Picking up the Pace
Safety Assessment
Lauren Black

Picking up the Pace

The Ebola outbreak has been shining a very bright light on accelerated drug development. Charles’ River’s resident FDA expert Lauren Black explains how the process works and why it’s important.

In recent months, US regulators have mounted what may seem like an unprecedented campaign to accelerate experimental drugs and vaccines for Ebola. But it was a far worse public health crisis that prompted the Food and Drug Administration (FDA), more than two decades ago, to focus on ways of expediting the drug development process in urgent situations. The agency's efforts back then ushered in one of the most successful chapters in antiviral drug history.

Today, it's not all that unusual for the developers of novel treatments for orphan diseases or advanced cancers or global outbreaks to seek waivers from the FDA that might expedite the preclinical/clinical process. Lauren Black, a senior scientific advisor at Charles River and an expert on FDA regulation, has a unique perspective and extensive experience on how the Investigational New Drug (IND) process works. She addresses for Eureka readers some of the leading questions pertaining to drug acceleration in the following Q&A.

Under what circumstances do drug candidate get accelerated by the FDA and how does the process work?

Before drugs advance to the clinical process, they must demonstrate in the preclinical process that they are safe and effective. Acceleration is really a matter of public health and public need. The US Food and Drug Administration (FDA) accelerate certain aspects of clinical work on a case by case basis.

With that said, when drug developers reach the First in Human (Clinical Trials) / IND approval stage US regulators will sometimes grant shortcuts that allow clinical studies to start up faster and with fewer animal studies than are usually required. These decisions are generally made by the FDA in cases of extreme or unmet medical need, such as the Ebola crisis in West Africa where there are no approved drugs to fight a disease that has infected well over over 11,000 people since the outbreak surfaced in March, and which carries a case-fatality rate of around 50%. Drugs for rare orphan diseases, late-stage cancers or end-stage renal disease would be other therapeutic examples where the FDA might decide to accelerate the IND approval process.

In addition to this, there are also certain IND regulatory pathways in the U.S. as well as in the European Union and the UK that allow more limited preclinical data and fast starts in a limited patient set. For instance, under the FDA's expanded access program (otherwise referred to as compassionate use) the Canadian company Tekmira was granted permission to provide its Ebola drug, TKM-Ebola, to a limited segment of patients. These patients have included Rick Sacra, a Boston obstetrician who contracted Ebola working in West Africa and was later flown to a Nebraska hospital for treatment. Expanded access allows a company with an experimental product to either create a new clinical trial for a patient through the use of an IND application or to add new types of participants by amending the protocol. The FDA is considering these individuals receiving the Ebola treatments as part of the clinical trial process.

It's important to remember, however, that "acceleration" at the IND stage still means both in vitro and animal studies are done, and activity and toxicology evaluated prior to the start of human trials. The US and most developed countries have strong ethical standards, and follow international agreements and laws that frame the basis for doing safety studies in animals prior to dosing in humans. It also should be pointed out that hastening the testing of a drug in the clinic to address an unmet medical need doesn't also equal accelerated development. For instance, if you have a dearth of solid toxicological data from your preclinical studies, the FDA might require you to test your drug on one patient at a time and report each patient's data to the FDA before proceeding to the next patient. This obviously takes a lot longer than testing multiple patients at one time.

How many drug candidates get accelerated by the FDA annually?

Though there is significant interest in drug development for unmet medical conditions, the exact number of drugs that the FDA accelerates is hard to pin down. Both small biotechs and large pharmaceutical companies have invested in developing drugs for novel therapies. All companies are looking to accelerate their drug development programs but the FDA makes the final decision on a case by case basis based on public health need.

Our role at Charles River, as a development partner, is to work with companies to hone their research and translational studies, aiming for just enough data to get them into the FIH trials as fast as possible. But with a long term aim, we also provide them with plans on how to avoid later slowdowns—staging nonclinical studies out in time so they can keep the clinical ball rolling. We employ highly experienced ex-pharma and ex-FDA scientists to advise our customers on the scientific design options available to them. Our scientists have served on project teams and know the spectrum of business and patient risk concerns.

What circumstances drive drug acceleration at the FDA?

The FDA's main criteria really come down to the risks and benefits to patients. FDA judgment is based on similar drugs that have come through their hands, of course, but more specifically they consider certain factors before making a decision to waive certain preclinical studies. For instance, they probably have seen data from a number of similar products in terms of chemistry, makeup, or target. So they have some sense of the likely risks of the product type. The FDA also has specialist clinicians on every drug review team, and these experts know the urgency of the medical need and the risks of the current standard of care.

So when there is a lethal disease that might affect millions of people, like Ebola, the FDA should be in a position to weigh all factors before deciding what preclinical data is enough to justify a clinical trial, how many patients are needed to assess in a Phase I safety study, and how carefully they have to proceed in humans. The variety of factors at play in every clinical scenario greatly affects the amount of risk mitigation used for preclinical work and clinical trials.

For instance, the perceived risks of the new biologics treatments for Ebola, like the monoclonal antibody therapy ZMAPP or the anti-Ebola serum from survivors, are much less than the disease. This is because biologic agents have been reasonably well tolerated in the past. When the risks seem far less than the risk of spreading a lethal infection, it's understandable that all brakes are off.

On the other hand, chemical or small molecule synthetics and antiviral synthetic agents are considered a higher risk than biologics, and so typically adhere to more standard approaches. Antiviral agents, for instance, have been associated with off-target toxicities to liver, kidney, and the immune system in the past since many of them are directed at enzymes or DNA in the virus that may have similarities to human cells.

Do CROs know when a drug candidate goes directly from its labs to a patient?

It depends on how much the sponsors share their plans. Optimally, our scientists are kept up to speed with key program milestones—we often know when the IND filing is because the GLP toxicology is often the last part of the initial IND package, and we are told when the report has to be ready. More broadly, we can look across the industry and look at approved drugs and those that have been studied in our labs.

We promote a fully collaborative model and we're best used when drug sponsors tell us about their clinical plan, so we can help them design the best preclinical plan. When they involve us in teams, we often do hear back about the IND outcomes, and often are involved in the whole program of subsequent studies throughout development; we cultivate a team approach and a parallel group consisting of a bioanalyst, toxicologist and pathologist assigned throughout the studies.

What special/additional studies need to be conducted at the preclinical stage in order for a drug to go directly to humans?

This varies from drug to drug based on the chemical nature and special concerns with the drug, formulation or route of dosing. For instance, if a drug acts only on a disease state, and has no known actions in normal animals, you may have to design and conduct a special study in an animal model of disease, such as a syngeneic model where the tumors that are implanted are genetically similar to the host. Or you might have to study mouse-specific drugs in the mouse to simulate human drug impact in the cancer patient. There is a lot of creativity in science when it comes to novel agents.

Safety pharmacology is an important issue to consider for most drugs, though different methods may be used, either built into ongoing normal toxicology, or conducted in tandem. For instance, safety pharmacology has been a key aspect of risk assessment for drugs that mimic DNA chemistry. These drugs have synthetic changes that have been shown to cause shock. TKM-Ebola and others in its class are structurally similar to these drugs, and therefore are carefully evaluated for these risks as well.

Has the current Ebola crisis provided the most dramatic example of rapid acceleration?

Actually, no. During the early days of the AIDS epidemic in the US, the Division of Antiviral Products (DAVP) was created to address the need for acceleration. Their mandate was to help sponsor and develop AIDS drugs as fast as possible. The fastest drug to market was AZT, which was approved in 1987, but the most novel ones and the ones that represented a sea change in treatment, were the protease inhibitors. From the publication of the HIV protease structure inScience in 1989 to IND approval of the first protease (saquinavir) in 1993 to its marketing approval in 1995 remains one of the best stories ever in drug development. By combining the protease drugs with other antiviral drugs, AIDS deaths, which had reached an all-time high by 1995, began declining in the US. The dawn of what we refer to as highly-active antiretroviral therapy or HAART is largely why AIDS is no longer considered a death sentence but a chronic, manageable condition among those who have access to the drugs.