Developing investigational gene therapies: A roadmap

By learning about that process—and seeking out genetic testing—those living with an inherited retinal disease (IRD) may better understand the value of clinical trials.


Scientists have made incredible progress in their understanding of genetics. To date, almost 2,600 gene therapy clinical trials have been approved, are ongoing, or have been completed worldwide1—each one developed with the goal of creating a potential treatment for people living with a genetic disease, including inherited retinal diseases (IRDs).

Even so, the progress of science can seem plodding at times. The Human Genome Project alone took 13 years to complete2 , and new drug approvals average 12 years from preclinical testing to reality.3 For those living with an IRD, it can be an arduous wait for potential new treatments.

By learning about the process followed in the United States to develop investigational gene therapies and apply for approval by the Food and Drug Administration (FDA), you and your doctor can make informed decisions about participation in clinical trials.

A path to treatment development in the USA

icon step 1

Step 1: Discovery and Development

Researchers at biotechnology companies, academic research labs, and other institutions discover a molecular compound or new insight that has a potential impact on a disease. To better understand the science behind their discoveries, researchers conduct various small-scale experiments to see how a compound may work, its potential side effects or toxicity, and other basic information like how best to dose.4,5

icon step 2

Step 2: Preclinical Trials

Before testing the compound in humans, researchers begin preclinical trials in vivo and in vitro. In vivo experiments take place inside of a living organism while in vitro experiments take place outside of a living organism such as in a test tube or petri dish. If the clinical trials show promise, the researchers submit an investigational new drug (IND) application to the Food and Drug Administration (FDA).4,6

icon step 3

Step 3: IND Application

The investigational new drug (IND) application step includes submitting the preclinical trial results, information on the drug’s composition, and a plan for clinical trials in humans. The FDA reviews the IND application to verify the information is sufficient and assure that clinical trial participants will not be put at unreasonable risk of harm.4

icon step 4

Step 4: Clinical Trials

If the FDA approves the IND application, the investigational drug moves on to clinical trials in humans, where safety and efficacy of the therapy are closely monitored. This process consists of 3 key phases. Phase 1 typically includes a small group of healthy volunteers and is focused on safety, such as what the drug’s most frequent side effects are. Moving into Phase 2, the focus is on efficacy. Participant numbers are increased while researchers look at preliminary data on whether the treatment works in people who have a certain disease or condition compared to a different treatment or placebo. Finally, in Phase 3, the largest group of participants is tested to collect further data on safety and effectiveness, including how it affects certain populations and how it may work at different doses or alongside other therapies and drugs.4

However, this process often differs when developing treatments, such as gene therapies, for rare diseases:

  • They may qualify for expedited programs like Fast Track, Breakthrough Therapy, and Priority Review, resulting in accelerated development and regulatory review.7-9
  • Phases 1 and 2 or phases 2 and 3 may be combined to further aid development.10,11
  • Trials may be smaller because the underlying disease is rare.7,8,12

Differences in patient populations, combined with modified phases, result in smaller studies by comparison. Even when using these adaptive trial designs, the research focus is similar: determining safety and efficacy of the investigational treatment.7,8

icon step 5

Step 5: Application Review

If the clinical trials are successful, a New Drug Application (NDA) or Biologics License Application (BLA) is submitted to the FDA. Once the FDA reviews the file and accepts the application, a decision whether to approve typically takes 6 to 10 months. The FDA also reviews labeling and inspects manufacturing facilities.4


The FDA can expedite the review of investigational prescription products in certain cases13 such as those that treat serious rare diseases, especially when they are the first available treatment or if the product may have advantages over existing treatments.

icon approved
Over $1 billion Entire cost for developing a new drug3

This is a rigorous and strict process. Only about 1 in 1000 potential treatments enter clinical trials, and almost 9 of every 10 fail the clinical trial phase.3 If the treatment is approved and made publicly available, safety issues must continue to be monitored and safety updates must be regularly submitted to the FDA.4

Accessing the path through genetic testing

Double helix with marker

Genetic testing may be able to identify the mutated gene (or genes) responsible for your or your child’s IRD. There are more than 260 genes linked to retinal degeneration14 with current and ongoing gene therapy research set to target some of these genes. Until you know the exact genes responsible for your family member’s IRD, it’s likely you and your physician won’t be able to assess which gene therapy clinical trials may be right for you or your family member.

Although the path to developing new gene and drug therapies can be slow, the methodical process is carefully followed to protect public health and help support the safety and efficacy of treatments.4 Today, thousands of clinical trials are underway, and researchers continue to modify and improve their techniques as they expand their knowledge base in order to make treatments a reality for patients.

“Until you know the exact genes responsible for your family member’s IRD, it’s likely you won’t be able to assess which gene therapy clinical trials may be right for you or your family member.”


  1. Ginn SL, Amaya AK, Alexander IE, et al. Gene therapy clinical trials worldwide to 2017: An update. J Gene Med. 2018;20:e3015.
  2. National Human Genome Research Institute. All about the Human Genome Project. Updated October 1, 2015. Accessed July 5, 2018.
  3. Van Norman GA. Drugs, devices, and the FDA: Part 1: An overview of approval processes for drugs. JACC: Basic to Translational Science. 2016;1(3):170-179.
  4. Food and Drug Administration, US Department of Health and Human Services. FDA drug approval process infographic. Updated February 26, 2016. Accessed June 22, 2018.
  5. Food and Drug Administration, US Department of Health and Human Services. The drug development process—Step 1: Discovery and development. Updated January 4, 2018. Accessed October 29, 2018.
  6. Food and Drug Administration, US Department of Health and Human Services. The drug development process—Step 2: Preclinical research. Updated January 4, 2018. Accessed October 29, 2018.
  7. Rare Toolkits, From Molecules to Medicine: How Are New Drugs and Therapies Developed? Section 1: The Drug Development Process. Accessed July 30, 2018.
  8. Wechsler J. The pull and tug on orphan drug development. Applied Clinical Trials 2018;27(4):5.
  9. Goldsmith J, Kempf L, Blumenrath S. The challenge of rare diseases – From drug development to approval. DIA Global Forum April 2018. Accessed July 30, 2018.
  10. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Human gene therapy for rare diseases: Draft guidance for industry. Published July 2018. Accessed October 29, 2018.
  11. Kempf L, Goldsmith JC, Temple R. Challenges of developing and conducting clinical trials in rare disorders. Am J Med Genet. 2018;176:773–783.
  12. Augustine EF, Adams HR, Mink JW. Clinical trials in rare disease: Challenges and opportunities. J. Child Neurol. 2013;28(9):1142-1150.
  13. Food and Drug Administration, US Department of Health and Human Services. Fast track, breakthrough therapy, accelerated approval, priority review. Updated February 23, 2018. Accessed June 30, 2018.
  14. RetNet. Summaries of genes and loci causing retinal diseases. By genes and loci, diseases or graph. Accessed June 26, 2018.

Share this story!

You might also be interested in:


Disclaimer: The opinions and references found in this community story belong to the author alone, and do not necessarily reflect the opinions of or Spark Therapeutics. Spark Therapeutics is not responsible for the accuracy of any of the information supplied by third-party sites referenced in this story.