Pharma, HCPs, and regulators walk tightrope in addressing early-access push while supporting biomedical R&D.
A national publicity campaign recently succeeded in obtaining early access to an experimental treatment for a seriously ill child, touching off a broader discussion of compassionate use policies and their impact on drug development and approval. As 7-year-old cancer patient Josh Hardy gained relief from a life-threatening infection following a bone marrow transplant, thanks to Chimerix's promising new antiviral drug brincidofovir, hundreds of patients turned to the Internet and social media to intensify pressure for similar compassionate access. The trend demonstrates the need for sponsors, health professionals and government regulators to find new ways to handle these difficult requests, while also supporting clinical research and biomedical R&D.
Biopharmaceutical companies receive dozens of requests for early access to promising therapies, but often turn them down. Clinical supplies usually are very limited, often just enough to conduct a study. Production costs for biologics are high, particularly for small firms struggling to finance complex research programs.
Moreover, sponsors fear that adverse events with patient populations outside a clinical trial could delay development and approval. And expanded access can interfere with clinical trial accrual; if patients can obtain treatment outside a regulated study, they won't want to enroll in a trial where they risk getting a placebo or a less effective comparator drug.
The social media phenomena raises serious ethical issues about whether hard decisions about who gets access to scarce therapies should be made on the basis of catchy publicity campaigns and political pressure—as opposed to who is most seriously ill and who is most likely to respond to treatment. Some consider lotteries or independent third parties as fairer ways to decide how to distribute a scarce, highly valuable resource. The prime ethical obligation of biotech companies, says the Biotechnology Industry Organization (BIO), is to develop safe and effective drugs as quickly as possible so that broad patient populations can benefit. Diversion of resources to deal with individual access requests can delay development and stymie efforts to achieve equitable distribution of limited supplies.
FDA's process for facilitating expanded access requests is a prime focus of reformers. The agency permits clinical trial sponsors to amend an investigational new drug application (IND) to grant patients access to experimental drugs for treatment purposes. Patients can't apply for such access; the request has to come from the sponsor, physician investigator, or a qualified treating physician, either for a single patient or a small group (up to 100 patients). The expanded access IND requires evidence that the individual(s) have serious or life-threatening conditions, do not qualify to participate in a clinical trial, have no other treatment options available, and that potential benefits are likely to outweigh possible risks.
Details on the process are provided on FDA's website and in a May 2013 Q&A guidance on expanded access to investigational drugs for treatment use. Jim Robinson, president of Astellas US, would like to see additional guidance on criteria for vetting requests for compassionate use, noting that demands for early access will only increase with some 3,000 drugs in development for cancer and other serious conditions.
FDA's Office of Health and Constituent Affairs, which provides information to health professionals and patients on expanded access policies and procedures, reports that the agency receives about 1,000 expanded access INDs and access protocols each year and approves virtually all of them. The vetting process includes review by an institutional review board (IRB) to ensure adequate informed consent, and by the relevant new drug review division.
FDA officials sometimes convey patient requests to pharmaceutical companies and offer assistance to willing firms and physicians in filing necessary information and navigating the application process, explains Patient Liaison Program director Richard Klein. Because the purpose of these programs is treatment, and not research, sponsors don't have to submit efficacy data from an expanded access study, but must report serious adverse events.
While FDA permits sponsors to charge patients for the cost of drugs provided under compassionate use, this provision is seldom used. Companies usually prefer to keep confidential information on production processes and costs, and limited supply is a larger concern than gaining revenue.
FDA's desire for flexibility can be seen in its handling of the Chimerix case. Amidst the public demand for access to brincidofovir for Josh Hardy, FDA worked with Chimerix to approve a 20-patient open-label clinical trial for treatment of adenovirus infection in immunocompromised pediatric patients. The company thus avoided a massive open-access program, and gained a strategy that it hopes will lead to a Phase III trial for this indication. Meanwhile, Chimerix is continuing its main development program (under new company leadership), which seeks accelerated approval of the drug for prevention of the more common cytomegalovirus (CMV) infection in adult bone marrow transplant patients. Chimerix launched its Phase III SUPPRESS trial last year at 40 transplant centers, with an eye to enrolling 450 patients, 150 receiving placebo; initial results are expected by mid-2015.
Although FDA and the sponsor addressed this compassionate use case successfully, there's continued pressure for new approaches. A bill before Congress would permit the manufacture, importation, and distribution of unapproved investigational products to terminally ill patients. State legislatures are considering "right to try" bills, as seen in an Arizona measure that permits physicians to prescribe investigational drugs for certain terminally ill patients. Such proposals raise constitutional questions about the right of states to challenge federal drug approval policies, an issue central to past lawsuits challenging FDA interference in patient treatment.
Faster approval of important new medicines could address some early-access concerns, a goal for regulators and sponsors alike. FDA held a public hearing in February 2013 on strategies for improving the accelerated approval process and whether FDA needs additional tools and authority to move promising therapies through the regulatory process—issues that will be explored further.
Jill Wechsler is Pharm Exec's Washington correspondent. She can be reached at firstname.lastname@example.org.