Experimental Drugs and the Compassionate Use Doctrine

People with chronic illnesses and incurable diseases are often willing to do almost anything to improve their health. That includes seeking alternative treatments and trying unapproved drugs. While gaining access to drugs not yet approved by the Food and Drug Administration (FDA) can be a difficult task, many people will go to nearly any lengths to get them, to include suing a drug manufacturer to force it to provide them the drug. That's what happened in the case of Gunvalson v. PTC Therapeutics Inc., Slip Copy, 2008 WL 4003377 (D.N.J.,2008), a case recently overturned on appeal. In this month's issue, we look at the reasoning of the district court. In next month's issue, we'll see why the appellate court disagreed, and discuss the implications of the compassionate use doctrine for drug research and for individual patient outcomes.

A Boy and His Family Fight for Medication

Jacob Gunvalson is a boy in his teens with the terminal disease Duchenne Muscular Dystrophy (DMD). DMD is a genetic disease that causes muscles, including the heart, to degenerate and become paralyzed. Most DMD victims die by the age of 25. Although no drug is currently available to treat DMD in any long-term meaningful way, there are medications that can help relieve symptoms or slow their progression.

Jacob was already taking Gentamicin to treat his DMD when his mother, Cherie Gunvalson, inquired about his taking part in a new drug study being performed by PTC Therapeutics Inc. The company was set to conduct a Phase 2 clinical trial of a drug to treat DMD, called PTC 124. The trial would last 28 days, during which time participants would not be permitted to take Gentamicin.

In their suit, the Gunvalsons alleged that PTC's Vice President, Claudia Hirawat, advised Mrs. Gunvalson that her son should remain on Gentamicin because it offered him some relief from his symptoms. The plaintiffs said that Hirawat advised them that Jacob should therefore wait to participate in a later PTC 124 trial. Because of this and other conversations with PTC representatives, the Gunvalsons claimed they were induced to forego treatment at the time of that first inquiry. Later, when the first trial was successful, PTC began an expanded trial of the drug, which was to last for two years. When Jacob sought to enter into the group of trial participants for the expanded testing, he and his parents learned that the group was limited to those who had taken part in the first, 28-day trial. Thus, Jacob was now ineligible to participate in a clinical trial of PTC 124. By the time he was rejected for this second clinical trial, Jacob's condition had deteriorated considerably.

Because he was barred from the clinical trial, Jacob tried a second method for gaining access to PTC 124; he sought permission to use the drug through the FDA-regulated “compassionate use” exception to the normal prohibition against drug-manufacturer distribution of unapproved medications.

'Compassionate Use'

Drug companies are permitted to give terminally ill people experimental drugs outside of the clinical trial setting in two ways: 1) on a group basis (expanded access program); or 2) on a single-patient basis. When the company is not offering an expanded access program, the single-patient basis for expanded access is the only route open. To use this option, the potential user of the pharmaceutical product must get his or her doctor to ask the drug company to let the patient use the investigational drug. If the company agrees, the doctor and the manufacturer can ask the FDA to approve the use of the drug for that single patient. The process can be completed in as little as a day, although it generally takes several weeks. In Jacob's case, PTC declined to apply to the FDA on his behalf for an exception.

When this last hope fell through, Jacob and his parents brought suit against PTC to compel the company to provide PTC 124 to Jacob. They claimed that PTC induced Jacob to pass up the chance to participate in the first trial group by promising him that he could take part in a second phase of testing, when in fact he could not take part in that second phase if he did not participate in the first. They sued on theories of promissory estoppel, fraudulent misrepresentation and negligent misrepresentation. Significantly to the holding of December 2008, the Gunvalsons also sought a preliminary injunction from the U.S. District Court for the District of New Jersey to immediately compel PTC to give Jacob the drug.

The district court had to consider four factors before granting the requested preliminary injunction. They were: 1) The Gunvalsons' likelihood of ultimate success on the merits; 2) The irreparable harm to Jacob if the injunction were denied; 3) The hardship the injunction would cause to PTC; and 4) the public interest in the issue.

Success on the Merits

Concerning the first hurdle, the district court broke the question of whether the Gunvalsons would ultimately prevail on the merits into two parts: 1) Could the plaintiffs show that PTC 124 comports with the requirements of the FDA's “compassionate use” exception?; and 2) Could they show that PTC had made them an enforceable promise that they would provide Jacob the drug?

To show that PTC 124 comports with the requirements of the FDA's “compassionate use” exception, such that the FDA would allow a drug company to distribute the unapproved drug, four conditions had to be met: 1) The drug must be intended for use in treating a serious or life-threatening disease; 2) There must be no good alternative; 3) The drug must currently be under investigation in a clinical trial; and 4) The sponsor must be actively pursuing marketing approval. 21 C.F.R. ' 312.34. The court noted also that, even if PTC 124 met these criteria, the FDA could still deny permission for Jacob to use the drug through the compassionate use exception if there was insufficient evidence of the drug's safety. Looking at all these criteria, however, the district court found no impediment to Jacob's being permitted to use PTC 124 under the compassionate use exception. Thus, the first prong of the test to see if the Gunvalsons might win on the merits was met.

The Second Prong

Moving on to the second prong, the court had to determine if a promise had been made to Jacob and his family that the company would provide Jacob with PTC 124. And because Jacob had offered nothing in return for the promise that he could take part in a later clinical trial (lack of consideration), he was relying on the doctrine of promissory estoppel to compel PTC to give him their medication. In order to win on a promissory estoppel theory, Jacob and his parents had to show: 1) That a clear and definite promise was made; 2) That the promise was made with the expectation that the plaintiffs would rely on it; 3) That the plaintiffs reasonably relied upon the promise; and 4) That the failure to make good on that promise resulted in a definite and substantial detriment to the plaintiffs. See, e.g., Lobiondo v. O'Callaghan, 357 N.J.Sup. 488 (N.J.Super.Ct.App.Div. 2003).

For evidence of the requisite clear and definite promise, the court noted these and other statements in Cherie Gunvalson's affidavit:

• That she “asked PTC Vice President Claudia Hirawat if Jacob should be enrolled in the initial Phase 2a trials, and Hirawat responded that 'it was not worth taking Jacob off of Gentamicin for only a 28-day dosage of PTC124.' (Aff. of Cherie Gunvalson 17.)”
• That she “asked Hirawat if there were any adverse effects on Jacob for not participating in the trial, and she told me there were none.” (Cherie Aff. 17.)
• That Hirawat told Cherie Gunvalson “that Jacob had no better or worse chance to be treated in the future based on his non-enrollment in the Phase IIa trial.” (Cherie Aff. 25.)
• That Hirawat “assured [Cherie] that Jacob would get access to PTC124.” (Cheri Aff. 26.)

The court also found that many statements in Hirawat's affidavit confirmed Cheri Gunvalson's contentions, even though other statements in Hirawat's affidavit contradicted them. The court explained its tendency to lean toward Cheri Gunvalson's version of the facts surrounding her interactions with PTC personnel, stating: “As an initial matter, all communications between PTC and Plaintiffs must be viewed in light of the unique relationship between Jacob's mother, Cherie, and PTC. Cherie worked at length to lobby funds from Congress for DMD research. In this capacity, she had relationships with PTC employees and officers that transcended the typical relationship that PTC had with parents of children with DMD. Of most relevance to this Court, Cherie appears to have had extensive communications on both a professional and social level with PTC Vice President Claudia Hirawat. Indeed, it is undisputed that Cherie and Jacob have even stayed overnight at Hirawat's home on at least one occasion. Because of these extended connections alone, it seems to the Court that PTC would be more likely to communicate to Plaintiffs more compassionately and less formally than with other parents of DMD children.”

Because of the corroborating statements of the opposing party and the witnesses' relationship with one another, the district court's determined that the promise had been made to the Gunvalsons.

The court next concluded that the last three elements required to make a case under the theory of promissory estoppel were present, stating it was “reasonably likely that Plaintiffs relied on these and other similar statements made by PTC in declining to enroll Jacob in the Phase 2a clinical trials. This failure to enroll Jacob worked to Plaintiffs' detriment, as Jacob is now not eligible for the extended Phase 2a trials. In summary, the Court finds it reasonably likely that Plaintiffs reasonably relied to their detriment on PTC's promises to provide PTC 124 to Jacob, so the Court prevents PTC from denying Plaintiffs that promise.”

In the district court's view, this settled the second prong of the question ' “Are the plaintiffs likely to succeed on the merits?”

Three More Elements

The court next moved on to the other requirements the plaintiffs were required to show before a preliminary injunction could be issued. They were: 2) The irreparable harm to Jacob if the injunction were denied; 3) The hardship the injunction would cause to PTC; and 4) the public interest in the issue.

Concerning irreparable harm, there was little question here. Jacob is dying of a disease with no currently available cure, and PTC 124 offers some minimal hope.

The hardship to PTC of having to provide the drug to Jacob was also easily dismissed as an impediment to injunction by the district court, as all the company could cite to was the difficulty of filing paperwork with and working with the FDA to obtain a compassionate use exception for the boy. According to PTC, this process could take weeks, but that seemed a small price to pay for, perhaps, saving or prolonging a life.

Finally, the district court found no harm to the public in issuing a preliminary injunction compelling PTC to provide Jacob with PTC 124, as the public has an interest in providing life-saving experimental drugs to terminally ill persons. This public interest was evidenced, the court said, by the FDA's very enactment of the compassionate use exception.

Having found that the plaintiffs met all the criteria for obtaining a preliminary injunction, the district court ordered PTC to attempt to get an FDA compassionate use exemption for Jacob so that the company could provide him with the drugs he needed.

Conclusion

In next month's issue, we'll see what happened when the district court ruling went up on appeal, and we'll look at the policy considerations at stake in rendering help to individual disease sufferers through the compassionate use exception.

Janice G. Inman is Editor-in-Chief of this newsletter.

People with chronic illnesses and incurable diseases are often willing to do almost anything to improve their health. That includes seeking alternative treatments and trying unapproved drugs. While gaining access to drugs not yet approved by the Food and Drug Administration (FDA) can be a difficult task, many people will go to nearly any lengths to get them, to include suing a drug manufacturer to force it to provide them the drug. That's what happened in the case of Gunvalson v. PTC Therapeutics Inc., Slip Copy, 2008 WL 4003377 (D.N.J.,2008), a case recently overturned on appeal. In this month's issue, we look at the reasoning of the district court. In next month's issue, we'll see why the appellate court disagreed, and discuss the implications of the compassionate use doctrine for drug research and for individual patient outcomes.

A Boy and His Family Fight for Medication

Jacob Gunvalson is a boy in his teens with the terminal disease Duchenne Muscular Dystrophy (DMD). DMD is a genetic disease that causes muscles, including the heart, to degenerate and become paralyzed. Most DMD victims die by the age of 25. Although no drug is currently available to treat DMD in any long-term meaningful way, there are medications that can help relieve symptoms or slow their progression.

Jacob was already taking Gentamicin to treat his DMD when his mother, Cherie Gunvalson, inquired about his taking part in a new drug study being performed by PTC Therapeutics Inc. The company was set to conduct a Phase 2 clinical trial of a drug to treat DMD, called PTC 124. The trial would last 28 days, during which time participants would not be permitted to take Gentamicin.

In their suit, the Gunvalsons alleged that PTC's Vice President, Claudia Hirawat, advised Mrs. Gunvalson that her son should remain on Gentamicin because it offered him some relief from his symptoms. The plaintiffs said that Hirawat advised them that Jacob should therefore wait to participate in a later PTC 124 trial. Because of this and other conversations with PTC representatives, the Gunvalsons claimed they were induced to forego treatment at the time of that first inquiry. Later, when the first trial was successful, PTC began an expanded trial of the drug, which was to last for two years. When Jacob sought to enter into the group of trial participants for the expanded testing, he and his parents learned that the group was limited to those who had taken part in the first, 28-day trial. Thus, Jacob was now ineligible to participate in a clinical trial of PTC 124. By the time he was rejected for this second clinical trial, Jacob's condition had deteriorated considerably.

Because he was barred from the clinical trial, Jacob tried a second method for gaining access to PTC 124; he sought permission to use the drug through the FDA-regulated “compassionate use” exception to the normal prohibition against drug-manufacturer distribution of unapproved medications.

'Compassionate Use'

Drug companies are permitted to give terminally ill people experimental drugs outside of the clinical trial setting in two ways: 1) on a group basis (expanded access program); or 2) on a single-patient basis. When the company is not offering an expanded access program, the single-patient basis for expanded access is the only route open. To use this option, the potential user of the pharmaceutical product must get his or her doctor to ask the drug company to let the patient use the investigational drug. If the company agrees, the doctor and the manufacturer can ask the FDA to approve the use of the drug for that single patient. The process can be completed in as little as a day, although it generally takes several weeks. In Jacob's case, PTC declined to apply to the FDA on his behalf for an exception.

When this last hope fell through, Jacob and his parents brought suit against PTC to compel the company to provide PTC 124 to Jacob. They claimed that PTC induced Jacob to pass up the chance to participate in the first trial group by promising him that he could take part in a second phase of testing, when in fact he could not take part in that second phase if he did not participate in the first. They sued on theories of promissory estoppel, fraudulent misrepresentation and negligent misrepresentation. Significantly to the holding of December 2008, the Gunvalsons also sought a preliminary injunction from the U.S. District Court for the District of New Jersey to immediately compel PTC to give Jacob the drug.

The district court had to consider four factors before granting the requested preliminary injunction. They were: 1) The Gunvalsons' likelihood of ultimate success on the merits; 2) The irreparable harm to Jacob if the injunction were denied; 3) The hardship the injunction would cause to PTC; and 4) the public interest in the issue.

Success on the Merits

Concerning the first hurdle, the district court broke the question of whether the Gunvalsons would ultimately prevail on the merits into two parts: 1) Could the plaintiffs show that PTC 124 comports with the requirements of the FDA's “compassionate use” exception?; and 2) Could they show that PTC had made them an enforceable promise that they would provide Jacob the drug?

To show that PTC 124 comports with the requirements of the FDA's “compassionate use” exception, such that the FDA would allow a drug company to distribute the unapproved drug, four conditions had to be met: 1) The drug must be intended for use in treating a serious or life-threatening disease; 2) There must be no good alternative; 3) The drug must currently be under investigation in a clinical trial; and 4) The sponsor must be actively pursuing marketing approval. 21 C.F.R. ' 312.34. The court noted also that, even if PTC 124 met these criteria, the FDA could still deny permission for Jacob to use the drug through the compassionate use exception if there was insufficient evidence of the drug's safety. Looking at all these criteria, however, the district court found no impediment to Jacob's being permitted to use PTC 124 under the compassionate use exception. Thus, the first prong of the test to see if the Gunvalsons might win on the merits was met.

The Second Prong

Moving on to the second prong, the court had to determine if a promise had been made to Jacob and his family that the company would provide Jacob with PTC 124. And because Jacob had offered nothing in return for the promise that he could take part in a later clinical trial (lack of consideration), he was relying on the doctrine of promissory estoppel to compel PTC to give him their medication. In order to win on a promissory estoppel theory, Jacob and his parents had to show: 1) That a clear and definite promise was made; 2) That the promise was made with the expectation that the plaintiffs would rely on it; 3) That the plaintiffs reasonably relied upon the promise; and 4) That the failure to make good on that promise resulted in a definite and substantial detriment to the plaintiffs. See, e.g., Lobiondo v. O'Callaghan , 357 N.J.Sup. 488 (N.J.Super.Ct.App.Div. 2003).

For evidence of the requisite clear and definite promise, the court noted these and other statements in Cherie Gunvalson's affidavit:

• That she “asked PTC Vice President Claudia Hirawat if Jacob should be enrolled in the initial Phase 2a trials, and Hirawat responded that 'it was not worth taking Jacob off of Gentamicin for only a 28-day dosage of PTC124.' (Aff. of Cherie Gunvalson 17.)”
• That she “asked Hirawat if there were any adverse effects on Jacob for not participating in the trial, and she told me there were none.” (Cherie Aff. 17.)
• That Hirawat told Cherie Gunvalson “that Jacob had no better or worse chance to be treated in the future based on his non-enrollment in the Phase IIa trial.” (Cherie Aff. 25.)
• That Hirawat “assured [Cherie] that Jacob would get access to PTC124.” (Cheri Aff. 26.)

The court also found that many statements in Hirawat's affidavit confirmed Cheri Gunvalson's contentions, even though other statements in Hirawat's affidavit contradicted them. The court explained its tendency to lean toward Cheri Gunvalson's version of the facts surrounding her interactions with PTC personnel, stating: “As an initial matter, all communications between PTC and Plaintiffs must be viewed in light of the unique relationship between Jacob's mother, Cherie, and PTC. Cherie worked at length to lobby funds from Congress for DMD research. In this capacity, she had relationships with PTC employees and officers that transcended the typical relationship that PTC had with parents of children with DMD. Of most relevance to this Court, Cherie appears to have had extensive communications on both a professional and social level with PTC Vice President Claudia Hirawat. Indeed, it is undisputed that Cherie and Jacob have even stayed overnight at Hirawat's home on at least one occasion. Because of these extended connections alone, it seems to the Court that PTC would be more likely to communicate to Plaintiffs more compassionately and less formally than with other parents of DMD children.”

Because of the corroborating statements of the opposing party and the witnesses' relationship with one another, the district court's determined that the promise had been made to the Gunvalsons.

The court next concluded that the last three elements required to make a case under the theory of promissory estoppel were present, stating it was “reasonably likely that Plaintiffs relied on these and other similar statements made by PTC in declining to enroll Jacob in the Phase 2a clinical trials. This failure to enroll Jacob worked to Plaintiffs' detriment, as Jacob is now not eligible for the extended Phase 2a trials. In summary, the Court finds it reasonably likely that Plaintiffs reasonably relied to their detriment on PTC's promises to provide PTC 124 to Jacob, so the Court prevents PTC from denying Plaintiffs that promise.”

In the district court's view, this settled the second prong of the question ' “Are the plaintiffs likely to succeed on the merits?”

Three More Elements

The court next moved on to the other requirements the plaintiffs were required to show before a preliminary injunction could be issued. They were: 2) The irreparable harm to Jacob if the injunction were denied; 3) The hardship the injunction would cause to PTC; and 4) the public interest in the issue.

Concerning irreparable harm, there was little question here. Jacob is dying of a disease with no currently available cure, and PTC 124 offers some minimal hope.

The hardship to PTC of having to provide the drug to Jacob was also easily dismissed as an impediment to injunction by the district court, as all the company could cite to was the difficulty of filing paperwork with and working with the FDA to obtain a compassionate use exception for the boy. According to PTC, this process could take weeks, but that seemed a small price to pay for, perhaps, saving or prolonging a life.

Finally, the district court found no harm to the public in issuing a preliminary injunction compelling PTC to provide Jacob with PTC 124, as the public has an interest in providing life-saving experimental drugs to terminally ill persons. This public interest was evidenced, the court said, by the FDA's very enactment of the compassionate use exception.

Having found that the plaintiffs met all the criteria for obtaining a preliminary injunction, the district court ordered PTC to attempt to get an FDA compassionate use exemption for Jacob so that the company could provide him with the drugs he needed.

Conclusion

In next month's issue, we'll see what happened when the district court ruling went up on appeal, and we'll look at the policy considerations at stake in rendering help to individual disease sufferers through the compassionate use exception.

Janice G. Inman is Editor-in-Chief of this newsletter.