by: Mark D. Ediger
The process of drug development is nothing if not arduous. The most recent analyses place a greater than $1 billion dollar price tag on a nearly fifteen-year journey. To be sure, the reward for this effort is a successful drug release, the pinnacle of the pharmaceutical industry. What happens, however, during the excruciating wait period for the patients of a deadly disease, when a drug product in development shows great promise? The standard answer is to enroll in an ongoing clinical trial and hope to stay out of the placebo group.

For many, this is not enough and the FDA has answered in agreement with various ‘loopholes’ through this wait period. In the case of a life-threatening disease where a patient is not able to enroll in a clinical trial, they can lobby the manufacturing pharmaceutical company to receive the drug in a process termed ‘compassionate use’. Similar loopholes may be called ‘expanded access’ or the new ‘Right to Try’ initiative.

Many factors of the changing pharmaceutical environment will lead to an increased number of requests for compassionate use. More and more pharma and biotech companies are expanding their pipelines into the lucrative oncology field, hoping for a major breakthrough. The biology of cancer itself is growing into a highly fragmented landscape, as we discover that the disease is made up of hundreds of variants, tissue-specific diagnoses are actually patient-specific, and all of this diversity may mean changes to drug responses. If the development of successful oncology therapies continues, the medical community must preparing for a huge influx of patients seeking early access to these drugs. What impact will this have on the pharmaceutical industry?

Economic Issues

In 2012, the biopharmaceutical company Chimerix was receiving good Phase II results from its antiviral drug brincidofovir, intended to treat deadly infections following stem cell transplants. Chimerix had approved over 200 instances of compassionate use licensing to dying patients, and this in part burned through their initial monetary capital. Hoping to focus on funding Phase III trials and an approval run, Chimerix stopped licensing brincidofovir for compassionate use.

The requests (and denials) continued until a grassroots campaign, driven largely by social media, exploded into public knowledge. The family of Josh Hardy, a seven-year old with a severe adenovirus infection, was seeking the drug to save his life. After initially denying the request, Chimerix found itself overrun with bad press and threats to management. Within days, they announced a special agreement with the FDA to initiate a small trial that included Josh Hardy.

Was this the best possible outcome? Chimerix CEO Ken Moch stated that the compassionate use requests were “swamping” his company and their resources; the entire organization was only 54 employees. Pulling time and money from a development effort, especially at a small company, drastically stresses the organization and risks the loss of FDA approval. Chimerix weighed the options and chose to push for faster approval of the drug, which, given the apparent early success of brincidofovir, could lead to hundreds of lives saved. With more and more innovative therapies coming from small, startup biopharmaceutical companies, the burden of compassionate use is actually building an economic wall between the ‘bench’ and the ‘bedside’ – a concept not easily understood by the public as social media storms accelerate and passion overcomes reason.

Regulatory Issues

There are currently no defined regulations governing compassionate use or any of its variations. All standard phases of drug research are designed to be deeply mined for all available information; every instance of drug intake by humans is monitored and analyzed. Without this regulation, instances of drug compassionate use cannot be used to further the safety and efficacy analyses of the drug – they are lost to the noise. Patients who do receive this route of therapy, in addition, often do not enroll in clinical trials regardless of the outcome of the attempt. Phase III trials are desperately reliant on a volume of patients to succeed; rare diseases and cancer variants in oncology rely on these even more so. By promoting the use of therapies outside of the regulated pathways, drug companies lose a number of highly valued volunteers. This can risk drug approval as much as any other factor.

The first argument for compassionate use is that ‘data is data’: the success or failure (again in terms of safety and efficacy) is binary, either true or false (safe or unsafe). Thus, the data from compassionate use cases can be easily merged into existing clinical trial data. Unfortunately, this is not the case; clinical trials are intricately designed with specific endpoints in mind. Often, as mentioned above, they rely on a certain volume of subjects taking the drug in the same methods. Compassionate use, rather than bowing to this organization, is delivered differently each time.

And so the unregulated use of drug inside their development window complicates the very important process of separating ‘signal’ from ‘noise’. Signal/noise ratios become poor when data is either strongly biased, or extremely noisy. Where regulated clinical protocols seek to collect clean data, this is not usually possible with compassionate use. Often the drug candidate is simply mailed to the patient, and so the dosing method and collection of data is never controlled. Bias is injected in compassionate use cases as well; often the patients are the sickest, or have progressed furthest in the disease state. This may make sense realistically, but proper clinical analyses require the subjects of clinical trials to be distributed and again, controlled. Biased, noisy data mean that, regardless of addition strict requirements placed on data collection during compassionate use, it will likely result in added difficulty during safety and efficacy assessments. Chemist Derek Lowe states, “The nightmare is having a drug that actually worked, but whose benefits were obscured because the patients were all worked up differently, and the signal sank into the noise.”


Surely the rare but vocal success stories are what keeps compassionate use alive. Looking at overall success rates in oncology, only 6% of early-phase clinical drug candidates receive approval and make it to market. These indeed are long odds to place on a process which potentially risks access to lifesaving therapies for millions. But what are the alternatives? The FDA’s ‘Breakthrough’ Status, given to therapies for life-threatening conditions that show great promise, has had success in the United States with Britain to follow suit shortly. The designation grants additional communication with regulators and product support, and will generally shave three years off final approval time. Additional FDA designations, Accelerated Approval and Priority Review, have similar goals: an emphasis on pure risk-to-benefit ratio of the drug, and moving safe products to market as fast as possible. These are the regulated programs that need emphasis to begin to rebuild the broken nature of clinical trials.

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