Only about 5% of rare diseases have treatments

Orphan drugs, those medications that are typically produced in small quantities for limited patient populations, are growing in importance worldwide. Once largely considered too costly to produce, given the limited number of patients affected by a particular disease, new technology and new breakthroughs in biopharma have changed the landscape, allowing more orphan drugs to be produced than ever before, thus saving countless lives that would otherwise be lost.

But bringing an orphan drug to market has its own unique set of challenges and considerations that must be overcome, many due to the narrow scope of use for which the drug is intended. Overcoming those challenges while endeavoring to produce a needed drug as quickly as possible requires the cooperation of clinical trial investigators, drug manufacturers, local and national governments, and more.

Where to start?
Typically, the need for an orphan drug is recognized by a doctor needing a specific drug in order to treat a rare disease. At this point, the doctor may apply for a research grant through one of many funding services, including the National Institute for Health (NIH), various philanthropic concerns, or private industry.

Alternatively, the need may be raised by a disease advocacy group, spotlighting a certain ailment that needs attention This was the case, for example, with the Muscular Dystrophy Association (MDA), who began advocating for cures for various neuromuscular diseases in 1950. Since its founding, MDA has funded research and clinical trials for a number of rare diseases, including Emery-Dreifuss muscular dystrophy(EDMD), ZASP-related myopathy, and Walker-Warburg syndrome (WWS).

The next step in the process is finding a drug manufacturer interested in producing the needed drug. Due to their limited audience and small production runs, orphan drugs can be very expensive to produce, and there is a very real possibility that the manufacturer may never break even on their investment. In the case of life-saving drugs, it is not uncommon for manufacturers to provide the approved medications through charitable access, or patient assistance programs, often at no charge for those that need it. On the other hand, the cost of clinical trials can be significantly lower than those investigating better known diseases, as the study samples are necessarily smaller and there is a lack of competing medications.

The health vs. economic benefits must be weighed when one contemplates taking on a treatment for a rare disease. These treatments can be very expensive, and the ramifications of such an investment must be considered. Someone somewhere has to make an objective decision about whether or not to move forward. Sadly, we live in a world in which there are very real restrictions. Consequently, we may have the ability, but not the resources, to cure everyone.

Second life
Of course, there is always the possibility that a drug intended to treat a rare disease may be found to have a secondary, more profitable use, as in the case of Botox. Derived from botulinium toxin, it was originally developed to treat spasms and dystonias due to its ability to weaken muscle function. More recently, it has been used in cosmetic treatments by paralyzing muscles and preventing the development of wrinkles. In 2012, more than 6 million Botox injections were administered in the United States at an average cost of $570 each, for a total cost of more than $3.42 billion. Of course, when a drug is found to have a second purpose, it must still go through trials for efficacy, even though safety has already been proven.

Trials and tribulations
The next step in the process is the holding of clinical trials. Like all clinical trials, the main purpose here is to prove the safety and efficacy of the drug in question although, due to the small patient sample size, some compromises must be made. While clinical trials for a drug to treat diabetes , for example, might require a sample size of several hundred, or even several thousand, patients, the required sample size for a drug to treat a rare disease might, by necessity, number fewer than 20. In some instances, historical consults - case histories of patients suffering from the disease - are used to supplement the actual live patient sample."

The key question that is asked in some of the orphan drug clinical trials conducted to prove the drug’s efficacy is, simply, whether or not the sample population made it to their first birthday. Being such a particular niche market with such a small number of patients in the study population, there's much more personal interaction with doctors, nurses, researchers, and subjects. This means that the researchers really get to know the people in their study, and losing one through the failure to come up with an effective treatment can be devastating.

Ethical and Practical considerations
Another consideration unique to studies of rare, life threatening diseases is whether or not it's ethical to give certain patients a placebo, as is regularly done in ordinary drug trials. That's a hard question to answer when you're trying to determine how much good a drug actually does. By providing certain patients with a placebo, are you sentencing them to death? And do you, as a researcher, have a right to do that in service of a greater good? That's a terrible question to answer.



In cases like these, lower safety standards may actually apply. Again, due to the small sample sizes, studies may accept a higher degree of toxicity in the study drug as doctors are more able to treat the results of the toxicity than they are the effects of the underlying disease. One has to consider the risk/benefit ratio, especially in the case of life-threatening diseases.

Another difference between trials of orphan and non- orphan drugs is the amount of follow-up that is done. In a typical non-orphan situation, follow -ups are usually part of the trial, examining the effects of the drug after a certain period of time. With orphan drugs, or with drugs that need to be moved to market quickly, additional surveillance of patients is allowed to be done after the trial, to facilitate getting the drugs out there in a timely fashion.

The Last Mile
Aside from the challenges that occur due to the small number of patients suffering from a rare disease, logistics can also be an issue. Particularly in the early stages of development many rare disease, or orphan, drugs tend to require cold chain logistics of one form or another, especially when going through regions in which temperature control can be a challenge. When dealing with drugs produced in such small quantities, any degree of damage or spoilage can be a major issue. In the case of life-saving drugs, the consequences may be severe. These days, some researchers might choose to have a quantity of study medications stored at the patient's home, to reduce the risk of damage in transit and to make administering the drugs easier. Practical solutions are available, for example, an RFID refrigerator that monitors when the unit is open, what drugs are removed or replaced, and even keeps track of expiration dates. Even with all that, however, it's critically important to have a shipper that intimately understands cold -chain and temperature-controlled logistics, otherwise all the efforts may be for naught.

There's an enormous pressure to get everything right in doing this kind of work. The difference between 95% right, which may be the case in non-orphan trials, and 99.5% right, in the case of rare disease trials, is enormous. This is why having good systems in place, and solid contingency plans as well, is absolutely critical. In many cases, paperwork can take an enormous amount of time, as after the trial is over, the licensing process starts.

Although orphan and non-orphan drugs go through the same licensing process, those in the pipeline clearly recognize the need for life-saving drugs and go the extra mile to make things happen quickly and efficiently. This greatly streamlines the process wherever possible; meaning that the drug can be released faster than it would otherwise.

Once the licensing portion of the journey is complete, the drug is taken to market. It's common in the case of rare diseases for key opinion leaders and patient advocacy groups to spread the word about a new treatment, supplementing the manufacturer's own marketing plan. At that point, the drug is out in the world, working to both improve, and save, lives. Whilst many of these drugs are expensive, it is not unknown for drug companies to have charitable programs in place, where the drug can be made available to patients without charge or at substantially reduced cost.