Skip to Main Content

Advertisement

Skip Nav Destination

You Really Got a Hold on Me

October 20, 2022

November 2022

Taking a close look at clinical holds reveals them to be an integral safety mechanism in the investigation and approval of important hematologic treatments.

Lara C. Pullen, PhD

Lara C. Pullen, PhD, is a freelance medical writer in Chicago.

When a clinical trial is halted by the U.S. Food and Drug Administration (FDA) and the therapy is put on a clinical hold, hematologists may be wary of the drug involved. But the clinical hold is a quality assurance step for new products that need a closer look before they can continue being developed for patients.

The drug development process is a bit like a three-legged stool, said Grzegorz S. Nowakowski, MD, a hematologist at Mayo Clinic in Rochester, Minnesota, and chair of the American Society of Hematology (ASH)-FDA Workshop Organizing Committee. The two organizations co-launched an October 2022 workshop that focused on careers in clinical or translational research, drug development, or regulatory medicine. The three legs consist of the regulator, patient, and physician. The sponsor holds the three legs together and develops the final product.

Although it’s a normal part of the drug development process, the clinical hold has some stigma attached to it. ASH Clinical News spoke with Dr. Nowakowski and other experts about clinical holds, how they’ve been used in the field of hematology, and why the stigma around them is unfounded.

Clinical Holds Explained

The FDA issues a clinical hold to a sponsor of an investigational new drug (IND) application to delay or to suspend a clinical investigation. There are a few reasons that the FDA might initiate a clinical hold:

  • Human subjects are exposed to an unreasonable or significant risk of illness or injury.
  • Clinical investigators named in the investigational new drug (IND) application are not qualified to conduct the investigation.
  • The investigator brochure is misleading or incomplete.
  • There is a concern about product quality or purity.
  • Safety assessments in a clinical trial do not fully address previously observed toxicities in the investigational drug.

When this happens, the sponsor may no longer recruit study participants or provide the investigational drug to patients. Patients who are already enrolled and receiving the drug must also be taken off therapy unless the FDA specifically permits treatment continuation in the interest of patient safety.

In the case of a partial clinical hold, patients receiving the test drug are permitted to continue taking it, but no new patients may be enrolled in the trial.

Clinical holds can elicit anxiety for patients and sponsors alike. For patients, a full clinical hold means they no longer have access to a drug that may be providing a benefit. For sponsors, a clinical hold can be stressful because it may affect the drug’s future status.

“An IND sponsor may not proceed with a clinical trial on which a clinical hold has been imposed until the FDA has determined that the sponsor has addressed all the deficiencies in the clinical hold,” said an FDA spokesperson. “The Agency will then lift the clinical hold and the sponsor may proceed with their clinical development program. When a drug is approved, the Agency has concluded that a drug provides benefits that outweigh its known and potential risks for the intended population.”

Cases in Point

In the field of hematology, many investigational drugs have triggered holds because of safety concerns but were ultimately approved and made available for patients. In some cases, approval was granted with the use of a black box warning, while in others the adverse events (AEs) were determined to be inherent to the patient population and not the result of treatment. A closer look reveals how clinical holds can come about and be resolved in a variety of ways. Any subsequent drug approvals should be considered a reinforcement of drug safety but not an equivocation of it.

Fedratinib

The story of fedratinib highlights the stilting effect that a hold can have on drug development and the perseverance – and funding – that is sometimes necessary to overcome the hold and bring the drug to market.

In 2008, John Hood, PhD, co-invented fedratinib while working at TargeGen. The company initiated the clinical trial program and then sold to Sanofi in 2010.1 In 2013, following reports of seven suspected cases of Wernicke encephalopathy among 877 patients who received fedratinib across eight clinical trials, the FDA placed a clinical hold on fedratinib. These trials were terminated, and patients receiving the drug were discontinued from ongoing treatment.

A paper published in 2015 revealed, however, that fedratinib significantly reduced splenomegaly and symptom burden in patients with myelofibrosis (MF). More than one-third of patients with intermediate-2 or high-risk MF achieved the primary endpoint of the clinical trial, which was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed four weeks later.2

Despite the positive results, the clinical hold prompted Sanofi to stop its pursuit of fedratinib. The clinical hold was a blow for Dr. Hood.

“I knew some of the patients who were benefitting from the drug, and I was motivated to get it to them,” he explained.

Dr. Hood and his collaborator, Catriona Jamieson, MD, PhD, professor of medicine at the University of California in San Diego, decided to do what they could to get fedratinib to the patients who needed it. They spoke to dozens of venture capitalists and raised funding. In 2016, they used that capital to acquire Sanofi’s full rights for the global development and commercialization of fedratinib and formed Impact Biomedicines. They made the case to investors that the FDA hold represented a “no” response to a complicated question.

“People so often look for binary answers to nonbinary questions,” he explained.

While the U.S. trial was placed on hold, research with fedratinib continued in Europe where investigators provided thymine supplementation to patients. Wernicke encephalopathy is preventable with such supplementation and, in 2017, investigators published the phase II results of fedratinib therapy.3 The study met its primary endpoint of spleen response, suggesting that patients with ruxolitinib-resistant or -intolerant MF may achieve significant clinical benefit with fedratinib.

There was a single case of encephalopathy in the new trial, but an independent safety panel determined the case was related to hepatic encephalopathy and was inconsistent with Wernicke.3 Consistent with this, the event resolved within one week of discontinuing fedratinib treatment. Also in 2017, the independent expert safety panel analyzed the Wernicke encephalopathy cases and submitted their analysis to the FDA. That report, along with time spent educating the FDA on the malnutrition commonly associated with advanced cancer, led to the lifting of the hold, Dr. Hood said. He emphasized that staff at the FDA were eager to listen and learn.

With all of this forward momentum built up, in 2018, U.S. biotech pharmaceutical firm Celgene Corp acquired Impact Biomedicines.4 Then, in August 2019, the FDA approved fedratinib for the treatment of adult patients with intermediate-2 or high-risk primary or secondary MF regardless of prior Janus kinase (JAK) inhibitor treatment with a warning. The package insert contains a black box warning about serious and fatal encephalopathy, including Wernicke.

The eventual approval of fedratinib is a story of persistence. It was also an important moment for the treatment of MF. It was the second therapy approved for the treatment of MF after ruxolitinib, which was approved eight years prior. Moreover, it offered a treatment that was effective even in situations where ruxolitinib was no longer working.3

Pacritinib

CTI Biopharma’s development of pacritinib is an illustration of the “three-legged stool” described by Dr. Nowakowski, and it required coordination between the FDA, the sponsor, and investigators to reach eventual drug approval.

The phase III PERSIST-2 trial of pacritinib demonstrated that patients, including those with platelet counts below 50 × 109/L, experienced improvements in splenomegaly and symptom burden when treated with a 200 mg twice-daily dose.5 However, early analysis of trial data also raised safety concerns about cardiovascular events and bleeding.

In early 2016, the FDA placed the trial on a full clinical hold until the data from PERSIST-2 could be reviewed. According to John Mascarenhas, MD, director of the Adult Leukemia Program at Mount Sinai in New York City, this hold resulted in patients losing access to a drug that in many cases was beneficial. Because of the hold, investigators were unable to fully enroll the trial, and it was consequently underpowered for the co-primary endpoints, which were patients achieving 35% or more reduction in spleen volume and 50% or more reduction in total symptom score at week 24.6 Moreover, long-term follow-up data were missing because of the hold. Nevertheless, the spleen response endpoint was met, although the symptom response endpoint was not.

In 2017, Adam Craig, MD, PhD, president and chief executive officer of CTI BioPharma, partnered with the FDA and clinical investigators, including Dr. Mascarenhas, to lift the hold so drug development could continue. Together, they determined the AEs were likely unrelated to treatment but were instead the result of the advanced disease state of the trial participants. As part of the agreement with the FDA, the sponsor launched the PAC203 study to confirm that the AEs occurred as the natural consequence of illness and not as a direct result of exposure to the drug.7

In February 2022, after the PAC203 study results were reviewed, the FDA approved the therapy for the treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera [PV] or post-essential thrombocythemia) MF with a platelet count below 50 × 109/L. Dr. Mascarenhas explained that this approval reflected the FDA’s recognition of the drug’s significance.

“The appetite for toxicity is different,” Dr. Mascarenhas said, describing patient and physician needs for treatments for advanced conditions that lack commercial options.

Magrolimab

The scenario with magrolimab highlights how a trial may be placed on hold because of suspected unexpected serious adverse reactions (SUSARs). SUSAR is the term used to refer to an AE that occurs in a clinical trial subject, which is assessed by the sponsor or study investigator as being unexpected and serious and having a reasonable possibility of a causal relationship with the study drug.

Magrolimab is a first-in-class, investigational, anti-CD47 monoclonal antibody and macrophage checkpoint inhibitor used for the treatment of several hematologic malignancies, including myelo­dysplastic syndromes. The FDA placed studies evaluating magrolimab in combination with azacitidine on partial clinical hold in January 2022 because of an apparent imbalance in SUSARs between study arms.8

The FDA reviewed the comprehensive safety data from each trial and identified no new safety signals, and the SUSARs did not point to a clear trend in AEs. The hold was lifted three months later without further modification of safety language, and the trial was ongoing as of August 2022.

“The lift for magrolimab was a relief, as this agent has shown promising activity in a disease area with unmet need,” Dr. Mascarenhas said, adding that he and his colleagues were “eager to provide access to patients waiting for this option and without approved alternative therapies.”

Gene Therapies in Hemophilia

There are two recent examples of gene therapies in hematology being placed on hold, both of which required resolutions to address potential serious AEs. This is perhaps unsurprising, as this class of drugs has been highly affected by clinical holds because of general technical and safety issues. In fact, in 2021, cell and gene therapy trials accounted for approximately 40% of all clinical holds even though they comprised far less than 40% of all trials.9

One such hold was placed in December 2020 for etranacogene dezaparvovec, a gene therapy for hemophilia B, because of a possibly related serious AE. One patient in the HOPE-B phase III trial received a preliminary diagnosis of hepatocellular carcinoma during a routine trial assessment one year after treatment.10

The AAV5-based gene therapy carries a gene cassette with the Padua variant of factor IX. After 26 weeks of post-treatment follow-up, the mean factor IX rate reached near normal levels, with a 36% increase from baseline. The patient whose case triggered the clinical hold had multiple risk factors for hepatocellular cancer, including chronic infections with hepatitis C and B viruses, evidence of non-alcoholic fatty liver disease, and advanced age. After four months, the FDA lifted the hold when it was determined that the gene therapy was highly unlikely to have caused the patient’s cancer.

In the case of giroctocogene fitelparvovec, research revealed a safety signal that the sponsors addressed in their protocol in order to lift the hold and continue drug development. In November 2021, the FDA placed the hemophilia A gene therapy program, including the phase III AFFINE study, on clinical hold until the review of a proposed protocol amendment.11 The multicenter study was designed to evaluate the safety and efficacy of a single infusion of giroctocogene fitelparvovec, which was expected to confer a healthy copy of the gene for factor VIII.

The sponsors observed factor VIII levels greater than 150% in some trial participants, putting them at substantial risk of blood clots. The FDA initiated the clinical hold to allow the sponsor to implement a protocol amendment. At the time of the hold, more than half of the 50 expected participants had received their dose of giroctocogene fitelparvovec. The sponsor modified the trial so that it could continue.

In May 2022, the FDA released the clinical hold, although the sponsor kept the trial on pause until the updated study protocols were approved. Dosing was planned to resume in the third quarter of 2022.

Rusfertide

The case of rusfertide illustrates how FDA holds may not always be based on clinical data. In September 2021, the FDA placed clinical studies of the therapy as a treatment for PV on a clinical hold. The hold followed the sponsor’s notification to the FDA of a non-clinical finding of benign and malignant subcutaneous skin tumors in a 26-week rasH2 transgenic mouse model study.12

The hold was thus based on laboratory studies that revealed that mice injected with large quantities of the drug developed skin tumors. In this case, the hold prompted a protocol improvement that required patients to meet with physicians to screen for skin cancer, and the hold was lifted a month later.

Eliminating the Stigma

To the casual observer, a clinical hold can look like a mark of disgrace – a reason for a sponsor to give up on the drug, for physicians to be wary of it, and for a patient to decline it.

“Unfortunately, good drugs are being sent out to pasture and patients are suffering,” Dr. Hood said.

In essence, a clinical hold is like a big train coming to a halt, Dr. Nowakowski said, and it can be very hard to get the engine going again. Rather than seeing holds as a negative, however, he emphasized they should simply be viewed as a safety mechanism, an opportunity for the FDA, investigators, and the sponsor to reevaluate risks and benefits of a particular therapy.

According to Dr. Hood, “Just because a drug is on clinical hold, you shouldn’t automatically assume that something about the drug is wrong, per se.”

When AEs occur in the patient population, as they frequently do, they are not necessarily associated with the investigational drug, but it’s important to figure that out for certain. Ultimately, the FDA only approves a drug if it can justify the risk-benefit ratio.

“If a drug ends up getting approved,” Dr. Mascarenhas said, “one has to trust the system.”

The regulatory system in the U.S. has been promoting safety and efficacy for more than 100 years. During that time, the FDA has become the world-wide gold standard in drug review, with clinical holds being just one part of that complex process.

References

  1. Fierce Biotech. Sanofi-aventis to acquire TargeGene Inc. June 30, 2010. Accessed September 21, 2022. https://www.fiercebiotech.com/biotech/anofi-aventis-to-acquire-targegen-inc.
  2. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651.
  3. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317-e324.
  4. Celgene to buy Impact Biomedicines for up to $7 billion. January 7, 2018. Accessed September 21, 2022. https://www.reuters.com/article/us-impact-biomedicines-m-a-celgene/celgene-to-buy-impact-biomedicines-for-up-to-7-billion-idUSKBN1EW0U9.
  5. Tremblay D & Mascarenhas J. Pacritinib to treat myelofibrosis patients with thrombocytopenia. Expert Rev Hematol. 2018;11(9):707-714.
  6. Mascarenhas J, Hoffman R, Talpaz M,et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis. JAMA Oncol. 2018;4(5):652-659.
  7. Gerds AT, Savona MR, Scott BL, et al. Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Blood Adv. 2020;4(22):5825-5835.
  8. Gilead announces partial clinical hold for studies evaluating magrolimab in combination with azacytidine. January 25, 2022. Accessed August 24, 2022. https://www.gilead.com/news-and-press/press-room/press-releases/2022/1/gilead-announces-partial-clinical-hold-for-studies-evaluating-magrolimab-in-combination-with-azacitidine.
  9. Cell & gene therapy fueled large surge in clinical holds last year. March 7, 2022. Accessed September 21, 2022. https://www.centerwatch.com/articles/26021-cell-gene-therapy-fueled-large-surge-in-clinical-holds-last-year.
  10. Pipe SW, Recht M, Key NS, et al. First data from the phase 3 HOPE-B gene therapy trial: efficacy and safety of etranacogene dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in adults with severe or moderate-severe hemophilia B treated irrespective of pre-existing anti-capsid neutralizing antibodies. Abstract #LBA-6. Presented at the 2020 American Society of Hematology Annual Meeting, December 8, 2020.
  11. National Hemophilia Foundation. FDA places the Pfizer/Sangamo Therapeutics phase 3 AFFINE haemophilia A gene therapy study on clinical hold. Accessed August 24, 2022. November 5, 2021. https://www.hemophilia.org/news/fda-places-the-pfizersangamo-therapeutics-phase-3-affine-haemophilia-a-gene-therapy-study-on-clinical-hold.
  12. Protagonist Therapeutics. Protagonist Therapeutics reports FDA clinical hold on rusfertide clinical development program. Cision PR Newswire. September 17, 2021. Accessed August 24, 2022. https://www.prnewswire.com/news-releases/protagonist-therapeutics-reports-fda-clinical-hold-on-rusfertide-clinical-development-program-301379332.html.

Some FDA Terms to Know

Center for Drug Evaluation and Research (CDER): The part of the FDA that ensures safe and effective drugs are available to improve the health of people in the U.S.

Clinical hold: A delay of a proposed clinical investigation or suspension of an ongoing investigation.

Sponsor: The individual or institution that takes responsibility for and initiates a clinical investigation.

Investigational new drug (IND): A substance that has been tested in the laboratory and has been approved by the FDA for testing in people.

New drug application (NDA): The vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S.

Serious adverse event (SAE): A serious and undesirable experience, such as death, hospitalization, or disability, associated with the use of a medical product in a patient.

Serious adverse reaction (SAR): An SAE that occurs during research with a medicinal product is an SAR if there is a certain degree of probability that the SAE is a harmful and undesired reaction to the investigational medicinal product, regardless of the administered dose.

Suspected unexpected serious adverse reaction (SUSAR): “Unexpected” means that the nature and severity of the SAR do not match with the reference safety information, such as the investigator’s brochure.

Advertisement

Connect with us:

CURRENT ISSUE
April 2024

Advertisement

Close Modal

or Create an Account

Close Modal
Close Modal

Advertisement