Accessing Experimental Drugs Through the Compassionate Use Doctrine

In last month's issue, we discussed how Jacob Gunvalson, when denied entry into a clinical trial for a drug that might offer valuable treatment for his terminal disease, Duchenne Muscular Dystrophy (DMD), sued the drug manufacturer to compel it to seek a “compassionate use” exemption from the FDA so that he could take the unapproved drug, PTC 124. In conjunction with that suit, he sought a preliminary injunction, which the district court granted. The drug's manufacturer, PTC Therapeutics Inc., appealed to the U.S. Court of Appeals for the Third Circuit, in Gunvalson v. PTC Therapeutics Inc., Slip Copy, 2008 WL 5227189 (C.A.3 (N.J.), 12/16/08).

The Third Circuit Reverses

The Third Circuit noted that it could reverse the lower court's grant of injunctive relief “only if the court abused its discretion, committed an obvious error in applying the law, or made a serious mistake in considering the proof.” Loretangeli v. Critelli, 853 F.2d 186 (3d Cit. 1988). Despite this high hurdle for the defense, the appellate court found it must reverse. So, what went wrong for Jacob and his family?

Absent a showing of probable success on the merits ' one of the four prerequisites to issuance of a preliminary injunction ' a preliminary injunction may not be granted. And although the district court had found that the Gunvalsons could prove the elements of promissory estoppel, the appellate court disagreed.

To succeed on the merits of their promissory estoppel claim under New Jersey law, the Gunvalsons had to plead facts establishing: 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).

In the Third Circuit's opinion, one problem with the Gunvalsons' claim was that they had failed to prove the first of these requirements: that a clear and definite promise had been made to them that Jacob would be able to take part in a later clinical trial of PTC 124. Stated the court, “The district court focused on that statement of Claudia Hirawat, PTC's Vice President, to Mrs. Gunvalson that Jacob's non-enrollment in Phase 2a trials would not by itself preclude him from participating in all of PTC's anticipated future clinical trials for PTC 124. This statement and other alleged statements by PTC officers fail as a clear and definite promise because it asserts nothing conclusive about Jacob's participation in future trials or his access to PTC 124.” Thus, although it turned out that the participants in the second trial were drawn only from those who had taken part in the first trial, it did not matter. Claudia Hirawat, PTC Threrapeutic's Vice President, had said nothing that rose to the level of a promise that Jacob would be allowed to participate in later trials. No guarantee was made.

In addition, the appellate court found that the district court erred in finding the Gunvalsons reasonably relied on the purported promises of PTC in not attempting to enroll Jacob in the Phase 2a trial. “The district court erred in its analysis,” said the Third Circuit, “by failing to recognize the Gunvalsons did not enroll Jacob in the Phase 2a trial because Dr. Finkel, the principal investigator for the Philadelphia area clinical trial, ruled Jacob ineligible based on the medical records Mrs. Gunvalson provided him, and not because the Gunvalsons had been promised PTC 124 via some other means.” The records the court referred to showed Jacob was, at the time of enrollment into the first trial, misdiagnosed with Beeker's Muscular Dystrophy (BMD), rather than DMD. The medical records also showed that Jacob had impaired kidney function and that he might have cardiac problems. According to the trial's eligibility criteria, these complications would have kept him from participating in the trial. Thus, as Jacob was ineligible to participate, the Gunvalsons could not rely on any statements of PTC officers to decide not to enroll Jacob in the trial. The choice was not theirs to make.

The Third Circuit rendered its decision with reluctance, stating,
“[W]e are sympathetic to the plight of Jacob and his family. Similarly, we are moved by the Gunvalsons' heroic efforts on behalf of their son and others afflicted with this devastating disease. Nevertheless, we are constrained by the law to conclude that the Gunvalsons cannot demonstrate either a clear and definite promise or detrimental reliance, requirements for a promissory estoppel claim.” The court's reading of the letter of the law had trumped compassion for a boy living on borrowed time, and the order granting the preliminary injunction was vacated.

Ethical Considerations

Based on the law alone, the Third Circuit decision may (or may not) have been correct. But was it ethical? There is room for debate on that issue.

Certainly, from the viewpoint of Jacob and his family ' and undoubtedly of many similarly situated people rejected for inclusion in clinical trials ' the appellate court's decision must have seemed heartless. How can technicalities and dry legal arguments counter the interests of a teenager who, without extraordinary intervention, has almost no chance of seeing his 30th birthday?

The counter-answer lies in the way drugs and medical devices are developed and tested for use by the larger public. Manufacturers test new medical products by recruiting volunteers who will be placed in different groups. One group may be given a placebo or an already approved drug, while another will receive the experimental drug. People in these different groups may experience different outcomes from their medication regimens, which is, of course, the point. To see if an experimental drug works better than another, there must be a control group against which to gauge its performance. The potential for unfair treatment of individual subjects under these circumstances is obvious.

However, this system is the only one we have. What would happen if people who thought they could benefit from an experimental drug had the choice of joining a study ' where they might receive the new drug, or might not ' and petitioning to the FDA to make sure that they got the experimental drug?

The specter of an unfair system was raised by a pair of muscular dystrophy advocacy groups in an amicus brief to the Third Circuit Court of Appeals in Gunvalson. The Parent Project for Muscular Dystrophy Research Inc. and United Parent Projects Muscular Dystrophy joined in stating, “The district court's order allows one individual to receive PTC124 while numerous other individuals are forced to wait until the clinical trial process is complete. Such a result is patently unfair ' There are many individuals with premature stop mutations that might benefit from access to PTC 124. The district court's order accords preferential treatment to one individual and, as a consequence, raises serious issues of fairness.”

The two organizations also argued that allowing the district court's injunction to stand would open the floodgates to litigation. The district court had dismissed this argument because, it concluded, the Gunvalsons' “unusually close relationship” with PTC 124's makers gave them a unique reason for relying on assurances given by PTC Therapeutics Inc.'s personnel. But the two groups pointed out that, when only a small number of victims are affected by a particular disease, close relationships between those individuals and the industry executives and medical personnel studying their affliction are quite common. In fact, such close relationships are actively cultivated by drug industry representatives so that they may better understand the impact of their therapies on test subjects. “In failing to acknowledge the commonality of close relationships between industry executives and individuals afflicted with DMD and their families,” the groups stated in their brief, “the district court's letter opinion understates the possibility of increased litigation based on theories like promissory estoppel. This case is simply not the narrow case that the district court believes it to be.”

Hindering Trial Participation

The fear that effective clinical trials might be hindered by injunctions like the one the Gunvalsons were granted was advanced by some seemingly unlikely “friends of the court”: Jacqui and Nicholas Fuca, parents of a 13-year-old boy who also has DMD, and who also was barred from the PTC 124 studies. In their amicus brief to the court, they asked, “Why would anyone enroll (or remain) in a clinical trial that presents a substantial risk of receiving a useless placebo pill when, through litigation, one can be certain of receiving what could be a life-saving drug? The problem is compounded where, as here, the underlying condition is thankfully rare and, therefore, the universe of potential clinical trial participants is small. We currently do not know whether PTC124 is safe or effective for treating ' DMD; if this lawsuit and the ones that may follow on its heels are successful, we may never find out.” So, the Fucas saw special individuals' access to drugs like PTC 124 as a detriment to scientific discovery of potentially life-saving drugs that could help even more people.

The Fucas also objected to the district court's attempt to set the Gunvalson case apart from others on the basis of the close relationship between Jacob's parents and PTC Therapeutics' employees. They argued that if that precedent stood, it would discourage drug company executives and medical personnel from getting too “close” to test subjects, which would in turn keep disease sufferers and their families from gaining valuable information about progress in finding treatments for their maladies.

Countering the contention that allowing Jacob to get access to PTC 124 outside the clinical trial setting would open the floodgates to others were the arguments advanced by several states in their own amicus brief. The states of Minnesota, Alaska, Connecticut, Florida, New Hampshire, New Mexico, Oklahoma, Utah, West Virginia, and the District of Columbia pointed out that the federal government, by creating the compassionate use exceptions, intended to help some individual patients. The FDA also retains final say over who will get such special treatment, because drug manufacturers must get FDA approval if they want to provide experimental drugs to patients not enrolled in their clinical trials. Therefore, if the FDA sees that the pool of people willing to take part in a clinical trial is being diminished by too many requests for compassionate use exceptions, they can shut down that avenue.

More importantly for Jacob Gunvalson's case, the states highlighted a point that the Third Circuit emphasized in deciding the Gunvalsons could not prove they had reasonably relied on assurances from PTC Therapeutics personnel: Jacob was ineligible to take part in any of the clinical trials of PTC 124. He was ineligible for the first trial because he was, at the time of enrollment, diagnosed as having Beeker's Muscular Dystrophy (BMD), rather than DMD. And, by the time of
the second phase of the clinical trial, Jacob's physical condition had deteriorated to the point that he was no longer eligible. So, what harm could it do to the viability of present and future clinical trials if the drug manufacturer were to give him the medication now? “Simply put,” argued the states, “because PTC Therapeutics has taken the position that Jacob is not eligible to participate in the clinical trials ' providing PTC124 to Jacob will not disincentivize eligible DMD patients from enrolling in the clinical trials.”

Conclusion

Despite the Third Circuit's ruling in Gunvalson, it is certain that the debate over individuals' access to experimental drugs vs. the integrity of the drug trial system will continue. How could it be otherwise, when the stakes are so high for so many?

Following the decision, PTC Therapeutics issued a statement, saying, “Today's decision in our favor is important not just for PTC124, but for the future of the clinical trial process for all experimental drugs for rare disease. We continue to believe our approach to the development of PTC124 is in the best interests of all boys suffering from this rare disease.”

Perhaps. But, then again, if Jacob Gunvalson was never eligible to participate in clinical trials of PTC 124, the only reason the manufacturer could reasonably advance for not attempting to get the drug for the boy would likely be this: that it just did not want to deal with the aggravation of applying to the FDA for an exception in Jacob's case (and perhaps in the cases of others similarly situated). If the Gunvalsons and others were correct in stating that the compassionate use exceptions were an expression of the public interest in providing possibly life-saving experimental drugs to terminally ill people, should PTC Therapeutics have the ultimate right to stand in the way of that interest?

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

In last month's issue, we discussed how Jacob Gunvalson, when denied entry into a clinical trial for a drug that might offer valuable treatment for his terminal disease, Duchenne Muscular Dystrophy (DMD), sued the drug manufacturer to compel it to seek a “compassionate use” exemption from the FDA so that he could take the unapproved drug, PTC 124. In conjunction with that suit, he sought a preliminary injunction, which the district court granted. The drug's manufacturer, PTC Therapeutics Inc., appealed to the U.S. Court of Appeals for the Third Circuit, in Gunvalson v. PTC Therapeutics Inc., Slip Copy, 2008 WL 5227189 (C.A.3 (N.J.), 12/16/08).

The Third Circuit Reverses

The Third Circuit noted that it could reverse the lower court's grant of injunctive relief “only if the court abused its discretion, committed an obvious error in applying the law, or made a serious mistake in considering the proof.” Loretangeli v. Critelli , 853 F.2d 186 (3d Cit. 1988). Despite this high hurdle for the defense, the appellate court found it must reverse. So, what went wrong for Jacob and his family?

Absent a showing of probable success on the merits ' one of the four prerequisites to issuance of a preliminary injunction ' a preliminary injunction may not be granted. And although the district court had found that the Gunvalsons could prove the elements of promissory estoppel, the appellate court disagreed.

To succeed on the merits of their promissory estoppel claim under New Jersey law, the Gunvalsons had to plead facts establishing: 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).

In the Third Circuit's opinion, one problem with the Gunvalsons' claim was that they had failed to prove the first of these requirements: that a clear and definite promise had been made to them that Jacob would be able to take part in a later clinical trial of PTC 124. Stated the court, “The district court focused on that statement of Claudia Hirawat, PTC's Vice President, to Mrs. Gunvalson that Jacob's non-enrollment in Phase 2a trials would not by itself preclude him from participating in all of PTC's anticipated future clinical trials for PTC 124. This statement and other alleged statements by PTC officers fail as a clear and definite promise because it asserts nothing conclusive about Jacob's participation in future trials or his access to PTC 124.” Thus, although it turned out that the participants in the second trial were drawn only from those who had taken part in the first trial, it did not matter. Claudia Hirawat, PTC Threrapeutic's Vice President, had said nothing that rose to the level of a promise that Jacob would be allowed to participate in later trials. No guarantee was made.

In addition, the appellate court found that the district court erred in finding the Gunvalsons reasonably relied on the purported promises of PTC in not attempting to enroll Jacob in the Phase 2a trial. “The district court erred in its analysis,” said the Third Circuit, “by failing to recognize the Gunvalsons did not enroll Jacob in the Phase 2a trial because Dr. Finkel, the principal investigator for the Philadelphia area clinical trial, ruled Jacob ineligible based on the medical records Mrs. Gunvalson provided him, and not because the Gunvalsons had been promised PTC 124 via some other means.” The records the court referred to showed Jacob was, at the time of enrollment into the first trial, misdiagnosed with Beeker's Muscular Dystrophy (BMD), rather than DMD. The medical records also showed that Jacob had impaired kidney function and that he might have cardiac problems. According to the trial's eligibility criteria, these complications would have kept him from participating in the trial. Thus, as Jacob was ineligible to participate, the Gunvalsons could not rely on any statements of PTC officers to decide not to enroll Jacob in the trial. The choice was not theirs to make.

The Third Circuit rendered its decision with reluctance, stating,
“[W]e are sympathetic to the plight of Jacob and his family. Similarly, we are moved by the Gunvalsons' heroic efforts on behalf of their son and others afflicted with this devastating disease. Nevertheless, we are constrained by the law to conclude that the Gunvalsons cannot demonstrate either a clear and definite promise or detrimental reliance, requirements for a promissory estoppel claim.” The court's reading of the letter of the law had trumped compassion for a boy living on borrowed time, and the order granting the preliminary injunction was vacated.

Ethical Considerations

Based on the law alone, the Third Circuit decision may (or may not) have been correct. But was it ethical? There is room for debate on that issue.

Certainly, from the viewpoint of Jacob and his family ' and undoubtedly of many similarly situated people rejected for inclusion in clinical trials ' the appellate court's decision must have seemed heartless. How can technicalities and dry legal arguments counter the interests of a teenager who, without extraordinary intervention, has almost no chance of seeing his 30th birthday?

The counter-answer lies in the way drugs and medical devices are developed and tested for use by the larger public. Manufacturers test new medical products by recruiting volunteers who will be placed in different groups. One group may be given a placebo or an already approved drug, while another will receive the experimental drug. People in these different groups may experience different outcomes from their medication regimens, which is, of course, the point. To see if an experimental drug works better than another, there must be a control group against which to gauge its performance. The potential for unfair treatment of individual subjects under these circumstances is obvious.

However, this system is the only one we have. What would happen if people who thought they could benefit from an experimental drug had the choice of joining a study ' where they might receive the new drug, or might not ' and petitioning to the FDA to make sure that they got the experimental drug?

The specter of an unfair system was raised by a pair of muscular dystrophy advocacy groups in an amicus brief to the Third Circuit Court of Appeals in Gunvalson. The Parent Project for Muscular Dystrophy Research Inc. and United Parent Projects Muscular Dystrophy joined in stating, “The district court's order allows one individual to receive PTC124 while numerous other individuals are forced to wait until the clinical trial process is complete. Such a result is patently unfair ' There are many individuals with premature stop mutations that might benefit from access to PTC 124. The district court's order accords preferential treatment to one individual and, as a consequence, raises serious issues of fairness.”

The two organizations also argued that allowing the district court's injunction to stand would open the floodgates to litigation. The district court had dismissed this argument because, it concluded, the Gunvalsons' “unusually close relationship” with PTC 124's makers gave them a unique reason for relying on assurances given by PTC Therapeutics Inc.'s personnel. But the two groups pointed out that, when only a small number of victims are affected by a particular disease, close relationships between those individuals and the industry executives and medical personnel studying their affliction are quite common. In fact, such close relationships are actively cultivated by drug industry representatives so that they may better understand the impact of their therapies on test subjects. “In failing to acknowledge the commonality of close relationships between industry executives and individuals afflicted with DMD and their families,” the groups stated in their brief, “the district court's letter opinion understates the possibility of increased litigation based on theories like promissory estoppel. This case is simply not the narrow case that the district court believes it to be.”

Hindering Trial Participation

The fear that effective clinical trials might be hindered by injunctions like the one the Gunvalsons were granted was advanced by some seemingly unlikely “friends of the court”: Jacqui and Nicholas Fuca, parents of a 13-year-old boy who also has DMD, and who also was barred from the PTC 124 studies. In their amicus brief to the court, they asked, “Why would anyone enroll (or remain) in a clinical trial that presents a substantial risk of receiving a useless placebo pill when, through litigation, one can be certain of receiving what could be a life-saving drug? The problem is compounded where, as here, the underlying condition is thankfully rare and, therefore, the universe of potential clinical trial participants is small. We currently do not know whether PTC124 is safe or effective for treating ' DMD; if this lawsuit and the ones that may follow on its heels are successful, we may never find out.” So, the Fucas saw special individuals' access to drugs like PTC 124 as a detriment to scientific discovery of potentially life-saving drugs that could help even more people.

The Fucas also objected to the district court's attempt to set the Gunvalson case apart from others on the basis of the close relationship between Jacob's parents and PTC Therapeutics' employees. They argued that if that precedent stood, it would discourage drug company executives and medical personnel from getting too “close” to test subjects, which would in turn keep disease sufferers and their families from gaining valuable information about progress in finding treatments for their maladies.

Countering the contention that allowing Jacob to get access to PTC 124 outside the clinical trial setting would open the floodgates to others were the arguments advanced by several states in their own amicus brief. The states of Minnesota, Alaska, Connecticut, Florida, New Hampshire, New Mexico, Oklahoma, Utah, West Virginia, and the District of Columbia pointed out that the federal government, by creating the compassionate use exceptions, intended to help some individual patients. The FDA also retains final say over who will get such special treatment, because drug manufacturers must get FDA approval if they want to provide experimental drugs to patients not enrolled in their clinical trials. Therefore, if the FDA sees that the pool of people willing to take part in a clinical trial is being diminished by too many requests for compassionate use exceptions, they can shut down that avenue.

More importantly for Jacob Gunvalson's case, the states highlighted a point that the Third Circuit emphasized in deciding the Gunvalsons could not prove they had reasonably relied on assurances from PTC Therapeutics personnel: Jacob was ineligible to take part in any of the clinical trials of PTC 124. He was ineligible for the first trial because he was, at the time of enrollment, diagnosed as having Beeker's Muscular Dystrophy (BMD), rather than DMD. And, by the time of
the second phase of the clinical trial, Jacob's physical condition had deteriorated to the point that he was no longer eligible. So, what harm could it do to the viability of present and future clinical trials if the drug manufacturer were to give him the medication now? “Simply put,” argued the states, “because PTC Therapeutics has taken the position that Jacob is not eligible to participate in the clinical trials ' providing PTC124 to Jacob will not disincentivize eligible DMD patients from enrolling in the clinical trials.”

Conclusion

Despite the Third Circuit's ruling in Gunvalson, it is certain that the debate over individuals' access to experimental drugs vs. the integrity of the drug trial system will continue. How could it be otherwise, when the stakes are so high for so many?

Following the decision, PTC Therapeutics issued a statement, saying, “Today's decision in our favor is important not just for PTC124, but for the future of the clinical trial process for all experimental drugs for rare disease. We continue to believe our approach to the development of PTC124 is in the best interests of all boys suffering from this rare disease.”

Perhaps. But, then again, if Jacob Gunvalson was never eligible to participate in clinical trials of PTC 124, the only reason the manufacturer could reasonably advance for not attempting to get the drug for the boy would likely be this: that it just did not want to deal with the aggravation of applying to the FDA for an exception in Jacob's case (and perhaps in the cases of others similarly situated). If the Gunvalsons and others were correct in stating that the compassionate use exceptions were an expression of the public interest in providing possibly life-saving experimental drugs to terminally ill people, should PTC Therapeutics have the ultimate right to stand in the way of that interest?

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