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Are there cases in medicine where ethical guidelines laid down by the FDA/EMA should be by-passed?
Experimental medicine is in use all over the world to produce new treatments for disease, or to demonstrate the pathology of various diseases in humans (or in a model organism, to which humans can be compared). Many ethical issues can arise from the development and usage of experimental medicine, ranging from who should be involved in clinical trials, to whether we should use unlicensed medicine as a last resort in patients. During the course of this paper, I will focus on the use of experimental medicine in an off label or unlicensed manner to provide a better quality of life. In my opinion, the ethical advice on drug use given by the Food and Drug Administration/European Medicines Agency should occasionally be reconsidered in order to produce medication at an increased rate for those in desperate need, or to provide better quality of treatment. This thesis can be explored by browsing the many examples in current medical research where crucial ethical steps or guidelines may have been by-passed.
One of the reasons steps in the drug discovery process may be quickened or ignored altogether in research is that the process usually takes around 12-15 years, and can be extremely costly (Paul et al, 2010). There are a number of key stages involved with the production of new medication, beginning with the identification of a need for a new treatment. A drug compound is synthesised and selected as the candidate. This candidate then undergoes toxicology testing in an appropriate animal model (Lombardino & Lowe, 2004). If the compound is deemed to have sufficient potential to proceed to in vivo studies in humans, then an application is filed with the Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Following approval, the drug moves on to clinical trials which can be split into three unique phases. The phase one trials are used to test the safety of the treatment on a small number of people (usually healthy adults). Phase two trials are undertaken in small, well-defined patient populations to evaluate drug response. The aim of phase three trials are to provide efficacy and tolerance data to support the marketing application (Hughes et al, 2011). These trials are undertaken with large patient populations. Less than 50% of the drugs that make it to phase three trials are actually marketed (Arrowsmith, 2011). Following clinical trials, approval is then needed by the FDA/EMA for the treatment to be marketed.
As can be seen above, the drug discovery process takes many years to complete and involves a number of crucial steps. This means that those in urgent need of treatment will not be able to receive it before the drug is officially approved, which can prove costly to the individual. There are examples where guidelines set by the FDA/EMA may be by-passed in order to make treatments accessible to those who would have not previously been eligible.
Practitioners’ often disregard ethical guidelines for orphan diseases, or to treat those not in the recommended categories set by the FDA for a certain drug. Orphan diseases are any disease that affects a very small percentage of the population. The drugs limited clinical use means it can be difficult to seek FDA/EMA approval. This is often due to a lack of profitability, but can also be because the countries in which the disease is prevalent are too poor to pay drug prices (Gericke et al, 2005). Because of this, practitioners often prescribe drugs to treat these diseases/conditions in an off-label manner. Off-label drug use (OLDU) is where currently available medications are prescribed for a disease or symptom that hasn’t received FDA/EMA approval (Wittich et al, 2012). OLDU is not illegal and is not uncommon, particularly in a paediatric setting, as most drugs are not approved for children (Wong & Kyle, 2006). Although not as extreme as completely going against the ethical implications laid down by the FDA/EMA, OLDU can still sometimes be considered a dangerous method of drug prescription. This raises ethical issues as the practitioner has to weigh up the dangerous side effects that can be caused by OLDU against the benefits it will provide to the patient. An example of dangerous OLDU comes from the usage of Fen-Phen to treat obesity. A large majority of the patients given the treatment developed very severe heart valve damage, leading to Fen-Phen being taken off the market in 1997 (Miller, 2009). However, OLDU can also be a lifesaving method of treatment. An example of this comes from the usage of beta-blockers for heart disease as opposed to its intended use for treatment of high blood pressure (Bennett, 2004). This off label usage led to the formal approval by the FDA of some beta blockers to be used in the treatment of heart disease. This is just one example of the many positive outcomes linked to the alteration of the medical standards set by the FDA/EMA.
A very current example of unlicensed drug use in experimental medicine is the Ebola epidemic, most prevalent in western Africa. With current death rates of roughly 50% on average for those who contract the virus (but can be up to 90%, in some areas), a hastened version of the drug discovery process seems necessary to save lives (WHO, 2014). There are currently two main ‘contenders’ for a potential treatment of Ebola virus disease (EVD): ZMapp and TKM-Ebola.
ZMapp is a molecular ‘cocktail’ of three monoclonal antibodies, which appears to have exceeded the efficacy of many other potential drug treatments (Qiu et al, 2014). This comes from extremely positive results in primates who were experimentally infected with the virus (McCarthy, 2014). A great deal of funding has recently been granted to the company ‘Mapp Pharmaceuticals’ in an attempt to quicken the drug discovery process to the point of FDA approval (Root, 2014). Although unlicensed, ZMapp has been administered by practitioners to treat extreme cases of Ebola in the US. Of the seven human patients treated with ZMapp, five survived (Zhang, 2014). Although we cannot rule out other factors lending to the patients survival, it cannot be ignored that without the ZMapp drug it seems likely these patients would have died from EVD. This adds substance to our original argument of using unlicensed or off label drugs in an emergency situation, going against recommendations of the FDA.
A further example for the use of unlicensed medicine to treat EVD comes from TKM-Ebola. The drug, produced by ‘Tekmira Pharmaceuticals Corporation’, works through an interfering RNA molecule that acts to ‘silence’ gene expression (Maurice, 2014). The treatment had already passed through to stage one of clinical trials until the FDA halted its progress due to alarming signs of cytokine release in patients. However, the FDA has since placed a ‘partial hold’ on the use of TKM-Ebola. This allows it to be used to treat patients who have already contracted Ebola virus disease (Goodman, 2014). An example of TKM-Ebolas benefits come from a case study in America. Dr. Rick Sacra received the TKM-Ebola treatment at the Nebraska Medical Centre in Omaha. Dr. Sacra was treated through a mixture of the TKM-Ebola drug and blood plasma transfusions taken from from an EVD survivor (Mai-Duc, 2014). Since the treatment, it is expected the doctor will make a full recovery. Although just one example, this could be the start of many recoveries through the unlicensed use of TKM-Ebola.
Examples of off label drug use can be clearly seen in many paediatric wards all over the globe. A study has shown that over half of the paediatric patients in Europe are receive drug treatments in either an off label or unlicensed manner (Conroy et al, 2000). This is because many of these treatments aren’t tested in children during clinical trials, so are not licensed for them. One of the most common off label use in children was found to be the drug ‘salbutamol’, used to treat respiratory illnesses such as asthma. The syrup form of salbutamol is not licensed for use in children under two years old, however it is commonly used for this age group (Tumer et al, 1997). Another example of OLDU in children includes the use of morphine for pain, which has never received formal FDA approval (Wittich et al, 2012). In these cases, it is down to the practitioner to weigh up potential side effects to decide the best course of action. These examples in my opinion show further proof of the beneficial outcomes that can arise from the use of off label medications.
From the evidence provided above, I believe it can be concluded that the use of unlicensed medication or off label drug use is increasingly common within society, and can be greatly beneficial. Using the example of Ebola virus disease, without treatment from ZMapp or TKM-Ebola, it is likely that the patients’ conditions would’ve been fatal. In a paediatric setting the use of unlicensed or off label medication is crucial for many children’s survival. Furthermore, in many cases of orphan diseases, treatments simply do not receive enough funding to gain approval from the FDA/EMA. In my opinion, the use of unlicensed medication is sometimes necessary for survival, and in these circumstances, if the patient agrees to the potential risks, then its use can be greatly beneficial to aid survival.