Drug names: brand name, proprietary name, trade name, generic name, and sponsor's drug code

Every Saturday, my favorite radio show is "Wait Wait... Don't Tell Me! | WUNC". In yesterday's episode, the host made fun of the brand name ('Comirnaty') of Pfizer/BioNTech Covid (Listen: 46.17 minutes).

Covid vaccines from Pfizer/BioNTech, Moderna, and J&J have become the household name in just about a year or so and have been administered to millions and millions of people under FDA's Emergency Use Authorization (EUA). Under the EUA, these vaccines are just called and differentiated by the company's name: Pfizer vaccine, Moderna vaccine, and J&J vaccine. However, when the vaccine (or any drug) is formally approved, according to the regulation, it must have a brand name - in the case of Pfizer/BioNTech Covid vaccine, the brand name is now 'Comirnaty'.

The meaning behind the name 'Comirnaty': Comirnaty is an agglomeration of the words “Covid-19 immunity” and “mRNA,” the latter indicating the technology that makes the vaccine work. As a whole, the word is intended to evoke “community,”

This brings a question about the drug names: the difference between the brand name and the generic name and how to record the drug names in clinical trials. According to the CDASH, the case report form will include a form for concomitant medication including the questions like

"What was the term for the medication/therapy taken?

or

"What was the term for the medication taken?"

Concomitant medications used by the study participants prior to the trial or during the trial period should all be recorded. Usually, there is no restriction on the medication term to be recorded. Either brand name or generic name can be recorded. 

The brand name of a medication is the name given by the company that makes the drug and is usually easy to say for sales and marketing purposes. The brand name may also be called the trade name. In FDA's guidance, the brand name is called proprietary name. The proprietary name of a drug product is its brand name. 

The generic name, on the other hand, is the name of the active ingredient. Generic drugs are copies of brand-name drugs that have exactly the same dosage, intended use, effects, side effects, route of administration, risks, safety, and strength as the original drug. In other words, their pharmacological effects are exactly the same as those of their brand-name counterparts. In FDA's guidance, the generic name may be called 'nonproprietary name' or 'proper name' for biological products. For biological products, the term proper name means the nonproprietary name designated by FDA in the license for a biological product licensed under the PHS Act. See also 105 21 CFR 600.3(k).

For drugs that make it all the way through development, testing, and regulatory acceptance, the pharmaceutical company then gives the drug a trade name, which is a standard term in the pharmaceutical industry for a brand name, trademark name, or proprietary name. The proprietary name must be approved by the FDA and included in the product label. FDA has its guidance for industry to govern the brand name approval process "Best Practices in DevelopingProprietary Names for HumanPrescription Drug Products".

During the development stage, sponsors of the clinical trials may use their code for the compound or drug in the development. These drug codes will not be used when a drug is approved. For example, the famous drug from Merck 'pembrolizumab' has its own code MK-3475 that can be used in the clinical development stage and registered in clinicaltrials.gov, but will not be used as the name once the product is approved or marketed. Sponsor's drug code: MK-3475 - > generic name: pembrolizumab -> brand name: Keytruda. Similarly, Gilead's COVID-19 treatment drug has sponsor's drug code GS-5734 -> generic name: remdesivir -> Veklery. Pfizer/BioNTech's COVID-19 vaccine has sponsor's drug code: BNT16b2 -> generic name: COVID-19 Vaccine, mRNA -> brand name (proprietary name): COMIRNATY.

Here are some examples of the sponsor's drug code, generic drug name, brand drug name, and the corresponding indications.

When recording the drug name in clinical trials, either brand name or generic name can be recorded, but not the drug code used by the sponsors. 

Before the statistical analyses of the concomitant medication data, the data management group will perform appropriate medical coding activities to map the recorded brand name or generic name to the corresponding ATC classifications according to WHODrug-Global dictionary. 

Retire Statistical Significance and p-value? - Revisited

In 2019, there was a public debate about the use or misuse of statistical significance and p-values. I wrote a post about it "Retire Statistical Significance and p-value?"

Obviously, the hypothesis testing, statistical significance, and p-value are still the cornerstone of our clinical trials, the basis for judging if a clinical trial is a success, and the basis for the decision-making for regulatory approvals by the FDA and other regulatory authorities. 

In the latest issue of AMSTATNews and also the Annals of Applied Statistics, there is an article "The ASA President’s Task Force Statement on Statistical Significance and Replicability". The statements confirmed that the significance and p-values are here to stay. 

"P-values are valid statistical measures that provide convenient conventions for communicating the uncertainty inherent in quantitative results. Indeed, p-values and significance tests are among the most studied and best understood statistical procedures in the statistical literature. They are important tools that have advanced science through their proper application."

"p-values and significance tests, when properly applied and interpreted, increase the rigor of the conclusions drawn from data. Analyzing data and summarizing results are often more complex than is sometimes popularly conveyed. Although all scientific methods have limitations, the proper application of statistical methods is essential for interpreting the results of data analyses and enhancing the applicability of scientific results."

I would say the following about the significant tests and p-values:

• We embrace it, not abandon it. 
• We focus on the appropriate use and interpretation
• We should not become the slave of the p-values

A quote from  Alfred Marshall, 1885:

"The most reckless and treacherous of all theorists is he who professes to let facts and figures speak for themselves, who keeps in the background the part he has played, perhaps unconsciously, in selecting and grouping them."

Randomized Withdrawal Design in Practice - Story of the HARMONY Trial

In previous posts, we discussed the "Randomized Withdrawal Design and Randomized Discontinuation Trial" and "Randomized Withdrawal Design - Examples for Defining the Criteria for Run-in and Randomized Withdrawal Periods".

Randomized Withdrawal Design (RWD) was discussed in FDA guidance "Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products" as one of the enrichment strategies and enable us to minimize the sample size of the study while demonstrating the efficacy of the experimental drug. 

"In a randomized withdrawal study, patients who have an apparent response to treatment in an open-label period or in the treatment arm of a randomized trial are randomized to continued drug treatment or to placebo treatment. Because such trials generally involve only patients who appear to have responded, this is a study enriched with apparent responders, an empiric strategy. The study evaluation can be based on signs or symptoms during a specified interval (e.g., BP, angina rate), on recurrence of a condition that had been controlled by the drug (e.g., depression), or on the fraction of patients developing a rate or severity of symptoms that exceeds some specified limit (i.e., a failure criterion). "

Even though the FDA encourages the use of the randomized withdrawal design in clinical trials, the use of RWD is still very limited, especially in pivotal, confirmatory studies. The reluctance in using the RWD is usually due to the safety concern - it will be perceived as unethical to discontinue the experimental treatment in the Placebo group when the experimental treatment has just been shown to be effective. Another concern is the size of the safety database - there is usually a sufficient number of patients exposed to the experimental drug so that the safety can be adequately assessed (see a previous post "The Size of Safety Database In Drug Development Program")

In the recent issue of the New England Journal of Medicine, the results of the HARMONY study (sponsored by Acadia Pharmaceuticals) were published: Tariot et al "Trial of Pimavanserin in Dementia-Related Psychosis". While the term 'randomized withdrawal' was not explicitly used in the study, the HARMONY study was a randomized withdrawal study and was described as the following:  

"a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions (SAPS–H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. "

As we can see from the study design diagram below, all patients received pimavanserin during the open-label period. Those subjects who had responses to the pimavanserin (i.e., reduction in SAPS-H+D) were randomized to continue the treatment of pimavanserin or withdraw the treatment of pimavanserin (i.e., receiving the placebo). 

HARMONY Study protocol and SAP were posted on clinicaltrials.gov.  

Study Protocol  [PDF] July 16, 2010

Statistical Analysis Plan  [PDF] August 5, 2014

With the HARMONY study using a randomized withdrawal design, the sponsor was able to demonstrate the efficacy of pimavanserin in treating patients with dementia-related psychosis. The reduced sample size due to the use of the randomized withdrawal design was further reduced after the sponsor stopped the study early for positive efficacy. The sponsor subsequently submitted the sNDA for pimavanserin in treating patients with dementia-related psychosis. Unfortunately, they received a complete response letter from FDA citing the reasons not related to the study design but related to the insufficient sample size for certain sub-groups. 

• ACADIA Pharmaceuticals Announces Pivotal Phase 3 HARMONY Trial Stopped Early for Positive Efficacy as Pimavanserin Meets the Primary Endpoint in Patients with Dementia-Related Psychosis
• ACADIA Pharmaceuticals Announces U.S. FDA Accepted for Filing the Supplemental New Drug Application for NUPLAZID® (pimavanserin) for the Treatment of Hallucinations and Delusions Associated with Dementia-Related Psychosis
• Acadia Pharmaceuticals Receives Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Pimavanserin for the Treatment of Hallucinations and Delusions Associated with Dementia-Related Psychosis
• Furious Acadia takes shot at FDA, alleging sudden about-face in costly Nuplazid rejection