September 8, 2015

FDA's Approval Protocol for New Drugs

Last week, Acadia Pharmaceuticals announced it had submitted an application with the Food & Drug Administration (FDA) for its new product Nuplazid (pimavanserin), a treatment for psychosis associated with Parkinson’s disease (PD).

Psychosis isn’t a condition we regularly hear associated with PD. Most often, we read about the motor symptoms of PD, including:
  • Resting tremor
  • Slowed movement (bradykinesia)
  • Rigidity
  • Involuntary muscle movements (dyskinesia)
  • Postural instability
  • Freezing of gait
  • Small, cramped handwriting (micrographia)
  • Mask-like expression
  • Stooped posture
  • Swallowing difficulties 
We hear often about PD’s non-motor symptoms, too, which typically include:
  • Constipation
  • Depression
  • Insomnia
  • Loss of sense of smell (anosmia)
  • Medication issues, such as compulsive behaviors
In its announcement about its new drug, Acadia’s website described Parkinson’s disease psychosis this way:
People are generally familiar with the motor disturbances associated with Parkinson’s disease such as tremors, limb stiffness, balance problems, and slowness of movement. However, there is increasing recognition that “non-motor” symptoms, such as psychosis, can be the most burdensome to Parkinson’s patients and deeply affect their quality of life. Studies have suggested that Parkinson’s disease psychosis (PDP), commonly consisting of visual hallucinations and delusions, occurs in about 40 percent of patients with Parkinson’s disease. PDP is associated with nursing home placement, increased morbidity and mortality, and increased caregiver distress and burden. Currently, no drug is approved to treat PDP in the United States.
This new application with the FDA seemed a good opportunity to recap the lengthy and complicated process that precedes the release of any new drug on the market.

Here’s how the FDA describes the approval protocol on its website:

"The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective"

The path a drug travels from a lab to your medicine cabinet is usually long, and every drug takes a unique route. Often, a drug is developed to treat a specific disease. An important use of a drug may also be discovered by accident.

For example, Retrovir (zidovudine, also known as AZT) was first studied as an anti-cancer drug in the 1960s with disappointing results. Twenty years later, researchers discovered the drug could treat AIDS, and Food and Drug Administration approved the drug, manufactured by GlaxoSmithKline, for that purpose in 1987.

Most drugs that undergo preclinical (animal) testing never even make it to human testing and review by the FDA. The drugs that do must undergo the agency's rigorous evaluation process, which scrutinizes everything about the drug--from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured.


Investigational New Drug Application (IND)--The pharmaceutical industry sometimes seeks advice from the FDA prior to submission of an IND.

Sponsors--companies, research institutions, and other organizations that take responsibility for developing a drug. They must show the FDA results of preclinical testing in laboratory animals and what they propose to do for human testing. At this stage, the FDA decides whether it is reasonably safe for the company to move forward with testing the drug in humans.

Clinical Trials--Drug studies in humans can begin only after an IND is reviewed by the FDA and a local institutional review board (IRB). The board is a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical research.

IRBs approve the clinical trial protocols, which describe the type of people who may participate in the clinical trial, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, the study's objectives, and other details. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm.

Phase 1 studies are usually conducted in healthy volunteers. The goal here is to determine what the drug's most frequent side effects are and, often, how the drug is metabolized and excreted. The number of subjects typically ranges from 20 to 80.

Phase 2 studies begin if Phase 1 studies don't reveal unacceptable toxicity. While the emphasis in Phase 1 is on safety, the emphasis in Phase 2 is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment--usually an inactive substance (placebo), or a different drug. Safety continues to be evaluated, and short-term side effects are studied. Typically, the number of subjects in Phase 2 studies ranges from a few dozen to about 300.

At the end of Phase 2, the FDA and sponsors try to come to an agreement on how large-scale studies in Phase 3 should be done. How often the FDA meets with a sponsor varies, but this is one of two most common meeting points prior to submission of a new drug application. The other most common time is pre-NDA--right before a new drug application is submitted.

Phase 3 studies begin if evidence of effectiveness is shown in Phase 2. These studies gather more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people.

Postmarket requirement and commitment studies are required of or agreed to by a sponsor, and are conducted after the FDA has approved a product for marketing. The FDA uses postmarket requirement and commitment studies to gather additional information about a product's safety, efficacy, or optimal use.

New Drug Application (NDA)--This is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured.

When an NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. The FDA can refuse to file an application that is incomplete. For example, some required studies may be missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90 percent of NDAs for standard drugs no later than 10 months after the applications are received. The review goal is six months for priority drugs. (See "The Role of User Fees.")

"It's the clinical trials that take so long--usually several years," says Sandra Kweder, M.D., deputy director of the Office of New Drugs in the CDER. "The emphasis on speed for FDA mostly relates to review time and timelines of being able to meet with sponsors during a drug's development," she says.

Drug Review Steps Simplified

1. Preclinical (animal) testing.

2. An investigational new drug application (IND) outlines what the sponsor of a new drug proposes for human testing in clinical trials.

3. Phase 1 studies (typically involve 20 to 80 people).

4. Phase 2 studies (typically involve a few dozen to about 300 people).

5. Phase 3 studies (typically involve several hundred to about 3,000 people).

6. The pre-NDA period, just before a new drug application (NDA) is submitted. A common time for the FDA and drug sponsors to meet.

7. Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval.

8. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed.

9. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor's research on the drug's safety and effectiveness.

10. The FDA reviews information that goes on a drug's professional labeling (information on how to use the drug).

11. The FDA inspects the facilities where the drug will be manufactured as part of the approval process.

12. FDA reviewers will approve the application or issue a complete response letter.

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