How Does the FDA Approve New Drugs?

DrugsLegal Analysis
FDA Approval

During his first address to a joint session of Congress, President Donald Trump vowed to “slash the restraints” on the “slow and burdensome approval process” at the U.S. Food and Drug Administration (FDA) that “keeps too many advances… from reaching those in need.”

Mr. Trump did not provide concrete reform proposals, but his comments echoed those he made about the agency on the campaign trail and are consistent with conservatives’ desire to slash what they see as excessive FDA red tape.

Mr. Trump’s posture suggests a significant shakeup of the FDA.

While many were quick to point out that the FDA not only approves new drugs about as fast as any regulatory agency in the world, but has also in recent years streamlined how it approves many new drugs. But focusing only on the “approval process,” while leaving out a discussion of clinical drug development—which can take 12 years or more—paints an incomplete pictur

FDA critics claim that the agency as it currently operates is not flexible enough to efficiently oversee a world of accelerating medical advancements and personalized medicine. Some have proposed, among other measures, a market-based solution that they argue would break the FDA’s monopoly on drug access and make new drugs available up to seven years earlier than they are at present.

The FDA’s future under President Trump should gain clarity when he finally announces his pick to lead the agency. However, Mr. Trump’s leading FDA chief candidates and his early comments to the pharmaceutical industry suggest significant FDA reforms.

How a New Drug Gets Approved

Before addressing FDA modernization, it’s important to understand the journey new drugs take from the laboratory to pharmacy shelves.

FDA approval is the final phase of a larger process known as the “new drug development process.” Although the FDA does not conduct its own new drug testing (this would be prohibitively expensive), it is actively engaged in all phases of the new drug development process.

For example, the FDA determines what evidence is needed to prove that a new drug is safe and effective, approves and monitors clinical trials, and at the end of the process, evaluates a company’s New Drug Application (NDA). A drug cannot be marketed to the public until the FDA approves its NDA.

This entire process takes an average of 12 years. Here’s how it breaks down:

  • Preclinical research: New drug research starts in the lab. Researchers identify a compound they believe has a clinical effect on a specific disease and then test it on cell cultures and eventually, on living animals. If lab results justify further testing on human subjects—a determination the FDA makes based on a lengthy application—the drug proceeds to clinical trials. The preclinical research phase can take up to 3.5 years.
  • Phase I trials: The first stage of clinical trials, Phase I studies involve 20-100 people with the disease/condition the drug intends to treat. Meant to establish the drug’s basic properties and human safety, Phase 1 studies last 1-2 years. About 70% of drugs clear this stage.
  • Phase II trials: Phase II clinical trials ascertain a drug’s efficacy and side effects. They use several hundred people with the disease being studied and take several months to 2 years. Approximately two-thirds of drugs move on to phase III trials.
  • Phase III trials: Phase III clinical trials are typically the most extensive and expensive phase of drug development. This phase involves testing the drug on 300-3,000 patients to confirm safety, effectiveness, and dosing. These trials take 2-4 years. About 10% of medicines fail in phase III trials.
  • New Drug Application: A drug that successfully completes all three clinical trial phases is eligible for a New Drug Application (NDA) with the FDA. It usually takes 1-2 years between the completion of a phase III trial and drug approval, including 6-10 months for the NDA review.

If the FDA approves the drug, physicians may then prescribe it to patients. In some cases, including Xarelto, the FDA orders phase IV (“post-marketing”) studies to evaluate long-term safety and efficacy.

Only one out of every 5,000-10,000 compounds that begin in preclinical testing is approved for marketing.

Expedited Drug Approval Programs

The multi-stage drug development and review process is intended to keep unsafe and/or ineffective drugs from reaching the public. However, because it takes so long, the process can be problematic for patients who have conditions that currently lack good treatment options.

This issue came to the fore during the AIDS crisis of the 1980s and 1990s, spawning FDA programs that expedite the approval of new therapies intended to treat unmet medical needs.

  • Orphan drug: The 1983 Organ Drug Act incentivizes new drugs that treat diseases affecting fewer than 200,000 patients per year by creating tax breaks and market exclusivity periods. Orphan drugs are often approved on the basis of less-rigorous clinical trials.
  • Fast track: The FDA’s “fast track” approval designation of 1988 allows drugs that treat life-threatening or debilitating diseases to be approved after a single phase II clinical study.
  • Accelerated approval: Implemented in 1992, the FDA’s “accelerated approval” pathway alters evidentiary standards for drugs that treat serious or life-threatening diseases.
  • Priority review: In 1992 the FDA formalized a 1975 program guaranteeing FDA review within six months of drugs offering a therapeutic advance over available treatment.
  • Breakthrough therapy: Since 2012, the FDA may designate a new drug a “breakthrough therapy” if it treats a serious or life-threatening disease and demonstrates substantial improvement over existing therapies. Designated breakthroughs receive expedited development and review.

Source: BMJ

How effective have these programs been at bringing new drugs to needy patients? A 2015 BMJ study suggests the programs aren’t exactly being used as they’re intended.

BMJ looked at nearly 800 drugs approved by the FDA through expedited development and review pathways between 1997 and 2014. It found that, “over time… a greater proportion of programs were being applied to drugs that were not the first in their class. Such drugs are more likely to be only incrementally innovative and many not represent a clinical advance.”

While such drugs may still have value, using the expedited programs for less innovative products can divert limited FDA resources, says BMJ.

How Trump Could Shake Up the FDA

Megan Crowley, a guest of first lady Melania Trump at the president’s congressional address, was held up as a “miracle” of drug innovation.

Megan is a 20-year-old college student who suffers from Pompe disease, a potentially fatal neuromuscular disease. She was not expected to live past age five, but her father founded a medical company that developed the enzyme replacement drug which helped save Megan’s life.

The drug, Myozyme, was approved in 2006 based on trials featuring only a few dozen patients and an expedited review.

“If we slash the restraints, not just at the FDA but across our government, then we will be blessed with far more miracles like Megan,” said Mr. Trump.

His comments to Congress on the FDA were very similar to those he made on the campaign trail, where he said he wanted to “speed the approval of life-saving medications” and mentioned “cutting the red tape at the FDA.”

When he spoke with pharmaceutical CEOs in January, the president mentioned eliminating 75-80 percent of all FDA regulations.

“We’re going to get the approval process much faster,” Mr. Trump told the pharma heads.

“Right to Try” Law

Mr. Trump has also signaled support for a national “right to try” law giving terminally ill patients the right to take drugs that are still in development. Thirty-three states have right-to-try laws on the books, and the FDA has a similar “compassionate use” program.

The FDA has denied only 39 of the 7,291 compassionate use requests made by physicians since 2009, making a national right-to-try law somewhat redundant, but it cannot make companies comply with physician requests for experimental drug access for their terminal patients. A national right-to-try law in theory could compel pharmaceutical and insurance companies to provide and pay for experimental drugs.

Reciprocal Approval

Another FDA reform President Trump could champion is “reciprocal approval” legislation, or a law that would allow new drugs approved in other countries with drug safety standards similar to the U.S. to be sold stateside.

On the campaign trail Mr. Trump said he would “remove barriers to entry” of “imported and safe dependable drugs from overseas.”

While reciprocal legislation might help fill drug gaps and lower drug prices by introducing greater competition, a BMJ study concluded that the legislation “would most likely benefit only a small number of US patients receiving treatment for rare diseases, and the benefit may be somewhat mitigated by an increased exposure to harms.”

(Click below for page 2.)

Next page