Gliead asked FDA to rescind the orphan drug designation for coronavirus treatment remdesivir it just received 48 hours earlier - Why?

Last Monday, Gilead received the orphan drug designation from US FDA for remdesivir to treat Covid-19. Two days later on Wednesday, we saw the news that Gilead asked FDA to rescind its orphan drug designation - it was really an unusual step taken by a company in 37-year history since Orphan Drug Act was enacted in 1983.

A drug with orphan designation will give many benefits to the drug developer.

• Exemption from PDUFA (Prescription Drug User Fee Act) marketing application fee (FY 2020: $2.94+ million)
• 7 years of exclusivity in the U.S.
• Tax credits related to clinical trial expenses
• Orphan products grants program
• Submission of a pediatric assessment per PREA is not required
• FDA assistance in clinical trial design

After Gilead received the orphan drug designation, it immediately drew a lot of critics. The company was criticized by lawmakers and patient advocates after receiving the orphan designation for the experimental antiviral drug, saying it was taking advantage of the rapidly accelerating health crisis.

"It's embarrassing to take something that's potentially the most widespread disease in the history of the pharmaceutical industry and claim it's a rare disease."

“This is an unconscionable abuse of a programme designed to incentivise research and development of treatments for rare diseases.”

“Calling COVID-19 a rare disease mocks people’s suffering and exploits a loophole in the law to profiteer off a deadly pandemic,”

Gilead had maintained that at the time that it had filed for the orphan designation, the coronavirus outbreak was nowhere near the level of severity it is at now. It also contended that it had sought the orphan status to expedite approval for the drug, in particular for a required paediatric study plan.

According to the Orphan Drug Act approved in 1983, the orphan drug designation was for drug development in rare disease or condition where the rare disease or condition means: 

(A) affects less than 200,000 persons in the United States, or
(B) affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will recovered from sales in the United States of such drug. Determinations under the preceding sentence with respect to any drug shall be made on the basis of the facts and circumstances as of the date the request for designation of the drug under this subsection is made.

Determining orphan drug designation based on the # of patients is usually good for ultra-rare diseases and for diseases with genetic disorders. However, it can be problematic when it comes to diseases with a dynamic feature in the number count (the Covid-19 pandemic is a great example):

• Defining and counting rare diseases is not straightforward.
• Difficulties in obtaining definitive diagnoses contribute
• Limitations in systems for reporting and tracking orphan disease diagnoses.
• Countries have adopted different definitions of a rare disease
• Researchers are continuously identifying new diseases or disease variants.

The epidemiology of rare diseases—including the determination of prevalence (the number of people affected at any one time), incidence (the number of new cases in a given year), and patterns of disease (e.g., age distribution) in the population—is inexact.

A rare disease may become a prevalent disease

• Some conditions that initially are classified as rare eventually outgrow that categorization. Covid-19 infection is a good example of this. Even though the # of confirmed cases is still below the 200,000 mark, very soon, the threshold of 200,000 cased will be crossed. Another example is HIV/AIDS. When AIDS emerged in the United States, it fit the legislative definition of a rare disease—affecting fewer than 200,000 individuals. As the infection spread, as diagnostic capabilities and data collection systems improved, and as researchers developed effective treatments that reduced mortality without curing the disease, the total number of individuals with AIDS grew to nearly 470,000 by 2007 and the number of individuals with HIV infection exceeded 1.1 million (CDC, 2009c). 
• If effective but not curative treatment can turn a rare disease into a common one,

A prevalent disease may become a rare disease

Effective prevention can, conversely, turn a common condition into a rare disease. This is the case with many once common childhood infections such as mumps and measles. Public health officials are concerned, however, that factors such as the development of drug-resistant infectious agents and the opposition of some parents to childhood vaccinations could reverse the situation for some now rare diseases. The former concern—drug resistance—is partly a significant scientific challenge (i.e., developing new anti-infectives) and partly a public health and clinical practice challenge (i.e., discouraging overuse of antibiotics). Preventing negative health consequences from anti-vaccination sentiment involves public health expertise, social science research, clinician communication skills, and public policy responses.

• Post-polio syndrome
• Precision Medicine – genetic biomarkers further divide the disease into subgroups

For the Covid-19 situation, if we purely base the orphan designation on the # of patients, it will meet the criteria in the beginning, then not meet the criteria, and meet the criteria again. In any way, obtaining an orphan drug designation for remdesivir in treating Covid-19 patients is indeed unethical.  

Six Pivotal Studies Investigating the Efficacy of Remdesivir: Does Calling it Phase II or III Matter?

During the Covid-19 pandemic, people are desperate to find effective treatments to combat the coronavirus. One promising drug is Gilead's Remdesivir. Although Gilead developed remdesivir for Ebola (and did not get FDA's approval though), which belongs to a different family of viruses than SARS-CoV-2, the viral machinery has elements in common. The remdesivir has been repurposed to be used to treat the Covid-19 infected patients under compassionate use or expanded access program and to be used in the clinical trials.

While there are individual cases and anecdotal experience, the efficacy and safety still need to be demonstrated through the pivotal clinical trials - the adequate, well-controlled clinical trials.

There are currently six pivotal clinical trials involving Remdesivir (summarized below). If the information provided in clinicaltrials.gov is accurate, we should be able to get a readout about Remdesivir's efficacy in the coming weeks. The first study to have the efficacy readout is the phase III study in China for severe Covid-19 patients (estimated primary completion date: Apri 3, 2020). Given that the Covid-19 outbreak in China has been under control and very few new cases are reported in China, two studies in China should be wrapped up even though there may be short of the required sample sizes.

The largest trial in Covid-19 is the French study with 3100 patients to be enrolled. In this study, Remdesivir will be compared with standard of care, also head-to-head compared with three other treatments: Lopinavir/ritonavir, interferon Beta-1A, Hydroxychloroquine. The projected study completion date is March 2023 - by that time, the Covid-19 should be long gone.  

Protocol Title	Study Features	Primary Efficacy Endpoints
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe COVID-19	Gilead Sciences Phase III, 400 Subjects Three arms: Remdesivir for 5 days, Remdesivir for 10 days, Standard of care Multi-national： US, Hong Kong, Italy, South Korea, Singapore, Spain, Taiwan Estimated Primary Completion Date: May 2020	Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14 This is a composite outcome measure. Criteria for fever normalization: Temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 24 hours and criteria for oxygen normalization: peripheral capillary oxygen saturation (Sp02) > 94% sustained for at least 24 hours.
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate COVID-19 Compared to Standard of Care Treatment	Gilead Sciences Phase III, 600 Subjects Three arms: Remdesivir for 5 days, Remdesivir for 10 days, Standard of care Multi-national： US, Hong Kong, Italy, South Korea, Singapore, Spain, Taiwan Estimated Primary Completion Date: May 2020	Proportion of Participants Discharged by Day 14
A Phase 3 Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Mild and Moderate 2019-nCoV Respiratory Disease.	Capital Medical University/Chinese Academy of Medical Sciences Phase III, 308 Subjects Two arms: Remdesivir, placebo Mainland China only Estimated Primary Completion Date: April 10, 2020	Time to Clinical recovery (TTCR)  TTCR is defined as the time (in hours) from initiation of study treatment (active or placebo) until normalisation of fever, respiratory rate, and oxygen saturation, and alleviation of cough, sustained for at least 72 hours. Normalisation and alleviation criteria: Fever - ≤36.9°C or -axilla, ≤37.2 °C oral, Respiratory rate - ≤24/minute on room air, Oxygen saturation - >94% on room air, Cough - mild or absent on a patient reported scale of severe, moderate, mild, absent.
A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Severe 2019-nCoV Respiratory Disease.	Capital Medical University Phase III, 453 Subjects Two arms: Remdesivir, placebo Mainland China only Estimated Primary Completion Date: April 3, 2020	Time to Clinical Improvement (TTCI) [Censored at Day 28] TTCI is defined as the time (in days) from initiation of study treatment (active or placebo) until a decline of two categories from status at randomisation on a six-category ordinal scale of clinical status which ranges from 1 (discharged) to 6 (death). Six-category ordinal scale: 6. Death; 5. ICU, requiring ECMO and/or IMV; 4. ICU/hospitalization, requiring NIV/ HFNC therapy; 3. Hospitalization, requiring supplemental oxygen (but not NIV/ HFNC); 2. Hospitalization, not requiring supplemental oxygen; 1. Hospital discharge or meet discharge criteria (discharge criteria are defined as clinical recovery, i.e. fever, respiratory rate, oxygen saturation return to normal, and cough relief).
A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults	National Institute of Allergy and Infectious Diseases (NIAID) Phase II, 440 Subjects Two arms: Placebo, Remdesivir with additional arms to be added Multi-National: US, Japan, South Korea, Singapore Estimated Primary Completion Date: April 3, 2020	Percentage of subjects reporting each severity rating on an 8-point ordinal scale. The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or ECMO; 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitation on activities.
Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults	Institut National de la Santé Et de la Recherche Médicale, France Phase III, 3100 Subjects Four arms: Remdesivir, Lopinavir/ritonavir, Interferon Beta-1A, Hydroxychloroquine, Standard of care France Only Estimated Primary Completion Date: March, 2023	Percentage of subjects reporting each severity rating on a 7-point ordinal scale a. Not hospitalized, no limitations on activities b. Not hospitalized, limitation on activities; c. Hospitalized, not requiring supplemental oxygen; d. Hospitalized, requiring supplemental oxygen; e. Hospitalized, on non-invasive ventilation or high flow oxygen devices; f. Hospitalized, on invasive mechanical ventilation or ECMO; g. Death.

While five of these pivotal trials are labeled as Phase III study, only the NIH study (with 440 subjects) is labeled as Phase II study. Several weeks ago, I attended a seminar and three statistical professors discussed the Remdesivir clinical trials and the difficulties in patient recruitments. One professor spent quite some time discussing why two trials in China were labeled as Phase III while the NIH trial was labeled as Phase II - he mistakenly thought that only studies labeled as phase III could be used to support the product approval/registration.

Traditionally, clinical trials are phased: pre-marketing: phase I, phase II, and phase III studies; post-marketing: phase IV study. However, nowadays, these phases are blurred. A clinical trial labeled as phase II can still be sufficient to support the product approval/registration as long as the study is adequate and well-controlled. With adaptive design, some of the different phases of clinical trials are combined - seamless design. In the oncology area, a phase I study with cohort expansion may be sufficient for product approval (see FDA's guidance "Expansion Cohorts: Use inFirst-In-Human Clinical Trialsto Expedite Development ofOncology Drugs and Biologics" and Prowell et al "Seamless Oncology-Drug Development".

21CFR part 314 section 126 defined Adequate and Well-Controlled Studies to provide substantial evidence to demonstrate the efficacy of an investigational drug - there is no mention of the phase of the study.

Sec. 314.126 Adequate and well-controlled studies.

(a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. The characteristics described in paragraph (b) of this section have been developed over a period of years and are recognized by the scientific community as the essentials of an adequate and well-controlled clinical investigation. The Food and Drug Administration considers these characteristics in determining whether an investigation is adequate and well-controlled for purposes of section 505 of the act. Reports of adequate and well-controlled investigations provide the primary basis for determining whether there is "substantial evidence" to support the claims of effectiveness for new drugs. Therefore, the study report should provide sufficient details of study design, conduct, and analysis to allow critical evaluation and a determination of whether the characteristics of an adequate and well-controlled study are present.

Similarly, in FDA's guidance (very important one) "Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products Guidance for Industry", there is no mention of the phases of clinical trials.

If a clinical trial is qualified for 'adequate and well-controlled', it can be used to demonstrate the substantial evidence of effectiveness regardless of the study phase.

PICO, PICOTS, PICOTT Framework for Clinical Questions as a Way to Design Clinical Trials

The PICO process (or framework) is a mnemonic used in evidence-based medicine to frame and answer a clinical question. The PICO framework is also used to develop literature search strategies, for instance in systematic reviews. The PICO acronym stands for:
        P – Patient, Problem or Population
        I – Intervention
       C – Comparison, control or comparator
       O – Outcome(s) (eg. pain, fatigue, nausea, infections, death)

The PICO framework can also be used in designing and planning a clinical trial. In doing so, people  suggest adding T and S to form PICOTS or PICOTT:
        T - Timing, duration or date of publication (eg. measured at 1-month of follow-up)
        S - Study type (eg. randomized controlled trial), sometimes S can be used to stand for Setting or 

              Sample Size

In a book by Matchar DB. Introduction to the Methods Guide for Medical Test Reviews, the PICO and PICOTS frameworks were discussed:

When well built, clinical questions usually have four components:
P: The patient situation, population, or problem of interest.
I: The main intervention, defined very broadly, including an exposure, a diagnostic test, a prognostic factor, a treatment, a patient perception and so forth.
C: A comparison intervention or exposure (also defined very broadly), if relevant.
O: The clinical outcome(s) of interest, including a time horizon, if relevant.

In addition to the standard PICO components, the broader PICOTS framework is extremely useful and important for defining key clinical questions and assessing whether a given study is applicable or not. T refers to Timing and S refers to Setting or Study Design.
T: Timing, i.e. the time it takes to demonstrate an outcome OR the period in which patients are observed.
S: Setting (e.g. ambulatory settings including primary, specialty care and inpatient settings), or sometimes Study Design (such as a randomized controlled trial). 

The PICOTS framework is also discussed in a book by Samson and Schoelles "Chapter 2: Medical Tests Guidance (2) Developing the Topic and Structuring Systematic Reviews of Medical Tests: Utility of PICOTS, Analytic Frameworks, Decision Trees, and Other Frameworks"

The content below is from FDA's website "Using the PICOTS Framework to Strengthen Evidence Gathered in Clinical Trials—Guidance from the AHRQ’s Evidence-based Practice Centers Program"

P: Patient population

Define the patient population that will be studied in the trial and consider how it compares to the general affected population. Consider patient baseline sociodemographic (e.g., age, race, socioeconomic status) and clinical characteristics (e.g., severity of condition, comorbidities) that may contribute to differences in treatment outcomes or treatment preferences. Define the selection criteria and consider how patients in the study may be diagnosed or treated differently in usual clinical care. Consider biases that may be introduced by the selection of patients or attrition of patients.

I: Intervention

Define the intervention, including all of its components. Consider contextual factors, such as prior, concurrent, posttreatments, or specialized training of the provider, which may affect the safety and/or effectiveness of the intervention.

C: Comparator

Define whether there is a placebo or active control comparator. Consider blinding. For placebo-controlled studies, consider the risk and benefit of using sham comparators. An active comparator should be relevant to current practice. If the comparator is “usual care,” define the components of the “usual care” clearly. Do not select an active comparator that has known poor effectiveness in specific subgroup populations.

O: Outcome

Define the safety and effectiveness outcomes that matter to patients and which predict long-term successful results. If surrogate outcomes, such as biochemical or physiological measures, are used, they should be clinically relevant. Consider the validity and reliability of outcome measures, including composite measures. Define the planned outcome measures and analyses in the protocol. Pre-specify subgroup analyses. Report all findings as defined in the protocol. Note any post hoc analyses.

T: Timing

Define the duration of treatment and the follow-up schedule that matter to patients. Consider both long- and short-term outcomes.

S: Setting

Define the setting (primary, specialty, inpatient, nursing homes, or other long-term care setting) where the study is implemented and the relevance of the study setting to real world use.

In summary, trials that provide high strength of evidence:

• Study patients who are likely to be offered the intervention in everyday practice.
• Examine clinical strategies and complexities that are more likely to be replicated in practice.
• Measure the most relevant set of benefits and harms.
• Have low risk of bias.
• Have adequate power to address subgroups.
• Directly compare interventions.
• Include all important intended and unintended effects including adherence and tolerability.

In Duke's website for Evidence-Based Practice, the PICOTT framework was defined as the following:

PATIENT OR PROBLEMHow would you describe a group of patients similar to yours? What are the most important characteristics of the patient?INTERVENTION, EXPOSURE, PROGNOSTIC FACTORWhat main intervention are you considering? What do you want to do with this patient?COMPARISONWhat is the main alternative being considered, if any?OUTCOMEWhat are you trying to accomplish, measure, improve or affect?Type of QuestionTherapy / Diagnosis / Harm / Prognosis / PreventionType of StudySystematic review / RCT / cohort study / case control

The other day, Dr. Sheng Lou from Duke University reviewed the clinical trial design for Remdesivir in treating Coronavirus infection and he used the PICOTS framework. There are two ongoing pivotal studies in China: one for mild/moderate patients and one for severe patients.