This article provides an overview of product safety with regard to the drug development process. For information on this topic for medical devices, please see Healthcare product safety: Medical devices.

Product safety is a major question to address during the drug development process. When undertaking drug development, the product safety profile of the investigational product must be properly evaluated to support the conduct of clinial studies and product licensing. This is because every single drug that affects the human body has some side effects. A drug can receive regulatory approval when its benefits (efficacy) outweigh its known risks (safety) for its intended use.1

Product safety: Non-clinical and clinical information

The product safety information presented in a submission dossier (for regulatory review) is generally comprised of non-clinical and clinical information. To understand the safety assessment of a drug, one needs to understanding the drug itself and its intended use. In addition to the drug itself, factors such as the dosing regimen, treatment duration and route of administration can affect the data required to establish product safety.2

The cost of new drug development is high, with only about 3% to 5% of products that enter initial clinical evaluation becoming marketed drugs. It is estimated that just getting to the point of opening a clinical trial (for example, an Investigational New Drug Application [IND]) costs a minimum of $2.2 million, plus the cost of drug synthesis. Biological therapeutics are more expensive yet, with the estimated cost to reach IND at $4.5 million.2 Because of these financial implications, minimizing the drug development time and cost is essential. To this end, design and perform clinical studies according to regulatory standards.

Non-clinical evaluation

Non-clinical safety assessments2,3 (such as all supportive toxicokinetic and metabolism activities and studies) are conducted to support:

  1. Clinical trial application filing for first-in-human studies: These non-clinical studies normally include acute and repeated dose systemic toxicity studies in rodent and non-rodent species, genetic toxicity and safety pharmacology studies to support repeat dose clinical studies up to at most four weeks in duration.
  2. Continual clinical evaluation and drug development, up to and through Phase III studies: For Phase III clinical trials that are often longer than four weeks of dosing, longer-term non-clinical toxicity studies must be conducted in both selected rodent and non-rodent species. Additionally, developmental and reproductive toxicity studies are usually required to include a broader range of patients in clinical trials.
  3. Marketing approval application (that is, a New Drug Submission or its equivalent): This includes long-term non-clinical studies including carcinogenicity studies and the final part of reproductive toxicity studies.

The International Conference on Harmonisation (ICH) has published guidance documents* that include the following safety topics.3

  • Carcinogenicity studies
  • Genotoxicity studies
  • Toxicokinetics and pharmacokinetics
  • Toxicity testing
  • Reproductive toxicity
  • Biotechnological products
  • Pharmacology studies
  • Immunotoxicology studies
  • Non-clinical evaluation for anticancer pharmaceuticals
  • Photosafety evaluation

In addition, the following joint safety/efficacy (multidisciplinary) guidance documents should be evaluated in support of the product safety information required for clinical studies:3

  • ICH M3(R2)and its Q&A documents: Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
  • ICH Topic E8: General Considerations for Clinical Trials

For drug products administered by routes other than oral, additional studies that address local tissue response to the administered clinical dosage are expected. These tests include studies such as:

  • Hemolysis (for intravenous products)
  • Pyrogenicity (for parenteral products)
  • Sensitization (for dermal products)
  • Route-specific irritation assays (for example, eye, skin, muscle, mucosal, nasal)2

As well, determine whether any local guidance documents apply to your product.

Drug development: Clinical safety assessment

As with all drug products, adequate and well-controlled clinical studies are conducted to evaluate the product safety in human use. It is critical to include such information in your submission to support regulatory approval.

Drug development: Product safety evaluations do not end

Drug safety evaluation is an ongoing activity as the premarket testing of drugs cannot detect all the problems that can occur with a drug, especially rare events (for example, those occurring in 1 in 10,000 people). Other problems such as medication errors and mix-ups with similar-sounding products are hard to foresee prior to regulatory approval. Thus, a vigorous program is needed after drugs are marketed to detect product safety problems and correct them as soon as possible.4

Compliance with any regional-specific requirements is critical to maintain your product licence and to protect public health. Such activities may include safety reporting, annual safety reports, post-approval studies, post-market surveillance studies and more. If the risk-benefit ratio changes, the product label may need to change, or the product may even need to be withdrawn to protect patient safety.

*Note: Guidance documents must reach Step 4 of the ICH process before they are ready for adoption by regulatory agencies.


The information presented in these articles is intended to outline the general processes, principles and concepts of the healthcare product development lifecycle. Since regulatory requirements are ever-changing, it is current only as of the date of publication and not intended to provide detailed instructions for product development. Every healthcare product is unique and therefore so is its associated product development lifecycle. Specific advice should be sought from a qualified healthcare or other appropriate professional.

Published: October 17, 2012


  1. U.S. Food and Drug Administration. (2012, June 6.) June 6, 2012: Once a drug is approved by FDA, it means the product is perfectly safe? Retrieved July 12, 2012, from
  2. Gad. S.C. (2011). Safety evaluation of pharmaceuticals and medical devices. International Regulatory Guidelines. NY: Springer.
  3. International Conference on Harmonisation. Retrieved July 12, 2012, from
  4. U.S. Food and Drug Administration. (2012, June 6.) June 6, 2012: If FDA’s role is to ensure safe drugs, why are so many drugs recalled or have problems? Retrieved July 12, 2012, from