Where Clinical Research Goes Wrong

Clinical trials are used for the evaluation of drugs, surgical procedures and medical devices. They also serve to assess dietary counseling, physiotherapy, and other possible interventions.?We are increasingly relying on these clinical trials to help us decide whether or not to allow a new treatment into our established medical practice.?All patient care should aim to select the best and most safest therapy.?

This is the Oath and commitment primum nocere of Hippocrates.?

One important social consequence of choosing the optimal treatment is that there is now more emphasis on cost-benefit in medicine.?Patients expect that health care professionals are knowledgeable about the best treatments. It is therefore important that physicians have the ability to critically review scientific publications and especially those that concern medications they may prescribe.?Most health care professionals are not trained in clinical trial evaluations or research methodology.?There are many excellent books on clinical trials issues and continuing medical education programs that can help fill this knowledge gap.?The available texts can be lengthy and focus on statistical and methodological issues which may not be of direct interest to patients.?The phase I trials are used to evaluate potential agents in animal models. However, they are not mentioned.?Phase II trials are also not discussed.

What's the purpose??it is important to review scientific evidence in order to understand the the three main goals of treatment - to make the patient feel better; - reduce the risk of future complications of disease; - improve survival. There are also those who include an additional goal, the "economic benefit," which is both for the patient and society. Economic benefit is a natural result of achieving one or more of these three goals.?A particular treatment may be effective but it might not achieve all three goals.?Although a painkiller or drug for nausea may temporarily improve the patient's wellbeing, it is unlikely to provide any long-term benefits.?A drug to treat hypertension might reduce long-term cardiovascular complications and prevent premature death.

However, most people suffering from high blood pressure are not symptomatic.?All three goals may be achieved by some interventions.?Acute bacterial meningitis can be treated with antibiotics. This reduces symptoms and the chance of developing neurologic complications. It also decreases short-term mortality.?What is the evidence of a treatment's benefit??For controlled clinical trials to establish whether a treatment prolongs life or lowers the risk of serious non-fatal complications, it is common for thousands of patients to be treated over many years.?

Manufacturers have seen a significant return on their investment in evaluating the effects of different treatments on risk factors such as elevated LDL cholesterol, high blood pressure, and high blood sugar.?Many widely prescribed drugs were approved for marketing on the basis of their positive effect on risk factors, rather than any definitive evidence that they provide a real health benefit to patients.?These markers have a value and drawbacks that make it difficult to draw conclusions about the clinical utility of treatment-induced changes. What is the evidence of harm from a treatment??There are always adverse effects and harm to any treatment.?Every treatment decision should be made by weighing the possible favorable effects against the potential negative ones.?Patients often complain that prescribed medications made them feel worse.?It could be something as simple as dryness in the mouth or more serious adverse effects that require treatment to stop.?

Even the simplest adverse effects can cause distress and reduce compliance.?Because the patient may not be able to attribute the effects immediately, adverse effects that have a gradual onset can be the most difficult to detect.?Sometimes, a patient's quality of life assessment may help detect small changes in well-being that are caused by medication.?

Sometimes, medications can have severe adverse effects, such as allergic reactions, heart arrhythmias, gastric ulcer, and cardiac arrhythmias.?It can be difficult to attribute an adverse effect to a particular treatment, especially if the event occurs suddenly, is not expected, or lasts for a long period of time.?Sometimes it can be hard to identify an adverse effect that may be part of the natural history or underlying condition.?A drug may have a lower benefit-to-harm ratio if it has less clinical experience when it's first launched.?As many as half of all new drugs will have at least one serious adverse reaction that is not known at the time they are approved.

Drug-drug interactions are becoming a concern because many drugs are metabolized in liver.?Toxicity can occur when one drug blocks the metabolism of another or when two drugs compete to use the same metabolic pathway.?The most frequently prescribed drugs can be evaluated before they are released for marketing.?The FDA approved mibefradil, (Posicor), for marketing in the United States in 1997.?After multiple drug interactions were documented, the FDA approved mibefradil (Posicor) for marketing in the United States. The most significant interaction was with simvastatin, which is Zocor.?Other harmful effects may be less obvious.?Some hormones, antibiotics, and medications that have a long half-life may cause ecological problems.?

Patients and society may find the high cost of treatment to be a problem.?Even though newer drugs have an incremental benefit, they are usually more expensive than older generics.?Drug treatment can have adverse effects such as "patient labeling".?People who have been treated with antihypertensive medication for other reasons may develop symptoms. This is because they take their medication as a reminder of how unhealthy they are.?

Why should off-label drug use be avoided??The important regulatory process for drug approval has one purpose: to ensure that approved drugs are safe and effective.?Randomized clinical trials are essential tools in drug assessment and are often required for regulatory approval.?Only approved indications allow manufacturers to market drugs to the public and health care providers.?Contrary to drug approval, medicine practice is not regulated.

Healthcare professionals may prescribe unapproved drugs if it is in the patient's best interest.?This is how the pharmaceutical industry profits by "indirect" marketing its drugs for non-approved uses.?This is known as "off-label use".?The majority of prescriptions for common drugs prescribed by office-based doctors were found to be off-label. A study of 160 of these drugs revealed that 21% had been written. However, there was very little scientific support for many of these uses.?Patients are exposed to unnecessary risks because there is limited evidence regarding safety and efficacy.?Direct risk is that off-label drug use can be ineffective, harmful, or both.?Indirect risk is that alternative treatments may not be available, even if they are proven.?Off-label use drugs is discouraged as it is not evidence-based.?

One exception is in oncology where it might be difficult to assess a chemotherapy agent in every type of tumor and stage of disease before marketing.?

The government attempted to regulate off label promotion in response to industry's subtle attempts to hide direct incentives payments to clinicians, questionable contract terms, and all-expense paid trips.?For $468 million, the government settled an alleged fraud in gabapentin's (Neurontin), off-label marketing.?This balance can vary between patients with the same diagnosis.?The major benefits of treatment range from symptomatic relief, prevention of disease complications, and improved survival.?When a new treatment is introduced, safety information is often limited.?The benefit-to-harm balance is often underestimated in the early stages.?

There are two sides to every coin