Opinion

VIEWPOINT

Michael Rosenblatt, MD Merck and Company, Kenilworth, New Jersey. Bruce Kuhlik, JD Merck and Company, Kenilworth, New Jersey.

Principles and Challenges in Access to Experimental Medicines Efforts by patients to obtain early access to experimental medicines have increased as novel therapies provide new evidence of their potential to treat or cure life-threatening diseases. As drug discovery efforts, particularly for cancer and orphan diseases, are increasingly based on molecular targets, success rates improve, generating further interest in early access to experimental drugs. Devising “expanded access programs” (EAPs), however, presents challenges.1,2 Fairness and ethical issues need to be addressed as do practical matters, such as efficient conduct of clinical trials, adequate drug supply, finances, and geography. The complexity of crafting EAPs is compounded by early, rapid, and broad communication by traditional and social media. This Viewpoint outlines general principles to help balance the competing interests of individuals facing life-threatening illness with practical concerns and broader societal interests in knowing which drugs do or do not work and making them generally available through expeditious regulatory approval. At least 5 parties participate in the EAP process: the patient, treating physician, institutional review board, US Food and Drug Administration (FDA), and

The public and media often find individual pleas more compelling the value of controlled trials.

Corresponding Author: Michael Rosenblatt, MD, Merck and Company, 2000 Galloping Hill Rd, K1-4118B, Kenilworth, NJ 07033 (michael.rosenblatt @merck.com).

the company developing the drug. Although differences exist depending on the drug and its development stage, most EAP requests that meet basic eligibility requirements are approved by institutional review boards and the FDA, leaving industry as the principal gatekeeper to early access. Despite successful efforts to speed “breakthrough therapies” through the regulatory process, many patients become trapped in a waiting period during which their projected life expectancy is shorter than the anticipated time until drug approval. Hence, the original name for EAPs—“compassionate use”—better reflects their nature. Patients requesting access to experimental drugs ask for “compassion” to try drugs that are neither proven safe and effective nor licensed; and the biopharmaceutical companies that make such drugs available generally do so as a result of mission and moral obligation, not financial incentive. In fact, EAPs often cost millions of dollars to administer; moreover, such programs pose real risks: conduct of an EAP may jeopardize enrollment or retention of patients in ongoing clinical trials of a drug that determine safety

and efficacy and ultimately gain regulatory approval. Adverse patient experiences in an EAP also can complicate determining a drug’s safety profile, even when causation is unclear, further slowing approval. Thus, in responding to patients’ understandable requests for compassionate access before approval, companies need to consider not only their concerns but also society’s greater interest in development and availability of the drug for the larger group in need. No simple solutions exist, but the following principles may be widely applicable. First, fairness, a foundational principle, should underlie selective opening of access to experimental medicines. From society’s standpoint, fairness requires prioritizing the effort to demonstrate safety and efficacy to make the drug widely available via regulatory approval as swiftly as possible; EAPs that jeopardize or slow essential clinical trials or regulatory review should not be undertaken. Within this constraint, EAPs should be administered in ways that fairly distinguish among individual requests and provide prompt responses. Second, to qualify for consideration, a patient must have a life-threatening or serious illness with no comparable therapy available or the patient’s disease must have progressed or failed to respond to treatment with the current standard of care. than The patient also must not meet eligibility or location criteria for participating in a clinical trial. In addition, data from human studies must support the belief that benefits outweigh risks. Accordingly, the patient’s diagnosis should align with the indication that will form the basis of approval, and the development process should be sufficiently advanced that enough data exist to make a reasonably informed benefit-to-risk decision. Safety risks or ultimate lack of benefit of unproven therapies is underappreciated. Even among patients with potentially terminal diseases, a guiding principle is to make decisions that maximize potential benefit and minimize harm. Third, programs should be offered only in countries where approval will be sought and likely obtained. Sufficient drug supply should be able to be produced without diversion or compromise of supplies needed for clinical trials.Biologics,suchasmonoclonalantibodies,areexpensive, often requiring months to years to produce on a large scale. The financial burden may present a formidable challenge, especially for start-up companies. Moreover, upon drug approval, the EAP should terminate in a manner that enables a smooth transition to conventional access without compromising the patient’s treatment program.

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(Reprinted) JAMA May 26, 2015 Volume 313, Number 20

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Opinion Viewpoint

Despite these suggested principles and practices, several important issues remain. 1. The public and media often find individual pleas more compelling than the value of controlled trials.3,4 There tends to be a presumption of efficacy or benefit regarding experimental medicines and little awareness of risks. Many patients look to physicians to promote understanding in these matters. Pharmaceutical companies, in turn, should clearly communicate criteria for EAP enrollment eligibility to avoid misunderstandings and disappointments for patients and physicians. Generally limiting access to drugs that are in phase 3 testing or, ideally, for which a marketing approval application has been submitted can help address this and other concerns. 2. Although the media’s “story line” regarding EAPs often pits patients against industry, it rarely presents the individual’s interest vs that of the larger group with the same disease. If early access slows or compromises clinical trials, then many patients will be deprived. Because many patients requesting early access are extremely ill and are outside the profile of patients eligible to participate in clinical trials, serious adverse events, including death, occur. If such an event occurs in an EAP, it might not be possible to determine if it is drug-related. As a result, a promising therapy might be delayed, or even abandoned before sufficient clinical trial data can be generated. 3. Based on earlier points, there should not be a legally recognized right to early access or a general presumption favoring it (right to try).5 4. EAPs resemble clinical trials in many features to satisfy regulators. Regulators require that safety findings be reported, although efficacy findings are generally not accepted outside formal clinical trials. EAPs are designed to provide access, and their priority is not clinical investigation. They usually take place in settings that do not routinely participate in clinical trials and involve physicians with little or no experience in clinical research. Hence, EAP data quality generally does not meet the same standards as that from clinical trials. It is important that this difference be recognized, perhaps by regulators viewing such data explicitly as similar to observational data or by utilizing some hierarchy of data value. 5. There will always be practical challenges. For example, in the US EAP for pembrolizumab, for a brief period (weeks), the patients of physician-investigators in the original clinical trial were given earlier access before opening a second stage to other qualified physicians and patients. This was done to place the drug in ARTICLE INFORMATION

REFERENCES

Published Online: April 23, 2015. doi:10.1001/jama.2015.4135.

1. Sanghavi D, George M, Bencic S. Health policy issue brief: the 4 As of expanding patient access to life saving treatments and the regulatory implications: Engelberg Center for Health Care Reform at Brookings. http://www.brookings.edu /research/papers/2014/07/29-compassionate-use -of-pharmaceutical-drugs. Published July 31, 2014. Accessed April 3, 2015.

Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Both authors report owning stock in Merck and Company. Additional Contributions: We thank Nancy Kass, ScD (Johns Hopkins University), and Steven Joffe, MD (University of Pennsylvania), both bioethicists, for their insights and helpful suggestions in the preparation of this article. They did not receive compensation for their contribution.

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the hands of physicians experienced in its use and to minimize erroneous safety or other issues before a larger data set could be generated. 6. Outside the United States, patient access to a new drug often occurs through a national health system. After drug approval by a regulatory agency, it still may take months to more than a year for health authorities to set price and agree to reimbursement. If companies implement EAPs to provide expeditious access to medicines before approval or reimbursement, then countries and payers should also be obliged to act expeditiously to provide true access for appropriate patients. 7. For cancer drugs, the approval process is based largely on clinical trials for each individual cancer type (eg, breast, lung, and kidney cancers). The histologic basis for classification is more than 100 years old. In the future, tumor classification and biological behavior likely will be better characterized based on biomarkers; a lung cancer bearing a certain marker may have more in common with another tumor that has the same marker than it does with other lung cancers that are negative for the marker. New biological insights are arising rapidly. Regulators will need to adjust accordingly. 8. Pediatric malignancies present special challenges. Cancer in children is rare, making it difficult to conduct robust clinical trials. Furthermore, cancers may be more aggressive in children than adults, and children may respond differently (better or worse than in adults) to therapeutic agents. 9. Decision making around patient eligibility for an EAP is often complex and emotionally charged. Regulatory authorities should retain their independent role in overseeing these programs. In addition, consideration should be given to establishing “appeals boards” that include members external to the biopharmaceutical company. The model for determining access for organ transplantation has elements that may guide EAPs, although substantial differences exist that weigh oppositely. 10. Additional complexity results from the need to craft different EAPs to meet regulatory requirements in different countries. Harmonization of regulatory practices across geographies would benefit patients and companies. While principles and practices should help guide decisions regarding access to experimental therapies, such therapies remain “unproven.” Furthermore, although some general principles apply, EAPs will vary for specific drugs and patients. Further debate and consideration of these important issues are warranted.

2. Darrow JJ, Sarpatwari A, Avorn J, Kesselheim AS. Practical, legal, and ethical issues in expanded access to investigational drugs. N Engl J Med. 2015; 372(3):279-286.

3. Leonard K. Seeking the right to try. US News. http://www.usnews.com/news/articles/2014/11/18 /right-to-try-laws-allowing-patients-to-try -experimental-drugs-bypass-fda. Published November 18, 2014. Accessed April 3, 2015. 4. Turkewitzjan J. Patients seek “right to try” new drugs. New York Times. http://www.nytimes.com /2015/01/11/us/patients-seek-right-to-try-new -drugs.html?_r=2#Accessed. Published January 10, 2015. Accessed April 3, 2015. 5. Lieu CH, Sorkin A, Messersmith WA. Right to try [published online March 16, 2015]? J Clin Oncol. doi:10.1200/JCO.2014.60.6004.

JAMA May 26, 2015 Volume 313, Number 20 (Reprinted)

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Principles and challenges in access to experimental medicines.

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