28Sep/06

FDA Drug Safety System Needs Fixing, IOM Report Says

By Daniel R. Matlis 

According to a report issued by the Institute of Medicine (IOM), the FDA suffers from a lack of clear regulatory authority, chronic under funding, organizational problems, and a scarcity of post-approval data about drugs’ risks and benefits.  

The report, entitled The Future of Drug Safety: Promoting and Protecting the Health of the Public”, was commissioned by the FDA and the Department of Health and Human Services in response to the growing public concern with health risks posed by approved drugs. The Agency asked the IOM to convene a committee to assess the U.S. drug safety system and to make recommendations to improve risk assessment, surveillance, and the safe use of drugs. 

“FDA has an enormous and complex mission — both to make innovative new drugs available to patients as quickly as possible and to assess the long-term risks and benefits of these products once they are on the market,” said Sheila Burke, chair of the committee that wrote the report.  “We found an imbalance in the regulatory attention and resources available before and after approval.  Staff and resources devoted to pre-approval functions are substantially greater.  Regulatory authority that is well-defined and robust before approval diminishes after a drug is introduced to the market.  Few high-quality studies are conducted after approval, and the data are generally quite limited.  Many of the report’s recommendations are intended to bring the strengths of the pre-approval process to the post-approval process, to ensure ongoing attention to medications’ risks and benefits for as long as the products are in use.” 

During its research, the committee found that

  1. There is a perception of crisis that has compromised the credibility of FDA and of the pharmaceutical industry.
  2. Most stakeholders–the agency, the industry, consumer organizations, Congress, professional societies, health care entities–appear to  agree on the need for certain improvements in the system.
  3. The drug safety system is impaired by the following factors: serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety; an organizational culture in CDER that is not optimally functional; and unclear and insufficient regulatory authorities particularly with respect to enforcement.
  4. FDA and the pharmaceutical industry do not consistently demonstrate accountability and transparency to the public by communicating safety concerns in a timely and effective fashion. 

To address these issues, the report offers a broad set of recommendations to ensure that consideration of safety extends from before product approval through the entire time the product is marketed and used.  
These recommendations include:

  • Labeling requirements and advertising limits for new medications
  • Clarified authority and additional enforcement tools for the agency
  • Clarification of FDA’s role in gathering and communicating additional information on marketed products’ risks and benefits 
  •  Mandatory registration of clinical trial results to facilitate public access to drug safety information
  • An increased role for FDA’s drug safety staff
  • A large boost in funding and staffing for the agency

“We have already called for making sure the FDA has adequate resources to perform its critical drug review, surveillance and monitoring functions: said Caroline Loew, Senior Vice President of the Pharmaceutical Research and Manufacturers of America (PhRMA), “Additionally, PhRMA supports recommendations for modernizing the post-market surveillance system for drugs, including more efficient use of the adverse reaction reporting system; maximizing use of large health care data bases; and building more expertise around epidemiological studies.”

I agree that the FDA and Industry need to do a better job monitoring medications’ risk-benefit profiles after approval. They must also improve communications to healthcare providers and patients on the uncertainties and potential risks associated with newly introduced drugs. 

However, as patients, we must recognize that there are no “risk free medicines”. Each patient must work with their healthcare provider to evaluate the risk-benefit profile associated with each recommended therapy and make an informed decision based on the facts available at that time. We must also remain vigilant and be ready to reassess those choices when new post approval data becomes available.

After all, our health is our responsibility.

20Sep/06

ImClone Loses Patent Decision for Cancer Drug Erbitux

By Leslie Gladstone Restaino, Esq.

ImClone Systems, Inc. is reeling from a court decision Monday invalidating ownership of a significant patent for the company’s cancer drug Erbitux. 

Yeda Research and Development Co., the licensing arm of the Weizmann Institute, filed suit in 2003, alleging that three researchers had not been properly designated as inventors on the patent which claims the use of certain antibodies to block a tumor grown protein, when used in combination with chemotherapy.  Aventis claimed that its scientists had already conceived of the use of the antibodies as tumor inhibitors when one of its scientists asked scientists at the Weismann Institute to test the idea in routine experiments.  Yeda claimed that Aventis scientists volunteered to supply the Weizmann scientists with an ingredient to do the experiments.  The New York District Court agreed with Yeda, crediting the invention solely to the Weizmann researchers.  In order to continue to sell Erbitux, Yeda may likely look to grant a license to ImClone, Aventis’ exclusive licensee of the patents, at a premium to the current terms of ImClone’s pre-existing agreement with Aventis.  Alternatively, Yeda may block ImClone’s ability to sell Erbitux for use in chemotherapy combination therapies.
 
This ruling underscores the need to correctly list patent inventors. Inventorship turns on conception.  Oftentimes however, researchers list all project participants on patent filings, mimicking the procedure used for article publication.  Where incorrect,  ownership can shift, or the patent invalidated. 
 
About the Author:
Leslie Gladstone Restaino is a Member of the Firm of  Sills Cummis Epstein & Gross, P.C in the Intellectual Property and Corporate Practice Groups. She concentrates her practice on the special business and legal needs of public and private life sciences companies. Ms. Restaino represents established pharmaceutical companies and start-ups in the life sciences industry throughout all phases of their life cycle and understands the business concerns of growing and established companies.

18Sep/06

Compounding Redux

By Daniel R. Matlis

Recently, I wrote an article calling for consistent federal regulatory requirements for the practice of compounding. Last month, the US District Court in Texas ruled against the FDA on this mater.

As I made clear in my previous article, I am a supporter of compounding. But in order to protect the public, it is imperative that the combination of FDA approved drugs into new compounds be tested for safety and effectiveness.

Critics may ask: Don’t two FDA approved compounds a safe new compound make?

Not always. Remember Fen-Phen?

Fen-Phen is the combination of fenfluramine or dexfenfluramine (marketed as Redux) and phentermine. All were prescription medications approved by the FDA as appetite suppressants. In 1996, physicians began prescribing the combination of Fen-Phen for use in weight loss programs. During that year, the number of prescriptions for Fen-Phen in the United States exceeded 18 million. The practice is known as “off-label use” since no studies are presented to the FDA to demonstrate the effectiveness or safety of the drugs taken in combination.

In July 1997, the New England Journal of Medicine published an article potentially linking heart valve disease with the use of Fen-Phen.  Later in that year, the FDA found that of 291 asymptomatic patients screened, about 30 percent had abnormal valve findings, primarily aortic regurgitation. Based on these data, the manufacturers agreed to withdraw the products from the market and FDA recommended that patients stop taking the drugs.

But this is not a recent phenomenon. In 1937 the manufacturer of “Elixir Sulfanilamide” was seeking a palatable solvent for its new sulfa drug. It decided to use a combination of diethylene glycol and water with raspberry flavoring.  Both the drug and the solvent are safe by themselves, but combined create they a lethal mixture that killed 107 people (mostly children) before the drug was recalled recalled.  Similar to Fen-Phen the combination compound had not been tested prior to release to the public.

By contrast before the introduction of Caduet, the combination of high blood pressure medicine Norvasc and high cholesterol Lipitor, the manufacturer conducted a double blind placebo controlled clinical trial of 1660 patients to evaluate the safety of the combination therapy.

I believe there are two approaches to address this issue; the first is to required safety testing for new compounds comprised of already approved drugs, regardless of who makes them, big Pharma or your neighborhood pharmacist.  This testing should focus on the safety and efficacy of the new compound.

The second alternative is to go the route of informed consent and experimental drugs.  I believe that doctors should have the right to prescribe compounded medicines, pharmacist the right to make then and patients the right to take them as long as we can evaluated all known risks and have meaningful  informed consent.

By the way, I checked with Andrew, my neighborhood pharmacist, and he will only mix in flavor for my kids prescriptions if the drug has been tested for safety in combination with the flavoring syrup.

06Sep/06

FDA Approves First Implantable Replacement Heart

The U.S. Food and Drug Administration (FDA) yesterday approved the AbioCor®, the world’s first completely self-contained, implantable Replacement Heart. 

This approval provides patients suffering from heart failure on both sides of their heart (bi-ventricular) and who have no other alternative, a viable option for extending the quality of their life.

“This device represents a significant advance in artificial heart technology and holds promise for critically ill heart patients who are not candidates for heart transplants due to age or other medical conditions,” said Daniel Schultz, M.D., Director, Center for Devices and Radiological Health, FDA. “We hope today’s approval will encourage the continued development of potentially life-saving technologies for critically ill patients.” 

The quest for an implantable artificial heart began in 1964 at the National Heart Institute (NHI), now the National Heart, Lung and Blood Institute (NHLBI). The goal was to create an Artificial Heart Program aimed at reducing death and disability from heart disease through the development of reliable cardiac assist and total replacement heart systems.

The AbioCor is intended to replace the severely damaged native heart for patients who are not eligible for a transplant and have no other treatment alternative. The AbioCor sustains the body’s circulatory system and is designed to extend the lives of patients who would otherwise die of heart failure, while also offering a probable benefit for a satisfactory quality of life. A post-market study is planned to allow Abiomed to monitor and optimize the introduction of the AbioCor into clinical use.

FDA based approval on the company’s laboratory and animal testing and on a small clinical study of 14 patients conducted by Abiomed. The study showed that the device is safe and has likely benefit for people with severe heart failure whose death is imminent and for whom no alternative treatments are available. In some cases the device extended survival by several months, allowing the patients to spend valuable time with family and friends. In two cases, the device extended survival by 10 and 17 months respectively, and one patient was discharged from the hospital to go home. 

AbioCor will be available under a Humanitarian Use Device (HUD) provisions and will be limited to a patient population in the United States under this approval, with no more than 4,000 patients receiving the technology each year. In order to ensure the highest standards of patient care, Abiomed intends to make the AbioCor available through a controlled roll-out at approximately five to ten heart hospitals in the United States, including qualified clinical trial sites and additional qualified centers once they have completed a comprehensive and rigorous training program which may take six to eight months. Under HDE approval, the FDA may request a panel review of the post-approval study data. 

AbioMed, maker of the Replacement Heart, will reportedly charge $250,000 for the device.

FDA’s approval of the First Implantable Replacement Heart marks the realization of a goal 25 years in the making.

28Aug/06

What’s More Sterile: the Band-Aid on Your Paper cut or Cardioplegia?

By Daniel R. Matlis

It’s a trick question. Technically both should be sterile. 

But you would think that cardioplegia, the solution used to stop the heart during bypass surgery, would be more stringently tested since it is infused directly into the heart.

According to a recent USA Today article, at least 11 cardiac surgery patients were stricken with an infection during a 10-month period from the end of December 2004 to September 2005, and three of them died at Mary Washington Hospital.  After a thorough investigation, tests confirmed the presence of several types of bacteria in the cardioplegia solution injected into patients’ hearts during surgery. 

I can already hear the cry from the trial lawyers: “Which Pharmaceutical Do We Go After? 

The answer? None, the reason is that the products leaving the Pharmaceutical companies were perfectly safe and sterile, but some drugs, including high-risk sterile preparations, are made in pharmacies under less-restrictive rules than those that drug companies follow.  Almost all hospital pharmacies do some type of drug making, called compounding. Pharmacist duties may range from low-risk procedures, such as grinding tablets to put them into liquid suspension, to high-risk work, such as making sterile treatments from scratch. 

I’m in favor of compounding, and cannot thank Andrew, my local pharmacist, enough for compounding prescriptions when my kids need them. Try to get a 3 year old to swallow an adult size tablet. It goes much smoother when it is ground and suspended in strawberry flavored syrup.

But there is a big difference between grinding tablets and preparing a sterile solution to be injected into the heart.  This is not an issue of qualifications, but one of oversight and facilities. Hospital pharmacies are regulated by each state, and the frequency and thoroughness of state inspections vary widely. The FDA’s role in oversight is hampered by questions of jurisdiction over what’s generally state matter. To make matters worse, in most states hospitals are not required to test the sterility or potency of products made in their own pharmacies or purchased from outside pharmacies.  So while a drug company could not sell saline solution without testing sterility, hospital pharmacies and their suppliers are not required to test for it. 

I am not a big proponent of government regulations, but this is a case of public safety and the proverbial “what’s good for the goose is good for the gander” theory of enforcement.  Having 50 different state statues regulating sterility and potency requirements for drugs is impractical, when the FDA has the mandate, know-how and capabilities to regulate them.  If hospital pharmacies and suppliers want to continue manufacturing sterile solutions, they ought to be held to the same standards as the Sesame Street Band-Aid I put on my kid’s “boo-boo”.