Posted 19 November 2014
By Alexander Gaffney, RAC
If you're trying to understand why some drug companies are reluctant to allow desperate patients to enroll in their early-stage clinical trials, look no further than the case of CytRx Corporation, whose clinical trial for the drug compound aldoxorubic is now partially on hold following the death of a patient enrolled in the trial on a compassionate use basis.
Companies seeking approval to market a drug product in the US must first prove to the US Food and Drug Administration (FDA) that their drugs are both safe and effective. To do this, companies undertake clinical testing by submitting investigational new drug applications (INDs) to FDA—essentially an application to start a clinical trial.
Those INDs specify the drug to be used in the trial, the design of the trial and, crucially, the types of patients to be enrolled in the prospective study. Since companies generally focus their pre-clinical development work on showing a product acts upon a certain disease and in certain types of patients, the trial is generally restricted to those patients, and even subsets of patients (such as those without other diseases or conditions).
There are, however, exceptions to this rule. Under FDA's expanded access program (also known as its "compassionate use" program), companies can allow patients to access their products as long as the patient has a serious or immediately life-threatening disease with no comparable or satisfactory therapeutic alternatives.
For some patients, in other words, access to these trials is literally their last chance at trying to save their lives.
The expanded access program works, in general, in one of two ways: Either a company with an experimental product creates a new clinical trial for a patient through the use of an IND, or it amends an existing clinical trial to add new types of participants through the use of a "protocol amendment."
Once a company determines which approach it wants to take, it then needs to decide on how many patients it is willing to accommodate. There are four general types of expanded access INDs and protocols:
- Single Patient (Emergency Access): Used to grant access to a single patient who does not have time to obtain written permission from FDA
- Single Patient (Regular Access): Used to allow a single patient access to a trial
- Intermediate Size: Used for intermediate-sized patient populations
- Treatment: Used for large patient populations (i.e. widespread use).
Both protocol amendments and INDs have all four types, resulting in eight different types of expanded access applications (i.e. single patient emergency IND and single patient emergency protocol).
For a more in-depth explanation of FDA's Compassionate Use Program, please see our Regulatory Explainer on the program here.
Companies Reluctant to Grant Access
The program is not without its problems, however. One of the most notable issues associated with the compassionate use program is that companies are not required to grant access to their products, and are often reluctant to do so.
From a pharmaceutical company's perspective, there are a few major risks associated with the program:
- There is a cost to the company to oversee the expanded trial, handle expanded access requests and ensure compliance with all federal trial regulations. For small startup companies without any revenue, this added expense can both diminish their funding more quickly and take staff resources away from the main clinical trial.
- If too many patients enroll in an expanded access trial, it may make it more difficult to conduct trials in the future since the pool of potential patients will be smaller. Patients may also avoid non-emergency access trials since there is a chance of them getting a placebo instead of the emergency treatment.
- The limited production capacity in early-stage trials can mean there may not be enough drug product to supply both the main clinical trial and compassionate use cases. Even when there is enough supply, shocks in the supply chain could put one or more groups of patients at risk of running out.
- While companies can charge patients a "reasonable cost" for the drug product, that can hurt them when trying to negotiate with healthcare payers after the drug is approved.
The Biggest Risk: Regulatory
The biggest risk of all, though, is that the expanded access trial might raise troubling questions about the safety or efficacy of a drug. Because existing pre-clinical and clinical data isn't always as applicable to expanded access patients (who are often quite ill to begin with), those trials can be especially risky.
"There's this sense from patients that these are miracle drugs," said Richard Klein, director of FDA's Office of Special Health Issues, to the Wall Street Journal in October 2012. Companies, however, are often cognizant of a product's potential to harm a patient.
If a drug is found to have harmed a patient, FDA can react by either increasing its scrutiny of a trial, stopping enrollment in a trial ("partial clinical hold"), or shutting down a trial entirely ("clinical hold"). For a company, this can be catastrophic, either shaking shareholder confidence (and negatively affecting its ability to raise new capital), lengthening its development time (and therefore depleting cash reserves) or destroying any chance of a product being approved.
CytRx Hit with a Clinical Hold
These concerns, in particular, aren't hypothetical.
On 18 November 2014, California-based CytRx Corporation announced FDA had initiated a partial clinical hold on its drug compound aldoxorubicin after a patient enrolled in its expanded access program died.
The trial will no longer be allowed to enroll new patients, CytRx said in its statement.
The company said the patient had advanced-stage cancer prior to enrolling in trials for the drug, and had not qualified for any of the company's existing trials. The death of the patient, however, is causing CytRx to "amend all aldoxorubicin study protocols to include an appropriate inclusion/exclusion criteria, an additional patient screening assessment and an evaluation of serum electrolytes prior to aldoxorubicin administration," CytRx explained.
CytRx says it expects the partial hold to be lifted by FDA "expeditiously."
But for watchers of FDA's expanded access program, it's another indication that compassion has its occasional downsides as well.