Important steps toward streamlining access to investigational drugs for patients in need

By: Richard A. Moscicki, M.D.

FDA is only too aware that there are many patients who have a serious or life-threatening medical condition for which there is no available FDA-approved therapy. For such patients, one option may be to obtain access to an investigational drug that has not yet been approved by FDA. To do this, a physician submits an application to the FDA requesting authorization to use the investigational drug in the treatment of their patient. This is called expanded access to investigational drugs.

Dr. Richard MoscickiWhile FDA has been helping physicians navigate the system for many years, we are aware there have been physician and patient concerns about this process, which can be time consuming and difficult to understand. Consequently, FDA has recently made significant changes to streamline and simplify the process for single patient expanded access requests.

To make the expanded access process more efficient, we’ve just introduced a much simpler application form called the Form FDA 3926, which will be the form doctors now will typically fill out when they want to provide an investigational drug for a patient through expanded access. While the Form 1571 had 26 information fields and seven attachments, the new Form 3926 has fewer fields (11) and only one attachment. With this streamlined format, we estimate that physicians will be able to complete the form in just 45 minutes, as compared to the more difficult and time consuming effort required previously.

Also, as part of our commitment to streamlining the expanded access process, on May 16, 2016, the FDA and the Reagan-Udall Foundation held a meeting with interested stakeholders to explore additional options that might help patients and their physicians understand the process to request access to unapproved drugs. A common theme of the meeting was that navigating the expanded access process really does take a village. The physician, the drug company, FDA, and the institutional review board (IRB) all have important roles and must work together for the expanded access process to succeed.

The FDA and Reagan-Udall Foundation convened this forum to listen to the public express their needs about expanded access and to discuss ideas with stakeholders on ways that the complex process can be made more efficient and effective. Much work on the details remains, but in general there was agreement on the need for a central repository or clearinghouse where useful and relevant information could be stored in one place — a sort of “one-stop-shop” for physicians and patients to seek information about the expanded access process. As our thinking about this resource develops, we’ll keep the public informed.

For physicians seeking more information about expanded access to an investigational drug, we have developed an educational webinar to help them become familiar with the new application form. This live webinar will occur on July 12 at 1:00 PM EDT and will offer one hour of Continuing Education (CE) credit. The webinar will be recorded for viewing without CE credit. We also have released a guidance regarding Form FDA 3926, a guidance with Questions and Answers on expanded access, as well as a guidance directed at industry addressing questions regarding charging for investigational drugs.

Expanded access is designed for seriously ill patients who have exhausted other options.  The last thing a patient suffering from a serious or life-threatening condition needs is red tape. For many years, FDA has dedicated staff to assist physicians and patients in navigating our system. We expect these important steps will help us continue our efforts to serve patients in need and to advance public health.

Richard A. Moscicki, M.D., is FDA’s Deputy Center Director for Science Operations, Center for Drug Evaluation and Research

Offering Hope: How FDA Engages With the Cancer Community

By: Deborah Miller, Ph.D., M.P.H., R.N.

Deborah Miller, Ph.D., M.P.H., R.N.It’s October and the pink ribbons representing breast cancer awareness month are again a common sighting. These ribbons are reminders that breast cancer is still to be overcome. Breast cancer remains the most common cancer among American women, except for skin cancers. Just about everyone knows someone affected by cancer in general, and many have been touched by breast cancer in some way.

For many years, I worked at the Government Accountability Office (GAO), where I became familiar with FDA. I joined FDA’s Office of Special Health Issues (OSHI) in September 2008 because I wanted to be involved more directly with patients again after working for years during my earlier career with seriously ill patients and their families as a neonatal nurse, research nurse, and hospice volunteer.

Like a lot of people, I have experience with cancer – personal, family members, and friends. As the manager of OSHI’s Cancer Liaison Program, I’ve had many experiences that have enhanced my compassion, respect, and patience as I strive to explain FDA’s role in medical product development and regulation to patients with breast and other cancers.

FDA’s Cancer Liaison Program interacts with many cancer patients and family members asking for help. The program seeks to meet the needs of patients and their families in three basic ways. Listening, educating, and assisting.

First and foremost, we listen to patients and caregivers. They tell us their story – when they were diagnosed, treatments they have tried, providers they have seen, and tests they have been through. Often, they tell us they’re scared.

Some of these patients have been dealing with cancer for a number of years, and they tell us that the approved therapies have not worked or have stopped working. Some have considered or joined a clinical trial of an investigational therapy. Some call with the hope of obtaining a “promising” new investigational product that they have heard about in the news and are convinced may be their last hope.

Secondly, we educate. We spend a significant amount of time explaining to patients and family members how cancer drug development, clinical trials, and expanded access, (known in the community as compassionate use) work. We explain FDA’s role, and what we can and cannot do for patients, and try to guide patients toward practical and appropriate options.

We help bridge the gap between patients, their treating physicians, and FDA scientists who are working to review and approve new treatment options for patients. We strive to provide a human touch for each patient or family member with whom we interact.

Finally, we assist the patients. For example, we try to find potential clinical trials for them, guide them through the expanded access process when it’s appropriate, and work with their healthcare providers throughout the expanded access application process. We give patients, family members, and healthcare providers our contact information so they can reach us to work through regulatory issues at any time, including evenings and weekends.  We periodically call them to see how they’re doing.

And if access to investigational drugs is not practical, we go back to listening. We listen to patients’ expressions of their disappointment, anger, frustration, and fears.

This month, I am thinking about the many breast cancer patients I worked with during this past year who benefited from FDA’s approval of Perjecta in June. But I am equally mindful of the many other patients who did not benefit from the drug and will be calling me, desperately searching for something more.

Deborah Miller, Ph.D., M.P.H., R.N., is the manager of the Cancer Liaison Program in FDA’s Office of Special Health Issues

Additional Protections for Children Who Participate in Clinical Research

By: Robert “Skip” Nelson, M.D., Ph.D.

Parents and guardians of seriously ill children often face difficult decisions about their child’s medical care. As a physician practicing for about 20 years in a pediatric intensive care unit, I knew that many of the interventions I used, while potentially life-saving, had no guarantee of success and carried a risk of significant harm or even death.

Robert "Skip" Nelson, MD PhD When faced with a life-threatening disease for which there are few good options, parents sometimes want to try a promising drug that is still under development. I have lived through this situation with parents many times, both in the intensive care unit and as a medical ethicist. Some parents see the drug as a lifeline where none had existed before. It is a natural instinct for parents to want to leave no stone unturned.

Many of the drugs that we use in children have not been approved by FDA for that use, and may not have been studied at all in children. They are available on the market because they have been studied and approved for use in adults, but not necessarily for the same disease for which they might be used in children. There are data available in adults describing the risks, benefits and side effects of drugs already in the marketplace. This information may reassure us a bit about the potential effects of a drug in children. But when that same drug is studied in children, we often discover that we should have been using a different dose, that the drug does not work, or that children may experience a concerning side effect.

The lack of information about the likely effects of a drug in children is more of a problem when the drug hasn’t yet been approved for any use. Most drugs in the early phases of drug development fail, either because they are ineffective in humans, or because of unacceptable side effects. So while it may be tempting to want to try any experimental drug in children with a life-threatening disease, we must be cautious.

Recently, my colleague Richard Pazdur shared his insight into the FDA “expanded access” regulations that allow patients with serious and life-threatening diseases or conditions access to investigational drugs outside of clinical trials. There are two important values at stake when considering expanded access in children. We want to do everything we can to restore a child to health, but we also want to protect that child, and other current and future children from ineffective, and potentially dangerous, interventions.

Physicians can apply for expanded access use for a patient by submitting certain medical information about the patient and important scientific and clinical information about the drug and its intended use to FDA. FDA then reviews this information and determines whether certain important criteria are met. These safeguards are in place to avoid exposing patients to unnecessary risks. Even if FDA determines that an expanded access request may go forward, the company manufacturing the drug has to be willing to supply it.

In implementing its expanded access regulations, FDA tries to strike a balance between two social goods: treating an individual child and demonstrating that a medical product is safe and effective. Children with a serious or immediately life-threatening disease for which there is no comparable or satisfactory alternative therapy are able to have access to investigational agents outside of a clinical trial. However, there must be some evidence that the potential benefit to the child justifies the risks of the treatment and that those risks are not unreasonable in the context of the disease to be treated. Providing the investigational drug must not interfere with the ability to initiate, conduct or complete a clinical trial of that drug that could be used to support its marketing approval for the disease. Otherwise, we would never collect the essential data needed to establish that the drug is truly safe and effective for that use, or whether one child’s seemingly miraculous response was the result of the drug or of something else.

FDA strongly supports the inclusion of children in FDA-regulated clinical trials, provided the trials are conducted in an ethical and scientifically sound manner. For the past 15 years, FDA has been actively involved in initiatives aimed at improving medical product research in children (including under the legislative mandates provided by the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act). Children must be protected from exploitation and exposure to unnecessary risks related to their inclusion in clinical research, and from the unwarranted use of investigational drugs outside of a clinical trial.

I am often asked about FDA’s role in protecting children who are receiving experimental treatments and who are participating in clinical trials. FDA’s regulations provide for specific additional protections to help ensure that children who participate in research are involved in ways that protect the children’s rights, safety, and welfare.  Protections include, for example, review of research by an Institutional Review Board (IRB) supplemented by pediatric expertise as appropriate. The risks posed by research interventions must be low if the interventions are done for the sake of knowledge rather than for the child’s medical benefit. For higher risk interventions, the intervention must offer the child a sufficient prospect of direct medical benefit to justify the potential risks. Investigators must also obtain permission from the child’s parent(s) or guardian(s), and in most clinical trials must obtain each child’s assent when the child is developmentally capable of providing it.

My heart goes out to those parents of children with a life-threatening disease for whom there are no satisfactory treatments. My personal belief is that responsible clinicians and investigators caring for critically ill children, parents, and FDA can work together to find the right path forward for our present and future children. 

Robert “Skip” Nelson, M.D., Ph.D., is Senior Pediatric Ethicist in FDA’s Office of Pediatric Therapeutics

Remembering Krebiozen: Why We Have Access to Unapproved Drugs and Why We Need Scientific Evidence

By: Richard Pazdur, M.D.

I was in the third grade in the early 1960’s when my mother hung up the receiver of our old rotary dial telephone on the kitchen wall and broke down in tears. Dorothy, the mother of my close friend Fred, had just died of breast cancer. Dorothy and my mother worked together on various PTA and Cub Scout projects at my elementary school in Calumet City, a southeast suburb of Chicago. When my mother ended the phone call, she lamented “if only she received Krebiozen.”

Richard Pazdur, M.D.Dorothy was a proud, tall woman with jet black hair, wearing it upswept in a bun, and always appearing with bright red lipstick. She had undergone all the medical therapies available in the early 1960’s for advanced breast cancer, which would appear primitive in the light of today’s advances – including the now infamous Halsted radical mastectomy, large doses of searing cobalt radiation therapy, and surgery to remove her ovaries and adrenal glands to control painful bone metastases.

In discussing Krebiozen years later with my mother, she noted that Dorothy had received chemotherapy drugs. The doctors “had just given up on her” since the drugs didn’t work and there was “nothing else to do and that’s why she wanted to try Krebiozen.”

In the late 1950’s and early 1960’s, Krebiozen was touted as an active drug for cancer, especially in Chicago. The drug, initially developed from the blood of horses that had been injected with bacteria, was touted in written articles by a University of Illinois researcher extolling its benefits as an anti-cancer drug. Dozens of patients provided testimonials about the drug’s benefits to local media. My mother heard these accounts and desperately wanted my friend’s mother to have access to this promising, yet unproven drug: “she’s a young mother and is leaving behind two small children.”

Years later, I still frequently recall this story and its lessons. Patients with cancer, especially those who have exhausted currently available treatment options, and their friends and families search for a drug, possibly a drug that is not yet FDA-approved, and are willing to “take chances” in the hope that it may work. However, access to unapproved drugs needs to be balanced with both the protection of patients against a drug that may ultimately prove to be ineffective, and the need for clinical trials. These trials will demonstrate the drug’s safety and efficacy, ensuring a foundation for the drug’s use for future patients.

In 1987, the FDA first established rules that allowed patients with serious and life-threatening diseases access to investigational drugs outside of clinical trials, even though the safety and effectiveness of the drug has not been fully established. In August 2009 FDA changed its rules to clarify and broaden them for patients and treating physicians.  This is often referred to as “expanded access.”

Expanded access refers to the use of an investigational drug when the primary purpose is to treat a patient rather than to obtain information about the drug that is generally derived from clinical trials. There are different types of expanded access programs, ranging from single patient access to those providing access to hundreds or even thousands of patients. Information regarding the unapproved drug’s safety and efficacy required for use in a single patient is far less than information for trials that might provide access to hundreds of patients.

Some patients, who have not received standard therapies, especially if those therapies have been shown to improve survival, may not be candidates to receive unapproved drugs through an expanded access program. FDA has coordinated educational efforts with the American Society of Clinical Oncology (ASCO) to educate health care professionals and patients regarding appropriate patients for expanded access programs, as well as procedures to obtain expanded access to unapproved drugs.

Patients and healthcare providers seeking expanded access to unapproved drugs need to understand that drug companies must agree to provide these drugs to patients. FDA cannot mandate or require a drug company to provide an unapproved drug to patients. In fact, FDA oncologists have agreed with patients and their physicians that an unapproved drug could be used, only to find later that a drug company is unwilling to provide the drug. 

There are a variety of explanations that drug companies have offered for not providing patients expanded access to promising, yet unapproved drugs. These include cost, the perception that this access would interfere with the drug’s development and approval, or simply “corporate policy.” Other issues may be more opaque and involve manufacturing problems that companies may be unwilling to disclose and FDA cannot publicly comment on, in the context of an unapproved drug. 

In June, ASCO will be holding its annual conference and many abstracts will probably provide preliminary data on breakthrough drugs for patients with limited treatment options. Many patients will believe they cannot wait for the drug’s further development or its approval. FDA has provided clear guidance on the appropriate avenues to access promising, yet unapproved drugs; however, the success of these programs depends on the alignment of the FDA, an informed patient and healthcare provider, and ultimately, a willing drug company. 

Whatever happened to Krebiozen? A 1973 review by an independent committee of 24 scientists of over 500 “best cases” found it had no anti-cancer activity. The NCI director at the time noted “….from a scientific standpoint we regard the case closed.”

Richard Pazdur, M.D., is the Director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research