Adverse Event of Special Interest (AESI), Standardized MedDRA Query (SMQs), Customer Queries (CQs), and SAS Programming

When we perform the safety analyses for clinical trial data or post-marketing pharmacovigilence data, one of the common approach is to identify and summarize the adverse events of special interest (AESI). FDA guidance for industry: E2F Development Safety Update Report defined the AESI as following:

“Adverse event of special interest: An adverse event of special interest (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid communication by the investigator to the sponsor can be appropriate. Such an event might warrant further investigation in order to characterize and understand it. Depending on the nature of the event, rapid communication by the trial sponsor to other parties (e.g., regulators) might also be warranted. (Based on CIOMS VI)”

ICH Topic E2F Development Safety Update Report also indicated the importance of identifying the AESIs:

“If important and appropriate, the report should also include adverse reactions of special interest within the line listings and adverse events of special interest in summary tabulations. The basis for selection of such events/reactions should be explained. “

Since the same AESI may include many verbatim (reported) terms or preferred (coded) terms, the first step of the analysis of AESI is to define the list of terms that will be considered as the specific AESI.

I used to do a large phase III study in Irritable Bowel Syndrome (IBS). The protocol specified the diarrhea and rectal bleeding events as AESI. In developing the statistical analysis plan (SAP), the following tables were included to to identify the diarrhea events and rectal bleeding events. .

Adverse Event of Special Interest

Group term	Preferred term
Diarrhea	Diarrhea NOS
	Loose stools, stools loose
	Loose bowel, loose bowels
	Watery diarrhea (diarrhoea)
	Stools watery
	Gastroenteritis
	Gastroenteritis NOS
	Gastroenteritis non-infectious
Rectal bleeding	Rectal bleeding
	Rectal haemorrhage
	Anal haemorrhage
	GI h(a)emorrhage
	GI h(a)emorrhage NOS
	Diarrhea haemorrhagic
	Haemorrhage rectum
	Blood in stool
	Occult blood
	Melaena
	Hematochezia
	Lower GI bleeding (not found)

In 131st Meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) in 2012, the adverse event of special interest regarding autoimmune events was discussed. The meeting minutes explained how the autoimmune events were identified:

"The first was adverse events of special interest. This involved the identification, categorization and analysis of adverse events in the safety database. It was performed using a list of autoimmune and inflammatory conditions. The system was used for all trials in the HEPLISAV clinical program including the Phase 3 trials."

In FDA’s advisory committee meeting to discuss BioMarin Vimizim (elosulfase alfa) for the treatment of Mucopolysaccharidosis Type IVA (Morquio A syndrome), the AESI of hypersensitivity and anaphylactic reaction events was discussed:

“Potential Hypersensitivity AEs were identified by utilizing the broad Anaphylactic Reaction algorithmic Standardized MedDRA query (SMQ) and the broad Angioedema SMQ, which represent a broad range of terms to detect signals possibly indicative of hypersensitivity. Hypersensitivity AEs were reported in 16.2% of subjects in the Proposed Dose Population. No correlation was found between higher titers of anti-BMN 110 antibodies and increased incidence or severity of hypersensitivity AEs. The Warnings and Precautions section of the proposed prescribing information includes language regarding the clinical study experience with anaphylaxis and severe allergic reactions and provides recommended management of and preventive measures for severe allergic-type hypersensitivity reactions. o BioMarin reviewed all reported adverse events against the NIAID/FAAN 2006 criteria for anaphylaxis (Sampson H et al, 2006). Of the 235 subjects exposed to BMN 110 in the development program, the sponsor identified  16 (6.8%) cases consistent with NIAID/FAAN 2006 criteria for anaphylaxis. The reactions were successfully managed with infusion rate adjustments and/or medical intervention, and all but 2 subjects continue to receive subsequent BMN 110 infusions. This rate of anaphylaxis is comparable to other enzyme replacement therapies”

To discuss the AESI, we must know the concept of SMQ. To assist in standardizing the AESI identification process, Standardised MedDRA Queries (SMQs) are developed to facilitate retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development. SMQs are validated, pre-determined sets of MedDRA terms grouped together after extensive review, testing, analysis, and expert discussion. SMQs are a unique feature of MedDRA and provide a strong tool to support safety analysis and reporting. The SMQ topics are intended to address the important pharmacovigilance topics needed by regulatory and industry users. SMQs have been developed with the CIOMS Working Group on Standardised MedDRA Queries that provides pharmacovigilance expertise and validation of SMQs. The SMQs are maintained with each release of MedDRA dictionary by the MSSO.

As of 1 September 2014, there are almost 100 SMQs available. The list of available SMQs can be found here from MSSO website.

If we need to identify a risk or AESI, if SMQ is available, SMQ should be used. If SMQ is not available, the customer-defined list of preferred terms (PTs), so-called CQs (customer queries), will be needed. For three AESIs discussed above, SMQs are available for Diarrhea (as Noninfectious diarrhoea) and Hypersensitivity, but not available for rectal bleeding events. In an ophthalmology paper, both SMQ and customer-defined PTs (CQs) were used to identify various risks. Similarly, in a T2DM study, both SMQ and customer-defined PTs were used to identified various AESIs.

• Introductory Guide for Standardised MedDRA Queries (SMQs) Version 16.0
• MedDRA®: Safety Data Analysis and SMQs MedDRA^® DATA RETRIEVAL AND PRESENTATION:  POINTS TO CONSIDER 

In practice, once we have the database containing all AEs and we have a list of preferred terms (either from SMQ or from the customer-defined [CQs]) to identify the AE of special interest, a simple SAS program with PROC SQL can be used to identify the reported events from the database.

Here the AE database is the base table. SMQ preferred terms or customer-defined preferred terms (CQs) is the look-up table. 

proc sql;

    ***Create a look up table where pt is preferred term;

    create table LookupTable as

    select distinct range, pt

    from smq

    where range = 'Narrow';

    ***Select records based on the look-up table;

    create table matched_terms as

    select subjid, aeterm, pt label='Preferred Term'

    from ae

    where upcase(pt) in (select upcase(pt) from LookupTable);

quit;

proc print data=matched_terms label noobs;

run;

The following papers discussed how to use SAS to perform the safety analysis using SMQ.

• Practice of SMQs for Adverse Events in Analysis of Safety Data and Pharmacovigilance
• Adverse Events of Special Interest and MedDRA Upgrades: A Dilemma and Proposed Solution

CDISC “Analysis Data Model (ADaM) Data Structure for Adverse Event Analysis” discussed MedDRA SMQ, included a specific section “4.1.9 MedDRA Query Variables”, and provided an example for analysis of Hemorrhages using SMQ. 

Dose Limiting Toxicity (DLT) and Common Toxicity Criteria (CTC) / Common Terminology Criteria for Adverse Events (CTCAE)

For the early clinical phase trials, especially first-in-man oncology studies, the major objective is usually to identify a safe dose, such as the MTD (maximal tolerated dose),  the highest dose that can be given with acceptable toxicity, and establish the safety profile. To identify the MTD, dose escalation studies are usually conducted. The determination of the MTD is based on the occurrence of the DLT (dose limiting toxicity), Dose-Limiting toxicity is defined to be a toxicity that prevents further administration of the agent at that dose level. One of the criteria for FDA to approve a Breakthrough Therapy designation for an experimental drug is that the experimental drug can significantly improve safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy.

The choice of DLT (dose-limiting toxicity) may vary from study to study based on the natural history of the disease and the level of toxicity expected from standard therapy. For example, one might accept a greater degree of toxicity for a patient with end-stage cancer who has no other options, but less toxicity for a healthy individual getting a preventive medicine. 

The DLT has close relationship with the CTC (common toxicity criteria) and CTCAE (common terminology criteria for adverse events).

CTC (Common Toxicity Criteria) is the precursor of what is today named the Common Terminology Criteria for Adverse Events (CTCAE). The original CTC was developed by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) in 1983 to aid in the documentation and analysis of adverse effects of chemotherapy. CTC, like CTCAE, included terms and a severity grading scale with descriptions of the allowed grades of each term. Starting from v3, the CTC was replaced by CTCAE v3.

CTCAE is a list of terms (adverse events) commonly encountered in oncology interventions. Each AE term is defined and associated with a rating scale of severity that indicates the severity of the AE. The rating scale is used in the definition of protocols parameters (Eligibility; Maximum Tolerated Dose; Dose modification; etc) and indicates what is reasonable to document, report, and analyze for patient safety oversight based on current oncology research interventions. CTCAE is available only in English and the most recent version of CTCAE is verion 4.0. In the new CTCAE v4.0, the AE terms are organized by the System Organ Classes (SOCs) defined by the Medical Dictionary for Regulatory Activities (MedDRA). CTCAE has been developed from the earlier vocabulary known as CTC (Common Toxicity Criteria).

While CTC / CTCAE were developed by NCI, they were being used for clinical trials outside cancer trials such as AIDS/HIV trials, hypertension trials, and others.

The definition of Dose-limiting Toxicity (DLT) is determined by the individual protocol, not the CTC or CTCAE. Although it would be convenient to assume that all Grade 3 adverse events based on CTC or CTCAE represent dose limiting toxicities, this may not be appropriate. Grade 3 or 4 adverse events (based on CTC or CTCAE) of complications such as nausea and vomiting can be controlled with appropriate supportive care measures and may not constitute DLTs. Prolonged grade 2 toxicities can be considered DLTs depending on the schedule of drug administration. Acceptable DLTs or adverse events vary with the patient population and the anticipated outcome of the treatment. More severe adverse events may be acceptable with a potentially curative regimen than with a palliative treatment.

Typically in clinical trials, investigators will base their clinical judgment to grade all reported adverse events (AEs) during the study with three categories: mild, moderate, and severe.

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not             interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.

Severe: An event that prevents normal everyday activities.

For oncology trials, the Grading should be based on CTCAE as following:

Grade 0 No Adverse Event	Sign/symptom within normal limits
Grade 1 Mild Adverse Event	Minor Mild symptoms and intervention not indicated Non-prescription intervention indicated No specific medical intervention Asymptomatic laboratory finding only Radiographic finding only Marginal clinical relevance
Grade 2 Moderate Adverse Event	Intervention indicated Minimal, local, noninvasive intervention (e.g. packing, cautery) Limiting instrumental ADL (e.g., shopping; laundry; transportation; ability to conduct finances)
Grade 3 Severe Adverse Event	Medically significant but not life-threatening Inpatient or prolongation of hospitalization indicated Important medical event that does not result in hospitalization but may jeopardize the patient or may require intervention either to prevent hospitalization or to prevent the AE from becoming life-threatening or potentially resulting in death Disabling - results in persistent or significant disability or incapacity Limiting self care ADL (e.g., getting in and out of bed; dressing; eating; getting around inside; bathing; using the toilet)
Grade 4 Life-threatening Adverse Event	Life-threatening consequences       Urgent intervention indicated Urgent operative intervention indicated Patient is at risk of death at the time of the event if immediate intervention is not undertaken
Grade 5 Fatal Adverse Event	Death

To map the CTCAE grading to AE severity / intensity, any AE graded as 1 using CTCAE can be categorized as mild, 2 be categorized as moderate and ≥3 be categorized as severe.

There are considerable discussions about the standardization in determining the dose limiting toxicities.

§         Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents – Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study

§         Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: Results of a DLT-TARGETT international survey

§         Definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents

§         Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: A review of the literature

§         Criteria for defining dose-limiting criteria

In a paper by Paoletti et al “Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: Results of a DLT-TARGETT international survey”, it was stated “DLT is traditionally defined as any grade 3–4 non-haematological or grade 4 haematological toxicity at least possibly related to the treatment, occurring during the first cycle of treatment. Some adjustments to this definition have been widely accepted, such as febrile neutropenia, or neutropenia grade 4 lasting more than 7 days or abnormal laboratory values rated as a DLT only in the presence of clinical symptoms.”

In study by Angevin et al “Phase I Study of Dovitinib (TKI258), an Oral FGFR, VEGFR, and PDGFR Inhibitor, in Advanced or Metastatic Renal Cell Carcinoma”, the following DLT criteria were provided in the study protocol appendix. 

Alternative phase I dose escalation study designs: CRM, BLRM, mTPI, and PGDE

The "3 + 3 design" is the most commonly used design in phase I dose escalation study and over 95% of phase I clinical trials in oncology use the "3 + 3 design". However, in some situations, the "3 + 3 design" may not be the best choice for finding the maximum tolerable dose (MTD) and alternative dose escalation study designs are necessary.

Cytel's EAST software version 6.3 introduced a new module 'ESCALATE' which includes additional phase I dose escalation study designs. In additional to the standard "3 + 3 design", it contains the following designs:

• CRM (Continual Reassessment Method)
• Modified CRM 
• BLRM (Bayesian Logistic Regression Method)
• mTPI (Modified Toxicity Probability Interval Design)

where CRM, modified CRM, and BLRM are model based method and mTPI is a mixture of both rule-based and model based method. 

The original CRM is a Bayesian model-based method and uses all available information from doses to guide assignment of the next dose cohort. A CRM simulator can be downloaded from MD Anderson biostatistics website. The modified CRM makes the CRM more like the "3 + 3 design" (can start at lowest dose, allow multiple patients per cohort, do not allow skipping when escalating) for acceptability. A CRM and modified CRM program developed by Dr Steven Piantados can be downloaded from his website. BLRM is commonly used with overdose control (so called EWOC - Escalation With Overdose Control). In this method, models begin with initial estimates of knowledge based on prior clinical data or pre-clinical data. Models are then updated with new information as it becomes available. Updated information forms the basis of dose escalation recommendations. The principles of Bayesian Logistic regression models are:

• precision of model estimates incorporated into dosing decisions 
• restriction of the chance of exposing patients to excessive toxicity, whilst allowing clinicians to make informed dosing decisions based on estimated probabilities of under-dosing and targeted-dosing 

mTPI is Bayesian like CRM and BLRM, but rule-based like the "3 + 3 design". The method is proposed by Yuan Ji et al in their paper "a modified toxicity probability interval method for dose-finding trials". The method can be implemented by excel add-on or R scripts (download for free).

These methods and their usage with EAST ESCALATE module were explained in a free online Webinar "New module for Phase 1 dose escalation study design". ESCALATE module in EAST can perform simulation and interim monitoring for each of these methods.

Phase I Clinical Trial Design by Drs. Rubinstein and Simon discussed additional study designs for phase I dose escalation studies in addition to the "3 + 3 design", original CRM, and amendments and alteration of CRMs:

Accelerated titration designs which are characterized by (i) A rapid initial escalation phase; (ii) Intra-patient dose escalation; and (iii) Analysis of results using a model that incorporates parameters for intra-patient variation in toxic effects, cumulative toxicity and steepness of dose-toxicity effects. The analytic model incorporates data from all courses of therapy and for graded toxicity levels.

Pharmacokinetically Guided Dose Escalation (PGDE) which is based on the mouse and human AUC to escalate to an MTD by targeting a maximal tolerated AUC. The efficiency of PGDE relies on the assumption that drug toxicity is really a function of drug AUC, and that equivalent AUC for human and mouse will result in equivalent toxicity.

Further readings:

• Phase 1 Trial Design: Is 3 + 3 the Best?
• Dose Escalation Methods in Phase I Cancer Clinical Trials
• Bayesian Continual Reassessment Method Designs for Phase I Dose-Finding Trials
• Phase I dose‑escalation study of the HSP90 inhibitor AUY922 in Japanese patients with advanced solid tumors
• Phase I Dose-Escalation Study of LCL161, an Oral Inhibitor of Apoptosis Proteins Inhibitor, in Patients With Advanced Solid Tumors

Phase I Dose Escalation Study Design: "3 + 3 Design"

For the first-in-human clinical trial, the dose escalation study design is often utilized. in dose escalation study, subjects are enrolled in cohorts (batches) with increasing doses. whether or not the study goes further to the higher dose depends on the assessment of the previous dose. The assessment is mainly based on the DLT (dose limiting toxicity) - side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment.

Dose escalation study can be with placebo control or without placebo control. For a dose escalation study with placebo control, the placebo control is within each dose cohort, not across the cohorts. A dose escalation study without placebo control is often used in studies for life-threatening diseases such as cancers and AIDS. 

The most common dose escalation study design is the rule-based "3 + 3 design". The "3 + 3 design" can be depicted as below: 

  The "3 + 3 design" is clearly explained in FDA guidance "Clinical Considerations for Therapeutic Cancer Vaccines" as following: 

The traditional standard dose escalation schedule in the development of cancer therapeutics uses the so-called “3 + 3 design” to avoid selection of a phase 2 clinical trial dose that causes a treatment-limiting toxicity in more than 17% of subjects, a standard considered acceptable as an outpatient therapeutic for patients with limited options and life-threatening diseases. In a “3 + 3 design,” three patients are initially enrolled into a given dose cohort. If there is no DLT observed in any of these subjects, the trial proceeds to enroll additional subjects into the next higher dose cohort. If one subject develops a DLT at a specific dose, an additional three subjects are enrolled into that same dose cohort. Development of DLTs in more than 1 of 6 subjects in a specific dose cohort suggests that the MTD has been exceeded, and further dose escalation is not pursued.

In summary, the "3 + 3 design" is:

• Rule based design
• Start by allocating lowest dose level to first cohort
• Adaptively escalate/de-escalate based on observed DLTs
• Repeat until MTD obtained or trial is stopped

The "3 + 3 design" is very straight forward, robust, simple and can be very well understood by clinicians and investigators. However, the "3 + 3 design" has its limitations. It is limitations may be summarized as the followings: 

• Ignores dosage history other than previous cohort
• Same action under qualitatively different situations (e.g., 0/3 and 1/6 lead to same action)
• Ignores uncertainty (if true DLT rate is p = 0.5, 11% of the time we will see 0 or 1 DLT in 6 patients)
• Cannot re-escalate
• Fixed cohort sizes (either 3 or 6)
• Pre-defined dose levels to be potentially tested
• Low probability of selecting true MTD
• High variability in MTD estimates
• MTD is not a dose with any particular probability of DLT, but in the range from 20% to 25% DLT.
• Can not estimate MTD with target probability of DLT less than 20% or greater than 33%.
• Not all toxicity data of all patients are used to determine the MTD.
• Many patients are likely to be treated at low doses.

The limitations are also cited in FDA's guidance "Clinical Considerations for Therapeutic Cancer Vaccines":

Many cancer vaccine trials have used the “3 + 3 design,” and the results show that, except in very rare situations, an MTD for a cancer vaccine may not be identified. In these trials, the dose-toxicity curve may be so flat that the highest dose that can be administered is limited by manufacturing or anatomic issues rather than toxicity. Therefore, this “3 + 3 design” may not be the most suitable approach to gathering information from early phase trials of cancer vaccines, and alternative trial designs should be considered.

Given the relatively acceptable safety profile of some classes of cancer vaccines, alternative dose-escalation approaches, such as accelerated titration or continuous reassessment, may be considered instead of the standard “3 + 3 design”. When using such designs, the protocol should describe acceptable parameters for the dosing endpoint (supported by data). Irrespective of which dose-escalation approach is chosen, the study protocol should clearly define DLTs, the subject “off-treatment” criteria, and the study stopping rules that will ensure subject safety. When no DLT is expected or achieved, optimization of other outcomes, such as the immune response, can be useful to identify doses for subsequent studies.

Because of these limitations, the alternative phase I dose escalation study designs have been proposed and used in the practice. These methods are:

• CRM (Continual Reassessment Method)
• Modified CRM 
• BLRM (Bayesian Logistic Regression Method)
• mTPI (Modified Toxicity Probability Interval Design)

Clinical trial design for treatment of Ebola virus disease versus Ebola vaccine

Ebola outbreak in West Africa has brought a lot of attentions to this deadly virus. The world is so unprepared for the Ebola treatment and prevention. Now that the developed countries including US are starting to develop the drugs for treating and preventing the Ebola virus, the discussions about the Ebola drug trials are in the center stage.

First of all, there is a big distinction between developing the drugs for treating Ebola virus disease and developing the Ebola vaccine. Many people may discuss the Ebola trial without clear distinction of the treatment and prevention. In a Forbes article “FDA: Some Ebola Patients Need To Get Placebo”, the author clearly mis-interpreted the original FDA paper and blurred the distinction between drug for treating Ebola patients and the Ebola vaccine.

The ethical dilemma and debate about the randomized, controlled trial are on the issues for drug trials targeting the treatment of the Ebola patients, not the Ebola vaccine. FDA’s article in New England Journal of Medicine “Evaluating Ebola Therapies — The Case for RCTs” discussed the issues with clinical trial design for Ebola therapies (treating Ebola infected patients), not for Ebola vaccine (preventing people from Ebola infection).

So far, the majority of the clinical trials are focusing on the Ebola virus vaccine, not on the Ebola treatment. According to clinicaltrials.gov, there are 21 clinical trials registered, except for 2 trials that are conducted in ebola patients or ebola virus infested patients, all other trials are for Ebola vaccine and conducted in healthy volunteers

The immediate need is to find effective therapies for treating the Ebola virus infected patients. Down the road, developing effective vaccines to prevent the Ebola virus infection (at least prevent the similar outbreaks) is more important. Without any incentives, the drug companies may be more interested in developing the Ebola vaccine because of its much greater marketing potential.

 A Comparison of Ebola Therapy and Ebola Vaccine

	Ebola Therapy	Ebola Vaccine
Purpose	Treatment of Ebola Virus Infected patients	Prevention people from Ebola virus infection
Target population	Ebola virus infected patients	General public or population at risk for Ebola infection (such as health care workers)
Study population	Ebola virus infected patients	Healthy volunteers
Efficacy Measure	Survival rate (proportion of patients who can survive in two weeks)	the immunogeneicity (i.e., the occurrence or titer of the anti-ebola virus antibodies).
Control group	Placebo-controlled study is not feasible, but the best supportive care as control group is feasible.	Placebo control is feasible.
Study endpoint	Survival is a hard endpoint	Titer of antibodies is a surrogate, soft endpoint. The overall effectiveness is difficult to measure.
Tolerance for safety	Comparing to the vaccine, there may be more tolerance in terms of the safety.	The new drug / therapy must be extremely safe since the vaccine will be used by the healthy people

Specifically for clinical trials to find effective therapies for Ebola virus infected patients, the clinical trial design is at the center of the debate. The experts in European countries prefer the clinical trials using the historical control (i.e., without the concurrent control group) while US (FDA and NIH) prefers the traditional randomized controlled trials with the best supportive care as the control group.

• Ethical dilemma for Ebola drug trials
• Evaluating Ebola Therapies — The Case for RCTs

With very high mortality rate, it is understandable to think that a randomized, supportive care controlled or placebo controlled study is ridiculous. If there is a new experimental therapy with even a slim of hope, people will jump on it. Just as it said in the article “The Ethical Issues In Using An Experimental Ebola Drug”.

“the World Health Organization said in a statement today that it is ethical to offer unproven drugs to treat or prevent the spread of the Ebola virus

Under American law, the Food and Drug Administration can permit a drug manufacturer to provide an unapproved drug to patients if they don't have any alternatives and the consequences are severe. It's called "compassionate use" and most of these exceptions are granted when the drug is in a clinical trial testing its safety, proper dose and efficacy.
The most profound example of this comes from the 1980s, in the early days of the AIDS epidemic. There was no approved drug that had any effect, and people were dying. Dr. Anthony Fauci [director of the National Institute of Allergy and Infectious Diseases] was key to changing this approach, and expanding access to AZT outside of clinical trials. But this is different in that the drugs for the Ebola virus have not yet entered clinical trials in humans.”

Considering the high mortality rate and no proven therapy for treating the Ebola virus disease, using a historical control seems to an easy choice. With this design, all patients will be given the experimental drug(s). If the survival rate in patients treated with experimental drug(s) is lower than a fixed number (historical control), the experimental treatment would be considered as effective. However, it all depends on how reliable the historical control is and whether or not the other best supportive cares have changed over time. The study design can still be randomized and controlled. It is just the concurrent control group is another experimental drug(s).

It is generally agreed that the clinical trials for Ebola virus disease treatment should have more than one arms and should be randomized, controlled. The European countries seem to prefer a study design with multiple experimental therapies to compare each other. US (FDA and NIH) seems to prefer a study design with experimental therapy compared with the concurrent control of the best supportive care. This can be essentially viewed as an add-on study design with one group to be the best supportive care only and another group to be the best supportive care + the experimental therapy. For the purpose of demonstrating the efficacy of the experimental therapy, this seems to be the most reasonable approach.

In the end, the action is always better than debate. Let’s put aside the debate and start the clinical trials for Ebola treatment. The clinical trials for Ebola virus disease treatment (new therapies) have begun.

• Chimerix An Open-Label, Multicenter Study of the Safety and Anti Viral Activity of Brincidofovir (BCV, CMX001) for Ebola Virus Disease
• Ebola treatment trials to be fast-tracked in West Africa
• First trials for Ebola treatments to start at MSF sites in December
• Ebola trials to start in December

 “US scientists have not yet announced which treatments will be tested in clinical trials that they plan to run in the United States and, possibly, in Liberia. Doctors and researchers organizing the trials met at the US National Institutes of Health in Bethesda, Maryland, on 11 November.
"We had good discussions,” says Clifford Lane, deputy director for clinical research and special projects at the US National Institute of Allergy and Infectious Diseases in Bethesda. “We are working on refining our adaptive-design protocol with specific arms based upon those discussions.”

MSF says that the trials at its sites will test whether the interventions boost the proportion of patients who survive for two weeks. It hopes to report initial results from the trials as early as February 2015.
MSF said previously that none of the trials run at its sites will assign patients to receive standard of care treatment rather than an experimental intervention. Whether or not to use a standard of care control group in these trials is a thorny and hotly debated question. The US trials plan to use a control group, but have not made final decisions about the trial design.”

It is reported that the first Ebola treatment trial has started in January, 2015. The study lead by Dr Jake Dunning is a study without concurrent control group - there is no randomization. The Ebola virus positive patients are asked if they are willing to participate in the trial to receive the experimental treatment. if they decline the participation, the patients will receive the standard supportive care. Hopefully, they will track the at least the mortality rate in those who decline the participation.

The Ebola vaccine trials has also begun and some of the studies have reported the success (safe and generating antibody response in healthy volunteers).

• Ebola booster vaccine starts first trials in Oxford
• First human trial of NIH-GSK Ebola vaccine shows promise
• Ebola: new study is first to report vaccine success in Africa

FDA's Priority Review Voucher Programs

A voucher is a bond of the redeemable transaction type which is worth a certain monetary value and which may be spent only for specific reasons or on specific goods. Examples include (but are not limited to) housing, travel, and food vouchers.

You may find it surprising, the voucher has been used by FDA as a tool to encourage the drug development in certain areas.

In 2008, FDA issued its 1st voucher guidance titled “Tropical Disease Priority Review Vouchers”. Last month, FDA has published its second guidance related to voucher. The draft guidance is called “Rare Pediatric Disease Priority Review Vouchers, Guidance for Industry”

How does it work?

• Sponsors must first have an NDA/BLA approved for an indication in designated tropical disease area or in qualified rare pediatric disease area. 
• Sponsor will then submit the application for priority review voucher
• Sponsor may need to pay additional application fee for voucher
• Once the priority review voucher is approved, the voucher can be sold and transferred to other sponsors
• Voucher can be redeemed for priority review for any NDA/BLA submission 

Both voucher programs are designed to provide incentives for drug developers to invest in the neglected disease area or in the disease area that return on investment (ROI) is very low.
According to FDA's MAPP "Review Designation Policy: Priority (P) and Standard (S)", applications or supplements submitted with a priority review voucher will automatically receive a priority review designation.

The tropical disease priority review voucher was issued in 2008 and it was not used often by the sponsors. However, the tropical disease priority review voucher may find new popularity thanks to the global fight against Ebola. Ironically, at the time when the Tropical Disease Priority Review Voucher guidance was issued, the deadly Ebola disease was not on the list of tropical disease areas.

Product applications for the prevention or treatment of the following tropical diseases may qualify:

• Tuberculosis
• Malaria
• Blinding trachoma
• Buruli Ulcer
• Cholera
• Dengue/Dengue haemorrhagic fever
• Dracunculiasis (guinea-worm disease)
• Fascioliasis
• Human African trypanosomiasis
• Leishmaniasis
• Leprosy
• Lymphatic filariasis
• Onchocerciasis
• Schistosomiasis
• Soil transmitted helminthiasis
• Yaws
• Any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations, designated by regulation by the Secretary (section 524(a)(3))

One may argue that the Ebola can be included in the last item “any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations, designated by regulation by the Secretary”.

To ensure that Ebola is included in the Tropical Disease Priority Review Voucher program and to remove the obstacles for voucher program to become popular, a Senate bill has been proposed. The bill passed the senate in November.

The newly issued guidance on Rare Pediatric Disease Priority Review Voucher program seems to be better designed and hopefully it will gain more popularity than the Tropical Disease Priority Review Voucher program. To avoid incentivizing sponsors to exclude adults affected by the rare pediatric disease from clinical trials, FDA expects adult patients to play a prominent role in process. Sponsors remain eligible for a voucher if they use adult patients in clinical trials or seek an adult indication in addition to the primary pediatric indication. The qualified rare pediatric disease will most likely also qualify for the orphan disease category. A sponsor may obtain the Orphan Drug Designation Status to avoid paying the application fee for voucher application.

How much is a priority review voucher worth?

The value of a priority review voucher is not entirely clear. There are very few transactions of a priority review voucher sold from one sponsor to another.

• On 30 July 2014, BioMarin announced that it had sold its voucher to Sanofi and Regeneron for $67.5 million.
• The Canadian pharmaceutical company Knight Therapeutics has reportedly sold its Neglected Tropical Disease Priority Review Voucher to Gilead Sciences for $125 million

FDA's Position on Use of SI Units for Lab Tests

Previously, I wrote an article to discuss the SI unit versus US conventional unit. FDA actually issued its position statement about these two units.

Position on Use of SI Units for Lab Tests:

CDER and CBER are evaluating an approach to transition to general acceptance of laboratory data in clinical trials that are measured and reported in Système International (SI) units instead of U.S. Conventional units. The objective is to establish an agency-wide policy on the acceptance of SI units in product submissions.
CDER and CBER recognize that SI units are the worldwide standard and international trials regularly measure and report lab tests using SI units. The Centers also acknowledge that the majority of U.S. healthcare providers are trained using U.S. conventional units. Lab results reported using U.S. conventional units often convey the most clinical meaning to U.S. healthcare providers, including CDER and CBER reviewers. In the absence of a holistic transition within the U.S. healthcare community to SI units, conversion of certain lab test results to U.S. conventional units may be a necessary interim step toward a transition to full SI unit reporting.
CDER and CBER are currently evaluating common and therapeutic area-specific lab tests to determine which pose significant interpretation risks during the review of new drug applications.  While this evaluation is underway, sponsors are strongly encouraged to solicit input from review divisions as early in the development cycle as possible to minimize the potential for conversion needs during NDA/BLA review. CDER and CBER encourage sponsors to discuss this issue with FDA before the start of Phase 3 trials.  In some cases the issue may warrant discussion with FDA at the End-of-Phase 2 meeting.
If conversion requests are received, sponsors are advised to discuss the conversion request as early as possible with the review division and if needed, provide a proposal for what can be reasonably accomplished to meet the review division’s needs without undue burden in time or costs.
October 25, 2013

For a specific clinical trial, it is prudent to ask the central laboratory to report the results in both units. It is not a bid deal for central laboratory to include results in both units in the data sets. for US sites, the lab reports may be in US conventional units and for non-US sites, the lab reports may be in SI units. For data presentations (table, listings, and figures), SI units may be used for international studies and US conventional unit may be used in US only studies.