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Soaring opioid use creates challenges for new drug development and supply-chain control.
The United States is caught in an epidemic of prescription-drug overuse and abuse, and federal enforcers are revving up forces to counter illegal diversion of approved drugs. Nearly 7 million Americans abuse psychotherapeutic drugs, according to a survey by the Department of Health and Human Services (HHS), and prescription drug abuse now exceeds that of cocaine and heroin. Consequently, manufacturers of opioids and other painkillers, along with 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 in April 2011 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. Subcommittee Chair Rep. Mary Bono Mack (R–CA), has pressed for policies to aggressively curb access to painkillers and anxiety drugs more severely since the suicide of her son related to oxycontin abuse.
Of the thousands of pharmaceuticals approved by FDA for US marketing, about 250 are regulated by the the Controlled Substances Act of 1970 (CSA). Some 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, while more than 130 schedule I drugs are dangerous and not approved for any uses.
DEA and other federal and state agencies have responded to the sharp rise in abuse of opioids and other legal drugs as part of 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 dispense thousands of prescriptions for pain medicines. A main DEA thrust is to target drug wholesalers and distributors that fail to detect and halt diversion; DEA recently moved to shut down a Cardinal Health distribution facility and four 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, and DEA is holding another national "take-back" initiative this month, aiming to collect tons of expired or unwanted medicines for proper incineration. Brand and generic-drug manufacturers support these efforts, but are wary of proposals from the state of Washington and a California county that call for manufacturers to foot the bill for more extensive collection of leftover prescriptions.
SEEKING DEA APPROVAL
Another concern for industry is that added requirements for bringing schedule II therapies to market can delay patient access to new drugs by six months or more. DEA also sets annual quotas on production of controlled drug substances, a factor that may aggravate shortages of certain widely used drugs.
FDA assesses about one-third of new drug applications (NDAs) to see whether they warrant additional scheduling review by the DEA, noted Douglas Throckmorton, deputy director of the Center for Drug Evaluation and Research (CDER), at a February 2012 seminar on controlled substance regulation sponsored by the Food and Drug Law Institute (FDLI). CDER's Controlled Substance Staff (CSS) determines whether DEA should evaluate the product further, which can lead to a complex scheduling process after FDA approves the NDA.
This DEA review, for example, delayed marketing 11 months after FDA approval in 2008 of Esai's sedation medication Lusedra (fospropofol). GlaxoSmithKline had to wait nearly six months to market its new epilepsy drug Potiga (ezogabine), despite early communication with DEA on the product's unique features. DEA scheduling "is a big black box for industry," observed Esai regulatory policy executive Ginny Beakes-Read, with no timelines for its actions and recommendations.
FDA officials advise manufacturers to address scheduling issues early in drug development to facilitate the review process. Sponsors need to characterize whether a drug produces positive psychoactive effects, such as sedation, euphoria and cognitive distortion, explained CSS pharmacology team leader Silvia Calderon-Gutkind. NDAs should clearly identify abuse liability— or its absence—through evaluation of chemical properties, pharmacological and pharmacokinetic characteristics and clinical data relevant to abuse.
CDER is working to improve its internal assessment process for controlled substances and to negotiate a memorandum of understanding with DEA to facilitate exchange of confidential information on new drugs earlier in the review process. FDA issued draft guidance last year on how manufacturers should assess the abuse potential of new drugs, and advice on developing abuse-deterrent formulations is expected this year.
Although there's great interest in abuse-resistant patches or capsules, so far none have emerged that are "truly effective," said Gary Boggs, executive assistant in DEA's Office of Diversion Control, at the FDLI meeting. Manufacturers look to add antagonists or change formulations to improve resistance, but DEA wants data to show that it works and warrants "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 issues, 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.
DEA quotas on active ingredient supplies and production volume for schedule II drugs also have drawn scrutiny as factors contributing to shortages in critical drugs. Manufacturers claim that such controls have reduced supplies for treatments for attention-deficit/hyperactivity disorder (ADHD), which often contain amphetamines. DEA can amend aggregate drug production quotas during the year when there is a "legitimate need," explained Boggs. But he noted that it's hard to quantify such need, and the amendment process involves a lengthy comment-and-rulemaking procedure. FDA has been able to work with DEA to prevent shortages in several cases, notes Valerie Jensen, associate director of CDER's drug-shortage program, and Congress may modify the DEA quota-setting policy as part of legislation to address drug shortages in development on Capitol Hill.
FDA is moving aggressively to deal with shortages of critical drugs on all sides, as witnessed in recent actions to ensure access to two key cancer medicines. Commissioner Margaret Hamburg announced at a February 2012 briefing that FDA remedied a serious shortage in a version of cancer drug Doxil (doxorubicin hydrochloride liposomal injection) by authorizing Caraco Pharmaceutical Laboratories to temporarily import a replacement drug, Lipodox, produced overseas by India's Sun Pharma Global FZE. Serious manufacturing problems at contract supplier Ben Venue Laboratories, a division of Boehringer Ingelheim, dried up Doxil production for Johnson & Johnson's Janssen Products, leaving physicians desperate for supplies of this important cancer and AIDS treatment. FDA officials emphasized that import of this unapproved foreign drug will be a temporary, limited arrangement and was authorized only after the agency evaluated Sun to ensure the quality and safety of the product.
FDA also resolved a critical shortage of methotrexate, also related to Ben Venue production problems, by expediting approval of a manufacturing supplement from APP Pharmaceuticals and release of thousands of vials produced by Hospira. Preservative-free methotrexate is needed to treat children diagnosed with acute lymphoblastic leukemia as well as other serious conditions. FDA also is working with Mylan and Novartis' Sandoz Pharmaceuticals to increase their methotrexate production.
Hamburg said that FDA is dealing with these problems by expanding its drug-shortage team, providing guidance to industry on drug shortage notification procedures, and backing legislation to expand required reporting. By working closely with generic- and brand-drug makers, FDA has prevented 114 shortages since October 2011, Hamburg pointed out.
Yet, the commissioner also noted in a speech to the annual meeting of the Generic Pharmaceutical Association in February that the majority of drug shortage problems are related to compliance issues affecting product safety and quality. On almost the same day that APP announced expanded methotrexate production, FDA issued a scathing Warning Letter citing the company for significant manufacturing violations at its Grand Island, NY. facility, primarily related to heparin production. Hospira was able to ship some 65,000 vials of methotrexate in February because it obtained additional supplies of active ingredient and invested hundreds of millions of dollars in extensive plant remediation efforts to resolve serious quality manufacturing issues cited multiple times by FDA.
Manufacturers of medically necessary drugs "must invest in their manufacturing facilities," Hamburg advised the generic-drug manufacturers, noting that "quality is crucial for all products," and that visible shortages involving generic drugs could lead to public "to equate generics with quality concerns."
In addition to relying on ever-greater user fees to finance FDA operations ($2 billion in fees on a $4.5-billion budget), the Obama administration's spending plan for fiscal year 2013 takes some heavy swipes at biopharmaceutical companies. The president proposes to lower the exclusivity period for innovator biologics to seven years from 12 and to ban brand-generic "pay-for-delay" settlements. There's also the Democratic favorite to extend Medicaid rebates to all low-income beneficiaries in Medicare Part D plans, which is calculated to cut spending by $156 billion over 10 years. John Castellani, president of the Pharmaceutical Research and Manufacturers of America (PhRMA), blasted these proposals in a statement as a counter to "Obama's many pronouncements to support innovation, advance biomedical research, promote job creation and control healthcare costs for seniors." Congressional Republicans rejected the Obama budget immediately, taking particular aim at the administration's request for another billion dollars to fund healthcare reform, along with the antipharmaceutical provisions.
US regulators have expanded the so-called "import alert" list to include 14 more Chinese producers of heparin and related products, for a total of 22 Chinese firms linked to the heparin contamination crisis of 2008 and still unable to meet FDA standards for manufacturing and quality control. The move additionally aims to assure Congressional Republicans that FDA is serious about ensuring the safety of heparin products in the US.
FDA also aims to bolster its presence in China by seeking an additional $10 million in its FY 2013 budget to expand the scope of in-country inspections and staff. A new FDA report to Congress on its foreign offices and operations, as required by recent food-safety legislation, summarizes FDA overseas activities and interactions with regulatory authorities in China, India, Latin America, Europe, Africa and the Middle East, designed to build rapport and obtain important information on local production and regulatory operations.
Manufacturers are supporting a new mandatory code of conduct for dealing with doctors and other providers around the world, largely to offset charges of violating the US Foreign Corrupt Practices Act (FCPA) and similar laws set by other countries. Spurred by a rise in investigations and charges levied against pharma companies by US and foreign enforcement agencies, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) has updated its ethical practice code to cover broader industry interactions with health professionals. Astra Zeneca CEO David Brennan, IFPMA president, said in a Mar. 1, 2012 statement, that the new policy can help industry "act with integrity and build trust." The code bans gifts and curtails entertainment to docs—and may save manufacturers in legal fees and fines: Johnson & Johnson paid some $70 million last year to settle charges of illegal payments overseas, and Serbia is investigating several bio/pharmaceutical companies for bribery and corruption.
Counterfeiters continue to become more sophisticated, as demonstrated in the recent discovery of fake Avastin sold to doctors in California, Texas, and Illinois. Unfortunately for patients, this "lower-priced European alternative" of Avastin has no active ingredient (bevacizumab). FDA sent letters to 19 doctors instructing them to stop using this unapproved product and pointing out the dangers of purchasing critical medicines from unknown sources, in this case from Quality Specialty Products (also known as Montana Healthcare Solutions). The doctors evidently were attracted by a $1900 price tag on a drug that usually costs about $2400 from Roche's Genentech. The Avastin incident prompted the Senate to approve a bill stiffening penalties on drug counterfeiters, and further legislation may authorize a better drug tracking system to distinguish genuine medicines from fakes. In addition, the Institute of Medicine is preparing a report for FDA on ways to detect and prevent drug counterfeiting and adulteration, hoping for delivery by year-end.
Biotech manufacturers are cheering new legislation to strengthen the nation's response to public health emergencies, which provides added support for developing new medical countermeasures critical to such efforts. The US House or Representatives approved the Pandemic and All-Hazards Preparedness Act (PAHPA) in late 2011, and the Senate followed suit last month. The bill authorizes about $8 billion over five years to bolster detection and response to threats by the Centers for Disease Control and Prevention (CDC) and increases funding for countermeasure development and procurement. FDA also gets support for expert teams to provide technical assistance to manufacturers of vaccines, treatments and diagnostic tests important for responding to threats.
Recently issued key guidance documents
Recent legislative proposals
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, email@example.com .