Oncology Drug Development: A Regulatory Perspective
Tatiana Prowell, MD US Food & Drug Administration, Silver Spring, Maryland, USA
Authored by Paolo Strati, MD, MD Anderson Cancer Center, Houston, Texas, USA
The Food and Drug Administration was created in 1906 in response to the rising prevalence of dangerous drugs and adulterated foods. Unfortunately, its monitoring role was limited to the post-marketing phase, and only after the elixir sulfanilamide incident was the need for a New Drug Application (NDA) to FDA realized. The thalidomide disaster helped to further refine FDA’s role, introducing stricter requirements for safety and efficacy, the need for an informed consent and adverse events reporting.
More recently, the HIV emergency has brought FDA to develop 4 pathways for expedited development, commonly misinterpreted among clinical investigators:
- Fast track designation: this is given to drugs in early development, with a specific indication, based on early data, such as pre-clinical data or a single response; while this entitles to the applicant to a rolling NDA, it doesn’t guarantee approval or abbreviate the process.
- Priority review: this is granted after NDA for very promising agents and abbreviates the application review from 10 months (regular approval) to 6 months.
- Accelerated approval: this is a type of approval based on surrogate endpoints instead of direct clinical benefit. As compared to regular (or full) approval, it is limited to life-threating diseases (such as cancer) and requires a confirmatory trial in the post-marketing phase. The confirmatory trial is usually a randomized trial that was started at the same time as the single arm trial that brought the drug to accelerated approval or a single arm trial in an earlier stage/lower risk population. While accelerated approval allows early marketing of the agent, it runs the risk of having the agent removed from the market in the case of a negative confirmatory trial.
- Breakthrough therapy designation: this is granted to very promising drugs with specific indications, typically toward the end of phase 2 studies. While it doesn’t guarantee approval, it is one of its best predictors. In fact, it entails early and strict collaboration with FDA, with prompt feedback in regard to study design and drug development. Agents that obtain breakthrough designation can eventually also qualify for priority review and/or accelerated approval.
Dr. Prowell concluded her enlightening and inspiring lecture with some historical examples of the role of biomarkers in clinical trials, highlighting the informative power of testing drugs also in biomarker-negative patients. She briefly touched on the modern need for seamless trial designs, likely to enable a quicker development of promising drugs based on convincing biological mechanisms and trumping the need for randomized trials, which are frequently unethical or not feasible.
Authored by Yi-Tsung Lu, MD, University of Southern California (USC) Norris Comprehensive Cancer Center, Los Angeles, California, USA
The history of FDA started in 1906. To regulate the claims of drug effects, the FDA was established to identify and correct baseless claims of drug efficacy. However, in the 1930s, a new formulation of an antibacterial (sulfanilamide) caused more than 100 deaths in children, but the owner and the pharmaceutical company did not take responsibility for it. Then, President Roosevelt signed the Federal Food, Drug, and Cosmetic Act (FD&C Act) in 1938, mandating that all drugs go through a safety test before they are sold on the market. This act stopped thalidomide from being sold in the US. However, a small number of victims in the US were not properly consented when they were exposed to thalidomide during the human subject experimentation. This led to the amendment of the FD&C Act to introduce the requirement of an informed consent to include the potential adverse effects of the experimental drug.
In 1992, several reforms were undertaken in FDA to expedite the approval of effective HIV medications during the era of the AIDS endemic. Now, a drug can get accelerated approval based on an early phase trial. There are several methods of drug approval expedition. The first one is the Fast Track Designation. This designation is easy to obtain and only grants the company the access to submit a Biologic License Application/New Drug Application (BLA/NDA) on a rolling basis. It does not expedite the process in a significant manner and is often obtained for fundraising purposes.
The second is Priority Review. This status was assigned by FDA after the submission of BLA/NDA if a drug provides a significant improvement over current therapy or the drug does not have a satisfactory alternative. It shortens the review time from ten months to six months. However, as the FDA is now better staffed, the difference in the review time between a priority review and a standard review is now less than four months.
The third method is an Accelerated Approval. When the significant improvement is observed in an early phase trial based on softer endpoints, such as overall response rate, the FDA can grant an accelerated approval so that patients can enjoy the benefit of a drug before a large-scale trial is conducted. Approved drugs under accelerated approval are required to provide randomized data of their efficacy after approval.
Finally, the fourth status is a Breakthrough Therapy Designation. When a new therapy is being developed for a life-threatening disease without currently available treatment, the FDA can grant the breakthrough therapy designation to a specific drug after reviewing early phase clinical data. Under this status, the FDA will actively support the development of the drug, including direct consultation on the trial design, faster review for an amendment of an ongoing trial, and consultation with manufacturing specialists to expedite scaling up production of the product.
Authored by Diego Adrianzen Herrera, MD, Albert Einstein College of Medicine/Montefiore, Bronx, New York, USA
Dr. Prowell’s talk summarized the FDA’s regulatory process for novel oncology drug approvals in the United States, with particular emphasis in common misunderstandings of clinicians and investigators, which were clarified with true examples of drugs we frequently use nowadays.
The talk started with a brief review of the history of drug laws in the US and the acts that enabled the FDA to enforce the regulations we now obey. Dr. Prowell provided several well documented examples of drug-related disasters such as those caused by elixir sulfanilamide and thalidomide, which exposed historical failures in drug safety policies. Building upon those historical failures, she explained the rationale behind the modern process of approving a drug for mass commercialization, with focus on oncological pharmaceuticals.
Dr. Prowell explained the process of expedited reviews and approvals, which are usually based on surrogate endpoints. The FDA modernization act of 1997 created mechanisms to expedite drug development for life-threatening diseases, including cancer, and these mechanisms are commonly applied to drugs we use in the clinic or in our research endeavors.
- Fast track designation: Granted early in development prior to a New-Drug-Application (NDA) and based on clinical responses in a specific indication
- Priority review category: Granted after an NDA if a product represents a significant improvement over existing therapeutic options; it expedites regulatory action.
- Accelerated approval: A drug approval based on surrogate endpoints that may reasonably predict clinical benefit. Though there is a lower certainty of clinical benefit, these endpoints usually demonstrate a large effect and are backed by scientific rationale. Confirmatory trials after marketing will be needed for drugs that receive accelerated approval, and multiple methods have been developed to confirm benefit in these cases without necessarily conducting a post-marketing randomized clinical trial.
- Breakthrough therapy designation: Limited for drugs treating life-threatening diseases with preliminary clinical evidence that predicts substantial improvement over existing therapies. The designation is a great value granted early in the development process which can lead to early access to FDA and manufacturing consultations but can be revoked and does not guarantee an approval.
The talk then dived into a broad definition of precision medicine from the regulatory perspective. This includes 3 key features:
- Securing the right drug is available to the right patient at the right time: In current times, this mainly means that potential biomarkers should be incorporated in drug development programs to select patients and monitor responses whenever possible, while recognizing that inclusion or marker-negative patients in the early steps of drug development is beneficial to understand the real impact of biomarkers in clinical results.
- Securing the right development program for the right drug in the right patient population: Emphasis was made on the current expanded early phase trials that use surrogate outcomes and include large numbers of patients and complex schemes, a model that is significantly distant from the classical three phases of drug development. This trend has implications in the approval process as it requires higher levels of IRB scrutiny and FDA oversight for early phase trials that historically were only conducted in a small number of patients. These designs are encouraged for breakthrough designated drugs but should not be the default model for oncology studies.
- Ensuring that clinical trial results are relevant to the US public: Including modernizing the eligibility criteria and preventing exclusion of patients that can benefit from studies.
The session was an interactive discussion with great practical advice from Drs. Levine and Flaherty tailored to the Forum participants.
Authored by Nazli Dizman, MD, City of Hope Comprehensive Cancer Center, Duarte, California, USA
Dr. Prowell has provided a detailed overview of the regulatory aspects of the United States (US) Food and Drug Administration (FDA). Her presentation started with historical incidents involving significant damage to human health at times when drug development and utilization were not regulated. She then discussed current methods of drug development and utilization. The presentation flow included the following:
Expedited drug development pathways: Four different pathways are included in this category: (1) Fast track, (2) priority review, (3) accelerated approval, and (4) breakthrough therapy design. Fast track designation is based on the clinical response to a medication with an acceptable development plan. Priority review is granted for drugs with a significant improvement over drugs currently being used in the same area or for situations in which no alternative exists. Accelerated approval pathway is based on a benefit observed in a surrogate endpoint that is likely to predict clinical benefit. Accelerated approval is granted for products used for serious or life-threatening conditions and is based on the benefit observed in surrogate endpoints. Accelerated approval requires a confirmatory trial and comparative efficacy assessment. These features distinguish accelerated approval from regular approval that applies to any disease type and is based on direct clinical benefit and does not require confirmatory trials or comparative efficacy assessment. A crucial point after accelerated approval is the method of confirming the benefit. This can be achieved in different ways, such as interim analysis of a surrogate endpoint in a randomized setting. Breakthrough therapy designation is granted for drugs intended to treat a serious or life threatening disease which demonstrate significant improvement in at least one clinical endpoint.
Precision Medicine: Dr. Prowell defines precision medicine in three essential steps: (1) right drug in right patient at the right time, (2) right trial design with right drug in the right population, (3) relevance of results to US population. In order to choose the right drug for the right patient, biomarkers are implemented, and this approach is helpful at different endpoints that include but are not limited to the selection of patients likely to benefit, predicting response, and informing the prognosis. However, there are caveats with biomarkers. Not every drug has identifiable or testable biomarkers, and some drugs may have more than one. Moreover, marker-negative patients should definitely be included early in development. The decision on the right trial program for right drug and patient may have different pathways. Novel trial designs can be used for highly promising agents, and single arm trials might be the answer for situations where no equipoise exists. The application of the results to the United States population should be achieved by modernizing eligibility criteria.
The rest of Dr. Prowell’s presentation included practical issues. The incidents in which randomized trials are not needed were discussed. This option applies to drugs that provide good response rates in an area with unmet need or to drugs with compelling biological rationale in a biomarker-selected population. The importance of using patient-reported outcomes logically was highlighted as well.