarker-based strategy to prolong patient survival, and next-generation technologies for genetic characterization of individual patients will be important to further develop a personalized treatment approach to NSCLC with molecularly targeted agents.

	Before 2005, chemotherapy was the standard of care for stage IV NSCLC, and typically consisted of platinum doublet chemotherapy. Subsequently, however, a major treatment paradigm shift resulted from the identification of driver mutations in genes that encode signaling protein important for cell proliferation, driving some NSCLCs. It is now the current standard of care in advanced NSCLC to assess tumors for these alterations, especially epidermal growth factor receptor (

) mutations and anaplastic lymphoma kinase (

) translocations, both of which occur predominantly in adenocarcinomas. Consequently, histological determination of NSCLC subclasses in patients is required to identify tumors for molecular testing for these alterations or for selection of optimal therapy.

	More than 50% of NSCLC cases express at least one of 10 known molecular biomarkers that identify the gene mutations that drive some lung cancers.

 and these patients have few treatment options because they respond poorly to cytotoxic chemotherapy and are refractory to tyrosine kinase inhibitors (TKIs). The oral small-molecule multikinase inhibitor sorafenib targets numerous pathways, including the Ras/Raf pathway, which is involved in cell growth and survival. In a prospective study involving pretreated patients with NSCLC, patients with 

 mutations were more likely to benefit from sorafenib. In 

-positive patients, the 8-week disease control rate was 79%, compared with the historical 8-week disease control rate of 30%.

 Data from another study in previously treated patients with advanced NSCLC and 

 mutations demonstrated that sorafenib treatment resulted in median progression-free survival (PFS) of 3 months, and three partial remissions were also observed.

 mutations are the second most common, and studies have shown that patients with specific 

 mutations benefit more from oral TKIs than patients with wild-type 

These patients also experience a longer time to progression when treated with the oral EGFR inhibitors gefitinib or erlotinib as compared with conventional chemotherapy.

 Cetuximab, a monoclonal EGFR antibody, has also shown benefit in patients with NSCLC in combination with chemotherapy.

 Furthermore, data have demonstrated that patients with high

 expression levels, as indicated by immunohistochemistry, are more likely to benefit from this combination, especially in cases of adenocarcinoma.

 fusion gene is a less common oncogenic driver in NSCLC,

 and crizotinib is a selective small-molecule competitive inhibitor of this gene. One study demonstrated a complete or partial response to treatment in patients with 

 and data from a later study showed a median PFS of 9.7 months (95% CI, 7.7-12.8); the estimated overall survival (OS) at 6 and 12 months was 87.9% (95% CI, 81.3-92.3) and 74.8% (95% CI, 66.4-81.5), respectively.

	Bevacizumab is the only FDA-approved antiangiogenic agent for advanced nonsquamous forms of NSCLC, as well as being the most clinically significant one.

 It is a recombinant human monoclonal antibody that selectively binds to and neutralizes the biological activity of VEGF, thereby inhibiting angiogenesis.

 Bevacizumab has been shown to be effective as a first-line treatment of patients with unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC when combined with chemotherapy in two randomized phase III trials.

 Based on these results, it was subsequently approved by the FDA for first-line treatment of locally advanced, recurrent, or metastatic nonsquamous NSCLC.

	Moreover, data from a meta-analysis of bevacizumab plus chemotherapy in advanced NSCLC confirmed that this regimen can be considered a standard option in selected patients with advanced NSCLC.

 Ongoing clinical trials continue to define the role of bevacizumab in the treatment of NSCLC, including its use in earlier stages of disease and in combination with other agents.22 Still, despite the success of bevacizumab, patients with advanced NSCLC who receive it will eventually experience disease progression.

	Data from two phase III trials has shown that bevacizumab combined with chemotherapy improves outcomes for patients with nonsquamous NSCLC. In patients with adenocarcinoma without 

 a maintenance therapy trial, the effect of maintenance bevacizumab plus pemetrexed after first-line cisplatin/pemetrexed/bevacizumab in advanced NSCLC was investigated. All patients received the first-line, triple-combination therapy and were then randomized to maintenance bevacizumab alone or bevacizumab/pemetrexed. A 4-month improved OS was observed in patients taking the bevacizumab/ pemetrexed combination. It appears that pemetrexed clearly adds to bevacizumab, but it is not clear whether bevacizumab adds to pemetrexed.

	Clinical research remains ongoing to evaluate the role of bevacizumab in different settings, including its use as a single agent for continuation maintenance therapy in advanced NSCLC, treatment beyond disease progression, adjuvant therapy in early-stage disease, or in combination with other targeted agents.

	HER2-targeted agents have been shown to be useful in a small percentage of patients with NSCLC in which the HER2 mutation is found. In a large retrospective study involving 3800 patients, 65 (1.7%) had the HER2 mutation. All 65 cases were adenocarcinoma, and of these, most of the patients were female, and approximately half of them were never-smokers. Half of those individuals had stage IV NSCLC. Anti-HER2 drugs such as trastuzumab and afatinib were used to treat 16 patients, and some tumor shrinkage occurred after one round of treatment, with shrinkage in an additional two patients after a second round of therapy.

	Two additional drugs that play an important role in the treatment of NSCLC are erlotinib and crizotinib. Erlotinib is an EGFR tyrosine kinase inhibitor (TKI), an orally administered small molecule that binds to the intracellular TK domain, and ultimately inhibits downstream cellular proliferation. 

 The drug originally gained FDA approval in 2004 for second-line treatment of NSCLC, as a result of data from the National Cancer Institute of Canada Clinical Trials Group Study BR.21. This investigated the efficacy of erlotinib in patients with previously treated stage IV NSCLC, and reported a 9% response rate and an OS of 6.7 months versus 4.7 months with placebo alone. The study was performed on an unselected patient population, however, and before the discovery of the sensitizing mutations in 

, and trials combining erlotinib and chemotherapy did not demonstrate increased benefit over chemotherapy alone. Subsequent trials, however, have demonstrated superior PFS and quality of life with initial treatment with erlotinib compared with platinum-based doublet therapy in patients with sensitizing somatic mutation.

	In 2010, erlotinib was also approved for maintenance treatment of patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based chemotherapy. In a randomized, doubleblind, placebo-controlled trial of erlotinib in 889 such patients, median PFS was significantly longer with erlotinib than with placebo (12.3 weeks vs 11.1 weeks; hazard ratio [HR] = 0.71; 95% CI, 0.62-0.82; 

 <.0001). PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib compared with 

-positive patients given placebo (median PFS, 12.3 weeks vs 11.1 weeks; HR = 0.69; 95% CI, 0.58-0.82; 

	In May 2013, erlotinib was also approved for the first-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (

) substitution mutations. FDA approval was based on data from a randomized, multicenter, open-label trial comparing erlotinib to platinum-based doublet chemotherapy in such patients. Tumor samples from 134 patients were tested retrospectively by the cobs EGFR Mutation Test. The median PFS was significantly increased in patients treated with erlotinib compared with platinum-based chemotherapy (10.4 months vs 5.2 months; HR = 0.34; 95% CI, 0.23-0.49; 

 <.001). The median OS was also increased with erlotinib (22.9 months vs 19.5 months; HR = 0.93; 95% CI, 0.64-1.35; 

 =.6482), as was objective response rate (ORR) (65% vs 16%). Analysis of PFS in patients who had a positive cobas EGFR Mutation Test was also consistent with the primary analysis.

	The cobas EGFR Mutation Test, a companion diagnostic, is a real-time polymerase chain reaction-based test to detect and identify exon 19 deletion or exon 21 (

 gene in DNA derived from formalin-fixed, paraffin-embedded NSCLC tumor tissue. The test is to be used to identify patients whose tumors harbor these mutations.

	Crizotinib is an ALK TKI, an oral small-molecule ATP competitive inhibitor of ALK and c-MET. It is the only currently available ALK TKI, and was approved by the FDA in 2011, but only for use as a single agent in patients with NSCLC positive for 

	In an expanded phase I trial involving 82 patients with advanced 

-positive disease, most of whom were previously treated and had received two or more therapies, results showed a 57% overall response, with 33% of patients achieving stable disease. In a later study involving 143 

-positive NSCLC patients with advanced disease, an ORR was observed in 61% (95% CI, 52-69%) of patients treated with crizotinib. The median duration of response was 49 weeks, and the median PFS was 9.7 months. Six- and 12-month survival were 88% and 75%, respectively. Similar survival results were reported in a retrospective study, in which survival of 56 

-positive patients treated with crizotinib was similar (median survival time [MST] not reached) to 63 

-positive patients treated with an EGFR TKI (MST, 24 months), and superior to 

-positive controls who did not receive crizotinib (MST, 20 months).

 mutations eventually acquire resistance to frontline treatment with TKIs. Studies have shown that the most common mechanism for this, accounting for up to 60% of cases, involves the 

 mutation. This secondary point mutation substitutes methionine for threonine at amino acid position 790.

	The problem of resistance to the EGFR TKIs led to the development of second- and even third-generation EGFR TKIs, as well as the use of combination therapy involving EGFR inhibitors with other targeted agents.

	Afatinib, approved by the FDA in July 2013, is a secondgeneration TKI that irreversibly binds both HER2 and EGFR. Afatinib is approved for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (

) substitution mutations as detected by an FDA-approved test concurrently approved with the therapy, the therascreen EGFR RGQ PCR Kit.

	Afatinib broadly blocks the molecular pathways involved in cancer growth, contributing to its enhanced potency compared with other therapies. Data from the pivotal phase III LUX-Lung 6 trial demonstrated that afatinib was more effective than standard chemotherapy (gemcitabine plus cisplatin) for patients with locally advanced or metastatic NSCLC with an 

 mutation. Afatinib increased PFS by 11.1 months, significantly better than the 6.9-month increase achieved with pemetrexed and cisplatin.

	“LUX-Lung 6 and LUX-Lung 3 together represent the largest clinical trial program in 

 mutation-positive NSCLC patients,” noted Professor James Chih-Hsin Yang, director of the Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan. “The results of both trials have shown us that afatinib could offer lung cancer patients with EGFR mutations a significant delay in tumor growth, and a better quality of life, compared to current standard of care chemotherapies.”

	Nintedanib is an investigational triple angiokinase inhibitor that targets three receptor tyrosine kinases involved in the regulation of angiogenesis: VEGFR, fibroblast growth factor (FGF) receptor, and platelet-derived growth factor (PDGF) receptor. In the LUME-Lung 2 clinical trial, nintedanib plus pemetrexed was compared with pemetrexed plus placebo in patients with advanced NSCLC who relapsed after first-line chemotherapy. The trial was halted prematurely but showed a significant improvement in PFS, and patients treated with nintedanib plus pemetrexed lived for a median of 4.4 months before tumor growth resumed, compared with 3.6 months with pemetrexed and placebo (HR = 0.83; 

	“The results of the LUME-Lung 1 trial are particularly exciting because we have not seen any advances in overall survival for NSCLC patients receiving second-line treatment in nearly 10 years. Additionally, this is the first time an antiangiogenic treatment has shown a real benefit for NSCLC patients after initial chemotherapy has failed,” said Martin Reck, MD, PhD, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany, and principal investigator of the LUME-Lung 1 trial. “It is important to understand that NSCLC patients have a very poor prognosis as their tumor will inevitably progress after first-line treatment. Nintedanib may therefore provide a muchneeded new option for treatment.”

	LDK378, a selective ALK inhibitor, is another investigational drug in clinical trials. In a phase I study involving 78 patients, there was a 60% overall response rate in patients with 

-positive NSCLC who had experienced disease progression after crizotinib treatment. Phase II clinical trials are currently under way to further investigate this response, and several phase III studies are planned for later this year, with first regulatory filing anticipated by early 2014.

	“These results confirm that LDK378 has activity in patients with 

-positive NSCLC, including those who have progressed on crizotinib, as well as those who haven’t taken crizotinib,” said lead investigator Alice T. Shaw, MD, PhD, Massachusetts General Hospital Cancer Center, Boston. “LDK378 may become another standard targeted therapy for these 

	The effectiveness of immunotherapy using monoclonal antiprogrammed death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies has been demonstrated in metastatic NSCLC. In a recent phase I trial of the anti-PD-L1 monoclonal antibody nivolumab (BMS 936558), 129 patients with previously treated advanced NSCLC were treated with three different dosages: 1 mg/kg, 3 mg/kg, and 10 mg/kg. Of the 75 patients with NSCLC, 49 were evaluable for response. Objective response was seen in five of the 49 patients. Tumor response was seen in squamous (1 of 13 patients; 8%) and nonsquamous (4 of 36 patients; 11%) histologies. An additional six patients (12%) had stable disease for at least 6 months.34 These results further support previous findings and suggest that PD-1 inhibition may be a feasible strategy in NSCLC.

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				Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. 

				Smit EF, Dingemans AM, Thunnissen FB, et al. Sorafenib in patients with advanced non-small cell lung cancer that harbor K-ras mutations: a brief report. 

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				Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

				Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. 

				Lynch TJ, Patel T, Dreisbach L, et al. Overall survival (OS) results from the phase III trial BMS 099: cetuximab plus taxane/carboplatin as 1st line treatment for advanced NSCLC. 

				Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. 

				Perner S, Wagner PL, Demichelis F, et al. EML4-ALK fusion lung cancer: a rare acquired event. 

				Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. 

				Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. 

				Schmid-Bindert G. Update on antiangiogenic treatment of advanced nonsmall cell lung cancer (NSCLC). 

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				Ferrara N, Hillan K, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. 

				Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small cell lung cancer. AVAiL. 

				Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. 

				Lima AB, Macedo LT, Sasse AD, et al. Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis. 

				Rossi A, Maione P, Ferrara ML, et al. Angiogenesis inhibitors and vascular disrupting agents in non-small cell lung cancer.

				Rogosin S, Sandler AB. Beyond bevacizumab: antiangiogenic agents. 

				Rittmeyer A, Scherpereel A, Gorbunova VA, et al. Effect of maintenance bevacizumab (Bev) plus pemetrexed (Pem) after first-line cisplatin/Pem/ Bev in advanced nonsquamous non-small cell lung cancer (nsNSCLC) on overall survival (OS) of patients (pts) on the AVAPERL (MO22089) phase III randomized trial. 

				Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors a HER2 mutation: epidemiologic characteristics and therapeutic perspectives [published online ahead of print April 22, 2013]. J Clin Oncol. doi: 10.1200/JCO.2012.45.6095.

				Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. 

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				Roche. FDA approves Tarceva (erlotinib) tablets and cobas EGFR Mutation Test for specific type of lung cancer. 2013. Available at: http:// www.roche.com/media/media_releases/med-cor-2013-05-15b.htm. Accessed July 30, 2013.

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Articles

Drug research and development continues to focus on regimens that select therapy according to the pathologic and molecular characteristics of the tumor. 

Individualized Treatment for Non-Small Cell Lung Cancer

Headlines from the June meeting of the American Society of Clinical Oncology (ASCO) in Chicago announced to the general public what oncologists and hematologists have known for more than two years: sporadic shortages of cancer drugs are forcing suboptimal treatment plans for patients, and government efforts have not filled the void.

Two months after three surveys were presented at ASCO’s 49th Annual Meeting, our editors asked both the FDA and Keerthi Gogineni, MD, MSHP, who presented one of the studies in Chicago, to offer updates on cancer drug shortages

Gogineni, a medical oncologist in the Abramson Cancer Center and the Perelman School of Medicine in Philadelphia, was a co-author of the study conducted at the University of Pennsylvania.

While the FDA’s Lisa Kubaska, PharmD, reports that the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) is helping the agency identify shortages and find temporary solutions, such as importations of drugs, Gogineni states that some shortages remain, even though the FDA is “doing what it can.”

“There are factors that contribute to drug shortages that the agency has limited control over,” Gogineni said.

Kubaska and Gogineni agree that the majority of shortages are due to quality control problems at several large drug manufacturing plants. Kubaska said preventing shortages is a “top priority,” and that passage of FDASIA has enhanced the agency’s ability to anticipate pending problems through an early notification system. However, the FDA and physicians like Gogineni on the front lines view things differently.

Said Kubaska, “There has been one new shortage in 2013, lomustine tablets, which was resolved through import of a drug with unapproved packaging until the approved package could be made available.”

Gogineni said that her own hospital “has had considerable difficulty acquiring this drug to treat patients with brain tumors. There is an ongoing attempt to obtain this drug by enabling NextSource Biotech to import the product but under a different trade name…Theoretically this should have made emergency supplies of the drug easier to obtain by July 2013, but practically speaking, this has not been the case.”

 94% of 214 oncologists and hematologists said their patients’ treatment had been affected by drug shortages between March and September of 2012. Of those doctors reporting shortages, 83% said they had been unable to provide standard chemotherapy at some point during that time period, and 13% reported that patient enrollment or continuing participation in clinical trials had been compromised due to drug unavailability.

Two-thirds of the respondents work in community oncology settings.

A separate pair of surveys conducted by ASCO reported that members of the organization noticed only a slight easing of drug shortages between October 2012 and April 2013, but during the same period became increasingly concerned about the limited availability of treatments critical to supportive cancer care, such as antiemetics, pain medications, and basic IV fluids and electrolytes.

In the University of Pennsylvania survey, respondents said that the drugs most commonly in shortage were leucovorin, liposomal doxorubicin, 5-fluorouracil, bleomycin, and cytarabine. (According to Kubaska, the FDA arranged to have the first two temporarily imported to address the shortage.) These drugs are commonly used in the treatment of various forms of cancer, including gastrointestinal, blood, breast, ovarian, and testicular cancers. Cytarabine is particularly critical for curing certain forms of acute leukemia, ASCO stated.

Researchers noted that doctors adapted to such shortages in different ways, including switching treatment regimens (78% of doctors), substituting alternate drugs partway through therapy (77%), delaying treatment (43%), choosing among patients to determine which should receive the available supply of the chemotherapeutic agent (37%), omitting doses (29%), reducing doses (20%), and referring patients to another practice where drugs in shortage were available (17%). Most providers (70%) said they had no institutional guideline or committee to help make the difficult treatment modification decisions.

“We were surprised by the large number of cancer doctors that had to make changes in the way they care for patients due to drug shortages,” Gogineni said in Chicago. “Unfortunately, cancer drug shortages will likely be a persistent issue. Doctors are adapting to this new reality as best they can, but more uniform guidance is needed to ensure that modifications are made in the most educated and ethical way.”

The research was supported, in part, by a Pfizer Medical and Academic Partnership Research Fellowship in Bioethics.

ASCO’s 2012 and 2013 surveys of its members asked whether, in the previous six months, legislative and regulatory efforts to address drug shortages had been effective. A total of 390 and 462 doctors, respectively, responded.

Although the results from the second survey suggested that chemotherapy drug shortages may have eased very slightly, the changes were small, and practices were still faced with the need for drug substitutions. Moreover, respondents expressed growing concern over the shortage of supportive care drugs.

In the more recent survey, 59% of responding physicians were aware of ongoing drug shortages in their own or colleagues’ practices, versus 70% in the earlier survey.

Also in the 2013 survey, more than 40% of doctors said that drug shortages had not been resolved. Seventeen percent said the shortages were worse than in the fall of 2012, 16% responded that they were the same, and 9% said that some shortages had improved while others had worsened.

“Quality cancer care also means providing patients with the right treatments at the right times, and we’re learning today that cancer drug shortages are still interfering with that mission,” said ASCO spokesperson Andrew D. Seidman, MD, an oncologist at Memorial Sloan-Kettering Cancer Center in New York City. “This ongoing crisis must not be forgotten—it demands urgent solutions from regulators, policy makers, and manufacturers today.”

According to ASCO, generic drugs, especially common chemotherapies, have been most affected by shortages. In oncology, there are often no replacements for the standard agents that have been shown to improve survival, the organization reported, and when there are substitutes available, they are sometimes brand name drugs, which can be several-hundredfold more expensive. This cost burden is shared by patients and institutions, as brand name drugs typically have higher copayments and out-of-pocket costs, ASCO stated.

In many cases, ASCO said, there is also a lack of clinical trial evidence to determine the appropriate dosage for the substitute drug. In addition, according to a survey taken by the Institute for Safe Medication Practices,2 mistakes are sometimes made in the formulations or strengths of drugs given as alternatives for medications in short supply.

Drug shortages have also spawned borrowing and hoarding among medical institutions, the sale of counterfeit drugs, and a gray market for medications in limited supply, experts have said.

“ASCO believes that there are likely numerous causes of drug shortages and will continue to call on Congress to convene a blue ribbon panel that includes providers, manufacturers, suppliers, FDA, and patients to develop comprehensive legislation to resolve these critical shortages,” said ASCO Chief Medical Officer Richard L. Schilsky, MD. “The Government Accountability Office is also conducting a comprehensive investigation of the causes of the shortages, and we will be eager to learn its assessment when the report is published early next year.”

At last year’s annual meeting of ASCO, Rear Admiral Sandra L. Kweder, MD, deputy director of the FDA’s Office of New Drugs, blamed the shortages on manufacturing and quality problems and the plant closures that often result. Most shortages have involved sterile injectable drugs, she said, and as of last June, more than half of those were “due to product quality issues such as particulates, microbial contamination, impurities, and stability changes resulting in crystallization.”

Shortages may also occur due to industry consolidation, increases in demand, and a lack of access to pharmaceutical ingredients, she said.

Why does one plant shutdown prove so disruptive? In late July, Gogineni told our editors that there are a combination of underlying reasons. “There is little redundancy in the system,” she said, and there is “a marked increase in new sterile injectable product applications without a concomitant increase in manufacturing capacity [which] has led firms to divert production to more expensive, branded agents.”

The FDA, Gogineni explained, is authorized to address quality issues, but its ability to boost manufacturing capacity is quite limited—it can expedite reviews of “new” manufacturers. “It can take years for a manufacturer to increase capacity. There are few penalties for failing to supply critical drugs, and no incentive for companies to invest in ‘excess’ capacity. This is not something the FDA would have control over,” she said.

Alongside the financial incentives to produce new drugs, Hagop M. Kantarjian, MD, a professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, has blamed the shortages on the extremely low price of generics, which he said can’t be raised to meet demand due to a Medicare physician reimbursement formula.

Under the recent government sequestration that slashed the budgets of many federal agencies, including the FDA, that formula became even more likely to hold down the prices of generic drugs, a dynamic that could further contribute to drug shortages, Schilsky said at the June 3rd press briefing.

The FDASIA, which became effective in October 2012, requires drug manufacturers to alert the FDA six months in advance about anticipated market withdrawals or drug-supply interruptions. The aim is to give the FDA time to step in with tactics such as helping to arrange for other companies to pick up the slack.

In the six months that followed the passage of the FDASIA, there was a six-fold increase in early notifications from manufacturers, Commissioner Margaret Hamburg, MD, wrote on the FDA’s website. In that six months, the FDA prevented 128 drug shortages and saw fewer occur—42 reported between January and May 2012, compared with 90 new shortages reported during that period in 2011, she stated.

“This data is a testament to how the FDA exercises flexibility and discretion in much of our work on drug shortages and the importance of strong collaboration and constant communication with industry, health professionals, and patients,” Hamburg wrote.

Schilsky added that he is hopeful about another tenet of the FDASIA, which requires generic drug makers to contribute money intended to bolster the FDA’s resources, so it can review generic drug applications more quickly and conduct swifter inspections of generic drug manufacturing facilities when questions about safety come up.

Based on anecdotal evidence, Schilsky said, he believes that similar shortages are ongoing in many European countries.

			Emanuel Z, Shuman K, Chinn D, Gogineni K. Impact of oncology drug shortages. Presented at: 49th Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, IL. Abstract CRA6510.

			A shortage of everything except errors: harm associated with drug shortages. Institute for Safe Medication Practices website. http://www.ismp. org/newsletters/acutecare/showarticle.asp?id=20. Published April 19, 2012. Accessed June 3, 2013.

Fall 2013 | Contemporary Oncology®

Individualized Treatment for Non-Small Cell Lung Cancer

Drug Shortages Persist in Wake of Surveys