Harold Burstein, MD, PhD; Richard M. Klein


July 17, 2015

Editorial Collaboration

Medscape &

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Harold Burstein, MD, PhD: I'm Dr Harold Burstein, associate professor of medicine at Harvard Medical School and a medical oncologist in the Breast Oncology Center at Dana-Farber Cancer Institute in Boston. Welcome to this edition of Medscape Oncology Insights. We are coming to you from Chicago and the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO).

When our cancer patients exhaust the available treatment options, it's hard to know how to advise them. In the current era when there is a lot of exciting research going on, we want to know when it would be appropriate to consider investigational drugs and how people might access those drugs. One important strategy for that access is to consult the US Food and Drug Administration's (FDA's) Expanded Access Program. Here to talk about that today is Richard Klein, director of the Patient Liaison Program of the FDA.

What is the Expanded Access Program and how does it differ from standard-of-care treatment?

Richard M. Klein: Standard-of-care treatment is an approved drug that has gone through the complete clinical trial process, so we know that the drug is safe and effective in comparison with the risks associated with the underlying disease. An expanded access drug is an investigational drug that is still going through the process of clinical trials. Patients who cannot get into the clinical trial and who have exhausted or are intolerant of the approved therapies can sometimes access an investigational drug for treatment as opposed to research. They would not be in the research protocol; they would be in a separate protocol.

Dr Burstein: I want to work on the terms a little bit. This is not off-label use. Off-label use is when a drug already exists in the market but a clinician wants to use it for a different purpose.

Mr Klein: Exactly. Off-label use is an indication different from the one for which the drug was studied and approved.

What Makes a Patient Eligible?

Dr Burstein: When you are thinking about expanded access, does the patient under consideration have to meet all of the eligibility criteria that would have been articulated in a clinical trial?

Mr Klein: No, and that is one of the big differences. There are certain criteria, one of which is that the drug is available. A company needs to be willing and able to provide that drug to patients outside of the clinical trial. Patients need to have a serious or life-threatening illness, and cancer would be a qualifying condition.

One of FDA's concerns is to ensure that the Expanded Access Program doesn't negatively affect the development program. We don't want these drugs to be given to people such that it would compromise people enrolling in the clinical trial and providing the data that are necessary to bring that drug to market.

Dr Burstein: If you had a drug for second-line colorectal cancer, for example, and a patient had already received third-line and fourth-line treatment, that patient could still be considered for expanded access? That might be possible even though the patient didn't match up in eligibility for the registrational study?

Mr Klein: Correct, because the studies try to enrich the population with people who are specific to what they are looking for, whereas expanded access would encompass people who couldn't get into the trial.

Dr Burstein: You mentioned that you needed to partner with pharmaceutical companies to make this happen. Who contacts the pharmaceutical company? How do they communicate that they will make the drug available for expanded access?

Mr Klein: There are different levels of expanded access. There are some very large programs in which hundreds to thousands of people would have access outside of the clinical trial. Generally, the company sponsors that program and makes that information available through clinicaltrials.gov.

Dr Burstein: Presumably the company is pretty confident that they are going to get an approval on the basis of whatever the data are, and they are gearing up to market the drug.

Mr Klein: Right. Generally, a large expanded access program occurs later in the clinical trial process, when there are already some interesting and positive results that suggest efficacy, plus a lot of safety data.

The doctor can contact the company and see whether the company is willing and able to provide that drug to the patient.

But there is another pathway for expanded access, and that is patients talking to their doctors. The doctor can contact the company and see whether the company is willing and able to provide that drug to the patient. If that's the case, the doctor generally would contact the FDA, talk to the review division (in this case, oncology), and receive a go-ahead to use that drug.

Dr Burstein: The company doesn't have to make a blanket statement that they are now offering expanded access. You can initiate that process without the company having made a broad public statement about it.

Mr Klein: Exactly. If a company is willing to obtain expanded access, they might put a statement on clinicaltrials.gov. But if they don't, it doesn't mean that they aren't willing to provide the drug. Quite a few people make these requests of companies, and companies often say yes.

Getting Access: The Steps

Dr Burstein: Let's walk through the steps that a clinical team and patient might need to take to get into an expanded access situation. Immunologic therapies are the hot tickets at this year's ASCO meeting. Let's say that a new immunologic drug that has shown promising activity with a survival benefit in a phase 3 study was included in a plenary talk at ASCO, but it's not commercially available yet. You are back home next week, and a patient in your office who has read the coverage in The New York Times asks, "How might I get access to that drug?" The doctor thinks it would be a good thing to try. What has to happen next?

Mr Klein: The doctor would contact the company, and if the company says yes, the doctor would file an application with the FDA. The application at the moment is Form 1571, which asks for certain information, including the initials of the patient (we don't ask for the name because of confidentiality), the condition being treated, a very short medical history of the patient to see what has already been tried and failed, and the proposed protocol—what drug the doctor wants to use and the dose. Immune therapies have significant side effects and toxicities, so any mitigation plans to be included in the protocol should be indicated on the form. We also need the doctor's credentials, including his or her CV, to show that the doctor is credentialed and able to oversee this patient's treatment.

The doctor would certify that he or she will have an institutional review board (IRB) and informed consent before the treatment begins. The IRB would look at the informed consent to make sure that the patient understands it is still an investigational drug, that there are still unknown risks, and that the benefits are not confirmed. Finally, we need the contact information for the doctor.

Dr Burstein: When you say "protocol," you don't mean a 400-page phase 1 protocol; you mean a statement that says, "I plan to treat Mrs Jones with this drug at 200 mg/m2 every 2 weeks as was done in a recent study, and continue until progression or intolerability of the drug."

Mr Klein: Exactly—it's a very short treatment protocol.

Dr Burstein: You mentioned that the doctor has to contact the company. That isn't something that most doctors do every day. Is that done through the medical liaisons in the field? In general, how does one go about reaching these companies?

Mr Klein: I'm in the office of Health and Constituent Affairs at the FDA, and we recommend that physicians call the regulatory affairs person at the company.

Dr Burstein: You also mentioned an IRB review, so that's part of this process as well.

Mr Klein: Right, because it's an investigational product.

Dr Burstein: What's the difference between this request and an individual investigational new drug (IND) application?

Mr. Klein: It's the same thing. It's called an individual patient IND.

Dr Burstein: We have a patient, we call the regulatory affairs office at a big pharmaceutical or small biotech company, and they have said, "Yes, we are willing to do this." Do they need to send a letter to that effect to your office?

Mr Klein: Part of the application is a letter of authorization, because part of any IND is what we call "chemistry manufacturing controls." These are designed to make sure that the agency can look at the manufacturing and the quality assurance, to ensure that the drug was produced under good manufacturing processes. They would obviously not give the formulation to the doctor, but it's included in the original IND that the company has filed with FDA. It gives FDA authorization to cross-reference all of the information in that original IND file.

Dr Burstein: Does the manufacturer speak to your office directly, or does that communication go to the clinician's office as part of the submission package?

Mr Klein: The company [most likely the regulatory affairs person] talks to the doctor. The doctor gets the okay from the company and then the FDA assigns a new IND number. Once the doctor has the IND number, he or she calls the company and the company can ship under that IND.

Dr Burstein: They would send the investigational supply to the physician's office?

Mr Klein: Yes.

How Fast Is the Process?

Dr Burstein: There are many layers to this. How long, in your recent experience, does it actually take—both for the clinical team to fill out the paperwork and then for the whole thing to lead to delivery of the drug? Does this take months? What kind of timeframe are we talking about?

Mr Klein: Depending on the complexity and where in the process of study this drug is, it can take anywhere from hours to days. The agency officially has 30 days to review any IND application, so the agency has up to 30 days, after which the drug can be used.

Dr Burstein: If there is no decision in 30 days, do you get that drug anyway?

These applications are given very high priority.

Mr Klein: Right, but it never gets to that point because generally, within a couple of days, the agency calls the doctor with the decision. These applications are given very high priority because these people are depending on these drugs.

Dr Burstein: What is the obligation of the clinical team in the way of reporting any side effects or administration issues?

Mr Klein: Ideally, the clinician should be reporting some summary outcome data. If there are severe, significant, and unexpected side effects, they should be reported to the agency. A lot of people think that if there is an expanded-access program, any significant side effects are going to influence the development of the drug. However, the people at FDA are very aware that, by definition, the patients getting expanded access are not the clinical trial population. These patients have insufficiencies in hepatic or kidney function; they are probably dealing with multiple medications and possibly have other diseases. Therefore, if something goes wrong, unless there is a definitive connection—a causal relationship to the drug—FDA will not look at that as part of the clinical trial.

Dr Burstein: And pharmaceutical companies understand this. They understand that if they are giving expanded access, the FDA is not going to hold that against them when it comes time to file their major results for a possible regulatory approval.

New and Improved Expanded Access Form

Dr Burstein: I gather that form 1571 has been streamlined and that a new form will be coming.

Mr Klein: Right. We now have the draft form 3926. The 3926 is essentially a distilled form of the 1571, because even though the same information is required, the 1571 has many fields for other purposes that people who are clinicians (and not researchers) are not familiar with. So we modified the form to contain only the eight elements that are required for this application.

Dr Burstein: Is that going to roll out soon?

Mr Klein: It has already rolled out for comment. The comment period has closed. We are going through the comments now and hope to get this finalized. The problem is that because it's a form and it asks for information, it has to go through the Office of Management and Budget to get an OMB number. It is very close to being finalized.

Dr Burstein: In the medical community, this process is often perceived as crazy, laborious, and complicated. But my general sense is that within FDA, although you acknowledge that some steps have to be taken, this is designed to be very streamlined. You are guaranteeing a fairly rapid turnaround, and it sounds as though most reasonable cases are being granted. Is that a fair summary?

Mr Klein: I think so. At FDA, the issue is confidence in safety more than expectation of or confidence in efficacy, because the agency is looking out to be sure that people are not being put at undue risk by taking these investigational drugs. Hopefully they will be helpful and useful.

In 2009, we began to look at the data on how many applications came in and how many were granted. Of all the expanded access requests (I don't have numbers specific to cancer), an average of 99.4% are allowed to go forward. The other 0.6% are safety issues. There might be a clinical hold and there might be manufacturing questions or issues, but that is a very small percentage.

Of all the expanded access requests...
99.4% are allowed
to go forward.

Dr Burstein: The Right to Try movement has been interested in expanded access. Can you describe what that dialogue has been about and how this FDA reform addresses some of their concerns?

Mr Klein: Right to Try is state legislation that allows people in certain states to bypass the FDA process. You still have to go through the company. There is no FDA or state authority to compel a company to provide a drug. There is a lot of controversy about whether they improve expanded access. People believe that expanded access is a very burdensome, prolonged process and that right-to-try laws would be a way to get around it. But when people look at the numbers, they are convinced that it's not such a burdensome or long-winded process.

Dr. Burstein: A 99% success rate is pretty good.

Mr Klein: And 99.4% is slightly better.

Expanded Access vs Off-Label Use

Dr Burstein: In the current era in oncology, we are often doing molecular profiling of tumors. I had a patient last week in whom we did genetic sequencing and found that she had a mutation in her breast cancer in the TSC locus, which is a marker that, in some studies, contributes to sensitivity to mTOR inhibition.[1,2] I want to use an mTOR inhibitor, which is an FDA-approved product, but she doesn't meet the FDA approval criteria. Is that expanded access or is that just off-label use that doesn't come under this rubric?

Mr Klein: It would not come under expanded access because the drug is already available on the open market. FDA regulates the product but we don't regulate the practice of medicine, and that example falls under practice of medicine.

Dr Burstein: Could you get this off-label drug by expanded access? Because a common retort that we get from patients is that their insurance company might not cover it because it's off-label.

Mr Klein: There is the rub, because FDA puts it on the market in the population it's studied in and for the indication for which it has been studied. A doctor is free to use it somewhere else, but a lot of insurance companies will balk because the prices are generally very high. Some people challenge the insurance companies and some insurance companies ultimately pay for it, while others decide against it.

Dr Burstein: We're at ASCO again. There is a lot of excitement about the new drugs here at ASCO, and there is a general feeling that there are more interesting ways to get drugs approved. We are seeing approvals on the basis of single-arm phase 2 trials; we are seeing randomized phase 2 trials lead to approval; we are seeing accelerated approvals. How is FDA responding to the innovation that is happening right now in cancer?

Mr Klein: Drugs are being approved faster in smaller study populations because the drugs are more effective. When you have a home-run result, it doesn't take a long time to see that progression has stopped, that people are doing better and living longer. Progression-free survival on a particular drug is so much easier to determine when you have a very effective drug.

People at FDA want to encourage companies to provide expanded access when a drug shows promise and is at a late stage of development, so that people who can't wait for the final approval have access to the drug.

Dr Burstein: It's very important, because we see this every day in clinic: patients who might benefit from some of these drugs, but the drugs are 6, 8, or 12 months away from approval.

Thank you so much, Richard, for talking to us about FDA and expanded access. It has been a great primer on how to do it, and it reminds people that it's a very doable task for patients who need it.

Thank you for joining us. I'm Harold Burstein, reporting from ASCO 2015. I have been with Richard Klein, the Patient Liaison Director at FDA, talking about expanded access to innovative drugs for patients with cancer.