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Regulatory News | 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:
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.
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:
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.
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.
Tags: Compassionate Use, Expanded Access, Clinical Hold