Jacob Gunvalson with his mother, Cheri, who is suing biotech company PTC for access to a drug that could help her son's muscular dystrophy. Credit: Steve Burmeister/The New York Times/Redux

A lawsuit filed by Cheri Gunvalson to force privately held biotech PTC Therapeutics to provide her son with access to its experimental drug could have widespread ramifications for the industry. In August, a federal judge in Newark ordered the small startup located in South Plainfield, New Jersey, to provide Jacob Gunvalson, 16, with its small molecule, despite the company's objections that the patient does not meet the clinical trial's criteria.

The company has appealed the decision, but already legal experts are cautioning biotech companies to manage their relationships with patients more cautiously. Others are warning that the case threatens the integrity of the clinical trial process, although patient advocacy groups are pointing to 'Gunvalson' as a sign that patients need easier access to experimental drugs.

The drug at the center of the controversy is PTC124. This oral, investigational new drug targets nonsense mutations, which cause between 5% and 70% of all genetic diseases, including Duchenne muscular dystrophy, cystic fibrosis, spinal muscular atrophy and lysosomal storage diseases. Nonsense mutations introduce a premature translation termination codon into the mRNA, resulting in truncated, nonfunctional proteins.

PTC124 is a suppressor of premature translational termination, enabling the ribosome to read through premature stop codons in mRNA, thereby restoring the synthesis of full-length protein. In May 2007, PTC published work showing that their small-molecule PTC124 could rescue muscle function in mice carrying a dystrophin nonsense allele and human muscle cells (Nature 447, 87–91, 2007) in vitro resulting in full-length, active dystrophin. PTC began enrolling patients to participate in clinical studies for Duchenne muscular dystrophy and cystic fibrosis.

Jacob, who has Duchenne muscular dystrophy, did not enroll in the phase 2a trial because, his parents told the court, the company led them to believe he would receive the experimental drug in a later study. When Jacob was denied access to the expanded study, in July 2008, his parents sued. They sought a court order to force PTC to provide their son with PTC124. Now, they are demanding the drug on a compassionate-use basis.

The court sided with the Gunvalsons saying PTC vice president Claudia Hirawat made many statements that seemed “tantamount” to a promise. The court also noted that the Gunvalsons had a “unique” relationship with PTC Therapeutics that “transcended” typical company/patient contact.

Brad Thompson, a partner at law firm Epstein, Becker and Green, who has been following the case, says: “This tells you that companies in this business have to be conservative, and constantly remind patients that they cannot offer them a drug, and put lots of disclaimers out there.”

In a statement released August 20, PTC Therapeutics CEO Stuart Peltz wrote that the Gunvalsons had never been promised the drug, and it would be “dangerous and counterproductive” to give the drug outside the clinical trial. Patients might forgo the trial if they can get the drug otherwise, and an adverse event in a compassionate-use case could “slow or prevent” the drug's approval, he said.

On August 29 the Biotechnology Industry Organization (BIO) filed a brief in support of PTC's request for a stay, or postponement, on the judgment against the company. “This case has broad implications for all companies involved in drug development,” says Sara Radcliffe, vice president for science & regulatory affairs at BIO. “Providing a drug outside of a trial could remove an incentive for patients to participate,” which could lead to “many drugs being left on the laboratory shelf,” BIO's brief stated. The brief also notes that BIO members routinely forge strong ties with patients and their advocates, and this case could have a chilling effect on such beneficial interactions.

Advocacy groups see the case as highlighting the need for easier access to investigational drugs for desperately ill patients. In 2003, the Abigail Alliance for Better Access to Developmental Drugs sued the FDA for broader access to experimental drugs—and lost. Frank Burroughs, a cofounder of the patient advocacy group Abigail Alliance, describes the Gunvalson case as “yet another example of the need for Congress to pay attention to and pass the Access Act.” Burroughs is referring to the “Expanded Access to Investigational Drugs for Treatment Use” bill, which Abigail Alliance and its allies now hope will replace the FDA's expanded access rules with more specific guidelines than existing ones.

Current regulations describe two main types of access: single-patient use, widely known as 'compassionate use', and the expanded access treatment investigational new drug application (IND), which can be used to provide larger numbers of patients a promising drug that is close to approval but not yet marketed. The process helps patients get drugs while companies complete the final steps toward approval. Single-patient use is less well defined, and there has been confusion about who is eligible and how to apply the process. In December 2006 the agency released new guidelines, and it has accepted comments on those but a final document has not been released.

Burroughs insists that providing wider access doesn't have to hurt trial enrollment, if patients are required to attempt to enroll in a trial before they can get the drug. The Access Act makes that provision.

Concerns over adverse events in cases of compassionate use may be overblown, notes Robert Temple, director of the office of medical policy in the FDA Center for Drug Evaluation and Research. “To the best of our knowledge that has never happened,” he says. But he adds that FDA never intended that companies would be obliged to provide drugs to specific patients before approval.

Temple says the agency's key concern is maintaining clinical trial integrity. “There was always a perception that we were hostile to allowing access, but that's not true. As long as it doesn't interfere with drug development we are not against it,” he says.

But Burroughs argues that the FDA's proposed regulations are “more public relations to show they are doing something about expanded access when it really does very little. They are just taking current FDA policy and putting it into regulation.”

Most biotech companies are familiar with the traditional approach to expanded access and compassionate use. Osiris Therapeutics of Columbia, Maryland, for example, began a compassionate-use program for children several years ago, after it became clear that the company's mesenchymal stem cell therapy, Prochymal, was very effective for treating graft-versus-host disease (GVHD).

“It's a horrible disease and people suffer terribly,” says Randy Mills, CEO of Osiris. The first child treated was an 8-month-old infant who had “peeled out of his skin and was shedding his intestinal lining,” Mills says. The baby's condition was dire, but he recovered completely after five days on the therapy. Word spread quickly and Osiris eventually gave Prochymal to a dozen children on a compassionate-use basis, concurrently to running their trials.

Now, the company's two Prochymal phase 3 trials in GVHD are wrapping up, and Osiris will be providing the therapy via expanded access until it is approved, which should be sometime in the second half of 2009.

Kim McBride at Nationwide Children's Hospital treats many patients with rare genetic diseases and was recently involved in an expanded access program for BioMarin's (Novato, CA, USA) sapropterin dihydrochloride, or sapropterin, an investigational treatment for phenylketonuria. “Once it was clear people were getting better results with the drug, than just diet alone, we wanted to get this drug to children as quickly as possible,” he says. Phenylketonuria is a rare genetic condition that can cause serious disability, including mental retardation.

McBride says that the most desperate patients, such as those with lysosomal storage diseases, “are ready to take greater risks, and giving those patients early access, through compassionate use, to investigational drugs gives us an early look at the drugs, too.”

As this article went to press, PTC had succeeded in postponing the court's order until after the appeal. “But, they will be legally obliged to give him [Gunvalson] the drug, unless their appeal is successful,” says Thompson. If the appeal fails, PTC's only recourse will be to try and get the Supreme Court to hear the case.