In 2011, a drug called Makena was approved by the US food and drug administration (FDA) on the basis of small trial showing that it helped prevent preterm. MAKENA is a prescription hormone medicine (progestin) used in pregnant women who have preterm delivered in the past. MAKENA is used to help lower the risk of having a preterm baby again. But it was later found in the larger studies that Makena didn’t work. One hospital even reported increase in gestational diabetes among the women. A larger trial further confirmed that Makena was just a placebo. But the question to withdraw Makena is still not decided by FDA.
In the drug approvals agencies around the world, there is a surge in medications being rushed to market. Such medicines are approved usually after limited testing. Drugs are approved based on preliminary findings or at times just authorised for a particular use. These drugs are then widely prescribed for something else.
This situation raises a very important question:
Are these agencies working for the interest of public or the drug companies?
The approved drugs, at times work for patients but sometimes it don’t. The reason behind are rushed decisions made by the FDA or European Medicines Agency (EMA). These both authorities approves more than 91 per cent of the time. This causes ripple effect on international ramifications. The US process of drug verification is viewed as the “gold standard” all over the world. The drugs granted fast approval by the FDA or EMA can easily be fast-tracked by authorities elsewhere.
But has speed always been the priority?
Well not really. In the late 1970s, the FDA used to take an average of 35 months for the review of a drug. Today, it takes less than a year. The reason behind of this fast approach are several measures that were introduced. These include largely in response to public demand who are facing life-threatening conditions. Hence, new ways were established to give quicker access to such medicines. Yet despite those virtuous goals of early days, many drugs are just now being hurried through.
In the late 1970s, the FDA used to take an average of 35 months for the review of a drug. Today, it takes less than a year.
With each day passing by, the FDA granted accelerated approval are just becoming the norms rather than the exception. Today, almost all of the drugs are granted an expedited approval of some kind. With such approvals, there is a trend toward a lower bar of evidence. Since 2006, the EMA grant a “conditional marketing authorisation” to new drugs that treat serious or rare disorders. But these drugs may not be able to meet the standard level of evidence. Those lower standards of evidence settle for “surrogate markers”. Instead of finding out if a drug can prevent heart attacks, for example, a pharmaceutical company may only need to show that it lowers blood pressure. Cancer therapy medicines often have debilitating side effects. In order to understand whether they will extend your life or not, could be critical. Between 2009 and 2013, the EMA approved 48 cancer drugs for 68 different uses. At the time of approval, the drugs had been shown to improve survival for only a third of those uses. The drugs worked in just 10 percent of the cases. Even after being on market for eight years, these drugs had still not shown to improve survival of life for half of the approved uses. Many cancer drugs authorised by the FDA also have unclear benefits. When drugs are approved on the basis of slim evidence, it is sometimes understood that testing will be carried out after they get the green light, but sometimes the trial for approval can take years to complete. In most of the cases, they just don’t happen. And yet such drugs remain on the market in both the US and European Union. Nearly half of post-marketing studies requested by the FDA haven’t been completed five years later. It is also more likely that drugs approved this way might have serious side effects. The drugs that receive the fastest reviews are also the ones that tend to have the most serious risks, and even serious risk resulting in death. The need to attach serious warnings on the drugs or at times withdrawing certain medicines are clear indications that these drugs should not have been approved in the first place. These medicines when once make their way to market, it can be hard to wrest them back.
Even after being on market for eight years, these drugs had still not shown to improve survival of life for half of the approved uses. Many cancer drugs authorised by the FDA also have unclear benefits.
Credit for the rushed approval of the medicines should also be given to the fact that at times ‘something is better than nothing’. The reality is that sometimes the drugs that doctors prescribe may simply be best guesses. Once approved for one purpose, drugs can be prescribed “off label” for other uses. Sometimes off-label prescribing can be useful. But 80 per cent of off-label uses for drugs aren’t supported by evidence because companies aren’t required to run clinical trials for such unofficial uses. Off-label prescribing can also benefit pharmaceutical firms that develop what are known as ‘orphan drugs’. These are medications intended to treat rare diseases. In places such as Europe and Australia, orphan drugs are granted fast-tracked approval and either reduced fees or tax breaks. After approval, drug developers are usually granted exclusive rights to market new medicines for several years. Once these drugs are on the market, they can be prescribed for much more common disorders. It is illegal for drug companies to deliberately market drugs for disorders that they haven’t been officially approved for.
But can FDA intervene if salesperson market drug for diseases it has not been official approved for?
The answer is now “a little bit hazy”. Thanks to a 2012 court case, where the FDA lost case over Xyrem drug to Alfred Caronia, a sales rep for the company that made Xyrem. After this defeat, FDA may now be unwilling to pursue similar cases. Because, it would lose the ability to effectively regulate drugs and medical devices. Since the Caronia case, the number of warning letters sent by the FDA to pharmaceutical companies appears to have dropped.
Yet it remains the case that off-label prescriptions can be dangerous. They are more likely to cause adverse or allergic reactions.
For many, the major source of worry: is the FDA prioritising the interests of drug companies over those of the public?
It is certainly. This might be due to an increasing amount of the agency’s funding which comes from industry. Under the Prescription Drug User Fee Act introduced in 1992, pharmaceutical companies agreed to pay fees to help fund additional FDA salaries. In return of which, the agency agreed to speed up approval times. Now, the fees have been repeatedly renewed and expanded since. For the FDA, this sums up to be 45 per cent of FDA total budget. This raises lots of concern about the quality of evidence and the willingness of the FDA to consider the industry as its primary client, rather than the public. According to the FDA official, “( the fees are used ) to hire additional staff and upgrade its information technology systems”, and that the user fee act “committed the Agency to speed the application review process for new drugs without compromising its high standards for new drug safety, efficacy, and quality”.
Upfront payments aren’t the only way the industry can influence the FDA. Drug companies may offer payment for work on advisory boards or cover accommodation or travel expenses for members of an FDA panel after a drug has been approved. This is done to simply avoid the need to report a conflict of interest beforehand. Once approved, the way drugs are promoted or prescribed, might also be influenced by drug company funds, even at a surprisingly small scale.
Pharmaceutical companies agreed to pay fees to help fund additional FDA salaries. In return of which, the agency agreed to speed up approval times.
The first step towards addressing these issues is to shine a light on them. An increasingly vocal group of physicians, researchers, lawyers and policy-makers are attempting to do just that. But change is slow in coming. Most doctors and scientists don’t necessarily blame regulatory bodies for the lack of evidence in support of many new drugs. They point out that organisations like the FDA are balancing the need for scientific evidence with pressure from doctors and patient groups. Frustratingly, direct efforts to change things have fallen short. A UK parliamentary select committee recommended that the government’s Regulatory Agency work with industry to test whether each drug is likely to improve a person’s life. It also limit on how much promotional material doctors receive about new drugs. There is a lot at stake in this case. The physician, in general, are losing ability to treat patients because medications are not being properly evaluated. If practitioners end up in a situation where less are known about the chemicals, then the health solutions should be modified desperately. That is why they and other outspoken critics won’t stop trying to raise the alarm.
The drugs should be evaluated on the basis of their overall survival benefit wherever possible. If data collection ahead of approval, were to take longer, people can be granted access by taking part in clinical trials or through compassionate access schemes.
Meanwhile, the wish list for how to do things better grows longer by the day. Experts thinks we need to make organisations like the FDA and EMA financially independent. Regulation should be funded out of public money, not out of user fees that the industry pays. The drugs should be evaluated on the basis of their overall survival benefit wherever possible. The use of expedited approval pathways shaves an average 11 months off the time it takes for a drug to get to market. If data collection ahead of approval, were to take longer, people can be granted access by taking part in clinical trials or through compassionate access schemes. When drugs are approved without clear evidence, then this should be made apparent on their packaging. Patients, at times, overestimate the value of new medications. Hence a drug fact box should be printed, on which such terms are mentioned that patients can understand. The approved drugs, which aren’t able to shown survival rate with set number of time, should be withdrawn from market.
Lot of responsibility should also be shown by general masses in this regard. If a doctor recommends a drug, ask questions about it. Ask if that drug is approved for your specific condition, and for the evidence supporting its use. Your doctor should also be able to tell you how new the treatment is, how much is known about its safety and if a new treatment out performs older ones. It may seem like a lot to ask of doctors who are pressed for time or who may struggle to keep up with the constantly evolving research. But when health is on the line, this may be the best chance of getting the medicine that is genuinely best for the disease.
-originally published in New Scientist