Access to Experimental Drugs

US Pharm. 2008;33(3):78-80.

Imagine that a family member is suffering from a horrible disease that has no apparent treatment. But you find out that there is a new drug being tested in clinical trials that might, just might, provide some relief, if only for a short while. Maybe a miracle would happen and the disease would go into remission. What would you do to try to get your loved one into one of the clinical trials? What happens when you learn that the individual does not meet the study protocols and therefore is not eligible to get the new drug? At this point, do you just give up and accept the inevitable, or do you try desperate measures to get the drug that offers some hope? What if somebody suggested to you that there might be a constitutional right to get the experimental drug? Would you seek a judicial solution to the dilemma?

Facts and Decision
These are the kinds of questions that the Abigail Alliance for Better Access to Developmental Drugs recently presented to the courts. This organization was formed by Frank Burroughs after his daughter, Abigail, passed away after a bout with head and neck cancer.¹ She was 21 years old at the time she was denied permission to obtain an experimental new drug that possibly could have benefited her. The alliance is an advocacy group of terminally ill patients and their supporters who have sought to advance the notion that individuals should have a right to obtain drugs that are in a clinical trial phase before the FDA has given the manufacturer permission to market the drug in the United States. In its initial lawsuit filed in 2003, the alliance was given an adverse opinion from a federal district court judge.² That court determined that there is no fundamental or constitutional right to access experimental drugs that have not yet been approved by the FDA for marketing to the general public.

However, a three-judge panel of the court of appeals reversed that decision. That opinion narrowly construed the arguments advanced by the alliance as "the right of a mentally competent, terminally ill adult patient to access potentially life saving post-Phase I investigational new drugs, upon a doctor's advice, even where that medication carries risks for the patient."³ The court stated that "upon examining our nation's history, legal traditions, and practices, the government has not blocked access to new drugs throughout the greater part of our history" and that "only in recent years has the government injected itself into consideration of the effectiveness of new drugs." This court determined that the Due Process clause of the U.S. Constitution protects "the right to access potentially life-sustaining medication where there are no alternative government-approved treatment options." The fundamental principal, according to these judges is "the patient's right to make the decision about her life free from government interference."⁴

The FDA sought review of this decision by all of the judges in the Court of Appeals for the District of Columbia. The en banc panel reversed the opinion of the three judges and reinstated the holding of the original district court judge.^5,6 These judges stated that "the nation's history and tradition did not establish a fundamental substantive due process right of access to experimental drugs for the terminally ill" and that "neither the common law doctrine of necessity, the tort of intentional interference with rescue, nor the right to self defense established a self-preservation right giving the terminally ill access to experimental drugs." The court went on to state, "The FDA's policy of limiting access to investigational drugs was rationally related to the legitimate state interest of protecting patients from potentially unsafe drugs with unknown therapeutic effects."

The case came to a sudden halt when the U.S. Supreme Court declined to hear an appeal from the en banc decision on January 14, 2008.⁷ In effect, this affirms the original district court opinion finding that there is no constitutional right to access experimental drugs that have not been approved by the FDA.

Background
While this might be the last word in the judicial sphere, it does not address the moral quandary of when it might be appropriate, as a matter of compassion, to let a terminally ill patient use an unapproved drug that is in the clinical phases of being tested. If the FDA has not approved a New Drug Application (NDA), meaning that there has not been a determination that the new drug is generally safe and effective for its intended purpose, but the drug has made it past the Phase I clinical trial stage, meaning that there is at least some preliminary evidence that the drug is safe and effective, what is the harm in letting a dying patient try the drug? Asked another way, just what is the FDA trying to protect when a terminally ill patient who has absolutely no other treatment options wants to use the drug?

As pharmacists, we know that drugs are used for unapproved purposes every single day without so much as an eyebrow raised by the FDA. Depending on the nature of a drug and its targeted population, the off-label uses may far outweigh the approved uses. It is estimated that about 80% of drugs given to pediatric patients are for off-label purposes. When it comes to using cancer drugs, as much as 90% are used for unlabeled purposes. For all classes of drugs, approximately 21% are prescribed for unapproved uses.⁸ Approximately 46% of cardiac medications are prescribed for off-label uses, which is the same percentage for all anticonvulsant prescriptions. Asthma medications are prescribed for nonapproved purposes 42% of the time. Now, the FDA is even proposing to let manufacturers promote drugs for off-label purposes. In February 2008, the FDA released a draft of proposed guidelines that would govern the practice.⁹

Addressing the nation's history of experimental drug use, it was not until 1906 that Congress passed the Pure Food and Drug Act, making it a crime to market misbranded or adulterated drugs. Prior to that legislation, anyone could get access to any drug without much governmental interference or regulation. During the first four decades of the 20th century, the FDA exerted little oversight of experimental drug use.¹⁰ It was not until 1938 when the Food, Drug, and Cosmetic Act went into effect that drugs had to be proven safe before they could be marketed in this country. Starting in 1962, manufacturers had to prove a new drug was both safe and effective. It was the Kefauver-Harris Amendment of that year that gave the FDA authority to oversee clinical trials of new drugs. This, however, created a problem. Clinical studies are almost always carried out at large academic universities in highly populated areas. People who do not live in such areas could not reasonably be expected to participate in the studies. This forecloses the opportunity for many to ever gain access to experimental drugs. Furthermore, large numbers of critically ill patients will not meet the intake protocol for any given study.

It was the AIDS epidemic of the 1980s that caused the FDA to rethink its position of protecting the public from drugs that have not first been shown to be safe and effective. The drugs that were used in this category were afforded "expanded access" so that patients not enrolled in formal studies could still get the experimental drugs under the supervision of a physician. In 1987, the FDA began to recognize a "compassionate use" protocol whereby drugs that made it past the Phase II clinical trials could be accessed by patients not participating in the drug studies. In practice, however, it is very difficult to pursue this option. The FDA has to grant an Investigational New Drug (IND) for the experimental drug to be used by an individual patient as determined on a case-by-case basis. The manufacturer still has to "sponsor" the experimental use by the patient. The company is prohibited from making any profit from selling the drug to the patient. A physician must agree to supervise the individual's use of the drug as a "principal investigator" and file mountains of paperwork with the sponsor and the FDA. The protocol for the patient to use the drug must be approved by an Institutional Review Board. In other words, the individual IND use has to meet the same criteria as a full-blown clinical trial. At any time, for practically any reason, the FDA or the sponsor may withdraw approval for the individual to continue using the drug.¹¹

Analysis
Many drug companies are reluctant to give experimental drugs to individuals not enrolled in clinical trials because of liability risks or out of fear that the FDA may require additional studies if the individual patient exhibits unanticipated effects that may or may not be attributable to the drug. Moreover, it is extremely expensive for a drug company to make experimental drugs available to anyone who asks for them, especially considering that large numbers of promising drugs never make it out of the trials. It is estimated that only about 10% of drugs tested in a Phase I trial ever make it to Phase II.¹²

The time that it takes a company to get the FDA's approval also works against the most seriously ill patients. It typically takes about six years from the date that a new drug is invented to even get permission for testing the drug in human beings. It usually takes another seven years to get the drug past all of the clinical testing phases. By the time that an NDA is approved, a manufacturer will have spent nearly a billion dollars. The number of NDAs granted per year seems to be spiraling downward. Between 1994 and 1997, the FDA approved an average of 36 drugs annually. However, between 2001 and 2004, the rate of approval fell to an average of 23 per year.¹³

The FDA's credibility as a watchdog organization is waning. It is taking hits from Congress on a number of fronts. Recently, the FDA was criticized for failing to inspect the Chinese factory that makes the active ingredient in Baxter International's heparin. ¹⁴ There have been at least 350 adverse reactions cited by Baxter, including four deaths. The FDA classified as many as 40% of the reactions as serious.

On February 14, 2008, Sen. Charles Grassley asked the FDA and Baxter for more data about the heparin and its supplier. Representatives of the House Committee on Energy and Commerce have been investigating import-safety issues with drugs and medical devices. A letter to the FDA stated that the limited oversight of foreign manufacturing is unnecessarily placing American lives at risk. Since 1980, the FDA has had a policy requiring inspection of foreign drug makers before allowing drugs to enter the U.S. A spokesperson for the FDA was quoted as saying "it was obviously a glitch" that the FDA failed to make the necessary inspections. ¹⁵

Rep. Bart Stupak, who heads an investigative panel that conducts oversight of the agency, said in an interview with the Associated Press on February 14, 2008, that FDA Commissioner Andrew von Eschenbach should step down because "it's just a total lack of leadership."¹⁶ He stated that "he had lost confidence in the commissioner and other top FDA officials over the handling of inspections and oversight by the agency." Rep. Stupak has been investigating the FDA's approval of Sanofi-Aventis' antibiotic Ketek. Rep. Stupak claims the FDA approved the drug despite knowing that a major safety study was faulty. Rep. Stupak and Rep. John Dingell, chairman of the House Committee on Energy and Commerce, threatened to hold U.S. Health and Human Services Secretary Michael Leavitt in contempt for refusing to turn over FDA briefing documents subpoenaed by the committee in the probe. Secretary Leavitt oversees the FDA and other health care agencies. The commissioner testified that the FDA did not use the flawed safety study to approve Ketek. But Rep. Stupak has called that statement untrue and subpoenaed Commissioner von Eschenbach's notes to determine if he lied under oath.

And then there is, or was, Vioxx.

It has to make you wonder who the FDA is protecting, an unknowing public or the drug companies it regulates. It is hard to see the harm in letting a terminally ill patient get access to an experimental drug under the rubric that the FDA is protecting us from exposure to drugs not proven safe and effective. Likewise, the liability fear cited by drug manufacturers could easily be taken care of through an informed consent agreement. If the patient wants to take the chance, is able to pay for the drug and is willing to waive liability, shouldn't he or she be allowed access anyway? In the meantime, pharmacists should be willing to help needy patients get into clinical studies or programs that allow compassionate use of experimental drugs

REFERENCES

1. Groopman J. The right to a trial. Should dying patients have access to experimental drugs? The New Yorker . December 18, 2006. www.newyorker.com/
archive/2006/12/18/061218fa_fact. Accessed February 15, 2008.

2. Abigail Alliance For Better Access To Developmental Drugs v. Mcclellan, Slip Op No. 03-1601 (RMU) (August 30, 2004), 2004 U.S. Dist. Lexis 29594.

3. Abigail Alliance v. Von Eschenbach, 370 U.S. App. DC 391; 445 F3d 470; 2006 U.S. App. Lexis 10874 (May 2, 2006).

4. Cruzan v. Director, Missouri Department of Health, 497 U.S. 261, 278, 110 S. Ct. 2841, 111 L. Ed. 2d 224 (1990).

5. En banc hearing." En banc is a French term meaning on the bench. A hearing is the formal examination of a civil or criminal cause before a judge according to the laws of a particular jurisdiction. When all of the judges who preside within geographic area covered by a court's jurisdiction gather to hear a case or matters related to a case they are said to meet en banc, that is, with the full authority of the court present. It refers to a case heard and decided by all of the judges of a court as opposed to judges acting individually." Texas Politics search glossary. http://texaspolitics.laits.utexas.edu/glossary/index.php?term=en%20banc%20hearing. Accessed February 15, 2008.

6. Abigail Alliance for Better Access to Developmental Drugs and Washington Legal Foundation v. Andrew Von Eschenbach, in his official capacity as Commissioner, Food and Drug Administration, and Michael O. Leavitt, in his official capacity as Secretary, U.S. Department of Health and Human Services; Slip Op No. 04-5350, U.S. Ct App. DC, 495 F3d 695; 2007 U.S. App. Lexis 18688 (August 7, 2007, Decided). Accessed February 15, 2008.

7. Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach, Slip Op No. 07-444, 2008 U.S. Lexis 836; 76 U.S.L.W. 3373.

8. Wild Mathews A, Johnson A. Boost for off-label drug use. The Wall Street Journal. February 16, 2008. Citing a 2006 analysis of drug use published in the Archives of Internal Medicine. http://online.wsj.com/article/SB120309931928071945.html. Accessed February 16, 2008.

9. Good reprint practices for the distribution of medical journal articles and medical or scientific reference publications on unapproved new uses of approved drugs and approved or cleared medical devices. U.S. Department of Health and Human Services. Draft guidance. February 2008. www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0053-gdl.pdf. Accessed February 16, 2008.

10. See note 1, supra.

11. Osentoski G. The ethical controversy of the use of unapproved drugs in terminally ill patients. December 2007. http://rxethics.org/osentoski.pdf. Accessed February 16, 2008.

12. See note 1, supra.

13. Sabin R. FDA lax in drug safety, journal warns. Independent agency is sought to prevent conflicts of interest. San Francisco Chronicle. November 23, 2004. www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2004/11/23/MNGSPA04NI1.DTL. Accessed February 16, 2008.

14. Burton TM, Wilde Mathews A, Zamiska N, Fairclough G. Heparin probe finds U.S. tie to Chinese plant. The Wall Street Journal. February 15, 2008. http://online.wsj.com/article/SB120302351904669441.html?mod=dist_smartbrief. Accessed February 15, 2008.

15. Harris G, Bogdanich W. FDA broke its rules by not inspecting Chinese plant with problem drug. The New York Times. February 15, 2008. www.nytimes.com/2008/02/15/washington/15fda.html?_r=1&adxnnl=1&oref=slogin&ref=us&adxnnlx=1203198324-4206n+j2WQuOVmJZUh526w. Accessed February 15, 2008.

16. Thomas K. Stupak calls for FDA resignation. Google News (Associated Press). February 14, 2008. http://ap.google.com/article/ALeqM5i_5Gdk-ys5eQMvHoQa8Km4P9lhZAD8UQGC4G0. Accessed February 15, 2008.

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