Category Archives: Regulatory

10Dec/06

Senate Confirms von Eschenbach as FDA Commissioner

Last week, Dr. Andrew von Eschenbach was confirmed by the Senate to head the U.S. Food and Drug Administration. Dr. von Eschenbach is 65-year-old oncologist, surgeon and cancer survivor. He has been acting commissioner at the FDA since September 2005, and is the former director of the National Cancer Institute.

His appointment will provide the agency with strong leadership as it heads into a potentially tumultuous year in light of legislative changes on Capitol Hill. The nomination, which passed the Senate by a vote of 80-11, will now be sent to the president.

Dr. von Eschenbach is a strong proponent of transforming the FDA to keep pace with changes in healthcare. He commented that the Agency must establish itself “as the bridge that supports new molecular-based interventions as they move across the discovery, development, and delivery continuum.” His vision for the Agency calls for aligning, adapting, and recognizing the importance of FDA’s leadership role and its responsibility in the metamorphosis that will define a new era in Healthcare.

 “This healthcare system of the future will be personalized by developing a sophisticated understanding of not only the disease process, but also of the individual patient. In understanding both the disease and the person at the molecular level, physicians will be able to provide treatment options uniquely suited to a patient’s particular needs. Instead of empirically prescribing a pill and hoping it works, patients will receive treatments designed specifically for them. We will use the new tools of molecular medicine to develop new individualized interventions and in the very process of molecularly monitored delivery to patients our understanding of the biology of disease in individual humans will be elucidated. In this way, delivery will become, in itself, a platform of discovery” commented Dr. von Eschenbach in a recent speech. He went on to say “I expect that this healthcare system will be much more participatory. Increased utilization of information technologies and improved communication strategies will allow patients to assume a substantially more active role in their healthcare.  It will be important for us at FDA to consider how we can work together with doctors and patients to make sure that they have the greatest opportunity to maximize the benefits of new medical products in a way that preserves their ability to make individualized choices free from restrictive burdens, and that the data derived from health care can be used to further enhance the safety and effectiveness of these products.”

It is clear from his comments that he has the right ideas to lead and transform FDA. However, implementing these ideas is not going to be easy. Although Industry and Agency staffers agree that the FDA is in need of increased funding, allocating resources may prove to be difficult under the current budget pressures.

17Oct/06

A Bar-Code In The Hand Is Worth Two RFID Tags In The Bush

On February 26, 2004, the FDA published its final rule onBar Code Label Requirements for Human Drug Products and Biological Products.  According to the Agency, “Bar Codes will allow health care professionals to use bar code scanning equipment to verify that the right drug (in the right dose and right route of administration) is being given to the right patient at the right time.  This new system is intended to help reduce the number of medication errors that occur in hospitals and health care settings.” 

The Bar-Code rule requires linear bar codes on most prescription drugs and on over-the-counter drugs commonly used in hospitals and dispensed pursuant to an order. The bar code is required to contain, at minimum, the drug’s National Drug Code (NDC) number, which uniquely identifies the drug. The rule also requires the use of machine-readable information for blood and blood components intended for transfusion. The machine-readable information must include, at a minimum, the facility identifier, the lot number relating to the donor, the product code, and the donor’s ABO and Rh. 

During the same month, February 2004, the FDA’s Counterfeit Drug Task Force issued its report on “Combating Counterfeit Drugs”. This report called for the implementation of Radio Frequency Identification (RFID) technology to allow the tracking of pedigree and mass serialization for all drug products. The Agency set forth a phased approach to the implementation of RFID technology starting at the case and pallet level for products likely to be counterfeited and progressively including all products at the case, pallet, and package level by 2007. 

In February of 2006, the FDA conducted a Counterfeit Workshop in Bethesda, MD to get an update from stakeholders on the status of RFID implementations. Affected stakeholders, including manufacturers, distributors and pharmacists, presented progress made and concerns associated with RFID and e-Pedigree initiatives. During my remarks to the Task Force, I stated that RFID technology should be used as an enabler, not a silver bullet. I conveyed the agency’s role to set regulatory requirements, gathered in cooperation with all affected stakeholders. However, in my opinion, the FDA should not mandate specific technologies to be utilized to achieve compliance.  

In June 2006, the task force issued its update on the FDA Counterfeit Drug Task Force Report. The agency admitted that although in 2004 it was optimistic that widespread implementation of e-pedigree was feasible by 2007, unfortunately, this goal most likely will not be met. The report went on to say:

“…it is clear from our recent fact-finding efforts that the voluntary approach that we advocated in the 2004 Task Force Report did not provide industry with enough incentives to meet FDA’s deadline.
We continue to believe that RFID is the most promising technology for electronic track and trace across the drug supply chain. However, we recognize that the goals can also be achieved by using other technologies.
Based on what we have recently heard, we are optimistic that this hybrid environment of electronic/paper and the use of RFID/bar code is achievable in the very near future. We believe that efforts to ensure that hybrid pedigrees are secure and verifiable should be a priority consideration.” 

Is this a case of one step forward and two steps back? I don’t believe so. I see it as a net gain for all stakeholders, especially patients.  The FDA estimates that the bar code rule, once implemented, will result in more than 500,000 fewer adverse events over the next 20 years.

Hospitals have recently made major investments in Bar-Code systems to comply with these regulations and minimize medication errors. Asking them to now reinvest in RFID technology without realizing the benefit of Bar-Codes would be a mistake. 

As the saying goes, A Bar-code in the hand is worth two RFID tags in the bush.
 

Copyright 2006 Daniel R. Matlis – AXENDIA

30Sep/06

FDA Issues Final cGMP Guidance

By Daniel R. Matlis
                            
Yesterday, on the heels of the release of a critical Institute of Medicine Report, the FDA issued a Final Guidance for Industry on a Quality Systems Approach to Pharmaceutical CGMP Regulations. The guidance covers the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM) and the Office of Regulatory Affairs (ORA).

This new guidance appears to be an interim step on the long awaited rewrite of the 1978 GMPs, known as the “GMPs for the 21st Century Initiative”.
According to the FDA, this guidance aims to address the following issues:

  • A quality system addresses the public and private sectors’ mutual goal of providing a high-quality drug product to patients and prescribers. 
  • A well-built quality system should reduce the number of (or prevent) recalls, returned or salvaged products, and defective products entering the marketplace. 
  • It is important that the CGMP regulations are harmonized to the extent possible with other widely used quality management systems, including ISO 9000, non-U.S. pharmaceutical quality management requirements, and FDA’s own medical device quality system regulations.  This guidance serves as a first step to highlight common elements between the CGMP regulations and Quality Management Systems.  With the globalization of pharmaceutical manufacturing and the increasing prevalence of drug- and biologic-device combination products, the convergence of quality management principles across different regions and among various product types is very desirable.
  •  The FDA has concluded that modern quality systems, when coupled with manufacturing process and product knowledge and the use of effective risk management practices, can handle many types of changes to facilities, equipment, and processes without the need for prior approval regulatory submissions. Manufacturers with a robust quality system and appropriate process knowledge can implement many types of improvements.   In addition, an effective quality system, by lowering the risk of manufacturing problems, may result in shorter and fewer FDA inspections.
  • A quality system can provide the necessary framework for implementing quality by design (building in quality from the development phase and throughout a product’s life cycle), continual improvement, and risk management in the drug manufacturing process.  A quality system adopted by a manufacturer can be tailored to fit the specific environment, taking into account factors such as scope of operations, complexity of processes, and appropriate use of finite resources.

This announcement is a step in the right direction. However, as stated in every guidance document it “does not create or confer any rights for or on any person and does not operate to bind FDA or the public”.

Let’s see what the “GMPs for the 21st Century” brings.

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.

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.