Drug and biologic developers have faced increasing pressure from patients and their advocates to make investigational drugs available for compassionate use prior to approval by the Food and Drug Administration (FDA). Over the past year social media campaigns have spotlighted patients seeking early access to potentially life-saving treatments, drawing attention to the growing debate between patient advocates promoting wider access to investigational drugs, and those urging more cautious approaches. Propelled by the plight of critically ill patients desperately seeking new treatments, several states have passed laws giving patients the “Right to Try” investigational drugs or biologics. FDA has also taken steps to make its “Expanded Access” process more user-friendly, and the Agency continues to solicit input from patient groups on risk-benefit analysis and available treatments as part of its Patient-Focused Drug Development Initiative.
Companies may want to monitor regulatory and legislative developments relating to early access to investigational treatments, and to adopt formal compassionate use policies.
Right-to-Try Laws
The Goldwater Institute in Phoenix, Arizona, with backing from patients and their advocates, drafted and successfully orchestrated introduction of “Right to Try” measures in 40 states, with 17 of the states enacting legislation and Arizona passing a ballot initiative. In theory, the laws provide terminally or seriously ill patients access to experimental treatments, while circumventing more rigorous requirements imposed by the FDA under its “expanded access” program. Proponents of the laws maintain that the “Right to Try” measures protect the “fundamental right of patients to save their own lives.”
Those on the other side of the debate, including the American Society of Clinical Oncology (ASCO), have raised concerns that the laws give patients false hope of a cure, noting that the unproven treatments are potentially toxic and may exacerbate symptoms and/or hasten death. Detractors also worry that allowing patients to obtain experimental drugs outside of the traditional clinical process will jeopardize patient enrollment in clinical trials and prevent drug companies from fulfilling their ethical duty to obtain timely FDA approval, so that patient populations—not just single patients–can be treated. Others also fault state laws for exempting insurers from paying for the experimental treatments and leaving patients at financial risk for covering the high costs of the experimental treatments and at risk for withdrawal of hospice care eligibility.
Some critics also question whether states have the power to regulate access to investigational treatments, when drug regulation falls under the purview of the FDA and the federal government. Some have re-dubbed the measures “Right to Ask” laws, noting that the new laws foster a second illusory hope of direct access to experimental treatments, when states cannot require drug manufacturers to provide the experimental therapeutics to patients. In fact, drug/biologic manufacturers subject to FDA regulation may insist on adherence to FDA’s stricter “expanded access” requirements before making investigational drugs available, if at all.
FDA’s More Streamlined and User-Friendly Expanded Access Procedure
Although it is unclear whether state Right-to-Try laws have had any direct benefit on patient access to investigation drugs,[1] the laws have served to inform FDA of the groundswell of public support for overhauling FDA’s cumbersome “expanded access” procedure. Accordingly, more sophisticated patient advocacy groups, such as The ALS Association (ALSA) have urged FDA to streamline its expanded access requirements, and to reconsider its benefit-risk assessment when deciding whether to approve new therapeutics to treat ALS. For example, ALSA joined with the Muscular Dystrophy Association (MDA) in providing comments to FDA as part of FDA’s ongoing Patient-Focused Drug Development Initiative to obtain patient perspectives on benefit-risk assessment, including disease severity and available treatment options.
These and other efforts have led to FDA’s recent release of a proposed updated form (Individual Patient Expanded Access Application), designed to streamline the application procedure for individual patients to apply for expanded access to investigational therapeutics. FDA expects that it will take only 45 minutes to fill out the new form, instead of the estimated 100 hours or more required to fill out the previous form.[2] FDA has also created webpages as a resource for patients and treating physicians requesting expanded access to experimental treatments. Contrary to popular perception, FDA grants over 99% of expanded access requests (e.g., 5,962 requests out of the 5,995 requests received between 2010 through 2014, even with the number of requests received by FDA nearly doubled over the last two years, from 974 in 2013 to 1873 in 2014).[3] Emergency requests can also be made over the phone.[4]
Although FDA is in the process of streamlining its application process, at least two FDA requirements are more demanding than the approach taken by most state Right-to-Try laws. First, to approve expanded access, FDA must determine that there is no “comparable or satisfactory alternative therapy” while Right to Try laws require only that the patient and treating physician have considered all alternative therapies. Second, FDA requires that the patient’s proposed use of the drug be reviewed by an institutional review board (IRB) or ethics committee to ensure that the risks are reasonable given the potential benefits. Most Right to Try laws do not require IRB or ethics committee review, although such review would be required under one pending Right–to-Try bill in California.[5] As in Right-to-Try counterparts, FDA’s expanded access program also permits drug/biologic manufacturers to request FDA authorization to charge patients for the costs associated with drug manufacturing.
Risks for Developers Providing Early Access to Drugs
Potential risks for companies receiving requests for compassionate use are highlighted by Chimerix’s experience with its experimental anti-viral drug, brincidofovir. In early 2014, Chimerix initially refused a request from 7-year-old cancer-patient Josh Hardy’s family for access to brincidofovir for a life-threatening adenovirus infection, a complication of immunosuppression treatment following a bone marrow transplant. A 55-person company, Chimerix initially cited its small size, limited resources, and need to focus its energies on obtaining FDA approval, but relented after a social media firestorm culminated in death threats to its CEO, who later left the company in the wake of the negative publicity.[6] In preparation for Josh’s treatment in March 2014, Chimerix worked with FDA to ensure that the treatment would not compromise Chimerix’s completion of its clinical trials. FDA also agreed that Josh Hardy could be enrolled as the first patient in an open label pilot study to evaluate brincidofovir for the treatment of adenovirus infections in immunocompromised pediatric and adult patients, and further agreed to work with Chimerix on the design of a pivotal Phase 3 study to continue the pilot study. After Josh Hardy was successfully treated for his infection, the tide of social media reversed and Chimerix stock rose almost 50 percent. On the other side of the spectrum, after a patient in the late stages of an Ebola infection died last October, despite treatment with brincidofovir, Chimerix’s shares fell as much as 15%.[7]
The impact of adverse events during compassionate use treatment is further illustrated by delays suffered by CytRx Corporation in its clinical trial enrollment following an adverse event that occurred during compassionate use of its experimental cancer drug, aldoxorubic. In November 2014, CytRx made its drug available to an advanced-stage cancer patient who did not qualify for any ongoing clinical trials through the company’s expanded access program. When the patient died, FDA put a partial clinical hold on CytRx’s ongoing clinical trials, preventing the enrollment of new patients. The hold lasted two months, until CytRx could add appropriate patient screening and inclusion/exclusion criteria to the clinical protocols.
Concerns over possible delays or derailment of clinical trials may lead companies to reconsider non-clinical access to investigational drugs. San Diego-based CoDa Therapeutics, Inc. is a developer of novel wound healing and ocular therapeutic treatments with a branch office in Auckland, NZ. On several occasions, following compliance with regulatory requirements, the company provided its investigational drug on a compassionate use basis to doctors in New Zealand and Australia, who used it to save their patients from sight-threatening eye chemical and thermal burns that had not responded to standard-of-care treatments.[8] CoDa also provided its experimental drug to a doctor who successfully treated a patient in danger of amputation of his leg above the knee due to a non-healing chronic leg ulcer. After its U.S. clinical trials began, CoDa did not provide further early access to the drug, thus avoiding potential obstacles or delays for its clinical trials.
Recognizing the dilemma companies face in turning away requests from patients and their treating physician, Biotechnology Industry Organization’s (BIO’s) Standing Committee on Bioethics notes that “a patient’s right to treatment based on his or her autonomous decision-making ability does not supersede a company’s ethical responsibility to develop and market safe and effective products as fast as possible” so that a wider patient population can be treated.[9]
Take-Aways for Drugs and Biologics Developers
- Even in states with Right-to-Try measures signed into law, drug/biologic developers have no legal or regulatory obligation to provide unapproved treatments in response to compassionate use requests. [10]
- Establishing a company policy and guidelines for expanded access early on in drug/biologic development will prepare companies to respond to compassionate use requests and ensure that decisions denying early access are made impartially and fairly.[11]
- If feasible, policies that provide criteria for declining requests and consider each patient’s expected benefit vs. risk assessment may be more acceptable to patients and their advocates, than policies emphasizing resources or financial considerations.
- Companies may want to also consider setting up an Early Access Committee or hiring an independent IRB to assist with early access decisions–At least one large drug company, Johnson & Johnson, has responded to increasing pressure to provide early access to investigational drugs by setting up an independent panel to review requests for compassionate use and to recommend which treatments are ethically justified and medically supported.
- An Early Access Policy should take into account the risk that any adverse event resulting from compassionate use treatment could negatively impact clinical development and/or the timeline for development
- If responding to a request for early access, companies may want to work with FDA to minimize any impact to ongoing clinical trials, and to determine if the treatment falls under any of FDA’s subpart E regulations for expediting the availability of promising new therapies ( 21 CFR part 312, subpart E).
[1] Federal bills aimed at relaxing and/or providing greater transparency for FDA’s and/or drug manufacturers’ expanded access policies have also been introduced. See H.R. 909: Andrea Sloan Compassionate Use Reform and Enhancement Act; H.R. 790 Compassionate Freedom of Choice Act of 2015. H.R. 6: To Accelerate the Discovery, Development and Delivery of 21st Century Cures, and for other Purposes (Subtitle E: Expediting Patient Access).
[2] http://blogs.fda.gov/fdavoice/index.php/2015/02/a-big-step-to-help-the-patients-most-in-need/
[3] See http://www.raps.org/Regulatory-Focus/News/2015/02/04/21243/From-100-Hours-to-1-FDA-Dramatically-Simplifies-its-Compassionate-Use-Process/#
[4] Further evidence of FDA’s growing responsiveness to its patient constituency is demonstrated by FDA’s website posting in response to a social media campaign seeking expedited approval of Genervon’s GM604 drug for treating ALS. On April 17, 2015, FDA took the unprecedented step of posting a notice on its website stating that “FDA knows that ALS patients, their families and others in the ALS community are concerned about the status of Genervon’s experimental drug . . .” and asking Genervon to “to release all the data from their recently completed trial in order to allow a more informed discussion of the trial findings among ALS stakeholders.” http://www.fda.gov/Drugs/DrugSafety/ucm443242.htm. Commentators have noted that Genervon recently acknowledged that it has not yet filed a New Drug Application for GM604, which would be a necessary precursor for FDA to make decision whether to grant approval for the drug.
[5] See AB159, as amended. The amended version of AB159 provides that the treating physician’s recommendation or prescription is “approved by the physician’s institutional review board or an accredited institutional review board.”
[6] Chimerix had previously provided brincidofovir to more than 215 patients under an expanded access program, using government funding from Health and Human Service’s Biomedical Advanced Research and Development Authority (BARDA) to treat 215 critically ill patients to gain insights into the potential use of brincidofovir as a medical countermeasure against smallpox. However, when BARDA funding ended in 2012, Chimerix stopped accepting new requests for compassionate use. See Arthur Caplan and Kenneth Moch, Rescue Me: The Challenge Of Compassionate Use In The Social Media Era at http://healthaffairs.org/blog/2014/08/27/rescue-me-the-challenge-of-compassionate-use-in-the-social-media-era/. Kenneth Moch was CEO of Chimerix in early 2014.
[7] In September 2014 physicians treating two Ebola patients requested expanded access for Chimerix’s drug, based on Chimerix’s in vitro lab results indicating that brincidofovir had activity against the Ebola virus. Thomas Duncan, the first patient diagnosed with Ebola in the U.S., was already critically ill at the time of his treatment, and died despite receiving brincidofovir. The second patient, American journalist Ashoka Mukpo, recovered.
[8] Treatment of five of these patients is described in Ormonde et al, J Membrane Biol 2012; 245: 381-388.
[9] BIO, Early Access Programs: Points to Consider, at https://www.bio.org/sites/default/files/20100416.pdf
[10] Critics of “Right to Try” laws also note that the D.C. Circuit Court of Appeal rejected the argument that there is a constitutional right to an investigational drug, “a potentially toxic drug with no proven therapeutic benefit.” Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach, 495 F.3d 695 (D.C. Cir. 2007) (en banc), cert denied 552 U.S. 1159 (2008) (holding that hold that FDA’s policy of limiting access to investigational drugs was rationally related to the legitimate state interest of protecting patients, including the terminally ill, from potentially unsafe drugs with unknown therapeutic effects).
[11] H.R. 909, the Andrea Sloan CURE Act, would require each sponsor of an investigational drug to make public its policy on requests for expanded access, including the contact for receiving and processing requests, the procedures for making the requests, the general criteria used to evaluate the request, and the amount of time the sponsor anticipates will be needed to respond to such requests.