Today, and in the coming weeks I shall review the increasingly complex phenomenon in the pharmaceutical industry called off-label drug use.
In February 2008, the FDA issued a statement in which it said that it “recognises that the public health can be served when healthcare professionals receive truthful and non-misleading scientific and medical information on unapproved uses of approved or cleared medical products”. Senator Henry Waxman (Democrat), chairman of the House of Representatives Energy and Commerce Committee, implied that the Bush administration had given drug companies a long desired “parting gift”.
Waxman added that “this direction by the FDA fundamentally undermines the requirement that companies prove to the FDA that each new use is safe and effective”. He expressed the wish that this policy would be carefully re-examined by the new administration.
However, Pharmaceutical Research and Manufacturers of America’s senior vice president Ken Johnson rebuked and said the FDA’s guidance will help assure that doctors receive “timely and accurate medical information prior to the lengthy process” (of securing approval for wider use).
Amidst this uncertainty, Allergan filed on October 1st a lawsuit against the FDA to seek a ruling on the FDA’s request for them to provide prescribing physicians with general guidelines and up to date information on off-label use on the drugs label or insert. While at the same time Allergan and other pharmaceutical companies are forbidden from openly marketing their products for off-label use. In time, it is believed that this paradox will be clarified through this case.
We should keep in mind that the starting point of the review of any (new) drug is to demonstrate that the drug under investigation is safe and effective prior to it being advertised, marketed or sold. Here, the policy is that the slightest doubt on safety results in delay of launch and further trials and tests, as often demanded by the FDA and European equivalent EMEA.
I witness multiple problems arising from the extended off-label phenomenon. Whereas product liability for the ‘labeled’ indications falls at all times within the scope of the marketing authorization holder (MAH), or pharmaceutical developer, extension of the product’s use by medical practitioners poses a new set of issues. Additionally, global regulators nowadays review new drug applications very much against the backdrop of the possibility of a new drug in off-label indications. This may potentially result in further and more lengthy trials and an increased burden to companies and shareholders. At Clinuvel, we have been well aware of the direction of the regulatory thought processes and have implemented early on in our development various measures to mitigate this off-label potential for the reasons mentioned.
To understand the context within which off-label drug use is defined and exists today, I go back to two historical events: the Federal Food, Drug and Cosmetic Act of 1938, inspired by the Elixir Sulfanilamide Tragedy of 1937 in which over 100 people died after consuming a known poison mixed with raspberry flavouring, and sold as an anti-microbial ‘elixir’. Second, the case law arising from the use of Thalidomide from 1957 until 1961. The birth defects associated with Thalidomide resulted in “the biggest medical tragedy of modern times”. These two events spurred the development of modern-day pharmaceutical regulations governing our sector.
The regulators have evolved from reactive ‘policing’ agencies (confiscating and controlling adulterated substances) into the guardians of public health, as seen and expected today. This shift puts the burden of proof and requirement very much onto the shoulders of the drug developers or MAH. In order to operate within the guidelines set forth in relation to safety, efficacy, truth and evidence, the developers can only make claims for successful treatment of ailments for which they have conducted the extensive research and clinical trials we still run today.
Yet, one area where off-label prescription is frequently seen is pediatrics. Children are physiologically different to adults and pediatric “on-label” drugs necessitate the completion of clinical trials involving children in order to adhere to regulations. Conducting clinical trials with children is difficult practically, ethically and morally. So the ‘clinical freedom’ created by off-label has enabled the provision of care and treatment to those most in need of it.
The balancing act from a company’s point of view is manageable thus far, as off-label may well be interpreted as a use of the drug whereby the physician and patient are requested to collect and report continuous data in exchange for drug supply. Ultimately, the responsibility will then need to be shared between company and physician to satisfy the regulators. Unequivocal agreements will need to be put in place to provide clarity in this complex domain.
- Philippe Wolgen