In opening his opinion striking down the Office of Mental Health’s regulations controlling the administration of experimental psychiatric medications to patients who lack the capacity to make decisions for themselves, Justice Edward J. Greenfield of the New York Supreme Court poignantly stated:
“The mere mention of experimental medical research on incapacitated human beings—the mentally ill, the profoundly retarded, and minor children summons up visceral reactions with recollections of the brutal Nazi experimentation with helpless subjects in concentration camps, and elicits shudders of revulsion when parallels are suggested”
Strong and powerful words, no doubt, yet, Judge Greenfield goes on to recognize the clear benefits that can be, and have been, obtained with the use of clinical trials on human subjects. And this is the dilemma we are left with. How do we devise protocols that will respect the dignity of the individual while at the same time allow for needed clinical trials on human subjects so that we may further medical science and alleviate the suffering of countless individuals in the future with the lessons these trials teach us?
This article will discuss how New York has attempted to meet these dual and at times juxtaposing goals. Initially, to gain a better understanding of how pharmaceutical drugs get to a stage of human trials this article will discuss the Food and Drug Administration (FDA) process by why drugs are tested, through three clinical stages, on human subjects and ultimately approved or rejected. Lastly, this article will discuss difficulties and potential points of conflict in the FDA process.
The FDA Approval Process
It is the responsibility of the FDA, and specifically, the Center for Drug Evaluation and Research (CDER) within the FDA, to approve new pharmaceutical drugs before they are allowed to be marketed to the public. The process is time consuming and expensive. On average, a new drug requires 8 years of testing and $350 million dollars in investment before it reaches a local pharmacist. Only one in 1000 compounds that begin laboratory testing will ever make it to the human testing stage.
Initially, before human trials are even contemplated, a pharmaceutical company wishing to market a new drug must synthesize and purify the drug in order to develop a compound that has some hope of efficacy. Some limited animal testing is performed and if the pharmaceutical company wishes to seek the approval of the FDA they must begin the human trial clinical stage of testing.
Phase 1 of clinical testing deals with a limited population of individuals, from 20-80 people. These people are mostly healthy and not afflicted with the condition that the drug is meant to treat. Generally, the purpose of this phase is to study the safety of the drug and determine what adverse side-effects the drug may have on the human body and its processes.
In phase 2 the drug is tested on patients with the specific disease the drug is anticipated to treat. The purpose of this phase is to test the efficacy of the drug. This phase is conducted on a much larger scale, typically involving hundreds of patients.
Phase 3 is meant to test the drug on the broader population in numbers that will allow those conducting the study to extrapolate the results of the clinical trial to the general population. In phase 3 the drug is tested on thousands of patients.
Throughout the clinical trial phase Institutional Review Boards (IRBs) are established as a check on these studies and to protect the welfare of the individuals who are the subjects of the study. The IRBs are usually created from a group of experts and laypersons from a diverse background to ensure that a complete review of the study is conducted from a multidisciplinary standpoint.
Assuming all goes well, at the conclusion of this process the drug manufacturer will submit a New Drug Application to the FDA seeking approval of the product. The FDA will consider the efficacy of the drug, the safety of the drug and the overall risk-benefit analysis in determining if the drug warrants approval. The FDA will also consider the labeling placed on the drug to determine if it is sufficient to warn not only clinicians of the proper use and potential side effects of the drug, but patients as well.
Even after a drug has been approved, the FDA as well as the pharmaceutical company that designed the drug, is charged with monitoring the safety of the product. Reports of serious adverse effects must be reported to the FDA for consideration on whether to alter the labeling on the drug, or most drastically, pull the drug from the market. The most famous example of this was the popular painkiller medication Vioxx.
Over the years, many have complained about the FDA drug approval process. Many of these complaints have revolved around the time and expense it takes for drugs to reach the approval process. The most pervasive complaints have come since the passage of the 1992 Prescription Drug User Fee Act, which altered the budget of the FDA by charging “user fees” to pharmaceutical firms. It is estimated that from 1993 to 2001 the FDA collected $825 million in user fees from drug companies. With money on such a staggering scale it is not difficult to see where the appearance of a conflict may arise.
While this alteration has resulted in quicker approval times, decreasing from an average of 27 months in 1993 to just 14 months in 2001, by contrast, it has also resulted in more drugs being pulled from the market after they have been approved by the FDA, to the tune of 5.35% of drugs for 1997-2001 as compared to just 1.56% for 1993-1996. Additionally, a review of FDA expert advisory panels, meant to advise the FDA on the drug approval process, revealed that since 1993 more than half of these members had a direct financial interest in the drug or area of research they were charged with evaluating.
Moreover, many of the clinical trials used to test the safety and efficacy of a proposed drug seeking FDA approval are controlled and paid for by the drug company that owns the drug. Hence, the results of clinical trials that produce unfavorable outcomes are often suppressed. Recently, some authorities have brought pressure to bear upon drug companies to publish the results of all clinical trials, regardless of the outcome. In 2004, the New York State Attorney General brought suit against GlaxoSmithKline alleging that the company had suppressed negative results of four studies of its anti-depressant, Paxil. As part of a negotiated settlement, GSK posted the results online of all of its studies from December, 2000-forward. Lastly, in 2004, largely in response to the Congressional testimony of Dr. David Graham a whistleblower within the FDA, the Journal of the American Medical Association published a series of papers criticizing certain aspects of the FDA process and suggesting potential reforms. This pressure has resulted in many more drug companies publishing most if not all of their clinical studies regardless of the favorability of the outcome.
New York Law on Experimental Medication
In 1975, in response to the many abuses levied against human subjects of experimental medication trials, the New York State Legislature passed Article 24-A of the Public Health Law to establish guidelines and rules on how experimental medications can be tested on human subjects within the State of New York. At its core, Article 24-A mandates that in order for an individual to be the subject of an experimental trial that individual must provide informed consent. In essence, that the individual fully understands the risks, any potential benefits, and alternatives of the experimental protocol and nevertheless agrees to take part in the clinical trial. The Public Health Law gave the Commissioner of the Department of Health the exclusive authority to promulgate rules and regulations on how to enact and comply with the mandates of Article 24-A. However, in studies conducted by and fully funded by the Federal government, Article 24-A does not apply, and instead, any applicable Federal regulations would control how the study was to be conducted.
In 1990, the Office of Mental Health (OMH) passed a series of rules regulating the provision of experimental psychotropic medications to patients at OMH licensed facilities. These regulations controlled the provision of experimental medication not only to those who maintained the capacity to provide informed consent, but also to those individuals who were incapacitated thereby leaving them unable to render a reasoned decision about whether or not they wanted to be a part of the study. While safeguards were put in place, the regulations allowed for the human experimentation on a population of individuals who could not, as a result of their mental illness, understand what they were a part of.
Due to the serious concerns raised by these new OMH regulations a series of mental health advocacy groups, including the Mental Hygiene Legal Service, collaborated in challenging the OMH regulations. In the seminal case of T.D. v. OMH, the Court struck down the OMH regulations as violative of the New York State and Federal Constitution. The Court reasoned that the Commissioner of OMH lacked any authority under State Law to issue these regulations as Article 24-A of the Public Health Law gave this exclusive authority to the Commissioner of the Department of Health. Moreover, the Court discussed the more troubling aspect of the OMH regulations, which allowed patients who were so mentally ill that they had no idea what medications they were taking or whether they were safe to take or not.
The Court had particular issue with the fact that pursuant to the regulations, if an individual was being considered for participation in a clinical trial, and that individual’s capacity to consent was in question, there was no provision that the individual be notified that his/her capacity was in question. Hence, it was quite possible that an individual may have been a part of a study without having any idea of their own involvement. Moreover, even if the individual was aware that he was adjudged incapacitated there was no provision within the regulations to test the determination of capacity. Lastly, the regulations allowed for testing on individuals even where the drug being tested held no hope for improving the mentally ill individual’s condition. Thus, this particular group of patients was truly being taken advantage of; suffering all of the risk with no potential benefit. The Court was particularly troubled by this aspect.
As noted previously, the Court struck down the OMH regulations, reverting the law back to its original position with Article 24-A controlling. Hence, if an individual is to be the subject of a clinical trial with an experimental drug that individual must provide informed consent, or a duly authorized representative must provide informed consent on behalf of that individual. Those individuals who lack the capacity to make a decision and have no legal representative to make that decision for them cannot be forced to participate in clinical human trials of experimental drugs.
Because of the extremely sensitive nature of experimental psychiatric medication it is not surprising that there is so much controversy over the issue. The venture has outstanding abilities to create a great deal of good for the mentally ill community if the promise of more effective and less dangerous medication can be discovered; human clinical trials is the only way this can be achieved. However, at what risk? This dilemma continues both in the FDA approval process and New York’s attempts to establish procedures that will allow for the obvious benefits of clinical trials while minimizing the risk to those participating in the study. What does seem clear, however, is that the regulations established by OMH, and struck down in T.D. v. OMH, went too far. It is difficult to contemplate a circumstance where a patient who lacks the ability to understand what he is involved in, be involuntarily made to participate in a study involving potentially dangerous experimental medications.