NIH and FDA Release Protocol Template for Phase 2 and 3 IND/IDE Clinical Trials and e-Protocol Writing Tool

In previous article 'Clinical Trial Protocol Template',  the draft template by NIH/FDA was mentioned. 

NIH/FDA has now finalized the clinical trial protocol template.

NIH and FDA Release Protocol Template for Phase 2 and 3 IND/IDE Clinical Trials

The National Institutes of Health (NIH) and Food and Drug Administration (FDA) developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require Investigational New Drug application (IND) or Investigational Device Exemption (IDE) applications.   In March 2016 a draft template was released for public comment generating nearly 200 comments from 60 respondents.  All comments were carefully considered and many were incorporated into the final template.  The agencies’ goal is to encourage and make it easier for investigators to prepare clinical trial protocols that are organized consistently and that contain all of the information necessary for the review of the protocol.  The template follows the International Conference on Harmonisation (ICH) E6 (R2) Good Clinical Practice and is available as a Word documentThe NIH also released a secure web-based e-Protocol Writing Tool that allows investigators to generate a new protocol using the NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template. The e-Protocol Writing Tool fosters protocol writing collaboration by allowing multiple writers and reviewers to participate in the protocol development process. The e-Protocol Writing Tool allows the author to assign writers and collaborators and the tool assists the author with tracking progress and document version control.
The NIH expects to expand the development of the e-Protocol Writing Tool by adding instructional text and sample text for other types of studies, such as a behavioral and phase 1 trials. Future releases of this e-Protocol Writing Tool will have improvements and enhanced tool functionality. 

CAR-T Gene Therapy Clinical Trials - Success Story and Beyond

Recently, two CAR-T (Chimeric Antigen Receptor T cell) gene therapies were approved by FDA. The first one is tisagenlecleucel manufactured by Novartis and is indicated for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). The second one is axicabtagene ciloleucel by Kite pharmaceutical (now part of Gilead) and it is indicated for treating adult patients with certain types of large B-cell lymphoma or certain types of non-Hodgkin lymphoma (NHL).who have not responded to or who have relapsed after at least two other kinds of treatment.

Before the approval of tisagenlecleucel, FDA summoned an advisory committee meeting for the safety concerns on July 12, 2017. The official approval came one and half months after advisory committee votes unanimously in favor of the approval.

The second CAR-T product approval came just one and half months after the first CAR-T approval and did not need to go through the advisory committee meeting process.

From the clinical trial design standpoint, both approvals were based on a pivotal study with relatively small, but sufficient sample size. Since the study was a single-arm with no control group, the results were compared with the historical control (or a commonly accepted criteria).

For Novartis’ tisagenlecleucel, the pivotal study is registered on clinicaltrials.gov as “A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia”. The briefing book of the advisory committee meeting detailed the background information of the CART, the study design, and the results.

The primary efficacy endpoint is the overall remission rate (ORR) during the 3 months after tisagenlecleucel administration; ORR includes complete remission (CR) and complete remission with incomplete hematologic recovery (CRi), as determined by independent review committee (IRC) assessment.

The pre-specified primary efficacy endpoint tested the null hypothesis of the ORR being less than or equal to 20% against the alternative hypothesis that the ORR was greater than 20% at an overall one-sided 2.5% level of significance. The study met its primary objective if the lower bound of the 2-sided 95% exact Clopper Pearson confidence intervals (CI) for ORR was greater than 20% (note: I wrote an article about Clopper Pearson confidence interval).

The study results showed the remarkable results. ORR is 82.5% (52/63). The lower bound of the 95% exact confidence interval using Clopper Pearson method is 70.9% - way above the pre-specified criterion of 20%.

The approval of Kite’s axicabtagene ciloleucel was based on a similar study design. In clinicaltrials.gov, the study was registered as “A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Subjects With Refractory Aggressive Non-Hodgkin Lymphoma (NHL)” – so called ‘ZUMA-1’ trial. The primary efficacy endpoint is ORR (Objective response rate) consisting of complete response [CR] plus partial response [PR] per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma.

The study results was announced in Kite’s press release. The results indicated that the ORR is 82% (83/101) – p value is less than 0.0001.  The 95% exact confidence interval for ORR was not provided, but with Clopper Pearson method, we can calculate the lower bound of the 95% confidence interval to be 73% - it is probably way above the pre-specified ORR (historical control if exist) for patients without CAR-T treatment. 

While we are excited about the advances in gene therapy, the long-term safety should still be followed. Both approved products carry the black box and the short term safety issue (could be life-threatening) is mainly the cytokine release syndrome (CRS).

It will be interesting to see how the cost of these CAR-T therapy will be managed and accepted by the community. The Novartis tisagenlecleucel (brand name Kymriah) is priced at $475,000 for a treatment course. Kite’s axicabtagene ciloleucel (brand name Yescarta) is priced at $373,000 for a treatment course.

The development of therapies like CAR-T requires great collaboration between the industry and the academic and government. The Novartis’s tisagenlecleucel was mainly developed by the University of Pennsylvania. Kite’s axicabtagene ciloleucel was developed by the National Cancer Institute.

There is an article in New England Journal of Medicine by Dr. Rosenbaum “Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy”.

CAR-T is now very popular in China. A lot of investigational clinical trials using CAR-T therapy are ongoing in China. Someone did a search in clinicaltrials.gov and found more CAR-T clinical trials in China than US.

Both CAR-T successes are hematologic cancers, the next challenge will be to find the successful CAR-T therapy in solid tumors.

The success in CAR-T should bring us a hope that someday we can transplant the pig organs into human - an area my company is a pioneer. See the article in New York Time "Gene Editing Spurs Hope for Transplanting Pig Organs Into Humans".

Efficient orphan drug development - clinical trial designs in rare disease area

For a long time, drug development in rare diseases is a niche area for biotechnology companies. With the rapid advanced in genetics and ‘-omics’ and in the precision medicine era, researchers are continuously identifying new diseases or disease variants. A prevalent disease can be dissected into many small pieces, each subset could become a rare disease.

Rare diseases pose challenges in clinical trial designs. Some of the challenges are:

• Small number of patients affected
• Small number of patients for clinical trials
• Heterogeneity of the disease
• Limited understanding of the disease’s natural history
• Lack of well-defined study endpoints
• Limited early phase clinical trial data

There are several initiatives in US and in European countries that are focusing on the clinical trial designs and methodologies in rare disease area.

In US, the NORD (National Organization for Rare Disorders) is a patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them.  NORD, along with its more than 260 patient organization members is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services. NORD’s visions include a culture of innovation that supports basic and translational research to create diagnostic tests and therapies for all rare diseases and a regulatory environment that encourages development and timely approval of safe, effective diagnostics and treatments.

This week, Nord’s Rare Diseases and Orphan ProductsBreakthrough Summit was held in Washington DC. During the meeting, FDAOfficials Offered Advice on Efficient Orphan Drug Development:

“Robert Temple, deputy center director for clinical science at CDER, said that one of his long held interests at FDA has been making clinical trials more efficient.
"This is particularly important in orphan territory because there are often few patients in total and there are usually very few near the centers that want to do the studies," Temple said.

Because of the challenges inherent in identifying and enrolling patients with rare disorders in studies, Temple said that having detailed natural history data "can make a tremendous difference in identifying the manifestations you want to try to treat and identifying the patients you should include" in a study.

Another important consideration, Temple said, is whether there are design features that can be built into a trial to make it more efficient.

For instance, Temple said that cross-over studies could be done in situations where enrolling patients is difficult and the disease being studied has a transient effect.
This isn't a new idea, Temple said, pointing to a 1976 cross-over study of the synthetic steroid danazol to treat hereditary angioedema that enrolled only nine patients. In that study the patients were randomized to the drug or a placebo until they had an attack, at which point they were moved to the other study arm.

Temple also said that FDA has seen some success with doing randomized withdrawal studies, particularly in situations where a placebo-controlled arm is not feasible.
"Sometimes in the course of development you'll have a lot of people who for one reason or another have been put on the drug because it's the only game in town…with a lot of people on the drug you can sometimes, if they're willing, do a randomized withdrawal study," Temple said.

But Temple emphasized that these types of studies are only appropriate in certain circumstances, and stressed that sponsors should consider approaches early on.
Billy Dunn, director of CDER's division of neurology products, said that especially for rare diseases FDA and industry need to look at novel approaches to studying drugs.
"We're not the cardiovascular division, we're not accustomed to having these multi-thousand patient trials…many things that might seem controversial or unusual in other settings, sometimes—not always, but sometimes—those can be more run-of-the-mill for us," Dunn said.

Dunn also said that different considerations must be made for studies of progressive diseases, where different stages or forms of a disease can vary considerably. In such situations, Dunn said that sponsors need to consider progression when determining enrollment criteria and, "while difficult to operationalize, having patient individualized outcomes where we attempt to assess, for a given stage or form of a disease, those aspects…that are most impairing."

Wilson Bryan, director of the Office of Tissues and Advanced Therapies at the Center for Biologics Evaluation and Research (CBER), said that one of the challenges for his office is working with academic sponsors and small biotech companies that do not have extensive experience in drug development.

This is an especially challenging issue in the rare disease space, Bryan said, because there are very few patients with a particular disease to begin with and any inefficiency in a study can waste precious time and resources. This is also true for advanced therapies as many are disease modifying and have prolonged or permanent effects, making it difficult for patients to enroll in additional studies in the future.
"Too often we have folks come in with [investigational new drug applications] INDs and they haven't started their natural history study yet, and they haven't started thinking about what their outcome measures are going to be for Phase III," Bryan said.
When should sponsors begin thinking about these things? According to Bryan, at the very early stages of drug development and well before a product is set to begin human studies.
"When I say early on in drug development I don't mean at Phase I, I mean when you first start to do preclinical studies, think about what is the target. The target is not getting into clinical trials … the target is getting a product on the market that's of use to patients," Bryan said.
Julia Beitz, director of CDER's Office of Drug Evaluation III, said that sponsors should also make sure to establish a baseline for patients' clinical, cognitive and developmental status before beginning a study and take repeat measurements of those features throughout the trial.

Beitz also said that sponsors should try, "to the extent that is possible," to stabilize patients' conditions before starting them on a drug, especially when patients are expected to need another intervention, such as surgery or a medical device.

"If these measures are instituted during the trial it becomes difficult to assess the independent effect of the new treatment on the patient," Beitz said.

In the social media era, it is important to have a platform for patients and caregivers to communicate and engage. INSPIRE is such an organization and provides the most authentic platform for patient engagement.

A group of people are forming a DIA working group called NEED (the Nature and Extent of Evidence Needed for Decision) engaging in the discussions about the clinical trial design in rare diseases including the natural history study, historical control, innovative study designs such as adaptive design and Bayesian design,…

In European countries, there are several initiatives focusing on the clinical trial design aspects of the rare diseases or small population group trials.

• IDEAL (Integrated Design and Analysis of Small Population Group Trials)
• ASterix (Advances in Small Trials dEsign for Regulatory Innovation and eXcellence)