Drug abuse, counterfeits, and critical shortages illustrate need for secure drug supplies
The United States is caught in an epidemic of prescription drug overuse and abuse, and efforts to counter such activity are affecting drug distribution, prescribing, and oversight. Just as troubling is the appearance of counterfeit versions of critical drugs, and continued shortages of vital medications have generated interest in new approaches to ensure that the drug supply chain can reliably deliver safe and effective therapies.
CRACKDOWN ON ABUSE
Nearly 7 million Americans abuse psychotherapeutic drugs, according to a survey by the Department of Health and Human Services (HHS), and illegal prescription drug use now exceeds that for cocaine and heroin. Consequently, manufacturers, prescribers, and drug distributors face increased scrutiny from the Drug Enforcement Administration (DEA) and other regulators seeking to monitor drug distribution and prescribing more aggressively. A House Energy and Commerce subcommittee held hearings last year and again in March 2012 to examine how DEA is tracking and preventing inappropriate prescription drug use, the effectiveness of state prescription drug monitoring programs, and how well manufacturers, distributors, and pharmacists prevent illegal diversion.
Of the thousands of pharmaceuticals approved by FDA for US marketing, about 250 are regulated by the Controlled Substances Act of 1970 (CSA). Approximately 80 drugs with high-abuse potential but important medical uses fall under Schedule II, including sleep aides, diet pills, antidepressants, psychiatric drugs, and antihyperactive therapies, as well as painkillers. Another 150 drugs have relatively low-abuse potential and are in schedules III-V with minimal restrictions, and more than 130 Schedule I drugs are dangerous and not approved for any uses.
DEA and other federal and state agencies have responded to rising abuse of opioids and other legal drugs through the 2011 Prescription Drug Abuse Action Plan released last year by the White House Office of National Drug Control Policy. DEA agents have been closing down illegal online pharmacy sites and rogue pain clinics, particularly in Florida, that have dispensed thousands of prescriptions for pain treatment. DEA also is targeting drug wholesalers and pharmacists that fail to detect and halt diversion; DEA recently moved to shut down a Cardinal Health distribution facility and 4 pharmacies in Florida allegedly for overlooking highly excessive oxycodone orders.
Recent legislation also authorizes more aggressive efforts to remove leftover prescription drugs from family medicine cabinets. DEA is holding another national "Take-Back" initiative this month, aiming to collect tons of expired or unwanted medications for proper incineration.
One response is for pharmaceutical manufacturers to develop abuse-deterrent formulations, such as patches or capsules, but so far, such products have not been found highly effective. Manufacturers look to add antagonists or change formulations to improve resistance, but DEA wants strong evidence to support "down-scheduling" to a DEA category that carries less regulation of production quantities, physical security, prescribing, and distribution.
Ultimately, better science may establish a clearer roadmap for assessing drug pharmacology and clinical studies related to abuse factors, particularly for new drugs with novel mechanisms of action. Criteria for identifying and reporting adverse events related to prescription drug abuse also could provide safety data that supports changes in controls, as would efforts to increase prescriber and patient education on the appropriate use of opioids and abused drugs.
SECURING THE SUPPLY CHAIN
Diversion of controlled substances might be prevented by the adoption of a new system to track drugs through the pharmaceutical supply chain. At a hearing before the House Energy and Commerce Health subcommittee last month, the legislators urged FDA and industry to collaborate on devising a "robust pedigree system" with special tags or barcodes on products to distinguish genuine drugs from fake medications throughout the distribution process.
Manufacturers, distributors, and pharmacists told the legislators that they have finally agreed on an efficient and affordable national serialization and tracking system dubbed RxTEC, which could replace the current "patchwork" of proliferating state pedigree laws. But FDA officials want a system that tracks drugs down to the unit level, claiming that traceability at the drug lot level, as proposed by industry, can only partially identify the distribution path of contaminated or counterfeit products. Drug production lots can include millions of pills or vials that are distributed to multiple wholesalers and customers around the world, making it almost impossible to identify how a product in a certain lot became adulterated or abused.
The need for a more effective drug tracking system was made all too clear by the recent appearance of highly sophisticated drug counterfeiters, as seen in the discovery of fake bevacizumab (Avastin) sold to doctors in California, Texas, and Illinois. Unfortunately for their patients, this "lower-priced European alternative" had no active ingredient. FDA sent letters to 19 doctors instructing them to stop using this unapproved product and pointing out the dangers of purchasing medications from unknown sources, in this case Quality Specialty Products, also known as Montana Healthcare Solutions. The physicians evidently were attracted by a $1,900 price tag on a drug that usually costs about $2,400 from Roche's Genentech. Investigators subsequently traced the phony drug to Asia and the United Kingdom prior to its appearance in the United States.
The bevacizumab incident prompted the US Senate to approve a bill that imposes much stiffer fines on drug counterfeiters, a crime that has long enjoyed fairly weak penalties. In addition, FDA has called on the Institute of Medicine (IOM) to form a blue-ribbon committee to report on ways to detect and prevent drug counterfeiting and adulteration. The aim is to finalize the analysis by early next year.
Legislation to deter counterfeiting and require drug pedigrees also is expected to address the continuing drug shortage crisis. Congressional leaders seem to agree with FDA that a broader group of drug companies should have to report more information to FDA about looming short-supply situations.
Meanwhile, FDA has demonstrated its flexibility in preventing and dealing with shortages of necessary therapies. FDA Commissioner Margaret Hamburg, MD, announced in February that the agency remedied a serious shortage of the cancer drug doxorubicin (Doxil) by authorizing Caraco Pharmaceutical Laboratories to temporarily import a replacement drug, Lipodox, produced overseas by India's Sun Pharma. FDA officials emphasized that importation of this unapproved foreign drug will be a temporary, limited arrangement and was authorized only after the agency evaluated the quality and safety of the Sun product.
FDA also resolved a critical shortage of methotrexate by expediting approval of a manufacturing supplement from APP Pharmaceuticals and release of thousands of vials produced by Hospira. FDA said it also is working with Mylan and Novartis' Sandoz Pharmaceuticals to boost their production of preservative-free methotrexate, which is needed to treat children diagnosed with acute lymphoblastic leukemia.
Yet, Dr Hamburg noted in a speech at the annual meeting of the Generic Pharmaceutical Association (GPhA) in February, that many drug shortages are related to quality-compliance issues. Companies making medically necessary drugs "must invest in their manufacturing facilities," Dr Hamburg advised the generics manufacturers, noting that visible shortages involving generic drugs could lead the public "to equate generics with quality concerns."
On another front, physicians and research organizations are grappling with new rules that require manufacturers of drugs and medical products to report all payments to doctors and teaching hospitals for inclusion in a new public database. The main thrust of this "Sunshine" policy, which was included in the Affordable Care Act of 2010, is to disclose all industry "transfers of value"—fees, grants, free meals—that theoretically could influence physician practice and prescribing. The reports also cover fees to physicians and teaching hospitals for research activities, a requirement that medical societies fear will make payments for bona fide research activities look like big handouts from pharma.
A long list of medical and professional groups addressed these issues in comments on the proposed rule for implementing Sunshine issued by the Centers for Medicare and Medicaid Services (CMS) in December 2011. Doctors and pharmacists voiced concerns about how payment data will be posted and the very limited time for review. Pharmacists and physicians want CMS to drop reports of payments to physicians participating in continuing medical education programs that are accredited and certified, noting that unrestricted grants from pharmaceutical companies prevent funders having any influence on program materials or presenters.
The research-related reporting provisions came under fire from medical societies and research organizations that claim the proposed policy far exceeds the intent of the law. The American Thoracic Society, for example, said that public reporting of research payments implies that "research is somehow an inappropriate activity for physicians." The Association of Clinical Research Organizations (ACRO) proposed cancelling reports on payments from manufacturers for legitimate research activities "as there is no evidence that such payments bias prescribing or other practice behavior." Without many of the proposed changes, says ACRO, data related to research will be "incomplete at best, terribly inaccurate at worst." CMS will consider these comments as it moves to revise its proposed rule, possibly by the end of the year.
Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.
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