Oncology Drug Development: A Regulatory Perspective

Tatiana Prowell, MD, US Food and Drug Administration, Silver Spring, Maryland, USA

Fellow Summary

Authored by Onyee Chan

Dr. Prowell delivered a fantastic, informative presentation regarding the regulatory aspect of oncology drug development. She began her talk by providing historical examples of what happened when there was a lack of drug safety policies. In the 1930s, elixir sulfanilamide was being used to treat strep infections without any safety testing and resulted in over a hundred deaths before the drug was discontinued for this indication. This led to the passage of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in 1938, which required pre-market safety testing of drugs prior to commercialization. However, another unfortunate event later occurred involving the drug thalidomide. Thalidomide was marketed as a sedative in Europe for the treatment of morning sickness and resulted in an unprecedented number of infants with phocomelia. While the impact on the U.S. population was limited due to refusal of approval by the FDA reviewer at the time, it led to amendments to the FD&C Act requiring better scientific evidence, informed consent, and reporting of adverse events to the FDA. In the late 20^th century, the emergence of HIV/AIDS and its rapid escalation prompted the FDA to institute the Accelerated Approval regulations in 1992, which allow drugs for serious and life-threatening conditions to be approved based on a surrogate endpoint instead of direct clinical benefit.

With this background information in mind, Dr. Prowell proceeded to describe in detail the different types of expedited development: 1) Fast Track designation, 2) Priority Review, 3) Accelerated Approval, and 4) Breakthrough Therapy designation. Drugs that are designated Fast Track, those that treat serious conditions and fill an unmet medical need, are granted approval early in clinical development prior to a New Drug Application (NDA) submission. Rolling review of Biologic License Application (BLA) or NDA can potentially lead to earlier drug approval. Other advantages include more frequent meetings with FDA to ensure that the drug’s development plan is on track, which may include but not be limited to feedback on clinical trial design and the use of biomarkers. Priority Review is part of the two-tiered system of review length that was established in 1992. It shortens review time from the standard time of 10 months to 6 months. Priority review is granted if, after the NDA/BLA submission, the product represents a significant improvement compared to existing marketed products in the treatment, prevention, and diagnosis of the condition of interest. Improvement may also include better tolerance and compliance. As already alluded to, Accelerated Approval allows approval based on a surrogate endpoint that the FDA reasonably believes would predict a clinical benefit. Confirmatory trials will still need to be done after the approval to show that there is indeed a real clinical benefit. Lastly, the Breakthrough Therapy designation is granted when preliminary clinical evidence indicates a potential substantial improvement over existing therapies. These drugs are eligible for intensive guidance by the FDA as early as Phase 1. It is not a guarantee of future drug approval, but this designation certainly expedites the approval process if the drug truly provides a clinical benefit.

In summary, Dr. Prowell’s presentation was wonderful, and her way of delivering the material kept the audience interested and made it easy to understand.

Fellow Summary

Authored by Rebecca Epperly

Dr. Prowell gave an excellent presentation on oncology drug development from a regulatory perspective, providing insight into FDA processes for expedited development and considerations for precision medicine. She discussed landmarks that have shaped the current regulatory landscape, including the elixir sulfanilamide and thalidomide disasters. She also noted the role of HIV and Cancer advocacy groups in pushing for expedited development.

The discussion of expedited development centered on four “fast sounding” processes:

1. Fast Track Designation is the easiest of these to acquire. This is granted early in the process, sometimes at the time of only preclinical data or first in human studies with one clinical response. It enables rolling submission of the New Drug Application (NDA) or Biologics License Application (BLA). While portions of the application may be reviewed as they are received, the PDUFA clock is still set by the submission of the final piece of the application.

2. Priority Review is determined after a complete NDA/BLA submission. If granted, it sets a goal date for regulatory action of 4 months, in contrast to 10 months with standard review. It is granted if the product represents a significant improvement compared to currently marketed products for treatment, prevention, or diagnosis and there is no satisfactory alternative therapy. Many oncologic therapeutics qualify for priority review, apart from “me too” drugs.

3. Accelerated Approval allows for approval based on surrogate markers or early clinical endpoints. To be eligible, the treatment must address a serious or life-threatening condition. Accelerated approval requires follow-up studies addressing comparative efficacy and confirming results with traditional endpoints. Completing these studies is sometimes challenging once accelerated approval is granted. Strategies to address these confirmatory studies include having international studies already ongoing (which can taper enrollment at US sites after approval), asking a different question such as combination with front line therapy or moving up in therapy, or allowing crossover accepting an expected decrease in effect size.

4. Breakthrough Therapy Designation is the most efficient opportunity and affords an “all hands on deck” approach to the NDA/BLA, with open access and support in development. For this designation, there must be indication of extreme activity in at least one serious or life-threatening disease. An early manufacturing consult is recommended as part of this process.

Precision Medicine can be defined broadly as getting the right drug to the right patient at the right time. This requires establishing the right development program for the right drug in the right patient population. Considerations include indications for which single-arm trials may be warranted, developing seamless designs, and the use of tissue-agnostic approaches for rare diseases with common predictive biomarkers. While the incorporation of biomarkers is key for the implementation of precision medicine strategies, it is important to note that not every drug has a testable biomarker, not all biomarkers are essential for effective use of the drug, some drugs may have multiple biomarkers, the first identified biomarker is not always the best, and inclusion of some “biomarker-negative” patients can be beneficial in early development.

Fellow Summary

Authored by Chi-Joan How

Dr. Prowell’s lecture “Oncology Drug Development: A Regulatory Perspective” was an interesting inside look at drug development from the perspective of the FDA and was one of the best lectures of the STOFF conference. She starts with background on the history of drug regulations. Unfortunately, the movement for greater drug regulation was due to tragedies in history: a simple antibiotic for Strep infections in children ended up killing many of its patients when mixed into a novel solvent, prompting public outcry and the creation of the 1938 Federal Food, Drug and Cosmetic Act. This act mandated for the first time the need for pre-market safety testing of drugs before their introduction. Further reform occurred after it was widely found that thalidomide resulted in devastating birth defects, allowing the development of the 1962 Kefauver-Harris Drug Amendment, which required demonstration of drug efficacy and safety as well as reporting of adverse effects and informed consent. With the arrival of the AIDS epidemic in the 1990s and the huge outpouring of patient advocacy that came with it, the concept of accelerated drug development within the FDA was born. These key milestones shaped the FDA into what it is today.

After this informing and engaging historical context, Dr. Prowell clarified terminology commonly associated with drug development which is useful for researchers to consider when thinking about new drugs that come onto the market. First, “fast-track designation” entitles a company to rolling new drug application submission; it is relatively easy to obtain and does not confer significant status onto a drug. Priority review, however, allows expedition of regulatory approval within 4 months and indicates that a product holds significant improvement compared to existing alternatives. Accelerated approval allows earlier approval based on surrogate endpoints and requires further confirmatory testing after approval. Breakthrough designation is the final means of early drug approval and is the most valuable in early drug development, allowing real-time development of a drug as the FDA tries to bring it to market.

Dr. Prowell then discussed the role of precision medicine within the FDA, namely how biomarkers are integrated into the drug development process. She emphasized some key points, including:

How to design trials to maximize biomarker development (for instance, enrolling biomarker-negative patients and how to enrich your trial with biomarker-positive patients) and
Recognizing that not all biomarkers are ideal, and multiple biomarkers can occur with one drug, just as not all drugs may have a biomarker.

She used a series of case studies (palbociclib, trastuzumab, crizotinib) in order to emphasize these teaching points.

Dr. Prowell’s insight into the machinations of the FDA and tips on conducting clinical trials with perspective toward regulatory drug development specifically were highlights of the conference.

Fellow Summary

Authored by Bridget Keenan

Dr. Prowell’s talk gave an in-depth perspective of the regulatory processes that govern drug development in our country, beginning with a historical overview. The impetus for the FDA to regulate drugs and medical devices developed out of several tragedies in a period in which there was less oversight. The sulfanilamide crisis in 1937, in which hundreds of people were poisoned by a toxic solvent present in an unregulated drug, led to the 1938 Federal Food, Drug & Cosmetic Act, which developed pre-marketing surveillance in which investigators must apply for an NDA (new drug application). Subsequent to the thalidomide disaster of the 1960s, the Kefauver-Harris drug amendment was passed, which stated that drugs have to be safe and effective based on well-controlled trials conducted by experts. Finally, the era of the HIV epidemic led to accelerated drug approvals for life-threatening illnesses, largely driven by patient advocates.

Dr. Prowell clarified the difference between various “fast” designations available at the FDA. Fast Track Designation is granted early in clinical development, prior to an NDA, and can be granted based on limited clinical data (such as a single trial or even single patient response) or pre-clinical data. The investigators are granted a rolling NDA/BLA submission as long as they can present a reasonable development plan. Priority Review is determined after the NDA/BLA submission is completed. It is granted if the product represents a significant improvement upon currently marketed products for treating or diagnosing disease, or if no satisfactory alternative exists, and can expedite the regulatory process by 4 months. Accelerated Approval provides a mechanism for drug approval based on a surrogate endpoint that can be measured sooner than a more distal endpoint such as overall survival. Because there is less certainty about surrogate endpoints, there needs be a large amount of convincing data presented, such as data showing that this drug represents an advance over the best current available therapy, sound scientific rationale, and/or a large magnitude of effect. Investigators are required to continue studying the drug, and post-marketing trials should be ongoing or planned by the time this approval is granted. Breakthrough Therapy Designation is granted for a drug and a life-threatening indication(not the drug alone). It accelerates the FDA process and results in a rapid response time with early input from subject matter experts but does not guarantee approval.

In addition to her primer on the regulatory process, Dr. Prowell discussed precision medicine and biomarker-driven trials. She gave several examples of how this has worked and not worked in trials in the past; for example, the success seen with PI3K inhibitors in breast cancer is not specific to patients with mutations in this pathway. She emphasized that not all drugs will have a biomarker; some drugs will have more than one biomarker, and the first biomarker developed may not be best one. Thus, we must carefully plan how we will design a trial and be careful in excluding patients who lack a biomarker from clinical trials.

Fellow Summary

Authored by Tanya Keenan

Dr. Prowell led a memorable and high yield interactive session about the regulatory perspective of oncology drug development. The key learning points she discussed are outlined below:

Fast track designation is not an approval and is the least impressive of the four approaches the FDA has developed to accelerate drug approval. All drugs being developed for serious or life-threatening conditions can get this designation, as it can be granted on the basis of even one clinical response. It entitles companies to rolling new drug application (NDA) or biologic license application (BLA) submissions, meaning they do not have to wait for the drug’s clinical trial to finish before submitting the initial sections of an NDA/BLA application.
Priority review is more impressive, as it expedites the goal date for regulatory action to occur within 6 months instead of 10 months from the date of initial submission.
Accelerated approval occurs when a drug is approved based on an earlier clinical or surrogate endpoint in cases where there is great scientific rationale and a large potential for benefit. Confirmatory post marketing trials to confirm clinical benefit are required after this approval is granted, and the FDA can withdraw approval if these trials fail to confirm benefit.
Breakthrough therapy designation is of greatest value early in drug development prior to the end of phase 2 trials. This is granted to a drug and indication when preliminary clinical evidence indicates potential substantial improvement over existing therapies on at least 1 clinically significant endpoint. It can be rescinded and does not guarantee approval. This designation activates an “all hands on deck” approach to the development of the drug and review of the NDA/BLA.
Precision medicine means developing the right drug for the right patient at the right time, which requires the right development program for the right drug in the right patient population.
- Seamless designs allow amending original protocols to explore new patient populations, doses, and/or treatment lines.
- Single arm trials may be required when equipoise is lacking.
- Common predictive biomarkers may allow tissue agnostic approaches for rare or unmet need diseases.
- Achieving precision medicine goals requires modernizing eligibility criteria for clinical trials.
In order to make the claim that a biomarker is predictive, a study must include biomarker-negative patients.
- If a study only includes biomarker positive patients, then it can only calculate positive predictive value and not negative predictive value, sensitivity, or specificity.
- As the prevalence of a biomarker and the biomarker negative response rate increase, fewer extra biomarker-negative patients are needed to adequately characterize the biomarker negative population.

Fellow Summary

Authored by Kamaneh Montazeri

Dr. Prowell’s talk provided an overview of the acts leading to the evolution of the Food and Drug Administration (FDA) and the formation of regulatory process for drug development.

The Pure Food and Drugs Act in 1906 was the first law on food and drugs, which enforced truthful labeling statements on food and drugs. However, it played no role in pre-marketing evaluation of the drugs.
In 1937 the Elixir sulfanilamide disaster took place. Diethylene glycol was used by S.E. Massengill as a solvent without safety testing on animals or humans, resulting in 100 deaths. This led to the birth of patient advocacy and the Food, Drug and Cosmetic Act (FDCA), giving the FDA the authority to regulate medical devices and cosmetics and to establish standards for foods.
In 1962, president Kennedy signed the Kefauver-Harris Drug Amendments as a result of the thalidomide disaster. Thalidomide was a sedative, used for morning sickness in pregnant women in Europe, which resulted in phocomelia in 1/500 live births. These amendments required the manufacturers to show safety and efficacy of their products to the FDA prior to marketing and to report adverse events to the FDA. In addition, in this year, the FDA formed the first advisory committee on Investigational New Drugs.
In the 1980s, HIV and AIDS advocacy groups, including ACT-UP, became vocal about the urgency for approval of new drugs in response to the escalating AIDS epidemic. Subsequently, the “accelerated approval” mechanisms were born in 1992.

Dr. Prowell further reviewed the four distinct approaches of the FDA to expedite drug approvals:

Fast Track Designation: This pathway entitles a company to submit a New Drug Application/Biologic License Application (NDA/BLA) on a rolling basis. This is often granted early in the drug development process, even prior to IND submission, with some preclinical data demonstrating potential to address an unmet need.
Priority review : This approach expedites the goal date for a regulatory action by 4 months. The product needs to represent a significant improvement compared to the existing treatment options in the absence of a satisfactory alternative therapy.
Accelerated approval: Approval is based on “surrogate” or earlier endpoints, and postmarking trials are required to confirm the clinical benefit. This type of approval is only given for the treatment of serious or life-threatening diseases, with a lower level of certainty for clinical benefit. About 9% of drugs approved in this setting fail to do the confirmatory trials, most of which are then withdrawn for that indication.
Breakthrough therapy designation: This pathway is limited to the drugs used for treating life-threatening or serious conditions with some clinical data indicating the potential for significant benefit over the existing therapies. For this purpose, the FDA provides an intensive cross-disciplinary guidance to the company: “All hands on deck” approach.

Fellow Summary

Authored by Jay Oza

Government regulation of drugs has been a fairly recent development and evolved during the 20^th century. The very first drug law was the Food and Drug Act of 1906, which arose in response to baseline “miracle cure” claims for inert and/or dangerous medicine and adulterated food. This law had no role in pre-market evaluation of drugs. It provided FDA authority to enforce laws forbidding misbranded and adulterated foods and drugs, but only if the violations could be detected. Subsequently, in 1937 about 243 gallons of elixir sulfanilamide (to treat Strep infections) were distributed using diethylene glycol as a solvent to make the drug available in a more palatable liquid formulation. However, this caused ~100 deaths in children in a matter of weeks. While FDA seized the drugs, the company could not be held legally accountable because there were no laws at the time penalizing such incidents. This event led to the Federal Food, Drug and Cosmetic Act (FD&C Act), which mandated pre-market safety testing of drugs. This act introduced a pre-marketing approval process by the FDA called the New Drug Application (NDA). There were no efficacy requirements. As a result of such regulations, thalidomide failed to get approval in the US (1957-1962) due to inadequate safety data, whereas the incidence of phocomelia in Europe rose from 1/100,000 to 1/500.

Modern standards of regulatory science were introduced in the 1962 Kefauver-Harris Drug Amendments to the FD&C Act. These amendments introduced the requirements of informed consent and reporting of adverse events (AEs) to the FDA in trials. Furthermore, the drugs must be safe and effective based on substantial evidence and consistent through adequate and well controlled trials, conducted by experts qualified by scientific training and experience.

In response to serious life threatening disease such as HIV and cancer in the late 1980s/early 1990s, accelerated approval was created. Patient advocacy groups, particularly in HIV/AIDS, were well-organized and vocal about the urgency to approve new drugs in response to the escalating epidemic. These approvals were based on “surrogate endpoint reasonably likely to predict clinical benefit”. Post-marketing data was still needed to verify and describe clinical benefit for regular approval. Over the next several years, four tracks were introduced (1. Fast track designation, 2. Priority review, 3. Accelerated approval, and 4. Breakthrough therapy designation) to promote expedited drug development.

1. Fast track designation: is granted early in clinical development (i.e. prior to an NDA submission), can be as early as first in human trial, can be based even on a single response, with an acceptable development plan, in a specific indication. It entitles company to a rolling NDA/BLA (biologic licensing application) submission.

2. Priority review: is determined after complete NDA/BLA submission. It is granted if the product represents a significant improvement compared to marketed products for treating, preventing, or diagnosing disease, or no satisfactory alternative therapy exists. It expedites the goal date for regulatory action from 10 months (standard review) to 6 months (priority review).

3. Accelerated approval: allows FDA to take regulatory action based on unregulated surrogate or earlier clinical endpoints (i.e, when there is greater uncertainty that the endpoint measures direct clinical benefit). This applies to serious/life-threatening diseases. About 9% of drugs fail to confirm benefit in confirmatory trial.

4. Breakthrough therapy designation: is granted to drugs intended (alone or in combination) to treat a serious or life-threatening disease, and preliminary clinical evidence indicates potential substantial improvement over existing therapies on at least one clinically significant end-point. This is granted for a drug in a specific indication, not for a drug alone. This designation does not guarantee a future drug approval.

Finally, the talk discussed precision medicine and biomarkers. Precision medicine is the use of the right drug for the right patient at the right time. Biomarkers can be used for risk stratification of patients with early stage disease to escalate/de-escalate therapy, trial enrichment, and tissue agnostic approaches for rare or unmet need diseases. While biomarkers have potential value across the full spectrum of drug development and clinical care, not every drug will have an identifiable, testable biomarker, and not every biomarker will be essential for safe and effective use of the drug. An ideal biomarker trial will teach us not only about the drug but also about the test and the drug-test interaction. Finally, it is also important to study marker negative patients, since without them one may incorrectly assume that biomarker is required for response and deny effective therapy to marker negative patients. Alternatively, one may select a wrong biomarker and abandon development of a potentially active drug if no efficacy is observed.

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