DID - Nov. 17, 2008 Issue

Vol. 7 No. 225

FDA Committee: Embeda Is an Improvement

Alpharma received positive feedback on its novel Embeda morphine formulation at a joint meeting of the Anesthetic and Life Support Drugs and Drug Safety and Risk Management advisory committees Friday.

Embeda (morphine sulfate/naltrexone HCl) is an extended-release morphine product under FDA review for the management of moderate-to-severe chronic pain. A majority of committee members said the drug is an incremental improvement over existing modified-release morphine products, such as Alpharma’s Kadian (morphine sulfate). Embeda’s action date is Dec. 30.

No official committee vote was taken, but DID counted only three committee members who indicated the drug was not an improvement, including consumer representative Sidney Wolfe, director of Public Citizen, the health research group.

Embeda contains naltrexone, an opioid antagonist. The chemical passes through the body with no clinical effects when the pill is taken as directed. But when the pill is crushed, both ingredients are released and naltrexone reduces the euphoric effect of the morphine, Alpharma says.

The company told the committee that with other extended-release formulations of morphine, only one step is needed — crushing the pill — to break the drug matrix. Multiple steps are required to extract morphine from Embeda.

Bob Rappaport, director of the FDA’s Division of Anesthesia, Analgesia and Rheumatology Products, said he heard the committee’s message but cautioned that effective surveillance methods are needed to monitor whether the product is being abused.

Meeting Success

The same advisory committee earlier considered Pain Therapeutics and King Pharmaceuticals’ novel oxycodone formulation Remoxy XRT. Despite reservations Rappaport expressed Thursday, he said the FDA received useful information from the meeting (DID, Nov. 14). He mentioned a suggestion to include in physician labeling what might happen to abusers if the product were misused. 

One committee member said Embeda’s label should include information that naltrexone might lead to opioid withdrawal symptoms if someone tampered with the product.

The FDA has unresolved issues with the Embeda application, specifically abuse-liability studies, Srikanth Nallani, a senior clinical pharmacologist with the agency’s Office of Clinical Pharmacology, said during the meeting.

Embeda Studies

Two abuse-liability studies tested Embeda in subjects who had been treated with opioids yet were not dependent on them. In one trial, crushed Embeda was administered orally to test its effects against those of immediate-release morphine.

Sandra Connor, associate professor of clinical neurobiology at Columbia University, presented the data from the studies on behalf of the company. During the first eight hours, the trials showed that subjects’ ratings of feeling high and euphoric were lower when they consumed crushed Embeda compared with immediate-release morphine.

About 88 percent of subjects liked crushed Embeda less, compared with extended-release morphine, and 69 percent reported less euphoria, she told the committee.

But Nallani said there was a high variability in how much patients liked the drugs and none of the subjects had a complete decrease in the drug-liking score when the product was crushed and consumed. “Is there adequate data to claim abuse deterrence via crushing and oral consumption?” Nallani asked the committee.

One study only tested Embeda when it was crushed and swallowed, and pharmacokinetic, safety and drug-likeability studies were not conducted to measure abuse when the crushed product was inhaled or when Embeda was chewed and swallowed. The issue is whether there is an adequate amount of naltrexone released and absorbed in those situations.

The other abuse liability trial compared IV morphine alone with IV morphine plus IV naltrexone in proportions that mimic the ratio of the two drugs in Embeda. That study showed subjects were three times more likely to report feeling high when injected only with morphine compared with those dosed with both morphine and naltrexone.

However, that study did not address situations in which only the morphine in the product was extracted and whether it was safe to inject Embeda after it had been manipulated by the user, Nallani said.

FDA briefing documents for the committee meeting noted that there was not enough data to gauge the effects of injecting the drug when it is crushed then prepared as a liquid. Alpharma has told the FDA that animal studies were under way to address that, Nallani said. — Christopher Hollis


Regulation of Overseas Clinical Trials Is Growing

The FDA is increasing its scrutiny of multinational trials as U.S. pharmaceutical firms and contract research organizations (CROs) expand into clinical trial sites in China, India, the Middle East, Latin America and Africa, an expert says.

The FDA has announced plans to open offices, including branches in Europe, Latin America, New Delhi and Beijing, by the end of the year to help oversee clinical trials performed by drugmakers seeking U.S. approvals (DID, Oct. 23). The Middle East will be added by the middle of next year, Ann Begley, a partner with K&L Gates, said in an RxTrials Institute audioconference.

In April, the agency published a final rule saying such trials must meet good clinical practice (GCP) standards (DID, April 28). Previously, a commitment to abide by the human subject protection rules of the Declaration of Helsinki was acceptable, but the FDA has become more cautious about standards it does not control, Begley said.

For example, the 2000 version of the Declaration of Helsinki contained restrictions on placebo-controlled trials that the FDA found unacceptable, she said. The FDA also will not commit itself to International Conference on Harmonisation (ICH) guidelines, since it does not control those either.

However, it may accept national standards that are equivalent to GCP, such as Brazil’s Resolution No. 196/96, which is based on several international guidelines on research involving human subjects: the Nuremberg Code, the Declaration of Helsinki, the International Agreement on Civil and Political Rights, the Proposed International Guidelines for Biomedical Research Involving Human Subjects and the International Guidelines for Ethical Review of Epidemiological Studies.

Sponsors, CROs Must Know Laws

Drugmakers and CROs are eager to conduct clinical trials in developing countries to gain potential marketing opportunities for drugs approved in those regions, to find patients from limited pools of potential subjects, to access qualified investigators in developed countries and to save money, Begley said.

U.S. sponsors and CROs should remember they are bound by the Foreign Corrupt Practices Act (FCPA) and the host country’s laws in addition to FDA regulations, Begley said.

The FCPA’s major provisions are: record-keeping provisions enforced by the SEC and an anti-bribery provision enforced by the Justice Department that prohibits U.S. individuals or businesses from paying, offering or authorizing anything of value, directly or indirectly, to a foreign official, political party or candidate to benefit the individual or business.

“For the purpose of clinical trials, a company must ensure that its expenditures are accurately reflected in its financial recordkeeping,” Begley said. Violators face fines or prison time, even if they were unaware of what was being done in their name.

For example, Schering-Plough’s Polish subsidiary donated about $76,000 to the Chudnow Castle Foundation from 1999—2002, leading to a disproportionate increase in sales of two oncology products in the Polish region where the foundation was based. Schering-Plough did not contest the charges and paid a $500,000 fine, Begley added.

To avoid such problems, Begley advised companies to maintain careful oversight of all third-party agents, offer compliance training to everyone, and separate research contracts, awards and grants from sales and marketing functions. If a drug company discovers an FCPA violation during an audit, it should report the problem to the SEC or Justice in hopes of leniency, she added.

Host country laws vary widely, Begley said. For example, the EU regards U.S. patient privacy laws as contained in the Health Insurance Portability and Accountability Act to be unacceptably lax while India has almost no privacy laws, although this may soon change. Sponsors also should know that in India, studies that have received a U.S. IND can clear the country’s Central Drugs Standard Control Organization within one to two weeks, but studies without an IND take eight to 12 weeks to clear.

When looking for a foreign clinical site, Begley advised sponsors and CROs to consider whether the site:

  • Has prior clinical trial experience;
  • Has adequate facilities;
  • Conducts self-audits;
  • Has adequate and properly trained staff;
  • Has been cited for regulatory violations, such as in an FDA warning letter — to date, the FDA has sent only one warning letter to a foreign site (DID, Oct. 10, 2006);
  • Has a working knowledge of GCP and local law, and implements and follows GCP standard operating procedures; and
  • Complies with additional requirements identified by the sponsor or CRO.

The sponsor or CRO should seek a strong clinical trial agreement that provides, among other things, that the site will admit FDA inspectors and sponsor or CRO representatives to conduct audits and monitoring as needed, Begley said. — Martin Gidron


FDA Warns Sinus Medication Company Over Unsubstantiated Claims

Aerosol Science Laboratories’ compounded aerosolized medications are misbranded and it has no record of approval for its aerosolizing device, an Oct. 29 FDA warning letter says.

The California-based company’s website posts “false and misleading claims” regarding the medications, which are used with the Sinus Science aerosol medication delivery system, the FDA letter says. Drugs with false or misleading labels or advertisements are considered misbranded.

The misbranded drugs include nasally inhaled antibiotics, antifungals, anti-inflammatories and mucolytics claimed to treat allergic rhinitis, chronic sinusitis, sinus headaches and loss of smell, according to the FDA.

Aerosol also makes unsubstantiated efficacy claims on its website, the FDA says. The website says, “Inhaled antibiotics, anti-fungals, anti-inflammatories and mucolytics are new treatment choices for allergic rhinitis, chronic sinusitis, sinus headaches and loss of smell.” But the FDA letter says, “The inhalation forms of these products have not been approved for the treatment of chronic sinusitis, allergic rhinitis, sinus headaches or loss of smell.”

The labeling also is missing adequate directions, the FDA says.

In addition, the agency found unsubstantiated superiority claims. The company website includes claims that its products are superior to FDA-approved products because they produce “tiny particles” instead of the larger droplets produced by nasal spray bottles.

Not only are such claims false or misleading, the FDA says, they also raise concern because particles smaller than 5 microns can be inhaled into the lungs and may have “potential safety concerns.”

Furthermore, the FDA has no record of approval for the device with which the drugs are used, the letter says. The device should not be marketed because it is in violation of the Federal Food, Drug, and Cosmetic Act.

The company did not respond to a request for comment by press time. The warning letter is available at www.fda.gov/cder/warn/2008/AerosolScienceLaboratoriesInc1WL.pdf. — Elizabeth Collins


Justice Lodges Complaint Against Actavis Subsidiary

The Justice Department has filed a complaint against a U.S. subsidiary of Icelandic drugmaker Actavis, alleging numerous good manufacturing practice (GMP) violations and unapproved new drug violations of the Food, Drug and Cosmetic Act.

The permanent injunction being sought by Justice would bar Actavis Totowa and two executives from making and distributing generic drug products until they demonstrate compliance with GMP requirements, Justice says in a statement. Justice has filed the complaint on the FDA’s behalf in the U.S. District Court for the District of New Jersey, the agency told DID.

The complaint follows five FDA inspections of Actavis Totowa facilities over the past three years.

An FDA inspection of Actavis Totowa’s facilities in Little Falls, N.J., earlier this year  revealed some operations at the facility did not meet GMP standards. The inspection resulted in a Class I nationwide recall of all strengths of Digitek (digoxin) after the commercial release of oversized tablets with possibly twice the approved level of the active ingredient, Justice says in a statement.

Too much digitalis can cause nausea, vomiting, dizziness, low blood pressure, cardiac instability, bradycardia and death. Several reports of illness and injury had been received, the FDA said at the time (DID, April 29).

Actavis says in a statement that the actions it has taken to remedy the compliance and manufacturing issues at its U.S. subsidiary will exceed FDA’s expectations and will more accurately represent the company’s standards for GMPs.

“We have taken a comprehensive approach to correcting all deficiencies within the Totowa business, and we’ve communicated regularly and candidly with the FDA, the public, our employees and our customers,” John LaRocca, Actavis chief legal officer, says in a statement. “Last month, we asked FDA to return to the Totowa facilities, conduct an inspection, and observe the substantial progress we have made.

“To this point, the FDA has not acted. We look forward to a quick and satisfactory resolution to these issues for the benefit of consumers, the agency and ourselves.”

Justice’s filing is the latest blow to the company this year. In August, the drugmaker recalled all drug products manufactured at the Little Falls plant (DID, Aug. 5). About 55 products were withdrawn, ranging from antiviral drug amantadine HCl to painkiller oxycodone. Tuberculosis antibiotic rifampin was affected as was Type 2 diabetes drug glyburide and the antidepressant mirtazapine.

According to the FDA’s July 30 Enforcement Report, the company recalled 117,469 amantadine HCl 100- and 500-count bottles because they contained products found to be subpotent after 18-month stability tests.

The company views the filing of this complaint as one step in a long regulatory process and is committed to working collaboratively and openly with the FDA in a timely manner, according to its statement. — Elizabeth Jones


Vytorin and Zetia Prescriptions Plummet

Doctors wrote 644,000 fewer prescriptions for Merck and Schering-Plough’s cholesterol-lowering drug Vytorin in October than in January, a decline of 35 percent, according to IMS Health data disclosed by Schering-Plough in a regulatory filing.

Schering-Plough’s Zetia (ezetimibe) cholesterol treatment had a 29 percent slide in October, or 397,000 fewer prescriptions compared with January, the data show. However, the total number of prescriptions in the cholesterol management market remained stable over the year, rising slightly to 20.6 million in October from 20.5 million in January, according to IMS Health.

The decline in sales of Vytorin (ezetimibe/simvastatin) and Zetia was steady through September but appeared to level last month. A competing cholesterol drug, Pfizer’s Lipitor (atorvastatin calcium), was the top-selling drug in the world for the 12 months through September, IMS Health says.

Pfizer’s revenue from Lipitor was $9.26 billion in the first nine months of the year, which was flat compared with the corresponding period of 2007. In the third quarter, sales were $3.14 billion, down 1 percent compared with the third quarter of 2007.

U.S. competition from generics, increased payer pressure, a sluggish lipid-lowering market amid a weakening economy and slower growth in the Medicare Part D population contributed to Pfizer’s results, the company says in a statement. This was partly offset by favorable foreign exchange rates and international operating growth, Pfizer adds.

Earlier this month, Merck and Schering-Plough received five civil investigative demands from 35 state attorneys general probing whether the companies violated state consumer protection laws in marketing Vytorin. The Justice Department also is looking at whether the promotion of Vytorin led to false claims being submitted to federal healthcare programs, according to an SEC filing from Merck (DID, Nov. 5). — Martin Gidron


UK Commission: More Regulation Needed for Nanomaterials

Urgent testing and regulation are needed to control the rapidly developing field of nanomaterials, according to British officials.

Nanomaterials have properties that can be used to restructure manufacturing and energy production. They typically have nanostructure-dependent properties — such as chemical, biological, optical or magnetic — that may make them desirable for medical products.

In the U.S., officials and researchers recognize a similar need for more regulation of this emerging technology. FDA scientists researching nanomaterials and nanotoxicology said at a media briefing last week that what they know about these materials is far less than what they need to know.

While there is no evidence to show nanomaterials may pose health and environmental risks, some experts are concerned that the pace at which such new materials are being developed and marketed exceeds the capacity of regulatory authorities to control their effects, according to a report by the UK’s Royal Commission on Environmental Pollution.

“We are … concerned that more sophisticated, later-generation nanoproducts will raise issues which cannot be dealt with by treating them as chemicals or mixtures of chemicals,” John Lawton, chairman of the commission, says in a statement. “Current testing arrangements and existing regulations are inadequate.”

U.S. scientists in the FDA’s Office of Science and Engineering Laboratories at the Center for Devices and Radiological Health said their research is focused on understanding risks associated with patient exposure to nano-based medical products and discovering what other scientific challenges the materials may pose.

On its website, the FDA says several issues related to its regulation of nanotechnology are being discussed in various forums. It expects that many nanotechnology products it oversees will span the regulatory boundaries between pharmaceuticals, medical devices and biologics.

The FDA’s Nanotechnology Task Force report from 2007 is available at www.fda.gov/nanotechnology/taskforce/report2007.html. The UK report, “Novel Materials in the Environment: The Case of Nanotechnology” can be found at http://www.rcep.org.uk/novel%20materials/Novel%20Materials%20report.pdf. — Renee Frojo

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