Judge's ruling may have ominous repercussions in CT industry
Decision could slow trial enrollment
A recent judge's ruling has shaken up the clinical research industry as experts try to determine how the court's interference in an investigational drug study might impact future CT recruitment.
Judge William J. Martini of the United States District Court in Newark, NJ, sided with plaintiff Jacob Gunvalson, age 16, of Gonvick, MN, ruling that the teenager should be allowed to receive an experimental drug called PTC124. CT investigators had determined Gunvalson was ineligible for the trial and had not enrolled him in a phase II trial. The teenager's mother sued, and on Aug. 20, 2008, the judge ruled in her favor.1
Experts say the ruling could give potential clinical trial participants the idea that they would be better off seeking the investigational drug outside of a study, rather than enrolling in placebo-controlled clinical research.
The judge's ruling could derail the whole process of drug development and, ultimately, slow down the industry's new drug pipeline, says Merit E. Cudkowicz, MD, an associate professor of neurology at Harvard Medical School in Charlestown, MA.
The danger is that the court ruling might encourage individuals to compel drug companies to provide investigational drugs, and this would defeat the CT sites' ability to enroll people in trials, says Mark S. Schreiner, MD, an associate professor of anesthesia in pediatrics at the University of Pennsylvania. Schreiner also is the chair of the committees for the protection of human subjects (IRB) at The Children's Hospital of Philadelphia in Philadelphia, PA.
"The motivation for someone to enter a placebo-controlled trial diminishes," Schreiner explains. "Why should you be in a placebo-controlled trial when you could get the drug anyway?"
PTC124 is a small-molecule drug that is being studied for treatment of cystic fibrosis and Duchenne muscular dystrophy. Gunvalson has Duchenne muscular dystrophy.
PTC Therapeutics of South Plainfield, NJ, has been investigating the drug's potential in treating "nonsense" mutations, which are a type of mutation that causes a genetic disorder by causing a defect in the production of a critical protein. Up to 15% of inherited diseases are due to nonsense mutations.2
In the recent course case, Gunvalson had participated in recruitment sessions for early phase clinical trials involving PTC124. He had spent the night at a PTC Therapeutics official's home, and his mother claimed that she had helped PTC Therapeutics obtain federal grants to study Duchenne muscular dystrophy. But ultimately Gunvalson was found to not meet the phase II study's inclusion/exclusion criteria, according to media reports.
PTC appeals 'dangerous' ruling
The District Court's decision will be appealed, according to an Aug. 20, 2008, statement issued by Stuart Peltz, president and chief executive officer of PTC Therapeutics.
"We understand that Mrs. Gunvalson would go to great lengths to provide her son with a treatment that has the potential to stop the progression of his disease," Peltz says in the statement. "But we believe it is dangerous and counterproductive to allow individual exceptions at this stage of the drug development process."
Such exceptions pose the risk that no patients will want to participate in clinical trials, Peltz adds.
"Delays in completing the FDA-required clinical study or adverse safety information from a protocol exception could slow or even prevent approval of PTC124," Peltz says.
While some investigational drugs have been made available to non-trial patients on a compassionate use basis, PTC124 has not yet had any proof of efficacy, and so it would be premature to offer it to patients on this basis, a PTC Therapeutics official and other experts say.
This legal case could have important consequences in the conduct of clinical research, says Ed Gaffney, PhD, executive director of clinical research at the Baptist Health System, Inc., of Birmingham, AL.
"It will be interesting to follow the outcome of the appeal in this case," Gaffney says. "We can only hope that the presiding judge and litigators fully understand the ethical restrictions that govern the conduct of clinical trials."
The placebo non-effect?
The court's ruling also could pose serious risks for patients who decide to bypass clinical studies to receive access to investigational treatments, the experts warn.
"There are an awful lot of trials where you're better off being in a placebo group," Schreiner says.
"The risks and benefits of PTC124 are not known, and they won't be known until the end of the trial," Schreiner says.
The best known example might be the drug Vioxx, where the people who received the medication had a higher rate of myocardial infarction than those who did not, he adds.
"There are many examples of drugs that have done worse than placebo in clinical trials," Cudkowicz says. "That's where I find the court order troublesome, mandating giving someone a drug that you don't know whether it's going to harm them."
Also, people who are taking an investigational drug outside of a clinical trial might not know that the drug is making them worse, she adds.
"Only in a clear clinical trial could you see that it's causing harm," Cudkowicz says.
"Unfortunately, the legal decision in this case appears to require a protocol violation and, therefore, undermines the built-in ethical and safety restrictions required in protocols by good clinical practices (GCPs)," Gaffney says.
Another potential problem with the court ruling involves the financial implications for sponsors. If a sponsor is forced to make an investigational drug for a compassionate use, then this decision also is forcing the sponsor to give the drug away for free since the sponsor cannot market the drug until it's been approved by the FDA.
If the person taking the drug is not being charged for it, then that means a company that has invested millions of dollars in time and effort in a drug will receive no reimbursement, even if it's being used more widely than it would be under a clinical trial, says LaDale K. George, JD, a health research attorney with Foley & Lardner in Chicago, IL.
Also, a previous court ruling has said that patients do not have a constitutional right to potentially toxic drugs that have no proven benefit, George says.
George refers to the ruling in Abigail Alliance v. Eschenbach in which the U.S. Supreme Court refused to hear a lower court's decision that terminally ill patients do not have a right of access to experimental drugs that have not been proven safe and effective.3
"The Abigail Alliance case involved a young woman who suffered from head and neck cancer, and she wanted access to cetuximab (Erbitux), which was still in phase I testing for colon cancer," George explains. "So she sued the FDA, saying she had a constitutional right to access this experimental treatment because of the severity of her illness."
The FDA had argued against the woman's request for access to the drug, saying that only 5 %of all cancer drugs that begin clinical testing are approved for patient use when the testing is completed, and that less than one-third of cancer drugs proceed from phase II trials to phase III trials.3
There is at least one possible way to solve the dilemma of wanting to help seriously ill patients while balancing the interest in producing solid clinical research for the greater public good, Cudkowicz notes.
"We could have trials that are a little more open," she says. "These small companies have one chance and want to do a good trial, so they try to keep it as homogenous with patients as they can."
But there typically are many patients who are interested in participating in these studies, but who do not qualify, Cudkowicz notes.
"One option people are talking about is having concurrent trials where one will measure efficacy, but the other will be used more for safety," she explains. "The safety one would enroll people who are further on in their illness, and it would allow them access to the drug so investigators can learn more about the drug's safety."
This is an expensive way to conduct a study, but it has been done successfully, Cudkowicz says.
"It produces large numbers of people taking the drug to show in safety data for the FDA," she adds. "It's expensive, but it has been done in other illnesses, and it brought good will to investigators."
References
- Grynbaum MM. Judge orders drug maker to provide experimental treatment to terminally ill teenager. NY Times. Aug. 21, 2008.
- Frequently asked questions about PTC124. PTC Therapeutics' resources for patients and families. 2008. Online: http://www.ptcbio.com/2.4_faqs.aspx
- Gambrill S. U.S. Supreme Court Will Not Hear Abigail Alliance v. Eschenbach. Clinical Trials Today. Jan. 14, 2008. Online: http://www.clinicaltrialstoday.com.
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