FDA Approvals: Why Do Promising Drugs Fail?

Why the FDA rejected a ‘breakthrough’ melanoma drug

A recently developed drug, RP1, emerged as a potential lifeline for patients with malignant melanoma, an advanced form of skin cancer that has spread to other parts of the body.

Early-stage melanoma is highly treatable with a survival rate of 99%. However, once metastasized, the survival rate in some patients drops to almost 16%. This is where RP1 shows promise.

RP1 is an immunotherapy-based drug built from a genetically engineered virus. The therapy is designed to specifically target melanoma cells. Once inside, the cancer cells rupture. The drug also activates the immune cells to recognize and kill the cancer cells effectively.

In the early stages of trials, this drug was recognized by the FDA as a ‘breakthrough therapy’ – a designation to ensure effective therapies can reach patients with serious conditions quickly.

However, despite its fast track status, this drug was rejected by the FDA- not once but twice, leaving researchers and drug developers puzzled and made them question – “if a drug looks promising, why would it still fail to gain approval?”

And that raises an even more important question: What happens behind the scenes of the drug approval process?

The drug discovery pipeline: pre-clinical and clinical trials

Developing a drug is far from simple. It takes several years for a drug to reach the market and has to pass through several hurdles. As a result, most drugs fail even before they reach the patients.

Briefly, here are the major stages involved in a drug discovery and approval process.

1. Target identification and validation- Researchers identify a gene, biological pathway, or protein associated with the disease. Once identified, they will validate if modifying the gene or protein could actually help treat the disease.
2. Hit identification and lead generation- Scientists screen several chemical compounds from their database and identify hits- molecules that show activity against the target. Promising hits then become lead compounds with therapeutic potential.
3. Lead optimization- Chemists modify the lead compounds to improve their potency, stability, and specificity while reducing their toxicity and side effects.
4. Pre-clinical research- Before human testing, the drug goes through intense in-vitro (lab tests/ cell cultures/ organoids) and in-vivo tests (in animal models) to ensure the safety, biological activity, and toxicity profile.
5. Investigational New Drug application- If preclinical trials look promising, an IND application needs to be submitted to the regulatory authorities, like the FDA, and permission needs to be acquired before starting clinical trials on humans.
6. Clinical trials
   1. Phase I- to test safety, dosage range, and side effects in a small group of healthy volunteers
   2. Phase II- to test safety and preliminary efficacy in a larger group of patients
   3. Phase III- Large-scale studies for final efficacy and safety confirmation.  It involves monitoring adverse effects, placebo effects, and comparing the treatment against existing therapies. At this stage, a lot of drugs actually fail- due to unexpected side effects, inconsistent results, or insufficient benefits.
7. Post-market monitoring (sometimes called the clinical trial phase IV)- once approved for marketing, a New Drug Application (NDA) is filed and followed by continuous monitoring post-release. This phase is equally important as stage III because certain rare and delayed side effects may become apparent several years after its widespread use.

While the drug discovery pipeline explains how a drug reaches clinical trials, the bigger question is: What exactly does the FDA look for in a drug before approving it?

What does the FDA actually evaluate?

The FDA doesn’t just check if the drug works. It also checks for several other important parameters.

1. Efficacy- Is the efficacy statistically significant? That is one of the first questions the FDA asks when it comes to drug approval. To determine this, it collects and reviews data submitted by pharmaceutical sponsors. The high quality directly comes from stage II or stage III clinical trials. This will prove that the benefits outweigh the risks. They keep in mind measurable endpoints to evaluate their safety, like mortality, blood pressure, tumour shrinkage, etc., rather than subjective endpoints like symptom relief.
   
2. Safety- Every drug carries a certain amount of risk. But are side effects acceptable? If yes, where do we draw the line between acceptable and unacceptable? When is it considered a serious side effect (Does it involve a life-threatening condition, hospitalization, or a congenital disability)? These are among the several questions asked by the FDA when it comes to assessing the safety of the drug. The FDA reviews all the data from preclinical to stage III clinical trials and looks into the manufacturing methods and proposes labeling to ensure the drug’s benefits outweigh the risks. It also inspects the manufacturing facilities to ensure quality, identity, and purity of the drug.
   
3. Risk vs Benefit- it is especially important in diseases like cancer. The FDA analyses clinical data and assesses the severity of the condition, considering alternative treatments to ensure benefits outweigh the risks. In some cases, like life-threatening diseases, more risk is acceptable, especially if very few treatment strategies are available. Certain FDA tools, like Risk Evaluation and Mitigation Strategies (REMS), can help manage risks.
   
4. Study design- Even a promising drug can fail if the clinical trial is not designed properly. It analyzes important questions like- Was the trial biased? Was the sample size enough?  The FDA analyzes whether the study could actually answer the research question. It focuses on the trial protocol, sample size, patient selection, control groups, and endpoints to minimize bias.
   
5. Endpoints- Finally, a very important question- did the study decrease mortality or merely reduce the symptoms? This is crucial in drug approval. It demonstrates a drug’s clinical benefit. It should make the patients feel better and function well after ingesting the drug. The appropriateness of the primary endpoints is evaluated. Surrogate endpoints are added if necessary. Some clinical trials may even require multiple endpoints.  

Why do promising drugs fail to get approval?

Despite showing early promise, many drug candidates never receive FDA approval. In fact, most drugs fail somewhere along the clinical development pipeline.

One major reason is that early success does not always translate into meaningful clinical benefit in larger patient populations. A drug may appear effective in preliminary studies but fail to demonstrate statistically significant improvements during large-scale clinical trials.

Safety is another critical factor. Once a drug reaches human trials, unexpected toxicities or severe adverse effects may emerge, making the treatment too risky for public use.

In some cases, the problem may not lie with the drug itself, but with the clinical trial design. Factors such as:

• Incorrect patient selection
• insufficient sample size
• poorly chosen endpoints
• inadequate control groups
• biased study protocols

can all affect the reliability of the results.

Outside the regulatory process, pharmaceutical companies may also discontinue promising drug programs due to financial limitations, manufacturing challenges, or poor commercial feasibility.

Ultimately, a drug can appear revolutionary in theory yet still fail under the rigorous scientific scrutiny required for approval.

So, Why Was RP1 Rejected?

At first glance, the rejection of RP1 surprised many researchers. In early Phase I/II clinical trials, nearly 33% of patients with treatment-resistant advanced melanoma showed improvement when treated with a combination of RP1 and Nivolumab.

For patients who had already exhausted other treatment options, these results appeared highly promising. However, the concern was not necessarily the drug itself. It was the clinical trial design.

According to reviewers, one major issue was that the study population was too heterogeneous. Patients differed in:

• prior treatments
• extent of disease progression
• clinical history
• other underlying variables

This made it difficult for regulators to confidently determine whether the observed benefits were truly due to RP1, the nivolumab combination, or other patient-specific factors.

Another major limitation was the absence of a placebo or control group.

Normally, control groups help researchers compare outcomes and determine whether a drug is genuinely effective. However, in this case, many participants had already failed to respond to therapies like nivolumab alone. Researchers argued that continuing patients on treatments that had previously failed them would be ethically questionable.

As a result, the trial prioritized patient welfare, but at the same time, it reduced the strength of the evidence needed for regulatory approval.

And that highlights one of the biggest challenges in modern medicine:

Sometimes, the most ethical clinical trial designs are not always the easiest to interpret scientifically.

In medicine, hope is important. But evidence is everything.

Because behind every drug approval lies a decision that could affect millions of lives.